1.

Drug Product Development

Introduction
Active pharmaceutical ingredient (API): component that produces pharmacological
activity (drug substance). May be produced by chemical synthesis, from natural p
roduct, enzymatic reaction, recombinant DNA, fermentation, etc. New chemical ent
ity (NCE): drug substance with unknown clinical, toxicological, physical, chemic
al properties. According to the FDA, NCE is an unapproved API. Drug product: fin
ished dosage form containing API and excipients. Generic drug products: after pa
tent expiration of brand drug. Therapeutically equivalent to the brand and has t
he same drug amount in the same dosage form. Must be bioequivalent (same rate an
d extent of absorption)
same clinical results. May differ from brand in excipien
ts (tablets only unless safety studies are done) or physical appearance. Abbrevi
ated New Drug Application (ANDA): submitted to the FDA for approval of generic d
rugs. Preclinical safety and efficacy studies are not required. Human bioequival
ence is needed (on healthy human volunteers). Chemistry, manufacturing and contr
ols for generics are similar to the brand. Specialty drug products: existing pro
ducts developed for new delivery system or new therapeutic indication. Safety an
d efficacy studies are not required. Example nitroglycerin transdermal patch aft
er sublignual tablets.
New drug approval
Preclinical (animal safety / pharma) IND
Phase I (healthy human safety)
Phase II
(# patients) Phase III (# patients)
NDA
FDA green light for marketing Phase IV (sc
ale up)
Phase V (continuous improvements). Preclinical stage: animal pharmacolog
y and toxicology to determine safety and efficacy. Formulation is not final. Pha
se I: Submit an Investigational New Drug (IND) clinical studies on healthy volun
teers to determine toxicity and tolerance. For oral drugs
simple hard gelatin ca
psule. Phase II: small number of patients under close supervision. Dose-response
studies to determine optimum dosage for treatment. Determine the therapeutic in
dex (toxic dose/effective dose). Develop final drug formulation (bioequivalent t
o that used in initial clinical studies). Start chronic toxicity studies for 2 y
ears in 2 species. Phase III: large-scale multicenter clinical studies with fina
l dosage form (from phase II) to determine safety and efficacy in patients. Watc
h for new, rare, toxic or side effects. NDA submission: FDA satisfaction with sa
fety and efficacy for marketing. Phase IV: scale-up in preparation for marketing
. Only minor modifications on the formulation are allowed. Phase V: continuous d
rug product improvements after marketing.
Product development
New chemical entities
Preformulation: Physical and chemical characterization of the drug and dosage fo
rm during preclinical phase. Includes general properties (particle size / shape,
polymorphism, crystalline structure, density, surface area, hygroscopicity), so
lubility (dissolution, pH-solubility profile, various solvents), chemical proper
ties (surface energy, pH stability profile, pKa, temperature stability, excipien
t interactions), stability analytical methods. Formulation development: continui
ng process. Injections: final formulation is developed in preclinical phase, sta
bility in solution is critical, few excipients allowed, no bioavailability for I
V. Topicals / local: final formulation developed in phase I, study release in in
vitro diffusion cell models, local irritation and systemic absorption are the i
ssues. Topicals / systemic: drug delivery through skin / mucosa / rectum, final
formulation in phase III.

Oral drugs: final formulation in phase II. Final product considerations: size, s
hape, color, taste, skin feel, viscosity, physical appearance, production equipm
ent / site.
Product line extensions:
Dosage forms with change in physical form or strength but not use or indication.
Usually occurs during Phases III, IV, V. Regulatory approval: based on stabilit
y, analytical / manufacturing controls, bioequivalence studies, clinical trials
Solid products: Different strength in a tablet or capsule form
only bioequivalen
ce required (simplest case). Easier if in vitro dissolution / in vivo bioavailab
ility correlation exists. Modified release: clinical trials required. If new ind
ication
new NDA and new efficacy studies. Liquid products: If an extension of a
liquid same as above for solids If an extension of a solid
if big difference in
extent / rate of absorption
new clinical trials.
Preapproval inspections
Manufacturing facility is inspected prior to NDA / ANDA approval or after a majo
r reported change to NDA / ANDA. Includes: general cGMP inspection, reviews docu
mentation, verifies traceability of information to documentation, consults the c
hemistry / manfucaturing / control (CMC) section of NDA / ANDA, make a final rec
ommendation.
Scale-up and post-approval changes (SUPAC)
Guidelines to # of manufacutring changes that require preapproval by the FDA. Ex
amples: minor formulation changes, change site of manufacture, batch size
or , ch
ange manufacturing process / equipment. 1. Very minor changes not requiring appr
oval are reported in an annual report. Examples: compliance with guidance, label
description, deletion of colorant, expiration date extension, container / closu
re type (not size), analytical method 2. Changes being effected supplement: mino
r changes but require some validation, documentation. A supplement but no pre-ap
proval is required. Examples: new specs, label changes on clinical info, differe
nt cGMP manufacturing facility but same process. 3. Preapproval supplement: majo
r changes require specific preapproval. Examples: adding or deleting an ingredie
nt, relaxing specs, deleting a spec or method, method of manufacture, in-process
controls. Therapeutic and Bio-equivalence: must be shown for any change. Minor
change comparable dissolution profiles. Major change
in vivo bioequivalence stud
y.
GMPs
Minimum requirements for manufacturing, processing, packing, or holding drugs. I
nclude criteria for personnel, facilities, processes to ensure final product has
the correct identity, strength, quality, purity. Quality Control (QC): departme
nt responsible for establishing process and product specifications. The QC dept
test the product and verifies specs are met. This includes acceptance / rejectio
n of incoming raw materials, packaging components, water, drug products, environ
mental conditions. Quality Assurance (QA): a department that determines that the
systems and facilities are adequate and that written procedures are followed.

2. Pharmaceutical Calculations and Statistics

Fundamentals of measurement and calculation
Inverse proportion: the inverse of the scissors method is used in case of dilution
s. Example: 100 ml of 10% solution is diluted to 200 ml, what is the final conce
ntration? Inverse scissors
200/10 = 100/x
5%. Aliquot: used when the sensitivity o
f the measurement device is not great enough for the required measurement. Examp
le: balance sensitivity is 6 mg, accuracy is +/-5% minimum weighable quantity is
: 5/100=6/x = 120 mg. If you need to weigh 10 mg drug
add a diluent to get a fin
al concentration of 120 mg drug in the diluted mixture (120x120 = 1440 mg) then
weigh 120 mg of the diluted mixture. Systems of measure: Apothecaries system of f
luid measure, Apothecaries system for measuring weight, Avoirdupois system for me
asuring weight (pound, ounce, grain=65 mg), metric system.
Children doses
First choice: body weight or mass and mg/kg dosing. Frieds rule for infants: (age
in month / 150) x adult dose Clarks rule: (weight in lb / 150) x adult dose Chil
ds dosage based on body surface area: (BSA in m2 / 1.73) x adult dose
Percentage, ratio strength, concentrations
Percentage w/v, Percentage v/v, Percentage w/w, Ratio strength Be careful 3 g dr
ug in 27 g water is 10% solution (3/30) BUT 3 g drug in 30 g water is 9% (3/33).
Molarity: number of moles of solute dissolved in 1 liter of solution Molality:
number of moles of solute dissolved in 1 kg of solution. Advantage over molarity
: using weight avoids problems with volume expansion or contraction upon the add
ition of solutes. Normality: is the number of equivalent weights of solute per l
iter of solution. Equivalent weight = atomic weight or molecular weight / valenc
e. Preferred way of expressing concentration of acids, bases and electrolytes. O
ne equivalent is the quantity that supplies or donates one mole of H+ or OH-. On
e equivalent of acid reacts with one equivalent of base. Mole fraction: ratio of
number of moles of one component to the total moles of a mixture or solution.
Dilution and concentration
Constant amount of drug
volume is inversely proportional to concentration. Quant
ity1 x concentration1 = quantity2 x concentration2. Allegation medial: method fo
r calculating average concentration of a mixture of two or more substances. Alle
gation alternate: method for calculating number of parts (relative amounts) of t
wo or more components of known concentration to be mixed when final concentratio
n is known. IMPORTANT. See example is page 16. Dilution of alcohols: alcohol + w
ater volume contraction. Use w/w instead of v/v for accuracy. Percentage strengt
h: of concentrated acids is expressed in w/w. For diluted acid
w/v. To determine
the volume of concentrated acid for dilution, use specific gravity.
Electrolyte solutions
Divalent: calcium, ferrous, magnesium, sulfate. Trivalent: aluminum, ferric, cit
rate. All others are monovalent.
Milliequivalents (mEq)
Definition: amount in mg equivalent to a solute equal to 0.001 of its gram equiv
alent weight. Unit used to express concentration of electrolytes
Milliosmoles (mOsmol)
Osmotic pressure is directly proportional to the total number of particles in so
lution. Unit for measuring osmotic concentration: mOsmol.

For non-electrolytes: 1 millimole = 1 mOsmol (1 molecule = 1 particle) For elect

rolytes: number of particles depends on degree of dissociation. Example: complet
ely dissociated KCl
1 millimole = 2 mOsmol (2 particles, K and Cl for each molec
ule). Example: completely dissociated CaCl2
1 millimole = 3 mOsmol solute concen
tration interaction between dissolved particles
actual osmolar concentration com
pared to ideal osmolar concentration.
Isotonic solutions
Isosmotic: solution with the same osmotic pressure. Isotonic: solution with the
same osmotic pressure as body fluids. Hypotonic: solution with osmotic pressure
than body fluid (opposite is hypertonic) Preparation of isotonic solutions Colli
gative properties (e.g. freezing point depression) are representative of the num
ber of particles in solution. Dissolve 1 g MWt of non-electrolyte in 1 L of wate
r depression of freezing point by -1.86 C. For electrolytes: freezing point depr
ession = -1.86 x number of species produces upon dissociation. Freezing point de
pression of body fluids = -0.52 C. Take dissociation of weak electrolytes into a
ccount. In weak solutions, every 2 ions produce 1.8 ions, every 3 ions produce 2
.6 ions (about 10% loss). NaCl equivalents Definition: the amount of NaCl that i
s equivalent to the amount of particular drug in question. Isotonic fluid: 0.9%
NaCl. Example: NaCl equivalent for KCl to 0.78
1 gram KCl = 0.78 g of NaCl. Calc
ulating amount of NaCl required to adjust isotonicity: calculate the total amoun
t of NaCl required (volume x 0.9%) calculate the NaCl equivalent of all substanc
es in the solution calculate and add the difference as NaCl or another material
(as NaCl equivalent).
Statistics
Frequency distribution: classify individual observations into categories corresp
onding to fixed numeric intervals (interval frequencies)
plot number of observat
ions in each category versus category descriptor. Normal distribution: bell-shap
ed (Gaussian) curve. Estimates of population mean: the population mean is the be
st estimate of the true value. Sample mean: arithmetic average. Accuracy: degree
to which measured value agrees with true value. Error (bias): difference betwee
n measured value and true value. Median: midmost value of a data distribution (a
verage of two midmost values if even number of observations). Normal distributio
n median = mean. Median is less affected by outliers or skewed distribution. Mod
e: most frequently occurring value in a distribution, it is useful for non-norma
l distributions especially bimodal distributions. Estimates of variability: infi
nite # of observations
population variance. Finite # of observations
sample vari
ance. Range: useful to describe variability only in very small number of observa
tions. Standard deviation: square root of variance. Precision (reproducibility):
degree to which replicate measurements made exactly the same way agree with eac
h other (expressed as relative standard deviation). Standard deviation of the me
an (standard error): estimate of variability or error in the mean obtained from
N observations. SE = SD/(sq. root of N). Used to establish confidence intervals.
3. Pharmaceutical Principles and Drug Dosage Forms
I. Intermolecular forces of attraction
Atoms vary in electronegativity, so, electron sharing between atoms will be uneq
ual. So, the molecule behaves like a dipole over a covalent bond. Dipole moment
(mu) = distance of charge separation X charge Nonpolar molecules: perfect symmet
ry and dipole moment = zero. Example: carbon tetrachloride.

When the negative pole of a dipole approach the positive pole of another
molecul
ar attraction called dipole-dipole interaction. If similar poles approach
molecula
r repulsion (intermolecular repulsive forces)
Types of intermolecular forces of attraction
Van der Waals forces (liquids) Induced dipole induced dipole (London dispersion
force): when a transient dipole in a nonpolar molecule induces another transient
dipole in another molecule. Force = 0.5-1 Kcal/mole Dipole-induced dipole (Deby
e induction force): A transient dipole is induced by a permanent dipole. Force =
2 Kcal/mole Permanent dipole (Keesom orientation force): 4 Kcal/mole Hydrogen b
onds Hydrogen ions are small and have a large electrostatic field, so it approac
hes highly electronegative atoms (O, F, Cl, N, S) and interact electrostatically
to form a hydrogen bond. Force = 5 Kcal/mole. Ion-ion, ion-dipole, ion-induced
dipole Force of positive-negative ion interaction in the solid state = 150 Kcal/
mole. Covalent and ionic forces are much stronger than van der Waals forces.
States of matter
Gases Molecules move in straight path at high speed until they randomly collide
with another molecule, creating pressure. Intermolecular forces ~ zero. Ideal ga
s law: Pressure (P) x Volume (V) = number of moles (n) X Molar Gas Constant (R)
X Temperature (T) Gases in pharmacy: anesthetics (nitrous oxide, halothane), com
pressed oxygen, liquefiable aerosol propellants (nitrogen, CO2, hydrocarbons, ha
lohydrocarbons), ethylene oxide for sterilization of heat labile objects. Volati
le liquids (ether, halothane, methoxyfurane) are used as anesthetics. Amyl nitri
te (volatile liquid) is inhaled as a vasodilator in acute angina. Sublimation: a
solid is heated directly to the gaseous or vapor state (or vice versa, also cal
led deposition) without passing through the liquid state. Examples: camphor, iod
ine. Liquids Van der Waals intermolecular forces are sufficient to impose some o
rdering. Hydrogen bonding cohesion in liquids. Surface and interfacial tension M
olecules at the surface of the liquid experience a net inward pull from the inte
rior and they tend to contract. This makes liquids assume a spherical shape as i
t is the volume with minimum surface and least free energy. Surface free energy
/ surface tension: the work required to
the surface area A of the liquid by 1 un
it area. Example: SFE for water = 72 mN/m. Interfacial tension: at the surface o
f two immiscible liquids. Viscosity Viscosity = shear stress / shear rate Non-Ne
wtonian viscosity: exhibit shear dependent or time dependent (apparent) viscosit
y. Shear dependent viscosity: Shear thickening (dilatancy) as in suspensions of
small deflocculated particles with high solid content. Shear thinning (pseudopla
stic): as in polymer solutions. Plastic (Bingham body): as in flocculated partic
les in concentrated suspensions that have yield value. Time dependent viscosity:
yield value of plastic systems may be time dependent. Thixotropic systems are s
hear thinning but they do not recover viscosity after shear is removed, i.e., st
ructural recovery is slow

compared to structural breakdown. It occurs in heterogenous systems with three d

imensional structural network (gel-sol transformation). Negative (anti)thixotrop
y: viscosity
with
shear up to an equilibrium (sol-gel transformation). Solids Hi
gh intermolecular forces. Crystalline solids: fixed molecular order, distinct me
lting point, anisotropic (properties are nto the same in all directions). Amorph
ous solids: randomly arranged molecules, nondistinct melting point, isotropic (p
roperties are the same in all direction). Polymorphs: substance has more than on
e crystalline form. Different molecular arrangments / crystalline lattice struct
ure, melting point, solubility, dissolution rate, density, stability. Polymorphs
are common in steroids, theobroma oil, cocoa butter. Latent heat of fusion: hea
t absorbed when 1 g of solid melts.
III. Physicochemical behavior
Homogenous systems
Solution: homogenous system in which a solute is molecularly dispersed or dissol
ved in a solvent. Nonelectrolytes: substances that do not form ions in solution,
e.g., estradiol, glycerin, urea, sucrose. Solution doesnt conduct electricity. E
lectrolytes: form ions in solutions. Solution conducts electricity. Can be stron
g (completely ionized in water; HCl, NaCl) or weak (partially ionized; aspirin,
atropine).
Colligative properties:
Depend on the total number of ionic and nonionic solute molecules in solution. T
hey are dependent on ionization but independent of other chemical properties of
the solute. Vapor pressure depression: (Raoults law): partial vapor pressure is e
qual to the product of the mole fraction of the component in solution and the va
por pressure of the pure component. Boiling point elevation and freezing / melti
ng point depression Osmotic pressure: Osmosis is the process by which solvent mo
lecules pass through semipermeable membrane from dilute solution to concentrated
solution. That is because solvent molecules have lower chemical potential in co
ncentrated solution. Osmotic pressure is the pressure that must be applied to so
lution to prevent the flow of pure solvent. It is defined by the vant Hoff equati
on.
Electrolyte solutions and ionic equilibria
Arrhenius dissociation theory: an acid is a substance that liberates H (donates
protons) in water, a base liberates OH (accpets protons). Lowry Bronsted theory:
applies to both aqueous and + nonaqueous systems. In water, a free proton combi
nes with water forming hydronium ion (H3O ). A strong acid in water can behave a
s a weak acid in a different solvent. Lewis theory: defines acid as a molecule o
r ion that accepts an electron pair from another atom. A base donates an electro
n pair to be shared with another atom. pH is the negative logarithm of molar H+
concentration. As pH , H+ concentration
exponentially. Ionization: is the complet
e separation fo the ions in a crystal lattice when the salt is dissolved. Dissoc
iation: is the separation of ions in solution when the ions are associated by in
terionic interactions. For weak electrolytes, dissociation is reversible. Accord
ing to the law of mass action, concentration of dissociation products results in
dissociation. pKa is the dissociation constant of a weak acid. pKb is used for
weak bases. Acids and bases that can accept or donate more than one proton will
have more than one dissociation constant. Henderson-Hasselbalch equation: descri
bes the relationship between ionized and nonionized species of a weak electrolyt
e (base is UP). pH = pKa when [dissociated species] = [nondissociated species],
i.e., 50% ionization. Solubility of a weak electrolyte varies as a function of p
H. Solubility of a weak acid
with
pH. Opposite is true for weak bases.
+

Buffer: a mixture of salt with acid or base that resists changes in pH when smal
l quantities of acid or salt are added. Buffer is a combination of weak acid and
its conjugate base (salt) (more common), or a weak base and its conjugate acid
(salt). Buffer capacity: is the number of gram equivalents in an acid or base th
at changes the pH of 1 liter buffer by 1 unit. Maximum buffer capacity occurs wh
en pH = pKa. Higher concentration of buffer constituents
buffer capacity due to
the acid or base reserve.
Heterogenous (disperse) systems:
Suspension: two phas system that is composed of solid material dispersed in a li
quid. Particle size is > 0.5 mm. Emulsion: heterogeneous system that consists of
one immiscible liquid dispersed in another as droplets. Droplets diameter > 0.1
micron. Emulsions are inherently unstable because the droplet tend to coalesce.
An emulsifying agent is used to prevent coalescence. In ideal (not real) disper
sion, the dispersed particles are uniform in size and do not interact. Stokess la
w defines Sedimentation rate. The rate
with
particle size and the difference in
density between particles and medium. The rate with
medium viscosity. High parti
culate (dispersed phase) concentration leads to particle collision and aggregati
on, coalsecnce, instability. Avoidance of particle-particle interactions: if par
ticles have similar electrical charge (e.g. from the surfactant). Zeta potential
(magnitude of the charge) is the difference in electrical potential between the
particle charged surface and dispesion medium. When zeta potential is high (<25
mV), interparticulate repulsive forces > attractive forces, which results in de
flocculation and stability. Coalescence of droplets in O/W emulsions is
by elect
rostatic repulsion of similarly charged particles. Creaming: is the reversible s
eparation of a layer of emulsified particles. Mixing or shaking may be sufficien
t to reconstitute the emulsion. Phase inversion: from o/w to w/o emulsion or vic
e versa.
IV Chemical kinetics and drug stability
Degradation rate depends on concentration, temperature, pH, solvents, additives,
light, radiation, catalysts (polyvalent cations), surfactants, buffers, complex
ing agents. Order of reaction: the way in which the concentration affects rate.
Zero order: rate is independent of concentration, e.g., 5 mg/hr, i.e., straight
line concentration vs. time. First order: rate depends on the first power of con
centration, e.g., 5% / hr. Concentration exponentially with time. Straight line
log concentration vs. time. t1/2 = 0.693/k, t90% = 0.104/k. Half life is concent
ration independent. Temperature: T
reaction rate (Arrenius equation). Solvent: m
ay change pKa, surface tension, viscosity, reaction rate, etc. Additional reacti
on pathways may be created (e.g. aspirin in ethanol). pH: H+ catalysis occurs at
pH, OH- catalysis occurs to
pH. Rate constant at intermediate pH range is usual
ly lower than at or
pH. pH of optimum stability (point of inflection) is measure
d. Aromatic esters (benzocaine, procaine, tetracaine)
t1/2 is presence of caffei
ne due to complex formation.
Modes of pharmaceutical degradation:
Hydrolysis: most common. Occurs for esters, amides, lactams. H+ and OH- are the
most common catalysts. Esters easily hydrolize and should be avoided in liquids.
Oxidation: by oxygen in the air or in solvent. Oxidizable compounds should be p
acked in an inert atmosphere (nitrogen or CO2). Oxidation involves free radical
mechanism and chain reaction. Free radicals take electrons from other compounds.
Antioxidants react with free radicals by providing electrons. Antioxidants incl
ude: ascorbic acid, tocopherols, sodium bisulfite, sodium sulfite, butylated hyd
roxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate. Photolysis: d
egradation in sunlight or room light. Molecules may absorb the proper wavelenght
of light (usually <400 nm) and acquire sufficient energy to undergo reaction. P
revent by using opaque container or amber glass bottle. Examle: sodium nitroprus
side in water.

Determination of shelf life. Its affected by storage temperature. Preparation is

considered fit if it varies from nominal concentration by no more than 65% provi
ded the decomposition products are not more toxic. Stability testing at 4 C and
room temperature (22C). Rate of decomposition is determined. Temperatureccelerat
ed stability is also conducted. Arrhenius equation can be used. T90% can also be
calculated.
Drug dosage forms:
Oral solutions
May contains polyols (e.g. sorbitol, glycerin) to crystallization, modify solubi
lity, taste, mouth feel. Advantages (over solid forms): more homogenous, easier
to swallow, bioavailability and onset of action for slow dissolution drugs. Disa
dvantage: bulkier, degrade faster, interactions with constituents Types of water
: Purified water USP: obtained from distillation, reverse osmosis, ion exchange.
Solids < 10 ppm. pH = 57. It can not be used for ophthalmics or parenterals. Wa
ter for injection USP: purified water that is pyrogen free Sterile water for inj
ection USP: water for injection that is sterilized and packaged in single dose c
ontainers < 1 liter for type I or II glass Bacteriostatic water for injection US
P: sterile water for injection containing bacteriostatic agent(s) in one or mult
iple dose containers < 30 ml in type I or II glass. Sterile water for inhalation
USP: purified by distillation or reverse osmosis and rendered sterile. It conta
ins no antimicrobials. Sterile water for irrigation USP: water for injection tha
t is sterilized and contains no antimicrobials. Oral drug solutions Syrups: cont
ains sugar concentration. Sweet and viscous. Syrup NF (simple syrup): 85% w/v su
gar. Sugars have low solvent capacity for water soluble drugs because hydrogen b
onding between sugar and water is very strong. Dilute sucrose solutions are exce
llent media for microbial growth. As sugar concentration approaches saturation,
the solution becomes self-preserved, however temperature fluctuations may cause
sugar crystallization. Syrup USP is self-preserved with crystallization potentia
l. Elixirs: contain alcohol as a solvent (5-40%). Elixirs become turbid when dil
uted by aqueous liquids. Alcohol salt taste. Salts also have limited solubility
in alcohol. Aromatic elixir NF: mixture of two alcohol concentrations resulting
in 22% alcohol.
Miscellaneous solutions
Aromatic waters: are saturated aqueous solutions of volatile oils. Used for flav
oring. Stored in tight, light resistant containers. Adding large amount of water
soluble drug may cause insoluble layer to form (salting out) due to better attr
action with the water solvent than the oils. Spirits (essences): volatile substa
nces in 50-90% alcohol. It water is added, oils separate. Used medicinally or as
flavors. Store in tight containers. Tinctures: stable alcohol solutions of chem
icals or soluble constituents or vegetable drugs. Prepared using extraction usin
g maceration or percolation. Alcohol content varies widely. Fluidextracts: liqui
d extracts of vegetable drugs that contain alcohol as a solvent, preservative, o
r both. Prepared by percolation. Ten times as concentrated and potent as tinctur
es (100% vs. 10%). Mouthwashes: use alcohol or glycerin to dissolve volatile ing
redients. Astringents: locally applied solutions that ppt protein. Astringents c
ell permeability without causing injury. They cause constriction, wrinkling and
blanching of skin. They secretions and are used as antiperspirants. Examples: al
ulminum acetate, aluminum subacetate, calcium hydroxide. Antibacterial topical s
olutions: e.g. benzalkonium chloride, strong iodine, providone-iodine. .
Suspensions
Magmas: suspensions of finely divided material in a small amount of water. Drugs
may be packed dry to avoid instability in aqueous dispersions. Advantages:

Sustained effect: requires dissolution or diffusion step. Stability: drug degrad

ation is slower than in a solution. Taste: for insoluble drugs used in suspensio
n. Solubility: when solvent is not available. Example: only water can be used in
ophthalmics, but suspension offer an alternative. Preparation: first solids are
wetted by levigation (addition of nonsolvent levigating agent to solid material
to form a paste). A surfactant can be used. Then suspending agent is added as a
queous dispersion by geometric dilution. Suspending agents: A. Hydrophilic collo
ids viscosity by binding with water. Support microbial growth and require preser
vation. Mostly anionic, except methyl cellulose (neutral) and chitosan (cationic
), therefore incompatible with quaternary antimicrobials. Insoluble in alcohol.
Acacia: used as 35% water dispersion (mucilage). Neutral pH. Tragacanth: 6% muci
lage (less needed). Methyl cellulose: heat and light stable polymer. Soluble in
cold but not hot water. Prepared using boiling water. Carboxy methyl cellulose:
anionic and water soluble. B. Clays Anionic silicates. Strongly hydrated and exh
ibit thixotropy. Examples: bentonite (5% magma), veegum.
Emulsions
Advantages: Solubility: e.g. oil soluble drug in aqueous formulation. Stability:
usually better than in aqueous solution. Drug action: as in IM injections. Tast
e: oil soluble drug hidden in aqueous outer phase. Appearance: as in oily materi
al for topical application. Phases of emulsions: most are 2-phases. Internal pha
se (dispersed or discontinuous phase) in an external phase (dispersion medium or
continuous phase). Type of emulsion is determined by relative phase volumes and
emulsifying agent used (more important). Maximum volume of internal phase is 74
%. Emulsifying agents: lower interfacial tension and form a film at the interfac
e. Natural emulsifying agents: see hydrophilic colloids under suspending agents
(acacia, tragacanth, celluloses). Also pectin, gelatin and agar. Agar: viscosity
. Gelatin: 1%, can be anionic or cationic. Preparation methods: 1. Wet gum (Engl
ish) method: emulsion of fixed oil, water, acacia. Make mucilage of water and ac
acia, then add oil gradually. 2. Dry gum (Continental) method: emulsion of fixed
oil, water, acacia. Fixed oil added to acacia and then water is all added at on
ce followed by rapid titration. Electrolyte in high concentration can break the
emulsion. Add last. Alcohol can dehydrate and ppt hyrocolloids. Use in concentra
tion. 3. Bottle method: similar to dry method. Used for volatile oils. 4. Nascen
t soap method: by mixing equal portions of oil and alkali solution to form soap,
which acts as an emulsifying agent. Example: olive oil (contains oleic acid, fr
calcium oleate for calamine lotion. The drug can b
ee fatty acid) and lime water
e added after emulsion formation if it is soluble in the external phase. If drug
is soluble in internal phase, it should be dissolved first during emulsion form
ation. Synthetic emulsifying agents: 1. Anionic: Soaps form w/o except alkali so
ap. Examples: SLS 2. Cationic: e.g. benzalkonium chloride. Incompatible with soa
p. 3. Nonionic: Spans (sorbitan esters, HLB) for w/o, Tweens (polysorbates, HLB)
for o/w
Ointments
Used as emollients (make skin more pliable), protective barriers, or vehicles fo
r drugs. Ointment bases 1. Oleaginous bases: not washable. Petrolatum: occlusive
, does not rancid, use wax to viscosity. Synthetic esters: e.g. glyceryl monoste
arate, isopropyl myristate, butyl palmitate, PEG, long chain alcohols. Lanolins:
e.g. lanolin oil and hydrogenated lanolin.

2. Absorption bases: anhydrous, water-insoluble, not washable, but can absorb wa

ter. Example: anhydrous lanolin (wool fat), hydrophilic petrolatum (petrolatum,
bees wax, stearyl alcohol, cholesterol), e.g. Aquaphor. 3. Emulsion bases: Hydro
us wool fat (lanolin): w/o with 25% water, emollient and occlusive. Cold cream:
w/o with almond oil, white wax, sodium borate. Vanishing cream: o/w with water a
nd humectants (PEG, glycerin). Hydrophilic ointment: o/w with SLS. 4. Water solu
ble bases: washable and absorb water. PEG ointment: PEG 400 and 4000 by fusion m
ethod. PG and PG-alcohol: forms clear gel with 2% hydroxypropyl cellulose. Prepa
ration: metal spatula may interact with iodine or mercuric salts. Use levigation
or fusion method. Fusion method: used for solids with melting point. Oil phase
melted with highest melting point materials first. Heat water soluble ingredient
separately to above the highest melting point. Mixed the two phases in the appr
opriate order for o/w or w/o.
Suppositories
Used for local (hemorrhoids, infection) or systemic effect. Systemic effect bypa
sses the first pass metabolism Used when oral route is not possible, e.g., infan
ts, nausea, vomiting, GI distress, coma, debilitation. Types of suppositories: 1
. Rectal: cylindrical, tapered bullet like. Adult: 2 g. 2. Vaginal: oval, 5 g, f
or antiseptics, contraceptives, anti-infective. 3. Urethral: long (6 cm), tapere
d, local anti-infective. Suppository bases: Minimum 30 C narrow, sharp melting p
oint. Oil soluble drug has mucous absorption from an oil base, and vice versa. B
ases that melt: cocoa butter (theobroma oil), witepsol (saturated fatty acid mix
ture), wecobee (from coconut oil); or Bases that dissolve: PEG. Preparation: the
suppository is molded with the fingers after a plastic mass is formed. 1. Handrolling: Correct the amount of base needed based on the quantity of the drug and
density of the base. 2. Compression: Mixture is placed into compression device.
Pressure is applied and mixture is forced into lubricated mold cavities. Used w
ith cocoa butter. 3. Fusion (molds): most common. Use mineral oil to lubricate m
old. Pour melt continuously to avoid layering. Avoid for thermolabile drugs and
insoluble powders (settle).
Powders
Advantages: compounding flexibility, chemical stability, rapid ingredients dispe
rsion. Disadvantages: time consuming preparation, inaccurate dosing, unsuitable
for bad taste / hygroscopic drugs. Milling: mechanical process of reducing parti
cle size (comminution). Micrometrics: is the study of particles. Advantages of m
dissolution rate and bioavailability (e.g. griseofulvin),
d
illing: surface area
rying of wet masses. ointment texture / stability / appearance. uniform distribu
tion of colorants. Particles of same size
mixing, segregation. Disadvantages of
milling: may change polymorphic form activity. heat / adsorption
degradation. Fl
ow problems and segregation. static charge particle aggregation / dissolution. s
urface area
air adsorption / wettability. Comminution techniques: Trituration
re
ducing particle size or mixing with a mortar and pestle. Pulverization by interv
ention a solvent is added to help pulverization and then evaporated (e.g. alcoho
l to camphor). Used with gummy substances that reagglomerate or resist grinding.
Levigation
add a nonsolvent (levigating agent, e.g., mineral oil) to form a pas
t and help pulverization in mortar and pestle or ointment slab and spatula. Avoi
d gritty feel of solids. Mixing powders: Spatulation: using spatula to mix small
amounts of powder on paper or pill tile. Not possible for potent drugs or large
quantities. Useful to eutectic mixtures (mixture melting point is lower than ea
ch ingredient), such as phenol, camphor, menthol, thymol, aspirin, phenyl salicy
late, phenacetin. Inert diluent can be used to minimize contact (MgO, MgCO3, kao
lin, starch). Trituration: used both to comminute and mix. For comminution, use
porcelain or ceramic mortar with rough surface. For mixing, colorants and easy c
leaning, use glass mortar.

Geometric dilution: used for mixing potent drugs with large amount of diluent. F
irst mix equal amounts of drug and diluent in a mortar by trituration, repeat un
til diluent is used up. Sifting: powders are passed through sifters similar to f
lour sifters, resulting in a light fluffy product. Not suitable for potent drugs
. Tumbling: mix powders in a large container rotated by motor. Use and packaging
of powders: As bulk powders or divided powders. For bulk powders, a perforated
sifter can is used for external dusting or an aerosol container is used for spra
ying onto skin. Powders dispensed in bulk: antacids and laxatives (e.g. PEG is m
ixed with a drink). Douches are mixed with water and applied vaginally. Dentifri
ces and dental cleansing powders. Powders for ear, nose, throat, tooth sockets,
vagina. Non potent substances. Divided powders: dispensed usually in folded pape
r (chartulae). If drug is not potent, approximate portions by block and divide m
ethod (do not weight). Special problems: volatile substances (camphor, menthol,
essential oils)
use sealed containers. Liquids added to divided powders in small
amounts. Hygroscopic substances become moist
divide, add diluent, double wrap.
Eutectic mixtures.
Capsules
Hard gelatin capsules Storage: contain 15% water, so when humidity capsules beco
me brittle, when humidity
capsules become shapeless. Size: empty capsules are nu
mbered (000 largest / 600 mg, 5
smallest / 30 mg). Large capsules are for veteri
nary use. May add lubricant to flow or wetting agent to dissolution. Filling: by
the punch method. Powder is placed on paper and the capsule is pressed into pow
der until filled. Soft gelatin capsules Preparation: from gelatin shells. Glycer
in or polyhydric alcohol (sorbitol) is added to make shells more elastic. Contai
n preservatives (sorbic acid, parabens). Uniformity and disintegration Uniformit
y is demonstrated by weight variation or content uniformity. Disintegration are
usually not requires unless they are enteric coated. Contents may be designed fo
r sprinkling on food (e.g. Theo-Dur Sprinkle).

Tablets
Advantages of solid dosage forms: accurate dose, easy shipping / handling, less
shelf space, no preservative, no taste masking problems, more stable / longer ex
piration. Advantages of liquid dosage forms: more effective (antacids, adsorbent
s), easier to swallow. Advantages of tablets; precise dose, content variability,
manufacturing cost, easy packaging and shipping, easy to identify, easy to swal
low, specific release forms, stable, tamperproof. Disadvantages of tablets: diff
icult compression, difficult formulation / bioavailability (poor wetting, dissol
ution, dose). Ideal tablet: free of defects, strong / durable, stable, predictab
le drug release. Tablet design and formulation (excipients) Diluents: fillers to
make up the tablet bulk of dose drugs. May cohesion, flow, or direct compressio
n. Examples: kaolin, lactose, mannitol, sugar, starch, microcrystalline cellulos
e, calcium phosphate. Do not use calcium salts with tetracycline ( absorption). B
inders / adhesives: added dry or liquid to granulation or direct compression. Ex
amples: cornstarch, glucose, molasses, natural gum (acacia, may be contaminated)
, celluloses (methylcellulose, CMC, microcrystalline cellulose), gelatins, provi
de (PVP). Liquid binders are more effective.
too hard, dissolution.
soft crumblin
tablets. Disintegrants: disintegration on gastric fluid contact (critical for d
issolution and bioavailability). They draw water to tablet, swell and burst. Exa
mples: cornstarch, potato starch, sodium starch glycolate, celluloses (sodium CM
C), clays (veegum, bentonite), cation exchange resins.

A portion can be added with the diluent and another with the lubricant after gra
nulation
double disintegration. Lubricants / antiadherents / glidants: lubricant
s friction between tablet and die upon ejection (talc, magnesium stearate, calci
um stearate). Anti-adherents
sticking, adhesion of granules to the punches or di
e. Glidants
particle friction
powder / granule flow. Colors / dyes: disguise off
-color drugs, product ID. FDC dyes are applied in solution. Lakes are dyes absor
bed on a hydrous oxide (dry powder). Flavoring agents: only for chewable or mout
h dissolving tablets. Flavor oils or powders are stable, water soluble flavor ar
e stable. Maximum: 0.75%. Artificial sweeteners: only for chewable or mouth diss
olving tablets. May come with diluent (mannitol, lactose). Other agents; sacchar
in, aspartame. Adsorbents: hold fluid in apparently dry state. Example: magnesiu
m oxide, magnesium carbonate, bentonite. Tablet types and classes For oral inges
tion: May be mask taste, color, odor, control release, enteric coating, incorpor
ate another drug, avoid incompatibility, appearance. Compressed: from powders, c
rystals or granules with or without excipients. No coating. Multiple compressed:
layered compress tablet granules around previously compressed granules, then re
peat. Compression coated / dry coated
made by feeding previously compressed tabl
et to a machine that compresses an shell around it separate incompatible drugs,
provide repeat action / prolonged action. Repeat-action: multiple compressed tab
let where the outer shell rapidly disintegrates in the stomach. Example: Repetab
s, Extentabs. The components of the inner layer are insoluble in the stomach but
soluble in the intestine. Delayed action / enteric coated: delays drug release
to prevent stomach destruction, prevent stomach irritation, or better stomach ab
sorption. Enteric: intact in stomach, release in intestine (e.g. Ecotrin). Sugar
/ chocolate-coated: to protect drug from air / humidity, mask taste / odor. Pro
cess includes seal coating (waterproofing), subcoating, syrup coating (for smoot
hing, coloring), polishing. Disadvantage: time consuming, require expertise, bul
ky coats. Film coated: compressed tablets coated with water soluble or insoluble
polymer (HPMC, povidone, PEG). Film is colored, durable, chipping, bulky (3% wt
), time consuming than sugar coating. May contain film former, plasticizer, surf
actant, opacifier, sweetner, color, flavor, glossant, volatile solvent. Air-susp
ension coated: fed into vertical cylinder and supported by air column (Wurster p
rocess) where the coating solution is applied. Chewable: disintegrate rapidly wh
en showed or dissolved. Contains flavored and colored mannitol. Used for childre
n, multivitamins, antacids, antibiotics. Used in oral cavity Buccal / sublingual
: allow absorption through oral mucosa after dissolution. Avoid gastric destruct
ion or intestinal absorption. Examples: sublingual nitroglycerin, buccal progest
erone. Troches / lozenges / dental cones: dissolves slowly in the mouth and prov
ide local effect. Used to prepare solutions: Effervescent: made by compressing g
ranular effervescent salts (citric acid, tartaric acid, sodium bicarbonate) that
release CO2 when contacting water. Example: alkalinizing analgesics (Alka-Seltz
er, dissolution, absorption). Other tablets to prepare solution: dispensing tabs
, hypodermic tabs, tab triturates. Processing problems Capping: separation of th
e top or bottom crown from main body of tab. Lamination: separation of tab into
two or layers. Usually due to air entrapment. Picking: removal of the surface ma
terial by a punch. Sticking: adhesion of material to the die wall. Due to excess
moisture or melting ingredient. Mottling: unequal color distribution. Due to di
fferent color drug vs. excipient or drug degradation.

Tablet evaluation and control General appearance: size, shape, color, odor, tast
e, surface, texture, physical flaws, consistency, marking legibility. Hardness /
friability resistance: Hardness affects dissolution / disintegration. Slow diss
olved tabs are harder, vice versa. Hardness tester measure force required to bre
ak tab. Friabilators measure weight loss when tabs roll and fall (<1%). Chewable
/ effervescent tabs are highly friable, require special packaging. Weight varia
tion: USP standards apply to tabs containing >50 mg drug where drug is > 50% of
total weight. Content uniformity: USP standards apply if drug <50 mg. Disintegra
tion: USP test is conducted in vitro. Disintegration time: nitroglycerin (2 min)
, aspirin (5 min), most other drugs (<30 min), buccal tabs (4hr), enteric coated
(none in 1 hr is simulated gastric fluid, within 2 hr in simulated intestinal f
luid). Dissolution: standards in USP. Increased emphasis on dissolution replaced
disintegration for many drugs.
Aerosols
Pressurized dosage forms that deliver drugs topically or systemically with the a
id of liquefied or propelled gas (propellant). Valve allows pressurized product
to be expelled continuously or intermittently when the actuator is pressed. Dip
tube conveys the formulation for the containers bottom to the valve. Metered dose
inhalers (MDIs): aerosol systems for systemic or pulmonary delivery. They conta
in fine drug mist solution or dispersion. 1 Actuation = 1 dose. Propellants: com
pressed gases (CO2, N2, NO), pressure with time due to head space. Liquefiable g
ases: saturated hydrocarbons, hydrofluorocarbons, dimethyl ether, chlorofluoroca
rbons (CFC). CFC are banned now. Advantages: push-button dispensing convenience,
stability of closed container (protects from light, moisture, air, microbes), t
ampering, wide product range. Disadvantage: propellants are environmental hazard
.
Controlled release dosage forms
They release drug slowly. Also known as delayed-release, sustained-action, prolo
nged-action, sustainedrelease, prolonged-release, timed-release, slow-release, e
xtended-action, extended-release. Advantages: compliance, total drug used, local
or systemic SE, drug accumulation / potentiation / loss of activity with prolon
ged use, treatment efficiency, rapid condition control, bioavailability, level f
luctuation, cost. Coated beads or granules: Examples: Theo-Dur Sprinke, Spansule
s, Sequels,. Produce drug level similar to multiple dosing. Non-aqueous (e.g. al
cohol) drug solution is coated onto small inert beads or granules (starch/sugar)
. Beads may be made of drug if dose is . Some granules take no further coating to
give immediate release. Otherwise, coats of a lipid (e.g. beeswax) or cellulosi
c (e.g. ethylcellulose) material are applied. Thickness is varied by varying # o
f coats to provide SR. Microencapsulation Example: Bayer time-release aspirin. S
olids, liquids or gases are encased in microscopic capsules. Coacervation: most
common method of encapsulation. A hydrophilic substance is added to a colloidal
drug dispersion and causes layering and formation of microcapsules. Film forming
substances for coating (natural or synthetic) include shellacs, waxes, gelatin,
starches, cellulose acetate phthalate, ethylcellulose. After the coating dissol
ves, the drug is immediately available. Matrix tablets: Examples: Gradumet, Lont
abs, Dospan, Slow-K Use hydrophilic polymers (methyl cellulose, HPMC), insoluble
plastics (polyethylene, polyvinyl acetate, polymethacrylate), fatty compounds (
waxes, glyceryl tristearate). The drug is mixed with matrix material then compre
ssed.

The immediate dose is coated as a top layer. Osmotic systems: Example: Oros syst
em (Alza) Oral osmotic pump composed of a core tablet and semipermeable coating
that has a small hole (0.4 mm) produced by laser beam for drug exit. The system
requires only osmotic pressure to be effective and is independent of pH. Drug re
lease rate is controlled by changing surface area, membrane nature, or hole diam
eter. Ion-exchange resins: Example: biphenamine (amphetamine and dextroamphetami
ne), lonamin (phentermine), Pennkinetic system. Ion exchange resins are complexe
d with drugs by passage of a cationic drug solution through a column that contai
ns the resin. The drug is complexed to the resin by replacement of hydrogen atom
s. Then the resin-drug complex is washed and tableted. Release is dependent on i
onic environment in GI and resin properties ( pH
release). Complex formation: Exa
mple: hydroxypropyl-beta-cyclodextrin forms a chemical complex slowly dissolves
depending on pH. Hydrocolloid systems: Example: Valrelease (SR diazepam) include
s hydrodynamically balanced system (HBS). HBS contains a matrix that is dense th
an gastric acid, so it remains buoyant. Multiple hydrocolloid layers swell when
contacting gastric acid and slowly erode releasing the drug.
4. Biopharmaceutics and Drug Delivery Systems
Drug transport and absorption
Transport across cell membranes
Cell membrane: is a semipermeable structure composed of lipids and proteins. Pro
teins, protein bound drugs and macromolecules do not cross cell membranes easily
. Nonpolar lipid soluble and smaller molecular weight drugs diffuse through cell
membranes faster. Passive diffusion / partitioning: passive diffusion is domina
nt within the cytoplasm or in interstitial fluid (Ficks law). Passive transport a
cross cell membranes involves successive partitioning of solute between aqueous
and lipid phase as well as diffusion within phases. Nonionized drugs are more li
pid soluble and partition better across cell membranes. Carrier-mediated transpo
rt: Active transport: drug moves against concentration gradient, requires energy
, carrier may be selective for drugs that resemble natural substrates, system ma
y saturate at concentrations, process may be competitive. Facilitated diffusion:
carrier mediated transport that occurs with a concentration gradient and does n
ot require energy. Paracellular transport: drug transport across tight junction
between cells or channels. It involves diffusion and convective (bulk) flow of w
ater and dissolved molecules Vesicular transport: the process of engulfing parti
cles by a cell. Only mechanism that does not require water solubility for absorp
tion. Pinocytosis: engulfment of small solute or fluid volumes. Phagocytosis: en
gulfment of large particles or macromolecules by macrophages. Endo/Exo-cytosis:
movement of macromolecules in and out of the cell. Transport proteins: (e.g. P-g
lycoprotein) are embedded in the lipid bilayer of cell membranes. These are ATP
energy dependent pumps. Work closely with cytochrome P450 3A4 to intracellullar
drug concentration. Substrates: cyclosporin, nifedipine, digoxin.
Routes of drug administration
Parenteral: IV Bolus is directly injected to the blood stream, very quick action
/ SE. IV infusion: constant input rate maintains constant plasma concentration.
Intra-arterial: to achieve
concentration in specific tissue before systemic dru
g absorption, mostly diagnostic and chemotherapy. IM: rate of

absorption depends on muscle vascularity, drug lipid solubility / matrix. SC:

va
sculature slow absorption. Intra-articular: into the joint. Intrathecal: into th
e spinal cord. Intradermal: into the dermis. Enteral: Buccal / sublingual: allow
s nonpolar lipid soluble drug absorption, bypassing first pass metabolism. Peror
al: most common, convenient, safe. Disadvantages: inconsistent / incomplete abso
rption (gastric emptying, intestinal motility), GI enzyme digestion, acid pH dec
omposition, GI irritation, first pass metabolism. Absorption is usually by passi
ve diffusion. Duodenum is the main absorption site (villi / microvilli
surface a
rea). Residence time (period of contact) is needed for absorption. Double peak:
cimetidine or acetaminophen as immediate release on empty stomach produce two pe
ak plasma level. Rectal: drug in solution (enama) or suppository is placed in th
e rectum. Drugs absorbed in the lower 2/3 bypass the liver first pass metabolism
. Respiratory: Intranasal: as spray or drops for local (decongestant, steroid) o
r systemic effect. Pulmonary: inhaled perorally (nebulizer, MDE) into pulmonary
tree. Particles > 60 um
deposit on trachea. Particles > 20 um
do not reach bronc
hioles. Particles 2-6 um reach alveolar ducts. Particles 1-2 um
retained in the
alveoli. Particles < 0.6 um exhaled, not deposited. Transdermal (percutaneous):
suitable for small lipid soluble molecules (clonidine, nitroglycerin, fentanyl,
scopolamine, testosterone, estradiol). Local activity: topical antibiotics, anti
-infectives, antifungals, loacal anesthetics. Minimum systemic absorption.
Biopharmaceutical principles
Physicochemical properties
Drug dissolution: bioavailability rate limiting step for drugs with limited solu
bility. Diffusion is described by Noyes Whitney equation (similar to Ficks law).
Drug solubility in a saturated solution is a static equilibrium property. Dissol
ution rate is a dynamic property with a rate. Particle size / surface area: inve
rsely related. surface area
dissolution rate. For some hydrophobic drugs,
particl
e size aggregation to
surface free energy. To prevent aggregate formation, small
particles are molecularly dispersed in PEG, PVP (povidone), dextrose. Examples:
Griseofluvin molecular dissolution in water soluble carrier (PEG 400)
bioavaila
bility. Partition coefficient: ratio of solubility at equilibrium in nonaqueous
solvent (n-octanol) to that in aqueous solvent (water). Hydrophilic drugs ( water
solubility) dissolution. Ionization: ionized form is more polar and more water
soluble. Based on Henerson-Hasselbalch equation. Salt formation: type of salt af
fects dissolution, bioavailability, duration of action, stability, irritation, t
oxicity. Soluble salt may be
stable than nonionized form (e.g. sodium aspirin vs
. aspirin). Effervescent forms: contains acid drug and sodium bicarobnate, tarta
ric acid, citric acid. Water is added prior to use. Excess sodium bicarbonate fo
rms an alkaline solution in which the drug dissolves. CO2 is formed by the decom
position of carbonic acid. For weak acids, potassium and sodium salts are more s
oluble than polyvalent cation salts. For weak bases, common water soluble salts
include hydrochloride, sulfate, citrate, gluconate. Polymorphism: ability to exi
st in > 1 crystalline form. Polymorphs have different physical properties. Amorp
hous non-crystalline forms have
dissolution. Chirality: drug exists as optically
active stereoisomers or enantiomers different PK / PD. Most chiral drugs are us
ed as racemic mixtures. Example: ibuprofen has R and S enantiomers, only S is ac
tive. Hydrates: drug may exist in hydrated, solvated form and anhydrous form. An
hydrous ampicillin dissolves faster than hydrated ampicillin. Complex formation:
Chelates are complexes involving a ring-like structure and a metal. Natural che
lates: hemoglobin, cyanocobalamin, insulin). Tetracycline forms a chelate with p
olyvalent metal ions
water solubility
absorption. Many drugs adsorb strongly on
charcoal or clay (kaolin, bentonite) by forming complexes. Theophylline + ethyle
ne diamine
water soluble complex (aminophylline). Many drugs are complexed with
cyclodextrins to
solubility. Large drug complexes (drug-protein) do not cross ce
ll membranes easily
free drug must first dissociate for absorption or glomerular
filtration.
Delivery system formulation
Complex formulation bioavailability issues. For oral solid dosage forms, dissolu

tion is the rate limiting step. For CR or SR, release from the delivery system i
s the rate limiting step.

Solutions: are homogeneous mixtures of solutes dispersed molecularly in a dissol

ving medium. Aqueous solution is the most bioavailable and consistent form (no d
issolution). Oral solutions are used as reference preparations for solid oral fo
rms. Elixir (drug dissolved in hydroalcoholic solution) has
bioavailability. Alc
ohol solubility. However, drug may ppt when elixir is diluted in the GI with foo
d, but absorption is still rapid because of
surface area. A viscous drug solutio
n (syrup) may mixing, dilution and GI gastric emptying. Suspensions: bioavailabi
lity from suspension is similar to solutions due to
surface area. Suspending age
nts: hydrophilic colloids (celluloses, acacia, xantham gum). viscosity may have
issues as syrups above. Capsules: Hard gelatin caps are simple (contain powders)
and preferred new drugs early clinical trials. Soft gelatin caps contain nonaqu
eous solution, suspension or powder. It may have bioavailability if water miscib
le vehicle is used (e.g. lanoxicaps), and vice versa. Aging and storage may affe
ct gelatin shell moisture content and bioavailability. Compressed tablets:
ratio
of excipients : drug
possiblity of excipients affecting bioavailability. Lubric
ants are usually hydrophobic, water-insoluble
drug surface wetting
dissolution a
nd bioavailability. Surfactants
dissolution and bioavailability. Modified releas
e dosage forms: products that alter the rate or timing of drug release. More str
ingent quality control is used. Dose dumping, abrupt drug release, is a problem.
Allows in dosing frequency. They provide more flat consistent plasma concentrat
ion that avoids toxicity and lack of efficacy. A loading dose may be used. Delay
ed release control the timing of release, e.g. enteric coating. Transdermals: ha
ve occlusive backing film to prevent TEWL to hydration and permeation. Concentra
tion gradient is maintained by a drug reservoir. Targeted drug delivery: place t
he drug at or near the receptor (e.g. specific cell such as tumor, organ, tissue
). Systems include macromolecular drug carriers (proteins), liposomes, nanoparti
cles, monoclonal antibodies. Inserts and implants: drug is impregnated into a bi
odegradable material and released slowly. Inserted into vaginal, buccal cavity,
skin. Example: l-norgestrol implant is inserted in the upper arm for 5-year cont
raception.
6. Basic Pharmacokinetics
Introduction
Rates and orders of reactions
Reaction rate: velocity of the reaction Reaction order: way in which the drug (r
eactant) affects the rate Zero order reaction: drug concentration changes with t
ime at a constant rate. Rate constant = Ko (concentration / time; mg/ml/hr). Lin
ear correlation of concentration vs. time with slope=Ko and intercept = Co. Firs
t order reaction: change of concentration with time is the product of the rate c
onstant and concentration of the remaining drug. Drug concentration decreases by
a fixed percent in each time unit. Linear correlation of log concentration with
time. Rate constant )K) = 1/hour. Half life t1/2=0.693/k.
Models and compartments
Model: mathematical description to express quantitative relations in a biologica
l system. Compartment: group of tissues with similar blood flow and drug affinit
y.
Drug distribution
Drugs distribute quickly to tissues with blood flow Drug cross capillaries by pa
ssive diffusion and hydrostatic pressure. Drugs easily cross the capillaries of
the kidney glomerulus. Brain capillaries are surrounded by glial cells forming a
thick lipid membrane (BBB)
diffusion of polar and ionic hydrophilic drugs. Tiss
ue accumulation due to drug/tissue physicochemical or affinity. Lipid soluble dr
ug accumulate in adipose (fat) tissue

Tetracycline
accumulate in bone (calcium Complexation). Plasma protein binding:
results in a big complex
cant cross membranes. Albumin: major plasma protein for
drug binding. Alpha1-glycoprotein: binds basic drugs (e.g. propranolol) in the p
lasma. bound drugs (e.g. phenytoin) can be displaced by other bound drug
free un
bound drug in effect / toxicity.
One-compartment model
Intravenous bolus injection
Very rapid drug entry. Rate of absorption is negligible. Entire body is one comp
artment
all tissue equilibrate rapidly. Drug elimination: first order kinetics.
Elimination rate constant = renal excretion rate constant + metabolism (biotrans
formation) rate constant Some controlled release oral drugs have zero absorption
rate constant. Apparent volume of distribution (Vd): hypothetical volume of bod
y fluid in which drug is dissolved. Vd is needed to estimate amount of drug in t
he body (Db) relative to concentration in plasma (Cp). Cp = Db / Vd More drug di
stribution into tissues
Cp Vd
Single oral dose
Rapid absorption then elimination, both with first order kinetics. Time to reach
max concentration (tmax) depends only on absorption and elimination rate consta
nts but not on Vd or Db. AUC: calculated using trapezoidal rule by integrating t
he plasma drug concentration over time. AUC depends on Do, Vd, elimination K but
not absorption K. Lag time: at the beginning of systemic drug absorption, e.g.
due to delay in gastric emptying.
Intravenous infusion
Absorption: zero order. Elimination: first order (when infusion stops) Steady st
ate concentration (Css): target plateau drug concentration where fraction of dru
g absorbed = fraction of drug eliminated. Loading dose (DL): initial IV bolus do
se to produce Css as rapidly as possible. Start IV infusion at the same time. DL
: amount of drug that, when dissolved in the apparent Vd, produces the desired D
ss. Reaching 07% of Css without DL takes ~ t1/2. Time to reach Css depends on th
e drug elimination half life. IV infusion: ideal for drugs with narrow therapeut
ic window (controls Cp).
Intermittent intravenous infusion
Drug is infused for short periods to prevent accumulation and toxicity. Used for
aminoglycosides (e.g. gentamicin).
Multiple doses
Drug is given intermittently in multiple-dose regimen for continuous or prolonge
d therapeutic activity to treat chronic disease. Give new dose before previous d
ose completely eliminated
Cp accumulation
to Css. At steady state: Cp fluctuatio
ns between a max and a min (C min-max). Superposition principle: assumes that pr
evious drug doses have no effect on subsequent doses total Cp = cumulative resid
ual Cp from each previous dose. Dosing rate = dose size (Do) / dose interval (e.
g. X mg/hr). Same dosing rate
same average Css but may be different (C min-max).
Some AB multiple rapid IV bolus injections. Oral immediate release drug product
s (multiple doses)
rapid absorption, slow elimination. Maintenance dose (DM): af
ter loading dose to maintain Cp at Css. If DM dosing interaval = elimination t1/
2 DL = 2 x DM

Multi-compartment models
Drug distributes into different tissue groups at different rates. Tissues with b
lood flow equilibrate rapidly with the drug. Two-compartment model (IV bolus): F
irst, rapid distribution into highly perfused tissue (central compartment)
rapid
decline in Cp (distribution phase). Both are first-order processes. Then, slow
distribution into peripheral tissues (tissue compartment)
slow decline in Cp aft
er equilibration (elimination phase). Vd = Vd at steady state + central + tissue
compartment volumes. Two-compartment model (oral): two-compartment ONLY if abso
rption is rapid but distribution is slow. Models with additional compartments: e
xample of a third compartment: deep tissue space. If frequent interval dosing
th
ird compartment accumulation. Elimination rate constant: two constants; one for
elimination from central compartment, the other for elimination after complete d
istribution.
Nonlinear pharmacokinetics
Also known as capacity-limited, dose-dependent, or saturation PK. Result from th
e saturation of an enzyme of carrier-mediated system. Do not follow first-order
kinetics as the dose . AUC or drug excreted in urine are not proportional to dose
Elimination t1/2 may at doses. Michaelis-Menten equation: describe velocity of
enzyme reactions in nonlinear PK. It described rate of change of Cp after IV bol
us. If Cp is the equation is a zero-order rate of elimination. If Cp is
first-ord
er. Note that first-order PK = linear PK
Clearance
Total body clearance (ClT)
ClT = drug elimination rate /
T1/2 is a dependent variable.
dy per unit time. First order
earance ClT
t1/2. Vd

Cp = K x Vd ClT and Vd are independent variables.

A constant volume of the Vd is cleared from the bo
PK: ClT = renal clearance + non-renal (hepatic) cl
t1/2

Renal drug excretion

Major route of elimination for: polar drugs, water-soluble drugs, drugs with MWt
(<500), drugs that are biotransformed slowly. Glomerular filtration: passive pr
ocess that filters small molecules. Drugs that are bound to plasma proteins are
too big to be filtered. Creatinine and inulin undergo only glomerular filtration
(not tubular secretion or reabsorption)
used to measure glomercular filtration
rate (GFR). Tubular reabsorption: passive process that follow Ficks first law of
diffusion to reabsorb lipid -soluble and non-ionized weak electrolytes drugs bac
k to the systemic circulation. If ionized or water-soluble
excreted in the urine
. Diuretic urine flow
time for reabsorption
drug excretion. Active tubular secre
tion: carrier-mediated active transport system that requires energy. Two systems
: for weak acids and weak bases. Competitive nature: e.g. probenecid (weak acid)
compete for the same system as penicillin penicillin excretion. Another example
: p-aminohippurate. Measure using effective renal blood flow (ERBF).
Renal clearance (ClR)
It is the volume of drug in the plasma remove by the kidney per unit time. ClR =
rate of drug excretion / Cp = ml/minute. Clearance ratio: relates drug clearanc
e to inulin clearance (GFR). If = 1
filtration only. If < 1
filtration + reabsor
ption. If > 1 filtration + active tubular secretion.

Hepatic clearance
Volume of drug-containing plasma cleared by the liver per unit time. Measurement
of hepatic clearance (ClH) Main mechanism for non-renal clearance. Measured ind
irectly (difference between total and renal clearance). ClH = hepatic blood flow
x extraction ratio. Extraction ratio: drug fraction irreversibly removed by an
organ or tissue as the drug-containing plasma perfuses the tissue. Blood flow, i
ntrinsic clearance, protein binding All these factors affect hepatic clearance.
Blood flow: to the liver is ~ 1.5 L/min. After oral GI absorption
to mesenteric
vessels to hepatic portal vein through the liver
to hepatic vein
to systemic cir
culation. Intrinsic clearance: ability of the liver to remove the drug independe
nt of blood flow due to inherent ability of the biotransformation enzymes (oxida
ses) to metabolize the drug as it enters the liver. This is affected by enzyme i
nducers (Phenobarbital, tobacco) and inhibitors (cimetidine, lead). Protein bind
ing: bound drugs are not easily cleared by the liver or kidney. Only free drug c
rosses the membrane into the tissue and is available to metabolizing enzymes. Bi
liary drug excretion Active transport (secretion) process. Separate systems for
weak acids and weak bases. Excretes MWt drugs (>500) or polar drugs (digoxin, re
serpine, glucuronide conjugates). Drugs may be recycled by enterohepatic circula
tion. GI absorption
mesenteric vessels hepatic portal veins
liver
secrete to the
bile store in gallbladder empty into the GI through the bile duct (recirculatio
n). First pass effect (pre-systemic elimination) Portion of oral drugs may be el
iminated before systemic absorption due to rapid drug biotransformation by liver
enzymes. Measure absolute bioavailability (F). If F < 1
some drug was eliminate
d before systemic absorption. Common for drug with high liver extraction ratio.
If first-pass effect dose (e.g. propranolol, penicillin), different route (e.g.
nitroglycerin, insulin), or modified dosage form (e.g. mesalamine).
Non-compartment models
Some PK parameters can be estimated with non-compartment methods using compariso
n of the AUCs. Mean residence time (MRT): average time for the drug molecules to
reside in the body. Called Mean Transit Time or Sojourn Time. It depends on the
route of administration. Assumes elimination from the central compartment. MRT
= total residence time of all drug molecules in the body / total number of drug
molecules. Mean absorption time (MAT): difference between MRT and MRTIV and an e
xtravascular route. Clearance: volume of plasma cleared of the drug per unit tim
e. Steady-state volume of distribution (Vss): amount of drug in the body at stea
dy sate and the average steady-state drug concentration.
Clinical pharmacokinetics
The application of PK principles to the rational design of an individualized dos
age regimen. Objectives: maintenance of an optimum drug concentration at the rec
eptor site to produce effect for the desired period, and minimization of SE.
Toxicokinetics
Application of PK principles to the design, conduct, and interpretation of drug
sate evaluation studies. Used to validate dose-related exposures in animals in p
reclinical drug development to predict human toxicity.

Clinical toxicology: study of SE of drugs and poisons. PK in intoxicated patient

( dose) may be very different from a patient taking therapeutic doses.
Population pharmacokinetics
Study of sources and correlation of variability in drug concentration in the tar
get patient population. Includes PK and non-PK parameters such as age, gender, w
eight, creatinine clearance, concomitant disease.
7. Bioavailability and bioequivalence
Definitions
Bioavailability: measurement of the rate and extent to which the active moiety b
ecomes available at the site of action. It is also the rate and extent of active
drug that is systemically absorbed. Bioequivalent drug products: a generic drug
product is considered bioequivalent to the reference brand drug product if both
products are pharmaceutical equivalents and have statistically the same bioavai
lability for the same dose, in the same chemical form, similar dosage form, by s
ame route of administration, under same experimental conditions. Generics: requi
res abbreviated NDA for FDA approval after patent expiration. Must be a therapeu
tic equivalent but may differ in shape, scoring, packaging, excipients, expirati
on dates, labeling. Pharmaceutical equivalents: drug product that contain the sa
me active drug, same salt, ester or chemical form, same dosage form, identical i
n strength and route of administration. May differ in release mechanism, shape,
scoring, packaging, excipients. Reference drug product: usually the currently ma
rketed brand name with full NDA and patent protection. Therapeutic equivalent dr
ug products: are pharmaceutical equivalents that can be expected to have the sam
e clinical effect and safety profile under same conditions. Pharmaceutical alter
natives: are drug products that contain the same therapeutic moiety but are diff
erent salts, ester or complexes or are different strength or dosage forms (table
t vs cap, instant release vs SR).
Bioavailability and bioequivalence
Acute pharmacologic effect
Examples: change in heart rate, blood pressure, ECG, clotting time, Forced Expir
atory Volume (FEV1). Alternative to plasma concentration when that is not possib
le or inappropriate. Measure effect vs. time. Onset time: time from drug adminis
tration till achieving the minimum effective concentration (MEC) at the receptor
site as evidenced by pharmacological response. Intensity: proportional to the #
of receptors occupied by the drug up to a maximum pharmacological effect, which
may occur before, at or after peak drug absorption. Duration of action: time fo
r which the drug concentration remains above MEC. Therapeutic window: concentrat
ion between the MEC and minimum toxic concentration (MTC). As concentration
othe
r receptor interactions lead to SE. In vitro test (e.g. dissolution) can be used
instead if statistical correlation to in vivo data has been established. Exampl
e: dermato-PK for topical drugs for local effect.
Plasma drug concentration
Most common method for measuring systemic bioavailability. Time for peak plasma
concentration (Tmax): relates the rate constant for drug absorption and eliminat
ion. Absorption depends on the dosage form and formula, while elimination is onl
y drug dependent. Peak plasma concentration (Cmax): Cmax at Tmax relates to the
intensity of pharmacological response. Ideally Cmax should be within the therape
utic window. AUC vs time: relates the amount or extent of systemic drug absorpti
on. AUC is calculated using the trapezoidal rule, expressed as mg.hr/ml

Urinary drug excretion

Accurate method if the active moiety is excreted unchanged in quantities in urin
e. Cumulative amount of active drug excreted in urine is related to extent of sy
stemic drug absorption. Rate of drug excretion is related to rate of systemic ab
sorption. Time for complete excretion relates to the total time for complete sys
temic absorption and excretion.
Relative and absolute bioavailability
Relative bioavailability: systemic availability of the drug from a dosage form a
s compared to reference standard given by the same route. It is a ratio of the A
UCs (maximum is 1 or 100%). Very important for generic bioequivalence studies. A
bsolute bioavailability (F): fraction of drug that is systemically absorbed. Its
the ratio of AUC for oral dosage form / AUC for IV. A parenteral IV drug solutio
n has F = 1.
Bioequivalence for solid dosage forms
Design of bioequivalence studies
Guidance provided by Division of Bioequivalence, Office of Generic Drugs, FDA. A
ll studies are done with healthy subjects. Fasting study: blood samples are take
n at zero time, and appropriate intervals to obtain adequate description of conc
entration vs. time profile. Food intervention study: required if bioavailability
is known to be affected by food. Give products immediately after a standard hig
h fat content breakfast. Multiple dose steady-state study: required for extended
release products in addition to single-dose fasting and food intervention study
. Measure three consecutive days of trough concentrations (Cmin) to ascertain st
eady state. Last morning dose is given after overnight fast, continue fasting fo
r 2 hours. Take blood samples. In vitro bioequivalence waiver: a comparative in
vitro dissolution may be used instead for some immediate release oral dosage for
ms. No bioequivalence study is required for certain solution products (oral, par
enteral, ophthalmic).
PK data evaluation
Single dose studies: calculate AUC to last quantifiable concentration, AUC to in
finity, Tmax, Cmax, elimination rate constant (K), elimination half life (t1/2).
Multiple dos studies: steady state AUC, AUC to last quantifiable concentration,
Tmax, Cmax, Cmin, % fluctuation (Cmax-Cmin / Cmin).
Statistical data evaluation
Drug considered bioequivalent if difference from reference is < -20% or +25%. AN
OVA is done on log transformed AUC and Cmax data. The 90% confidence interavals
of the means of AUC and Cmax should be 80-125% of the reference product.
Drug production selection
Generic drug substitution
Its dispensing generic drug in place the prescribed product. The substituted drug
has to be a therapeutic equivalent. Prescribability: current basis for FDA appr
oval of therapeutic equivalent generic product. Its measurement of average bioequ
ivalence where test and reference population means are statistically the same. S
witchability: assures that the substituted product produces the same response in
the individual patient. Its the measurement of the individual bioequivalence inc
luding intra-subject variability and subject-byformulation effects.

Therapeutic substitution
The process of dispensing a therapeutic alternative. For example: dispensing amo
xicillin for ampicillin. The substituted drug is usually in the same therapeutic
class (e.g. calcium channel blockers) and is expected to have a similar clinica
l profile.
Formulary issues
A formulary is a list of drugs. Positive formulary: lists all drugs that may be
substituted. Negative formulary: lists drugs which cant be substituted. Restricti
ve formulary: lists only drugs that may be reimbursed without justification by t
he prescriber. States provide guidance for drug product selection through formul
ary. FDA annually publishes Approved Drug Products with Therapeutic Equivalence
Evaluations (the Orange Book). It is also published in the USP/DI Volume III. Oran
ge Book Codes: A Rated: drug products that are considered therapeutically equiva
lent. B Rated: drug products that are not considered therapeutically equivalent.
AB Rated: products meeting bioequivalence requirements.
8. Organic Chemistry and Biochemistry
Organic chemistry
Functional groups affect hydrophilicity, lipophilicity, reactivity, shelf life,
stability, biotransformation, metabolism.
Alkanes
Also called paraffins, saturated hydrocarbons. General formula: R-CH2-CH3. Lipid
soluble. Common reactions: halogenation, combustion. Chemically inert to air, h
eat, light, acids, bases. Stable in vivo.
Alkenes
Also called olefins, unsaturated hydrocarbons. General formula: R-CH=CH2. Lipid
soluble. Common reactions: addition of hydrogen or halogen, hydration (to form g
lycols), oxidation (to form peroxides). Volatile alkenes and peroxides may explo
de in presence of O2 and spark Stable in vivo. Hydration, peroxidation, reductio
n may occur.
Aromatic hydrocarbons
Based on benzene. Exhibit multicenter bonding. Lipid soluble. Common reactions:
halogenation, alkylation, nitration, sulfonation. Chemically stable. In vivo: hy
droxylation, diol formation.
Alkyl halides
Halogenated hydrocarbons. General formula: R-CH2-X. Lipid soluble. degree of hal
ogenation
Solubility. Common reactions: dehyro-halogenation, nucleophilic substi
tution. Stable on the shelf. Not readily metabolized in vivo.
Alcohols
Contains OH group. May be primary (R-CH2-OH), secondary (R1/R2-CH-OH), or tertia
ry (R1/R2/R3-COH). Alcohols are lipid soluble. Low molecular weight alcohols are
water soluble. hydrocarbon chain length water solubility.

Common reactions: oxidation, esterification. Oxidation: primary alcohol

aldehyde
acid. Secondary alcohol
ketone. Tertiary alcohol
not oxidized. Stable on shelf.
In vivo: oxidation, sulfation, glucuronidation.
Phenols
Aromatic compounds containing OH groups directly connected to aromatic ring. Mon
ophenols one OH. Catechols
two OH. Phenol (carbolic acid): water soluble. ring s
ubstitution
water solubility. Most phenols are lipid soluble. Common reactions:
with strong bases to form phenoxide ion, esterification with acids, oxidation to
form colored quinones. On the shelf: oxidation with air or ferric ions. In vivo
: sulfation, glucuronidation, aromatic hydroxylation, o-methylation.
Ethers
General formula: R-O-R. Lipid soluble. Partially water soluble. hydrocarbon chai
n water solubility. Common reaction: oxidation to form peroxides (may explode).
In vivo: o-dealkylation. Stability with size of alkyl group.
Aldehydes
General formula: R-CHO (contains a carbonyl group C=O). Lipid soluble. Low molec
ular weight aldehytes are also water soluble. Common reactions: oxidation (to ac
ids, in vivo and in vitro) and acetal formation.
Ketones
General formula: R-CO-R (contains a carbonyl group C=O). Lipid soluble. Low mole
cular weight ketones are also water soluble. Nonreactive and very stable on the
shelf. In vivo: some oxidation or reduction.
Amines
Contain an amino group (-NH2). Primary (R-NH2), secondary (R1/R2-NH), tertiary (
R1/R2/R3-N), quaternary (R1/R2/R3/R4-N+ X-). Lipid soluble. Low molecular weight
amines
water solubility. branching
water solubility (primary amines and most so
luble). Quaternary amines (ionic) and amine salts are water soluble. Common reac
tions: oxidation (air oxidation on shelf), salt formation with acids. Aromatic a
mines are basic reactive with acids. In vivo: glucuronidatin, sulfation, methyla
tion. 1ry oxidative deaminatin. 12y/2ry
acetylation. 2ry/3ry
dealkylation.
Carboxylic acids
General formula: R-COOH (Carboxyl group COOH). Lipid soluble. Low molecular weigh
t acid and Na/K salts water soluble. Common reactions: salt formation with bases
, esterification, decarboxylation. Very stable on shelf. In vivo: conjugation (w
ith glucuronic acid, glycine, glutamine), beta oxidation.
Esters
General formula (R-COOR). Lipid soluble. Low molecular weight esters are slightl
y water soluble. Common reaction: hydrolysis to form carboxylic acid and alcohol
(in vivo by esterases / in vitro).

Amides
General formula: R-CONH2 or R-CONR1/R2 (lactam form). Lipid soluble. Low molecul
ar weight amides are slightly water soluble. No common reactions. Very stable on
shelf. In vivo: enzymatic hydrolysis by amidases in the liver.
Biochemistry
Amino acid and proteins
Monomeric units of protein (peptide bonds). Formula: NH2-CH-R/-COOH. Proteins ar
e made of 20 AA, differ in R side chain (alpha (C)). Protein hydrolysis to AAs b
y acids, bases, enzymes. + AA ionize (depending on pH) to zwitterions structure
(NH3 -CH-COO /R)
water solubility, melting point. Levels of protein structure: p
rimary, secondary (alpha/beta), 3ry, 4ry.
Carbohydrates
Polyhydroxy aldehydes or ketones Monosaccharides: simple single unit sugars, e.g
., glucose, fructose. Oligosaccharides: short chains of monosaccharides joined c
ovalently, e.g. sucrose (has to convert into glucose, fructose before GI absorpt
ion), maltose (hydrolyzed by maltase into 2x glucose), lactose (milk sugar, has
to convert into galactose, glucose before GI absorption). Polysaccharides: long
chains of monosaccharides, e.g., cellulose, glycogen.
Pyrimidines and purines
Bases
bond with ribose nucleosides
bond with phosphoric acid
nucleotides
g blocks of nucleic acid. Exhibit tautomerism (isomerism): can be keto or enol.
Pyrimidines bases: cytosine, uracil, thymine. Purine bases: adenine, guanine DNA
bases: thymine, cytosine, adenine, guanine RNA bases: uracil, cytosine, adenine
, guanine.

buildin

Biopolymers
Enzymes Linked amino acid chains (proteins)
catalysts for biological reactions.
They reactions activation energy but do not change reaction equilibrium point, ar
e used up or changed in the reaction. May require cofactors or coenzymes. Cofact
or: inorganic (metal ion) or nonprotein organic molecule. Prosthetic group: cofa
ctor firmly bound to apoenzyme (protein portion of a complex enzyme). Coenzymes:
organic cofactor that is not firmly bound but actively involved in catalysis. H
oloenzyme: complete catalytically active enzyme system. Lyases: removes function
al group (deaminase, decarboxylase). Ligases: bind two molecules (e.g. DNA ligas
e 2 nucleotides). Isomerases: change D L, cis trans, vice versa. Polysaccharides Als
o called glycans. Long chain polymers of carbohydrates. Homopolysaccharides: Con
tains one type of monomeric units. Starch
plants reserve food, two glucose polyme
rs (linear water soluble amylose, and branched water insoluble amylopectin), enz
ymatic hydrolysis maltose (glucose disaccharide). Glycogen branched D-glucose ch
ain, polysaccharide storage in animal cells (liver, muscles). Cellulose
water so
luble, in plant cell wall, linear D-glucose chain, cant be digested (hydrolyzed)
by humans.

Heteropolysaccharides: contains two or more monomeric units. Heparin

acid mucopo
lysaccharide with sulfate derivatives, contains glucosamine, in lung tissue, use
d to prevent clotting. Hyaluronic acid in bacterial cell wall, virteous humor, s
ynovial fluid, contains glucosamine. Nucleic acids Linear polymers of nucleotide
s pyrimidine and purine bases linked to ribose or deoxyribose sugars (nucleoside
s) and bound to phosphate groups. Phosphodiester bonds: join successive DNA / RN
A nucleotides. DNA: compared to RNA it lacks an OH group and contains T rather t
han U. (D T, R U). DNA: two complementary alpha helical strands coiled to form doub
le helix. Hydrogen bonding between specific base pairs hold the strands together
. Hydrophobic bases are on the inside of the helix. Hydrophilic deoxyribose phos
phate on the outside. Backbone: alternating phosphate and pentose units with a p
urine or pyrimidine attached to each. Strong acids associated with cellular cati
ons and basic proteins (histones, protamines). rRNA (ribosomal): in ribosomes. m
RNA (messenger): the template for protein synthesis
specifies the polypeptide am
ino acid sequence. tRNA (transfer): carries activated amino acids to ribosomes f
or incorporation to the growing polypeptide chain.
Biochemical metabolism
Factors affecting metabolism: substrate concentration, enzymes, allosteric (regu
latory) enzymes, hormones, compartmentation. Catabolism: degradation reactions t
hat release energy for useful work (e.g. mechanical, osmotic, biosynthetic). Ana
bolism: biosynthetic (build-up) reactions that consumer energy to form new bioch
emical compounds (metabolites). Amphibolic pathways: may be used for anabolic or
catabolic purposes. Example: Krebs cycle, it breaks down metabolites to release
90% of the organisms energy, but it also uses metabolites for form compounds suc
h as AA.
Bioenergetics
Substrate level phosphorylation: forms one unit of ATP per unit of metabolite, n
o oxygen required. Oxidative phosphorylation: forms 2 or more ATP per unit of me
tabolite. Uses oxidoreductase enzymes (e.g. dehydrogenases) using cofactors NAD
(nicotinamide A dinucleotide) or FAD (flavin). Energy released from the reaction
is used to form ATP in the mitochondria.
Carbohydrate metabolism
Catabolism: releases energy from carbohydrates. Glycogenolysis: breakdown of gly
cogen into glucose phosphate in the liver, skeletal muscles
controlled by glucag
on and epinephrine. Glycolysis: breakdown of sugar phosphates (e.g. glucose, fru
ctose, glycerol) into pyruvate (aerobically) or lactate (anaerobically) to produ
ce energy (ATP) Anabolism: consumes energy to build complex from simple molecule
s Glycogenesis: formation of glycogen in the liver and muscles from glucose in d
iet controlled by insulin. Gluconeogenesis: formation of glucose from noncarbohy
drate sources (e.g. lactate, pyruvate).
Krebs cycle
Location: in the mitochondria. Absent in RBCs (no mitochondria) Catabolism: conv
erts pyruvate (glycolysis), acetyl CoA (fatty acid degradation) and amino acids
into CO2 and water with release of energy. Oxygen dependent (aerobic). Anabolism
: forms amino acids (aspartate, glutamate) and heme ring from metabolites. Elect
ron transport: accept electrons and hydrogen from oxidation of Krebs cycle metab
olites and couples the energy released to make ATP.

Lipid metabolism
Catabolism Triglycerides stores in fat cells (adipocytes) are hydrolyzed by horm
one-sensitive lipases into three fatty acids and glycerol Fatty acids: broken do
wn by beta oxidation to acetyl CoA
to Krebs cycle
breaks down to CO2, water and
energy release. Ketogenesis: very rapid break down of fatty acids leading to for
mation of ketone bodies (as in DM). Glycerol: enters glycolysis
oxidized to pyru
vate to Krebs cycle
CO2 and water. Steroids: may be converted to bile acids, vit
amin D, hormones. Anabolism Fatty acids: formed in the cytoplasm. Unsaturation o
ccurs I the mitochondria or endoplasmic reticulum. Essential fatty acids: linole
ic acid (can not be synthesized, diet is only sources). Terpenes: derived from a
cetyl CoA. Include: cholesterol, steroids, fat soluble vitamins (ADEK), bile aci
ds. Sphingolipids: forms a ceramide backbone with fatty acids. Joins with other
compounds to form cerebrosides, sphingomyelin Phosphatidyl compounds: i.e. phosp
hatidyl choline (lecithin), ethanolamine.
Nitrogen metabolism
Catabolism Amino acids: amino group is removed by transaminase. Carbon skeleton
is broken down to acetyl CoA or citric acid derivatives
oxidized to CO2 and wate
r for energy. Glycogenic amino acids form glucose as needed by guconeogenesis. P
urines: 90% is salvaged, 10% degrade to uric acid using xanthine oxidase. Pyrimi
dines: breaks down to B-alanine, ammonia, CO2 Anabolism Amino acids: from citric
acid cycle intermediates. Essential AA: TIM (threonine, isoleucine, methionine)
, HALL (histidine, arginine, lysine, leucine), PVT (phenylalanine, valine, trypt
ophan) PVT TIM HALL Purines / Pyrimidines: from aspartate, carbamoyl phosphate,
CO2, other AA.
Nitrogen excretion
Excess nitrogen is toxic
must be eliminated, mainly as urea. Urea synthesis: in
the liver using the Krebs-Henseleit pathway. Amino acid
AA transferases (transam
inases) + pyridoxine (vitamin B6) as coenzyme Ammonia
+ glutamate
glutamine
+ CO
2 carbamoyl phosphate
urea cycle urea. Uric acid synthesis: most purines are sal
vages. Remaining purines are excreted as uric acid.
9.
Microbiology
Taxonomy and nomenclature
Taxonomy
Classification or ordering into groups based on degree of relatedness. Bacteria
are named using the Linnaean or binomial system (genus species = homo sapiens =
human)
Morphology
Cultural morphology Based on size, shape and texture or colonies grown inj axeni
c (pure) cultures Each colony originates from a Colony Forming Unit (CFU) consis
ting of a single cell or group of adherent cells

Microscopic morphology Based on size, shape and arrangement of bacterial cells

Stains
Bacteria are small and transparent
must be stained to be examined by light micro
scopy Simple Single dye colors the cells (e.g. gentian violet, safranin) Gram Gr
am-positive = purple Gram-negative = pink Acid-fast Stains only cells that have
an outer layer of a waxy lipid (acid-fast) not those lacking that layer (non aci
dfast) Spore Heat is used to facilitate the dye entering the spore Capsule Two d
yes stain the cell and backgrounds allowing the visualization of the unstained c
apsular material
Bacterial cell shape and arrangement
Cocci (spherical) -Chains (streptococci) -Clusters (staphylocci) -Pairs / diploc
occi (streptococcus pneumoniae) -Packets
Bacilli Cylindrical rod-shaped (pseudomonads, Escherichia) Coccobacilli (combina
tion of small rods or flattened cocci) Spirochetes (helical like a corkscrew) Fu
sobacteria (tapered ends and slightly curved) Filamentous (organisms are branchi
ng) Vibrios (comma shaped) Pleomorphic (exist in varied forms)
Other parameters
Presence or spores, capsules or slime layers Mobility or type of flagella Monotr
ichous = single flagella at either pole Amphitrichous = flagellum at both poles
Lophotrichous = flagella at either or both poles Peritrichous = flagella distrib
uted evenly all around

Structure of the prokaryotic cell

Overview
Small and simple in design Less complex inside, more complex outside Lack a true
nucleus, nuclear membrane or intracytoplasmic membraneous organelles (e.g., end
oplasmic reticulum) Cytoplasm is immobile (no endo or exocytosis) Multiply asexu
ally by binary fission (no mitosis) Protein synthesis mediated by 70s not 80s ri
bosomes Genetic material single supercoiled circular strand of DNA (nucleoid)
External structures
Capsule and slime layer Flagella Pili (fimbriae)
Cell wall periplasmic space and cytoplasmic membrane Internal structures
Microbial physiology Metabolism and energy production Genetics
10. Immunology 11. Biotechnology 12. Principles of PD / Med Chemistry
Effects of drugs
Drug action is the results of interaction between drug molecules and cellular co
mponents (receptors) modulate ongoing cellular processes
alteration of function.
Drug receptor: any macromolecular component Physiological receptors: receptors
for endogenous ligands. Example: adrenergic receptors for catecholamines. Agonis
t: drugs that resemble the effects of endogenous molecules. Example: bethanechol
stimulates cholinergic receptors. Pharmacologic antagonists: drugs that lack in
trinsic activity and produce effects by action of endogenous molecules at recept
ors. Competitive: propranolol competes with catecholamines at beta receptors. No
ncompetitive: MAO irreversible inhibitor tranylcypromine. Partial antagonist: in
hibits endogenous ligand from binding to the receptor but has some intrinsic act
ivity. Example: nalorphine on opiate receptors. Physiological antagonism: drug a
cts independently at different receptor to produce opposing action. Example: epi
nephrine and acetylcholine. Neutralizing antagonism: two drugs bind to each othe
r to form inactive compound. Example: digoxinbinding antibody sequesters digoxin
.

Mechanisms of drug action

Cell surface receptors: can be proteins, glycoproteins or nucleic acids. Can be
located at the cell surface, cytoplasm, or inside the nucleus. Receptor binding
is very specific. Interactions: van der Waals, ionic, hydrogen, covalent
influen
ce duration and reversibility of drug action. Interaction depends on chemical st
ructure of drug and receptor. Signal transduction by cell-surface receptors: dru
g receptor binding triggers signal through second messenger or effector in the c
ycoplasm. Example: isoproterenol binds beta receptor (coupled to adenylate cycla
se via stimulatory G protein) cAMP. Second messengers may cause change in protein
synthesis. Signaling mediated by intracellular receptors: drugs bind to soluble
DNA-binding protein cytoplasmic receptors regulate gene transcription. Examples
: thyroid hormone, steroid hormones, vitamin D, retinoids. Target cell desensiti
zation / hypersensitization: cellular protective mechanisms exist to maintain ho
meostasis and prevent overstimulation / understimulation of target cells. Down r
egulation: occur due to continuous prolonged drug exposure
receptor #. Desensiti
zation: is the result of down regulation. Effect of subsequent drug exposure is .
Example: chronic albuterol use
down regulation of beta receptors
tolerance. Het
erogenous desensitization: nonspecific desensitization by altering components of
the signaling pathway. Hyperactivity/hypersensitivity: due to long term exposur
e to antagonists followed by abrupt cessation new receptor synthesis upregulatio
n. Pharmacologic effects not mediated by receptors: Colligative drug effects lac
k requirement for specific structures. Examples: volatile general anesthetics ar
e lipophilic interact with cell membrane lipid bilayer
excitability. Cathartics
(mg sulfate, sorbitol) osmolarity of intestinal fluids. Antimetabolites: structu
ral analogs of endogenous compounds
incorporated into cellular components, examp
les: methotrexate, 5-fluorouracil, cytarabine. Antacids: such as Al hydroxide, C
a carbonate, Mg hydroxide act by ionic interaction to gastric acidity
Concentration-effect relationship
dose concentration at site of action
effect
up to a ceiling. Quantal dose-respon
se curve: # of patients exhibiting a defined response by specific drug dose. Bel
l shaped. Graded dose-response curve: magnitude of drug effect vs. drug dose. Ef
ficacy is measured by the maximum effect. Potency compared different molar doses
of different drugs needed to produce the same effect. Log dose-response curve:
drug effect vs. log dose. Used to compare efficacy and potency of different drug
s with same mechanism of action (same slope). Efficacy; determined by the height
of the curve (Emax). Potency: compared using ED50 (dose producing 50% of Emax).
Competitive antagonist: parallel shift to the right, same Emax is achieve but a
t dose. Noncompetitive antagonist: nonparallel shift to the right, lower Emax (a
ction cannot overcome if more agonist is present).
Enhancement of drug effect
Addition: two different drugs with same effect cumulative effect. Example: trime
thoprim and sulfamethoxazole inhibit two different steps in folic acid synthesis
bacterial growth. Synergism: two different drug with same effect
effect is than
cumulative sum. Example: penicillin and gentamicin against pseudomonas. Potentia
tion: one drug with no effect alone will effect of another active drug. Example:
carbidopa (inactive dopa analog) degradation of levodopa.
Selectivity of drug action
Therapeutic index: TD50/ED50 (median toxic dose / median effective dose). Margin
of safety: minimum toxic dose for 0.1% of population (TD0.1) / minimum effectiv
e dose for 99.9% of population (ED99.9). More practical

Drug sources and major classes

Natural products
Alkaloids (x-ine): plant-derived nitrogen containing compounds. Alkaline. Exampl
es: morphine (opium poppy), atropine (belladonna), colchicine (autumn crocus, ne
utral). Peptides / polypeptides: polymers of amino acids. From humans or animals
. Smaller than proteins. No oral activity, short half life. Example: somatostati
n, glucagon. Steroids: from humans or animal. Estradiol, testosterone, hydrocort
isone. Hormones: chemicals formed in one organ and carried in the blood to anoth
er. Mostly steroids or proteins. Made synthetically, by recombinant DNA (insulin
) or from animals (thyroid, conjugated estrogens). Glycosides: sugar moiety boun
d to non-sugar (aglycone) moiety by glycosidic bond. From plant (digitoxin) or m
icrobial (streptomycin, doxorubicin). Vitamins: Water soluble: B1 (thiamine), B2
(riboflavin), B3 (niacin), B6 (pyridoxine), B12 (cyanocobalamin), C (ascorbic a
cid), folic acid, pantothenic acid, H (biotic). Lipid soluble: A (retinol), D (e
rgocalciferol), E (alpha-tocopherol), K (phytonadione). Polysaccharides: polymer
s of sugar from animals or humans (heparin). Antibiotics: penicillin, tetracycli
ne, doxorubicin.
Synthetic products
Drugs synthesized from organic compounds. May have chemical structure resembling
active natural products (hydroxymorphone
morphine, ampicillin penicillin). Pept
idomimetics: molecules with no peptide bonds, molecular weight < 700, activity s
imilar to original peptide (e.g. losartan).
Drug action and physiochemical properties
Drugs must enter and be transported by body fluids. Drugs must pass membrane bar
riers, escape distribution to site of loss, penetrate to active site, be removed
from active site, metabolized to a form easily excreted. Drug polarity: relativ
e measure of lipid and water solubility. Measured in Partition Coefficient: rati
o of solubility in organic solvent to solubility in aqueous solvent (log value).
Water solubility: depends on ionic character and hydrogen ion bonding. Nitrogen
and oxygen containing functional groups water solubility. Required for GI disso
lution, parenteral solutions, ophthalmic solutions, good urine concentration. Li
pid solubility: by nonionizable hydrocarbon chains and ring systems. Required fo
r penetrating GI lipid barrier, penetrating BBB, IM depot injectables. Ionizatio
n constant (Ka): indicates the relative strength of acids and bases. Expressed i
n negative log (pKa). Strong acids: HCl, H2SO4, HNO3 (nitric), HClO4 (perchloric
), HBr, HIO3 (iodic). Strong bases: NaOH, KOH, MgOH2, CaOH2, BaOH2, quaternary a
mmonium hydroxides. Weak acids: organic acids containing carboxylic (-COOH), phe
nolic (Ar-OH), sulfonic (-SO2H), sulfonamide (-SO2NH-R), imide (-CO-NH-CO-), bet
a carbonyl (-CO-CHR-CO-) groups. Weak bases: organic bases containing amino grou
ps (1ry NH2, 2ry -NHR, 3ry NR2) and saturated heterocyclic nitrogen. Aromatic or u
nsaturated heterocyclic nitrogen are very weak bases
do not form salts. Le Chate
liers priniciple governs ionization (weak acid at pH
ionization cross lipid membr
anes). Rule of nines: |pH-pKa|=1 90:10 (1 nine), |pH-pKa|=2
99:1 (2 nines). Salt
s: virtually all salts are strong electrolytes. Inorganic salts: made by combini
ng drugs with inorganic acids or bases (HCl, NaOH). Salt form has water solubili
ty dissolution. Organic salts: made by combining acidic and basic organic molecu
les lipid solubility
depot injections (e.g. penicillin procaine). Amphoteric sal
ts: contain acidic and basic functional groups
form internal salts or zwitterion
s solubility problems. Neutralization reaction: e.g., occur when an acidic solut
ion of an organic salt is mixed with a basic solution. The nonionized organic ac
id or base will ppt
IV drug incompatibility. Drugs whose cation ends with onium o
r inium and anoic is Cl, Br, I, nitrate, sulfate (e.g. benzalkonium chloride, cet
ylpyridinium chloride) are quaternary ammonium salts neural solution in water.

Structure and pharmacologic activity

Drug structure specificity
Structurally non-specific drugs: drug interaction with cell membrane depends mor
e on the drugs physical properties than on its chemical structure. Interaction us
ually depends on cell membranes lipid nature and drugs lipid attraction. Examples:
general anesthetics, some hypnotics, some bactericidal agents. Structurally spe
cific drugs: pharmacologic activity depends on drug binding to specific endogeno
us receptors.
Drug receptor binding
Receptor site theories: Lock-key theory: over-simplification that assumes a comp
lete complementary relationship between drug and receptor. Induced fit theory: a
lso assumes a complete complementary relationship between drug and receptor but
provides for mutual conformational changes between drug and receptor, it can exp
lain phenomenon of allosteric inhibition. Occupational theory of response: furth
er postulates that intensity of pharmacologic response is proportional to number
of occupied receptors. Receptor site binding: ability of a drug to bind to spec
ific receptor is mostly determined by its chemical structure not physical proper
ties. Chemical reactivity influences its bonding ability and exactness of fit to
the receptor. Drug interaction is similar to fitting a jigsaw puzzle pieces, on
ly drugs of similar shape and chemical structure can bind and producer response.
Usually only a portion of the drug molecule is involved in receptor binding. Ph
armacophore: functional group that is critical for receptor interaction. Drugs w
ith similar pharmacophores may have similar qualitative but not quantitative act
affinity response. Antagonist: drug with some
ivity. Agonist: good receptor fit
binding but no pharmacophore no response but it blocks other drugs from binding.
Stereochemistry
Types of stereoisomers: optical, geometric, conformational. Optical isomers: con
tains at least one chiral (asymmetric) carbon (four different substitutes). Enan
tiomers: optical isomers that are mirror image of each other, identical physical
and chemical properties, potentially different potency, receptor fit, activity,
metabolism, etc. One enantiomer rotate the plane of polarized light clockwise (
dextro, D, +), the other counter clockwise (Leve, L, -). Example: dextrorphanol
narcotic analgesic and antitussive, levorphanl only antitussive. Racemic mixture
: equal mixgture of D and L enantiomers, optically inactive. Diastereomers: ster
eoisomers which are neither mirror image, nor superimposable. Drug must have a m
inimum of 2 chiral centers. Different physicochemical properties (solubility, vo
latility, melting point). Epimers: special type of diastereomers, compounds are
identical in all aspects except stereochemistry around one chiral center. Epimer
ization is important for drug degradation and inactivation. Geometric (cis-trans
) isomers: occurs due to restricted rotation around a chemical bond (double bond
, rigid ring system). Cis-trans are not mirror images, have different physicoche
mical and pharmacologic properties, because functional groups can be separated b
y different distances
not equal fit to receptors. If functional groups are pharm
acophores different biologic activity. Example: cis-diethylstilbestrol has 7% es
trogenic activity of trans-diethylstilbestrol. Conformational isomers (rotamers,
conformers): non-superimposable molecule orientations due to atoms rotation aro
und single bonds. Common for most drugs, allows drugs to bind to multiple recept
ors. Example: Ach 2-forms: trans muscarinic, gauche
nicotinic Bioisosteres: molecu
les containing groups that are spatially and electronically equivalent, same phy
sicochemical properties. Isosteric replacement of functional groups
alter metabo
lism potency, SE, activity, duration of action (e.g. procainamide, an amide, has
longer duration of action than procaine, an ester). Isosteric analogs: may act
as antagonists (e.g. alloxanthine is a xanthine oxidase inhibitor, compared to i
ts isostere, xanthine, the enzyme substrate).
Mechanisms of drug action
Interaction with receptors
Agonists: have both affinity and intrinsic activity with the receptor.

Partial agonists: interact with same receptors but with similar affinity but low
er intrinsic activity
response. Pharmacologic antagonists: bind to the same rece
ptor as the agonist but with no intrinsic activity. Can be reversible, irreversi
ble, competitive, noncompetitive (like enzyme inhibitors). Chemical antagonists:
two compounds react inactivation of both. Example: heparin (acidic polysacchari
de) with protamine (basic protein), chelating agents as metal poisoning antidote
s (EDTA for calcium / lead, penicillamine for copper, dimercaprol for mercury /
gold / arsenic). Functional / physical antagonists: produce antagonistic physiol
ogic actions by binding at separate receptors. Example: acetylcholine, NEp.
Interaction with enzymes
Activation Due to enzyme protein synthesis. Examples: barbiturates, antiepilepti
cs (phenytoin), rifampin, antihistamines, griseofulvin, oral contraceptives. Mec
hanism: by allosteric binding or coezymes such as vitamins (esp vitamin B comple
x), cofactors (Na, , Mg, Ca, Zn, Fe). Inhibition Due to interaction with the apo
enzyme, coenzyme or enzyme. Reversible inhibition: results from non-covalent int
eraction. Equilibrium exists between bound and free drug. Irreversible inhibitio
n: results from covalent stable interaction. Competitive inhibition: occurs when
there is a mutually exclusive binding of the substrate and inhibitor. Noncompet
itive inhibition: occurs when the drug binds to an allosteric site on the enzyme
.
Interaction with DNA/RNA
Inhibition of nucleotide biosynthesis: caused by folate, purine, pyrimidine anti
metabolites. Folic acid analogs: e.g. methotrexate, trimetrexate, dihydrofolate
reductase
purine, thymidylate. Purine analogs: e.g. 6-mercaptopurine, thioguanin
e, act as antagonists in the purine bases synthesis. Pyrimidine analog: e.g. 5-f
luorouracil, thymidine synthase. Inhibition of RNA/DNA biosynthesis: due to inte
rference with nucleic acid synthesis. Use mainly as antineoplastic agents (Cance
r chapter).
Inhibition of protein synthesis
Tetracyclines: tRNA binding to ribosomes and block release of completed peptides
from ribosomes. Erythromycin, chloramphenicol: bind to ribosomes, peptidyl tran
sferase, formation of peptide bond, peptide chain formation Aminoglycosides: bin
ding to ribosomes
formation of abnormal protein, addition of AAs to peptide chai
n, misreading of mRNA tempelate
incorporation of incorrect AAs in peptide chain.
Interaction with cell membranes
Digitalis glycosides: cell membrane Na-K pump
K influx, Na outflow. Quinidine: p
rolong polarized and depolarized states of membrane potential in myocardial memb
ranes. Local anesthetics: interfere with membrane permeability to Na-K block imp
ulse conduction in nerve cell membranes. Polyene antifungals: e.g. nystatin, amp
hotericin B, alter membrane permeability. Antibiotics: e.g. polymyxin B, colisti
n, alter membrane permeability Acetylcholine: membrane permeability to cations.
Proton pump inhibitors: H+/K+ pump in parietal cell membranes
efflux of protons
to the stomach.
Nonspecific action
Form monomolecular layer over entire areas of cells. Large dose is given. Exampl
es: volatile general anesthetic gases (ether, nitrous oxide), some depressants (
ethanol, chloral hydrate), antiseptics (phenol, rubbing alcohol).

13. Autonomic and Central Nervous Systems

Receptor summary tables
Inhibitory receptors Types: M2, Alpha-2, D2, GABA, Opioid (mu, delta, kappa) Act
ion: cAMP, K conductance, Ca conductance, Cl conductance (GABA) Mechanism Gangli
on blocker neurotransmitter synthesis neurotransmitter release neurotransmitter
release neurotransmitter storage neurotransmitter metabolism Adrenergic Excitato
ry receptors Types: M1, Nicotinic, Alpha1, Beta-1, D1, Glutamate, H1-2. Action:
cAMP, K conductance, Ca (cation) conductance, IP3/DAG
Cholinergic Hexamethonium, mecamylamine Bretylium, guanethidine Botulinum toxin
Amphetamine, tyramine Reserpine Cocaine, desipramine Not a major mechanism Pargy
line (MAOAI), selegiline Neostigmine, physostigmine (MAOBI), tolcapone (COMTI) A
ction conduction velocity, contraction rate /force conduction velocity, contract
ion rate /force Constricts cerebra, cutaneous, visceral arterioles Dilates skele
tal muscle arterioles Iris contracts
mydriasis Sphincter / ciliary contraction
m
iosis Relaxes bronchial / tracheal muscles Contraction, secretions Contracts sph
incter muscles Relax sphincters, contracts smooth muscles. peristalsis Contracts
sphincter motility (perisalsis), relax sphincters, secretions Contraction Relax
ation Adipolysis, mobilize fatty acids secretions (eye, sweat, saliva, nasal)
Organ / tissue Heart Arterioles Eye Lung Urinary bladder Intestine
Uterus Fat (adipose) tissue Glands
Receptor B1 M Alpha-1 Beta-2 Alpha-1 M Beta-2 M Alpha-1 M Alphabeta Apha-1 M Alp
ha-1 Beta-2 Beta-3 M
Adrenergic agonists
Direct-acting agonists: Examples: Ep, NEp, terbutaline, dobutamine, naphazoline.
Alpha agonist: phenhylephrine. Beta agonist: isoproterenol Catecholamine (Ep, N
Ep) synthesis: Tyrosinse tyrosine hydroxylase
DOPA dopa decaroxylase
dopamine
pamine hydroxylase NEp
Ep. Catecholamine deactivation: methylation by catechol O
-methyltransferase (COMT) and oxidative deamination by monoamine oxidase (MAO).
Indirect acting agonists (sympathomimetics): Chemically related to catecholamine
s. Act by neurotransmitter release. Examples: amphetamine, tyramine, ephedrine.
Post-junctional alpha-1: Location: iris, arteries, veins, hair follicle muscles,
heart, GI sphincters. Agonist effect: vasoconstriction, smooth muscle contracti
on. Examples: phenylephrine. Pre-junctional alpha-2: Effect: neurotransmitter re
lease, lipolysis, platelet aggregation. Examples: clonidine, methylnorepinephrin
e. Beta-1: Location: heart. Effect: force / rate of contraction. Examples: dobut
amine. Beta-2: Location: bronchial / vascular smooth muscles. Effect: smooth mus
cle dilatation / relaxation. Examples: albuterol, terbutaline. Beta-3: Location:
fat cells. Effect: lipolysis (for obesity).

do

Epinephrine: medullary hormone, stimulate all receptors (alpha1-2, beta1-2). Use

: treat bronchospasm, hypersensitivity / anaphylactic reactions, duration effect
of local anesthetics (SC), restore cardiac activity in cardiac arrest, glaucoma
(topically, vasoconstriction
aqueous humor production). Norepinephrine: adrener
gic neurotransmitter, stimulate alpha1-2, beta-1 (weak beta-2). Phenylephrine: a
lpha-1 agonist. Use: pressor in hypotensive emergency, duration effect of local
anesthetics, nasal decongestion Alpha-1 agonists for nasal decongestion: phenyle
phrine, oxymetazoline, xylometazoline, phenylpropanolamine Alpha-2 agonists (clo
nidine, methyldopa, guanfacine, guanabenz): for BP. Clonidine is used to intraoc
ular pressure during surgery. Isoproterenol: beta1-2 agonist, bronchodilator, ca
rdiac stimulant in cardiac shock / arrest. Dobutamine: beta-1 agonist, improve h
eart function in CHF emergency. Beta-2 agonists (albuterol, terbutaline, metapro
terenol): systemic or local bronchodilators for asthma. General SE: arrhythmias,
pulmonary hypertension, edema, cerebral hemorrhage, rebound nasal congestion, a
nxiety.
Adrenergic antagonists
Alpha blockers: include ergotamine, prazosin (alpha-1), phenoxybenzamine (nonsel
ecive, irreversible), tolazoline. Beta blockers: similar structure to beta agoni
sts. Examples: metoprolol (beta-1), propranolol (nonselective). Prazosin (x-azos
in): vasodilation for hypertension and BPH symptoms. SE: first dose syncope, de
BP, dizziness, drowsiness, palpitation, fluid retention, priapism (continuous pe
nis erection). Phenoxybenzamine / phentolamine: nonselective alpha blockers, tre
at vasospasm, acute hypertensive emergency (e.g. pheochromocytoma, MAOI, sympath
omimetics). SE: BP, tachycardia, ejaculation, miosis, nasal congesion. Tolazolin
e: for neonatal pulmonary hypertension. Labetolol: alpha-1 and beta1-2 blocker,
for hypertension. Propranolol: nonselective beta blocker, for prophylaxis of ang
ina pectoris, ventricular arrhythmias, migraine, for hypertension, heart rate in
anxiety and hyperthyroidism. SE: bradycardia, CHF, bronchoconstriction, triglyc
erides, HDL, depression. Sudden d/c is cadiotoxic. B1 blockers (acetbutolol, met
oprolol, atenolol): for hypetension, arrhythmia, angina. For glaucoma: eye drops
of timolol (B1-2 blocker) and betaxolol (B1 blocker).
Cholinegic agonists
Nicotinic receptors: Location: at postganglionic neuroeffector sites. Muscarinic
receptors: Location: at all autonomic ganglia and at the neuromuscular junction
of somatic nervous system. Acetylcholine: endogenous neurotransmitter, very sho
rt half life (v. rapid hydrolysis by AChE), ester of acetic acid and choline, ve
ry potent. Direct acting agonists: structurally similar to acetylcholine but mor
e resistant to AChE longer duration. Examples: methacholine, bethanecol. Use: no
n-obstructive urinary retention (bethanechol), glaucoma (pilocarpine, miosis). I
ndirect acting agonists: most are AChE inhibitors. Reversible inhibitors: most a
re carbamates (carbamic acid esters), e.g. physostigmine, neostigmine, pyridosti
gmine. Irreversible inhibitors: organophosphate esters, insecticides, nerve gas,
e.g. isoflurophate, echothiophate. Use: glaucoma (miosis), myasthenia gravis, h
ypercholinergic crisis (neuromuscular junction depolarization blockade), anticho
linergic toxicity. General SE: bronchospasm, abdominal cramps, BP, syncope, hear
t rate, salivation, sweating, lacrimation, miosis, flushing, tremors, diarrhea.
Cholinegic antagonists
Quaternary nitrogen: doesnt pass BBB, e.g. ipratropium, glycopyrrolate, propanthe
line. Tertiary nitrogen: pass BBB, e.g. benztropine, dicyclomine, pirenzepine, t
ropicamide. Uses: gland / bronchial secretion before anesthesia (atropine, glyco
pyrrolate), induce sedation / motion sickness (scopolamine), vagal stimulation o
f the heart (atropine), produce mydriasis / cycloplegia (homatropine), GI spasms
(propantheline), asthma (ipratropium), Parkinsons / extrapyramidal disorders (be
nztropine, trihexyphenidyl), cholinergic toxicity (atropine).

Ganglionic blockers: e.g. mecamylamine, trimethaphan, for hypertensive crisis. S

E: mydriasis, intraocular pressure, blurred vision, dry mouth, constipation, uri
nary retention, fever, nervousness, drowsiness, dizziness, tachycardia.
Neuromuscular blockers
Nondepolarizing (competitive) drugs
Examples (x-curine, x-curonium, x-curium): curare alkaloids (tubocurarine, metoc
urine, contain a tertiary amine), and synthetic analogs (atracurium, doxacurium,
mivacurium, pancuronium, vecuronium, pipercuronium). Mechanism: compete with AC
h for nicotinic receptors at the NMJ
end-palate potential
depolarization potenti
al not reached. Action is overcome by dose cholinesterase inhibitor. Uses: SE: r
espiratory paralysis, histamine release, bronchospasm, tachycardia
Depolarizing (noncompetitive) drugs
Examples: succinyl choline (pseudo-cholinesterase metabolism short action), gala
ntamine. Contain quaternary nitrogen. Mechanism: desensitize nicotinic receptors
at NMJ. React with nicotinic receptors
long (2 min) depolarization of excitable
membrane receptor sensitivity unresponsive. Similar effect to excess ACh. Uses:
SE: respiratory paralysis, painful muscle fasciculation, Muscarinic response (b
radycardia, secretion, cardiac arrest).
General anesthetics
Effect: depress CNS and induce reversible state of analgesia, amnesia, unconscio
usness, sensory / autonomic reflexes, skeletal muscle relaxation, loss of all se
nsation. Ideal drug: rapid smooth induction and rapid recovery. General SE: resp
iratory / CNS / CV depression. Halothane
sensitivity to catecholamines.
Volatile (inhalation) anesthetics:
Examples: simple lipophilic molecules, nitrous oxide (N2O, inorganic), halothane
(halogenated HC), ethers (x-flurane, methoxyflurane, isoflurane, desflurane, se
voflurane). Mechanism: absorbed and excreted through the lungs. May be supplemen
ted with analgesics ( anesthetic dose), skeletal muscle relaxants, antimuscarinic
s ( bronichial secretions during surgery). Halothane
heart sensitivity to catecho
lamines, arrhythmia.
Nonvolatile (IV) anesthetics
Water soluble: Ultra-short acting barbiturates (thiopental), ketamine, BZD (diaz
epam, midazolam), morphine, fentanyl, droperidol. Imidazole: propylene glycol so
lution. Propofol: emulsion. Use: induce drowsiness and relaxation before inhalat
ional general anesthesia.
Local anesthetics
Most are structurally similar to cocaine. Ester drugs: rapid hydrolysis by plasm
a esterases short action. Examples: cocaine, procaine, chloroprocaine, benzocain
e, tetracaine. Amide drugs: longer acting, liver metabolism. Examples: lidocaine
, dibucaine, mepivacaine, bupivacaine, etidoacione, prilocaine. (VELD) Mechanism
: block Na channels in nerve membrane
reversible block of nerve impulse conducti
on, reversible loss of sensation, no loss of consciousness. At tissue pH lipophi
lic, uncharged, 2ry or 3ry amine form
diffuse through connective tissue and cell
membrane enter nerve cells
convert to ionized charged ammonium cation active fo
rm block generation of action potential
remain trapped in cell (ionized
cant cros
s cell membrane).

Epinephrine: mix with local anesthetic

vasoconstriction
blood flow systemic abso
rption longer local effect, no systemic toxicity. Use: regional nerve block for
pain relief, anesthesia for minor operations, topical anesthesia (dyclonine and
pramoxine as throat lozenges and hemorrhoids cream), anesthesia for lower limb /
pelvic / obstetric surgery when injected in the epidural. SE: systemic absorpti
on seizures, CNS / respiratory / myocardial depression.
Antipsychotics
Typical (classical) drugs: phenothiazines, thioxanthines (x-othixene, thiothixen
e, chlorprothixene), butyrophenones (haloperidol). Atypical (newer) drugs: cloza
pine, risperidone, pimozide, loxapine, molindone, quetapione, sertindole, remoxi
pride. Advantages: more effective for negative symptoms, extrapyramidal SE. Phen
othiazines (x-omazine, x-perazine): chlorpromazine, triflupromazine, prochlorper
azine, trifluoperazine, fluphenazine, thioridazine. Fluphenazine esters (decanoa
te, enanthate)
very lipophilic
very long acting. Mechanism: block dopamine recep
tors in the brain (extrapyramidal SE). Other possible effects: H1, alpha1, musca
rinic. Atypical drugs: also serotonin antagonism. SE: Central: drowsiness, extra
pyramidal (akathesia, dystonia, akinesia, tardive dyskinesia), poikilothermy, ap
petite, weight gain, release of hormones. Peripheral: postural hypotension, refl
ex tachycardia, impaired ejaculation, dry mouth, blurred vision, liver toxicity.
Antidepresseants / antimanics
MAO-I: phenelzine, isocarboxazid ( potent), tanylcypromine ( potent). Mechanism: b
lock oxidative deamination of brain biogenic amines (NEp, serotonin). Effect tak
es 3 weeks. Use: depression, phobic anxiety, narcolepsy, SE
use. SE: CNS (stimul
ation, tremor, agitation, mania, insomnia), BP, anticholinergic SE (constipation
, dry mouth, urinary retention). DI: tyramine foods, sympathomimetic drugs (hype
rtensive crises), TCA: secondary or tertiary amines, x-ipramine, x-triptyline, x
-pin (doxepin, amoxapine, dibenzoxazepine). Mechanism: CNS re-reuptake of biogen
ic amines (Nep, serotonin). Also block beta, serotonin receptors, reuptake. Use:
depression, enuresis (bedwetting), obsessive-compulsion, anxiety. SE: CNS (drow
siness, confusion), BP, tachycardia, anticholinergic SE, bone marrow depression,
m ania. Atypical antidepressants: bupropion, trazadone, mefazadone, SSRI, venla
faxine. Mechanism: CNS re-reuptake of biogenic amines. SE: similar to TCA + blur
red vision, tinnitus, sex dysfunction. Antimanics (mood stabilizers): lithium ca
rbonate, valproic acid, carbamazepine. Mechanism: lithium transmembrane Na excha
nge, neurotransmitter release, inositol metabolism. Use: manic depression / bipo
lar disease. SE: lithium causes urination, fine hand tremor ( with time).

Anxiolytics / sedative-hypnotics
Examples: BZD (diazepam, alprozlam, flurazepam, halazepam, oxazepam, prazepam, l
orazepam, chlordiazepoxide, clorazepate), buspirone, zolpidem. Old drugs: barbit
urates, hydroxyzine no longer used due to risk of tolerance, dependence, withdra
wal reactions, and SE ( CNS depression). Diazepam: not basic enough to form water
soluble salt with acid
dissolve in propylene glycol for IV, may ppt if mixed wi
th water. Barbiturates: derivatives of barbituric acid. Long / branched / unsatu
rated side chain lipid solubility
metabolism, onset, duration of action, potenc
. Phenobarbital (barbiturates) strong enzyme inducer. Weak acids, in overdose
al
kalinize the urine excretion. BZD: Mechanism: GABA-ergic, chloride channel openi
ng chloride conduction
membrane hyperpolarization. Also CNS depression (hypnotic
, anesthetic, anticonvulsant, muscle relaxant, alcohol depression). Use: anxiety
, insomnia, pre-anesthesia, during acute alcohol withdrawal. SE: CNS depression,
ataxia, confusion, abuse / dependence. Buspirone (x-pirone): Mechanism: bind to
central dopamine, serotonin receptors. No CNS depression (hypnosis, anti-convul
sion, alcohol interaction, no abuse, no rebound anxiety). Use: anxiolytic (effec
t takes a week). SE: headache, dizziness. Zolpidem (Ambien): Mechanism: strong s
edation but anxiolytic effect (for insomnia). Use: insomnia. No abuse, rebound i
nsomnia, or respiratory depression.

Barbiturate: Mechanism: similar to BZD. Use: Ultra-short acting barbiturates (th

iopental): induce anesthesia. Long acting barbiturates (phenobarb): antiepilepti
cs. SE: hypnosis, drowsiness, nystagmus, bradycardia, BP, anemia, liver toxicity
, respiratory depression. DI: enzyme induction Chloral hydrate: aldehyde prodrug
. Use: induce sleep, pre-anesthesia. SE: toxic active cumulative metabolite, CNS
depression, alcohol effect, leukopenia. DI: enzyme induction
Antiepileptics
Older agents: long-acting barbiturates (phenobarb, mephobarb, metharbital, primi
done), phenytoin (hydantoin), succinimides (ethosuximide, phensuximide), valproi
c acid, trimethadione, dimethadione. Newer agents: carbamazepine, BZD (diazepam,
clonazepam, clorazepate), gabapentin (GABA analog), lamotrigine, felbamate. Pha
rmacology: or prevent excessive discharge and spread of excitation from CNS seiz
ure c enter. Phenytoin: Na efflux Barbiturates, BZD, valproic acid: GABA-ergic i
nhibitory neuronal function. Tonic-clonic (grand mal)
carbamazepine, pheytoin, p
henobarb. Uses: Status epilepticus diazepam, phenytoin, phenobarb Absence (petit
mal)
clonazepam, phenobarb, valpric acid Myoclonic
clonazepam Partial gabapenti
n, lamotrigine, flebamate Pscyhomotor
carbamazepine, phenytoin, phenobarb Genera
l SE: CNS (drowsiness, confusion, diplobia, nystagmus), blood toxicity, allergy,
Stevens-Johnson, birth defects (no safe drugs here). Phenytoin: gingival hyperp
lasia, arrhythmias. IV barbiturates / BZD SE: CV collapse, respiratory depressio
n
14. Autacoids
Autacoids are local autopharmacological agents or local hormones. May also funct
ion as neurotransmitters (e.g. histamine, serotonin). Also include leukotrienes
(discussed later).
Histamine
Chemistry: bioamine derived from dietary histidine. H1-antagonists: diphenhydram
ine, dimenhydrinate, doxylamine, clemastine, meclizine, cyclizine, hydroxyzine,
cyproheptadine, promethazine, chlorpheniramine, brompheniramine, tripelennamine,
pyrilamine. New H1 antagonists (loratadine, desloratadine, fexofenadine, cetiri
zine, astemazole, acrivastine) are less sedating due to their inability to cross
BBB. H2-antagonists: ranitidine, cimetidine, famotidine, nizatidine. Pharmacolo
gy: H1-receptors: allergic and anaphylactic responses (bronchoconstriction, vaso
dilation, spasmodic GI smooth muscle contraction, capillary permeability, itchin
g, pain). H2-receptors: secretion of gastric acid, pepsin, intrinsic factor. Ind
ications: exogenous histamine may be used for diagnosing gastric acid function (
not very safe). H1-blockers: allergy symptoms (seasonal rhinitis, conjunctivitis
), common cold (rhinovirus) infection, urticaria. Agents with anticholinergic ef
fect (meclizine, cyclizine, dimenhydrinate, diphenhydramine): motion sickness an
d vertigo nausea and vomiting. Promethazine: antiemetic. Hydoxyzine: mild anxiol
ytic. H2-blockers: gastric hypersecrtion (ulcers, Zollinger-Ellison, GERD). SE:
H1-blockers: CNS (sedation, depression, fatigue, except in new agents), GI upset
, anticholinergic (dry mouth, constipation). Non-sedating H1-blockers: arrhythmi
a, especially with hepatic enzyme inhibitors, grapefruit. H2-blockers: CNS (dizz
iness, confusion), liver / kidney damage, liver enzyme inhibition (cimetidine),
androgenic effects (cimetidine).
Serotonin
Chemistry: serotonin is 5-HT (5-hydroxytryptamine). Bioamine synthesized from tr
yptophan. Serotonin agonists (triptans): idole derivatives of serotonin. Also ci
sapride, benzamide, ergot alkaloids (ergonovine, dihydroergotamine, bromocriptin
e, methylsergide, partial agonists / antagonists). Serotonin antagonists: ondase
tron, granisetron.

Pharmacology: Serotonin: vasoconstriction, platelet aggregation, nausea / vomiti

ng, anxiety, depression, appetite, acetylcholine release. Serotonin agonists: Ci
sapride: releases Ach (treat GERD, off market). Serotonin antagonists: prevents
nausea / vomiting. Indications: Agonists: drugs use the serotonin system to affe
ct the CNS and modulate behavior (dexfenfluramine as anorexiant, buspirone as an
xiolytic, SSRI for depression). Triptans and ergots are used for migraines. Ergo
ts are used to postpartum hemorrhage (vasoconstriction uterine contraction). Bro
mocriptine is used to prevent post partum breast enlargement. Antagonists: preve
nts nausea and vomiting due to cancer chemotherapy. SE: Agonists: dizziness, tig
ht chest, coronary vasoconstriction (CI in angina, BP). Cisapride: arrhythmia, di
arrhea. Ergots: cold / ischemic extremities, GI upset. Antagonists: headache, di
zziness, constipation.
Prostaglandins
Chemistry: derivatives of prostanoic acid (ringed structure). Membrance phosphol
ipids
phospholipase A2 arachidonic acid
COX enzyme PG. COX I: protects gastric m
ucosa (PG), homeostasis (thromboxane synthesis). COX II: expressed only in respo
nse to inflammation or injury. PG classification subscripts relates to the numbe
r and position of double bonds in the aliphatic chains. Pharmacology: Endogenous
: release in response to insults (chemical, bacterial, mechanical). Cause pain a
nd edema. Physiologic responses: PGI: vasodilation, platelet aggregation, gastri
c release of bicarbonate and mucus (protect epithelium). PGE: platelet aggregati
on, gastric acid secretion, broncho-relaxation. PGD/PGF: bronchoconstriction. In
dications: PGE1 analogs: misoprostol to prevent NSAID induced GI ulcers, alprost
adil for impotence due to erectile dysfunction. PGE2 analogs: dinoprostone is ab
ortifacient, for cervical ripening in pregnancy. PGF2alpha analogs: latanoprost
topically to intraocular pressure in glaucoma, carboprost is abortifacient (not
available in US). PGI analog: epoprostenol treats pulmonary hypertension. SE for
PGE: CNS (irritability, fever, seizures, headache), cardiovascular (hypotention
, arrhythmia, flushing), respiratory depression, hematologic (anemia, thrombocyt
openia), diarrhea, abortion.
16. Endocrinology
Pituitary hormones
Posterior pituitary hormones
Oxytocin: octapeptide. Action: stimulate uterine contraction, induce labor. Use:
promote delivery, control postpartum bleeding. SE: uterine spasm / rupture, fet
al effects (bradycardia, jaundice), water intoxication / coma. Vasopressin: octa
peptide. Action: vasopressor and anti-diuretic. hormone (ADH) activity. It reabs
orption of water at distal renal tubules. Use: neurogenic diabetes insipidus, po
stoperative abdominal distention. SE: GI cramps, vomiting, tremor, sweating, bro
nchoconstriction.
Anterior pituitary hormones
Protein molecules: available therapeutically, include: corticotropin, thyrotropi
n, thyrotropin-releasing hormone, growth hormone Corticotropin: also known as Ad
renocorticotropic hormone (ACTH). Single chain 39-AA polypeptide. Action: stimul
ate adrenal cortex to secrete adrenocorticosteroids. Use: diagnosis of adrenal i
nsufficiency. Growth Hormone: also known as Somatotropin, 191-AA chain. Action:
stimulate protein, carbohydrate and lipid metabolism to cell, tissue, organ grow
th. Use: for children with growth failure due to endogenous growth hormone secre
tion. SE: antibody formation. Thyrotropin: also known as Thyroid Stimulating Hor
mone (T SH). Its a glycoprotein. Thyrotropin-Releasing Hormone: tripeptide. Pitui
tary gonadotropins: not available therapeutically, include: Follicle-Stimulating
Hormone (FSH), Luetinizing Hormone (LH), Prolactin (Luteotropic Hormone, LH), m
enotropin (human Menopausal gonadotropin, hMG).

Menotropin: produce ovarian follicular growth and induce ovulation by FSH and LH
-like actions. Use: induce ovulation and pregnancy in anovulatory infertile wome
n, spermatogenesis in men. SE: gynecomastia in men, hypersensitivity, thromboemb
olism, ovary enlargement.
Gonadal hormones
Estrogen
Estrogen receptors: in the nucleus in the vagina, uterus, mammary glands, anteri
or pituitary, hypothalamus
alter mRNA. Uses: oral contraceptives (with progestin
s), menopause symptoms, acne, osteoporosis, prostate cancer. SE: edema / fluid r
etention, weight gain, triglycerides, hypertension, thromboembolism, M I, stroke
, GI upset, endometrial cancer. Estradiol: principal estrogenic hormone, in equi
librium with estrone. Estradiol esters are used as IM injections in oil for depo
t action (valerate, cypionate). The esters hydrolyze slowly in muscle tissue bef
ore absorption (prodrugs). Synthetic estrogens: resist first pass metabolism
ora
l efficacy. Examples: ethinyl estradiol, 3methyl ether mestranol (contraceptives
), quinestrol (ERT). Non-steroidal synthetic estrogens: e.g. diethylstilbestrol.
Estrogen antagonists: e.g. clomiphene, tamoxifen citrate, toremifene citrate. U
ses: clomiphene
induce ovulation, tamoxifen
breast cancer. Aromatase inhibitors:
anastrozole, letrozole (non-steroidal) conversion of androgens to estrogens. Us
e: advanced breast cancer. Selective estrogen receptor modulators (SERM): raloxi
fene bone resorption, bone turnover. Estrogen effect on bone and lipids but estr
ogen antagonist effect on uterus and breast. Use: prevention of osteoporosis.
Progestins
Progesterone: C-21 natural steroidal progestin. Synthetic progestins: 17alpha-hy
droxyprogesterones, 17alpha-ethinylandrogens. lipid solubility, first pass metab
olism, oral effect Mechanism: similar to estrogens (intracellular receptors
mRNA
). Uses: oral contraceptives (alone or with estrogens), uterine bleeding, dysmen
orrhea, endometriosis. SE: irregular period, breakthrough bleading, amenorrhea,
weight gain, edema. 17alpha-hydroxyprogesterones: e.g. medroxyprogesterone aceta
te, megestrol acetate 17alpha-ethinylandrogens: e.g. norethindrone, norgestrel,
androgens with progesterone activity. Used as oral contraceptives.
Androgens / anabolic steroids
Testosterone: C-19 steroid natural androgen / anabolic agent. Androgens: testost
erone 17-enanthate (ester with long IM action), fluoxymesterone (oral). Anabolic
s: oxandrolone, dromostanolone. Mechanism: testosterone 5alpha-reductase (in cyt
oplasm) dihydrotestosterone
bind to androgen receptor in nucleus mRNA Uses: andr
ogen replacement, breast cancer, endometriosis, female hypopituitarism (with est
rogens), treating ve nitrogen balance, anemia. SE: fluid retention, LDL, HDL, fem
ale masculinity, female fertility. Anti-androgens: flutamide, bicalutamide, nilu
tamide (all non-steroids)
competitive androgen inhibition by receptor binding. U
se: prostate cancer (with luteinizing hormone releasing hormone). 5alpha-reducat
se inhibitors: finasteride conversion of testosterone to dihydrotestosterone. Us
e: BPH, androgenic alopecia.
Adrenocorticosteroids
Synthesis: in the adrenal cortex. All steroids have fused reduced 17-carbon-atom
ring. Most natural steroids have some mineralo- and gluco- effect. All require
cytoplasmic receptors to transfer to the nuclei of target tissue cells.

Uses: replacement therapy (adrenal insufficiency), last resort for severe disabl
ing arthritis, severe allergic reactions, ulcerative colitis, kidney disease, ce
rebral edema, topical anti-inflammatory. SE: peptic ulcer, GI bleeding, intraocu
lar / intracranial pressure, headache, muscle weakness, skin atrophy, edema, wei
ght gain, excitation, irritability, hypertension, hyperglycemia, osteoporosis, f
lushing, hirsutism, cushingoid moon face / buffalo hump, immunity, infections. M
ineralocorticoids: Na retention, K excretion. Glucocorticoids: anti-inflammatory
, protein-catabolic, immunosuppressant. Cortisone / hydrocortisone: natural gluc
ocorticoids. Synthetic and semi-synthetic glucocorticoids try to mineralocortico
id activity. Examples: prednisone, prednisolone, triamcinolone, betamethasone, d
examethasone. Aldosterone: natural mineralocoritoid. Synthetics: fludrocortisone
acetate, desoxycoriticosterone acetate.
Antianemic agents
Iron
Iron preparations: ferrous salts are better absorbed from GI than ferric salts.
Examples: ferrous sulfate, ferrous gluconate, ferrous fumarate. Iron dextran (IV
) = colloidal complex of ferric hydroxide and low molecular weight dextrans. Iro
n (ferrous salts): easy GI absorption
stored in bone marrow, liver, spleen as fe
rritin and hemosiderin incorporate into hemoglobin
iron reversibly binds molecul
ar oxygen. Iron (ferrous salts): iron deficiency anemia (hypochromic, microcytic
RBCs
poor oxygen transport). Cyanbocobalamin (Vit B12): nucleotide-like macro-m
olecule. Includes cyanide and cobalt. Iron (ferrous salts): GI distress, constip
ation, diarrhea, heartburn
Vitamin B12 (cyanocobalamin)
Vit B12: easy GI absorption in the presence of intrinsic (Castles) factor (glycop
rotein produced by gastric parietal cells). Deficiency causes megaloblastic anem
ia and demyelination of nerve cells
irreversible CNS damage. Important for cell
growth. Vit B12: megaloblastic anemia due to vit B12 deficiency (hyperchromic, m
acrocytic, immature RBCs). Vit B12: no common SE
Folic acid
Folic acid: structure includes PABA, glutamic acid. Folic acid: easy GI absorpti
on, stored intracellularly. Precursor for several coenzymes (derivatives of tetr
ahydrofolic acid). Deficiency causes megaloblastic anemia but not neurologic dam
age. Folic acid: megaloblastic anemia due to folic acid deficiency. Folic acid:
rare allergy if taken parenterally.
Thyroid hormones / inhibitors (52)
Synthesis of thyroid hormones
Concentration of iodide in thyroid gland iodination of tyrosine residues on thyr
ogobulin (glycoprotein)
proteolysis of thyroglobulin into T4 (thyroxine, levothy
roxine), and T3 (triiodothyronine, liothyronine). T4 is less potent but has long
er duration than T3. T4 converts to T3 by peripheral deiodination. Control: invo
lves hypothalamic-pituitary-thyroid feedback. TRH is secreted by hypothalamus
re
lease of TSH (thyrotropin) by the anterior pituitary production of T4/T3 in thyr
oid.
Thyroid preparations
Action: mimic the activity of endogenous thyroid hormones
regulate growth and de
velopment, calorigenic and metabolic activity, positive inotropic / chronotropic
effects (sensitize beta receptors). Use: hypothyroidism (e.g. Myxedema), Myxede
ma coma, cretinism, simple goiter, endemic goiter. SE: rare, palpitations, nervo
usness, insomnia, weight loss. Sodium salts of T4/T3. T4 can be given alone (con
verts to T3).

Liotrix: 4:1 mixture of levothyroxine sodium to liothyronine sodium, no advantag

es over levothyroxine only. Thyroid USP: from dried defatted thyroid gland of do
mestic animals. Standardized based on iodine content. Thyroglobulin: purified ex
tract of frozen porcine or bovine thyroid gland, contains T4 and T3. Thyrotropin
(TSH): purified and lyophilized hormone from bovine anterior pituitary. Use: de
tection and treatment of thyroid cancer. SE: anaphylaxis, urticaria, gland swell
ing, tachycardia, arrhythmia, GI upset.
Thyroid inhibitors
Use: treat hyperthyroidism (e.g. Graves disease, toxic adenoma). Ionic inhibitors
: such as thiocyanate (SCN-) and perchlorate (ClO4-), inorganic monovalent anion
s concentration of iodide by the thyroid. Use: rarely use as drugs, but metaboli
sm of foods (e.g. cabbage) and drugs (e.g. nitroprusside) can produce excess SCN
-. concentration iodides: such as Lugols solution, iodides their own transport, s
ynthesis of mediators, hormone release. Use: before thyroid surgery to make glan
d firmed and its size. SE: Iodism ( salivation, skin rashes, eyelid swelling, sor
e gum/teeth/larynx/pharynx). 131 Radioactive iodine ( I) sodium: trapped by thyr
oid gland
incorporated into tyrosine / thyroid hormone. Radioactive beta particl
es local destruction of thyroid cells. SE: delayed hypothyroidism. 131 Thiouryle
nes: thyroid synthesis. Examples: propylthiouracil, methimazole. Use: with I to
control mild hyperthyroidism. SE: urticaria, dermatitis, blood toxicity, joint p
ain / stiffness.
17. Drug Metabolism and Interactions
Drug metabolism
Definition: drug metabolism (or biotransformation) is the biochemical changes dr
ugs an foreign chemicals (xenobiotics) undergo in the body leading to formation
of metabolites. Inactive metabolites: examples: hydrolysis of procaine to p-amin
obenzoic acid, oxidation of 6mercaptopurine to 6-mercapturic acid. Metabolites w
ith similar activity: examples: codeine is demethylated to morphine ( activity),
acetohexamide is reduced to l-hydroxyhexamide ( activity), imipramine demethylate
d to desipramine (same activity). Metabolites with altered activity: retinoic ac
id (vitamin A) is isomerized to anti-cancer agent isoretinoic acid, antidepressa
nt iproniazid is dealkylated to anti-TB isoniazid. Bioactivated metabolites (pro
drugs): enalapril hydrolyzed to enalaprilat, suldinac is reduce to the active su
lfide, levodopa is decarboxylated to dopamine.
Biotransformation pathways
Phase I reactions
Polar functional groups are introduced to the molecule, or unmasked by oxidation
, reduction, hydrolysis. Oxidation: Most common reaction. Mostly in the liver. C
atalyzed by cytochrome P450. Cytochrome P450: oxidases, bound to smooth endoplas
mic reticulum, require NADH, exist in multiple isoforms (CYP11Ax, CYP17By, etc)
large # of substrates. Involved in metabolism or bile acids, steroids, xenobioti
cs / drugs. Oxidized drug polarity / water solubility
tubular reabsorption
excretion. Reduction Same goal as oxidation ( polarity by reductases). GI bacter
ial flora
azo and nitro reduction reactions. Enzymatic hydrolysis Addition of wa
ter across a bond
polar metabolites.

urine

Esterase: present in the plasma and tissues, nonspecific, hydrolyzes esters to a

lcohol and acid, responsible for activation of many prodrugs. Example: procaine.
Amidase: hydrolyze amides into amines and acid (deamidation) in the liver. Exam
ple: procainamide.
Phase II reactions
Functional groups of the original drug or a phase I metabolite are masked by a c
onjugation reaction
polar metabolites excretion, no crossing of cell membranes (p
harmacologically inactive, no toxicity). Conjugation reactions: combine parent d
rug (or metabolite) with certain natural endogenous constituents (glucuronic aci
d, glutamine, glycine, sulfate, glutathione). Requires high energy molecule and
an enzyme. High energy molecule: consist of coenzyme bound to endogenous substra
te, parent drug, or metabolite. Enzyme: called transferases, found in the liver
and catalyze the reaction. Glucuronidation: most common conjugation pathway due
to large supply of glucuronic acid (high energy form reacts using glucuronyl tra
nsferase). Common with OH group (form ethers) and COOh group (form esters). Reac
tion adds 3-OH groups and 1-COOH group hydrophilicity. Glucuronides with MWt
bile
excretion to intestines
intestinal beta-glucuronidase hydrolyze the conjugate
r
eabsorption. Sulfate conjugation: using sulfo-transferase. Amino acid conjugatio
n: reaction of glycine or glutamine with aliphatic or aromatic acids to form ami
des using N-acyltransferase. Glutathione conjugation: very critical for preventi
ng toxicity from harmful electrophilic agents (halides, epoxides). Glutathione (
tripeptide) + electrophile + glutathione S-transferase mercapturic acid. Methyla
tion: of oxygen- nitrogen- or sulfer-containing drugs
less polar but inactive me
tabolites. Example: COMT methylates catecholamines such as epinephrine. Acetylat
ion: less polar metabolites with N-acetyl-transferase. Metabolites (e.g. of sulf
onamides) may accumulate in the kidney
crystalluria / tissue damage.
Factors influencing metabolism
Species differences
Qualitative differences: occur mainly in Phase II reactions. Determines the actu
al metabolic pathway. It can result from a genetic deficiency of a particular en
zyme or difference in a particular endogenous substrate. Quantitative difference
s: occur mainly in phase I reactions. Due to difference in the enzyme level, pre
sence of species specific isozymes, amount of endogenous inhibitor or inducer, e
xtent of competing reactions.
Physiologic / disease state
Due to pathologic factors that alter liver function. Congestive heart failure: o
utput hepatic blood flow
metabolism albumin production
fraction of bound drug.
Genetic variations
Acetylation rate: depends on the amount of N-acetyl-transferase, which depends o
n genetic factors. Fast acetylators hepatotoxicity from isoniazid. Slow acetylat
ors other isoniazid SE. PM Phenotype: metabolism of B-blockers, antiarrhythmics,
opioids, antidepressants.
Drug dosage
dose may saturated metabolic enzymes. As the saturation approaches 100%
change f
rom first to zero-order metabolism. When metabolic pathway is saturated > possib
le alternative pathways. Example: therapeutic APAP doses glucuronic / sulfate co
njugation, toxic doses conjugation is saturated
N-hydroxylation
liver toxicity
Nutritional status
Conjugation agent levels (sulfate, glutathione) is dependent on nutrition

 protein diet
glycine, oxidative drug metabolism capacity. Diet in essential fatt
y acids (linoleic acid)
synthesis of certain enzymes metabolism of hexobarbital.
Diet in minerals (Ca, Mg, Zn) metabolism. Fe
metabolism. Diet in vitamins (A,
, C, E): C oxidation. E
dealkylation, hydroxylation.
Age
Metabolic enzyme systems are not fully developed at birth
doses in infants / chi
ldren to avoid SE, especially for glucuronide conjugation. Older children
liver
develops faster than in body weight efficacy. Elderly
metabolizing enzymes
nation Cp
SE
Gender
Due to androgen, estrogen, adrenocorticoid activity
idative metabolism is faster in men.

elim

CYP450 isozymes. Example: ox

Administration route
Oral: first-pass effect oral dose IV: by pass first-pass effect
dose compared to
oral dose. Sublingual / rectal: also bypass first-pass effect. Variable absorpti
on from rectal administration.
Chemical structure
Presence of certain functional groups influences drugs metabolic pathway (route,
extent, degree of metabolism).
Circadian rhythm
Nocturnal Cp of theophylline, diazepam are than diurnal Cp.
Extra-hepatic metabolism
Plasma: contains esterases (hydrolyze esters). Simple esters (procaine, succinyl
choline) are rapidly hydrolyzed in the blood. Esterases can also activate prodr
ugs. Intestinal mucosa: microsomal oxidation, conjugation (glucuronide, sulfate)
first pass effect of lipid soluble drugs during absorption. Intestinal bacteria
l flora: secrete metabolizing enzymes. Ulcerative colitis
flora. Diarrhea, antib
iotics flora. Flora secrete beta glucuronidase
hydrolyze polar glururonide conju
gates of bile
reabsorption of free nonpolar bile acids eneterohepatic circulatio
n. Flora convert vitamin K to active form, and cyclamate (sweetener) to cyclohex
ylamine (carcinogen). Flora produce azoreductase converts sulfasalazine to 5-ami
nosalicylic acid (anti-inflammatory) and sulfapyridine (antibacterial). Stomach
acidity: degradation of penicillin G, carbenicillin, erythromycin, tetracycline,
peptides / proteins (insulin). Nasal mucosa: CYP450 activity and metabolism on
nasal decongestants, anesthetics, nicotine, cocaine. Lung: first pass metabolism
of IV, IM, transdermal, SC drugs but to degree than the liver. Also, second pas
s metabolism for drugs leaving the liver. Placenta: if drug is lipid soluble eno
ugh to get to circulation
pass through the placenta too. Placenta is not a physi
cal or metabolic barrier to xenobiotics. Very little metabolism occurs. Smoking
induce certain enzymes in pregnant women carcinogens from polycyclic HC. Fetus:
depends on fetal age, glucuronic acid conjugation. Chloramphenical
glucuronidatio
n gray baby syndrome. bilirubin glucuronide
neonatal hyperbilirubinemia.

Strategies to manage metabolism

Pharmaceutical
Sublingual tablets: deliver drugs directly to systemic circulation, bypassing he
patic first pass metabolism. Example: nitroglycerin. Transdermal products: conti
nuous drug supply for long period of time. Example: nitroglycerin. IM depots: co
ntinuous drug supply for long period of time. Example: highly lipid soluble este
rs of esradiol (benzoate) and testosterone (enanthate)
slow absorption and activ
ation by hydrolysis. Enteric coated tablets: protect acid sensitive drugs. Examp
les: omeprazole, erythromycin, methenamine. Nasal administration: for lung deliv
ery of peptides (e.g. calcitonin salmon) which has no oral bioavailability. Lung
contains protease inhibitors
peptide stability.
Pharmacologic
Levodopa (L-dopa): amino acid precursor of dopamine (for Parkinsons). Unlike dopa
mine, it can penetrate BBB and reach CNS to be decarboxylated to dopamine. Carbi
dopa: DOPA decarboxylase inhibitor that does not cross BBB peripheral activation
and SE. Beta-lactam AB: use clavulanic acid (a beta-lactamase inhibitor). Ifosf
amide: alkylating agent
in vivo metabolic activation nitrogen mustard. Acrolein
is a byproduct of metabolic activation react with nucleophiles on renal proteins
hemorrhagic cystitis. Combine ifosfamide. with mesna (neutralizes acrolein in t
he kidney).
Chemical
Testosterone: not orally active due to rapid oxidation of 17-OH group. Methyl-te
stosterone: 17alphamethyl group
potent but no rapid first pass metabolic deactiv
ation used orally. Same for estradiol analogs. Tolbutamide: oxidation of para-me
thyl group rapid deactivation. Chlorpropamide: non-metabolizable para-chloro gro
up long t1/2. Isoproterenol: potent beta agonist for asthma. Rapid metabolism by
COMT (catechol)
poor oral activity. Metaproterenol: not metabolized by COMT
ora
lly active, long t1/2. Octreotide: synthetic octa-peptide
severe diarrhea in tum
ors, SC. It mimics action of somatostatin (14-AA peptide, short t1/2, only IV in
fusion) but resistant to hydrolysis, proteolysis.
Prodrugs
Require in vivo biotransformation (phase I) to produce activity The following ar
e potential advantages for prodrugs:
water solubility
Useful for ophthalmic and parenteral formulations Example: sodium succinate este
rs, sodium phosphate esters to make water-soluble steroid prodrugs
lipid solubility
duration of action: estradiol lipid-soluble esters (benzoate, valerate, cypionat
e) prolonged activity (IM of esters in oil). oral absorption: by converting carb
oxylic acid groups to esters
converted back to active acids by plasma esterases.
Example: lipophilic orally absorbed enalapril
very potent orally inactive enala
prilat. topical absorption: of steroids by masking hydroxyl groups as esters or
acetonides polar
dermal permeability. Examples: triamcinolone acetonide, betamet
hosone valerate, diflorasone diacetete. palatability: sulfisoxazole acetyl (este
r, water solubility, ok taste for children)
sulfisoxazole (bitter)
GI irritation
NSAIDs ulceration by direct irritant effect of acidic molecules and of gastro -p
rotective PG. Sulindac, nabumetone
prodrugs with GI effect

Site specificity
Methyldopa: structurally similar to L-dopa
transported to CNS
metabolized to act
ive alphamethyldopamine central alpha-2 agonist Omeprazole: activated at acidic
pH < 1 inhibition of H+/K+ATPase. Formaldehyde: effective urinary tract antisept
ic. Orally
toxicity. Methenamine
non-toxic prodrug
hydrolyzes to formaldehyde an
d ammonium ions in acidic urine (pH<5.5). Use enteric coating to prevent activat
ion in the stomach. Olsalazine: polar dimer of 5-aminosalisalyic acid
poor oral
absorption. In large intestine colonic bacteria cleave azo bond
free active. Die
thylstilbestrol: synthetic estrogen for prostate cancer feminizing SE. Diethylst
ilbestrol diphosphate (ester prodrug) activated by acid phosphatase in prostate
tumor cells local action, systemic SE.
shelf-life
Cefamandole: 2 generation cephalosporin, unstable in solid dosage forms. Cefaman
dole nafate: stable formic acid ester
hydrolyzed by plasma esterases. Cyclophosp
hamide: stable prodrug in vivo oxidation + nonenzymatic decomposition
active pho
sphoramide mustard.
nd
Drug interactions
Types of interactions: drug-drug, drug-food, drug-chemical, drug-laboratory. Pre
cipitant: drug, food or chemical causing the interaction. Object: drug affected
by the interaction. Epinephrine, erythromycin decompose in IV alkaline pH
do not
mix with aminophylline (alkaline).
PK interactions
Due to in absorption, distribution (protein / tissue binding), elimination (excr
etion / metabolism).

Absorption
Epinephrine (vasoconstrictor) percutaneous absorption of lidocaine (local anesth
etic). CHF GI blood flow
drug absorption MAO inhibitors + foods w/ tyramine metab
olism hypertensive crisis Antibiotics (erythromycin)
intestinal flora digoxin mic
robial deactivation
bioavailability. Antacids / H2 antagonists GI pH
ketoconazol
e dissolution intestinal motility (anticholinergics
, laxatives )
absorption Chol
styramine / kaolin digoxin adsorption
bioavailability Complexation by divalent c
ations tetracycline bioavailability
Distribution
Due to in plasma protein binding / displacement or tissue / cellular interaction
s. Valproic acid displaces phenytoin and its liver metabolism
phenytoin. Quinidin
e displaces digoxin and digoxin clearance digoxin.
Elimination / clearance
Due to in kidney or liver clearance (enzyme induction / inhibition, enzyme subst
rate competition, blood flow) . Grapefruit juice is a powerful inhibitor of CYP3
A4. Enzyme inducers: tobacco (polycyclic aromatic HC), barbiturates, rifampin, c
arbamazepine, phenytoin, omeprazole, troglitazone. Enzyme inhibitors: cimetidine
, ketoconazole, ciprofloxacin, erythromycin, ritonavir / nelfinavir, clopidrogel
.
Food-drug interactions
drug absorption. Example: Complexation of tetracycline + calcium

Delayed/ absorption: NSAIDs, APAP, antibiotics, ethanol. absorption: griseoflulv

in, metoprolol, phenytoin, propoxyphene
Chemical-drug interactions
Smoking (enzyme induction)
clearance of theophylline, BZD, TCA Alcohol: acute us
e metabolism, chronic use
metabolism.
PD interactions
Antagonistic, additive or synergistic effect. Similar action excessive or toxic
response. Example: alcohol + antihistamine both CNS depressants, promethazine +
antihistamine
both anticholinergic. Thiazide diuretic
deplete potassium
sensitiv
ity to digoxin, deplete sodium lithium toxicity, anticoagulant + aspirin
risk of
bleeding.
Significance and management of interactions
Potential drug interactions
Multiple-drug therapy: including Rx and OTC. # potential. Multiple prescribers:
different prescribers are not aware of history Patient compliance: example: tetr
acycline not on empty stomach. Patient risk factors: elderly at risk ( body compo
sition, GI transit, drug absorption, distribution, protein binding, drug clearan
ce). Patients with diseases (DB, AIDS, etc) and atopic (hyper-responsive) patien
ts are at risk.
Clinical significance
Not all interactions are dangerous. Interacting drugs can be prescribed under su
pervision with monitoring. Example: cimetidine with antacids
do not take both at
the same time Some interactions are good
efficacy, SE. Examples: trimethoprim +
sulfamethoxazole ( efficacy in UTI), amoxicillin + clavulanate potassium (beta l
actamase inhibitor spectrum), hydrochlorothiazide + enalapril (balance potassium
), penicillin + probenicid ( tubular secretion, t1/2), saquinavir + food ( absorpt
ion). Likelihood: established, probable, suspected, possible, unlikely Consider
dose side and duration, interaction onset / severity.
Management of drug interactions
Review patient profile: drug history and risk factors Avoid complex therapeutic
regimens Determine probability of a significant interaction Suggest alternatives
: APAP not aspirin for headache with warfarin Monitor SE. Monitor prothrombin ti
me if warfarin is given with sulfonamides (may be prolonged). Re-evaluate profil
e when changing therapy. Example: if d/c a thiazide diuretic
d/c potassium suppl
ement also.
20. Drug information resources
Drug information resources
Primary (journals)
Benefits: most current source, learn from case studies, new developments, commun
ications with professionals / consumers, CE credits, prepare for board certifica
tion exams. Limitations: information is not always 100% accurate.

Secondary (abstracts / indexes)

Benefits: enable quick and selective screening of primary literature for specifi
c information. May have enough info to answer the question. Limitations: only fi
nite number of journal reviewed, lag time between article publication and citati
on in the index, usually good only to locate the original article (no full answe
rs), contain only interpretations / description of the study which may be mislea
ding (not whole story).
Tertiary (textbooks)
Benefits: easy and convenient access to large number of topics, include backgrou
nd information on drugs / diseases, validity and accuracy of information can be
verified by using references. Limitations: may take years to publish
information
may be outdated, chapter author may not have done a thorough literature search,
author may have misrepresented the original article. Considerations: author, pu
blisher, edition, year of publication, scope, presence of bibliography.
Internet
Benefits: expanded searching capabilities, most useful for company specific info
rmation, issues currently in the news, alterative medicine, government informati
on. Limitations: may not be peer reviewed or edited, not always reliable (evalua
te source).
Strategies for evaluating information requests
Talk with the inquirer
Determine reason for inquiry: news-related question, medical condition Clarify d
rug ID / availability: correct name spelling, generic vs. brand, manufacturer, c
ountry, Rx vs. OTC, under investigation drug, dosage form, purpose for use.
Identify / assess product / resource availability
US drugs: American Drug Index, Drug Facts and Comparisons, Drug Topics Red Book,
PDR, Martindale the Extra Pharmacopoeia, American Hospital Formulary Service Fo
reign drugs: Martindale the Extra Pharmacopoeia, Index Nominum, US Adopted Names
, USP Dictionary of Drug Names. Investigational drugs: Martindale the Extra Phar
macopoeia, Drug Facts and Comparisons, Unlisted Drugs, NDA Pipeline. Orphan drug
s: for rare disease affected < 200,000 people
cost of development is unlikely to
be offset by sales FDA offers assistance and financial incentives to encourage
development. Drug Facts and Comparisons, National Information Center for Orphan
Drugs and Rare Diseases (NICODARD). Unknown drugs: are drugs on hand but are not
identified identify by physical characteristics or chemical analysis. Sources:
PDR, Facts and Comparisons, Drug Topics Red Book, Ident-A-Drug Handbook, Lexi-Co
mp, manufacturer, lab. Unapproved (off-label) uses: Drug Facts and Comparisons,
Martindale the Extra Pharmacopoeia, Index Medicus, Drugdex, USP DI, AHFS Drug in
teractions: Drug Interactions Facts, Evaluations of Drug Interactions, Hanstens D
rug Interactions Analysis and Management. Drug stability / compatibility: Trisse
ls Handbook of Injectable Drugs, Trissels Stability of Compounded Formulations, Ki
ngs Guide to Parenteral Admixtures. Manufacturer: good source for any missing inf
ormation.
Facts and Comparisons Martindale extra pharmacopiea PDR Index Nominum Red book A
merican Drug Index Hospital Formulary US Drugs X X X X X X Foreign Drugs Orphan
Drugs X Unknown Drugs X Investigational Drugs X X X X X X Unapproved Drugs X X I
nteractions X
X
US Adopted
X

Names
USP Dictionary Unlisted Drugs USP DI Index Medicus X X X X
Search strategies
Is it a clinical or research-related question? Define as specifically as possibl
e. Identify appropriate index search terms (keywords, descriptors). Determine qu
antity and quality of needed information. Ascertain as much as possible about th
e drug and the inquirer. What is the drug indication? Is the drug approved or no
t? Patient information (age, sex, weight, medical conditions, other drugs, signs
of SE, allergies, etc).
Guidelines for responding to information requests
Do NOT guess Intended use of information (abuse, misuse). Organize information a
nd response first. Tailor to the inquirers background (e.g. public vs. profession
al).
Evaluating a clinical study
Study objective: was the objective clearly stated? One or more objectives? Study
subjects: profile of study population. Healthy subjects or patients? Degree of
disease severity if patients? Volunteers? Number / ID of subjects (sex, age, rac
e, etc)? Co-morbidities? Inclusion / exclusion criteria? Stratification can be u
sed in case of inter-patient variability. Administration of drug treatment: dose
, frequency, time of day, route, drug source, dosage form, timing vs. factors af
fecting absorption (e.g. food), duration. Study setting: environment, dates, typ
e of professionals making observations, inpatient vs. outpatient, length of stud
y. Study methods / design: are methods and design clearly described? Retrospecti
ve vs. prospective: Retrospective
examination of past events to find links betwe
en variables, relies on patient memory and accurate records, used for rare disea
se, may lead to a decision to conduct prospective study. Prospective looks forwa
rd in time, can be observational or experimental (clinical trials). Treatment al
location: Parallel different patient groups are studied concurrently, identical
treatment for all groups except for one variable. Crossover
good control of inte
r- / intra-patient variability, each group undergoes each treatment, with the se
quence reversed for one group vs. the other, includes a washout period. Control
measures: own control (crossover design), concurrent controls, stratification, m
atched subgroups, run-in period. Controls: blind assessment / blind patients (do
uble blind vs. open label (non-blind)), randomization, matching dummies (placebo
s), comparison (to placebo or standard drug). Analysis: appropriate statistical
methods should be used
22. Clinical Toxicology
Overview
Definitions
Clinical toxicology: studies the effects of substances on patients caused by acc
idental poisoning or intentional overdose of medications, abuse drugs, household
products or other chemicals. Intoxication: toxicity associated with any chemica
l substance Poisoning: clinical toxicity secondary to accidental exposure Overdo
se: intentional exposure to cause self-injury or death

Information resources
Computerized databases: Poisindex: CD database updated quarterly and used by poi
son control centers. TOMES: Toxicologic, Occupational Medicine and Environmental
Series
info on industrial chemicals. Printed publications: textbooks and manual
s are useful but suffer a lag time of information published in primary literatur
e. Internet: Center for Disease Control and Prevention, FDA, and National Librar
y of Medicine websites. Poison control centers: accredited by the AAPCC. Provide
s info for the public and health care providers. Most reliable and up to date so
urces of information.
General management
Supportive care
Evaluate and support vital functions as a first step until patient is stabilized
. Airway, Breathing, Circulation (ABC).
Patients with depressed mental status
Hypoglycemia: to rule out or treat 50 ml of 50% dextrose IV Glucose can ppt Wern
icke-Korsakoff syndrome in thiamine-deficient patients
give IV thiamine push. Op
iate: give naloxone IV push.
History of exposure
Identity: of ingested substance, route of exposure, quantity ingested, time sinc
e ingestion, symptoms of overdose, associated illness / injury. Neurologic exami
nation: seizures, altered consciousness, confusion, ataxia, slurred speech, trem
or, headache, syncope. Cardiopulmonary examination: syncope, palpitations, cough
, chest pain, shortness of breath, upper airway burning / irritation. GI examina
tion: abdominal pain, nausea, vomiting, diarrhea, difficulty swallowing. Past me
dical history: Rx/OTC drugs, herbal medicines, alcohol / drug abuse, psychiatric
history, allergies, occupational / hobby exposures, travel, domestic violence /
neglect. Routine lab assessment: Complete blood count (CBC), serum electrolytes
, BUN, serum creatinine, BG, urinalysis, ECG
Toxicology lab tests
Advantages: confirm or determine substance identity, predict severity of toxic e
ffects, may help guide therapy Disadvantages: diagnosis is not always specific,
not available for all poisons, supportive care is the first priority. Generally,
only qualitative determination is need. However, quantitative determination is
required for some substances (e.g metals, lithium, methanol, APAP, salicylate, t
heophylline, ethylene glycol)
Skin decontamination
Required when skin absorption may cause systemic toxicity or when contamination
substance may produce toxic effects (e.g. acid burns). Remove clothes, irrigate
area with plenty of water. DO NOT neutralized (exothermic reaction).
Gastric decontamination
Emesis Contraindications: children < 6 months, CNS depression, seizures, strong
acids / alkali, sharp object, compromised airway, coma, convulsions, HC or petro
leum distillates, patients already vomiting, substance that are very fast acting
.

Syrup of ipecac: consider only if within 60 (even 30) minutes since ingestion, o
therwise, no benefit. Onset of emesis: within 30 minutes, 3 vomiting episodes in
1 hour. SE: diarrhea, drowsiness, lethargy Gastric lavage Use: if patient is no
t alert or has gag reflex, if quantity was ingestion short while ago or if not re
sponding to ipecac Procedure: aspire gastric contents
instill 250 ml tap water o
r saline aspire
repeat until content is clear for 2 liters. Activated charcoal A
dsorbs the majority of substances. Always give ASAP. Exceptions: iron, lead, mer
cury, cyanide, lithium, ethanol, methanol, organic solvents, strong acids / alka
li. Form: colloidal dispersion with water or sorbitol. Avoid multiple doses of c
athartics may cause electrolyte imbalance, dehydration. SE: charcoal aspiration
avoid if vomiting, bowel obstruction with multiple doses.
Whole bowel irrigation
Effective when charcoal is not available / effective. Use osmotic cathartic solu
tion (e.g. PEG (Golytely, Colyte). Continue until rectal effluent is clear.
Forced diuresis / urine pH manipulation
Use: for substance with kidney elimination, Vd, protein binding Alkaline diuresi
s: ionization of weak acids (aspirin, long-acting barbiturates (phenobarbital))
kidney reabsorption elimination. Use IV sodium bicarbonate urine pH at 8.0, main
tain adequate urine output. SE: metabolic alkalosis, hypernatremia, hyperosmolar
ity, fluid overload. Acid diuresis: ionization of weak alkali (amphetamines, phe
ncyclidine, quinidine) kidney reabsorption
elimination. Use ascorbic acid (vitam
in C) or ammonium chloride urine pH at 5.0.
Dialysis
Last resort for decontamination. Hemodialysis or peritoneal dialysis. Hemodialys
is: used for water soluble substances with Vd, MWt, protein binding. Use for lif
e threatening ingestions of ethylene glycol, methanol. Can correct fluid and ele
ctrolyte abnormalities.
Hemoperfusion
Anticoagulated blood is passed through (perfused) a column containing activated
charcoal or resin particles. Quicker than hemodialysis. Can NOT correct electrol
yte / fluid abnormalities. Less effective for methanol / ethanol. SE: thrombocyt
openia, leukopenia, hypoglycemia, hypocalcemia.
Management of specific ingestions
Acetaminophen
Toxicokinetics: mostly metabolized in the liver (Cytochrome P450) toxic metabolit
e liver toxicity, especially in alcoholics / elderly. Symptoms: phase I (1 day):
nausea, vomiting, phase II (2 days): no symptoms, phase III (3 days): abdominal
pain, coma, death. Treatment: ipecac or gastric lavage (within 2 hr), N-acetylc
ystein (specific antidote, oral / IV). Metoclopramide: emesis during / absorptio
n of N-acetylcysteine therapy.
Alcohols
Ethylene glycol Forms: antifreeze, windshield deicing. Colorless, sweet taste.

Toxicokinetics: live metabolism by alcohol dehydrogenase

glycoaldehydge
by aldeh
yde dehydrogenase glycolic acid
glyoxylic acid oxalic acid (most toxic). Symptom
s: phase I (12 hr): tendon reflex, ataxia, nystagmus, metabolic acidosis, hypoca
lcemia, phase II (1 day): tachypnea, cyanosis, tachycardia, pulmonary edema, ph
ase III (2 days): flank pain, oligouric renal failure. Treatment: gastric lavage
(within 30 min), IV ethanol, fomepizole (alcohol dehyrogenase inhibitor), pyrid
oxine / thiamine (convert glyoxylic acid to non-oxalate metabolites), sodium bic
arbonate (correct acidosis), hemodialysis. Methanol Forms: gas-line antifreeze,
windshield washe. Toxicokinetics: alcohol dehyrogenase
formaldehyde
formic acid.
Symptoms: phase I: euphoria, muscle weakness, phase II: vomiting, diarrhea, diz
ziness, headache, dyspnea, blurred vision, photophobia, blindness, cardiac / res
piratory depression, metabolic acidosis, hyperglycemia, coma, seizures, death. T
reatment: gastric lavage (NOT charcoal), IV ethanol, fomepizole (alcohol dehydro
genase inhibitor), folic acid ( metabolism of format), sodium bicarbonate (correc
t acidosis), hemodialysis.
Antidepressants
Tricyclic antidpressants Toxicokinetics: t1/2 = 24 hr, liver metabolism, enteroh
epatic circulation, plasma protein binding. Symptoms: atropine-like SE (mydriasis
, urinary retention, fever), tachycardia, BP, pulmonary edema, agitation, confus
ion, hallucinations, seizures. Lab data: ECG Treatment: GI decontamination (acti
vated charcoal), alkalinzation (sodium bicarbonate to arterial blood pH), phenyt
oin / BZD (to control seizures, fosphenytoin cause less hypotension than phenyto
in) , physostigmine (for anticholinergic symptoms, may cause asystole (no heart
beat)) . Selective serotonin reuptake inhibitors (SSRI) Toxicokinetics: t1/2 = 2
4 hr, liver metabolism Symptoms: agitation, drowsiness, confusion, seizures Lab
data: ECG Treatment: gastric lavage, supportive treatment
Anticoagulants
Heparin Dosage forms: IV, SC Toxicokinetics: t1/2 = 1 hr, liver metabolism Sympt
oms: bleeding, bruising Lab data: PTT, bleeding time, platelet count Treatment:
Protamine IV (combines with and neutralized heparin), 1 mg protamine neutralized
100 heparin units. Warfarin Dosage forms: oral, parenteral Toxicokinetics: abso
rbed orally, t1/2 = 36 hr, 99% protein bound, 5-day activity duration. Symptoms:
bleeding, bruising, hematuria, conjunctiva hemorrhage, GI / intracranial bleedi
ng. Lab data: PT, INR, bleeding time. Treatment: Phytonadione (vitamin K), blood
products with clotting factors.
BZD
Toxicokinetics: liver metabolism Symptoms: drowsiness, confusion, ataxia

Treatment: supportive (gastric emptying, activated charcoal, cathartic), Flumaze

nil (IV, short t1/2, careful observation for re-sedation in case of long acting
BZD).
Beta blockers
Symptoms: hypotension, bradycardia, atrioventricular block, bronchospasm, hypogl
ycemia. Treatment: gastric lavage, activated charcoal, Glucagon, Epinephrine (.
Calcium channel blockers
Symptoms: hypotension, bradycardia, atrioventricular block. Nifedipine does not
affect the heart. Verapamil
pulmonary edema, seizures. Treatment: GI decontamina
tion (gastric lavage, activated charcoal, whole bowel irrigation). Clacium chlro
die (IV) for hypotension, bradycardia, heart block. Glucagon.
Cocaine
Forms: alkaloid from Erythroxylon coca Toxicokinetics: good absorption from oral
, inhalation, intranasal, IV route. Metabolized in the liver, excreted in the ur
ine. Symptoms: CNS / sympathetic stimulation (BP, tachycardia, seizures, tachypne
a). Death due to respiratory failure, cardiac arrest, MI. Treatment: Symptomatic
. BZD for seizures. Labetolol for hypertension. Neuroleptics for psychosis.
Corrosives
Symptoms: strong acids and alkali cause skin burns. Treatment: decontamination.
Irrigate exposed skin with water. AVOID neutralization (exothermic reactions mor
e burns and tissue damage).
Cyanide
Forms: industrial chemicals, nail polish removers. Toxicokinetics: quick absorbe
d orally or by inhalation. Symptoms: headache, dyspnea, ataxia, coma, seizures,
death Treatment: amyl or sodium nitrite
converts hemoglobin to methemoglobin bin
ds to cyanide ion (cyano-methemoglobin)
sodium thiosulfate to regenerate hemoglo
bin. Oxygen for dyspnea. Sodium bicarbonate for acidosis.
Digoxin
Symptoms: confusion, anorexia, GI upset, dysrhythmia. Lab data: digoxin Cp, seru
m potassium, ECG. Treatment: ipecac or activated charcoal, correct blood potassi
um, heart support, Digoxin specific fab antibodies.
Electrolytes
Magnesium Forms: cathartics (mg citrate) mg with charcoal. Toxicokinetics: Mg is
found intracellularly kidney elimination Symptoms: Mild
weakness, tendon reflex
es. Severe respiratory paralysis, heart block, ECG abnormalities. Treatment: 10%
calcium chloride to temporarily antagonize cardiac effects of Mg. Use hemodialy
sis in severe cases. Potassium Toxicokinetics: main intracellular cation. acid-b
ase balance
potassium. pH
potassium. Symptoms: cardiac irritability, peripheral
weakness, bradycardia, dysrhythmia, ECG abnormalities.

Treatment: Calcium: antagonize cardiac effects of potassium , sodium bicarbonate

: serum pH
move potassium from extracellular to intracellular space, Glucose + i
nsulin: move potassium from extracellular to intracellular space, cation exchang
e resins (sodium polystyrene sulfonate): bind potassium in exchange for sodium ,
hemodialysis: last resort for life-threatening hyperkalemia.
Iron
Elemental iron: 33% in fumarate, 20% in sulfate, 12% in gluconate. Symptoms: pha
se I (nausea, vomiting, diarrhea, GI bleeding), phase II (improvement within 24
hr), phase III (metabolic acidosis, renal / hepatic failure, pulmonary edema, de
ath). Lab data: serum iron, hemoglobin, hematocrit, radiopaque pills in radiogra
phy. Treatment: Deferoxime chelates iron (red urine). Ipecac emesis if within mi
nutes of small quantity ingestion. Whole bowel irrigation for quantities. Also,
supportive treatment.
Isoniazid
Symptoms: nausea, vomiting, slow speech, ataxia, seizures, coma Lab data: lactic
acidosis, hypoglycemia, hyperkalemia, leukocytosis Treatment: AVOID emesis (due
to risk of seizures), quantity
activated charcoal gastric lavage. Pyridoxine re
verses isoniazid induced seizures (infusion in D5W). Sodium bicarbonate for acid
osis.
Lead
Forms: paint or gasoline fume inhalation. Toxicokinetics: slow distribution (t1/
2; 2 months). Symptoms: nausea, vomiting, GI pain, peripheral neuropathy, convul
sions, coma. Lab data: anemia, lead level in blood. Treatment: Calcium EDTA (IM/
IV), dimercaprol (IM).
Lithium
Toxicokinetics: absorbed orally, not plasma protein bound, small Vd, kidney elim
inatin. Symptoms: Mild polyuria, blurred vision, tremor, weakness. Severe
seizur
es, coma, delirium, fever. Lab data: determine the degree of toxicity form lithi
um Cp. Treatment: sodium polystyrene sulfonate, ipecac (within minutes), whole b
owel irrigation (if quantity), hemodialysis (if acute exposure + severe symptoms
).
Opiates
Toxicokinetics: methadone / heroin t1/2 Symptoms: respiratory depression, miosis
, consiousness, hypotension, bradycardia. opiates are downers. Treatment: Naloxo
ne (short t1/2, repeated dosing), Nalmefene (longer t1/2).
Organophosphates
Forms: pesticides, chemical warfare agents Toxicokinetics: absorbed through lung
s, skin, GI, conjunctiva Symptoms: DUMBELSS: diarrhea, urination, miosis, bronch
oconstriction, excitation, lacrimation, salivation, sweating. Lab data: RBC acet
ylcholinesterase activity. Treatment: atropine, pralidoxime (both IV).
Salicylates
Toxicokinetics: longer t1/2 at toxic doses Symptoms: Mild
nausea, vomiting, tinn
itus, malaise. Severe metabolic acidosis, convulsions, coma. Other SE: BI bleedi
ng, PT. Treatment: ipecac emesis (if within minutes), doses
repeated activated c
harcoal + a cathartic dose, moderate doses whole bowel irrigation, doses
hemodia
lysis. Alkaline diuresis: with sodium bicarbonate to excretion. Fluid / electrol
yte replacement. Vitamin K to correct coagulation.

Theophylline
Toxicokinetics: liver metabolism
highly variable (depends on age, other drugs, d
isease). Symptoms: nausea, vomiting, seizures, dysrhythmias. Acute toxicity
hype
rglycemia, hypokalemia. SE are due to cAMP. Treatment: supportive (maintain airw
ays, treat seizures, beta blocker (esmolol) treats tachycardia, disrhythmia), ip
ecac (if within minutes), repeated activated charcoal, whole bowel irrigation (i
f quantitiy), charcoal hemoperfusion or hemodialysis. Dosage forms: Toxicokineti
cs: Symptoms: Lab data: Treatment:
23. Federal Pharmacy Law
Federal Controlled Substances Act
Schedules of controlled substances
Drugs that have potential for abuse leading to physical or psychological depende
nce. Lists are published annually. US attorney general has the authority to modi
fy lists. Schedules II-V have accpeted medical uses but schedule I does not. Sch
edule II has the highest potential for abuse / severe dependence and Schedule V
has the least. Schedule I: drugs can not be kept in the pharmacy or dispensed ex
cept for authorized research or investigative reasons. Drugs with abuse potentia
l but no accepted medical use or esablished safety record. Examples: heroin, mar
ijuana, LSD, ecstacy, Schedule II: Highly restricted. Examples: morphine, oxycod
one, methyphenidate, amphetamine, methamphetamine, cocaine, opium, fentanyl, sho
rt acting barbiturates. Schedule III: Less potential for abuse / dependence than
CI or CII. Examples: anabolic steroids (testosterone, androgens), hydrocodone /
codeine with APAP / aspirin, intermediate acting barbiturates (talbutal). Sched
ule IV: Examples: BZD (diazepam, chlordiazepoxide, alprazolam, long acting barbi
turates (phenobarbital), propoxyphene, pentazocine, pemoline Schedule V: May be
available w/o Rx but sales are documented. Examples: small amounts of opium or c
odeine.
Registration requirements
All handlers of controlled drugs have to register with the DEA. DEA issues an Or
der To Show Cause to allow the registrant to appeal. Entities that must register
: wholesalers (annual renewals), dispensers (pharmacies, practitioners) (renew e
very 3 years). Pharmacists / pharmacy employees do not have to register. Registr
ation for separate activities: certain activies require separate registartion. E
xamples: manufacturing, distributing, dispensing, conducting research, narcotic
treatment programs, chemical analysis, importing / exporting, maintenance, dispo
sal, detoxification, packaging. Registration for separate locations: separate re
gistration for each pharmacy, pharmacy chain, clinic, hospital. Wholesalers do n
ot have to register if distributing to a registered location. Registration proce
dure: submit application to DEA by individual, partners, corporate officer, or p
erson with power of attorney. Registration action by the DEA: certificate of reg
istration is granted by DEA if appropriate, otherwise it may be denied. Modifica
tion of registration: e.g. for change of name, address, extension of authorized
activities, etc. Transfer of registration: not allowed except in case of pharmac
y ownership transfer.

Suspension / revocation of registration: May be due to imminent danger to public

health or safety. If revoced / suspended
deliver certificate or registration, a
ny DEA 222 order forms, all controlled substances or place them under seal. Exem
ptions from registration: Military officials: can prescribe, administer or dispe
nse but not purchase. Law-enforcement officials: federal and state. Civil defens
e officials: and disaster relief organizations during prolaimed emergencies or d
isasters. Agents and employees of registrants: such as pharmacists or delivery p
ersonnel. Termination of registration: death, cease of legal existence (company)
, d/c business or pratice. DEA must be notified and drugs disposed of.
Required inventories
All registered entities have to conduct biennial inventory. Initial inventory: m
ust be taken on the day of start or end of business or change of ownership. If n
o controlled substances in possession must be documented. Biennial inventory: an
y date within 2 years of the previous inventory. Inventory procedures: conducted
at either the open or close of business. Separate inventory record required for
CII keep drugs separate. Inventory content: inventory must contain: date of inv
entory, dosage form, strength, number of units or volume in each container. Exac
t count is required for open bottle of only CII (estimate is OK for other Cs, un
less containers contains > 1000 tablets). Inventory record maintenance: keep inv
entory separate at the registered location for 2 years. Keep CII inventory separ
ate. Must be readily retrievable. Submission to DEA is not required. Perpetual i
nventories: not required. New or changes in schedules: inventory required for th
at drug only.
Obtaining controlled substances
CII: DEA Order Form 222 is required. Forms are issued by DEA, serially numbered
with the certificate of registration inforamtion. Triplicate copies each. List i
nfo for drugs and supplier (one supplier per form). Form is invalid for purchasi
ng 60 days of signature. Only used by previously authorized and deisgnated indiv
iduals. Send copy 1 and 2 to supplier, retain copy 3. Maintain for 2 years. A pu
rchaser / supplier may cancel part or all of the order by notifying the other pa
rty in writing. CIII-V: no form is required but records need to be maintained (2
years).
Storage of controlled substances
One of two ways: in a securely locked well constructed cabinet OR dispersed thro
ughout the stock of other drugs to prevent theft. Report theft or significant lo
ss immediately to DEA using Form 106.
Disposal of controlled substances
DEA Form 41 must be submitted and pre-authorized. Always keep records. Options f
or disposal: transfer to a registered person or entity (use Form 222 for CII), d
elivery to or destroy in the presence of DEA agent or office. Regular disposal o
f controlled substances: DEA may authorize disposal without pior approval. Alway
s keep records.
Disposal (dispensing) pursuant to a valid Rx
Authorized prescribers Only by a practioner who is licensed by the state (not fe
derally). Usually: physicians, dentists, vets, podiatrists (DEA starts with A or
B). Other professionals may be licensed but with restrictions (DEA starts with
M). Authentication of DEA number (7 digits): (1 + 3 + 5) + 2x(2 + 4+ 6)
double d
igit the right digit has to match digit 7. Purpose for prescribing Must be in go
od faith only for legitimate medical reasons during the normal course of pratice
(medical history and physical exam performed). A vet can not prescribe for huma
ns. It does not have to be within

specialty if physician is a specialist. Can not prescibe controlled drugs for th

e sole purpose of detoxification of maintenance of addiction (only if within a t
reatment program). Prescribing CII must be written unless it is an emergency
ora
l drugs only, no alternative, written Rx is not possible, only necessary quantit
y, prescriber must be known to the pharmacist
written Rx must be provided within
7 days of oral Rx (mail or in person), otherwise notify DEA. CIII-V can be oral
or fax. Faxed Rx: ok for CIII-V. For CII ok to prepare the Rx but no released t
o the patient without written Rx exceptions include injectable home health, hosp
ice, and LTC Rx (no written Rx required) . Dispensing a Rx Time validity: 6 mont
hs for CIII-IV and no time limit for CII and CV (although questionable after 6 m
onths). No limitation on quantity either. Apply good faith principles. All infor
mation on the Rx must be complete (including S/N). Label: must have pharmacy nam
e / address, S/N, date of original filling, patient name, prescriber name, drug
info, directions, Cautionary Auxilliary Sticker. Separate record files: CII, CII
I-V, other Rx all separate, OR Combine all C with CIII-V or combine CIII-V with
non control as long as C is stamped in red on CIII-V. Refills: no refills for CI
I. For CIII-IV up to 5 refills in 6 months. No limit for C-V (use good faith). M
aintain either physical or computerized records (certain characteristics). Parti
al dispensing: allowed for CIII-IV within 6 months. For CII: allowed only if not
enough stock(within 72 hr), or terminally ill patient / LTC (within 60 days). T
ransfer of refills (CIII-V): allowed only once. Write Void or Transfer on Rx.
Dispensing without a prescription
Only if not a prescription drug. Only pharmacist can dispense only limited quant
ities (wihtin 48 hr period) with records kept (2 years), in good faith. Purchase
r must be 18 years and present an ID (if not familiar).
Security considerations
Seals / seals: seals required for all packages and containers. Labels must clear
ly designate the schedule (II-V). Felony convictions: no registrant may employ f
elons conviced with a narcotic offense.
DEA inspections
Inspected are conducted only in a reasonable manner and during business hours, o
nly after registrant notification or court warrant. Specifics of the inspection
scope must be provided.
Violation under the act
Penalties depend on type of schedule, nature of violation, and knowledge and int
ent of the violator, first or recurrent offense. Pharmacist must be proven to be
negligent not only an inadvertent mistake. May include civil penalty or impriso
nment.
Federal Food, Drug and Cosmetic Act
Passed following the sale of sulfanilamide elixir with deadly diethylene glycol
(car antifreeze) in 1937. Act requires the use of NDA to prove to the FDA that t
he drug is safe and effective. Drug: articles intended for use in diagnosis, cur
e, mitigation, treatment or prevention of disease in man or animals. Also, artic
les other than food intended to affect the structure or function of the body. Al
so, articles in the USP.
Legend (Rx) drugs
Includes the following types of drugs: Habit-forming drugs: such as narcotics or
hypnotics. Safety: drugs that are not safe except under supervision of a licens
ed practioner. IND: files on a NCE. Allows the conduct of research to prove safe
ty and efficacy (exemption from the Act). Include phases 1-3.

Phase 1: use on healthy humans to determien metabolism, pharmacology, mechanism,

SE. Phase 2: well-controlled closely monitored studies on small # of patients t
o evaluate efficacy for a certain indication and also SE and risks. Phase 3: exp
anded clinical trials on patients to confirm safety and efficacy and risk/benefi
t relationship NDA: acceptable proof of safety and efficacy to the FDA
approved
for use in certain indications. Treatment INDs (treatment protocols): allows a p
ractioner to use an investigational drug as treatmetn in serious and life-threat
ening disease when no alternatives are available.
OTC medications
FDA determined drug is safe for self-administration. Usually, drugs are not habi
t forming, toxicity / SE. Must have adequate clear directions and must comply wi
th FDA monograph (to avoid misbranding). A legend (Rx) drug may be converted by
the FDA to OTC.
Generic / Proprietary drugs
Generic name is the chemical name, common name or official name in the compendiu
m. ANDA: submitted for drugs that have already been proven safe and effective. T
he brand / generic must have the same active, dosage form, strength, route, indi
cations, conditions of use. Only bioavailability and bioequivalence have to be s
hown. Approved bioequivalent drugs are listed in the orange book.
Established names for drugs
Established name: Commissioner of the FDA has the authority to designate names.
Name has to be simple and useful. The FDA recongizes the US Adopted Names Counci
l (USAN) in deriving names for NCE. Otherwise, use the name in the official comp
endium title. Otherwise, common or usual name is used.
Drug recall
Voluntary manufacturer recall: may be completely voluntary or after several atte
mpts by the FDA to receive court ordered recalls. Drug recall classification: as
signed by the FDA. Class I: potential for serious SE and death. Class II: potent
ial for temporary or reversible SE or when serious SE are unlikely. Class III: n
ot likely to cause serious SE Recall procedure: strategy should consider the dep
th of the recall, need for public warning. First layer of notification (to whole
salers) is done by the company. Public notification is made by the FDA in the we
ekly FDA Enforcement Report.
Misbranding and adulteration
Adulteration: change or variation from official formulary or manufacturers standa
rds. Drug contains filthy, putrid, decomposed substance. Drug was prepared, pack
ed, held under unsanitary conditions where it might have been contaminated. Cont
ainer has poisonous substance. Drug contains unsafe color. Drug strength, qualit
y or purity is different from claimed compendium standard. Drug contains another
substance that
its quality or strength. OTC that is not properly packaged (tamp
er-proof) or labeled. Ophthalmic product that is not sterile. cGMP: a drug is ad
ultrated if not manufactured in conformity with cGMP. Misbranding: a drug is sol
d or dispensed with a violative label. False or misleading label. Imitation or n
ame used of another drug. Insulin or antibiotic that is not batch certified. Dru
g dispensed in non-child proof container. Label without proper info (drug info,
precautions, pharmacy info, Rx#, date, names of patient / prescriber, directions
, etc), oral contraceptive / estrogen / progesterone / IUD without patient inser
t, package, Rx drug without Rx, ophthalmic preparation that is not sterile. Viol
ations under the Act: exemption in certain cases of good faith (violative produc
t receive by the pharmacy in good faith), receipt of drug with a signed written
guaranty from the wholesaler. Seizures: of adultrated / misbranded product after
a court hearing or without a hearing if there is propable cause of danger to pu
blic health. Investigations and inspections: done by the US Secretary of Health
and Human Services. Investigations must be authorized, within reasonable limits,
time, manner and scope.

Package inserts
Manufacturers insert: full disclosure is required by the manufacturer. Enclosed w
ith every commercial container. Contains essential informative and accurate scie
ntific information for safe and effective drug use. It cant be promotional in ton
e, false or misleading. Patient package insert: due to certain SE with certain p
roducts, patient inserts must be dispensed, including refills. That includes the
following: Oral contraceptives, IUDs, Estrogen products, Porgestational product
s, Isoproterenol inhalation products, Miscellaneous (e.g. Isotretinoin
serious f
etal harm if pregnant). For isoproterenol, label with Do not exceed prescribed do
se. Contact physician if difficult persists.
Prescription drug samples
Currently, sample distribution is very restricted. All sale, purchase, trade of
samples are banned. Sample records are maintained by the manufacturer for 3 year
s. Pharmacies can not accept samples. Importation after exporting is illegal.
Medical devices
Safety and effectiveness are required. Class I: reasonable assurance of safety a
nd quality Class II: no reasonable assurance of safety and quality, but has suff
icient info to establish controls to ensure safety and quality Class III: no rea
sonable assurance of safety and quality (generally, they can not be marketed). M
edical device tracking: required if failure may lead to serious SE. Tracking all
ows recalls. Manufacturers reports: manufacturer, hospitals, pharmacies, etc are
required to report to the FDA potential link to death or adverse SE. Misbranding
and adulteration: same as drugs
Poison Prevention Packaging Act
The Act (1970) require child-resistant containers for all drugs (difficult for c
hildren under age of 5 to open easily within short period of time). Enforced by
the Consumer Product Safety Comission. Requests for non-child resistant containe
r: request can be made by the prescriber in a specific prescription, but a blank
et request cant be made. Patient can request that for one or all Rx (does not hav
e to be in writing). Reuse of child-resistant containers: generally prohibited.
Allowed for glass containers when a new child resistant cap is used. Manufacture
rs packaging: no child-resistant container if the product will be repackaged by t
he pharmacist, but is required if product will be dispensed directly to the pati
ent. Exemptions for easy access: OTC non-child-resistant packaged can be sold as
long as child-resistant alternative is offered. Label For Households Withouth Ch
ildren or Package Not Child Resistant. Hospitals and institutions: the Act applies
to houshold substances (any substance produced or distributed for sale for consum
ption or use by individuals in the household). Act does not apply if drug is give
n by hosptial personnel and not directly dispensed to the patient. Miscellaneous
special packaging: such as furniture polish containing petroleum distillates, d
rain pipe cleaners, turpentine, pain solvents, lighter fluid.
Exceptions
Sublingual nitroglycerin and sublingual / chewable isosorbide dinitrate at low d
oses. Erythromycin ethylsuccinate granules for oral suspension ( doses). Oral co
ntracpetives / conjugated estrogen / norethindrone acetate in memory-aid (mnemon
ic) packages ( dose). Medroxyprogesterone acetate tablets. Anhydrous cholestyrami
ne powder. Colestipol powder ( dose) Potassium supplements (effervescent tablets,
liquid, powder) ( dose). Sodium fluoride (tablet / liquid,
dose). Betamethasone
tablets in dispenser packages ( dose).

Prednisone or methylprednisolone tablets (

wder ( dose) Mebendazole tablets ( dose)

dose) Pancrelipase tablet, capsule, po

Anti-Tampering Act
Act passed in 1984 due to death from OTC capsules containing cyanide. Applies to
consumer products (food, drug, device, cosmetic, other articles). OTC tamper-re
sistant packaging: required from some products (contact lens, ophthalmic solutio
ns). Contain a visible indicator of breach or tampering. Product / tamper-resist
ant technology design must be distinct to avoid easy duplication by commonly ava
ilable processes. OTC tamper-resistant labeling: clearly alert consumers to spec
ific tamper-resistant feature on the package. Medical devices and cosmetics: req
uired for certain products Violations: include tampering, false communication or
conspiracy for either.
Mailing Prescription Medications
All drugs, including narcotics, can be mailed by the physician or pharmacist. Pl
ace drugs in a plain outer container or securely wrap in plain paper. Make no ou
tside markings that indicate nature of content. Exception: do not mail flammable
liquids or alcoholic beverages.
Omnibus Budget Reconciliation Act (OBRA)
The US Constitution states that the federal government has no authority to regul
ate the practice of pharmacy (done by the states). Federal government can indire
ctly affect practice by attaching conditions of participation and reimbursement
for federally funded programs. Medicaid: Rx are paid jointly by federal and stat
e governments. Federal reimbursement require the pharmacist to get a patient and
medication history, conduct DUR, offer counseling to the patient. Manufacturers
best price: for manufacturers to participate in Medicaid, they must offer best pri
ce (lowest price for the purchaser).
Narcotic Treatment Programs
Methadone can be used as part of a total narcotic addition treatment program. Re
gulations were established by the FDA and DEA. It is used for maintenance or det
oxification. Facility has to be approved by the FDA, DEA and state authority. De
toxification treatment: dispensing a narcotic drug in
doses to withdrawal physio
logic or psychologic symptoms. Maximum period: 6 months. Maintenance treatment:
dispensing a narcotic drug at stable dosage levels to treat heroin or morphineli
ke dependence. Requirments for patient admittance: has been physiologically depe
ndent on a narcotic for one year and still is. Patient participation must be vol
untary. Patient has to sign Conset to Methadone Treatment after being infomred pro
perly. Take home methadone: only to patients, judged by the physician, are respo
nsible in handling narcotic drugs. Patient must come to the clinic for observati
on at least 6 days a week, then gradually
observations to once a week. Dispense
methadone as any CII drug.
24. Reviewing and dispensing prescriptions
Definitions
Prescriptions: orders for medications, non-drug products, and services. Practiti
oners may prescribe medications only in their field of practice. Information in
the Rx: patient name and address, date, name and dosage form of the product, pro
duct strength, quantity (directly or indirectly), directions to the pharmacist (
preparation, labeling), directions for the patient (quantity, schedule, duration
, avoid as directed), refill information (as needed means one year), prescriber info
rmation (signature, DEA if controlled). Medical orders: orders for medications i
ntended for use by patients in an institutional setting.

Information in medication order: patient information, date and time, name and do
sage form, product strength, route of administration, signature, directions to t
he pharmacist, instructions for administration.
Understanding the Rx
Understanding the order: all info must be understood and consistent, including d
isease condition, reason for treatment, type of units used. Evaluating appropria
teness: follow up if incomplete info was provided. Evaluate allergies, route of
administration, drug-drug / food / disease interactions, safety for intended use
, proper quantity and dosage, incompatibilities, legitimate prescriber. Discover
ing inappropriate Rx: Drug Utilization Review: review medication profiles to ens
ure appropriateness. Therapeutic intervention: calling the prescriber to discuss
concerns regarding the Rx. Following the intervention, the Rx may be dispensed
as written, with changes or not at all.
Processing the Rx
Involves use of technicians and automation, save pharmacists time for patient cou
nseling and education. Record Rx number, original date of filling, product and
quantity dispensed, pharmacists initials. Product selection: involves generic sub
stitution, formulary / therapeutic substitution policies. Product preparation st
eps: obtain proper medication amount, reconstitute if necessary, extemporaneous
compounding, assembly of delivery unit, selection of proper package or container
. Labeling: contains name and address of pharmacy, patients name, original date o
f filling, Rx number, directions for use, product name and manufacturer, product
strength, quantity dispensed, prescriber name, expiration date, pharmacist init
ials. Unit-dose packages: contain one dose or unit of medication, label identifi
es drug name, strength, lot#, expiration date. Auxiliary labels: to ensure prope
r medication use, storage, federal transfer of narcotics, etc. Record-keeping: i
nclude patient profile system that includes demographic information (allergies,
DOB, disease, weight, occupation, OTC use) and record of all medications.
Dispensing medication and counseling
Counseling patients: evaluate patients understanding, supply additional informati
on, proper use, storage, appearance, name, route of administration, duration of
use, reason for the Rx, SE (frequency, severity, actions to manage and minimize)
, OTC or food interactions. Counseling health professionals: especially in insti
tutional setting where the professional administers the drug. Other information:
cost, drug-drug or nutrition interactions, physical incompatibilities, interfer
ence with lab tests,
Patient monitoring
Pharmaceutical care plan: to frequency and benefits of desired outcomes. Include
s: assessment (review medical conditions and symptoms), plan (decision on approp
riate therapy), monitoring (review outcome goals and endpoints). Drug-related pr
oblems: unnecessary therapy, wrong drug, wrong dose, SE, poor compliance, need f
or additional therapy.
25. Sterile Products and Parenterals
Introduction
Sterile products: parenterals, irrigating solutions, ophthalmics Aseptic techniq
ue: preparation procedures to maintain sterility Pyrogens: metabolic byproducts
of live and dead microorganisms that cause fever upon injection. Tonicity: relat
ed to osmotic pressure. Hypotonic solution: osmotic pressure than blood or 0.9%
NaCl. Cause cells to expand
hemolysis, pain. Isotonic: exert same osmotic pressu
re as blood or 0.9% NaCl. Hypertonic: must be administered through a large vein
to avoid phlebitis and ensure rapid dilution. Clean rooms: areas constructed and
maintained to probability of environmental contamination of sterile products. T
hey have the following:

High-efficiency particulate air (HEPA) filters: used to clean the air entering t
he room. Remove all particulates < 0.3 mm with efficiency ~ 100%. HEPA filtered
rooms are Federal Class 10,000, i.e., they contain <10,000 particles 0.5 mm or l
arger per cubic foot of air. Positive-air pressure flow: used to prevent contami
nated air from entering a clean room. Counters: in the clean room are made of ea
sily cleaned nonporous material, e.g., stainless steel. Wall / floors: free from
cracks / crevices, rounded corners, made of nonporous material, easily disinfec
ted. Air flow: air moved with uniform velocity (90 fpm) along parallel lines. La
minar flow hoods: clean air work benches in clean rooms designed as aseptic envi
ronment for making sterile products (Class 100). Horizontal: air flow moves acro
ss the surface of the work area (disadvantage: no protection for the operator).
Vertical: advantages: air flows down on the work space, which protects the opera
tor, portion of the air is circulated a second time. Inspection / certification:
for clean rooms and laminar flow hoods is done annually or when moved. The dioc
tyl phthalate (DOP) smoke test ensures that no particle > 0.3 mm passes through
HEPA filter. Anemometer is used to measure air flow velocity and a particle coun
ter is used to count particles.
Sterilization methods and equipment
Thermal: using either moist or dry heat. Moist heat (autoclave): most reliable a
nd widely used. Microorganisms are destroyed by cellular protein coagulation. Mi
nimum 121 C for 15 minutes. Dry heat: minimum 160 C for 120 minutes. More potent
ial damage to product due to temperature. Chemical (gas): used for surfaces and
porous materials (e.g. surgical dressings). Ethylene oxide is used with gas and
moisture. Residual gas must be dissipated before product use. Radioactive: for i
ndustrial sterilization of products in sealed packages that can not be heated (e
.g. surgical equipment, ophthalmic ointments). Use either electromagnetic or par
ticulate radiation. May accelerate drug decomposition. Mechanical (filtration):
removes but does not destroy and clarifies solutions by eliminating particulates
. Depth filter: consists of fritted glass or unglazed porcelain. Membrane (scree
n) filter: with thickness of 1-200 mm. A mesh of millions of microcapillary pore
flow rat
s filter the solution by physical sieving. Pores make up 75% of surface
e than depth filters. Particulate filters (0.5-5 mm): remove particles or glass,
rubber, plastic, etc. Used to risk of phlebitis by removing undissolved particl
es of reconstituted powders, cannot be used for blood, emulsions, suspensions,
colloids. Microbial filters (<0.22 mm): ensures microbe removal (cold sterilizat
ion). Either filter can be used as part of the tubing in drug administration (in
-line filter).
Packaging
Ampules: made entirely of glass. Single use. Disadvantages: glass fragments may
contaminate the product during opening must be filtered, not multiple use. Not c
ommonly used now. Vials: glass or plastic closed with a rubber stopper and seale
d with aluminum crimp. Advantages: can be multiple use (if bacteriostatic agent
is added), easier to remove product, no glass fragment risk, no need for filtrat
ion. Disadvantages: coring of rubber stopping can get into product, multiple use
can cause microbial contamination. Drugs that are unstable in solution are pack
aged in solid form and must be reconstituted with a diluent (sterile water or Na
Cl) before use. Lyophilization (freeze drying) can be used to dissolution rate a
nd permit rapid reconstitution. Double chamber system: one chamber with sterile
water for injection is separated from unreconstituted drug chamber by rubber clo
sure no need to enter vial twice
contamination risk. Add-vantage system: drug is
in a vial attacked to an IV bag for reconstitution. Add-vantage vial is screwed
into the top of Add-vantage IV bag and rubber diaphragm is dislodged to allow t
he mixing. Prefilled syringed: for immediate drug administration in an emergency
(epinephrine, atropine). Prefilled cartridges: ready to use parenteral packages
with accuracy and sterility. Used for narcotics. Infusion solutions: Small Volu
me Parenterals (SVP): volume < 100ml. Large VP (LVP): volume > 100ml. Packaging
materials: Glass: clarity for easy inspection, interaction with content. Plastic
polymers: durability, easy storage / disposal, weight, safety, e.g., PVC and po

lyolefin.
Routes of administration
Subcutaneous: usually in the arm or thigh. Example: insulin.

Intramuscular: e.g. mid-deltoid, gluteus medicus, < 5ml. Used for prolonged or d
elayed absorption (e.g. methylprednisolone). Intravenous: most important and com
mon, immediate therapeutic response, no recall of inadvertent overdose, e.g., an
tibiotics, cardiac drugs. Intradermal: only very limited volume, e.g., skin test
s and vaccines. Intra-arterial: deliver drug concentration into target side with
little dilution by circulation, e.g., diagnostic radiopaque materials and antin
eoplastics. Hypodermoclysis: injection of large volumes of solution into SC tiss
ue to provide continuous abundant drug supply, e.g., antibiotics for children. I
ntraspinal: e.g. local anesthetics during surgery (lidocaine, bupivacaine). Intr
a-articular: injection into joint space, e.g., corticosteroids (hydrocortisone,
methylprednisone) for arthritis. Intrathecal: injection into the spinal fluid, e
.g., antibiotics, cancer chemotherapy.
Parenteral preparations
IV admixtures: one or more sterile drug product added to an IV fluid.
IV fluids
Used in preparation of parenteral products (vehicles for IV admixtures). Dextros
e (d-glucose): 5% dextrose in water (D5W). Used for reconstitution, as hydrating
solution. Higher concentration dextrose (e.g. D10W) provide source of carbohydr
ates in parenteral nutrition. pH of D5W is 3.5-6.5
instability of acid-labile dr
ugs. Concentration > 15% give through central vein. Use cautiously in DM. Sodium
chloride: usually as 0.9% solution
isotonic (normal saline). NaCl 0.45% is half
-normal saline. Used for admixtures, fluid and electrolyte replacement. Bacterio
static NaCl for injection (0.9%): for multiple reconstitutions (bacteriostatic b
enzyl alcohol, propylparaben, methylparaben). Water: for reconstitution and dilu
tion of NaCl, dextrose. Use Sterile or Bacteriostatic Water for Injection. Ringe
rs solution: used post-surgically for fluid and electrolyte replacement. Lactated
Ringers (Hartmanns solution): contains sodium lactate, NaCl, KCl, CaCl2, may be c
ombined with D5W. Ringers injection: does not contain sodium lactate, may be comb
ined with D5W.
IV electrolytes
Cations: Sodium: main extracellular cation, important for interstitial osmotic p
ressure, tissue hydration, acid-base balance, nerve-impulse transmission, muscle
contraction. Examples: Na chloride, acetate, phosphate. Potassium: main intrace
llular cation, important for muscle (esp cardiac) contraction, neuromuscular exc
itability, protein synthesis, carbohydrate metabolism. Examples: potassium chlor
ide, phosphate, acetate. Calcium: important for nerve impulse transmission, musc
le contraction, cardiac function, bone formation, cell membrane permeability. Ex
amples: calcium chloride, gluconate, gluceptate. Magnesium: important for enzyme
activities, muscle excitability, neuromuscular transmission. Example: magnesium
sulfate. Anions: Chloride: main extracellular anion. With sodium, it controls i
nterstitial osmotic pressure, blood pH. Examples: sodium, potassium, calcium chl
oride. Phosphate: main intracellular anion. Important for enzyme activities, con
trolling calcium levels, buffer to prevent changes in acid-base balance. Example
s: sodium, potassium phosphate. Acetate: bicarbonate precursor used as alkali to
preserve plasma pH. Examples: sodium, potassium acetate.
Parenteral antibiotics
Route: direct IV, short term IV infusion, IM, intrathecal. Use: serious infectio
ns requiring concentration, GI is inaccessible.

Parenteral antineoplastics
May be toxic and hazardous during prep, administration. Safe handling: use verti
cal laminar flow hood, syringes and IV tubing with Luer-Lok fittings, closed-fro
nt cuffed surgical gowns, double layered gloves, negative pressure technique, fi
nal dosage adjustment with care, special care priming IV sets, prime before addi
ng the drug, special disposal, wash hands, monitor health of personnel. Patient
problems: Infusion phlebitis: vein inflammation, pain, swelling, heat sensation,
site redness, avoid by drug dilution and filtration. Extravasation: infiltratio
n of the drug into SC tissues surround the vein. Response: local hydrocortisone
or anti-inflammatory, antidote with cold compress, warm compress to blood flow a
nd wash vesicant away from damage tissue.
Parenteral biotechnology products
Examples: monoclonal antibodies, vaccines, colony-stimulating factors. Uses: can
cer chemotherapy, HIV, hepatitis B, infections, transplant rejection, rheumatoid
arthritis, inflammatory bowel, respiratory diseases. Characteristics: protein a
nd peptide biotechnology drugs: short t1/2, special storage (freezing, refrigera
tion), avoid vigorous shaking not to destroy protein molecules. Route: direct IV
, IV infusion, IM, SC. Require reconstitution.
Irrigating solutions
Manufactured by the same standards for IV products but not intended for injectio
n. Labeling differenced specified in USP, i.e., different acceptable particulate
matter levels, volume, container design. Topical administration: packaged in po
ur bottles into desired. For irrigating wounds, moistening dressings, cleaning s
urgical instruments. Infusion: e.g., perfuse tissues to maintain integrity of su
rgical field, remove blood, clear field of view as in urologic surgeries. Add Ne
osporin G.U. irrigant, an antibiotic, to risk of infection. Dialysis (dialysates
): e.g., in renal failure, poisoning, electrolyte disturbances. They remove wast
e matter, serum electrolytes, toxic products. Peritoneal dialysis: hypertonic di
alysate (dextrose, electrolytes) is infused in the peritoneal cavity via surgica
lly implanted catheter
remove toxins by osmosis and diffusion
finally drain. Ant
ibiotics, heparin may be added. Hemodialysis: patients blood is transfused throug
h a dialyzing membrane that removes toxins.
Needles and syringes
Hypodermic needles
Stainless steel or aluminum. Gauge: the outside diameter of the shaft. Large num
ber (27) small diameter (13). SC: 24-25. IM: 1922. Compounding: 18-20. Bevels: sl
anting edges cut into needle tips to facilitate insertion. Regular bevel: most c
ommon, for SC, IM. Short bevel: used onlyfor shallow penetration (IV). Intraderm
al bevel: most beveled. Lenghts: from to 6 inches, depending on desired penetrat
ion. IV: 1 - 2 inch. Compounding parenterals: 1. Intradermal / SC: . Intra-cardiac:
3.
Syringes
Glass or plastic barrel and tight-fitting plunger, small opening to accommodate
needle. Luer syringe: oldest, universal attachment for all needle sizes. Syringe
volumes: 0.3 60 ml. Insulin syringes have unit graduations (100 units/ml) rathe
r than volume graduations. Calibrations: may be metric or English, vary dependin
g on size. Syringe tips: Luer-Lok: threaded to ensure needle fit tightly, for an
tineoplastic drugs. Luer-Slip: unthreaded so needle does not lock into place, ma
y be dislodged. Eccentric: set off center to allow needle to remain to injection
site and minimize venous irritation. Catheter: used for wound irrigation and en
teral feedings and not for injections.

Intravenous drug delivery

Injections sites
Peripheral vein injection: preferred for non-irritating drugs, isotonic solution
s, short term IV therapy. Use dorsal forearm for venipuncture. Central vein inje
ction: preferred for hypertonic solutions, long-term IV therapy. Use thoracic ca
vity vein, e.g., subcalvian.
Intermittent infusion
Continuous drip infusion: slow infusion to maintain therapeutic level ro provide
fluid and electrolyte replacement. Rate: ml/hr or drops/min. Use for drugs with
narrow therapeutic index, e.g., heparin, aminophylline. Intermittent infusion:
infusion at specific intervals (4hr), for antibiotics. Direct bolus injection: r
apidly deliver small volume of undiluted drug. Use for immediate effect as in em
ergency. Additive set infusion: using volume control device, for intermittent de
livery of small amounts. Piggyback method: used when drug cannot be mixed with p
rimary solution, a supplemental secondary solution is infused through the primar
y system, avoids a second puncture or further dilution. Admixtures: also called
manufacturers piggyback, a vehicle is added to the drug, example: Add-Vantage sys
tem. Intermittent infusion injection devices: also called scalp-vein, heparin-lo
ck, butterfly infusion set. Permit intermittent delivery without multiple punctu
res or prolonged venous access. Use dilute heparin or normal saline to prevent c
lotting in the cannula.
Pumps and controllers
Pumps Piston-cylinder mechanism: a syringe like apparatus Linear peristaltic mec
hanism: external pressure to expel fluid out of the pumping chamber. Volumetric
pump: for intermittent infusion (e.g. antibiotics), continuous infusion, parente
ral nutrition, etc. Syringe pump: used for intermittent or continuous infusion o
f drug in concentrated form (e.g. antibiotics, opiates). Mobile infusion pump: s
mall infusion devices for ambulatory and home patients. For chemotherapy and opi
ates. Implantable pump: surgically planted under skin to provide continuous drug
release, usually an opiate. The pump reservoir is refilled by injecting drug in
to pump diaphragm. Patient-controlled analgesia (PCA) pump: used for intermitten
t or on demand delivery of narcotics. Benefits: cost, training, accurate flow ra
te, detect infiltration, occlusion and air, save nurse time. Controllers Use no
pumping pressure. Use gravity and control infusion rate by electronic counting o
f drops. Compared to pumps: complex, expensive, reasonable accuracy, used for un
complicated infusion but not arterial or small vein infusion.
IV incompatibilities
Types of incompatibilities Physical: mixing causes visible change in appearance.
Example: evolution of CO2 when sodium bicarbonate and HCl are mixed. It can be
a visible color change or pptn (e.g. phosphate and calcium). Chemical: chemical
degradation causing toxicity or loss of activity. Complexation: such as calcium
and tetracycline
inactive tetracycline complex. Oxidation: when a drug loses ele
ctrons color change, inactivity. Reduction: when a drug gains electrons. Photoly
sis: chemical decomposition by light
hydrolysis or oxidation
color change. Thera
peutic: e.g. bacteriostatic (tetracycline) then bactericidal (penicillin G)
acti
vity of penicillin G. Factors affecting compatibility pH: in pH incompatibility.
Acid + base = salt may ppt.

Temperature: temp
degradation. Use fridge or freezer. Degree of dilution: diluti
on ion interaction
incompatibility. Length of time in solution: time
chance of
ncompatibility Order or mixing: do not add incompatible drugs in sequence (e.g.
calcium, phosphate), mix well. Preventing incompatibilities Administer solutions
quickly after mixing, mix each drug well after addition, number of mixed drugs,
consult references.
Hazards of parenteral drug therapy
Physical Phlebitis: usually a minor problem, minimize by proper IV insertion tec
hnique, dilution of irritating drugs, infusion rate. Extravasation: caused by ve
sicant drugs Irritation: by varying injection site and applying moisturizer Pain
: common with peripheral infusion of concentration drugs, by diluting the drug o
r switching to central vein. Air embolism: can be fatal Infection: critical in c
entral IV lines, can be local or systemic (septicemia). Allergic reaction: due t
o hypersensitivity to IV solution, additive Central catheter misplacement: may c
ause air embolism or pneumothorax, verify proper placement radiologically Hypoth
ermia: due to shock or cardiac arrest, may be due to cold IV solution, injection
solution at room temp only. Neurotoxicity: serious problem in intrathecal / int
raspinal injection of drugs containing preservatives (avoid preservatives) Mecha
nical Pump/controller failure: may cause fluid overload, incorrect dose, or runa
way infusion. IV tubing: can become kinked, split, cracked, produce particles Gl
ass containers: may break
injury Rubber vial closures: may interact with drug so
lution Particulate matter Therapeutic Drug instability: may lead to therapeutic
ineffectiveness Incompatibility: may cause toxicity or effectiveness Labeling er
rors: may cause using incorrect drug or dosage Drug overdose: may be caused by r
unaway IV infusion, pump / controller failure, nursing / pharmacy errors. Preser
vative toxicity: can be serious, esp in children. Example: benzyl alcohol in pre
mature infants gasping syndrome (fatal acidotic toxic state).
Quality Control / Quality Assurance
Quality control: day-to-day assessment of all operations including analytical te
sting of raw materials and finished product. Quality assurance: oversight functi
on, involves the auditing of QC procedures and systems. Sterility testing: USP s
tandard calls for 10-test samples from large batches, minimum of 2 samples from
small batches. Test conducting using membrane sterilization method
membrane is c
ultured for microbial growth. Pyrogen testing: qualitative fever response in rab
bits or in vitro limulus lysate testing. Clarity testing: to check for particula
te matter. Swirl and look it against light source and dark background. QA progra
ms: include training, monitoring the manufacturing process, QC check, documentat
ion. Process validation: a mechanism for ensuring processes consistently result
in sterile products of acceptable quality. Includes written procedures, evaluati
on of aseptic technique by process simulation.

Process stimulation testing: duplicate sterile product production except that a

growth media is used instead of drug product. Incubate final product: no growth
successful aseptic technique. Documentation: of training procedures, QC results,
laminar flow hood certification, production records, etc.
35. Drug use in special patient populations
Pediatrics
PK consideration
PK parameters change as children mature from birth to adolescence. Gastrointesti
nal absorption: Gastric pH: neonates are achlohydric (pH >4) but pH quickly in t
he first few weeks of life absorption of basic drugs and absorption of acidic dr
ugs, absorption of drugs destroyed by acidic pH (penicillins). Gastric emptying:
long and highly variable in neonates and preemies, normal by age 6 months (t1/2
65 min). Drugs absorbed in the intestine: emptying rate
absorption, peak concen
tration. Formula has caloric density 2x as fast gastric emptying in breast fed i
nfants. Underlying disease state: may gastric emptying rate, total surface area,
absorption of lipids Bile acid production: in preemies (1/2) than adults
fat an
d drug absorption (e.g. Vitamin D). Pancreatic enzyme function: affects absorpti
on of lipid soluble drugs. Neonates have lipases absorption of chloramphenicol o
ral suspension. Percutaneous absorption Skin hydration
in neonates and preemies.
SC thickness
normal in newborns, in preemies. TEWL
in neonates. Intramuscular a
bsorption Affected by absorption surface area, blood flow, injection site, muscl
e activity. Preemies muscle mass, muscle contractility
erratic IM absorption. IM
absorption is normal in infants and children but is discouraged due to pain. Di
stribution Protein binding: acidic drugs bind to albumin. Basic drugs bind to al
pha1-acid glycoprotein. Both proteins are in neonates
free drug. Normal levels a
t 1 year old of age. Size of body compartments: Extracellular fluid volume is 40
% in neonates, 20% at age one. Polar compounds (e.g. aminoglycosides) distribute
into extracullar fluids loading dose is requires in neonates to rapidly achieve
therapeutic concentrations. Body fat is in preemies, higher in newborns and reac
hes a peak at one year. A body fat
Vd for lipophilic drugs (diazepam). Endogenou
s substances: neonates may have free fatty acid and unconjugated bilirubin
bind
to plasma proteins and degree of drug protein binding ( unbound drug). Bilirubin
competes with certain drugs for albumin binding sites. If displaced
potential dr
ug induced kernicterus. Metabolism Mostly occur in the liver. Some occur in the
intestine, lung, skin. Liver metabolism is affected by enzyme inducers (Phenobar
bital, phenytoin, carbamazepine, rafampin) and enzyme inhibitors (cimetidine, er
ythromycin). Phase I reactions: non-synthetic reactions (oxidation, reduction, h
ydrolysis, hydroxylation) that usually result in inactive or activity metabolite
s. Most important enzymes are cytochrome P -450 monoxygenase system (50% of adul
t level at birth). Phase II reactions: synthetic conjugation reactions (with gly
cine, glucuronide, sulfate) that result in polar water soluble inactive compound
s for renal and bile elimination. Enzymes systems are at birth and with age. Glu
curonide conjugation chloramphenical, sulfate conjugation
acetaminophen, sulfona
mides acetylation,

Elimination Kidney is the major route of elimination for water soluble drugs and
metabolites. Processes involved: glomerular filtration, tubular secretion, tubu
lar reabsorption. Filtration and secretion eilimination, reabsorption eliminatio
n. All processes are in neonates. Renal blood flow (important for glomerular fil
tration) is in neonates. Only unbound drugs undergo glomerular filtration.
Problems in drug monitoring
Therapeutic monitoring depends on correlation between serum concentration and th
erapeutic effect. The relationships are established for adults and may not work
for infants. Side effects: Most common with antibiotics (vancomycin, penicillins
, cephalosporins), anticonvulsants, narcotics, antiemetics, contrast agents. Exa
mples: red-man syndrome with vancoymcin, syndrome of inappropriate antidiuretic
hormone (SIADH) with carbamazepine. Dosing consideration: Body surface area = sq
uare root of (height x weight / 3600). Dose intervals: may be longer for neonate
s and shorter for older children.
Pregnancy
Fetal development
Withdraw all unnecessary medications 3-6 months before plans for conception. Bla
stogenesis: first 2-3 weeks after fertilization. Germ formation occurs. Embryoni
c cells are undifferentiated. Organogenesis: 2-8 weeks. Most critical period of
development as organs start to develop. Drug exposure may cause major congenital
malformations. Fetal period: 9 weeks to birth. At 9 weeks, the embryo is called
a fetus. Maturation and growth occurs. Low risk of major congenital malformatio
ns.
Placental transfer of drugs
Functions of placenta: nutrition, respiration, metabolism, excretion, endocrine
activity to maintain fetal and maternal well being. In order for a drug to cause
teratogenic or pharmacological effect, it has to pass from the maternal circula
tion to the fetal circulation through the placenta. Placenta is not a protective
barrier: most substances pass the placenta by passive diffusion due to concentr
ation gradient. Placenta acts similar to any other lipid membrane. Factors affec
ting drug transfer: Molecular weight: (< 500 dalton)
cross easily, large (hepari
n) does not cross. pH: weakly acidic and weakly basic drugs cross easily. Lipid
solubility:
cross easily. Most oral drugs are designed for optimal lipid membran
e transfer. Drug absorption: during pregnancy
gastric tone and motility
delayed
gastric emptying absorption. Drug distribution: during pregnancy
Vd with gestati
onal age, fat content, total body fluid. Plasma protein binding: only free unbou
nd drugs cross placenta. Albumin and alpha1-acid glycroprotein are during pregna
ncy free drugs. Placenta membrane becomes thinner with gestational age. Blood fl
ow with meals, exercise, drugs and may placental crossing. Embyotoxic drugs: may
terminate or shortens pregnancy, especially in early pregnancy. Examples: ACE i
nhibitors, hormones, antidepressants. st Teratogenic drugs: risk of teratogenesi
s is highest during the 1 trimester
physical malformations, mental abnormalities
. Teratogenic effect depend on the time during gestation when the drug is taken,
and organs developing at this point. FDA Classification: Category A (safety doc
umented in humans), Category B (safety documented in animals, or safe in humans
but damaging in animals), Category C (human safety unknown, may be damaging in a
nimals), Category D (damaging in humans, only use in life-threatening situations
), Category X (highly damaging in humans and may be animals, absolute contraindi
cation). Examples: vitamin A derivatives (isotretinoin), ACE inhibitors, warfari
n (use heparin instead), estrogens, androgens, thyroids (methimazole, carbimazol
e, propylthiouracil), cortisone, ethanol (Fetal Alcohol Syndrome, FAS), antibiot
ics (tetracycline (teeth), metronidazole, quinolone), anticonvulsants (phenytoin
, valproic acid, sodium valproate, trimethadione), lithium (Ebsteins anomaly), an
tineoplastics (methotrexate, cyclophosphamide, chlorambucil, busulfan), finaster
ide (avoid handling of tablets and semen of male users). Fetotoxic drugs: more l
ikely during fetal period (9 weeks to birth). CNS depression (barbiturates, tran
quilizers, antidepressants, narcotics), Neonatal bleeding (NSAIDs, anticoagulant

s, use Tylenol

instead), Drug withdrawal (habitual maternal use of barbiturates, narcotics, ben

zodiazepines, alcohol), Reduced birth weight (cigarette smokers, alcoholics, dru
g abusers), constriction of ductus arteriosus rd (NSAIDs in 3 trimester may caus
e pulmonary hypertension).
Drug excretion in breast milk
Transfer from plasma to breast milk: affected by factors influencing human membr
ane transfer. This is, like other membranes, a semipermeable lipid barrier. Unio
nized drugs may pass by passive diffusion. Low molecular weight molecules pass t
hrough small pores. Larger molecules must dissolve first in the lipid membrane.
Drugs physicochemical properties: human milk is more acidic than plasma. Acidic d
rugs are unionized
diffuse into milk and back. Basic drugs become ionized in mil
k trapped in milk. Plasma protein bound drugs cant pass into milk. lipid solubili
ty passage to milk. Drugs affecting hormonal influence: primary hormone is prola
ctin. Bromocriptine
prolactin
suppress lactation if desired. Other drugs to prol
actin: L-dopa, ergot alkaloids. Drugs to prolactin: metoclopramide, sulpiride. M
inimizing infants drug exposure: choose drugs with no active metabolites, short t
1/2, no milk accumulation. Adjust route of administration, dosing schedule to in
fants exposure. Drugs that enter breast milk: narcotics, barbiturates, BZD, alcoh
ol, antidepressants, antipsychotics, metoclopramide, anticholinergics (dicyclomi
ne).
Geriatrics
People >65 years use 33-50% of all prescriptions. 75% of elderly are Rx users. 2
0% of elderly experience SE. Incidence of SE is 2-3x higher in elderly. SE may b
e overlooked in elderly because they are similar to disease symptoms. Causes of
SE in elderly: polypharmacy, multiple diseases, more severe diseases, drug elimi
nation, sensitivity to drug effects. One third of elderly use => 6 drugs. Polyph
armacy drug interactions, drug-disease interactions. noncompliance in elderly es
pecially with females, socioeconomic status, living alone, polypharmacy, multipl
e disease, complicated regimens. Disease
noncompliance. Example: macular degener
ation, cataract, hearing loss, arthritis, Alzheimer. Clinical trials during drug
development may not test drugs on the elderly ( SE). osteoporosis
fractures due
to falls because of drugs causing dizziness, drowsiness, syncope, hypotension, b
lurred vision. Avoid long acting BZD, use lorazepam, oxazepam (no active metabol
ites, phase I metabolism).
Pharmacokinetics
liver metabolism (phase I) drug accumulation Absorption: can be affected by dela
yed gastric emptying, gastric pH, GI motility. Usually, the rate but not the ext
ent of absorption is affected. Distribution: body fat / lean muscle mass ratio
V
d of fat soluble drugs (diazepam, propranolol). total body water Vd of water sol
uble drugs (acetaminophen). serum albumin
protein binding
free drug (warfarin, p
henytoin). Kidney excretion: very important. glomerular filtration, tubular secr
etion rate. 50% in renal function by age 70 in normal patients. Serum creatinine
is not a good measure of renal function as creatinine also with age. dose of re
nally eliminated drugs to avoid SE and toxicity. Examples: digoxin, procainamide
, H2 antagonists, lithium, aminoglycosides. Liver metabolism: phase I (but not p
hase II) metabolism and blood flow t1/2, SE of BZD, some analgesics.
Pharmacodynamics
Altered response to certain drugs. response to beta blockers, response to analge
sics, BZD, warfarin. Generally, start low and titrate slow. sensitivity to antic
holinergic SE
avoid if possible.

36. Clinical laboratory tests

General principles
Monitor therapeutic / SE: e.g. serum uric acid after allopurinol, or liver funct
ion after isoniazid. Estimate proper dose: serum creatinine or creatinine cleara
nce before giving renally excreted drug Decide on alternative / additional thera
py: WBC count after AB Drug-caused test misinterpretation: false positive urine
glucose test after cephalosporin. Normal test values: usually mean +/- 2 SD. Sta
ndardization: using international system of units (SI). Basic SI unit is the mol
e (more physiologically meaningful as reaction occurs at molecular level). Lab e
rror: due to specimens (spoiled, incomplete, wrong sampling time), bad reagents,
inaccurate procedure, technical errors. Basic battery of tests: with routine ph
ysical and hospital admission include ECG, chest x-ray, electrolytes, urinalysis
, hemogram. Types of test: quantitative (normal range), qualitative (-ve / +ve),
semi-quantitiatve (1+, 2+, e.g. urine glucose).
Hematological tests
RBCs
RBC count: number of RBCs per cubic mm of blood, an estimate of the blood Hb con
tent. Normal: 4.5 million/mm3 (higher in men). Hematocrit or packed cell volume
(PCV): measures percentage (fraction) by volume of packed RBCs in whole blood af
ter centrifugation. Hct is usually 3x the Hb value. Normal: 45% (higher in men).
Low Hct
anemia, over hydration, blood loss. High Hct
polycythemia, dehydration.
Hemoglobin test: measures grams of Hb in 100 ml (1dl) of whole blood, an estima
te of the oxygen carrying capacity of RBCs. It depends on the number of RBCs and
amount of Hb in each RBC. Normal: 15 g/dl (higher in men). Low Hb anemia. RBC (
Wintrobe) indices: info on the size, Hb concent, Hb weight of RBCs. Used to cate
gorize anemias. Poikilocytosis: in RBC shape as in sickle-cell anemia. Anisocyto
sis: in RBC size as in folic acid and iron deficiency anemia. Mean corpuscular v
olume (MCV): ratio of Hct to RBC count. Measures average RBC size (anisocytosis)
. Normal: 90. Low MCV
microcytic anemia (iron deficiency). High MCV
macrocytic a
nemia (folic acid or vitamin B12 deficiency). Mean cell Hb (MCH): measures amoun
t of Hb in average RBC. Normal: 30. Mean cell Hb concentration (MCHC): measures
average Hb concentration in average RBC. Normal: 35. Low MCHC hypochroma (pale R
BCs) as in iron deficiency. RBC distribution width (RDW): normal RBCs are equal
in size bell-shape normal histogram distribution high RDW in anemia (iron, folic
acid, vitamin B12 deficiency). RDW is never below normal. Reticulocyte count: m
easures immature RBCs (reticulocytes), which contain nuclear material (reticulum
), Normal: 1% of all RBCs. It measures bone marrow production of mature RBCs. Hi
gh reticulocyte count
hemolytic anemia, acute blood loss, response to treatment
of factor deficiency anemia. Low reticulocyte count
drug-induced aplastic anemia
. Erythrocyte sedimentation rate (ESR): measures rate of RBC sedimentation of wh
ole uncoagulated blood. It reflects plasma composition. Normal: 10 mm/hr (higher
in females). High ESR acute or chronic infection, tissue necrosis, infarction,
malignancy. Use to follow disease course, differentiate diagnosis (angina
normal
ESR, MI ESR).
WBCS
WBC count: number of WBCs in whole blood. Normal: 7000 / mm3. High WBC count (le
ukocytosis)
due to infection (esp. bacterial), leukemia, tissue necrosis. Low WB
C count (leukocytopenia) due to bone marrow depression due to cancer, lymphoma o
r antineoplastic drugs. WBC differential: evaluates the distribution and morphol
ogy of WBC cell types including granulocytes (neutrophils, basophils, eosinophil
s), and non-granulocytes (lymphocytes, monocytes).

Neutrophils: may be mature or immature. Chemotaxis: congregation of neutrophils

at site of tissue damage of foreign body invasion
first line defense phagocytosi
s and degradation of invaders. Neutrophilic leukocytosis (#, fraction of immature
cells)
systemic bacterial infection (e.g. pneumonia), viral infection, fungi, s
tress (physical, emotional, blood loss), inflammatory disease (rheumatism), drug
hypersensitivity, tissue necrosis, leukemia, certain drugs (Ep, lithium). Neutr
openia (#, < 1000/mm3)
overwhelming infection as bone marrow is unable to keep up
with demand, viral infections, chemotherapy drug reactions. Basophils: called m
ast cells in the tissues. Basophilia (#)
leukemia. Eosinophils: associated with i
mmune reactions. Eosinophilia (#) acute allergic reaction (asthma, hay fever, all
ergy), parasitic infections. Lymphocytes: critical for immunologic activity, pro
duce antibodies. Types: T and B. Lymphocytosis (#)
viral infection. Lymphocytopen
ia (#) severe debilitating disease, immunodeficiency, AIDS. Atypical lymphocytes
in infectious mononucleosis. Monocytes: phagocytic cells. Monocytosis (#) TB, bac
terial endocarditis, during recovery of acute infections.
Platelets (thrombocytes)
Smallest in size. Involved in clotting. Normal: 225,000 / mm3. Thrombocytopenia:
platelets due to disease or drugs. Moderate: < 100,000. Severe: < 50,000.
Serum enzyme tests
Creatinine kinase (CK)
Location: heart, skeletal muscle, brain tissue Use: aid diagnosis of acute MI (n
ecrosis) or skeletal muscle damage. Isoenzymes of CK: CK-MM in skeletal muscle (
major), CK-MB in heart, CK-BB in brain used to identify source of damage. CK-MB
heart necrosis Interference: exercise, fall, IM injection.
Lactate dehydrogenase (LDH)
LDH converts lactate to pyruvate and vice versa. Found in all cells. Isoenzymes:
1 and 2 (heart), 3 (lungs), 4 and 5 (liver, skeletal muscles). Use: aid diagnos
is of MI, liver / lung disease.
Alkaline pohsphatase (ALP)
Location: produced mainly in the liver and bones Use: serum ALP is sensitive () t
o biliary obstruction as in bile duct stone. Serum ALP due to osteoblastic activ
ity (e.g. Pagets disease, hyperparathyroidism, osteomalacia).
Asparatate aminotransferase (AST)
Formerly known as serum glutamic-oxaloacetic transaminase (SGOT) Location: mainl
y in the heart and liver. Use: AST in acute hepatitis, cirrhosis, fatty liver, p
assive liver congestion (as in CHF).
Alanine aminotransferase (ALT)
Formerly known as serum glutamic-pyruvic transaminase (SGPT) Location: mainly in
the liver Use: more specific but less sensitive than AST for liver damage. ALT
only in severe liver damage.
Cardiac troponins
Use: identify MI injury, prognosis of unstable angina. More specific than CK-MB.
Troponin T in cardiac and skeletal muscles. Tropnonin I only in cardiac muscle.
Normal: Troponin T
< 0.1 ng/ml, Toponin I < 1.5 ng/ml.

Liver function tests

Liver enzymes
Certain enzymes (LDH, ALP, AST, ALT) with liver dysfunction. They indicate only
liver damage but not ability to function
Serum bilirubin
Bilirubin is a breakdown product of hemoglobin, main bile pigment. Indirect bili
rubin (unconjugated): bilirubin released from Hb breakdown, bound to albumin, wa
ter insoluble, not filtered by glomerulus. Direct bilirubin (conjugated): Unconj
ugated bilirubin travel to the liver
separate from albumin
conjugate
actively se
cret to the bile filtered by the glomerulus. Normal values: Total bilirubin
0.5
mg/dl. Direct bilirubin 0.1 mg/dl. bilirubin tissue deposition
jaundice. Causes:
hemolysis, biliary obstruction, liver cell necrosis. Hemolysis: total but not d
irect bilirubin. Normal urine. Biliary obstruction: may be intra-hepatic (e.g. d
ue to chlorpromazine), or extra-hepatic (biliary stone)
total and direct bilirub
in. Bilirubin present in urine dark color. Liver cell necrosis: due to viral hep
atitis total and direct bilirubin. Bilirubin present in urine
dark color.
Serum proteins
Normal total serum protein level: 7 g/dL. Transport agents. Albumin: made in the
liver (liver disease albumin ) Globulin: albumin compensatory in globulin.
Urinalysis
Appearance
Normal urine: clear, pale yellow to deep gold color. Red urine: presence of bloo
d or phenolphthalein (laxative) Brownish-yellow urine: presence of conjugated bi
lirubin.
pH
Normal urine: slightly acidic (pH = 6) Alkaline pH: due to acetazolamide use (bi
caronaturia), or due to leaving urine sample at room temperature.
Specific gravity
Normal urine: 1.015 specific gravity: DM, glucose in urine, nephrosis (protein i
n urin) specific gravity: due to diabetes insipidus ( urine concentration).
Protein
Normal: 65 mg/24 hr. Glomerular membrane prevents most blood protein from enteri
ng urine Albuminurea: abnormal glomerular permeability. Proteinuria: due to kidn
ey disease, bladder infection, fever
Glucose
Normal renal threshold for glucose: blood glucose of 180 mg/dl. Glycosuria: due
to DM.

Ketones
Usually absent in urine. Excreted when body has used available glucose stores an
d began to metabolize fat due to uncontrolled DM, or due to carbohydrate diet
onuria. Ketone bodies: betahydroxybutyric acid (major), acetoacetic acid, aceton
e.

Ket

Microscopy
Hematuria: presence of RBCs may indicate trauma, tumor, systemic bleeding. Squam
ous cells indicated vaginal contamination due to menstruation in women. Casts: p
rotein conglomerations may be due to renal disease. Crystals: pH-dependent, uric
acid crystals in acidic urine, phosphate crystals in alkaline urine. Bacteria:
usually absent in urine (sterile), if present may be due to UTI or urethral cont
amination.
Renal function tests
Renal function with age. Use results to adjust drug dosage if needed. renal func
tion urea / creatinine excretion
their blood levels. Azotemia/uremia: retention
of nitrogenous waste (BUN / creatinine) in blood. Renal azotemia: due to renal d
isease, e.g. glomerculonephritis. Prerenal azotemia: due to dehydration, protein
intake, hemorrhagic shock. Postrenal azotemia: tumors or stones in the uterers,
urethra, prostate. Clearance: volume of plasma from which a measured amount of
substance is eliminated (cleared) into urine per unit time. Use to measure glome
rular function
BUN (blood urea nitrogen)
Urea: end product of protein metabolism, produced in the liver. Urea is filtered
at the glomerulus, then 40% is reabsorbed at the tubules
urea clearance is 60%
of true GFR Normal BUN: 13 mg/dl. BUN: due to liver disease BUN: due to renal di
sease, renal blood flow, protein intake.
Serum creatinine
Creatinine: metabolic breakdown product of muscle creatine phosphate Normal leve
l: 1 mg/dl, but varies based on the muscle mass Creatinine excretion: by glomeru
lar filtration and tubular secretion. serum creatinine renal insufficiency. 50%
in GFR doubling of serum creatinine.
Creatinine clearance
Rate at which creatinine is removed from blood by the kidney. Normal value: 100
ml/min (100 ml of blood cleared of creatinine / min). Creatinine clearance paral
lels GFR, more sensitive than BUN. Creatinine clearance = (urine creatinine conc
entration x urine rate) / serum creatinine. Cockroft and Gault equation: used to
estimate Clcr based on body weight, age, gender, and serum Cr when urine inform
ation is N/A.
Electrolytes
Sodium
Major extracellular cation. Cellular osmosis and water balance: controlled by so
dium, potassium, chloride and water. Normal level: 140 mEq/L. Concentration is a
ratio of Na to water. Na
water balance not electrolyte balance. Na control: by
antidiuretic hormone (ADH) and aldosterone. Hypothalamus release ADH from pituit
ary gland
renal reabsorption of sodium.

 blood Na, blood K, angiontesin II

aldosterone (mineralocorticoid) release from ad
renal cortex Na reabsorption in exchange for K urine secretion. Hyponatremia: du
e to Na loss (kidney disease), Na intake, overhydration (non -saline fluid repla
cement, water intake), mineralocorticoid ( Na reabsorption), SIADH. Hypernatremia
: due to Na excretion, Na intake (hypertonic IV), dehydration (loss of free wate
r as in diabetes insipidus), mineralocorticoid, Na drug (Na bicarbonate, ticarci
llin).
Potassium
Most common intracellular cation. Normal level: 140 mEq/L intracellular, 4.5 mEq
/L in blood (10% extracellular
can not use that measure). Role: electrical condu
ction in heart and skeletal muscles, water balance, acid-base balance. K regulat
ion: by kidneys, aldosterone, blood pH, insulin, K intake. blood pH
blood potass
ium / blood sodium Hypokalemia: most K is lost through kidneys, due to vomiting,
diarrhea, laxative abuse, diuretics (mannitol, thiazides, loop), mineralocortic
oids, glucosuria, K intake, metabolic alkalosis / insulin / glucose (all move K
intacellularly). Signs: fatigue, dizziness, ECG, pain, confusion Hyperkalemia: d
ue to kidney elimination, K intake, cellular breakdown (tissue damage, hemolysis
, burns, infections), metabolic acidosis, potassium sparing diuretics, ACE inhib
itors.
Chloride
Major extracellular anion critical for acid-base balance. Not important clinical
ly. Only confirms Na levels. Normal: 100 mEq/L Cl retention usually happens with
Na and water retention. Anion gap = sodium (chloride + bicarbonate) Hypochlorem
ia: due to fasting, diarrhea, vomiting, diuretics. Hyperchloremia: usually due t
o metabolic acidosis, or dehydrat ion, Cl intake, renal failure.
Bicarbonate / CO2
HCO3-/CO2 is the most important buffering system to maintain pH (acid base balan
ce). Normal level: 25 mEq/L. Bicarbonate binds to hydrogen to form carbonic acid
which can convert to CO2 and water. Hypobicarbonatemia: due to metabolic acidos
is, renal failure, hyperventilation, diarrhea, carbonic anhydrase inhibitors, dr
ug toxicity (salicylate, methanol, ethylene glycol). Hyperbicarbonatemia: due to
metabolic alkalosis, hypoventilation, bicarbonate intak e, diuretics.
Minerals
Calcium
Role: bone integrity, nerve impulse transmission, muscle contraction, pancreatic
insulin release, gastric hydrogen ion release, blood coagulation. Normal level:
10 mg/dl. Ca reservoir in bones (44% calcium) maintains plasma level. 40% of ca
lcium is bound to plasma proteins (albumin) Only free unbound ionic calcium is i
mportant physiologically depends on amount of serum protein (albumin) Hypocalcem
ia: due to parathyroid hormone or vitamin D. Can be caused by loop diuretics. Hy
percalcemia: due to malignancy or metastasis, hyperparathyroidism, Pagets disease
, thiazide diuretics, Ca intake, vitamin D.
Phosphate
PO4 is a major intracellular anion
source of phosphate for ATP and phospholipids
synthesis. Normal level: 4 mg/dl. Ca and PO4 are affected by same factors
consi
der together Hypophosphatemia: due to vitamin D, hyperparathyroidism, malnutriti
on / anabolism, aluminum antacids, Ca acetate, alcoholism Hyperphosphatemia: ren
al insufficiency, vitamin D, parathyroid

Magnesium
Second most abundant intracellular and extracellular cation. Role: activates enz
ymes for carbohydrate / fat / electrolyte metabolism, protein synthesis, nerve c
onduction, muscle contraction. Normal level: 2 mEq/L. Hypomagnesemia: more commo
n, due to GI absorption, GI fluid loss, renal loss. Signs: weakness, tremor, ref
lexes, arrhythmia. Hypermagnesemia: due to Mg intake with renal insufficiency, A
ddisons disease. Signs: bradycardia, flushing, sweating, Ca.
Summary table Indicator RBC Count Hematocrit (packed cell volume) Hemoglobin Poi
kilocytosis Anisocytosis Mean corpuscular volume Normal 4.5 million/mm3 45% (~3x
Hb) 15 g/dl RBC shape RBC size 90: average RBC size, (Hct / RBC count) 35: avera
ge Hb / RBC Normal distribution 1% immature RBCs (reticulocytes) 10 mm/hr High i
n men, erythropoiesis as in hypoxemia in men, polycythemia, dehydration in men s
ickle-cell anemia folic acid, iron deficiency anemia folic acid or vitamin B12 d
eficiency anemia Low
anemia, blood loss, overhydration anemia
iron deficiency anemia hypochroma (pale RBCs), iron anemia
Mean cell Hb concentration RBC distribution width Reticulocyte count
anemia (iron, folic acid, vitamin B12 deficiency) hemolytic anemia, acute blood
loss in females, acute or chronic infection, rheumatoid arthritis, tissue necros
infection (esp. bacterial), leukemia, tissue nec
is, MI, malignancy Leukocytosis
rosis Neutrophilic leukocytosis bacteria (pneumonia), viral, fungi, stress, rheu
matism, drug hypersensitivity, tissue necrosis, leukemia Lymphocytosis viral inf
ection Basophilia
leukemia Monocytosis TB, bacterial endocarditis Eosinophilia
cute allergy, parasite infection
drug-induced aplastic anemia
Erythrocyte sedimentation rate
WBC Count
7000 / mm3
Neutrophils
Leukocytopenia bone marrow depression due to cancer, lymphoma, antineoplastic dr
ugs Neutropenia (<1000/mm3)
overwhelming infection, chemothrepay Lymphocytopenia
severe debilitating disease, immunity, AIDS
Lymphocytes
Basophils Monocytes Eosinophils
Platelet Count
225,000 / mm3
Thrombocytopenia (disease or drugs) acute MI (necrosis), skeletal muscle damage
MI injury, prognosis of unstable angina MI, liver / lung disease biliary obstruc
tion (bile duct stone), Pagets disease, osteomalacia, hyperparathyroidism Acute h
epatitis, cirrhosis, fatty liver, liver congestion (as in CHF). severe liver dam
age, less sensitive / more specific than
Creatinine kinase (CK) Cardiac troponins Troponin-T<0.1 Toponin I < 1.5 ng/ml.
Lactate dehydrogenase (LDH) Alkaline pohsphatase (ALP)

Asparatate aminotransferase (AST) (also celld SGOT) Alanine aminotransferase (AL

T) (also called SGPT)

AST Liver enzymes Total serum bilirubin (Indirect / unconjugated + direct conjug
ated) Direct serum bilirubin (conjugated) Serum proteins LDH/ALP/AST/ ALT (above
) 0.5 mg/dl liver dysfunction / damage Jaundice (hemolysis, biliary obstruction,
liver cell necrosis) biliary obstruction, liver cell necrosis ( bilirubin may al
so show in urine
dark urine) (not bound to albumin, secreted to bile, filtered)
Liver disease, nephritic syndrome, cystic fibrosis) Brownish-yellow
conjugated b
ilirubin Acidic: vitamin C, ammonium chloride diabetes insipidus ( urine concentr
ation).
0.1 mg/dl 7 g/dL
Urine color pH Specific gravity Protein Glucose Ketones RBCs Squamous cells Cast
s Crystals Bacteria Blood urea nitrogen Serum creatinine Creatinine clearance So
dium
Clear yellow to deep gold Slightly acidic (6) 1.015 65 mg/24 hr. 180 mg/dl None
None None None None None 13 mg/dl. (60% of GRF) 1 mg/dl 100 ml/min 140 mEq/L
Red blood or phenolphthalein Alkaline: acetazolamide, bicaronaturia DM, glucose
or protein (nephrosis) in urine glomerular permeability, infection, disease Glyco
suria: due to DM Ketonuria: uncontrolled DM trauma, tumor, systemic bleeding vag
inal contamination due to menstruation protein conglomerations due to renal dise
ase Acidic uric acid crystals Alkaline
phosphate UTI, urethral contamination rena
l disease, renal bl. flow, protein intake renal insufficiency Na intake, hyperton
ic IV, dehydration, diabetes insipidus, Na drug (Na bicarb), mineralocorticoid).
intake, cellular breakdown (hemolysis, burns, infections), metabolic acidosis,
K sparing diuretics, ACE-I metabolic acidosis, intake, dehydration, renal failure
metabolic alkalosis, hypoventilation, bicarbonate intake, diuretics. parathyroi
d, vitamin D, thiazides, Pagets disease, intake, malignancy, metastasis, vitamin
D, parathyroid, renal insufficiency intake, renal insufficiency, Addisons disease
.
liver disease (protein is broken to urea in liver) renal insufficiency kidney di
sease, dietary intake, water intake, overhydration, mineralocorticoid, SIADH K i
ntake, vomiting, diarrhea, laxative abuse, diuretics, glucosuria, metabolic alka
losis, insulin / glucose, mineralocorticoids fasting, diarrhea, vomiting, diuret
ics metabolic acidosis, renal failure, hyperventilation, diarrhea, carbonic anhy
drase inhibitors, salicylate, methanol parathyroid, vitamin D, loop diuretics vi
tamin D, parathyroid, malnutrition / anabolism, aluminum antacids, Ca acetate, a
lcoholism GI absorption, GI fluid loss, renal loss
Potassium
140 mEq/L (only 10% extracellular)
Chloride Bicarbonate
100 mEq/L 25 mEq/L
Calcium
10 mg/dl
Phosphate
4 mg/dl
Magnesium
2 mEq/L

38. Cardiac Arrhythmias

Introduction
Definition: deviations from the normal heartbeat pattern
cardiac output,
BP,
vit
al organ perfusion. Causes include the following. Abnormal impulse formation:
he
art rate ( autmaticity, brady- tachy-cardia), rhythm, site of impulse origin Abno
rmal impulse conduction: abnormal sequence of atrial / ventricular activation, c
onduction block / delay, re-entry (impulse re-routed through areas where it has
already traveled double-depolarization
extra impulse). Supraventricular arrhythm
ia: atuomaticity (from SA node) or re-enntry conduction. Ventricular arrhythmia:
due abnormal (ectopic) pacemaker triggering ventricular contraction before SA n
ode fires. Common in MI. Causes: heart disease (coronary artery / valvular / rhe
umatic / ischemic disease, infections), MI, drug toxicity (digitalis),
sympathet
ic tone, parasympathetic tone, vagal stimulation (stool straining),
oxygen deman
d (stress, exercise, fever), metabolic disturbances, hypertension, hyperkalemia,
hypocalcemia, COPD, thryoid .
Electrophysiology
Conduction system Two electrical sequences: 1. Impulse formation: occurs first a
s a result of automatic electrical impulse. 2. Impulse transmission: occurs seco
nd to signaling the heart to contract. SA node AV node
Bundle of His
Purkinje fi
bers Conduction system structures (see figure): tissues that can generate or con
duct electrical impulses. Sinoatrial (SA) node: main heart pacemaker, in the wal
l of the right atrium, spontaneously start action potential triggering atrium co
ntraction. Atrioventricular (AV) node: in the lower interatrial septum, delays i
mpulse briefly to allow complete atrium contraction and ventricle filling before
ventricle contraction. Bundle of His: muscle fibers from the AV junction, impul
ses travel along bundle branches. Purkinje fibers: network that ends in the vent
ricular surface
ventricle contraction. Latent pacemakers: AV node, bundle of His
and Purkinje fibers contain cells that can generate impulses but at slower firi
ng rate (called Overdrive Suppression in case of SA node damage or depression).
Myocardial action potential Depolarization and repolarization: caused due to Na
/ K exchange
in electrical potential across cell membrane. Has to occur before c
ardiac contraction. Phase 0 (rapid depolarization): rapid sodium influx to cell,
cell membrane electrical charge changes from ve to +ve. Phase 1 (early rapid rep
olarization): Na channels close, potassium leaves the cell
return to resting pot
ential. Phase 2 (plateau, absolute refractory period): more potassium out, also
calcium enters the cell, cell cannot respond to any stimulus Phase 3 (final rapi
d ventricular repolarization): more potassium ions out complete repolarization
m
embrane electrical charge back to ve. Called relative refractory period: phase 3,
responds only to strong stimuli. Phase 4 (slow depolarization): back to resting
state with potassium in and sodium and calcium out. Fast channels (sodium): in
heart muscle cells rapid depolarization. Slow channels (calcium): electrical cel
ls of SA node and AV junction
slow depolarization. Electrocardiography (ECG) (PQ
RST) P wave: atrium depolarization (activation). PR inverval: impulse spreads fr
om atria to Purkinje fibers. Delay by AV node to allow ventricle filling. by dig
italis. QRS complex: ventricular depolarization. by mexiletine, quinidine, class
IC ST segment: beginning of ventricular repolarization, phase 2 (absolute refra
ctory period), in angina

T wave: ventricular repolarization (phase 3), inverted in angina QT: ventricular

depolarization and repolarization. by quinidine, procainamide, sotalol,
Clinical evaluation
Physical findings Chest pain,
brain perfusion
anxiety / confusion, dyspnea, cyan
osis, abnormal pulse rate / rhythm, palpitations, BP, syncope, weakness, convuls
ions, urine output. Diagnostic test results ECG: a 12-lead ECG provides definiti
ve diagnosis. Electrophysiologic testing: intracardiac procedure that determines
the location of ectopic center and the need for packemaker / surgery. Probes ar
e hooked through veins and arteries
each heart segment is stimulated until arrhy
thmia occurs. His bundle study: locates origin of heart block / re-entry pattern
Laboratory findings: test for hyperkalemia or hypocalcemia.
Drugs
Class IA IB IC II III IV Other Action Sodium channel blockers, conduction Also p
rolong repolaziation (K blocker) Sodium channel blockers,
condcution Sodium chan
nel blockers,
condcution Beta blockers Potassium channel blocker
prolong action p
otential. Calcium (slow) channel blockers Drugs quinidine, procainamide, disopyr
amide lidocaine, phenytoin, tocainide, mexiletine flecainide, propafenone, moric
izine propranolol, acebutolol, esmolol Bretylium, sotalol, amiodarone verapamil,
diltiazem adeonsine, magnesium, atropine, digoxin
Class I (sodium / fast channel blockers)
Mechanism: slow sodium flow into cells during phase 0 (rapid depolarization) slo
w impulse conduction through AV node. IA prolong repolarization (refractory peri
od). IB shorten repolarization. Class IA CI: cardiogenic shock, AV block (w/o pa
cemaker). If
AV conduction: slow conduction using verapamil / digoxin. If toxic a
rrhythmia occurs: give catecholamines, glucagon, or sodium lactate. Quinidine Ci
nchona alkaloids: quinidine is an optical isomer of quinine. Quinine oral sulfat
e or gluconate salt (not preferred IM/IV).

Mechanism: Na and also K channel blocker. SE: GI upset, diarrhea (use Al hydroxi
de), Narrow therapeutic index (target 3 ug/ml). Toxicity:
conduction SA block. C
inchonism: tinnitus, hearing loss, blurred vision, photophobia, diplobia, psycho
sis. CI: AV block, prolonged QT interval (may cause torsades, quinidine syncope
and sudden death). dose in liver dysfunction and elderly. DI: cause digitalis to
xicity, severe BP with vasodilators, alkalinizers cause
toxicity. Procainamide I
V/IM (acute) and as SR orally (long term therapy). N-acetylprocainamide: active
metabolite. SE: SLE (arthlagia, myalgia, fatigue), anticholinergic,
GI upset tha
n quinidine. Narrow therapeutic index (target 7 ug/ml). Toxicity: ventricular ar
rhythmia, conduction SA block. CI: procaine hypersensitivity, myasthenia gravis,
prolonged QT interval, torsades, AV block, SLE.
dose in CHF (due to
Vd), in kid
ney or liver damage. Disopyramide SE: ventricular dysfucntion, anticholinergic (
dry mouth, constipation, etc). Targel level: 3 ug/ml. Used orally CI: AV block,
cardiogenic shock, CHF, myasthenia gravis. Class IB Lidocaine IV/IM. For arrhyth
mia due to MI and heart surgery SE: hemodynamic compromise, CNS (dizziness, resl
tessness, tremors, convulsions), tinnitus, blurred vision. Target: 4 ug/ml. Toxi
c metabolites (glycinexylidide). DI: toxicity with phenytoin and beta blockers.
Phenytoin Orally or IV. To treat digitalis-induced arrhythmia (mostly), acute MI
, heart surgery. SE: SLE, gingival hyperplasia, nystagmus, CNS (drowsiness, atax
ia, vertigo), cardiac SE. Target: 14 ug/ml. Chronic use can cause toxicity. Mult
iple drug intractions
toxicity. Hypersensitivity reactions: blood, skin, Stevens
-Johnson, and liver. Tocainide Similar structure to lidocaine except taken orall
y (avoid in lidocaine hypersensitivity). SE: CNS (dizziness, restlessness, tremo
rs, confusion), GI upset, diarrhea, blurred vision, blood. Target: 6 ug/ml. Mexi
letine Similar structure to lidocaine but
first-pass metabolism
taken orally. SE
: dizziness, ataxia, BP,
QRS complex, blood, liver. Toxicity: tremor. Target: 1
ug/ml. Class IC Prolong QRS complex, slow of phase 0 (rapid depolarization) and
slow conduction, no effect on repolarization. May
mortality due to pro-arrhythmi
c effect use is questionable. Orally. Flecainide: Use only in refractory life-th
reatening ventricular arrhythmia. SE: -ve inotropic effect (CI in CHF), CNS (diz
ziness, headache, tremor), GI upset, blurred vision. Target: 1 ug/ml. Propafenon
e: SE: dizziness, headache, GI upset, bitter taste. Target: 0.5 ug/ml. Moricizin
e: SE: dizziness, headache, GI upset. IC: CV (arrhythmia esp in MI), eye toxicit
y (blurring, diplobia)
+
+
Class II (beta blockers)
Approved drugs for arrhythmia: propranolol, esmolol, acebutolol

Mechanism: heart stimulation, AV impulse conduction, refractory period

heart rat
e, heart oxygen demand. Propranolol: IV or oral for tachy-arrhythmia due to cate
cholamine stimulation, digitalis-induced ventricular arrhythmias. SE: BP, cardia
c arrest ( AV conduction), fatigue, bronchospasm. Sudden d/c
acute MI, arrhythmia
, angina dose gradually. CI: AV block, cardiogenic shock, CHF, asthma, DB (masks
hypoglycemia). Esmolol: very short t1/2 (minutes), give IV. SE: BP, dizziness,
headache, fatigue, GI upset, bronchospasm. CI: CHF.
Class III (potassium channel blockers)
Mechanism: potassium channel blockers, prolong refractory period and action pote
ntial / repolarization. No effect on conduction or contractility. Amiodarone: or
al or IV, prophylactically to control refractory ventricular arrhythmia. Oral ef
fect may take days / weeks, very long t1/2 (2 months). Mechanism: sodium, beta,
potassium and calcium blocker properties. SE: pulmonary toxicity, eye damage, ph
otosensitivity, liver toxicity, thyroid toxicity (hypo / hyper), CNS toxicity, B
P, heart rate. DI: level / effect of many drugs (calcium channel blockers, beta
blockers, IA antiarrhythmics, digitalis, warfarin). Bretylium: quaternary ammoni
um, short term IV or IM only for life-threatening ventricular arrhythmias. SE: B
P. CI: digitalis-induced arrhythmia Sotalol: orally, also a beta blocker. SE: be
ta blocker ( BP, prolonged repolarization (QT), bronchospasm, bradycardia).
Class IV (calcium / slow channel blockers)
Use: supraventricular arrhythmias. Verpamil and diltiazem but not nifedipine are
used for arrhythmias (IV and oral). Mechanism: calcium influx in phase 2 (actio
n potential plateau, sustained depolarization), effective refractory period, dep
ress phase 4 depolarization, SA and AV conduction (dominant calcium channels) SE
: verapamil may cause constipation. CI: AV block,
BP, beta blockers, CHF / digita
ls use, MI DI: affected by and affect other drugs that are liver metabolized. Cl
ass IV: verapamil, diltiazem, block slow inward.
Unclassified antiarrhythmics
Adenosine Mechanism: naturally occurring nucleoside in all body cells. Acts on G
-protein coupled adenosine receptors AV node refractoriness
AV conduction, re-en
try through AV node. Given IV (very short t1/2, 10 seconds). SE: short-lived flu
shing, BP, sweating, palpitations, short breath, chest pressure (bronchospasm, X
theophylline). DI: antagonize methylxanthines (caffeine, theophylline) effect.
Other uses:
exercise tolerance during exercise testing. Atropine Use: IV for sym
pathetic sinus bradycardia. Mechanism: blocks vagal effects on SA node
AV conduc
tion
heart rate. Initial doses may cause reflex bradycardia. Also Digoxin: vagot
onic response of impulse generation
AV node refractoriness.
37. Coronary Artery Disease
Definition
Ischemic heart disease: insufficient supply of oxygen to the heart (oxygen deman
d > supply).

Risk factors: hyperlipidemia (cholesterol > 200 mg/dl, LDL > 130 mg/dl, HDL < 35
mg/dl), hypertension, smoking, diabetes, obesity, family history, sedentary lif
e style, chronic stress type A personality, age, male gender, oral contraceptive
s, gout. Factors that O2 demand: exercise, smoking, cold temp.
Etiology
1. blood flow: atherosclerosis with or without coronary thrombosis is the most c
ommon cause. Coronary arteries are progressively narrowed by smooth muscle cell
proliferation and accumulation of lipid deposits (plaque). Coronary artery spasm
is a sustained contraction that can occur spontaneously or induced by irritatio
n (catheter, hemorrhage), cold exposure, ergot drugs. The spasm can cause Prinzm
etal angina or MI. Traumatic injury such as impact of steering wheel on the ches
t. Embolic events can also occur abruptly. 2. blood oxygenation: blood oxygen ca
rrying capacity in anemia. 3. oxygen demand: can occur with exertion or emotiona
l stress (sympathetic stimulation). Systole: two phases (contraction and ejectio
n). Contractile (inotropic) state affects oxygen requirement. ejection time
oxyg
en demand.
Angina Pectoris
Episodic reversible oxygen insufficiency. May be caused oxygen imbalance (tachyc
ardia, anemia, hyperthyroidism, hypotension, arterial hypoxemia). . Patient comp
laints: squeezing pressure, sharp pain, burning, aching, bursting, indigestion-l
ike discomfort, radiating pain to the arms / legs / neck / shoulders / back. Phy
sical examination: usually not revealing, especially between attacks. Note histo
ry, risk factors, description of attacks, precipitation patterns, intensity, dur
ation, relieving factors. Treat risk factors: Hypertension should be controlled.
Obesity should be through diet and exercise. Smoking should be stopped, but wat
ch for anxiety. Quitting results in 50% in morality. Transdermal nicotine patche
s helps quitting over 10 weeks using decreasing doses of nicotine. Nicotine gum
and bupropion can also be used. Also, clonidine. Types Stable (classic / exertio
n) angina: most common form, usually due to a fixed obstruction in a coronary ar
tery. Triggered by exertion, emotional stress or heavy meal and relieved by rest
or nitroglycerin. The pain builds a peak radiating to the jaw, neck, shoulder,
arms and then subsides. Prinzmetals angina (vasospastic or variant angina): due t
o coronary artery spasm ( blood flow). Initially occurs at rest, pain may disrupt
sleep. Calcium channel blockers are preferred over beta blockers. Nitroglycerin
may not help. Unstable angina: due to significant coronary artery vasospasm and
platelet aggregation. Characteristics: may occur at rest, response to nitroglyc
erin, pattern change / severity. Progressive unstable angina may signal imminent
MI. Immediate hospitalization required. Nocturnal angina (angina decubitus): oc
curs in the recumbent position and is not related to rest or exertion. Occurs du
e to ventricular volume ( demand). Relieved by diuretics ( left ventricular volume
). Nitrates may improve nocturnal dyspnea. Diagnostic tests ECG: normal in 60% o
f patients. May show Q-wave, T-wave inversion, ST segment. Stress / exercise ECG
: helps diagnose patients with normal ECG. ST -segment. 201 99m Stress perfusion
imaging: with thallium or technetium sestamibi. Expensive. Pharmacologic stress
test: when coronary artery disease is suspected but patient cant exercise. Use I
V dipyridamole, adenosine ( AV conduction), dobumatime to induce cardiac ischemia
in ECG. Coronary arteriography / cardiac catheterization: very specific, sensit
ive, invasive, expensive, risky (2% mortality rate). Antihyperlipidemics Bile ac
id sequestrants: Cholestyramine chloride is a basic anion-exchange resin. Colest
ipol HCl is a copolymer. Mechanism: insoluble, nonabsorbable, hydrophilic, anion
-exchange resins bind bile acids in the intestine bile acid synthesis from chole
sterol cholesterol depletion. SE: bad taste (before

meals), GI upset, constipation, bloating, dyspepsia, other drugs absorption (e.g.

digoxin, may use in toxicity), fat soluble vitamine (ADEK) deficiency. Statins:
lovastatin, atrovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin.
Preferred in the evening. Mechanism: HMG-CoA reductase (converts HMG-CoA to meva
lonate; precursor for cholesterol)
cholesterol synthesis. SE: liver toxicity, mo
nitor creatine kinase (CK) in case of skeletal muscle complaints (myopathy, rhab
domyolysis), headache, rash. CI: fibrates / cyclosporins
risk of liver damage. F
ibric acid derivatives: gemfibrozil, clofibrate, fenofibrate (micronized prodrug
). Mechanism: synthesis / catabolism of triglycerides / cholesterol. SE: GI upse
t, liver function (monitor combined use for statins). Niacin (nicotinic acid): S
E: flushing / itching (tolerance in 2 weeks, may be with aspirin), liver functio
n, GI upset. Other drugs: probucol, eicosapentaenoic acid (EPA), docashexanoic a
cid (DHA). Probucol SE: arrhythmia, syncope. Nitrates Chemistry: Nitrites (amyl
nitrite) organic esters of nitrous acid, Amyl nitrite: very volatile, flammable
liquid, by inhalation for CN poisoning. Nitrates (nitroglycerin, isosorbide)
org
anic esters of nitric acid. Nitroglycerin: very volatile, flammable, special sto
rage, dispense in original glass container, protect from body heat, special IV p
lastic tubes to avoid absorption and loss of effect, extensive first pass effect
(use transdermal or sublingual). Dosage form: Nitroglycerin: sublingual / bucca
l tabs, topical ointment, transdermal, IV. Isosorbide mono / dinitrate: tablets.
Mechanism: fast acting, form free radical nitric oxide (NO, endothelium-derived
relaxing factor, EDRF)
activates guanylyl cyclase cGMP
dephosphorylation of myo
sin light chain muscle relaxation, venous dilation ( vascular resistance) periphe
ral blood pooling
venous return
preload (left ventricular volume) respiratory sym
ptoms (shortness of breath, nocturnal dyspnea). Also arterial pressure afterload
oxygen demand. Also some in afterload. Use: use sublinigual (up to 3 tabs in 15
minutes), transmucosal (buccal tabs / spary) or IV nitroglycerin for acute atta
cks of angina pectoris. Sublingual tabs / oral tablets / transdermals can be use
d prophylactically before known stress (eating, sex). IV nitroglycerin is used f
or emergency unstable angina. SE: may BP
reflex tachycardia / postural hypotensi
on, headache (transient, temporary, prevented by Tylenol 15-30 beforehand), dizz
iness, methemoglobinemia Nitrate tolerance: loss of efficacy, avoid by requiring
12hr nitrate free periods. Otherwise, higher doses may be required. Beta blocke
rs Mechanism: sympathetic heart stimulation (B1)
heart rate and contractility (ve inotropic / chronotropic) oxygen demand at rest / exertion, arterial blood pr
essure. Use: with nitrates to frequency and severity of exertional angina. May n
arrow coronary artery
combine with calcium blocker, avoid in Pr inzmetals angina.
Use propranolol. SE: bronchoconstriction, mask hypoglycemia (tachycardia), card
iac compensation (fatigue, shortness of breath, edema, dyspnea). Withdrawal synd
rome and angina / MI if suddenly d/c. Calcium channel blockers Mechanism: preven
t / reverse coronary spasm by calcium influx into smooth / cardiac muscle
blood
flow / oxygen supply. Also dilate arterioles and heart contractility total perip
heral resistance oxygen demand / afterload. nd Use: 2 choice to nitrates and bet
a blockers in stable angina (may combine). Critical in Prinzmetals angina / angin
a at rest. Diltiazem / verapamil / bepridil: watch for heart block / cardiac com
pensation due to ve inotropic effect. Careful with other ve inotropic drugs (beta
blockers, anti-arrhythmics). Verapamil constipation
straining and oxygen demand.
Nifedipine: peripheral vasodilation, limited ve inotropic effect. SE: hypotensio
n, tachycardia (combine with beta blocker), dizziness, edema.

Other drugs: Maximal therapy: nitrate, CCB, beta blocker combination. Morphine:
in unstable angina when nitroglycerin fails. Aspirin: use indefinitely in stable
and unstable angina. Heparin/enoxaparin/dalteparin: with aspirin in unstable an
gina.
Myocardial infarction
Severe prolonged deprivation of oxygen to part of the heart
irreversible necrosi
s. Usually due to occlusive thrombus near a ruptured atherosclerotic plaque. May
lead to ventricular fibrillation (most disorganized arrhythmia) cardiac arrest
and death (sudden death syndrome). Mortality rate: 30%. Signs and symptoms: Pers
istent severe chest pain or pressure (crushing, squeezing, elephant heavy). Pain
s beings in the chest and may radiate to the left arm, neck, leg, etc. Onset of
pain is not associated with exertion. Unlike in angina, pain persists > 30 minut
es and is not relieved by nitroglycerin. MI may be silent (no pain). Other sympt
oms: anxiety, impending doom, sweating, GI upset. Complications Lethal (ventricu
lar) arrhythmia: arrhythmias resistant to lidocaine may respond to procainamide
and bretylium. CHF: left ventricular failure pulmonary congestion
diuretics. Dig
oxin contractility, compensate for heart damage. Cardiogenic shock: due to cardi
ac output. Occurs when area of infarction > 40% and compensatory mechanisms are
ineffective. Vasopressors (alpha stimulants to BP) and inotropes may be used. Us
e vasodilators (nitropursside) to preload and afterload. Intra-aortic balloon pu
mp may be used. Diagnostic tests Because MI is life threatening emergency, diagn
osis is presumed and treatment is initiated based on complaints and immediate 12
-lead ECG. Serial 12-lead ECG: abnormalities may be absent in the first few hour
s. ST elevation. Ventricular premature beats and ventricular arrhythmia are the
most common arrhythmia. Cardiac enzymes: creatine kinase (MB-CK) is elevated wit
hin hours, peaks at 24 h and back to normal at 72 h. Cardiac troponin I and T (c
TnI, cTnT) patterns are similar to MB-CK but more sensitive. 99m Lactase dehydro
genase (LDH) use is not longer common. Cardiac imaging include tc pyrophosphate
scintigraphy, myocardial perfusion, radionucleotide ventriculography, coronary a
ngiography. Treatment: Nitrates: may chest pain anxiety and catecholamine releas
e ( coronary spasm less in oxygen demand). Morphine: causes venous pooling and pr
eload, cardiac workload, oxygen consumption (IV). Drug of choice to MI pain and
anxiety. SE: orthostatic hypotension, respiratory depression, constipation (use
docusate). Vagomimetic effect
bradyarrhythmia (if excessive
reverse using atropi
ne). Oxygen: Three liters/min via nasal cannula for chest pain, hypoxia and isch
emia Warfarin: for treatment of acute MI to mortality, prevent recurrence, compl
ications (stroke). Target INR: 2.5-3.5. Antiplatelet agents: abciximab, eptifiba
tide, tirofiban platelet glycoprotein receptors. Beta blockers: propranolol, met
oprolol, atenolol. Given in early acute MI to oxygen demand, cardiac workload, i
schemia, infarction
post MI mortality. ACE inhibitors: after MI to exercise capa
city, mortality in case of CHF, ventricular remodeling. Antihyperlipidemics: cho
lesterol MI mortality. Calcium channel blockers: avoid in acute MI or in left ve
ntricular malfunction. incidence of reinfarction. Dipyridamole: relax smooth mus
cles, coronary vascular resistance (blood flow). Also, anti -platelet action. Use
d for angina pectoris prophylaxis. SE: BP, headache, dizziness. Others: intra-ao
rtic balloon, coronary angiography, PTCA.

Thrombolytic agents Atherosclerotic plaques are made of lipids and fibrous prote
ins. Lesion rupture triggers release of serotonins, thromboxane A2 and adenosine
diphosphate alteplase
platelet aggregation
clot. The resulting fibrin traps RBC
s, platelets, plasma proteins to form thrombus. Clot dissolution is caused by co
nversion of plasminogen to plasmin mediated by plasmingoen activators. Use as ea
rly as possible (<12 h after pain starts). Absolute CI: internal / eye hemorrhag
e, intracranial / intraspinal injury, pregnancy, aneurysm, hypertension. Recombin
ant tissue plasminogen activator (t-PA): front-loaded regimen (IV bolus then inf
usion). Streptokinase (SK): SE: systemic antibody formation
chances of refractor
y response and allergy if repeated within 6 months (avoid if unknown). Monitor f
or bleeding, reperfusion arrhythmia (within 30 min), hypotension, anaphylaxis. O
ther thrombolytic agents: reteplase, tenecteplase, anisoylated plasminogen strep
tokinase activator complex (APSAC). Post thrombolysis adjunctive therapy: antipl
atelet and anticoagulant therapy after reperfusion to prevent reoccolusion, isch
emia and reinfarcation. Aspirin: during thrombolyic therapy post-infarct mortali
ty. Also: clopidrogel, ticlopidine, dipyridamole. Heparin: with thrombolytics to
prevent reocclusion after reperfusion, mortality in MI. Give bolus then infusio
n. Goal: maintain APTT (activated partial thromboplastin time) at 1.5 20 times c
ontrol. Avoid combining with streptokinase ( bleeding). Give SC, but not IM. Alte
rnatives: MWt heparins (enoxaparin, dalteparin).
39. Hypertension
Pathophysiology
Arterial pressure = cardiac output X Peripheral Resistance Cardiac output = hear
t rate X stroke volume Conditions that increase stroke volume: fever, aortic reg
urgitation, thyrotoxicosis Starling s Law: ventricular stretch
myocardial contra
ctility blood volume returning ventricular dilation Initiators of baroreceptor r
eflexes: stretch receptors located in the wall of large chest and neck arteries
Causes of hypertension: Cushing s disease, oral contraceptives, acromegaly, poly
cystic kidney disease Hypertension of unknown etiology: essential hypertension,
toxemia of pregnancy, acute intermittent porphyria Essential hypertension: unkno
wn cause (90% of cases). Chronic vasoconstriction ( tone). Endocrine hypertension
: pheochromocytoma (tumor causing in catecholamine release) Renal hypertension:
chronic pyelonephritis. Neurogenic hypertension: familial dysautonomia Other cau
ses: aortic coarctation Factors causing systolic hypertension with wide pulse pr
essure: stroke volume. aortic compliance Anesthetized patients receiving antihyp
ertensives responses to body position changes and acute blood loss, altered respo
nses to sympathomimetic drugs Perioperatively: antihypertensive drug treatment s
hould be maintained Rapid increases in BP vagal center excitation
negative iontro
pic effect ( contractility), negative chronotropic effect ( heart rate). Africans:
use Ca channel blockers and diuretic (CaD) (ACE inhibitors/beta blockers less ef
fective) Generally, avoid prescribing two drugs from the same therapeutic class.
Effectiveness of antihypertensive drugs is highly unpredictable, requires dose/
drug adjustments. Withdrawal antihypertensives gradually to reduce SE (e.g. MI w
ith b-blocker) Elderly: esp. vulnerable to CNS SE, orthostatic hypotension. Lowe
r doses may be needed.
Diuretics
Use: recommended (with beta blockers) as initial therapy for BP. Diuretics are a
lso used for CHF, edema, fluid retention. Precaution: take during the day to avo
id interruption of sleep due to frequent urination. May raise lithium level (CI)

Thiazide diuretics
Examples: Chlorthiazide, hydrochlorthiazide, cyclothiazide, polythiazide, trichl
ormethiazide, methyclothiazide, hydroflumethiazide, benzthizide, bendroflumethia
zide, chlorthalidone, metolazone, indapamide. Structure: most are related to sul
fonamides. + Mechanism: Act on Na /Cl co-transporter at the distal convoluted tu
bule. Other actions: directly dilate arterioles, total fluid (extravascular) vol
ume, cardiac output. Effects: + 1. urinary excretion of Na / water due to Na / C
l reabsorption + 2. urinary excretion of K and bicarbonate
hypokalemia potassium
dietary intake, use supplements / potassium sparing diuretics 3. blood glucose (
hyperglycermia, care with diabetics), uric acid retention (hyperuricemia, care w
ith gout), serum lipids (hyperlipidemia), calcium levels (hypercalcemia) 4. effe
ct on other antihypertensives by re-expansion of extracellular / plasma volumes.
SE: electrolyte imbalance (K, Mg, Ca dehydration, postural hypotension, dizziness, h
eadache, fatigue, hypovolemic shock, arrhythmia, palpitation), metabolic alkalos
is, K muscle cramps, light sensitivity / rash (use sunscreen), uric acid / gout,
lipoproteins, BG, sulfonamide hypersensitivity. Interactions: NSAIDs (e.g. ibup
rofen) renal perfusion
effect of thiazides. Sulfasenstivity. Hyperlipidemia
risk
of coronary artery disease. Digitoxin ( toxicity due to hypokalemia) urinary Ca
excretion use for kidney stones (calcium nephrolithiasis). Metolazone: most effe
ctive thiazide diuretic. Chronic use water reabsoprtion polyuria and polydipsia in d
iabetes insipidus (ins tead of ADH) (??)
Loop (high-ceiling) diuretics
Examples: furosemide, torsemide, bumetanide (all are sulfonamide derivatives), e
thacrynic acid. Most intense, shortest duration action. Use: patients intolerant
/ irresponsive to thiazides, or with renal imp airment ( golmerular filtration ra
te). Very strong diuretics not routinely used for hypertension. Used in edema in C
HF / liver cirrhosis / kidney disease / lungs, hypercalcemia + + Mechanism: Bloc
ks Na /K /2Cl co-transporter in the thick ascending limb of Loop of Henle (lumin
al + + 2+ 2+ side) excretion of water, Na , K , Ca , Mg , Cl
metabolic alkalosis.
BG, blood lipids, uric acid. SE: dehydration, BP, hypovolemia, K, Ca, metabolic
alkalosis, uric acid, BG, lipids, tinnitus, transient hearing loss (CI aminoglyc
osides), sulfonamide hypersensitivity, blurred vision, blood toxicity, distal tu
bular hypertrophy (with chronic use). Interactions: like thiazeds NSAIDs (e.g. ibu
profen)
effect, aminoglycosides
ototoxicity, digoxin toxicity ( K).
Potassium sparing diuretics
Examples: spironolactone, amiloride, triametrene. + Use: when if K loss and not
corrected by supplements. May combine with thiazides / loops to balance potassiu
m. Least potent diuretics. Uses: prevent hypokalemia from thiazide / loop diuret
ics, edema from CHF, liver cirrhosis, hyperaldosteronism (Spironolactone). + + +
Triamterene, amiloride mechanism: block Na channels at collecting duct
Na excha
nge with K + + and H K and H excretion
alkaline urine. Triamterene SE: hyperkale
mia, headache, dizziness, uric acid, dihyrofolate reductase
methemoglobinemia in
case of alcoholic cirrhosis. CI: history of kidney stones Spironolactone: synth
etic steroidal competitive inhibitor of aldosterone at mineralocorticoid recepto
rs at the collecting duct sodium-potassium exchange
potassium excretion
alkaline
urine use in hyperaldosteronism. SE: gynecomastia, hirsutism, menstrual disrupt
ion, lethargy, hyperkalemia. Interactions: ACE inhibitors and potassium suppleme
nts risk of hyperkalemia. Renal impairment.
Osmotic diuretics
Examples: mannitol, glycerin, urea Mechanism: highly polar, water soluble inert
chemicals, freely filtered at the glomerulus but poorly reabsorbed from renal tu
bules
osmolarity of glomerular filtrate
tubular reabsorption of water
+ diuresis
water, Na , Cl , bicarbonate excretion
alkaline urine.

Use: prevent oliguria, anuria, cerebral edema, intracranial pressure, intraocula

r pressure (glaucoma). SE: headache, blurred vision. Not absorbed well by the gu
t (causes osmotic diarrhea) only given IV.
Carbonic anhydrase inhibitors
Examples: acetazolamide, related to sulfonamides Mechanism: carbonic anhydrase a
t the proximal tubules sodium bicarbonate / Na reabsorption + +
water, Na , K ,
bicarbonate excretion alkaline urine. affect due to Na reabsorption in distal si
tes Use: glaucoma (aqueous humor has bicarbonate), acute mountain sickness, alka
line urine and excretion of acidic drugs (aspirin, urate), edema. SE: hyperchlor
emic metabolic acidosis (due to bicarbonate loss), sulfonamide hypersensitivity,
CNS depression, drowsiness, fatigue, constipation, blood SE (bone marrow depres
sion, thrombocytopenia, hemolytic anemia, leukopenia, agranulocytosis)
Sympatholytics
Beta blockers
Use: recommended (with diuretics) as initial therapy, especially for patients wi
th rapid resting heart rate (atrial fibrillation, tachycardia), ischemic heart d
isease (angina pectoris, MI) Mechanism: cAMP heart contraction and rate. Other:
rennin secretion cardiac output, central in sympathetic output. Block autonomic r
eflex response (e.g tachycardia). Examples (x-olol): atenolol, , propranolol, ti
molol, acebutolol, betaxolol, bisoprolol, carteolol, metoprolol, nadolol, penbut
olol, pindolol, esmolol, labetalol, carvedilol Nonselective B1 (heart) - B2 (lun
g) blockers: propranolol, nadolol, timolol. Selective B1 (heart) blockers: ateno
lol, metoprolol, acebutolol (A.M.A.), betaxolol, bisoprolol. Less likely to mask
hypoglycemia use in DM. Intrinsic sympathomimetics (partial agonists, P.A.): pind
olol, acebutolol, carteolol, penbutolol Labetalol: beta (1/2) and alpha-1 blocke
r (racemic mixture), for hypertensive crisis due to pheochromocytoma (tumor with
catecholamines). SE: bronchospam, orthostatic hypotension, urinary retention. C
arvedilol: beta (1/2) + alpha blocker and vasodilator. Timolol: mainly for ocula
r hypertension (B1/B2). Esmolol: ultrashort duration of action, IV. Carteolol: l
ipid solubility CNS penetration. Propranolol: -ve inotrophic/chronotropic
oxygen d
emand angina Side effects, interactions, and precautions:
Withdrawal syndrome if
suddenly d/c anginal attacks, MI, rebound in BP above normal lipids, hypertrigly
ceridemia
Impotence and libido compliance
NSAIDs
may effect of beta blockers
ith neurologic disorders if drug enters CNS poor memory, depression, fatigue, le
thargy kidney blood flow
glomerular filtration. Contraindications:
Ca channel bl
ockers CHF
cardiac decompensation due to contractibility and electrical conducti
on DM may mask tachycardia (hypoglycemia), BG COPD, asthma, bronchospams (selecti
vity is dose dependent)
Peripheral vascular disease / Raynauds phenomenon vasocon
striction
Peripherial alpha-1 blockers
Examples (x-osin): prazosin, terazosin, doxazosin Mechanism: block peripheral po
stsynaptic alpha-1 adrenergic receptors
vasodilation (arterioles and veins). Fir
st dose syncope: within 60 min of first dose postural hypotension, dizziness, he
adache, palpitation, tachycardia, sweating. Minimize by starting with low dose a
t bedtime. Other SE: diarrhea, weight gain, edema, dry mouth, sexual dysfunction
. Uses: refractory BP, CHF,

Central alpha-2 agonists

Mechanism: act on central presynaptic alpha-2 inhibitory receptors to sympatheti
c flow to cardiovascular system
peripheral resistance Examples: methyldopa, clon
idine, guanabenz, guanfacine. General SE: rebound hypertension (if abruptly d/c)
, sedation, dry mouth Methyldopa: SE: hemolytic anemia (+ve Coombs test) with pro
longed use, SLE, orthostatic hypotension, fluid accumulation, fever/flu-symptoms
(due to liver damage). CI: MAOI ( methyldopa activity), hepatic disease. Safest
in pregnancy. Clonidine: safer with renal impairment. BP, heart rate. SE: depres
sion (CI: alcohol), initial then in BP (with IV). No orthostatic hypotension (ca
rdiovascular reflex blocked). Available as weekly patch. Also analgesic (alpha-2
agonist in spinal cord) and used pre-anesthetically to BP. Rapid onset, long du
ration. Guanabenz/guanfacine: SE: dizziness, heart rate. CI: other sedatives, co
ronary insufficiency, MI, hepatic/renal disease.
Postganglionic adrenergic neuron transmitter blockers
Use: SE avoid if possible, obsolete. Possibly for severe refractory hypertension
(other drugs ineffective). Guanethidine / Guanadrel: very powerful
not first cho
ice for BP. Mechanism: release norepinephrine from adrenergic nerve endings (depl
etes NEp). Does not enter CNS
not sedation. SE: sodium / water retention, orthost
atic hypotension, impotence, diarrhea. CI: cocaine/TCA effect Reserpine: Low dos
e with other antihypertensives (e.g. diuretics). Mechanism: depletes catecholami
nes centrally and peripherally. SE: drowsiness, dizziness. CI: depression (cause
nightmares, suicide), peptic ulcer.
Vasodilators
Use: last line of treatment. Do not use alone (cause heart rate, heart output, p
lasma rennin). Directly relax peripheral vascular smooth muscles. Commonly used
in hypertensive crisis (IV). General SE: tachycardia, headache, dizziness, fluid
retention, nasal congestion. CI: coronary vascular disease
the reflex cardiac s
timulation (tachycardia) will myocardial oxygen demand. Diazoxide, Minoxidil pot
assium channel activators
membrane hyperpolarization arteriolar vasodilation. Hy
dralazine
NO (EDRF)
arteriolar vasodilation. Hydralazine: dilates arteries (rena
l, cerebral). Triggers sympathetic compensatory reactions. SE: reflex (barorecce
ptor) heart rate/output (may cause angina), stroke volume, reversible systemic l
upus erythematosus (SLE) fatigue, fever
regular blood counts. Minoxidil: dilates
arteries. SE: Hypertrichosis (used to treat male pattern baldness; alopecia), t
achycardia reflex (give beta blocker), pulmonary hypertension. Diazoxide: dilate
s arteries. Quick and prolonged action. For hypertensive crisis. Nitroprusside:
dilates arteries and veins. 44% cyanide. Mechanism: reacts with oxyhemoglobin (f
orms methemoglobin), forms nitric oxide which activates guanylyl cyclase. First
choice for hypertensive crisis (IV, short duration). Use for controlled hypotens
ion during surgical anesthesia (bloodless surgery, good cerebral perfusion). Als
o for heart failure (acute/chronic). Avoid in infants. Solution in water is susc
eptible to photolysis.
Calcium channel blockers
Use: initial treatment for patients with angina, bronchospam, Raynauds disease. F
or BP in eld erly / Africans with low renin. Mechanism: block voltage-gated slow
calcium channels Ca influx
vascular smooth muscle relaxation (more for arteries)
BP. Different agents: systemic / coronary vasodilation, SA/AV nodal depression,
myocardial contractility. SE: BP, dizziness, headache, flushing, edema, beta bl
ocker effect (AV block). Amlodipine: pruritus Diltiazem / Verapamil cardiac contr
actility, AV conduction. Diltiazem: for arrhythmia and angina. Verapamil: simila
r action to diltiazem (more electrical conduction). Verapamil SE: constipation,
bradycardia. CI: beta blockers CHF / bradychardia, electrical conduction to AV n
ode. Avoid diltiazem and verapamil in patients with AV / SA node problems.

Dihydropyridines (nifedipine / nicardipine / nitredipine)

vasodilation but no ca
rdiac effects (no effect on SA / AV node) reflex sympathethetic response tachyca
rdia. SE with SR form. Second generation dihydropyridine derivatives (related to
nifedipine): amlodipine, isradipine, felodipine, nicardipine, nisoldipine. Chem
ically related to nifedipine. Selective effect on target tissues. Less reflex ta
chycardia. Nimodipine: lipid solubility enters brain for cerebral spasm
Angiotensin Converting Enzyme (ACE) inhibitors
Examples (x-pril): benazepril, captopril, enalapril, fosinopril, lisinopril, moe
xipril, perindopril, quinapril, ramipril, trandolapril, perindopril. Use: BP, di
abetes with renal problems (delays diabetic neuropathy and glomerculosclerosis),
renal disease, left ventricular dysfunction, good for CHF. Mechanism: renin-ang
iotensin-aldosterone system long term BP control. Renin (aspartyl protease)
hydr
olysis of angiotensiongen to angiotensin I. ACE (peptidyl dipeptidase) conversio
n of angiotensin I (weak peptide vasoconstrictor) to angiotensin II (potent rapi
d peptide vasoconstrictor, i.e. pressor) release of aldosterone Na/water retentio
n fluid volume. ACE blocks the breakdown of bradykinin ( cough). SE: initial dry c
ough, angioedema (skin swelling), hyperkalemia ( aldosterone K excretion), syncope
, neutropenia, proteinuria, rhinorrhea, renal damage. + + CI: effect by NSAID (e
.g. ibuprofen), renal problems, K sparing diuretics / K supplements ( hyperkalemia
). Pregnancy X. dose gradually. Enalapril: prodrug, converts to the active metab
olite enalaprilat (w/ can be used for hypertensive crisis). Lisinopril: long-act
ing enalapril analog. . Longer duration ACE inhibitors (once daily): benazepril,
fosinopril, moexipril, trandolapril, perindopril, ramipril, quinapril. Zankiren
: renin inhibitor
Angiotensin II (type I) receptor antagonists
Examples (x-sartan): candesartan cilexetil, eprosartan, irbesartan, losartan, te
lmisartan, valsartan. Mechanism: nonpeptide antagonists of angiotensin II recept
or (AT1 subtype) in vasculature, heart, kidney, brain
vasodilation, aldosterone
release from adrenal gland Na/water excretion
blood volume. Less effective than
ACE inhibitors. No effect on bradykinin. SE: hyperkalemia (monitor renal functio
n), NO cough or angioedema (unlike ACE inhibitors). + + CI: K supplements, K spa
ring diuretics, diabetics with nephropathy, CHF.
Hypertensive crisis
Definition: systolic > 200 or diastolic > 140 quick organ damage. Reduction of BP
must be gradual (15 mmHg over first hour) to avoid compromising organ perfusion
(esp. cerebral) Drugs: vasodilatos (nitroprusside, hydralazine, diazoxide, nica
rdipine, nitroglycerin), enalaprilat, adrenergic inhibitors (labetolol, esmolol,
phentolamine (alpha blocker)), fenoldopam (dopamine D1 agonist, vasodilator), t
rimethaphan (ganglionic blocker)

40. Congestive Heart Failure

Introduction
Definition: condition due the inability of the ventricle to deliver adequate qua
ntities of blood to the metabolizing tissues during normal activity or at rest.
Its called Congestive because of the edema caused by fluid backup due to poor pump
function. Etiology: common in the elderly. CHF is not an independent diagnosis a
s it is superimposed on an underlying cause (usually coronary artery disease). L
ow-output failure: metabolic demands are normal but heart is unable to deliver b
e enough blood output. This is the most common type. High-output failure: due to
metabolic demands (hyperthyroidism, anemia). Treatment goals: remove underlying
cause (drugs, anemia, hyperthyroid); relieve symptoms / pump function ( metaboli
c demand, fluid volume excess, digitalis, inotropes, cardiac transplant).
Pathophysiology
CHF
compensatory mechanisms to normalize cardiac output (stroke volume x heart r
ate) left ventricle geometry
ventricular dilation, hypertrophy, cardiac wall thi
ckness (cardiac remodeling).

Compensation
Sympathetic response: cardiac output
sympathetic activation
Ep, NEp
heart rate,
blood flow to vital organs (brain, heart). Hormonal stimulation: sympathetic blo
od flow redistribution renal perfusion
glomerular filtration rate
sodium / water
retention, activation of renin-angioensin-aldosterone system more sodium retent
ion, volume expansion. Concentric cardiac hypertrophy: ventricular remodeling. F
rank-Starling mechanism: blood volume cardiac chamber stretch to accommodate exc
ess fluid (distention) contractile force to expel fluid to the arteries.
Decompensation
Over time, compensatory mechanisms become exhausted and ineffective
viscous cycl
e of compensation compensation become self-defeating. Afterload: tension in vent
ricular muscles during contraction, amount of force needed for the ventricle to
overcome pressure in the artery, also called intravascular systolic pressure. Prel
oad: force exerted on the ventricular muscle at the end of diastole that determi
nes degree of muscle stretch, also called ventricular end diastolic pressure. As f
luid volume demand on exhausted pump fluid backup
symptoms of CHF.
Clinical evaluation
Symptoms are due to blood backing up behind the failing ventricle. Symptoms are
first related to the failing side, then to both sides. Left-sided CHF Blood cant
be pumped from the left ventricle to the peripheral circulation
left ventricle c
ant accept blood from left atrium and lung blood back up in pulmonary alveoli pul
monary edema. Symptoms: dyspnea, less effort to trigger exertional dyspnea, whee
zing cough, exertional fatigue, nocturia. Paroxysmal (sudden) nocturnal dyspnea
and orthopnea result from volume pooling in the recumbent position relieved by p
ropping with pillow or sitting upright. Physical findings: Crackles indicate air
movement through fluid-filled passages, tachycardia (early compensatory mechani
sm). Diagnostic tests: cardiomegaly (heart enlargement), left ventricular hypert
rophy, pulmonary congestion. Right-sided CHF Blood cant be pumped from the right
ventricle to the lung
right ventricle cant accept blood from right atrium and cir
culation blood back up in whole body
systemic edema.

Symptoms: tightness and swelling (fingers, skin), nausea, vomiting, abdominal pa

in on exertion due to liver enlargement. Physical findings: vein distention due
to venous pressure, tender enlarged liver, bilateral leg edema. Diagnostic tests
: liver enzymes (ALT) due to liver congestion.
Therapy
Bed rest
Advantages: metabolic needs, heart workload, heart rate and dyspnea, diuresis
uid volume. Disadvantages: venous stasis thromboembolism, risk by using anti-emb
olism stockings, leg exercises.

fl

Dietary controls
Small frequent meals with calories metabolic demand sodium (3g/d) to volume. Edu
cation patient about sodium containing products (antacids, NSAIDs, sodium bicarb
onate, baking soda, water softeners).
Drug-related actions
ejection fraction can be achieved by: 1. Directly heart contractility using inot
ropic agents: dopamine, dobutamine, milrinone, amrinone. 2. resistance to ejecti
on by relaxing peripheral blood vessels: vasodilators such as hydralazine, nitro
prusside, nitrates 3. Affecting cardiac remodeling: ACE inhibitors, beta blocker
s, vasodilators (nitrates). Addressing the underlying problem is more important
than symptoms.
Digitalis glycosides (Digoxin)
Source: Plant steroidal glycosides. Digoxin: from Digitalis lanata; Digitoxin: f
rom Digitalis pupurea; Ouabain: from Strophanthus gratus. Chemistry: Sugar (glyc
one portion) + steroidal nucleus (aglycone/genin portion) bonded with glycoside
(ether) linkage. hydroxyl groups polarity protein binding / liver biotransformatio
n / renal reabsorption duration of action. Ouabin v. short duration only IV. + + +
+ Mechanism: Inhibit Na /K ATPase
intracellular Na , intracellular K , calcium e
ntry +ve inotropic effect, CO, renal blood flow (perfusion)
deactivate RAAS
diur
esis, edema, prolongs PR interval in EKG. Also: vagal tone in SA node -ve chronot
ropic effect, CNS sympathetic flow, systemic vasoconstriction. Use: CHF, left ve
ntricular systolic dysfunction, rapid atrial fibrillations / flutter, paroxysmal
atrial tachycardia. (CI in ventricular fibrillation / flutter). Dosage forms: t
ablet, capsule, injection, elixir. Dosing: Rapid digitalization: IV in acute nee
d, steady state in 1 day. Slow digitalization: orally, steady state in 1 week. S
erum levels: first sharply and then sharply as drug enters the heart. Measure af
ter 5 hr of dosing (steady state). Target: 1 ng/ml. Potassium: antagonize digita
lis effect. potassium
digitalis toxicity. DI with potassium altering drugs (diur
etics, ACE inhibitors). Magnesium: inversely related to digitalis effect ( Mg tox
icity) (similar to potassium). Calcium: digitalis inotropic effect. calcium
arrh
ythmia. Metabolism: in the kidneys. Serum creatinine affects elimination. Toxici
ty: common due to narrow therapeutic index. Can be fatal. toxicity with quinidin
e, verapamil, amiodarone. Early: GI (anorexia, diarrhea, nausea, vomiting), CNS
(headache, confusion, delirium, muscle weakness, fatigue, visual disturbance). L
ater: ventricular fibrillation / flutter, AV block, atrial tachycardia, prematur
e ventricular contraction. Treatment of toxicity: d/c digitalis and any potassiu
m depleting drug, give potassium IV if hypokalemic, treat arrhythmia with lidoca
ine IV, cholestyramine to prevent absorption (binds digitalis), purified digoxin
-specific Fab fragment antibodies.

Inotropic drugs (IV emergency use)

Dopamine: dose: kidney blood flow, urine output. Moderate dose: cardiac output.
dose: peripheral resistance, pulmonary pressure, tachycardia. Very short t1/2. D
obutamine: similar chemical/pharmacological alternative to dopamine. Amrinone /
milrinone
bipyridine derivatives. Mechanism: inhibit phosphodiesterate (PDE) iso
zyme in heart cells
cAMP vasodilation, cardiac contractility. SE: thrombocytopen
ia, hypotension, headache. Amrinone: nonglycoside, non-sympathomimetic inotrope.
Unstable in dextrose
use saline for IV (sodium may also be a problem in CHF). M
ilrinone: renally excreted.
Diuretics
Used for all CHF patients with fluid retention / edema. Monitor fluid loss and i
n edema by following body weight Thiazides: effective, commonly used. Disadv: we
ak, hypokalemia. Loop: v. effective, orally / IV for acute pulmonary edema. Hypo
kalemia. Potassium sparing: weak, balance the hypokalemia. Aldosterone antagonis
ts: e.g. spironolactone.

ACE inhibitors
For long term, not acute, management of CHF. First line agents. Mechanism: enzym
e for converting angiotensin I to angiotensin II (potent vasoconstrictor)
total
peripheral resistance afterload. angiotensin II also aldosterone release
sodium
/ water retension
venous return and preload.
Vasodilators
Mechanism: afterload (artery dilation) / preload (venous dilation) pulmonary con
gestion, cardiac output. Nitroprusside: IV, dilates both veins and arteries. Pra
zosin: alpha-1 blocker, dilates both veins and arteries. Hydralazine: dilates ar
teries. Nitrates: dilates veins. Higher dose for CHF than for angina.
Beta blockers
For long term, not acute, management of CHF. Only carvedilol (Beta-1-2-Alpha-1 b
locker) is approved for CHF. Actions of norepinephrine: peripheral vasoconstrict
ion, sodium retention by the kidney, cardiac hypertrophy, arrhythmia, hypokalemi
a, cell death (apoptosis) due to stress.
Calcium channel blockers
No evidence of benefit in CHF symptoms. Do not use. Verapamil is particularly co
ntraindicated because of the significant ve inotropic effect. Nifidipines are les
s dangerous (no heart effect)
41. Thromboembolic Disease
Introduction
Defintion: venous thromboembolic disease (VTED) occurs when elements of the Virc
hows triad (vascular injury, venous stasis, hypercoaglate state ( protein C / S, a
ntirhombin III)) are present resulting in deep venous thrombosis (DVT) and pulmo
nary embolism (PE). Incidence: total is 500K, symptomatic is 250K. Risk factors:
patient specific (age>40, obesity, varicose veins, immobility, pregnancy, dose
estrogen, hypercoagulate state, lupus anticoagulant), illness / surgery (pelvic
/ hip / lower limb trauma or surgery or cancer, MI, heart failure, inflammatory
bowel, sepsis, kidney disease, polycythemia).

Prevention: nonpharmacologic ( venous stasis with external pneumatic compression

or graduate compression stockings), pharmacologic (anticoagulant drugs or hepari
ns).
Oral anticoagulants warfarin
Indications
Prevention of: VTED (1ry, 2ry), systemic arterial embolism in prosthetic heart v
alve or atrial fibrillation, acute MI in peripheral arterial disease, stroke and
death in acute MI, venous thrombosis, pulmonary embolism, coronary occlusion in
acute MI.
Mechanism
Chemistry: Coumarin derivatives (warfarin, dicumarol) are water insoluble weak a
cids. Chemically related to vitamin K. protein bound. liver metabolism. therapeu
tic index. Therefore, drug interactions. Mechanism: antagonists of vitamin K. red
uctase responsible for interconversion of vitamin K and its epoxide
liver produc
tion of defective ( ) vitamin K-dependent coagulant proteins or clotting factors (
2 (prothrombin), 7, 9, 10). Does not work in vivo.
PK
Warfarin is a racemic mixtuer of equal R/S forms Rapid absorption
Cmax in 90 min
utes. inter-individual variability in dose response. Used mostly orally, but als
o IV. Pregnancy X. Effect and depletion of clotting factors occurs after 3 day.
Meanwhile, use UFH or LMWH if needed (5 day overlap). Effect also take time to w
ear off after d/c. Dose: 2.5-10 mg. Duration: 3-12 months.
Monitoring
Initial daily monitoring of prothrombin time (PT) and international normalized r
atio (INR). Then frequency of monitoring gradually to every 4 weeks. PT results
are highly dependent of type of reagent. INR = patient PT / mean lab control PT.
Target: 2-3 ( risk
2.5-3.5). ISI: International Sensitivity Index, a measure of t
hromboplastin responsiveness to
in clotting factors. ISI
responsive reagent
PT ~
INR Warfarin is sensitive to metabolic enhancers / inhibitors, vitamin K. Antib
iotics GI bacterial flora
vitramin K warfarin toxicity. SE: hemorrhage / bleedin
g (treat with vitamin K, i.e. phytonadione IM/SC), skin necrosis (due to protein
C), urticaria, purpura, alopecia.
Unfractionated heparin
Chemistry: large very acidic muco-polysaccharide molecule Indications: IV/SC wit
h warfarin for proven VTED. Prevents / treats DVT, PE. Works in vivo to prevent
clotting of blood samples. Avoid IM ( hematoma). Mechanism: inhibition / inactiva
tion of thrombin (factor IIa, converts fibrinogen to fibrin clot), activated fac
tor Xa (converts prothrombin II to thrombin IIa), by antithrombin (AT) III. PK:
plasma proteins other than AT III compete for heparin binding. Short t1/2. Large
molecule
cant cross placenta safer in pregnancy. Clearance: combination of satur
able and non-saturable first-order kinetic models. Involve rapid followed by gra
dual elimination.
inter- and intra- individual variability (due to plasma protei
ns and clearance). Administration: start with a 70 units/kg loading dose for fas
t response, then continuous dose (1000 unit/hr or weight-based) SE: hemorrhage,
thrombocytopenia (common), urticaria. Antidote: protamine sulfate (ver basic pro
tein). Monitoring: measure activated partial thromboplastin time (aPTT) (patient
aPTT / mean lab control aPTT) target: 1.5-2.5, but is dependent on the reagent.
Heparin assay may also be used for monitoring.

Low molecular weight heparin

Examples (x-parin): enoxaparin (Lovenox), dalteparin, ardeparin Chemistry: fragm
ents of standard heparin produced by controlled chemical or enzymatic depolymeri
zation of heparin. Minimum 18 saccharide units. Very acidic
anions at physiologi
c pH absorption from GI. Given only parenterally as sodium salts. Heparin: mean
MWt 15K. LMWH: mean MWt 5K. Indications: prevention and treatment of venous thro
mboembolism (venous thrombosis, VTED, unstable angina pectoris, MI, surgery). Me
chanism: very similar to heparin with more effect on Xa than on IIa. PK:
binding
to heparin-binding proteins than heparin
bioavailability at
doses and more predi
ctable effect / uniform absorption. binding to endothelial cells
plasma t1/2 and
doseindependent renal clearance. SE than heparin. aPTTT can NOT be used to moni
tor effect. No approbriate assay available. Danaparoid: low MWt heparinoid. Its a
glycosaminoglycan from porcine mucosa. Similar mechanism / uses. CI: bleeding a
nd pork product sensitivity.
Lepirudin
Chemistry: recombinant DNA (almost identical to hirudin). Mechanism: thrombin (f
actor IIa) thrombogenic activity (antithrombin). Use: anticoagulant in case of h
eparin-induced thrombocytopenia. SE: cerebral bleeding, allergic/ skin reactions
.
Antiplatelet agents
Aspirin: Mechanism: dose permanent inhibition of COX
thromboxane A2. Use: mortal
ity post-MI, prevent MI reinfarction. Ticlopidine / clopidrogel: Mechanism: inte
rfere with ADP-induced platelet-fibrinogen binding glycoprotein GPIIb/IIIa recep
tor. Use: MI, stroke risk. SE: , diarrhea, rash, GI upset, neutropenia. Fab fragme
nts (Abciximab): Mechanism: monoclonal antibodies against GPIIb/IIIa receptor
pl
atelet interaction. Use: coronary angioplasty, atheroctomy. SE: bleeding, thromb
ocytopenia, antibody formation, arrhythmia. Eptifibatide / Tirofiban: Mechanism:
same as Abciximab. Use: acute coronary syndrome, coronary angioplasty. Glycopro
tein IIb/IIIa receptor antagonists fibrinogen, adhesion ligands. SE: bleeding, f
ever, headache. Dipyridamole: Mechanism: RBC adenosine, phosphodiesterase ( cAMP)
, thromboxane A2. Use: for thromboembolism prophylaxis after valve replacement.
SE: nausea, GI upset, headache, rash, dizziness. Also relax smooth muscles, coro
nary vascular resistance (blood flow). Anagrelide: Mechanism: platelet production
. Use: platelet count in thrombocythemia. SE: CHF, MI, heart block, arrhythmia.
Cilostazol: Mechanism: PDE III inhibitors
cAMP vasodilation. SE: CHF.
Thrombolytic agents
General Mechanism: conversion of plasminogen to plasmin (serine protease), which
hydrolyzes fibrin and dissolves clots. General SE: bleeding (GI / GU / intracra
nial / catheter site), and allergic reactions (skin rash, bronchospasm, edema, u
rticaria). Alteplase / reteplase (t-PA): recombinant DNA-derived tissue plasmino
gen activators (t-PA) consisting of amino acids. Called Clot Selective because it
acts on fibrin-bound plasminogen. SE: acute MI, acute pulmonary embolism. No all
ergy issues (human-derived) Streptokinase: protein derived from cultures of Grou
p C beta-hemolytic streptococci ( hypersensitivity). fibrinogen and factors 5 & 8
. Acts on bound & free plasminogen (not selective). Use: acute MI, DVT, arterial
thrombosis. Anistreplase: also called Anisolyated Plasminogen Streptokinase Acti
vator Complex, APSAC . Prodrug, activated in vivo by deacylation. Use: acute MI,
coronary arterial thromobi. SE: arrhythmia, BP Urokinase: two-chain serine prote
ase from cultured human kidney cells. Mechanism: enzymatically active (plasminog
en plasmin). Use: coronary arterial thrombi, pulmonary embolism.

42. Infectious Diseases 43. Seizure Disorders 44. Parkinsons disease

Disease state and pathology
Slowly progressive degenerative neurologic disease. Incidence: over 50 years of
age (mostly 60s)= 0.1%. Pathogenesis: Depigmentation of substantia nigra. Loss of
dopaminergic input to the basal ganglia (extrapyramidal system) which is respon
sible for initiating, modulating, sequencing motor activity
motor disability. Pa
rkinsons is due to imbalance between dopamine (inhibitory neurotransmitter, ) and
acetylcholine (excitatory neurotransmitter, ). Diagnosis: depends on clinical fin
dings, tests to rule out secondary cause, PET scan to visualize dopamine uptake
in substantia nigra and basal ganglia.
Etiology
Primary (idiopathic): called classic Parkinsons or paralysis agitans. Most common
. Incurable disease. Can be due to absorption of highly potent neurotoxins (CO,
manganese solvent, MPTP) or exposure to cell toxic hydrogen peroxide and free ra
dicals; both products of dopamine catabolism. Secondary: small percentage, usual
ly curable. Drugs: dopamine antagonists / antipsychotics (phenothiazines (chlorp
romazine, perphenazine), haloperidol, reserpine). Toxins: CO, heavy metals (mang
anese, mercury, MPTP). Infections: syphilis, encephalitis. Others: Wilsons diseas
e, arteriosclerosis. Pseudo-Parkinsons: due dose of older (traditional) antipsych
otic agents, more in the elderly
Signs and symptoms
Tremor: initial complaint. Most evident at rest (resting tremor) and with
freque
ncy movement. Pillrolling tremor: involve thumb and forefinger. Action tremor: w
ith activity. Limb rigidity: ratchet-like movement when limb is moved passively
Akinesia (difficult) / bradykinesia (slow): including masked-face (fixed express
ion) with spontaneous emotional responses. Postural difficulty: walking with sto
oped, flexed posture,
arm swing in rhythm with the legs. Mental status: depressi
on (50%), dementia (25%), psychosis. 2ry disease effects: cardiovascular (orthos
tatic hypotension, arrhythmia), GI (constipation,
salivation), urinary frequency
, impotence, hallucinations. Unified Parkinsons Disease Rating Scale (UPDRS): use
d to monitor disease progress and evaluate drug efficacy. Includes: mental statu
s, behavior, mood, daily activities (speech, swallowing, walking, etc), clinicia
ns motor evaluation (speech, mobility, tremor, etc).
Treatment:
Non-drug: Exercise / physical therapy: very beneficial for mobility and mood. Nu
trition: to
risk of poor nutrition, weight loss, muscle mass.
fiber and fluid in
take to prevent constipation. calcium to preserve bone structure.
antioxidants (
e.g. vitamin E) to oxidative stress. Psychological rehabilitation: support for p
atient, family. May need to treat depression, dementia. Drugs: TCA (anticholiner
gic, dopaminergic, for depression). Beta blocker (propranolol,
lipid solubility)
, BZD, primidone for action tremor. Diphenhydramine: antihistamine with antichol
inergic effect for mild tremor (CNS SE, avoid in elderly). Principles of therapy
: if drug fails
use another class, except bromocriptine and pergolide (try both
in sequence). Build dose gradually up. Never d/c drug suddenly. Late disease dis
abilities: Levodopa
motor fluctuation, dyskinesia, response
control by changing
dose and timing. Non-levodopa: urinary urgency oxybutynin, constipation
fiber /
PEG, salivation
antihistamines / anticholinergics, sweating
beta blocker / antic
holinergic, orthostatic

hypotension
desmopressin, pain amitriptyline, depression / dysphagia
liquid levo
dopa, daytime sleepiness selegiline. Definitions: Dyskinesias: reversible jerky
movements. On-off effect: oscillations in response and sudden changes in mobilit
y from no symptoms to full symptoms within minutes. End-dose (wearing-off) effec
t: may improve by shortening the dosing interval. Drug holiday: temporary d/c of
levodopa to reverse down-regulation of dopamine receptors and regain efficacy.
Individual drugs
Anticholinergic agents
Examples: benztropine, trihexyphenidyl (both structurally related to atropine),
biperidene, procyclidine, orphenadrine. Use: mild symptoms, esp. tremors (not br
adykinesia / pos. imbalance). Mechanism: block action of acetylcholine in basal
ganglia. SE: dry mouth,
sweating (
heat tolerance), urinary retention, constipati
on (use stool softener), delayed gastric emptying, intraocular tension, GI upset
, dizziness, agitation, hallucinations, hypotension. CI: obstructed GI or GU, gl
aucoma, cardiac disease. Avoid drugs with anticholinergic activity (antihistamin
es, antidepressants, phenothiazines),
digoxin level. Avoid combo with haloperido
l ( tardive dyskinesia severeity, schizophrenia,
haloperidol level).
Dopamine precursor (Levodopa/carbidopa)
Most effective. effect / SE in 4 years. Dopamine cant cross BBB (not used). Mecha
nism: Levodopa: converted by dopa decarboxylase to dopamine
dopamine in CNS (cro
sses BBB). Carbidopa: levodopa analog that does not cross BBB
peripheral decarbo
xylation of levodopa
peripheral SE,
CNS bioavailability, dose needed by 75%. SE:
due to peripheral conversion to dopamine (GI upset, arrhythmia, postural hypote
nsion). Others: hallucinations, psychosis, blood dyscriasis, GI upset, insomnia
CI: glaucoma, may activate malignant melanoma. Pyridoxine (vit B6)
peripheral de
caroxylation effect. MAOI hypertension. TCA / Food
absorption. Metoclopramide:
le
vodopa level. General dopamine agonist SE: BP, syncope, arrhythmia, insomnia, ha
llucinations, psychosis.
Direct acting dopamine agonists
Ergot alkaloids (ergolines): bromocriptine, pergolide. Others: pramipexole, ropi
nirole. All mimic dopamine effect (direct agonist). Bromocriptine SE: first-dose
cardiovascular collapse (postrual hypotension, fainting, tachycardia, dysrhythm
ias, dizziness), hallucinations, pulmonary toxicity, GI upset. V. long t1/2. res
ponse variability. Pergolide Mechanism: semisynthetic ergosine derivative. 1000x
more potent than bromocriptine. prolactin,
LH,
growth hormone. SE: dysrhythmias
, BP, hallucinations, insomnia, GI upset CI: 90% protein bound (cautious with ot
her protein bound drugs), antipscychotics contradictory effects. Non-ergot dopam
ine agonists Examples: pramipexole, ropinirole Mechanism: bind to dopamine D2/D3
receptors. Also, antioxidant/O2 free radical scavenger, moderate antidepressant
. Start dose and gradually to titrate best balance of efficacy / SE. Also d/c gr
adually. levodopa dose if used together. SE:
compared to non-selective agonists
(motor fluctuations, dyskinesia). Orthostatic hypotension, syncope, bradycardia,
hallucinations, GI upset,

CI: liver metabolism. pramipexole: cimetidine

abolism, ciprofloxacin metabolism.

clearance. Ropinirole: smoking

met

Indirect acting dopamine agonists

MAO-I: Selegiline Mechanism: MAO-B selective inhibitor
catecholamine (dopamine)
breakdown in the brain (MAO-A is in the GI, MAO-B is in the brain). Used when le
vodopa wears off. Only MAO-A metabolizes tyramine (exogenous amine in beer, wine
, cheese, smoked meat) hypertensive crisis if inhibited. SE: hypertensive crisis
(possibly with tyramine but risk),
levodopa SE, dizziness, hallucinations, inso
mnia, orthostatic hypotension, syncope, arrhythmia, GI upset/bleeding. CI: meper
idine, other opioids. Catechol-O-methyltransferase (COMT) inhibitors Examples (x
-capone): tolcapone Mechanism: Selective reversible inhibitor of COMT; main enzy
me for peripheral and central metabolism of catecholamines including levodopa to
O-methyldopa (doubles levodopa t1/2). It can be combined with selective MAO-B i
nhibitor (selegiline). SE: liver toxicity (jaundice, lethargy, fatigue, appetite
loss, clay colored feces, monitor ALS/AST), orthostatic hypotension, hallucinat
ions, diarrhea, levodopa SE, rhabdomyolysis. Amantadine Mechanism: antiviral age
nt used to prevent influenza. It dopamine pre-synaptic reuptake,
dopamine synthe
sis and release. Some anticholinergic effect ( tremor, ridigity, bradykinesia). F
ast acting drug (effect within few weeks). Drug tolerance occurs (d/c for a few
weeks or use only when needed). SE: anticholinergic SE, hallucinations, dizzines
s, seizures, CHF, reversible skin rash (livedo reticularis), blood effect, insom
nia, speech. CI: effect of anticholinergics, HCTZ/triamterene
excretion
blood le
vel.
Surgical treatment
Require needle insertion in the brain possible hemorrhage. Deep brain stimulatio
n: implant frequency electrode into target site and connect lead to SC pace make
r functional inhibition of target regions in the brain. Globus pallidus internus
pallidotomy: surgical resection of parts of the globus pallidus. Retal nigral t
ransplantation: implantation of embryonic dopaminergic cells to replace degenera
ted neuronal cells.
45. Schizophrenia
Pathophysiology
Genetic studies: 10x
in risk with family history. 50% chance in both of monozygo
tic twins. Neurophysiologic theories: mainly due to
dopamine. Serotonin and glut
amate may play a role. Dopamine may in some brain areas. Psychosocial theories:
may be triggers but not causes. Stress,
interpersonal skills, bad family communi
cations, socioeconomic factors. Population prevalence: 1%.
Diagnosis
Using Diagnostic and Statistical Manual (DSM) of Mental Disorders. Diagnosis by
exclusion after ruling out medical and mental causes of psychosis. Symptoms: del
usions, hallucinations, disorganized speech / behavior, negative symptoms (6 mon
ths + 1 month active symptoms causing social or occupational dysfunction). Types
: paranoid (delusions of grandeur or persecution), catatonic (psychomotor distur
bances), disorganized (incoherent responses), residual (history but no acute psy
chosis), undifferentiated.

No known cure. Objective is to relieve symptoms and restore function. Treatment:

pharmacotherapy, psychotherapy.
Antipsychotics
Agent selection: based on patient history and drug safety. Atypical antipsychoti
cs in new diagnosis or first episode (safer drugs). Antipsychotics are more effe
ctive for
positive symptoms. Maximum effect: 6-8 weeks. One episode
d/c graduall
y after 6 months. Multiple episodes: indefinite treatment.
Typical antipsychotics
Examples: phenothiazines (chlorpromazine, thioridazine, mesoridazine, fluphenazi
ne, perphenazine, trifluperazine), haloperidol, loxapine, molindone. Mechanism:
block dopamine (D2) activity. Cause hyperprolactinemia. Potency: potency
extrapy
ramidal symptoms.
potency
sedation, anti-cholinergic, cardiovascular SE. Efficac
y: as good as the typical drugs for the positive but not the negative symptoms.
Generally, more SE than the typical drugs. Extra-pyramidal SE Acute dystonias: s
udden muscle spasms (neck, jaw, back, eyes). Common in the first 2 days. Treatme
nt: IV/IM anticholinergic (diphenhydramine, benztropine). Akathisia: motor restl
essness, inner tension and agitation, urge to move (pacing). Common in the first
weeks or months. Treatment; anticholinergic, beta blocker, BZD. Pseudoparkinson
ism: parkinsonism induce by dopmine blockade. Common in the first weeks or month
s. Treatment: anticholinergic or switch to atyptical drug. Tardive dyskinesia (T
D): latent extrapyramidal effect (after months / years). Abnormal movement (face
, tongue, shoulders, hipds, extremities, fingers, toes, etc). Movements are fixe
d (dystonic) and rhythmic. Its due to prolonged dopamine blockade dopamine recept
or up-regulation
sensitivity to stimulation. Treatment: may be irreversible, d/c
therapy, when dose symptoms may first worsen due to dopmaine blockade and still
up-regulated receptors,
dose may initially mask symptoms but will remerge later
. Best approach is prevention (monitor). Neuroleptic malignant syndrome (NMS) Un
common but sudden onset, serious and may be fatal. Symptoms: extrapyramidal effe
cts, hyperthermia, tachycardia,
BP, incontinence. Management: d/c drug, bromocrip
tine or dantrolene (muscle relaxant), supportive therapy.
Atypical antipsychotics
Examples: risperidone, olanzapine, clozapine, quetiapine. Block serotonin more t
han dopamione-2 receptors. Less extrapyramidal SE than typicals. No hyper-prolac
tinemia. Treat negative symptoms better than typicals. Clozapine: only drug with
no EPS/TD. Only effective drug for refractory patients. However, use as last re
sort due to agranulocytosis (monitor CBC weekly). It has
anticholinergic SE.
Other condiserations
SE by recptor type: histamine H1 sedation; serotonin 5-HT
weight gain; dopamine
D2 EPS / hyperprolactinemia; muscarinic
anticholinergic / cognitive / tachycardi
a; alpha-1 orthostatic hypotension / reflex tachycardia. Rapid tranquilization:
for acute psychosis with agitation and aggression. Use injectable typical drug (
IM haloperidol). Noncompliant patient: use long acting IM drugs every 3 weeks; e
ither haloperidol decanoate or fluphenazine decanoate. Convert existing oral dos
e to its injectable equivalent. Switching drugs: cross taper and titrate ( old, n
ew). Adjunctive therapy: if 3 agent tried unsuccesfully
use clozapine or augment
ative therapy (BZD anixiolytics or modd stabilizers such as lithium, valproic ac
id or carbamazepine).

46. Mood Disorders

Mood range: depression dysthymia (dysphoria) euthymia euphoria (hypomania) mania Dysphor
ia (dysthemia): mood depression below normal range but above depression. Euphori
a (hypomania): mood elevations above normal range but below mania extreme. Euthy
mia: the range of normal fluctuation in mood Mood disorders: sustained elevation
or depression in mood that impairs ability to function in the society. Risk of
suicide:x10-20.

Major Depression
Incidence: more in women (2x men). 15-20% chance in womans lifetime. Etiology: Bi
ogenic amine theory: due to depletion of serotonin and norepinephrine. Dysregula
tion theory: cyclic nature of depression is due to impaired balance of neutrotra
nsmitters not absolute or . Familial history plays a role. Clinical depression: m
ood,anhedonia, appetite , weight , sleep , psychomotor , fatigue, worthlessness,
ild, thinking / concentration, suicidal Diagnosis: using Diagnostic and Statisti
cal Manual (DSM) IV criteria. Patient must have persistent symptoms for 2 weeks.
Treatment:
Psychotherapy, pharmacotherapy, and electroconvulsive therapy. Pharmacotherapy w
ith antiderpssants is 50-60% effective. It has three phases: acute (6 wk, resolv
e symptoms), continuation (6-9 months, prevents relapse) and maintenance (3 or >
years, prevents recurrence). Drug selection: all drugs are equally effective wi
th different mechanisms and SE. Select drug with SE profile that complements the
disease process. For example, depression with psychomotor agitation sedative an
tidepressant, depression with psychomotor retardation
activating antidepressant.
Therapy initiation: start with half of the lowest dose to minimize SE to target
range in 1-2 weeks, then titrate based on response. GRADUAL. Lag time exists be
tween therapy initiation and clinical response due to changes in postsynaptic re
ceptor sensitivity. Resolution of anxiety and insomnia in 1-2 week. Full effect
in 4-6 weeks. Serotonin syndrome: tremor, seizure, hyperreflexia, hypomania, agi
tation, fever, diarrhea, confusion. May occur when two serotonin enhancing drugs
are used concomitantly or close to each other (e.g. MAOI, SSRI). Serotonin with
drawal syndrome: lethargy, myalgia, chills, dizziness, flu-like symptoms Tricycl
ic Amines (TCA) Examples: amitriptyline, nortriptyline, protriptyline, imipramin
e, trimipramine, desipramine, doexpin Serum concentrations are established for s
ome drugs. Mechanism: blocks serotonin and norepinephrine reuptake. Also bind to
cholinergic, histaminergic, alpha-adrenergic receptors (SE). SE: anticholinergi
c (blurred vision, dry mouth, constipation, urinary retention), alpha blockade (
orthostatic hypotension), antihistamine (sedation, take at bedtime), seizure thr
eshold, ECG changes, lethal if overdoes. Not first choice for depression. Other
uses: neuropathic pain, insomnia. Monoamine oxidase inhibitors (MAOI) Examples:
phenelzine, tranylcypromine, isocarboxazid. Mechanism: monoamine oxidase
block b
reak down of biogenic amines serotonin and norepinephrine in the brain Not first
choice for depression. Only for depression with agitation, hypersomnia, anxiety
. SE: orthostatic hypotension, weight gain, edema, sexual dysfunction. Isocarbox
azid liver damage. May result in accumulation of sympathomimetic amines
hyperten
sive crisis CI with decongestants, foods with tyramines (aged cheese, wine). MAO
: 2 wk washout period before start or when D/C.

Bupropion (Wellbuterin) Mechanism: reuptake of epinephrine, serotonin, dopamine.

SE: stimulation similar to SSRI
give in the morning, seizure esp with eating di
sorders. Selective Serotonin Reuptake Inhibitors (SSRI) Examples: fluoxetine, no
rfluoxetine, sertraline, paroxetine, citalopram, demethylsertraline, fluvoxamine
(for OCD). Mechanism: selectively block serotonin reuptake
level SE: stimulatio
n and insomnia (give in the morning), GI, sexual dysfunction, (weight gain?). Ab
rupt D/C serotonin withdrawal syndrome (except fluoxetine)
D/C gradually. Metabo
lized by cytochrome P-450
drug interactions. Fluoxetine: norfluoxetine has long
t1/2 5 wk washout period after D/C. Venlafaxine (Effexor) Mechanism: reuptake of
epinephrine, serotonin, dopamine (similar to bupropion). CI: MAOI. Dose graduall
y. SE: nausea, GI (take with food), sustained hypertension (monitor BP). Trazado
ne Low dose is commonly used for insomnia with stimulating antidepressants. Mech
anism: serotonin. SE: sedation, hypotension, GI Nefazodone Structure is similar
to trazadone. Mechanism: serotonin. SE ( than trazadone): sedation, hypotension,
GI, dry mouth. Interaction: protein binding
interact with warfarin, phenytoin. C
ytochrome P-450 inhibitor drugs metabolized by P-450. Mirtazapine Mechanism: pre
synaptic alpha-2 receptors norepinephrine and 5-HT central concentration. Specif
ic affinity to 5-HT1 receptors
SE compared to SSI (no insomnia, agitation, sexua
l dysfunction). Blocks H1
sedation, and 5-HT2c appetite. SE: sedation (take at b
edtime), weight gain, dry mouth.
Bipolar disorder
Incidence: 1% of the population. More common in female teens or early 20s. Etiolo
gy: Family history in 90% (genetics). Due to imbalance and fluctuation in neurot
ransmitter levels. norepinephrine
manic episode, norepinephrine
depression. GABA
(gamma-aminobutyric acid, inhibitory neurotransmitter) mania, due to unopposed
excitatory neurotransmitters (norepinephrine, dopamine). calcium in CSF
mania. c
alcium in CSF depression. G protein: involved in signal transduction and activat
ion of other neurotransmitters. Hyperactive G protein
mood instability. Glutamat
e binding to G proteins linked to NMDA is involved. Psychosocial and physical st
ressors trigger early episodes. Diagnosis: using DSM-IV and history of mania and
depression. Mania: elevated, expansive or irritable mood for 1 week. Grandiose
ideations, expansive self-esteem, sleep, racing thoughts, distraction, psychomot
or agitation, dangerous activities. Mixed episode (mood incongruent): mania and
depression symptoms. Bipolar I: manic or mixed episode. Bipolar II: depressive a
nd hypomanic episode. Cyclothymia: depressive and manic symptoms for 2 years. Ra
pid cycling: four depressive, manic, hypmanic or mixed episodes in 12 months Cli
nical course: untreated episodes last days to months. Interval between episodes:
1-2 years. Episode sequence is unpredictable. Early onset bad prognosis.

Treatment
Acute, maintenance and continuation phases (like depression). Antipsychotics, an
tidepressants, and mood stabilizers may be used. Antipsychotics: short term ther
apy during acute mania to psychosis and agitation. Antidepressants: use for depr
ession with suicidal tendency. Use cautiously to avoid triggering mania. Lithium
First line therapy (except for mixed episodes or rapid cycling). Monovalent cat
ion like Na and K. Citrate salt
liquid, carbonate salt tablet. Food may delay ab
sorption. Take with food to avoid rapid rise in serum concentration and SE. High
ly distributed but takes 3 days
delayed response. Eliminated through the kidneys
with no metabolism. nd Mechanism: unknown. norepinephrine / serotonin, membrane
stabilization, cAMP / cGMP (2 messengers). Dose: narrow therapeutic index. Can
be used to acute mania ( and dose gradually, quick action for mania but slow for
deperssion) or preventative maintenance (mania, depression). Require Cp monitori
ng. If high dose psychosis, psychomotor agitation
give BZD or antipsychotics. SE
: . Monitor Cp. Categorized into early, long term, and toxicity. Polydipsia, polyur
ia, nocturia, dry mouth, weight gain, libido, tremors, CNS. Toxicity: use emesis
, gastric lavage, hemo- or peritoneal dialysis but not charcoal. st CI: renal fa
ilure, pregnancy 1 trimester. Interactions: drugs that serotonin serotonin syndr
ome. With BZD, antipsychotics
neurotoxicit y. Valproic Acid (VA) Indications: an
ticonvulsant that works as a mood stabilizer. Can be used in acute episodes or a
s a mood stabilizer. Forms: elixir sodium valproate, capsules
VPA, enteric coate
d tabs divalproex, injections
sodium valproate sodium SE: . Monitor Cp. Blood (agr
anulocytosis, thrombocytopenia), weight gain, liver / pancreas damage, GI upset
( in divalproex). CI: sensitive to enzyme inhibitors and inducers. CBZ Indication
s: anticonvulsant that works as a mood stabilizer. Use in bipolar if lithium fai
ls. nd Mechanism: modulate NEp and cAMP (G protein-linked 2 messenger system). S
E: CNS: drowsiness, dizziness, blurred vision, diplobia, nystagmus, confusion, h
eadache. Dose related: blood dyscrasias, dose gradually to avoid SE, GI upset (t
ake with food). Non dose related: skin SE. Metabolic enzyme inducer (drug intera
ctions, monitor Cp). Complete monitoring (blood count, live function, BUN, elect
rolytes, TSH). New Mood stabilizers (anticonvulsants) (gabapentin, lamotrigine)
Indications: both mood elevation during epilepsy. Not approved, though, for mood
stabilization (no systematic data). Lamotrigine: structure is similar to phenyt
oin and CBZ. Mechanism: block sodium-mediated release of glutamate and aspartate
, may also block GABA and Ach release. SE: dizziness, blurred vision / diplobia,
GI upset, rash / photosensitivity. Gabapentin: structure is similar to GABA (bu
t no effect on GABA). Mechanism: unknown. dose gradually. Short t1/2 frequent ad
ministration. SE: somnolence, dizziness, nystagmus, fatigue.
Other topics
Use of dual mood stabilizers Combination of lithium and CBZ or VPA. Watch for le
ukocytosis / leukopenia. Do not combine CBZ and VPA ( blood dyscrasias). May also
combine one of the three (older drugs) with one o f the two newer drugs (above).

Mood stabilizers in pregnancy nd rd Older drugs (lithium, VPA, CBZ) may cause bi
rth defects. If necessary, use lithium only in 2 and 3 trimester. If necessary,
give folic acid with VPA to risk.
47. Asthma and COPD
Asthma
Definition
Reversible chronic airway inflammation. It involves obstruction, airway responsi
veness, episodic asthma symptoms. Pathologic changes are not permanent. Classifi
cation: mild intermittent, and persistent (mild, moderate, severe) Incidence: 15
million Americans (one third children). 50% of children outgrow asthma by mid-t
eens, may return to asthma later in life.
Etiology
Allergens (pollen, dust mite, animal dander, mold, food), occupational exposures
(chemicals, flour, wood, textile dust), viral respiratory infections, exercise,
emotions (anxiety, laughter, stress, crying), irritant exposure (odors, chemica
ls, irritants), environmental exposure (weather change, cold air, smoke, sulfer
dioxide), drugs (hypersensitivity, aspirin, NSAID, cholinergics (bethanechol), a
nti-adrenergics (B blockers)). Allergic rhinitis is twice as common in asthmatic
s.
Pathology / pathophysiology
Postmortem examination: smooth muscle hypertrophy, airway plugs (inflammatory ce
lls, debris, proteins, mucus), vessel vasodilatation, inflammatory cellular infi
ltrate, collagen deposition. Major contributing processes Inflammatory cells: su
ch as mast cells, eosinophils, activated T cells, macrophages, epithelial cells
secrete mediators. Airway obstruction: due to bronchoconstriction, airway wall e
dema, mucus plug formation, airway remodeling, smooth muscle hypertrophy, hyperp
lasia. Obstruction ventilation
ventilation / perfusion (V/Q) imbalance
hypoxemia
and partial pressure of arterial oxygen (PaO2). Hyper-responsiveness: response
to stimuli due to inflammatory mediators and infiltration by inflammatory cells.
Airway inflammation: contributes to hyper-responsiveness, obstruction, respirat
ory symptoms, muco ciliary function, airway permeability to allergens / irritant
s. Autonomic neutral control: cholinergic sensitivity parasympathetic tone, refle
x bronchoconstriction. Airway remodeling: due to persistent inflammation in poor
ly controlled asthma collagen deposition and fibrosis
permanent airway abnormali
ties. Sequencing of events in asthma Triggering: exposure to trigger (allergen,
aspirin, virus, etc) antigen binds to IgE
attach to activated mast cells. Early
response: begins in < 30 min and resolves in < 2hr, blocked by beta agonist or c
romolyns. Late response: begins 6 hr after trigger, persistent airway obstructio
n, inflammation, hyperresponsiveness, occurs in 50% of cases, may last several d
ays, blocked by corticosteroids or cromolyns. Signaling: inflammatory cells (mas
t cells, lymphocytes, eosinophils, macrophages, epithelial cells) release chemic
al signals (cytokines, chemokines, eicosanoids, leukotrienes)
attract more infla
mmatory cells. Migration: influx of inflammatory cells (eosinophils, lymphocytes
, monocytes, granulocytes); adhesion molecules attract cells to the airways. Cel
l activation: required before cells can release inflammatory mediators. Eosinoph
ils activation inflammatory mediators
smooth muscle constriction, initiate chemo
taxis. Leukotrienes

bronchoconstriction, mucus, vascular permeability, responsiveness. Other mediato

rs recruit more inflammatory cells to the airways in the late asthmatic response
. Tissue stimulation and damage: due to release of inflammatory mediators from a
ctivated cells. Epithelial damage
airway responsiveness
may cause remodeling.
Clinical evaluation
Physical findings Acute exacerbations: occur suddenly or gradually, usually at n
ight or early morning. Shortness of breath, tachypnea, tachycardia, wheezing at
end of exhalation, chest tightness, cough. Chronic poorly controlled severe asth
ma: chronic hyper-inflation, barrel chest. Signs of respiratory distress: cyanos
is ( PaO2 / PaCO2), use of accessory muscles, inability to speak in sentences, me
ntal status, PEFR < 50% of normal. Potentially fatal asthma: history of sudden s
evere exacerbations, poor self-perception of asthma, history of intubation or IC
U admission, visits to ER or hospitalization for asthma, frequent beta agonist u
se (>2 canisters / month). Diagnostic tests Pulmonary function tests: determine
degree of obstruction, may be normal between exacerbations. Forced expiratory vo
lume in 1 second (FEV1): during exacerbation. Air trapping and lung hyperventila
tion residual volume (RV), total lung capacity (TLC). Peak expiratory flow rate
(PEFR): correlates with FEV1, used to monitor therapy, triggers, need for emerge
ncy care. Measure PEFR in early morning before medications, and may be again mid
day. Diurnal variation > 20% in PEFR indicate responsiveness, and poor control.
Blood analysis: WBC count during acute exacerbation, eosinophilia, leukocytosis
(due to WBC demargination due to corticosteroids). Sputum analysis: may reveal e
osinophils, clumps of epithelial cells, bacterial if infected, mucous in small a
irways. Pulse oximetry: noninvasive measure of degree of hypoxemia during acute
exacerbation. It measures oxygen saturation in arterial blood (SaO2) and pulse.
Arterial blood gas: help gauge the severity of exacerbations. Early stages
hyper
-ventilation PaCO2
fatigue of respiratory muscles. Respiratory acidosis: poor pr
ognostic sign
respiratory fatigue
respiratory rate PaCO2. ECG: may show sinus ta
chycardia, especially in the elderly. Chest radiograph: may show pneumonia, hype
rinflation. Allergy skin and radioallergosorbent test: identify possible allergi
c triggers.
Complications
Status asthmaticus: severe asthma exacerbation that fails to respond to therapy
life threatening. Symptoms: consciousness, cyanosis, PaCO2, PEFR < 100 L/min or
FEV1 < 1 liter. Treatment: oxygen, inhaled beta agonist, anticholinergic, IV ste
roids. If respiratory acidosis tracheal intubation, mechanical ventilation. Pneu
mothorax: acute exacerbation with air accumulation in the pleural space. Symptom
s: chest pain, dyspnea, cough, anxiety, lung collapse. Treatment: oxygen, pleura
l air aspiration, analgesics. Atelectasis: airway obstruction
gas exchange durin
g respiration collapsed lung. Symptoms: worsening dyspnea and anxiety, hypervent
ilation, breath sounds, cyanosis. Treatment: postural drainage, chest percussion
, coughing / breathing exercise, bronchodilators, bronchoscopy to remove secreti
ons.
Therapy principles
Acute exacerbations At home: depends on EFV or PEFR. If < 50% of personal best a
ggressive treatment. Limit inhaled albuterol to 3 treatments of 3 buffs by MDI a
t 20 min intervals or one nebulizer treatment. If response is poor use oral cort
icosteroid, go to ER if needed. In the hospital: inhaled albuterol, mechanical o
xygen ventilation (up to 90% saturation), anticholinergic, oral or IV corticoste
roids, intubation.

Persistent asthma Step-down approach: aggressive. Start treatment one step above
assessed severity for rapid control, review every 3 months. Then, do gradual st
ep-wise reduction in treatment. Step-up approach: start treatment at the same st
ep as assessed severity, and adjust upward as needed. Always, control environmen
t to avoid triggers. If daily or use of inhaled albuterol
consider long-term the
rapy (e.g. anti-inflammatory). A rescue course of systemic corticosteroids may b
e used. Exercise-induced bronchospasm (EIB) Warm-up period helps prevent EIB. Pr
event EIB by using short acting beta agonist (albuterol) 15 min before exercise,
long acting beta agonist (salmeterol) 45 min before exercise, or cromolyn sodiu
m 1 hr before exercise. Keep albuterol handy. Chronic asthma (NIH guidelines) Se
vere persistent: dose inhaled steroid + dose oral steroid + long acting bronchod
ilator (inhaled or oral salmeterol, SR theophylline). Moderate persistent: inhal
ed steroid + long acting bronchodilator for nigh time symptoms (inhaled or oral
salmeterol, SR theophylline) (drop oral steroid). Mild persistent: only one of t
he following: dose inhaled steroid, inhaled cromolyn, SR theophylline, leukotrie
ne modifier. Mild intermittent: no daily medications. Albuterol for attacks.

Therapeutic agents
Beta agonists Short acting: albuterol (R- and S- isomers), levalbuterol (only ac
tive R-enantiomer), metaproterenol, pirbuterol, for acute exacerbation and EIB p
rophylaxis. Long acting: salmeterol, formoterol for asthma maintenance, EIB prop
hylaxis, nocturnal symptoms, albuterol use, COPD. Mechanism: stimulate beta 2 re
ceptors adenyl cyclase cAMP
bronchodilation, mucociliary clearance, inflammator
cell mediator release. SE: tremors (due to B2 activation in skeletal muscles),
gluconeogenesis ( glucose), activation of Na K ATPase, cardiac stimulation (due t
o partial B1 stimulation: palpitation, tachycardia), nervousness, headache. Admi
nistration: inhalation systemic SE (preferred over oral). Always use salmeterol
with in haled steroid, except for EIB prophylaxis. May combine long and short ac
ting. Tachyphylaxis: occurs due to regular use. Its due to down-regulation due to
moving of beta receptors from cell surface to inside the cell. Effect may be re
versed with steroids. Paradoxical bronchoconstriction: due to cold-Freon effect
or use of adjuvants. bronchial hyperactivity: due to irritants such as methachol
ine and histamine. May be due to albuterols S-isomer. Drug interactions: hyperten
sive crisis with MAO inhibitors, TCA and methyldopa. Beta blockers (e.g. propran
olol) bronchospasm. Combined with sympathomimetics heart effect, vasoconstrictio
n (prevent by alpha blockers, phenolamine). Corticosteroids Mechanism: Bind to g
lucocorticoid receptors in the cell cytoplasm
alter gene transcription inflammat
ory response, airway hyper-responsiveness, mucus. Use: in case of allergic compo
nent. Added only when anticholinergic / beta agonist combo is ineffective. Syste
mic steroids: used for rapid response during acute exacerbations (few hours). IV
steroids: hydrocortisone and methylprednisone. Alternative to oral steroids to
prevent respiratory arrest in hospitals. Switch to oral steroids after stabiliza
tion. Oral steroids: prednisone, prednisolone. Used in emergencies if possible w
hen there is no risk of respiratory arrest. Used in burst doses for a week. Dose
tapering may be required. Inhaled steroids: fluticasone, flunisolide, triamcino
lone, beclomethasone, budesonide. Used for chronic treatment, not for acute exac
erbations. Less SE and less efficacy. steroid penetration into bronchial tree by
giving bronchodilator several minutes prior.

Systemic steroids SE: hyperglycemia, BP, CHF, peptic ulcer, immunosuppression, c

hronic infections, osteoporosis, glaucoma, depression, psychosis, cataract, skin
changes. If long term, minimize SE by giving morning dose or alternate day dosi
ng. Inhaled steroids SE: fungal infection, voice hoarseness, dry mouth. May chil
dren growth velocity, but uncontrolled asthma also retards growth. Systemic SE w
ith large doses. Gargle and wash mouth after use to fungal infections, systemic
absorption. Interactions: enzyme inducers (rifampin, barbiturates, hydantoins)
s
teroid metabolism. Oral contraceptives, estrogens, enzyme inhibitors steroid cle
arance. hypokalemia with thiazide and loop diuretics, amphoterecin
digitalis toxi
city. Cyclosporine steroid concentration. Leukotriene modifiers Leukotrienes: de
rivatives of fatty acids formed by lipoxygenase. No ring structure. Covalently l
inked to 23 amino acids. Slow reacting substances of anaphylaxis. eosinophil and
neutrophil migration, leukocyte adhesion, neutrophil and monocyte aggregation, c
apillary permeability, smooth muscl e contraction, mucous secretion, bronchocons
triction, . Effect: anti-inflammatory and bronchodilation
steroid dose. Leukotri
ene receptor antagonists (x-lukast) Examples: zafirlukast, montelukast Mechanism
: prevent interaction of leukotrienes with receptors by cysteinyl leukotriene-1
block effect of histamine in asthma and allergy reactions. Take zafirlukast on e
mpty stomach (max absorption). SE: , can be used in children. GI upset, dizziness.
Churg-Strauss syndrome: eosinophilic vasculitis angiitus when steroids are d/c
or . DI: enzyme inhibitor, effect of warfarin / theophylline. Lipoxygenase inhibi
tor (Zileuton) Mechanism: blocks 5-lipoxygenase leukotrienes synthesis from arac
hidonic acid. SE: liver dysfunction and ALT (m onitor, esp in alcoholics). Other
s (mild): headache, GI upset, myalgia. DI: effect of warfarin, theophylline, pro
pranolol. Mast cell stabilizers (Cromolyn, nedocromil Na) Effects: Nonsteroidal
anti-inflammatory. Less effective than steroids. Used only for asthma maintenanc
e, EIB prevention. Mechanism: mast cell degranulation, inflammatory cells. SE: , u
sed in children. Wheezing, coughing, nasal congestion, throat irritation / dryne
ss. Methyl xanthines (theophylline) Use: alternative to B-agonists and steroids
in acute attacks and to long acting B-agonist in persistent asthma. Combine with
inhaled steroids control night or early morning symptoms. Effects: mucus, mucoc
iliary transport, respiration, anti-inflammatory, renal diuresis. Mechanism: pho
sphodiesterase cAMP, antagonize adenosine receptors. Less bronchodilation than B
-agonists. Oral (SR): compliance. fat tissue distribution, calculate dose based
on lean body weight. Gradually titrate dose upward. IV: rare. Start with loading
dose, then maintenance infusion. Theophylline anhydrous
oral solids, theophylli
ne monohydrate oral solutions. Aminophylline
IV. SE: palpitations, restlessness,
nervousness, insomnia, seizures, GI upset, diarrhea, dizziness. Do not use in p
regnancy. Therapeutic drug monitoring: monitor SE, serum level, other drugs use.
Clearance is age and condition specific. Interactions: multiple drug and other
interactions. clearance ( level) with smoking, protein. clearance ( level) with ag
e ( or ) , fats and carbohydrates, CHF. CI: peptic ulcer or uncontrolled seizure. An
ticholinergics Postganglionic muscarinic block bronchodilation.

Use: more effective in COPD than in asthma. Ipratropium sodium: quaternary ammon
ium compound. Used with or as an alternative to beta agonist in acute attacks. S
low onset and long duration compared to beta agonists
give regularly. SE: intrao
cular pressure if touches the eye, anticholinergic. Atropine aerosols, glycopyrr
olate (quaternary ammonium compound): rarely used due to SE and efficacy. Used i
n nebulizers Other drugs Antihistamines: if patient has allergic rhinitis. Preve
nt release of histamine mediated response that influence asthma. Antibiotics: us
ed to treat infections (change in volume, color, viscosity of sputum). Sputum cu
ltures are useless because COPD are chronically seeded. Chronic antibiotic preve
ntative used can be considered in case of frequent exacerbations. M. pneumoniae
or Legionella pneumophilia macrolide . C. nd rd pneumoniae
oral doxycycline. Pne
umonia in the hospital 2 or 3 generation cephalosporin or beta-lactam with b-lac
tamase inhibitor. Magnesium sulfate (IV): cause little bronchodilation, respirat
ory muscle strength in hypomagn esemic patients. Immunotherapy: may lung functio
n, symptoms. Non-pharmacologic Humidified O2: flow rate helps reverse hypoxemia
(use if PaO2 < 55 mmHg), esp. at night/during exercise. Goal: SaO2 > 90%. Heliox
: helium / oxygen mixture that is less dense than air
ventilation during acute a
ttack. IV fluids: and electrolytes are given if volume is depleted. Environmenta
l control: avoid allergens and triggers. Use allergen-resistant mattresses / pil
low encasements, filtration vacuum cleaners, avoid ferry pets, carpets and drape
ries. Vaccines: used to prevent infections that may trigger asthma (e.g. influen
za and polyvalent pneumococcals). Drug delivery options MDIs: accurate with good
technique and a spacer. A facemask may be needed for children. Wait 1 min betwe
en buffs. Spacers and holding chambers: drug deposition in the upper airway, ora
l absorption, local / systemic SE. Spacers are important for dose steroids or if
hand-lung coordination is poor. Nebulizers: require patient coordination. Disad
vantages: cost, time consuming, size, inconsistent drug delivery. Used in dose b
eta agonists, anticholinergics, cromolyn in children. Dry powder inhalers: more
common, avoid the use of Freon propellants, easier to use. First load the dose,
and then inhale rapidly. No spacers. Keep away from moisture.
COPD
Chronic bronchitis
Definition: excessive mucus production by the tracheo-bronchial tree edema and b
ronchial inflammation
airway obstruction. Pathophysiology: respiratory tissue in
flammation vasodilation, congestion, mucosal edema
mucus. Neutrophils infiltrati
on. Cilia impairment. Cartilage atrophy. Airways become blocked by thick, tenaci
ous mucus secretions sputum rich productive cough. Normally sterile airways beco
me colonized by Strept pneumoniae, H influenza, Mycoplasma. Recurrent viral / ba
cterial infections body defenses, mucus accumulation, ciliary activity. Airway d
egeneration
gas exchange exertional dyspnea. Hypoximia, PaCO2 (hypercapnia). Phy
sical findings: chronic productive cough after age 45 (first in winter, worse in
the morning). Progressive exertional dyspnea, obesity, wheezing, prolonged expi
ration, right ventricular failure, cyanosis (called blue bloater) Diagnostic tests
: hypoxemia
erythropoiesis polycythemia ( RBCs). WBC due to infections. Sputum: t
hick, colored (if infected), neutrophils, microorganisms. Arterial blood gas: Pa
O2 (hypoxemia), PaCO2 (hypercapnia). FEV1. Right ventricular hypertrophy and cor
pulmonale in ECG.

Emphysema
Definition: permanent alveolar enlargement and destruction of the alveolar walls
, alveolar surface area. Pathophysiology: Inflammation, mucus secretion
alveoli
air trapping. tissue damage
space into which normal lung tissue expands.. Alveol
i merge space for air trapping. Alveolar wall destruction
small airways collapse
. Hypercapnia and respiratory acidosis are uncommon because of compensatory in r
espiratory rate. Physical findings: cough is chronic but less productive than in
chronic bronchitis, starts at age 55. Exertional dyspnea is progressive, consta
nt, more severe than in bronchitis. Other findings: weight loss, tachypnea, prol
onged expiration, breath sounds. Patient usually maintain good oxygenation throu
gh tachypnea pink buffer. Diagnostic tests: small chance of AAT in blood or infect
ions in sputum. PaO2 and PaCO2 in arterial blood gas, FEV1.
Etiology
Smoking: causes pulmonary hyperactivity and persistent airway obstruction. Alpha
-1 antitrypsin (AAT) is a serine protease inhibitor
neutrophil elastase. risk of
COPD when smoking is combined with genetic ATT deficiency. Others: exposure to
irritants (sulfur dioxide, polluted air, noxious gases, dusts), family history,
social, economic factors.
Complications
Pulmonary hypertension: lung congestion pulmonary vascular bed space pulmonary h
ypertension
cor pulmonale (right ventricular hypertrophy)
right heart failure. A
cute respiratory failure: advanced emphysema brain respiratory center damage
cer
ebral oxygenation
PaCO2
hypoxia, respiratory acidosis
respiratory failure. Infec
tion: chronic bronchitis trapping of excessive air, mucus, bacteria and coughing
and deep breathing
infection. Polycythemia: in RBCs hypercoagulate state, embol
ism, stroke.
Therapy
Anticholinergics: First line treatment for COPD. Beta blockers, corticosteroids,
theophylline, O2, etc (see above) Mucolytics: such as acetylcysteine
sputum cle
arance, mucus plugs. May cause bronchospasm. Expectorants: such as guaifenesin.
Avoid potassium iodide. Chest physiotherapy: loosens secretions, re-expand lungs
, efficacy of respiratory muscle. More important in outpatient. Physical rehabil
itation: exercise tolerance and diaphragm and abdominal muscle tone. Smoking ces
sation: and avoidance of irritants. Use drugs with behavior intervention for max
imum success. Surgery: lung volume reduction therapy
48. Rheumatoid Arthritis
Introduction
Definition: chronic, systemic, autoimmune, inflammation of the synovial joint. M
ore common in women (2-3:1). 2% of the population.
Classification:
Four of the following criteria have to be met 1. Morning stiffness for 1 hour be
fore improvement 2. Three joints have fluid or soft tissue swelling 3. One joint
in the hand joints must be swollen. 4. Symmetric arthritis: involvement on both
sides of the body.

5. Subcutaneous (rheumatoid) nodules 6. serum rheumatoid factor 7. Radiological

erosion or decalcification of bones May also include extra-articular organ manif
estations (GI, infections, etc)
Etiology
Human leukocyte antigen (HLA-DR4) + environmental factor
inappropriate immune re
sponse chronic inflammation Tumor necrosis factor (TNF) in RA and Crohns disease.
Infections may ppt RA in predisposed patients, e.g., polyarthritis with lyme di
sease
Pathogenesis
Vasodilation, edema, sensation of heat, loss of function, production of thick bo
ggy synovial fluid, effusion accumulation. Pannus: exuberant synovial thickening
due to inward overgrowth of enlarged synovium across the surface of articular c
artilage cartilage degradation, bone loss, x-rayed marginal erosions, bone rubbi
ng, pain.
Clinical course
Variable and unpredictable, polycyclic course (intermittent remissions) or progr
essive course (relentless rapidly advancing destructive deforming inflammation
p
ermanent join deformities
progressive functional decline, range of motion, work
disability, loss of 4 -10 years of life expectancy. Early symptoms: aching, join
t pain, fatigue, then hand and feet synovitis (swelling, warmth, tenderness). Mo
rning stiffness: maximal pain and stiffness on awakening (30 min)
Diagnosis and clinical evaluation
Mainly clinical joint evaluation with lab and x-ray results. Rheumatoid nodules:
firm, round, rubbery masses in the SC of joints prone to pressure (e.g. elbows)
. X-ray: soft tissue swelling, osteoporosis, erosions. Laboratory findings: Rheu
matoid factors (antibodies) especially IgG and IgM, erythrocyte sedimentation ra
te due to inflammation, microcytic anemia, antinuclear antibody test. Monitoring
parameters: morning stiffness duration, number of affected joints, severity of
pain, range of motion, deformity and circumference of joints, time to walk 50 fe
et, depression, weight loss, sedimentation rate.
Therapy
Mechanical therapy
A balanced daily program of rest and exercise ( muscle strength and joint motion)
. Use lightweight splints during night (or even day) to align joints. Avoid comp
lete immobilization. Consider joint replacement.
Symptomatic pharmacological therapy
Aspirin First line agent, first as analgesic and then dose for inflammation. Dos
e: 4 -5 g daily. SE: bleeding and platelet function (7 days after d/c), tinnitus
in doses, GI ( by enteric coating or taking with food) Nonacetylated salicylates
Examples: salsalate, choline salicylate safer for aspirin sensitive patients. a
nti-inflammatory effect, respiratory SE, effect on platelets.

Other NSAID Examples: naproxen, ibuprofen, sulindac, piroxicam. May be better to

lerated than aspirin. Try for 2 weeks before change. Chemistry: x-en
propionic a
cids, others acetic acids. Avoid in asthmatics
may trigger bronchospasm. bleedin
g time / platelet function (effect reverse quickly if d/c) GI upset, ulceration,
hemorrhage ( platelets). GI ulcers by using misoprostol (Cytotec, SE: diarrhea) o
r H2-antagonists. Ibuprofen, naproxen
GI SE
available OTC. Piroxicam GI SE, CI i
n elderly. renal blood flow
renal failure (esp with diuretics or CHF). Temporary
CNS effects (headache, drowsiness, confusion, anxiety, etc) esp. with indometha
cin. Avoid in the elderly. Meclofenamate: diarrhea COX-2 inhibitors Rofecoxib, c
elecoxib, valdecoxib. Anti-inflammatory, analgesic, antipyretic with GI SE.
Second line agents
Known as Slow Acting Anti-rheumatic Drugs (SAARD) or Disease Modifying Anti-Rheu
matic Drugs (DMARD). They modulate immune response to progression of erosion. Al
l slow are acti ng (min 3 months for effect), except methotrexate. Used w/ NSAID
. All have SE. Methotrexate (Rheumatrex) First line for severe RA. Immunosuppress
ive folic acid antagonist and antineoplastic. Give a weekly dose, oral or IM. As
pirin methotrexate secretion toxicity SE: GI, bone marrow suppression, hepatitis
, infection. Give folic acid supplements. CI in creatinine < 40. Pregnancy X. Az
athioprine (Imuran) Purine analogue immunosuppressive antimetabolite. Converts t
o 6-mercaptopurine purine synthesis
cytotoxicity to dividing cells
lymphocyte pr
oliferation. SE: GI, hepatitis, bone marrow depression. Also for leukemia. 2 Ant
idote: Leucovorin Ca (tetrahydrofolic acid derivative) Gold compounds IM: gold s
odium thiomalate, aurothioglucose. SE: proteinuria. Oral: auranofin. SE: metalli
c taste, diarrhea, GI, stomatitis General SE: blood toxicity, rash. Gradual buil
d up of dose. Try for a min of 6 months Penicillamine (Depen) immune response. T
aken on empty stomach to absorption. Dosing: do low-go slow. SE: rash, fever, pr
oteinuria, hematologic, autoimmune diseases. Other drugs Hydroxychloroquine (Pla
quenil): antimalarial for mild RA. SE: Retinal toxicity (retinopathy) due to dru
g deposition in the cones
monitor for vision acuity. GI upset. Sulfasalazine (Az
ulfidine): very effective in slowing progress of joint damage. SE: GI, rash, rar
e blood dyscrasias, hepatitis Cyclophosphamide (Cytoxan): Toxic antineoplastic p
rodrug. SE: , hemorrhagic cystitis (treat with mesna), bone marrow depression, ste
rility, alopecia. Etanercept / Infliximab: TNF-alpha inhibitor TNF (cytokine) bi
nding to inflammatory cell surface. Biological Response Modifier. Given SC. SE:
respiratory infections, autoantibody formation. NO effect of kidney function. Le
flunomide: immuno-modulator. Mechanism: dihydroorotate dehydrogenase (critical f
or pyrimidine synthesis). SE: rash, diarrhea, alopecia, rash, anemia. Pregnancy
X.

Mycophenolate mofetil: immuno-suppressant. SE: diarrhea, GI, hematologic. Used t

o prevent cardiact and renal allograft rejection. Other drugs: chlorambucil, cyc
losporine, minocycline. Corticosteroids Prednisone. Last resort. They do not alt
er the course of RA. Used for acute flare ups, before action of slow acting drug
s kicks in, systemic RA symptoms, or in case of intolerance to other drugs. Can
be used as intra-articular injection if symptoms are localized. SE: GI bleeding,
slow wound healing, hyperglycemia, hypertension, osteoporosis.
Topical therapy
Capsaicin: for symptomatic treatment. Its the pungent ingredient of hot pepper. M
echanism: depletes and prevents accumulation of substance P, a chemical mediator
in pain transmission from the periphery to CNS (sensory nerve fibers). It produ
ces a sensation of warmth. Use: joint pain, arthritis tenderness, neuralgia, pso
riasis. SE: erythema (reflex vasodilation), histamine release. Counter-irritants
: methyl salicylate, menthol, allyl isothiocyanate, produce a mild inflammatory
reaction. Effect may be actually due to the massage during application not the d
rug itself.
Combination second line therapy
Step-down bridge approach: combo of antimalarial, oral gold, parenteral gold and
methotrexate. Remove medications and taper dosage after 3 months to the antimal
arial alone. Saw-tooth strategy: use second line agent early and serially substi
tutes with other agents before previous agents lose efficacy. Graduated-step par
adigm: combo therapy only for patients at active disease. Escalate treatment as
needed.
49. Hyperuricemia and Gout
Introduction
Hyperuricemia: serum uric acid > 7 mg/dl. Gout: recurrent acute attacks of urate
crystal-induced arthritis. It may include tophi-deposits of monosodium urate. I
ncidence: 1% of the population, almost all men. risk with alcoholism, obesity. U
xanthine oxidaze
urice acid (adenine and guanine are
ric acid synthesis: purine
purine bases). One gram in the body. No biological function. 66% daily turnover.
Uric acid elimination: 66% through the kidneys, 33% through the GI. At urine pH
(acidic, 4-5) poorly soluble free uric acid. At physiologic pH (7.4)
uric acid
as monosodium urate salt. Asymptomatic hyperuricemia: serum uric acid but no sym
ptoms of arthritis. May be harmless. Drug treatment may be unnecessary. May deve
lop gout later. Maintain good urine output to prevent stone formation, purine fo
ods, monitor.
Etiology
Primary: due to defect in purine metabolism or uric acid excretion. It is due to
uric acid production or renal clearance or both. Under-excretors (90%): excrete
< 600 mg/day on a purine restricted diet. Secondary: renal failure ( excretion),
hematologic diseases ( nucleic acid breakdown to uric acid). Drug induced gout:
Ethanol production and secretion. Aspirin and salicylates
uric acid tubular secr
etion ( excretion). Diuretics (except spironolactone) volume depletion / tubular se
cretion. Cyclosporine, pyrazinamide, levodopa urate renal clearance. Ethambutol,
nicotinic acid compete for urate secretion
excretion Cytotoxic drugs
nucleic ac
id turnover.

Pathophysiology
Gouty arthritis develop when monosodium urate crystals deposit in the join synov
ium
inflammatory response
gout attack
join swelling, redness, warmth, tenderness
tophi (urate deposits)
joint deformity, disability, renal impairment. Renal com
plications: Acute tubular obstruction: due to uric acid pptn in the ureters and
collecting tubes. Urolithiasis: uric acid stones due to low urine pH. Chronic ur
ate nephropathy: urate deposits in the renal interstitium.
Acute gouty arthritis
Painful arthritic attacks of sudden onset. Triggers: trauma, cold exposure. Init
ial attack is abrupt and usually occur at night or early morning very hot swolle
n, tender joints. Podagra: attack in the metatorso-phalangeal joint. Attacks las
t 1-2 weeks (longer as the disease progresses). May include fever, chills, malai
se. Diagnosis: Urate needle-shaped crystals in synovial fluid (-ve birefringence
). Serum urate, erythrocyte sedimentation rate, leukocytes. Dramatic therapeutic
response to colchicine. Acute attack pattern with remission periods.
Therapy
Immobilize affected joints. Start anti-inflammatory drugs immediately. Start ura
te-lowering drugs after attack is over. Colchicine: drug of choice for pain and
inflammation and ending the attack. Mechanism: antimitotic, chemotaxis of leukoc
yte to inflamed area, phagocytosis and urate deposition. Orally or IV (never IM
or SC due to irritation). SE: diarrhea, GI, bone marrow depression, irritation i
f given IM. NSAIDs: if first choice is colchicine is not tolerated or not starte
d immediately. Examples: indomethacin, naproxen, sulindac. SE: GI, CNS headache
and drowsiness / dizziness. Take with food. Aspirin dose uric acid secretion, do
se uric acid secretion. Corticosteroids: Methylprednisolone acetate given intraarticular with diagnostic / therapeutic aspiration. Prednisone (oral), Triamcino
lone acetonide (IM) or methylprednisolone (IV).
Intercritical gout
Symptom free period between attacks. Non-drug urate lowering: high-purine diet (
meats, legumes), obesity, alcohol. Limited effect. Prophylaxis: dose colchicine
or NSAID. Urate lowering therapy (<6 mg/dl): lifelong treatment. Allopurinol (is
opurine): production. Mechanism: xanthine oxidese ( xanthine
hypoxanthine uric ac
id). Long acting active metabolite: oxypurinol. Preferred over uricosurics in ca
se of renal impairment ( dose). SE: reversible rash ( incidence with ampicillin),
exfoliative dermatitis treat with prednisone, Stevens-Johnson syndrome. May gout
attacks if given during the attack due to mobilization of stored urate (give co
lchicine). May dissolves tophi. Uricosurics
excretion. Examples: sulfinpyrazone,
probenecid (benzoic acid derivative). Mechanism: uric acid reabsorption at the
proximal convoluted tubules. Do not initiate during acute attacks or give with c
olchicine. During the first 6-12 months may attacks. Maintain fluid intake, urin
e output and alkaline urine to risk of renal urate pptn. Build up dose gradually
. Action is antagonized by salicylates. SE: GI, blood dyscriasis (sulfinpyrazone
). CI: urinary tract stones. Chronic tophaceous gout: urate pool. Large SC tophic
. Allopurinol / probenecid combo.
50. Peptic Ulcer Disease
Introduction
Definitions
Peptic ulcer disease (PUD): circumscribed lesions of upper GI mucosa.

Gastro-esophageal reflux disease (GERD): retrograde movement of gastric contents

from stomach into esophagus. When reflux leads to inflammation and/or ulceratio
ns, its called reflux (erosive) esophagitis. Dyspepsia: persistent / recurrent, p
ain / discomfort in upper abdomen.
Manifestations
Duodenal ulcers: develop in the first cm of duodenum (bulb). Gastric ulcers: com
mon in the antrum or antral-fundal junction. Stress ulcers: from serious trauma
or illness, major burn, sepsis. Zollinger-Ellison syndrome: severe peptic intrac
table ulcer with extreme gastric hyperacidity and gastrionoma (non-beta islet ce
ll tumor). Diagnosed by fasting plasma gastrin concentration. Stomal (marginal)
ulcers: after ulcer surgery or subsequent ulcer recurrence after symptom free pe
riod. Drug-associated ulcers: chronic ulcerative drug users (e.g. NSAIDs) Reflex
esophagitis: recurrent symptoms (heartburn), altered epithelial morphology. Hear
tburn may radiate to the neck. Other symptoms: belching, chest pain, asthma, cou
gh, hoarseness, laryngitis. Epidemiology: Duodenal ulcers: 7% incidence. Gastric
ulcers: 0.05%. May have both gastric and duodenal ulcers. Onset: 30-50 years. 4
5% of the population experience heartburn once a month. 15% take indigestion dru
g twice a week. Prevalence of dyspepsia: 25% (3% of doctor consultations). Hospi
talization / mortality for peptic ulcer are . Description: Duodenal ulcers < 1 cm
diameter. Gastric ulcer: slightly larger. Edges are sharply demarcated. Surroun
ding mucosa is inflamed and edematous. Scar may form after healing. Gastric ulce
rs may be malignant (10%).
Etiology
Helicobacter pylori (campylobacter pylori): gram negative spiral bacteria with m
hydrolyzes urea i
ultiple flagella living in the gastric mucosa. Produces urease
nto ammonia
neutralizes gastric HCl
bacteria survives. H pylori prevalence with
age. 15% of positive persons develop ulcer. H pylori is present in 90% of gastri
c and duodenal ulcer and cancer cases. Eradication may help ulcers and dyspepsia
. Genetics: ulcer prevalence with first degree relative is 3x the normal rate. M
ay be due to H pylori presence. Blood type O have incidence. + NSAIDs: chronic u
se COX-I
PG synthesis (cytoprotective to mucosa). Also, allow H back diffusion i
nto mucosa injure mucosa Smoking: incidence of ulcer, ulcer healing and incidenc
e of relapse. Nicotine biliary and pancreatic bicarbonate secretion, stomach emp
tying into the duodenum. Alcohol: known mucosal irritant, especially at concentr
ations > 20%. Coffee: peptides in regular and decaf coffee
gastrin release
gastr
ic juice flow. A direct coffeeulcer link is not proven. Associated disorders: in
cidence with hyper-parathyroidism, emphysema, rheumatoid arthritis, alcohol cirr
hosis. Advanced age: pylorus degradation bile reflux into the stomach
ulcers. Co
rticosteroids: NO link between corticosteroids and ulcers. Psychological factors
: minor factor, contrary to the opposite belief.
Pathophysiology
Ulcers occur due to imbalance between factors protecting gastric mucosa and fact
ors causing mucosal corrosion. Protective factors: thick mucosal mucus is a barr
ier between luminal acid and epithelial cells. This barrier inward movement of h
ydrogen ions and allow neutralization by bicarbonate ions in fluids secreted by
the stomach and duodenum. Alkaline and neutral pancreatic biliary juices buffer
acid entering duodenum from the stomach. Corrosive factors: gastric mucosa is un
able to resist corrosion by irritants such as HCl and pepsin. Mucosal barrier ma
y not be intact. Physiologic factors: Duodenal ulcer: gastric emptying rate, pos
t-prandial acid secretion, serum pepsinogen I, pepsin secretion, # of acid produ
cing parietal cells. Gastric ulcer: gastric emptying rate, mucosal resistance, s
erum gastrin, mucosal PG.

GERD: reflux occur via transient lower esophageal sphincter relaxation (TLESR).
People with GERD
TLESR frequency. Dyspepsia: caused by PUD, GERD, gastric cancer
, biliary tract disease.
Clinical presentation
Only 50% of patients experience classic ulcer symptoms. Pain: heartburn, aching,
burning, cramping. May be due to chemical stimulation or spasm. Duodenal ulcer
pain: more localized and often peaks between 12-2 AM. Gastric ulcer pain: less l
ocalized. Food: may duodenal ulcer pain but gastric ulcer and GERD pain. So, duo
denal ulcer patients may gain weight and gastric ulcer patients may lose weight.
Pain occurs 1.5-3 hr after meals in duodenal but only 1 hr after meals in gastr
ic ulcer. Disease course: usually chronic with remissions and exacerbations. Rel
apse may be more common in spring and autumn. Test for and eradicate H pylori an
d use maintenance drugs to recurrence.
Clinical evaluation
Blood test hypochromic anemia. Stool test
occult blood in chronic ulcers. Gastri
c secretion tests hyper-HCl secretion in duodenal ulcers, normal or subnormal HC
l secretion in gastric ulcer. Upper GI barium x-ray: reveals ulcer crater. Upper
GI endoscopy: most conclusive test. Biopsy: may be necessary to detect malignan
cy. H pylori status: using non-invasive (serology or breath test, false negative
breath test with PPI, antibiotics or bismuth compounds) or invasive (histologic
al bacterial visualization or urease activity test) tests.
Complications
Hemorrhage
Clinical picture: fresh blood vomit, bloody / tarry stool, coma, hypovolemic sho
ck (heart rate > 110, systolic BP < 100). Management: ensure airway, breathing,
circulation. IV crystalloids or colloids (e.g. hetastarch), monitor / correct el
ectrolytes, gastric lavage, vasoconstrictors, antacids, H2 antagonists, PPI, vas
opressin (GI muscle and blood vessel contraction).
Perforation
Sudden acute upper abdominal pain, rebound tenderness, and finally, peritonitis
and shock. Symptoms may with time (dangerously misleading). Emergency surgery is
needed.
Obstruction
Occurs due to inflammatory edema, spasm or scarring. Clinical picture: postprand
ial vomiting / bloating, appetite / weight loss, abdominal distension. Managemen
t: continuous gastric suction, monitor fluids and electrolyte status, perform sa
line load test to measure degree of obstruction. Liquids feeding and daily aspir
ations may be needed.
Post-surgical complications
Dumping syndrome: rapid gastric emptying in 10% of patients after partial gastre
ctomy. Clinical picture: weakness, dizziness, anxiety, tachycardia, flushing, sw
eating, abdominal cramps, nausea, vomiting, diarrhea. Occur between 15 and 120 m
inutes after the meal. Management: eat six small meals, protein and fat and carb
. Ingest fluids 1 hr before or after a meal but not with it. Give anticholinergi
cs to delay gastric emptying. Other complications: reflux gastritis, stomal ulce
ration, diarrhea, malabsorption, early satiety, iron deficiency anemia.
Refractory ulcers
Dyspeptic symptoms after 8 wk therapy. Perform gastroscopy and biopsy to exclude
: Crohns disease, TB, lymphoma, carcinoma. Treatment: only PPI offer maximum acid
. Eradicate H pylori. D/C NSAID. Perform surgery if all fails.

Maintenance regimens
70% of ulcers recur in a year (90% in 2 years) after healing and therapy d/c. Us
e long-term maintenance therapy in: concomitant disease, 4 relapses / year, many
risk factors (old, male, NSAID, alcohol, smoking, family history, history of co
mplications). H pyloric eradication need for continuous therapy.
Therapy
Antacids
As effective as H2 antagonists. Examples: magnesium, aluminum and calcium salts.
Antacids are not widely used for PUD. Continue therapy for only 7 weeks. Typica
lly given 2 hours after meals at bedtime. Effect lasts for 3-4 hours. Mechanism:
Neutralize gastric acid
gastric pH
pepsin activity and mucosal barrier
heat and
treat ulcer pain. Non-systemic antacids: such as magnesium or aluminum are pref
erred over systemic antacids (e.g. sodium bicarbonate) to avoid alkalosis. Liqui
d antacid: buffering capacity than tablets but not as convenient. Antacid mixtur
es: such as aluminum hydroxide and magnesium hydroxide each drug dose and effect
. Side effects are negated (aluminum constipation, magnesium
diarrhea). Calcium
carbonate: not preferred ( acid rebound, delayed pain relief and ulcer healing, c
onstipation, hypercalcemia). It may produce milk-alkali syndrome esp with milk (
hypercalcemia, alkalosis, kidney damage). Acid neutralizing capacity (ANC): numb
er of mEq of a 1 N solution of HCl that can be brought to a pH of 3.5 (99% neutr
alization) in 15 minutes. For duodenal ulcers, 50 mEq/hr or 125 mEq/day of antac
id is needed for neutralization. Precautions: Use calcium and magnesium carefull
y in renal disease (e.g. elderly). Sodium bicarbonate is CI in hypertension, CHF
, renal disease, edema. Use aluminum carefully in patients with dehydration, GI
obstruction. Calcium carbonate + alkali (sodium carbonate) + milk = milk-alkali
Long term aluminum hydroxide use hypo-phosphatemia, osteomalacia. Aluminum hydro
xide is used to treat hyperphosphatemia. Interactions: Generally, take other dru
gs 30-60 min before antacids. Avoid antacids (polyvalent cations) with tetracycl
ine ( absorption), cipro. May destroy enteric coating leading to premature releas
e in the stomach. Interfere with absorption of: ranitidine, cimetidine, iron, di
goxin, phenothiazines, anticholinergics. effect of sucralfate.
H2 receptor antagonists
Preferred in mild-moderate GERD due to lack of effect on GI motility. Mechanism:
competitively action of histamine at parietal cell H2 receptors
volume and H+ c
oncentration of gastric acid. General SE: nausea, dizziness, renal damage (adjus
t). Absorption is with antacids (give 1 hr befor e antacids). All available oral
or IV. Cimetidine: first drug, gastric acid by 50%. SE: liver damage, hematolog
ic (thrombocytopenia, agranulocytosis, aplastic anemia), weak androgenic (gyneco
mastia), confusion. Cytochrome P-450 inhibitor metabolism of phenytoin, theophyl
line, Phenobarbital, lidocaine, warfarin, imipramine, diazepam, propranolol, pro
cainamide. Ranitidine: more potent drug, gastric acid by 70%. Used with bismuth
citrate and clarithromycin to eradicate H pylori. Famotidine: most potent, gastr
ic acid by 94% for 10 hr. Nizatidine: newest drug, similar to ranitidine. Oral.
DI: absorption of drugs requiring acidic pH (e.g. ketoconazole).
Sucralfate
Non-absorbable disaccharide containing sucrose and aluminum.

Mechanism: adheres to the base of ulcer crater forming a mucosal protectant barr
ier against acids and bile salts (esp. in duodenal ulcers). Acidic pH is require
d for polymerization. SE: constipation. Give 1 hr before meals and at bedtime fo
r 6 weeks. Interactions: antacids sucralfate mucosal binding, give 45 min apart.
Surcralfate absorption of digoxin, iron, phenytoin, cimetidine, tetracyclines,
ciprofloxacin.
GI anticholinergics
Examples: atropine, propantheline. No proven value in ulcer healing Mechanism: b
asal and stimulated gastric acid and pepsin secretion. Most effective at night i
n large doses with antacids
delay gastric emptying. Or, take 30 min before food
( acid by 40%) SE: dry mouth, blurred vision, urinary retention, constipation, ta
chycardia CI: gastric ulcer (they prolong gastric emptying), narrow angle glauco
ma.
Prostaglandins (misoprostol)
Mechanism: PG E1 analgoue mucus
protect gastric mucosa against NSAID damage, bic
arbonate, acid. NSAID prostaglandins bicarbonate and mucus secretion
damage. Use
: QID prevention of NSAID induced gastric ulcer in risk patients. SE: diarrhea,
GI pain (take with food). CI: abortifacient, pregnancy category X.
Proton pump inhibitors
Examples (x-prazole): omeprazole, lansoprazole, esmoprazole, rabeprazole, pantop
razole. Omperazole sulfenamide is the active form. Mechanism: forms a stable dis
ulfide bond with sulfhydryl group near potassium binding site on luminal + + sid
e of gastric proton pump H K ATPase
pump shuts down. Very rapid ulcer healing an
d symptom control compared to other drugs (e.g. H 2 blockers). 90% acid reductio
n for 24 hr with no achlorhydria. Omeprazole is better than ranitidine or misopr
ostol for preventing or healing NSAID ulcers. Omperazole can be used in infants.
SE: headache, diarrhea, GI pain / upset, flatulence. Take before food. Interact
ions: absorption of drugs requiring acid pH (ketoconazole, ampicillin, iron). Om
eprazle may or cytochrome P-450 metabolism.
Bismuth compounds
Examples: bismuth subsalicylate (Pepto-Bismol), ranitidine bismuth citrate (RBC)
, colloidal bismuth subcitrate (not FDA approved). Mechanism: bismuth prevents a
dhesion of H pylori to gastric mucosa, H pylori growth, release of proteolytic e
nzymes. Use: most effective in combination with PPI or antibiotics. SE: CNS/neut
rotoxicity, dark stool / tongue, headache, diarrhea, rash, salicylism in doses (
tinnitus, hyperpyrexia, confusion, tachycardia). Antibiotics for H pylori: metro
nidazole, tetracycline, clarithromycin, amoxicillin, bismuth subsalicylate, ompe
razole / lansoprazole. Optimum regimen: bismuth subsalicylate QID + metronidazol
e QID + tetracycline QID + omperazole QD = 2 wk
90% eradication.
Prokinetic agents
Example: metoclopramide, erythromycin, cisapride (d/c due to incidence of arrhyt
hmia / torsades). Mechanism: ACh release gastric emptying (no effect on acid sec
retion). SE: diarrhea, GI upset, headache. Interactions: antifungals (ketoconazo
le, itraconazole, fluconazole, miconazole) cisapride metabolism
severe arrhythmia
. Rapid gastric emptying can affect absorption of narrow therapeutic drugs. CI:
arrhythmia, CHF, ischemic heart, renal failure, respiratory failure.

Diet / social modification

Milk may gastric acid (used to be recommended, no more). Milk leaves the stomach
quickly
no extended buffering. Small frequent meals may ulcer pain by causing a
cid rebound (used to be recommended, no more) Strict dietary limitations are now
considered unnecessary. Avoid certain foods: caffeinated drinks, alcohol, smoki
ng, NSAIDs.
Surgery
Used in complicated, incapacitating ulcer unresponsive to therapy. Vagotomy: sev
ers a branch of the vagus nerve
HCl secretion. Antrectomy: removes the antrum
me acid secreting mucosa. Others: gastrectomy, funoplication.

so

51. Diabetes
Introduction
Definition
1. Dysfunction in metabolism of fat, carbohydrate, protein, insulin 2. Dysfuncti
on of blood vessels and nerves function and structure 2-10% of US population (ha
lf undiagnosed)
Classification
General common symptoms: polydipsia, polyuria, dry skin, polyphagia, fatigue, fr
equent skin / vaginal infections, visual disturbances. 1. Type 1 (Insulin-Depend
ent, Juvenile-Onset, Ketosis-Prone) Insulin production/secretion is destroyed. U
sually in children and adults <30. Prone to ketoacidosis (accumulation of ketone
bodies). Dependent on exogenous insulin replacement. 10% of all diabetes. Etiol
ogy: a. Genetics: w/ family history. Linked to Human Leukocyte Antigen ( HLA) sy
stem. b. Environment: virus (e.g. rubella), toxic chemical triggers genetics / a
utoimmunity. c. Autoimmunity: anti-insulin and anti-beta-cell antibodies usually
present Clinical presentation: abrupt onset, acute presentation. Unintentional
weight loss w/ or w/o ketoacidosis. 2. Type 2 (Non-Insulin-Dependent, Adult-Onse
t) Endogenous insulin is normal, or . May or may not need exogenous insulin. 90%
of all diabetes (esp. in the elderly). Adults >30. 80% are also obese. Not prone
to ketosis except during stress (infection, surgery, trauma). Etiology: a. Gene
tics: 90% concordance between monozygotic twins. 15% chance in offspring of diab
etics. b. beta cell: insulin. c. Insulin site defect
insulin-resistant tissue (i
nsensitivity) Clinical presentation: develops gradually. Evidence of damage to r
etina, kidneys, peripheral vasculature. 3. Gestational (pregnancy) Glucose intol
erance detected during (late) pregnancy (3% of pregnants). Test tolerance 6 wk p
ostpartum. Usually returns to normal. 4. Other types (Secondary Diabetes) Due to
disease of pancreas, genetics, endocrinopathies (Cushings), drugs (thiazides, lo
ops, corticostroids, hyperglycemia) 5. Diabetes insipidus: Cause: pituitary dise
ase with production of antidiuretic hormone (ADH)
kidney cant conserve water, lit
hium ( sodium reabsorption). Symptoms: polyuria (20 L / d), severe thirst, polydi
psia, watch for dehydration. Treatment: anti-diuretic hormone (vasopressin) anal
ogs desmopressin (oral), lypressin (nasal), maintain fluids / electrolytes. (Des
mopressin is also used in Hemophilia A and von Willebrands disease).
Pathophysiology
Normal glucose regulation Insulin:

Structure: endocrine hormone secreted by beta-cells of pancreas. It is a 51-amin

o acid chain with two polypeptide chains and two inter-chain disulfide bonds. It
is derived from proinsulin (86 amino acids). Proinsulin can be used to determin
e the purity fo insulin products. Mechanism: glucose
ATP closes potassium channe
ls membrane depolarization
calcium influx
fusion of insulin granules insulin rel
ease. Insulin and glucose
activate N/K ATPase force potassium into the cells hyp
okalemia.
Glucose effects: glucose transport across cell membranes, glucose stor
age as glycogen in muscles / liver (glycogenesis), glucose formation from glycog
en in muscles / liver (glycogenolysis), glucose formation from amino acids (gluc
oneogenesis) breakdown of fatty acids to ketone bodies (lipolysis) (insulin prev
ents ketoacidosis
absent in type II DM), adipose (fat) tissue formation from tri
glycerides and fatty acids.
incorporation of amino acids into proteins Counter-r
egulatory hormones: glucagon (from pancreas alpha-cells), epinephrine, norepinep
hrine, growth hormone, cortisol. Glycogen: carbohydrate consisting of branched c
hains of glucose units. Principal form of carbohydrate storage, mainly in the li
ver and muscles. Breaks down easily to glucose when needed.
Abnormal glucose regulation General Insulin insufficiency, resistance
hyperglyce
mia. Liver: glycogenolysis, neoglucogenesis, glycogenesis. Muscle (peripheral ti
ssue): glucose uptake cells use protein as energy source protein breakdown
carbo
hydrates / glucose hyperglycemia. Renal glucose threshold: 180 mg/dl. BG concent
ration exceeds kidneys glucose reabsorptive capacity
glucose excreted into urine
(glucosuria) osmotic diuresis
dehydration, electrolyte abnormalities coma, death
. Diabetic Ketoacidosis (DK) (Type 1) No insulin to break glucose
triglycerides
breakdown (lipolysis) free fatty acids and glycerol. glycerol
liver glucose prod
uction hyperglycemia. Free fatty acids
acidosis
breakdown in the liver ketone bo
dies kidney excretion
ketonuria
exceeds kidney excretion limit ketonemia
coma, d
eath. A ketone body: acetoacetate
converted in the liver to acetone
excreted + 3 through the lungs acetone fruity breath. anion gap (Na (Cl + HCO )) Ketone bod
ies urine detection: add sodium nitroprusside and ammonia
purple color. May also
occur in severe vomiting or starvation. Initially, the body compensates for aci
dosis by breathing patterns ( Kussmaul: rapid deep breathing) and by blood buffe
ring systems (bicarbonates, proteins). If Type 2 DM Hyperglycemic hyperosmolar n
onketotic syndrome (HHNK), presence of even insulin prevents fat breakdown, keto
nemia, ketoacidosis (Ketosis-resistant).
Laboratory findings
Diagnostic criteria: 1. Random BG > 200 mg/dl with classic DM symptoms (polydips
ia, polyuria, polyphagia, weight loss). 2. Fasting BG > 125 mg/dl. 3. 2-hour BG
> 200 mg/dl during an oral glucose tolerance test (OGTT) using 75 g anhydrous gl
ucose in water. DM predisposition: Impaired fasting glucose (IFG): fasting BG 11
0-125 mg/dl. Impaired glucose tolerance (IGT): 2-hr OGTT BG 140-200 mg/dl. Gesta
tional diabetes: testing is done at 26 weeks in all women (unless risk: normal w
eight, no family history, and <25 year). Glucose tolerance: 50 g, after 1 hr if
> 140
glucose tolerance: 100 g, 3 hr. Goals of management: euglycemia with no sy
mptoms, prevent acute complications, prevent vascular and neuropathic disease, p
revent / treat risk factors ( BP, blood lipids), normal life expectancy and quali
ty of life.

Patient education and self care

Modifiable risk factors: smoking, BP, blood lipids, BMI > 27. Identify BG patter
ns: effect of diet, exercise, medications on BG. Foot care: lower-extremity comp
lications due to neuropathy, peripheral vascular disease, trauma, infections. In
spect shoes and feet skin color and integrity daily. Clean feet daily and dry we
ll. Do not use hand to sense water temperature if neuropathic (sensation loss).
Trim nails. Moisturize dry skin but NOT between the toes. Wear well fitting shoe
s and cotton socks. Avoid walking barefooted. Do not self-treat skin foot condit
ions. Skin care: dry skin is common due to diuresis and dehydration or anhidrosi
s (autonomic in perspiration,)
use aqueous non-alcoholic moisturizers. skin infe
ctions due to BG and circulation. Always use sunscreen (sun burn
BG). Avoid skin
trauma. Keep skin clean and regularly inspect for abrasions, swelling, pain. De
ntal care: DM accelerates periodontal disease. Should effectively brush and flos
s, and have an annual exam. Eye care: DM is the leading cause of visual impairme
nt and blindness. Should have annual dilated eye exam.
Assessment of glycemic control
Self monitoring of blood glucose (SMBG): allows assessment of response to factor
s affecting BG (diet, drugs, stress, etc). Gives immediate feedback to adjust di
et, exercise, insulin, etc. Urine glucose testing: only retrospective informatio
n (not recommended). Urine ketone monitoring: more important during illness, inf
ection, trauma (even for type 2), type 1 patients with BG consistently >250 mg/d
l, pregnant diabetics, patients on a diet to lose weight. Hemoglobin A1c test (g
lycol-hemoglobin, glycosylated hemoglobin): long term BG monitoring, reflects av
erage BG over 7-16 weeks. Stable for 120 days (RBC lifespan). Perform 1-2x / yea
r. Hemoglobin A1c < 7% is targeted (normal = 6% (130 mg/dl), if >8%
additional i
ntervention). BG ~ A1c x 20-30. Glycosylated fructosamine test: measures BG cont
rol over 3 weeks. Useful for short-term follow-ups (e.g. pregnancy).
Acute changes in glycemic control
Hyperglycemia
Mild to moderate hyperglycemia BG 200-250 mg/dl. Rapid onset (hr). No metabolic
abnormalities. Acute: due to illness, emotional distress, or dietary calories. R
ebound (Somogyi effect): rebound hyperglycemia following severe/prolonged hypogl
ycemia, e.g. overnight insulin reaction). May be BG pattern in early morning due
to counter-regulatory hormones. Moderate to servere hyperglycemia BG > 250 mg//
dl. Few days duration with acidosis or ketosis (Diabetic Ketoacidosis, DKA). Com
mon in children with undiagnosed Type 1 DM. Precipitating factors: stress, infec
tion, alcohol consumption, improper insulin therapy, dietary noncompliance. Phys
ical findings: Kussmauls respirations, acetone breath odor, dehydrati on, dry ski
n, consciousness (confusion, coma), abdominal pain. Can be deadly. Therapy: insu
lin IV infusion (Regular), fluid / electrolyte replacement. Severe hyperglycemia
BG > 500 mg/dl. serum osmolarity. Duration: days/weeks. Mostly in Type 2 DM. Hi
gher mortality rate than DKA. Precipitating factors: conditions that insulin req
uirement and predispose to dehydration (burns, GI bleeding, CNS injury, MI), use
of glucogenic drugs (steroids, glucagon, thiazide diuretics), high glucose prod
ucts (peritoneal dialysis, enteral nutrition).

Physical findings: dehydration, serum osmolarity (> 280 mOs), no ketosis / acidos
is (hyperglycemic hyperosmolar nonketotic syndrome, HHNK), polyuria, polydipsia,
hypotension, tachycardia, palpitations, rapid respiration, nausea, vomiting, ab
dominal discomfort, CNS function (confusion, coma, seizures, myoclonic jerking).
Therapy: insulin, fluid / electrolyte replacement.
Hypoglycemia
Mild hypoglycemia symptoms: adrenergic (tachycardia, palpitations, shakiness), c
holinergic (sweating), mild CNS glucopenia ( concentration, dizziness, hunger). M
oderate hypoglycemia: CNS effect
confusion, motor impairment, no unconsciousness
. Severe hypoglycemia: coma, seizure, motor impairment. Pseudo- hypoglycemia: hy
poglycemic symptoms perceived (mostly adrenergic) but BG is normal. Hypoglycemia
unawareness: no or little symptoms but BG is low. Sweating or neurologic impair
ment is noticed. Precipitating factors: excess insulin or oral hypoglycermic, de
layed or food, exercise, alcohol, drug interaction BG, progesterone in menstruat
ion, new insulin bottle with full potency, gastroparesis (delayed stomach emptyi
ng), change in insulin injection site ( absorption if SC near exercising muscle)
. Treatment of hypoglycemia: if conscious
10-15 g fast acting simple oral carboh
ydrate (milk, juice, regular soda), 3 g glucose tablet or hard candy, honey, glu
cose gel. Repeat in 10-15 min if BG is not back to normal. If unconscious
IV glu
cose (10-15% dextrose) or glucagons injection (1 mg IM, SC, or IV).
Long-term complications
Macrovascular
Atherosclerosis: coronary, cerebrovascular, peripheral Peripheral vascular disea
se: pain, chronic cold feet, insufficient circulation to heal distal lesions gangr
ene Hypertension: with diabetes
cardiovascular disease, stroke, transient ischemi
c events. Causes acceleration of retinopathy, nephropathy, atherosclerosis. Hype
rinsulinemia / insulin resistance diabetic hypertension. Coronary artery disease
: autonomic neuropathy Silent myocardial infarction (atypical, no chest pain). M
anagement: daily dose aspirin, ACE inhibitor (for BP), cardio selective beta blo
cker (for cardiac disease).
Eye (retionopathy)
Consequence of microvascular changes, leading cause of new blindness. Treatment:
laser photocoagulation. Nonproliferative (background) retinophathy: retinal mic
roaneurysms, blot hemorrhages, retinal edema, hard exudates, macula edema Prepro
liferative retinopathy: abnormality of tiny vessels, retinal ischemia, white pat
ches of oxygenstarved retina (soft or cotton-wool spots). Proliferative retinopa
thy: lack of oxygen
weak vessel grow or proliferate (neovascularization) from re
tinal surface to vitreous cavity. Fragile vessels may bleed into vitreous cavity
hemorrhage
obscured vision
scar tissue and new vessels grow vitreous pull on th
e retina retinal detachment.
Nephropathy
Most common cause of End Stage Renal Disease (ESRD) microalbuminuria, positive d
ipstick (clinical) albuminuria, proteinuria / BP, glomerular filtration, creatin
ine. ACE inhibitors helpful, protein intake, treat UTI. For ESRD
fluid / electro
lyte restriction, dialysis.

Neuropathy
Peripheral neuropathy: esp. in sensiomotor nervous system. Symptoms first in dis
tal lower extremities then upper extremities (Stocking-glove distribution). Sign
s: impaired perception of pain / temperature
numbness / tingling, impaired balan
ce, proprioception (perception of body parts movement), motor nerve damage
muscl
e weakness / atrophy. Autonomic neuropathy: genitourinary
neurogenic bladder, se
xual dysfunction. GI gastroparesis, nocturnal diarrhea, fecal incontinence, chro
nic constipation. Cardiovascular
orthostatic hypotension, cardiac denervation.
Foot, skin and mucous membranes
Due vascular changes and peripheral neuropathy
alter nerves that control blood f
low and skin hydration Infection by staph, beta-hemolytic strept, fungus
cutaneo
us infection (furunculosis, carbuncles), Candida (genital, upper thighs, under b
reast), cellulites, lower-extremity vascular ulcers Atrophic round painless lesi
ons, diabetic dermopathy (red-brown popular spots) esp. in lower extremities. Ne
crobiosis lipoidica diabeticorum (ulcerative necrotic lesion) Peripheral neuropa
thy loss of protective sensation, inability to detect minor trauma
ulcers Infect
ion, injury, neuropathy, vascular disease
gangrene Sensory exam of feet (protect
ive sensation) 10 g monofilament Protective footwear (deep sole shoes, molded sh
oes, orthotics)
Significant interactions affecting glycemic control
Hyperglycemia (direct glucogenic effect): corticosteroids, furosemide, thiazides
, sunburns, nicotinic acid, phenytoin, pentamidine, protease inhibitors, sympath
omimetics, isoniazid, sulfinpyrazone, theophylline toxicity. Hypoglycemia: MAO-I
, fluoxetine, salicylates ( dose), alcohol, fenfluramine, pentamidine Prolonged h
ypoglycemia / masking hypoglycemic symptoms: B1 beta blockers (e.g. propranolol)
Therapy
Medical nutrition therapy (MNT)
Carbohydrate counting: 50% of total calories. DM therapy may include pre-meal sh
ort acting bolus insulin (lispro, regular, semilente). Otherwise, maintain consi
stent CHO intake. Fat: limitations on type and amount. Critical for weight loss
and treating hyperlipidemia. Target: < 30% of calorie intake and < 300 mg/day ch
olesterol. Protein: important in end stage renal disease and may delay dialysis.
Fiber: bran, beans, fruits, vegetables may help BG and lipids. Alter diet based
on stress, illness, exercise, etc. Spaced meal intervals help match hypoglycemi
c therapy effect.
Physical activity
Careful exercise cell glucose uptake
BG Careful if patient has severe retinopath
y. Patients with cardiovascular disease or over 45
cardiovascular evaluation and
stress test. Aerobic activity: e.g. swimming, walking, running, preferred due t
o positive effect on BG ( ), cardiovascular, BP, lipids, circulation, weight loss
. Anaerobic activity: e.g. weight lifting, should be avoided. Potential negative
cardiovascular, BP, retinopathy effects.
Insulin and insulin analogues
For type 1 DM and only uncontrolled type 2. Mechanism / structure: see above Fac
tors insulin requirement: infections, weight gain, puberty, inactivity, hyperthy
roidism, Cushings disease

Factors insulin requirement: renal failure, weight loss, exercise, nutrient mala
bsorption, hypopituitarism, adrenal insufficiency. Concentration: U-100 or U-500
for insulin resistance. Source: human, bovine, porcine, synthetic (Lispro insul
in, Humalog), or a mixture. Human insulins are made by enzymatic conversion of t
erminal amino acid of porcine insulin (Novolin, semisynthetic), or by recombinan
t DNA (Humulin). Human insulin
antigenicity. Short-acting: Lispro
synthetic, sho
rtest onset and duration. Regular soluble insulin with neutral pH, only clear in
sulin (IV), only insulin that can be mixed freely. Semilente (prompt insulin zin
c suspension) finely divided amorphous prep, use acetate buffer, mix only with o
ther lente, similar duration to Regular, Aspart insulin analogues. Intermediateacting: NPH (isophane insulin suspension)
similar to protamine zinc but with no
excess protamine. Lente (insulin zinc suspension)
mixture of 70% ultralente crys
tals and 30% semilente powder. Long-acting: Protamine zinc use phosphate buffer.
Ultralente (extended release zinc suspension) large crystalline. Glargine insul
in analogue (very long acting). Pre-mixed insulin: 50/50 Regular/NPH, 70/30 Regu
lar/NPH, 75/25 Lispro/Protamine Lispro regular as pre-meal bolus and NPH interme
diate for later control of hyperglycemia. Other mixtures can be prepared extempo
raneously for tailored ratios. DM Type 1 example: pre-breakfast is 2/3 of total
daily dose (TDD) 1:2 short : intermediate. Bedtime is 1/3 of TDD 1:2 like pre-br
eakfast. Or give pre-supper rapid/short and then bedtime intermediate. DM type 2
example: bedtime only or 2-3 daily injections. Subcutaneous: for routine admini
stration. Absorption of regular insulin is fastest from abdomen > arm > buttock
> thigh. Monitor variations in absorption. Randomly rotate injection site to avo
id lipohypertropy. If variations avoid random rotation of injection site. Exerci
se, hot showers, baths, massages blood flow to injection site. Abdomen is least
likely to have absorption
preferred site for preexercise insulin. Continuous Int
ravenous (insulin drip): provide Regular insulin for acute hyperglycemia, ketoac
idosis, HHNK, or during surgery. Continuous SC infusion (insulin pump): short ac
ting insulin is infused continuously during the day to deliver doses (basal insu
lin). Bolus dose (determined by algorithms) is delivered by the patient before e
ach meal. Offers tighter glycemic control. Used for diabetics with BG fluctuatio
ns, irregular work schedules, lifestyles, or meals. Require frequent SMBG (BG se
lf-monitoring) and training. SE: hypoglycemia (tachycardia, sweating, hunger, co
nvulsions and insulin shock), hypersensitivity, injection site local irritation.
Insulin secretagogues
Drugs (all acidic): Sulfonyrlureas: First gen: chlorpropamide, tolbutamide, acet
ohexamide, tolazamide, more lipid-soluble, more potent. Second gen: glyburide, g
lipizide, glimperide. Also repaglinide. Mechanism: block ATP-sensitive potassium
channels insulin pancreatic release (primary), and also as sensitizers with tim
e (secondary). Use: Type 2 (useless in type 1, require functioning beta cells).
Chlorpropamide: longest duration of action. CI in liver and kidney disease. SE s
everity and frequency, disulfiram-reaction (also with tolbutamide). Use insulin
instead during stressful conditions ( risk of hyperglycemia due to counter-regula
tory hormones release). SE: severe / prolonged hypoglycemia (esp. in the elderly
, w/ glipizide / glyburide), GI upset, sulfa sensitivity, sun sensitivity, heada
che, rash, tachycardia, hematologic problems, cholestatic jaundice. CI: allergy
to sulfa drugs, pregnancy, lactation. Altered protein binding of sulfonylureas:
alcohol, salicylates, NSAIDs, methyldopa, chloramphenicol, MAO-I, clofibrate, pro
benecid. Therapy failure: due to number of functioning beta cells. Primary: failu
re to control BG within 4 weeks. Secondary: initial control of BG, but fails to
maintain control, due to progression of DM. Repaglinide: less hypoglycemia.
Insulin sensitizers
Drugs: biguanides (metformin, basic drug), thiazolidinediones (rosiglitazone, pi
oglitazone).

Mechanism: anti-hyperglycermic not hypoglycemic. sensitivity to insulin,

(metfor
min work on liver, hepatic glucose production, gluconeogenesis), (glitazones
sen
sitivity / insulin resistance in muscle and adipose tissue). Thiazolidinediones
bind to PPARs. Use: significant insulin resistance. Biguanides SE: fatal lactic
acidosis, metallic taste, GI upset, vitamin B12, no hypoglycemia. May be fatal i
f at risk of lactic acidosis (liver / kidney disease, hypoperfusion, hypoxia, ra
diography). Phenformin was d/c. Glitazones SE: liver toxicity / failure (monitor
), weight gain, edema, GI upset, no hypoglycemia. Troglitazone was d/c due to li
ver toxicity. CI: liver disease. May resume ovulation in premenopausal women. Hi
ghly protein bound (99%).
Alpha-glucosidase inhibitors
Drugs: acarbose (polysaccharide), miglitol (basic monosaccharide) Mechanism: inh
ibit intestinal enzyme alpha-glucosidase absorption of complex carbohydrates (st
arch, dextrins, disaccharides). Use only glucose or lactose for correcting hypog
lycermia if it occurs. Use: significant post-prandial hyperglycemia. Minimal eff
ect on pre-prandial or fasting BG. Good combination with insulin secretagogues.
Take with first bite of meal. SE: GI (diarrhea, abdominal pain, flatulence) due
to undigested carbohydrates in the lower GI, no hypoglycemia. CI: GI conditions
(inflammatory bowel, colonic ulcer, obstructive bowel, intestinal gas), liver ci
rrhosis (monitor liver function), pregnancy.
52. Thyroid Disease
Physiology
Thyroid hormone regulation / function
Thyrotropicn-releasing hormone (TRH): secreted by the hypothalamus, triggers the
release of TSH through negative feedback mechanism. Thyroid stimulating hormone
(TSH): released by the anterior pituitary gland, controls thyroid hormone secre
tion and transport. Thyroid gland produces thyroxine (T4), triiodothyronine (T3)
(both for growth, development, metabolic rate), and calcitonin ( blood calcium).
Thyroid hormone is transported in the circulation by thyroxine-binding globulin
(TBG), and albumin. Protein binding protects hormone from premature metabolism,
excretion, and prolongs its t1/2. Metabolism: T4 T3 conversion in pituitary gland
, liver, kidneys. Degradation: by deiodination feces / urine excretion. Function
: Activate mRNA and protein synthesis or catabolism ( dose). growth, development,
basic metabolic rate, blood flow, cardiac output, heart rate, fine muscle tremo
r, fatigue wakefulness, lipid mobilization and degradation, bone remodeling (rat
e of resorption > rate of formation).
Biosynthesis
Dietary iodine: critical for thyroid hormone synthesis, reduced to inorganic iod
ide then exracted from plasma by the thyroid by iodide trapping (iodide pump). O
rganification: oxidation of iodide by peroxidase. Synthesis starts with iodide-t
yrosine binding
modoiodo then dioiodo-tyrosine.
Thyroid function studies
Serum total thyroxine (TT4): Most direct reflection of thyroid function by indic
ating hormone availability in tissues. Total (free and bound) T4 is determined b
y radio-immunoassay (sensitive, rapid). TBG during pregnancy misleading results
(bound T4).

 TT4
hyperthyroidism, and vice versa Serum total triiodothyronine (TT3): Measures
total (free and bound) T3. TT3 rise before TT4, useful for early detection. in h
yperthyroidism (more than T4), responsible for symptoms. Pregnancy TT3. Resin tr
iiodothyronine (RT3U): Evaluates the binding capacity of TBG. Clarifies whether
abnormal T4 is due to thyroid disorder or abnormal protein binding. If abnormal
thyroid in the blood RT3U changes in same direction ( in hyperthyroid). If abnorm
al protein binding RT3U changes in opposite direction ( in hyperthyroid). Serum t
hyrotropin (TSH) assay: Serum TSH assay: most sensitive test for hypothyroid, bu
t nor reliable in hyperthyroid (TSH is suppressed). Sensitive TSH assay: uses mo
noclonal antibodies known as immuno-radiometric or immunometric (IMA) method (vs
. the older radio-immunoassay). sensitivity, cost, more commonly used to control
over treatment of replacement therapy. Free thyroxine (T4) index (FTI): Not a s
eparate test but rather an estimation of free T4 level by a calculation involvin
g serum T4 and RT3U. FTI
hyperthyroid or TBG. Strategies for testing Most common
and expensive: TT4, RT3U, FTI. Thyroid disease screening for healthy population
is not cost effective. Screen only target population (elderly, chronic disease
hospitalization, Use FTI and Sensitive TSH for disease diagnosis.
Hypothyroidism
Classification
Primary hypothyroidism: due to gland destruction or dysfunction caused by diseas
e or therapy (radiation, surgery). Secondary hypothyroidism: due to TSH secretio
n (pituitary disorder). Thyroid gland is normal but not enough TSH stimulation.
Tertiary hypothyroidism: TRH (hypothalamus) to stimulate pituitary
Causes
Hashimotos thyroiditis: chronic autoimmune thyroiditis. Treatment of hyperthyroid
ism: e.g. radioactive iodine, subtotal thyroidectoym, antithyroid drugs. Goiter:
enlargement of the thyroid gland. Endemic goiter: due to inadequate dietary iod
ine (malnutrition). Sporadic goiter: due to foods or drugs containing progoitrin
(inactive hydrolysis
active goitrin)
oxidation of iodine to iodide. Goitrogenic
drugs: propylthiouracil (PTU), iodides, cobalt, lithium, phenylbutazone. Other
causes: thyroiditis, thyroid cancer. Surgical excision
Signs and symptoms
Vague early symptoms: lethargy, fatigue, sensitivity to cold, weight gain, const
ipation. Later: features of Myxedema such as dry flaky inelastic sin, coarse hai
r, puffy face / hands / feet, eyelid droop, slow speech / thought, libido, coma
(if not controlled). Myxedema coma Life threatening condition in old patient wit
h undiagnosed hypothyroidism Precipitating factors: alcohol, sedative / narcotic
use, antithyroid overdose, d/c thyroid replacement, infection, cold exposure, r
adiation, surgery.

Symptoms: coma, hypothermia, respiratory rate

failure, hypometabolism
fluid / el
ectrolyte retention fluid retention, hyponatremia, heart rate / contractility, h
eart output. Treatment: rapid restoration of T3 and T4 to normal levels. IV bolu
s levothyroxine, oral liothyronine, then oral levothyroxine.
Drugs
Desiccated thyroid preparations: not commonly used anymore. Different preparatio
ns are not bioequivalent (varying amounts of actives depending on source (bovine
, ovine, porcine). Fixed ratio (liotrix) preparations: standard ratio of T4/T3.
T3 is, however, unnecessary (T4 converts to T3)
cause SE tremor, headache, palpi
tations, diarrhea. Levothyroxine: agent of choice, predictable results, no T3. I
ndividual variable response to different preparations
care if to switch. Use dos
e for elderly or chronically ill patients. Results start after 2 wk, full respon
se after 4-5 months (TSH levels to normal levels).
Precautions
Careful in the elderly and in case of cardiac disease. S tart with doses. Watch
for cardiac complications (palpitations, arrhythmia, angina). Monitor thyroid le
vels (T4, RT3U, FTI, sensitive TSH). Long term levothyroxine therapy can cause t
hyrotoxicosis. Accelerated bone loss due to over treatment nontraumatic fracture
. CI: cholestyramine (bile acid sequestrant) thyroxine bioavailability. Separate
drug by 6 hours.
Hyperthyroidism / thyrotoxicosis
Graves disease (diffuse toxic goiter)
Most common form. Occurs usually in young women. Autoimmune disease, antibodies
(long-acting thyroid stimulators, LATS) bind to and activate TSH receptors (does
not actually increase TSH itself). Symptoms: enlarged goiter, exophthalmos, sta
re, nervousness, irritability, anxiety, insomnia, heat intolerance, sweating, ap
petite, weight, muscle tremor / weakness, tachycardia, palpitations, diarrhea. S
igns:
Plummers disease (toxic nodular goiter)
Less common. Common in the elderly. Caused by adenoma nodules autonomously secre
ting excessive thyroid. Symptoms: same as Graves with nodular masses rather than
diffusion enlargement.
Other forms
Jodbasedow phenomenon: hyperthyroid due to iodine ingestion or amiodarone. Factit
ious hyperthyroidism: due to abusive ingestion of thyroid replacement drugs to l
ose weight.
Drugs
Beta blockers propranolol Propranolol peripheral symptoms (tachycardia, sweating
, tremor, nervousness). It also peripheral T4 T3 conversion (deiodonation). Antith
yroid drugs Examples: propylthiouracil (PTU), methimazole. Mechanism: interferes
with thyroid hormone synthesis by iodide oxidation. PTU peripheral T4 T3. Dosing
: initial dose (2 mo), maintenance dose (12 mo), gradual withdrawal (2 mo). Rest
art therapy if signs of hyperthyroidism appear. Monitor serum thyroid, FTI and g
oiter size.

SE: skin rash, urticaria, pruritus, hair loss, skin piementation, drowsiness, my
algia, arthralgia. Severe SE: blood (agranulocytosis, granulocytopenia, thromboc
ytopenia), monitor blood count. Radioactive iodine (RAI) Mechanism: thyroid glan
d picks up the radioactive element iodine-131 as it would regular iodine. Radioa
ctivity destroys cells. Advantages: cure rate (100%), avoid surgical risks, cost
Disadvantages: risk of delayed hypothyroidism, delayed effect. SE: only for wom
en past childbearing years. Response is hard to gauge (too much, too little). Su
btotal thyroidectomy Partial removal of the thyroid gland. Last resort. Advantag
es: success rate, rapid cure. SE: thyroid storm, permanent hypothyroidism.
Complications
Hypothyroidism: may follow Graves disease. Thyroid storm (thyrotoxic crisis): is
a sudden exacerbation of hyperthyroidism caused by rapid release (leakage) of th
yroid hormone ( T4)
fever, tachycardia, restlessness, tremor, hyper-meabolism
dehy
dration, shock, death if not treated rapidly. Precipitating factors: thyroid tra
uma, surgery, radiation, infection, sudden d/c of antithyroid therapy. Treatment
: PTU, methimazole, proproanolol, potassium iodide ( intrathyroidal iodine intake
), supportive therapy (rehydration, cooling, AB, rest, sedation).
54. Cancer Chemotherapy
Principles of oncology
Cancel cells
Tumors arise form a single abnormal cell, which continues to divide indefinitely
. Characteristics: no growth control, can invade local tissues, can spread (meta
stasize).
Incidence
Second leading cause of death in the US. Affects 30% of all people at some point
in life. Some forms of cancer are curable if detected / treated early.
Etiology
Viruses: Epstein-Barr virus, hepatitis B, human papilloma viruses. Environmental
/ occupational exposures: ionizing / UV radiation, chemicals (benzene, asbestos
, vinyl chloride). Life-style: fat, fiber diet, ethanol, tobacco. Medications: a
lkylating agents, immunosuppressants. Genetics: inherited mutations, cancer-caus
ing genes (oncogenes).
Detection / diagnosis
Warning signs: CAUTION. Change in bowel / bladder habits, A sore that does not h
eal, Unusual bleeding / discharge, Tissue thickening or lumps (e.g. breast), Ind
igestion of difficulty swallowing, Obvious change in a wart or mole, Nagging cou
gh or hoarseness. Guidelines for screening: for asymptomatic people mammography
(breast cancer), fecal occult blood test (colon cancer), Pap smears (cervical ca
ncer). Tumor markers: biochemical indicators of the presence of neoplastic proli
feration in serum, plasma, other body fluids. Not definitive. Include: prostate
specific antigen (PSA), carcinoembryonic antigen (CEA), alpha fetoprotein (AFP).
Tumor biopsy: definitive test for cancer cells is pathology of a biopsy.

Imaging studies: x-ray, computerized tomography scans, MRI, positive emission to

mography. Lab tests: complete blood count, blood chemistries.
Staging
It is the categorizing of patients according to extent of the disease. Used to d
etermine prognosis. Two system are used for neoplasm staging. TNM: T = tumor siz
e (0-4), N = regional lymph node spread (0-3), M = presence of absence of distan
t metastases (0-1). Example: T2N1M0. AJC: by the American Joint Committee on sta
ging. Scale: 0-IV.
Survival
Depends on tumor size, disease extent, treatment received. 60% survive more than
5 years, but not all survivors are cured. Complete response or remission when no
evidence of disease after treatment. Slow growing tumors
10-15 disease free year
s.
Cell life cycle
Phases of the cell cycle
M phase (mitosis): cell divides into two daughter cells G1 phase (postmitotic ga
p): synthesis of RNA and proteins S phase (synthesis): synthesis of DNA G2 phase
(premitotic / postsynthetic gap): production of RNA and topoisomerisae I/II enz
ymes (important for DNA replication and RNA transcription). G0 phase (resting):
cell is not dividing. Cells now are not sensitive to chemotherapy. Recruitment:
resting cells re-enter actively divided cell cycle caused by some chemotherapy a
gents.
Cell growth kinetics
Cell growth fraction: proportion of the cells in the tumor dividing or preparing
to divide. Large tumor
nutrients and blood supply to some cells cell growth fra
ction. Cell cycle time: average time for a cell that has just completed mitosis
to grow and again pass through mitosis (divide). Cycle time is specific for each
individual tumor. Tumor doubling time: time for the tumor to double in size. La
rge tumor
cell growth fraction doubling time Gompertzian growth curve: illustrat
es cell growth kinetics concepts.
Tumor cell burden
Number of tumor cells in the body. Number required for clinical symptoms: 10 (la
rge number)
tumor may be in plateau phase of growth curve when detected. Body im
munologic defenses may be able to keep tumor cells less than 1000 under control.
Each cycle of cancer chemotherapy kills a certain percentage of tumor cells (de
pending on the dose). When tumor cells are killed
Cells in G0 phase may be recru
ited to G1 phase tumor regrowth. Therefore, repeated cycles of treatment are req
uired for complete response or remission.
9
Drug reliance on cell cycle kinetics for cytotoxic effect
Phase specific agents: M
vinca alkaloids / taxanes, G1
asparaginase / prednisone
, S antimetabolites, G2 > bleomycin / etoposide. Phase nonspecific agents: effec
tive when cell are at any phase of the active cycle. Examples: alkylating agents
, cisplastin, antitumor antibiotics. Cell cycle nonspecific agents: effective in
all phases including G0. Example: nitrosoureas, radiation. Combination of drugs
that are active in different cell cycle phases will result in greater cell kill
.

Chemotherapy
Therapy objectives
Cure: sought with aggressive therapy for long time to eradicate all disease. Exa
mple for leukemia: remission induction, attempt maximal cell kill and therapy co
nsolidation to eradicate all clinically detectable disease and get tumor cell co
unt 1000. Palliation: goal is to control symptoms when complete eradication of t
umor is unlikely or if patient refuses aggressive therapy. Adjuvant: given after
more definitive therapy (e.g. surgery) to eliminate any remaining disease. Neoa
djuvant: goal is to tumor burden before surgery or radiation.
Dosing
May be bases on body weight, BSA or AUC. BSA is preferred (correlates with cardi
ac output which determines renal / hepatic blood flow / elimination). Adjust dos
e for liver or kidney dysfunction. Dosing is usually given as short courses in c
ycles.
Combination chemotherapy
To overcome or prevent resistance, achieve cytotoxicity to resting and dividing
cells, enhance biochemical effect, rescue normal cells. Acronyms are often used
to indicate certain combinations.
Administration
IV is the most common Inrathecal: for methotrexate, hydrocortisone, cytarabine,
thiotepa.
Response to chemotherapy
Does not always correlate with survival. Complete response: disappearance of all
disease (clinical, gross, microscopic). Partial response: > 50 reduction in tum
or size for a period of time. Response rate: defined as complete response + part
ial response. Progression or no response: > 25 increase in tumor size or appeara
nce of new lesions.
Classification of chemotherapeutic agents
Alkylating agents
Prototype: mechlorethamine (nitrogen mustard) Mechanism: cross-linking and abnor
DNA replication. Nitrogen mustards: chlorambucil
mal base-pairing of DNA strands
, cyclophosphamide, ifosfamide, mechlorethamine, melphalan. Ethylenimines / meth
ylmelamines: thiotepa, altretamine. Alkyl sulfonates: bisulfan Nitrosoureas: car
mustine, lomustine, semustine, streptozocin. Triazenes: dacarbazine Platinum coo
rdination complexes: cisplatin, carboplatin Substituted ureas: hydroxyurea Other
s: procarbazine, temozolomide.
Antitumor antibiotics
Most come from Streptomyces Mechanism: alkylation (mitomycin) or intercalation.
Intercalation: drug slides between DNA base pairs and DNA synthesis. Anthracycli
nes: daunorubicin (daunomycin), doxorubicin (adriamycin, hydroxydaunorubicin), e
pirubicin, idarubicin. Anthracendiones: mitoxantrone Others: bleomycin, dactinom
ycin, mitomycin, plicamycin (mithramycin).

Antimetablites
Structural analogs of naturally occurring substrates for biochemical reactions.
Mechanism: false substitution in production of nucleic acid
DNA synthesis. Adeno
sine analogs: cladribine, fluudarabine, pentostatin (deoxycoformycin). Folic aci
d analogs (folate antagonists): methotrexate, trimetrexate, raltitrexed. Purine
analogs (purine antagonists): mercaptopurine, thioguanine Pyrimidine analogs (py
rimidine antagonists): fluorouracil, capecitabine, cytarabine, gemcitabine.
Plant alkaloids
Vinca prevent formation of the mitotic spindle arrest cell division. Examples: v
inblastine, vincristine, vindesine, vinorelbine. Camptothecins
inhibit topoisome
rase I. Examples: irinotecan, topotecan. Podophyllotoxins
inhibit topoisomerase
II. Examples: etoposide, teniposide. Taxanes microtubule assembly / stabilizatio
n cell division. Examples: taxol (paclitaxel), taxotere (docetaxel).
Hormones
Androgens: testosterone, fluoxymesterone Antiandrogens: bicalutamide, flutamide,
nilutammide. Antiestrogens: tamoxifen, toremifene. Aromatase inhibitors: letroz
ole, anastrozole, exemestane, aminoglutethimide. Corticosteroids: prednisone, de
xamthasone Estrogens: ethinyl estradiol, diethylstilbestrol. Estrogen/nitrogen m
ustard: estramustine Progestins: medroxyprogesterone, megestrol Luteinizing horm
one releasing hormone analogs: leuprolide, goserelin
Asparaginase
Mechanism: enzyme that causes the degradation of essential AA asparagine to aspa
rtic acid and ammonia. Normal cells can synthesize asparagine but tumor cells ca
n not.
Biologic response modifiers
Mechanism: alter the patients immune system to fight cancer or to SE of cancer tr
eatment. Examples: Bacillus Calmette-Guerin (BCG), Colony-stimulating factors (e
rythropoietin, filgrastim, sargramostim), interferons (alpha, beta, gamma), inte
rleukins (IL-2, IL-11), levamisole, monoclonal antibodies (rituximab, trastuzuma
b).
Toxicity of chemotherapeutic agents
Most toxic to the most rapidly proliferating cells (mucous membranes, cells, hai
r, GI tract, bone marrow).
Bone marrow depression
Most life threatening SE. Effect is dose related. WBC (especially neutrophils; n
eutropenia)
serious infections. Colony stimulating factors: used to extent of ne
utropenia. platelets (thrombocytopenia)
bleeding give platelet transfusion. Anem
ia is not as common because RBC lifespan is 120 days. Time course: onset
1 week,
lowest count point (nadir)
2 weeks, count recovery
3 weeks.
Dermatological
Alopecia: partial or complete, can not be prevented. Local necrosis: results fro
m extravasation during administration of vesicant drugs immediate pain / burning
+ possible delayed reaction tissue damage, necrosis, ulceration
require plastic
surgery. Treatment: cold for all drugs except vinca and taxanes (use heat). Ski
n changes: dryness, sun sensitivity (methotrexate, fluorouracil).

GI toxicity
Nausea and vomiting Most distressing SE from the patients viewpoint. Acute, delay
ed or anticipatory. Antiemetics are used for prophylaxis. Vomiting
dehydration,
electrolyte imbalance, esophageal tears
d/c therapy. Stomatitis Common with meth
otrexate, fluorouracil (same as skin changes) General inflammation of the oral m
ucosa or other areas of the GI with rapid turnover of cells. Symptoms: erythema,
pain, mouth dryness, lip tingling / burning, ulceration, bleeding infection, in
ability to eat. Time course: starts in 1 week, resolve in 2 weeks. Other SE: flu
orouracil
diarrhea, vincristine
constipation.
Pulmonary
Irreversible and may be fatal. Especially with bleomycin, mitomycin. Symptoms: b
reath shortness, unproductive cough.
Cardiac
Acute: transient ECG abnormalities. Not important. Chronic: irreversible CHF due
to drugs or radiation. Dexrazoxane: cardioprotective (use with doxorubicin).
Neurotoxicity
Due to intrathecal or systemic therapy. Autonomic / peripheral neuropathy: due t
o vincristine. Vincristine is fatal if given intrathecally. Peripheral neuropath
y / ototoxicity: due to cisplatin. Arachnoiditis: due to intrathecal methotrexat
e, cytarabine.
Hemorrhagic cystitis
Bladder toxicity due to cyclophosphamide and ifosfamide. Acrolein: metabolite of
these drugs chemical irritation of bladder mucosa
bleeding. Prevention: aggress
ive hydration with frequent urination, mesna (binds to acroltein
prevents it fro
m contacting bladder mucosa).
Other
Hypersensitivity: may be life threatening (anaphylaxis). Chills / fever: especia
lly with bleomycin. Hepatoxocity: liver function tests, jaundice, hepatitis. Nep
hrotoxicity: serum creatinine, BUN, electrolyte imbalance. Use amifostine to pro
tect the kidney if using cisplatin. Secondary malignancies: such as leukemia, so
lid tumors, lymphoma. Female infertility: may be temporary or permanent .
Other chemotherapeutic modalities
Surgery: can be diagnostic or therapeutic Radiation: doses of ionizing radiation
directed at the cancerous tissue. SE: stomatitis, myelosuppression, GI (nausea,
vomiting, diarrhea). Its common to combine drugs, surgery and radiation.

55. Pain Management

Definitions
Pain: unpleasant sensory and emotional experience that usually is associated wit
h structural or tissue damage. No objective measurement. Acute pain: lasts < 30
days. Occurs after muscle strains and tissue injury. Self limiting, w/ time as i
njury heals, linear process with beginning and end, autonomic NS: heart rate, br
eath rate, BP, mydriasis, anxiety. Chronic pain: persistent or episodic, > 6 mon
ths. Chronic non-malignant pain: complication of acute injury, disease (osteoart
hritis, rheumatoid arthritis, fibromyalgia, degenerative disorders). Cyclic, con
stant, does not improve w/ time. No ANS stimulation. Depression, insomnia, weigh
t loss, sexual dysfunction Chronic cancer pain: similar to non-malignant pain, d
epression, fear, anger, agony. Due to cancer therapy or tumor (bone metastasis,
compression of nerves, occlusion of blood vessels, obstruction of bowel, infiltr
ation of soft tissue). Breakthrough pain: intermittent, transitory in pain.
Principles of pain management
Comprehensive pain management: chronology, history, symptomatology, onset, locat
ion, intensity, duration, quality, distribution, provoking factors, underlying d
isease / trauma, allergies, analgesic response, side effects. Pain management ta
rgets: patient comfort (may aid healing in acute pain), break pain cycle (chroni
c pain), breakthrough pain, improve sleep, well-being, self-esteem, mobility, ps
ychology, etc. Individual management regimens: dose, intervals, mode of administ
ration, adjunct therapy. Avoid narcotics for chronic non-malignant pain. Long ac
ting analgesics (round the clock) for cancer pain. Intermittent prn short-acting
analgesics for breakthrough and acute pain. Reassess and change regiment as nee
ded.
Analgesics
Non narcotic analgesics
General uses: antipyretic, anti-inflammatory (except acetaminophen), analgesic c
eiling effect, no tolerance, no dependence. OTC: aspirin, acetaminophen, ibuprof
en, ketoprofen, naproxen (low doses). General SE 1. Gastro-intestinal: Due to PG
inhibition. With all except acetaminophen, COX-II inhibitors, choline magnesium
trisalicylate, etanercept. Symptoms: dyspepsia, ulceration, bleeding, perforati
on. Especially in the elderly, ulcers, smokers, alcoholics. Avoid by combo thera
py with GI protectants (PPI, misoprostol, H2-antagonists, antacids, sucralfate)
or enteric coating (aspirin). 2. Hematologic: Exceptions: acetaminophen, choline
mg trisalicylate, etanercept. Inhibit platelet aggregation by reversibly inhibi
ting PG synthase. Aspirin is an irreversible inhibitor. Contraindicated with ant
icoagulants (warfarin, heparin, etc) 3. Renal:

PG inhibition, interstitial nephritis, impaired renin secretion, tubular water/N

a reabsorption
reversible abrupt oliguria Salicylates Chemistry: derivatives of
salicylic acid (from Willow bark). Weak acids with excretion by pH. Aspirin is a
cetyl salicylic acid, hydrolyses easily, unstable in water, moisture. Other sali
cylates: diflunisal, methyl salicylate (topical, wintergreen oil), salsalate, me
salamine, olsalazine, sulphasalazine, sodium thiosalicylate (injection), choline
salicylate (oral liquid). Pharmacology: cyclooxygenase (COXI/II)
local PG analg
esic, antipyretic, anti-inflammatory. Aspirin is the only salicylate that COX ir
reversibly by covalent acetylation. Also, platelet COX thromboxane A2 formation

platelet aggregation / thrombus formation. Indications: analgesics (skeletal mus

cle pain, headache, neuralgia, myalgia, spasmodic dysmenorrhea), anti-inflammato
ry (arthritis, rheumatic fever), antipyretic (avoid in children with viral infec
tion Ryes syndrome), prophylaxis of MI. Mesalamine, sulphasalazine, olsalazine
in
flammation in inflammatory bowel disease, Crohns disease. Methyl salicylate topic
al counter irritant. SE: GI upset (nausea, vomiting, discomfort, irritation, ulc
eration, hemorrhage), bleeding, delayed labor, depth of respiration, hyperglycem
ia, glycosuria. Low dose (2 g) urate excretion ( blood level). High dose (5 g)
op
posite. Toxicity: salicylism (tinnitus). Oral methyl salicylate can be fatal. Su
lphasalazine male infertility. Acute hypersensitivity (asthma, rhinitis, urticar
ia, shock, etc). May have cross-sensitivity to other NSAID DI: Oral anticoagulan
ts (due to platelet inhibition and gastric mucosal damage bleeding). Methotrexate
: toxicity with salicylates by blocking methotrexate renal tubular secretion. NS
AIDs Examples: (x-profen) ibuprofen, ketoprofen, fenoprofen, flurbiprofen, napro
xen (sodium), indomethacin, piroxicam, diclofenac, ketorolac (oral, IM), etodola
c, oxyprazocin, tolmetin, sulindac, meclofenamate, mefanemic acid, nabumetone. C
OXII inhibitors: celecoxib, rofecoxib, valdecoxib. Chemistry: Many are acid deri
vatives. Most are from propionic (x-en) or acetic acid. Others: fentamates, oxic
ams or anthanilic acid derivatives. COX-II inhibitors pyrazole derivatives. Phar
macology: COX-I produces PG cytoprotective of stomach lining. COX-II produces PG
for pain / inflammation. NSAIDs: COXI/II local PG synthesis. COX-II inhibitors:
COXII only. Indications: NSAIDs: mild to moderate pain, rheumatoid arthritis, o
steoarthritis, gout, additive analgesia with narcotics. COX-II inhibitors: rheum
atoid arthritis and osteoarthritis. Ketorolac IM: for moderate to severe pain (s
trongest NSAID for analgesia) when narcotic are undesirable (addicts, respirator
y depression, sedation). Indomethacin: strongest NSAIDS for inflammation, CNS SE
. Use for ductus arterisous in premature infants. SE: NSAIDs: GI upset (dyspepsi
a, mucosal erosion), CNS depression / drowsiness, platelet function, skin rash,
kidney damage. COX-II inhibitors: kidney damage, GI upset. DI: NSAIDs effect of
diuretics (due to renal perfusion). COXII inhibitors are CI in allergy to sulfon
amides, aspirin, NSAIDs p-Aminophenols Acetaminophen is the prototype (APAP, acet
yl para-amino phenol). Also, phenacetin. Mechanism: central PG analgesic, antipy
retic. No peripheral PG blocking no effect on inflammation, platelets. Use: alte
rnative antipyretic, analgesic to salicylate. Unlike aspirin, safe as antipyreti
c for children with viral infections. SE: at normal doses (skin rash). Acute ove
rdose
liver failure. Antidote: N-acetyl cysteine. CI: alcoholism. Pyrazolones Ch
emistry: prototype is phenylbutazone, its metabolite is oxyphenbutazone. Also su
lfinpyrazone. Mechanism: PG synthesis, stabilize lysosomal membrane
analgesic, a
ntipyretic, anti-inflammatory, uricosuric. Sulfinpyrazone only uricosuric hyperur
icemia in gout.

Use: (oxy)phenylbutazone
short term treatment of rheumatoid arthritis and gout (
not first choice). SE: SE. blood dyscrasias (agranulocytosis, thrombocytopenia,
anemias), GI uspet, ulceration, kidney damage, hyperglycemia, skin rash, CNS (dr
owsiness, headache).
Narcotic analgesics (opioids)
Chemistry Include natural opiate alkaloids and synthetic analogs Derived from op
ium (oldest drug) from poppy seed capsule. Morphine: phenolic hydroxyl group is
critical for activity. Most important alkaloid (pharmacologically and quantitati
vely). Amphoteric structure
erratic oral absorption. Agonists: morphine, codeine
, heroin, oxycodone, oxymorphone, hydromorphone, hydrocodone, dihydrocodone, mep
eridine, fentanyl (transdermal), propoxyphene, loperamide, methadone / levorphan
ol (both long t1/2), diphenoxylate, sufentanil, dezocine. Antagonists: methyl gr
oup on nitrogen atom is replaced by bulkier group. Examples: naltrexone, naloxon
e, levallorphan (?). Mixed agonists-antagonists: nalbuphine, buprenorphine, buto
rphanol, pentazocine, can ppt withdrawal symptoms if used after agonists. Mechan
ism Endogenous peptides (enkephalins, endorphins, dynorphins) provide self-pain
relief. Opioid receptors: in the brain / spinal cord (Types: , , , , ) Eff
ct of mu
r
c
ptor timulation (morphin
-li
): analg
ia, 
ation, mioi,
uphoria, phy
ical 
p
n
nc
, r
piratory 
pr
ion, braycaria Oth
r action: cough uppr

ion, CTZ timulation (nau
a, vomiting). Opioi mimic th
action of
nog
no
u opioi p
pti
 at CNS opioi r
c
ptor
pain thr
hol an tol
ranc
. Clinica
l u
Mo
rat
to 
v
r
pain, acut
or chronic, of vic
ral or omatic origin,

.g. MI, canc
r, labor,
tc. Pr
an
th
ia an ajunct uring an
th
ia. Antituiv
 (co
in
, 
xtrom
thorphan). Antiiarrh
al (lop
rami
, iph
noxylat
).
Pur
antagonit ar
u
 a antiot
 to r
v
r
SE of agonit or agonit-an
tagonit (r
piratory 
pr
ion, CV 
pr
ion, rowin
). Naltr
xon
i u

 for opioi aition. Do
i incr
a
 graually until th
app
aranc
of limit
ing SE Mix
 agonit-antagonit pr
f
rr
 for acut
pain r
piratory 
pr
ion
ri i . Avoi with chronic opioi
withrawal. Oral: pr
f
rr

p. for chronic
tabl
pain. CR morphin
an oxycoon
availabl
for continuou pain (
.g. canc

r) IM, SC: u
 pot-op
rativ
ly. Aborption i not pr
ictabl
. IV bolu: mot
rapi, pr
ictabl
on
t for br
athrough pain IV infuion: to titrat
pain r
l
i
f rapily for untabl
chronic pain,
p. morphin
. IV PCA: for acut
pot-op

rativ
pain. Small o
 
liv
r
 at fr
qu
nt int
rval (10 min). Epiural / in
trath
cal: for acut
pot-op
rativ
pain an chronic canc
r pain. Intrath
cal o

= 0.1
piural o
. Mut b
pr

rvativ
fr

u
to n
urotoxicity of parab

n an b
nzyl alcohol. Intrath
cal local SE: itching, urinary r
t
ntion. Epiura
l: brain l
v
l SE
giv
if r
piratory 
pr
ion ri i . Labor m
p
riin
(l

n
onatal r
piratory 
pr
ion). R
ctal: alt
rnativ
to oral. Pati
nt un-pr
f

rr
, poor aborption. Tran
rmal: CR f
ntanyl (3 ay). Alt
rnativ
to oral fo
r chronic pain. Slow on
t, r
quir
oral uppl
m
nt. Av
r

ff
ct Contipatio
n: u
to int
tinal ton
an p
ritali. Aft
r 
v
ral ay ( with co
in
). P
rophylaxi: laxativ
/ tool oft
n
r combo (biacoyl / ocuat
) if to b
u

chronically. R
piratory 
pr
ion: mot 
riou. Monitor r
piratory rat
if
at ri. U
IV naloxon
(antagonit) to r
v
r
lif
-thr
at
ning 
pr
ion, bu
t may ppt withrawal if on chronic opiat
.

Nau
a / vomiting: u
to c
ntral timulation of ch
mor
c
ptor trigg
r zon
,
p

. in par
nt
ral oing for acut
pain. May n

 anti-
m
tic (hyroxyzin
, prochl
orp
razin
), but may 
ation. S
ation: o
-r
lat
 an with oth
r 
ativ
 (
BZD, anti-
m
tic). Tol
ranc

v
lop if chronically u
. May n

 CNS timula
nt (m
thylph
niat
, 
xtroamph
tamin
). Diff
r
nt from phyiological l

p (pai
n i controll

pati
nt r
t). Anticholin
rgic: ry mouth, urinary r
t
ntion. H
yp
r
nitivity: not tru
all
rgy. Itching or wh

l at inj
ction it
u
to hi
tamin
r
l
a
,
p. with intrath
cal or
piural. M
p
riin

CNS
xcitation: 

izur
-li
,
p. in r
nal failur
pati
nt. Du
to accumulation of norm
p
riin

m
tabolit
. Tol
ranc
: to analg
ic, 
ativ
an
uphoric
ff
ct. Combo with
NSAID may h
lp ov
rcom
thi probl
m. Oth
r SE: mioi,
uphoria, confuion / ha
llucination, coma, orthotatic hypot
nion, arrhythmia, hitamin
r
l
a
(itc
hing, vaoilation BP, bronchocontriction). D
p
n
nc
: Withrawal ymptom: an
xi
ty, irritability, inomnia, chill, alivation, rhinorrh
a, iaphor
i, nau

a, vomiting, GI cramping, iarrh
a, pilo
r
ction. Long t 1/2 l
 int
n
/ 
l
ay
 withrawal. R
uc
acut
withrawal by uing antagonit (naloxon
) or agoni
t-antagonit (p
ntazocin
). Drug int
raction: aitiv
CNS 
pr
ion (alcohol
, an
th
tic, anti
pr
ant, antihitamin
, barbiturat
, b
nzoiaz
pin
, p
h
nothiazin
). M
p
riin
with MAO inhibitor
hyp
rt
nion,
xcitation, rigiit
y.
Tramaol
Oral, c
ntrally acting, non-controll
, analg
ic with w
a opiat
(mu) activity
for mo
rat
to 
v
r
pain. Ch
mically unr
lat
 to opioi. M
chanim: bin t
o opiat
r
c
ptor
nor
pin
phrin
, 
rotonin r
upta
. Naloxon
i a partial ant
agonit. SE: GI (nau
a, contipation, ry mouth), CNS (izzin
, rowin
, h

aach
), r
piratory 
pr
ion, hitamin
r
l
a
. DI: 
ation with alcohol an
 hypnotic. Inhibit MAO avoi with MAO inhibitor ( 
izur
)
Mic
llan
ou ag
nt
Glucoamin
ulfat
an chonroitin ulfat
For 
g
n
rativ
joint i
a
(arth
riti) Glucoamin
: ubtrat
an timulant for bioynth
i of hyalouronic aci
an glucoaminoglycan forming prot
oglycan in tructural matrix of joint. SE
: GI, rowin
, h
aach
, rah. Chonroitin: ubtrat
for formation of h
alth
y joint matrix Analg
ic ajunct Oth
r rug aff
ct non-opiat
pain pathway
ma
y h
lp with c
rtain typ
 of pain (
.g. n
urog
nic / n
urologic), or to SE Examp
l
: tricyclic anti
pr
ant, anticonvulant, BZD, n
urol
ptic, corticot
ro
i, antihitamin
, amph
tamin
. Non-pharmacological pain manag
m
nt Inclu
C
ognitiv
B
havioral Int
rv
ntion (
ucation, intruction, r
laxation, biof

ba
c, hypnoi), an Phyical m
tho (acupunctur
, phyical th
rapy, compr
ion
glov
, orthotic 
vic
, h
at / col, maag
, immobilization,
x
rci
, r
t,
trancutan
ou
l
ctrical n
rv
timulation (TENS)

56. Nutrition an th
Hopitaliz
 Pati
nt

I. Nutritional probl
m in hopitaliz
 pati
nt
a. Malnutrition:
Pathologic tat
r
ulting from th
r
lativ
or abolut

fici
ncy or
xc
 of
on
or mor


ntial nutri
nt.
b. Maramu:
Chornic tat
(ov
r month or y
ar) that r
ult from 
fici
ncy in th
total ca
lori
inta


pl
tion of fat tor
 an 
l
tal prot
in to m

t m
tabolic n


. Vic
ral prot
in i pr

rv
 (normal 
rum albumin, pr
albumin, tranf
rrin
). Immun
comp
t
nc
, woun h
aling an ability to hanl
hort t
rm tr
 ar

pr

rv
 Aggr
iv
nutritional r
pl
tion can r
ult in m
tabolic itrubanc

(
.g. hypoal
mia, hypophophat
mia)
c. Kwahioror
Acut
pric
 (within w

) u
to ina
quat
prot
in inta
Vic
ral prot
in 

pl
tion, impair
 immun
function Hyp
rm
taboim (
.g. trauma, inf
ction, urg

ry) + prot
in 
privation wahioror malnutrion, hypoalbumin
mia,

ma Aggr

iv
nutritional prot
in r
pl
tion i warrant


. Mix
 maramu wahioror

S
v
r
prot
in-calori
malnutrition wh
n maramic pati
nt ar
hyp
rm
tabolic
II. Nutritional a
m
nt of m
tabolic r
quir
m
nt
A. Nutritional a
m
nt
1. Subj
ctiv
global a
m
nt (SGA): r
li
 on pati
nt hitory 2. Prognotic n
utritional in
x (PNI) D
riv
 from a formula that quantifi
 pati
nt ri of 

v
loping complication ba
 on mar
r of nutritional tatu uch a: 
rum alb
umin (vic
ral prot
in), tric
p n fol thicn
 an 
lay
 hyp
r
nitivity
in-t
t r
activity (immun
comp
t
nc
). PNI<40 low ri, PNI>50% high ri. 3
. Boy compoition analyi: m
aur
an compar
 th
ratio of boy compartm
nt
. a. Bio
l
ctrical imp

nc
: calculat
 l
an boy ma ba
 on r
itanc
to

l
ctrical curr
nt. Inaccurat
in critically ill pati
nt, an tho
with flui
or
l
ctrolyt
abnormaliti
. b. Dual
n
rgy x-ray aborptiom
try: m
aur
 fat
an l
an boy ma. D
p
n on hyration tatu c. Total boy potaium: u
 who
l
boy count
r to m
aur
potaum iotop
conc
ntrat
 in l
an tiu

m
aur

l
an boy ma . Total boy wat
r: m
aur
 l
an boy ma from 
ut
rium tota
l boy wat
r (impractical).
. In-vivo n
utron activation analyi: ivi
 th

boy into compartm
nt. R
quir
 larg
o
of raiation. 4. T
t of phyiologic
function: Quantify malnutrition ba
 on 
cr
a
in mucl
tr
ngth u
to ami
no aci mobilization. a. Maximum voluntary grip tr
ngth: m
aur
 with ioin
t
ic ynamom
try an corr
lat
 to total boy prot
in. b. El
ctrical timulation o
f th
ulnar n
rv
: m
aur
 mucl
contraction.
B. M
tabolic r
quirm
nt:
1. En
rgy r
quirm
nt D
t
rmin
 a nonprot
in calori
 (NPC). Can b
m
au
 by
:

a. Inir
ct calorim
try or M
aur
 En
rgy Exp
nur
(MEE) Mot accurat
. Dir
ct

ly m
aur
 O2 conumption an CO2 prouction. En
rgy r
quirm
nt i ir
ctly r
l
at
 to oxyg
n conumption. R
piratory quoti
nt (RQ) = CO2 prouc
 / O2 conum

 Oxiation of nutri
nt: carobohyrat
 RQ = 1.0, fat RQ = 0.7, Lipog
n
i: co
nv
rion of
xc
 carbohyrat
calori
 to fat, prouc
 mor
CO2 than oxiation
. b. Etimat

n
rgy
xp
nur
(EEE) R
quir
 calculation of baal
n
rgy
xp
n
ur
(BEE) from Harri-B
n
ict
quation. BEE i th
n multipli
 by tr
 an 
ubtrat
utilization factor. c. Simpl
nomogram Ba
 on pati
nt w
ight, l
at
accurat
. Rang
from 2535 Kcal/g/ay 
p
ning on 
gr

of tr
. 2. Prot
in
(nitrog
n) r
quirm
nt a. Nitrog
n balanc
t
chniqu
 16% of prot
in i compri

 of nitrog
n Nitrog
n balanc
= 24hr nitrog
n inta
24hr nitrog
n output Nitro
g
n output = urin
ur
a nitrog
n + nonur
a urin
nitrog
n (ammonia, cr
atinin
)
+ nonurin
nitrog
n lo (in/f
c
) Poitiv
nitrog
n balanc
of 3-6 g i th

goal (not for th
r
nally impair
) b. Nomogram m
tho:
timat
 prot
in n


ba
 on l
an boy w
ight (1.5-2.0 g prot
in/g/ay) c. Nonprot
in calori
to ni
trog
n (NPC:N) ratio: normally 125-150:1 3. E
ntial fatty aci (EFA): EFA a
r
polyunaturat
 fatty aci not ynth
iz
 by human. Linol
ic aci: princip
al EFA. It om
ga-6 polyunaturat
 fatty aci. Linol
ic aci 
fici
ncy iarrh
a
, 
rmatiti, hair lo Pr
v
nt EFA 
fici
ncy by giving ~5% of pati
nt calori

inta
a linol
ic aci from lipi
multion. 4. Vitamin: Fat olubl
: A, D, E
, K; Wat
r olubl
: B, C Vitamin A:

ntial for viion, growth, r
prouction.
IV form bin to platic an gla. Vitamin D: r
gulat
calcium / phophorou ho
m
otai tog
th
r with calcitonin an parathormon
. Vitamin E: antioxiant, oxi
ation of fr

unaturat
 fatty aci. N

 to Vitamin E in i
t in unaturat

 fatty aci. Vitamin K: critical for ynth
i of clotting factor. Vitamin B1
(thiamin
): co
nzym
in phophogluconat
, tructural compon
nt of n
rvou yt

m m
mbran
. D
fici
ncy
acut
p
rniciou b
rib
ri. Prolong
 
fici
ncy
W
rnic


nc
phalopathy. Vitamin B2 (riboflavin): co
nzym
in oxiativ
phophorylation.
No intrac
llular tor
 maintain
. Vitamin B3 (niacin): con
nzym
in oxiativ

phophorylation. D
fici
ncy
p
llagra. Vitamin B5 (pantoth
nic aci): functional
form i co
nzym
A,

ntial for all acylation r
action. Vitamin B6 (pyrioxi
n
): co
nzym
in
nzymatic r
action. D
fici
ncy wh
n taing ionizi, p
nicilla
min
, cyclo
rin
. Vitamin B7 (biotin): ynth
iz
 by int
tinal floar. Involv

 in carboxylation r
action. Vitamin B9 (folic aci): folat
cofactor ar
n



 for puri
n an pyrimiin
(DNA) ynth
i. D
fici
ncy in B12

fici
ncy in (B
9) folat

m
galoblatic an
mia. D
fici
ncy uring pr
gnancy
n
ural tub
f
tal 

f
ct. Vitamin B12 (cyanocobalamin): larg
tor


fici
ncy 
v
lop in y
ar.
D
fici
ncy: m
galoblatic (p
rniciou) an
mia, p
riph
ral n
uropathy (n


 for
my
lin ynth
i). 5. Trac
min
ral Iron: n
c
ary for h
moglobin an myoglob
in prouction,
nzymatic r
action (cofactor). D
fici
ncy: hypochromic, microcyt
ic an
mia, immun

fici
ncy. Zinc: n
c
ary for RNA, DNA ynth
i an
nzymat
ic r
action (cofactor). D
fici
ncy: impari
 woun h
aling, growth r
taration,
hair lo, anor
xia.
ri of 
fici
ncy in long-t
rm t
roi th
rapy, malaborp
tion, urg
ry. Copp
r: n
c
ary for h
m
ynth
i,
l
ctron tranport, woun h

aling. D
fici
ncy: an
mia, l
uop
nia, n
utrop
nia.

Mangan

: involv
 in prot
in ynth
i S
l
nium: for antioxiant r
action. D

fici
ncy: mucl
pain, cariomyopathy. Ioin
: compon
nt of thyroi hormon
. D

fici
ncy: goit
r Chromium: critical for gluco
u
,
inluin
ff
ct. D
fici
ncy:
hyp
rglyc
mia, gluco
intol
ranc
. Molyb
num:

ntial to xanthin
oxia

100. Th
Pati
nt B
havioral D
t
rimant 102. Drug Eucation 103. Pati
nt complia
nc

D
finition:
xt
nt to which an iniviual b
havior coinci
 with m
ical or h
a
lth avic
. Noncomplianc
can b
int
ntional or unint
ntional. About 50% of th

population i noncompliant with rug th
rapy in om
way. Cau
 in th

l
rly:
complicat
 rug r
gim
n, inability to r
a lab
l, ifficulty op
ning li,
t
c. Noncomplianc
can aff
ct an bia th
r
ult of clinical tui
.
Typ
 of noncomplianc

Not filling Rx: b
cau
th
y o not f

l th
y n

 or want th
Rx. Exampl
: an i
nf
ction with Tyl
nol i f

ling b
tt
r an improving. May b
b
cau
of cot. O
miion of o
: common for rug that ar
ta
n fr
qu
ntly for long tim
. Wrong
o
: amount of o
 or fr
qu
ncy of aminitration i incorr
ct. Incorr
ct am
initration: for
xampl
, not uing th
right t
chniqu
with a
rool, or wrong
rout
of aminitration. Wrong tim
: for
xampl
, rug ta
n at th
wrong tim
i
n r
lationhip to m
al. Drug uch a t
tracyclin
, fluoroquinolon
,
rythromy
cin houl b
ta
n on
mpty tomach. Diur
tic houl b
ta
n in th
morning. P
r
matur
/c: common with antibiotic (ymptom ubi
) or chronic rug uch a
 for BP (aymptomatic). Storag
: improp
r torag
an improp
r ipoal of unu

 rug.
Con
qu
nc
 of noncomplianc

Ov
r an un
r utilization hav
major
conomic impact. Alway, th
b
n
fit from
complianc
outw
igh th
cot of complianc

nhancing program. Ov
rutilization
: may cau
toxicity. Exampl
: oubl
o
to ma
up for mi
 o
, if on
p
ill i goo th
n mor
mut b

v
n b
tt
r. Noncomplianc
i on
of th
mot comm
only mi
 iagno
 (
.g. poorly controll
 BP). Con
qu
nc
 of noncomplianc

ar
not alway n
gativ
. Som
pati
nt ar
int
llig
nt noncompliant wh
r
th
y al
t
r th
o
ba
 on SE
m
rg
nc
whil
tr
atm
nt goal i till achi
v
.
D
t
ction of noncomplianc

Diagnoi of th
probl
m i a 
y. B
havior may chang
with tim
. I
al 
t
ctio
n ta
 plac
at th
tim
an plac
of taing th
m
ication.
Inir
ct m
aur
:
S
lf-r
port an int
rvi
w: impl
t, but ov
r
timat
 complianc
. Mot p
opl
h
av
troubl
r
m
mb
ring to ta
th
ir m
icin
. Do you hav
troubl
r
m
mb
ring
to ta
your? Pill count: commonly u
 in clinical tui
. Pill umping i a
common probl
m (tuy participant try to 
c
iv
phyician). Ov
r
timat
comp
lianc
. Chang
of w
ight of MDI can b
u
. Achi
v
m
nt of tr
atm
nt goal:
xam
pl
: normal BP, BG, intraocular pr
ur
. How
v
r, pati
nt may loa-up on m
i
cation or u
oth
r r
gim
n (i
t) b
for
octor viit. Thi i call
 toothbru
h
ff
ct (p
opl
toothbruh b
for

ntit viit).

Comput
riz
 complianc
monitor: mot r
liabl
inir
ct m
tho. Start
 with
l

ctronic
y
-rop ip
n
r. A microproc
or i locat
 in th
cap of th
cont
ain
r. Tim
an at
ar
r
cor

v
ry tim
th
pati
nt r
mov
 th
cap. V
ry u

ful in clinical tui
. R
fill rat
: commonly u
 in community pharmacy 
tt
ing.
Dir
ct m
aur
:
Dir
ct m
tho ar
mor
r
liabl
. U
of at l
at 2 m
tho i r
comm
n
. Biol
ogical mar
r an trac
r compoun: inicat
pati
nt complianc
ov
r
xt
n
 p

rio. Exampl
: glycoylat
 h
moglobin a

 BG control ov
r th
pr
c
ing 3
-month. Trac
r compoun: mall amount of ag
nt uch a Ph
nobarbital or igo
xin (long half lif
, inicat
complianc
for pat w

) ar
a
 to rug an
m
aur
 in biological flui. Drug conc
ntration in biological flui: limit

u
fuln
 u
to variability b
tw

n iniviual, o
 not inicat
th
timing
of th
o
, can b
fool
 by loaing-up prior to biological flui ampling.
Th
noncompliant pati
nt
No conit
nt patt
rn ha b

n ob
rv
 r
garing noncomplianc
with c
rtain ag

,
ucation, occupation, ocio
conomic tatu, p
ronality, rac
, 
v
rity or ty
p
of illn
,
tc. Int
ntional noncomplianc
i mor
common in pati
nt who u

 two or mor
rug or two or mor
phyician. H
alth B
li
f Mo
l: 
v
lop
 in
itially to
xplain pr
v
ntativ
h
alth b
havior uch a immunization an proph
ylactic 
ntal car
. It alo appli
 to complianc
with pr
crib
 m
ical r
gim

n. Thir G
n
ration Mo
l: focu
 on h
alth 
ciion. H
alth D
ciion Mo
l:
combin
 
ciion analyi, b
havioral 
ciion th
ory, an h
alth b
li
f to gi
v
a mo
l for h
alth 
ciion an r
ultant b
havior. Complianc
an h
alth b

li
f: pati
nt ha to b
li
v
that: h
ha th
illn
 iagno
, illn
 can ca
u

v
r
con
qu
nc
 to aily functioning, tr
atm
nt will pr

nt an futur


v
rity of conition, b
n
fit or r
gim
n outw
igh p
rc
iv
 iavantag
 an
cot. Stimulu to trigg
r poitiv
h
alth b
havior can b
int
rnal (pati
nt con
c
rn) or
xt
rnal (int
raction with phyician or pharmacit). Myth: n

 to ta

m
ication only wh
n
xp
ri
ncing ymptom , n

 to /c m
ication occaionally
to pr
v
nt 
p
n
nc
an maintain
fficacy. Oth
r factor: pati
nt who liv
alon

ar
mor
noncompliant. Pati
nt may hav
f
ar of 
p
n
nc
for any rug that i
 u
 chronically. Th
y may /c or o
occaionally to pr
v
nt thi or to prov

to th
m
lv
 that i not th
ca
.
Factor aociat
 with noncomplianc

Di
a

Pychiatric pati
nt ar
mor
noncomplianc
u
to an attitu
or inability to co
op
rat
. Pati
nt with chronic aymptomatic i
a
ar
mor
noncompliant (hyp
r
t
nion, hyp
rchol
t
rol
mia, tub
rculoi). Occurr
nc
of ignificant ymptom
upon /c may complianc
. iability cau
 by th
i
a

complianc
. No g
n
ra
l corr
lation b
tw

n i
a

v
rity an complianc
.
Th
rap
utic r
gim
n
Multipl
rug th
rapy: numb
r of rug
noncomplianc
(
.g. in g
riatric). Th

imilarity in app
aranc
of rug may l
a to confuion. Combination rug may h

lp but th
rapy houl tart with iniviual rug an th
n witch
 to th
combo
wh
n optimum o
i r
ach
. Fr
qu
ncy of aminitration: may cau
int
rrupti
on of normal routin
or wor ch
ul

inconv
ni
nc
,
mbarram
nt, forg
t. V
ry
critical factor in complianc
. How
v
r, pati
nt may b

ptical about th

ff

ctiv
of a QD rug. Duration of th
rapy: rat
of noncomplianc
a uration . Av

r

ff
ct: chang
oag
or u
alt
rnativ
rug if poibl
. Big probl
m wh

n th
m
ication ma
 th
pati
nt f

l wor
than b
for
(
.g., BP rug). S
xu
al yfunction i common cau
(
.g.

with antipychotic, antihyp
rt
niv
). Jut communicating pot
ntial SE may cau


th
pati
nt not to ta
th
rug. Aymptomatic conition: inclu
 lac of 
ymptom b
for
th
rug, lac of app
aranc
of ymptom if rug i /c, iapp
a
ranc
of ymptom (antibiotic). Cot: cot Rx not fill
, o
i ta
n, fr
qu
nc
y, pr
matur
ly /c. Aminitration: for
xampl
, incorr
ct m
aur
of liqui m

ication, MDI u
, oral antibiotic rop for
ar inf
ction intill
 in th

ar,
uing uppoitory by th
oral rout
. Tat
: common for oral liqui in chilr
n
(
.g. liqui KCl).
Pati
nt/pharmacit int
raction
Pychological upport houl b
provi
 in a compaionat
mann
r. Pati
nt ar

complianc
with a phyician th
y now an r
p
ct. Not appr
ciating importanc

of th
rapy: if th
rapy o
 not m

t th
ir own or taught
xp
ctation
noncomplia
nc
. Poor un
rtaning of intruction: a ir
ct
 houl b
avoi
 on lab
l.
v

ry 8 hour i mor
p
cific than thr

tim
 a ay. Auxiliary intruction ar
al
o 
y. Exampl
: apply on
nitroglyc
rin patch a ay, pati
nt got confu
 an a

 a n
w patch without r
moving th
ol on
.
Improving complianc

I
ntification of ri factor
All pati
nt houl b
vi
w
 a pot
ntial noncomlpi
r. Evaluat
th
probabilit
y of b
ing noncompliant ba
 on th
ri factor.
D
v
lopm
nt of tr
atm
nt plan
R
comm
n long
r acting rug or oag
form. Th
mor
activ
ly participating p
ati
nt in th
plan i mor
compliant. Plan houl b
iniviualiz
. Tailor r
gi
m
n to inconv
ni
nc
an forg
tfuln
 by fitting it to r
gular activiti
 in th

pati
nt ch
ul
. Inicat
p
cific tim
 of th
ay to ta
m
ication if po
ibl
.
Pati
nt
ucation
Eff
ctiv
communication i th

y for complianc
. Pati
nt houl b
a
 to r

p
at th
intruction to how un
rtaning. K
y point: nam
of m
ication, ac
tion, how much to ta
, wh
n, for how long, foo int
raction, poibl
SE, what
to o about SE, information h

t. Oral communication / coun
ling: mor
import
ant than writt
n, a it giv
 pati
nt a chanc
to int
ract an a qu
tion. En
ur
privacy an itraction. S
parat
conultation ar
a i i
al. Call th
pat
i
nt if poibl
if fac
to fac
i not poibl
. Writt
n communication: importa
nt i a futur
r
f
r
nc
for th
pati
nt a h
i not
xp
ct
 to r
m
mb
r all 

tail. Writt
n info complianc
only for hort t
rm th
rapy (
.g. antibiotic).
Auioviual mat
rial: v
ry u
ful in c
rtain ituation (
.g. inulin, umatrip
tan, MDI). Controll
 th
rapy: it i r
comm
n
 that pati
nt tart 
lf-m
ica
tion b
for
hopital icharg
to tranition th
m from compl
t

p
n
nc
in th

hopital to compl
t
in
p
n
nc
at hom
. Sp
cial complianc
program:
xampl

: b
havioral program for chizophr
nic. Training inclu
l
arning on obtaining
information about rug b
n
fit, corr
ct 
lf-aminitration an
valuation of

ff
ct, i
ntify SE, taling about iu
with prof
ional. Program may b
u

ful alo for ight or h
aring impair
 pati
nt.
Pati
nt motivation
Goo nowl
g
about th
illn
 an m
ication o
 not n
c
arily tranlat
t
o complianc
. Pati
nt n

 to b
motivat
 not only
ucat
. Information mut
b
pr

nt
 in a mann
r that i not co
rciv
, thr
at
ning, or 
m
aning. U
p

cial pacaging or r
min
r yt
m if poibl
. A contract approach may b
u
f
ul with om
pati
nt wh
r
agr

m
nt i r
ach
 on p
cific action.

Complianc
ai
Lab
ling / auxiliary: mut b
cl
ar, accurat
an p
cific Cal
nar / R
min
r
chart: h
lp th
pati
nt un
rtan which m
ication to ta
an wh
n to ta
i
t. Sp
cial contain
r / cap: for
xampl
, yt
m with four compartm
nt for if
f
r
nt tim
p
rio (morning, noon,
v
ning, b
tim
) for
ach ay of th
w

.
Sp
cial cap can iplay th
tim
of th
ay wh
n th
lat o
wa ta
n. It fl
ah
 / b

p wh
n it i tim
for th
n
xt o
. Complianc
pacaging: 
fin
 a
 pr
-pacag
 unit that provi
 on
tr
atm
nt cycl
of th
m
ication. Uually
ba
 on blit
r pacag
. A goo
xampl
i p
cial pacaging for birth contro
l pill. Anoth
r
xampl
: pr
nion

cr
aing o
r
gim
n. Chil-proof cap m
ay b
a probl
m for th

l
rly or pati
nt with arthriti. Doag
form: for
x
ampl
ER, XR an tran
rmal patch
.
Monitoring th
rapy
S
lf monitoring: by th
pati
nt of th
tr
atm
nt r
gim
n, r
pon
param
t
r. P
harmacit monitoring: ba
 on ina
quat
fr
qu
ncy of r
fill, follow up by pho
n
or mail r
min
r. Automatic phon
call r
min
r yt
m hav
b

n u
. Brow
n bag program:
l
rly pull all m
ication in a bag an ta
th
m to a prof
i
onal for r
vi
w. Dir
ctly ob
rv
 tr
atm
nt: watch pati
nt wallow rug (
.g. i
n TB).
112. Pharmaco
conomic
Innovativ
rol
 for pharmacit: hom
IV th
rapy, rug l
v
l monitoring, par
nt

ral nutrition manag
m
nt, 
lf-car
coun
ling. Pharmacy 
rvic
 may provi
p
oitiv
outcom
 by morbiity, th
rap
utic control, cot of tr
atm
nt by uing

ffici
nt th
rapy, # of phyician viit, rat
of rug r
lat
 hopitalization, i
nci
nc
an int
nity of SE. Extra y
ar of lif
for a pati
nt population can b

conv
rt
 to ollar for oci
ty. Economic m
tho T
chniqu
Input Output Cl
aical op
ration analyi Unit (
.g. pharmacy hr) Unit (
.g. pati
nt monit
or
) Cot
ff
ctiv
n
 analyi Dollar Natural unit Cot b
n
fit analyi Do
llar Dollar Cot utility analyi Dollar Util
/pr
f
r
nc
 Cot minimization
analyi Dollar Aum

qual
Cot b
n
fit analyi
M
ical car
i an inv
tm
nt goo (in human capital) an a conumption goo. M

aur
of inv
tm
nt b
n
fit: pr

nt valu
of a p
ron lif
tim
prouctivity. Bo
th input (cot) an output (b
n
fit) hav
to b
quantifi
 in ollar. Both
$ amount ar
icount
 to th
ir pr

nt valu
at a c
rtain int
r
t rat
. Econ
omic valu
= pr

nt valu
of b
n
fit pr

nt valu
of cot. B
n
fit may b

ifficult to m
aur
or to conv
rt to $, or both.
B
n
fit
B
n
fit: 
fin
 a th
in cot r
aliz
 u
to program impl
m
ntation. Can b

ir
ct, inir
ct, or intangibl
. Dir
ct b
n
fit: aving on ir
ct cot in m

ical car
. Eay to m
aur
. Inir
ct b
n
fit: aving on inir
ct cot in th

m
ical car
. Difficult to m
aur
. It avoianc
of
arning an prouctivity l
o
 which woul hav
b

n incurr
 without th
h
alth program. Intangibl
b
n

fit: ifficult, if not impoibl
, to m
aur
. Intangibl
cot ar
pychologic
al (pain, uff
ring an gri
f).
Dicount rat

Dicount rat
i th
conv
rion of ollar amount to pr

nt valu
 through th
u

of int
r
t rat
. icount rat
: favor proj
ct with b
n
fit occurring in 
itant futur
. icount rat
: favor proj
ct with cot occurring in itant fu
tur
.

Commonly u
 icount rat
i th
yi
l rat
on long t
rm gov bon. Math
matic
al mo
l ar
u
 to calculat
b
n
fit/cot ratio. N
t Pr

nt Valu
(NPV): a n

w mo
l for calculating b
n
fit-cot. V
ry popular an curr
ntly r
comm
n

by many
conomit. Rat
of R
turn on Inv
tm
nt: calculat
 th
int
r
t rat
f
rom an initial program inv
tm
nt ov
r a pot
ntial tr
am of b
n
fit ov
r tim
.
Cot
ff
ctiv
n
 analyi
Alt
rnativ
way ar
compar
 for achi
ving r
ult ( BP, lif

xp
ctancy). Simil
ar output m
aur
m
nt mut b
achi
v
 to compar
program. Cot B
n
fit Analy
i Cot Eff
ctiv
n
 Analyi Output: ollar valu
 Output: unit not ollar D

t
rmin
 maximum b
n
fit or inv
tm
nt D
t
rmin
 l
at cot combination Aum

 limit
 r
ourc
 Aum
 a
quat
r
ourc
 Fat comparion of program Diff

r
nt way to r
ach am
obj
ctiv
 L
 fl
xibl
Mor
fl
xibl

Economic p
rp
ctiv

A pharmacy 
rvic
with poitiv
b
n
fit/cot ratio may b
goo for th
oci
ty
a a whol
but not to
v
ry 
gm
nt of th
oci
ty. Exampl
: rug r
gim
nt that
# of pati
nt ay in acut
car
i goo for th
oci
ty but may not b
goo for
th
hopital that 
p
n on pati
nt tay for r
v
nu
. Alway coni
r who pay
th
cot an who r
c
iv
 th
b
n
fit.
Quality of lif
outcom
 an pati
nt 
ciion
Quality of lif
an atifaction with 
rvic
ar
critical. El
m
nt may inclu

: probability of ucc
, aociat
 pain, li
ly outcom
,
tc. Exampl
: th
qu
ality of y
ar within lif

xt
nion (h
althy y
ar?). Exampl
: untr
at
 hyp
rt

nion may not critical aff
ct aily lif
, but a MI woul quality of lif
. H
alt
h-r
lat
 quality of lif
(HRQL) i a humanitic outcom
. Uing 
ciion-analyi
 t
chniqu
, a 
ciion tr

can b
ma
of what happ
n to th
pati
nt from i
agnoi to cur
. Th
FDA ha b

n l

ry of rug that quality but lif

xp
ctanc
y. Di
a
 ar
aociat
 with phyical, m
ntal an ocial impairm
nt (which c
an b
ifficult to m
aur
).
Pharmacy Manag
m
nt (PDF fil
)
Baic accounting
Accounting: proc
 of coll
cting, r
coring, ummarizing, uing financial ata
Auiting: accounting that 
al with v
rifying that r
cor ar

pt an computa
tion ar
ma
. Boo

ping: proc
 that ocum
nt flow of r
ourc
 ($$, goo
) into / out of th
buin
, an claim of cr
itor / own
r to tho
r
ourc

 Dual
ff
ct of accounting: mot tranaction ar
r
cor
 twic
with th
r
u
lt of a balanc
 h

t. T Account: with 
bt on th
l
ft an cr
it on th
right
. D
bit = Cr
it. Tranaction: fical / financial
v
nt that ar
r
cor
. A
ccounting p
rio: p
rio of tim
ov
r which tranaction ar
r
cor
, at th

n
 of which incom
i m
aur
. Uually 1 y
ar. Not alway a cal
nar y
ar. M
tho
 of r
coring tranaction: Accrual: tranaction ar
r
cor
 at th
tim
th

y occur. Cah: tranaction ar
r
cor
 wh
n cah tranf
r han. R
v
nu
: m
a
ur
m
nt of goo ol or 
rvic
 r
n
r
 for which th
buin
 r
c
iv
 cah
or th
promi
of cah. Exp
n
: r
ourc
 u
 up uring a p
rio of tim
to

arn r
v
nu
. Typ
 of account: own
r
quity = a
t - liabiliti
. A
t: r

ourc
 own
 by th
buin
,
.g. cah, account r
c
ivabl
, builing, inv
nto
ry,
quipm
nt, furnitur
, pr
pai inuranc
.

Liabiliti
: 
bt own
 by th
buin
 to cr
itor. It ari
 wh
n buin
 bo

rrow cah (
.g. ban loan) or purcha
 goo or 
rvic
 on cr
it. Exampl
:
account payabl
, not
 payabl
. Own
r
quity (N
t Worth): claim of th
own
r t
o th
a
t of th
buin
 aft
r all cr
itor hav
b

n pai. It wh
n own
r
ma
inv
tm
nt in buin
 or wh
n r
v
nu
i
arn
. It wh
n
xp
n
 ar
pai
. Exampl
: contribut
 capital, al
 r
v
nu
, 
rvic
r
v
nu
,
xp
n
accoun
t. Exp
n
: not a liability b
cau
th
y ar
u
 up r
ourc
 that r
quir
th

imm
iat
paym
nt of cah for th
amount in full, oth
rwi

liability. Pr
pai

xp
n
 ar
a
t b
cau
th
yr
r
ourc
 that hav
not y
t b

n u
 up. Inc
om
= r
v
nu

xp
n
. Cot of Goo on Han: on lat ay of accounting p
rio
phyical inv
ntory to 
t
rmin
cot of inv
ntory not ol. No phyical inv
nto
ry i n


 if p
rp
tual inv
ntory i 
pt by comput
r yt
m. Fix
 a
t: t
angibl
, long-liv
 r
ourc
 u
 in buin
 op
ration,
.g. builing, machin

ry, fixtur
,
quipm
nt,
tc. Curr
nt a
t: r
ourc
 own
 by th
buin
 wh
ich ar

xp
ct
 to b
r
aliz
 in cah, ol or conum
 in on
y
ar,
.g. acco
unt r
c
ivabl
, inv
ntory,
tc. D
pr
ciation: w
ar an t
ar that occur on fix

a
t calculat
 a an
xp
n
. Mot fix
 a
t,
xc
pt lan, ar

pr
ciat

. Contra (off
t) account: r
i
ir
ctly b
low th
fix
 a
t account to wh
ich th
y p
rtain.
Incom
tat
m
nt
Summary of op
ration, incom

arn
 uring accounting p
rio. Contruct
 uing
r
v
nu
an
xp
n
account balanc
. R
v
nu
: al
 of goo an 
rvic
 Cot
of goo ol: uch a inv
ntory an tranportation
xp
n
. Gro margin = r
v

nu
cot of goo ol. N
t profit (incom
) = r
v
nu
all
xp
n
. N
t incom

= n
t profit incom
tax
Balanc
h

t
Pr

nt th
financial poition of th
buin
 at a c
rtain point in tim
Cont
ruct
 uing all a
t account, liability account, OE account R
tain

arning
: lin incom
tat
m
nt an balanc
h

t.
Purchaing an inv
ntory
Inv
ntory manag
m
nt
Involv
 planning, organizing, controlling inv
ntory for profitability Inv
ntory
control obj
ctiv
: inv
tm
nt, purchaing / carrying cot, balanc
upply an

man. Inv
ntory i th
larg
t pharmacy inv
tm
nt critical to manag
. Total
inv
ntory cot = acquiition cot + toc out cot + carrying cot + procur

m
nt cot. Acquiition cot: amount th
pharmacy pay for th
prouct. Stoc ou
t cot: cot of not having th
prouct availabl
wh
n n


 Carrying cot: t
orag
, hanling, inuranc
, lo/th
ft, amag
, capital Procur
m
nt cot: cot
of placing or
r, r
c
iving it
m, tocing h
lv
, proc
ing ocum
ntation O
bj
ctiv
of holing inv
ntory: to guar againt fluctuation in 
man an lat
r

liv
ry, ta
avantag
of bul icount. Goal of inv
ntory manag
m
nt: minim
iz
inv
tm
nt in carrying an procuring inv
ntory by balancing upply an 
man
ignificant impact on financial. procur
m
nt an carrying co
. Inv
ntory cot
t, al
 by avoiing toc-out Cah flow: prompt paym
nt, COGS, gro margin
Inv
ntory turn-ov
r rat
(ITOR) = COGS/av
rag
inv
ntory. Targ
t: ITOR to r
turn
on inv
tm
nt in inv
ntory, inv
tm
nt in inv
ntory to fr

up capital for oth

r v
ntur
. Inv
ntory r
turn on inv
tm
nt = n
t profit/av
rag
inv
ntory. What
to buy? prouct, manufactur
r, comp
titor coni
ration. Wh
r
to buy? coni
r
or
r cycl
tim
, minimum or
r r
quir
. How much an wh
n to buy? ifficult to

t
rmin
.

Cycl
toc: inv
ntory 
pt on han to fulfill or
r Buff
r/af
ty toc: inv
n
tory for ca
of upply/
man fluctuation. Anticipatory/p
culativ
toc: inv

ntory for
xp
ct
 in 
man
St
p of purchaing
Cot of goo ol (COGS): hav
ramatic
ff
ct on profit Purchaing obj
ctiv

: right prouct / vari
ty, quality, quantity, pric
, tim
1. Mar
t r

arch: to

t
rmin
n

/want of pati
nt / pr
crib
r, i
ntify pharmacy imag
an bu
in
 goal, pac
limitation, pot
ntial al
. D
t
rmining n

: uag
r
por
t, oth
r pharmaci
, pharmacy
mploy

, qu
tionnair
, al
 r
p, publih

top X rug, formulari
. Exampl
: ar
a with young famili

chilr
n it
m, ol


l
rly it
m. Coni
r p
cial i
a
manag
m
nt ar
a,
.g. athma
r famili

, iab
t
. 2. Eff
ctiv
purchaing polici
: U
op
n-to-buy purcha
bug
t. Con
trol total $ inv
tm
nt in inv
ntory. U
prior y
ar ata to for
cat purcha
b
ug
t for
ach month in th
upcoming y
ar, ba
 on al
 an COSG. Ajut ( / )

ach month purcha
 ba
 on pr
viou month al
 an purcha
. Gro margin =
al
 COGS. 3. S
l
cting upply ourc
: mut b

p
nabl
, prompt, fr
qu
nt 

liv
ry, goo r
turn policy, fr
qu
ncy of out-of-toc, cutom
r 
rvic
, pric
,
financing arrang
m
nt. Option: whol
al
, manufactur
, buying group, rac jo
bb
r,
tc. Whol
al
: avantag
 inclu
torag
of goo until n


, rapi 

liv
ry, financing option, h
lp with av
rtiing promotion, tor
layout an 

ign. Rac jobb
r: toc an maintain a p
cifi
 aortm
nt of goo (
.g.
y

gla
) in a fixtur
in th
pharmacy. Manufactur
r: not common, larg
minimum
purcha
. C
ntral purchaing group: pool buying pow
r of in
p
n
nt pharmaci

 for b
tt
r t
rm. 4. N
gotiating t
rm: pric
, icount, ating, r
turn poli
cy. Pharmacy margin = ugg
t
 r
tail pric
pharmacy cot. Quantity icount:
cumulativ
(g
n
ric r
bat
) or non-cumulativ
($ or % p
r quantity). Cah icou
nt: for prompt paym
nt (typical: 2% if pai in 10 ay, n
t amount u
in 30 ay
), or icount for El
ctronic Fun Tranf
r. Final pric
i calculat
 aft
r u
btracting tra
, quantity an cah icount. Dating: tim
for icount an paym

nt (pr
paym
nt, coll
ct-on-
liv
ry (COD), 
lay
). R
turn
 goo policy: ful
l cr
it within x ay, partial cr
it aft
r y ay, non-r
turnabl
aft
r z ay
. Ch
c h
lv
 r
gularly for it
m not ol. Coni
r uing a r
turn
 goo 

rvic
company (charg
a f

). 5. Tranf
rring m
rchani
titl
(?) 6. R
c
iving
, maring, tocing: count hipm
nt, ch
c for amag
, ch
c invoic
, mar pric

 (m
rchani
, comput
r), toc. Stoc 
pth coni
ration: av
rag

man, r

vi
w tim
, l
a tim
, af
ty toc. Inv
ntory control inclu
 th
following: 1
. Viual: loo at # of unit in inv
ntory an compar
with how many houl b
ca
rri
, or
r mor
if n


. 2. P
rioic: count toc on han at c
rtain int
rva
l, compar
to minimum targ
t l
v
l, or
r mor
if n


. 3. P
rp
tual: monito
r inv
ntory all th
tim
(uually uing a comput
r). Comput
r yt
m: al
, an
alyi, tr
n, p
rp
tual, automatic or
ring, int
rfac
inv
ntory an ip
nin
g yt
m at point of al
.
Financial analyi / planning
Comparativ
analyi:
xpr

ach financial tat
m
nt compon
nt a p
rc
nt of 
al
, an compar
with Dig
t ata. Ratio analyi: compar
financial ratio wit
h ratio for th
am
company uring r
c
nt y
ar, an imilar group of pharmaci

 in NCPA Pharmacia Dig
t. Solv
ncy: ov
rall ability to pay l
gal 
bt. Calcu
lat
Curr
nt an Aci T
t ratio Curr
nt Ratio = curr
nt a
t / curr
nt liabil
iti
. Targ
t > 2 Aci T
t Ratio = (Cah + account r
c
ivabl
) / curr
nt liabil
iti
. Targ
t > 1 Oth
r olv
ncy ratio: curr
nt liabiliti
 / inv
ntory, total
liabiliti
 / n
t worth, long-t
rm liabiliti
 / n
t woring capital, fix
 a

t / n
t worth, Effici
ncy: how w
ll availabl
capital i u
. Inv
ntory turnov

r ratio. Inv
ntory turn ov
r ratio = COGS / av
rag
inv
ntory. Targ
t: 5-6. Oth

r
ffici
ncy ratio: n
t al
 / inv
ntory, account r
c
ivabl
an account paya
bl
coll
ction p
rio, n
t woring capital turnov
r.

Profitability: th
bottom lin
, important but not th
only m
aur
of ucc
. R

turn on n
t worth = n
t profit / n
t worth. Targ
t 25%. N
t worth = total a
t
 total liabiliti
. N
t profit / n
t al
: targ
t 5%. N
t profit / total a
t
. Targ
t 15%. N
t profit / inv
ntory. Targ
t 20%. Exp
n
: alari
, wag
, r

nt, utiliti
, accounting / l
gal f

, tax
, lic
n
, inuranc
, int
r
t,
q
uipm
nt, 
pr
ciation. Balanc
h

t: inclu
 a
t an liabiliti
. Curr
nt a

t: cah, account r
c
ivabl
, inv
ntory. Curr
nt liabiliti
: account payabl

, accru

xp
n
.
Pricing
Compon
nt of pric
= ingr
i
nt cot + 
rvic
cot (ip
ning) + incom
. Actu
al Acquiition Cot (AAC): pric
th
pharmacy pay for th
prouct. Vari
 
p
n
ing on ourc
, volum
, inc
ntiv
 an 
al, typ
of pharmacy Av
rag
Whol
al

Pric
(AWP): NOT (?) th
av
rag
pric
th
whol
al
r 
ll th
prouct at. Co
t aign
 to prouct by manufactur
r, ov
rtat
 AAC Etimat
 Acquiition Cot
(EAC):
tablih
 by thir party pay
r to
timat
AAC. Uually a p
rc
ntag

of AWP (
.g. 90%). S
rvic
cot: av
rag
or p
r unit cot of proviing a 
rvic

. Cov
r
xp
n
 uch a alari
, r
nt, utiliti
, 
pr
ciation. Inclu
 cot
to ip
n
. Dir
ct cot: r
ult ir
ctly from proviing th

rvic
. No ir

ct cot if 
rvic
i not provi
. Dip
ning ir
ct cot: lab
l, contain
r,
comput
r, 
liv
ry cot, pati
nt
ucation mat
rial, pharmacy lic
n
. Inir

ct cot: cot har
 by all 
rvic
,
.g. r
nt, utiliti
, alari
, b
n
fit
, av
rtiing,
tc. Cot of proviing a 
rvic
= all ir
ct cot + fair har
o
f inir
c t cot. Cot allocation: 
t
rmining th
fair har
of inir
ct cot
. Difficult. Etimat
% of
mploy

 tim
an facility pac

vot
 to ip
ni
ng. Cot to ip
n
(COD): total ip
ning cot /
xp
ct
 Rx volum
. It i a
n
timation of th
av
rag
cot to ip
n
Rx. S
nitiv
to volum
. Diff
r
nti
al cot; iff
r among alt
rnativ
cour
 of action, i.
. aitional cot th

pharmacy incur for proviing a n
w 
rvic
. Non-cot factor: 
man, comp
titi
on, imag
, quality ignaling, goal, non-mon
tary cot. D
man: quantity conum

r will b
at a c
rtain pric
. Function of pric
. Elaticity of 
man: m
aur

 
nitivity of 
man to pric
. Elastic demand: small in price results in big
in demand. Sellers make money by lowerin g the price. Inelastic demand is opposi
te ( price
profit) Consumers are more sensitive to price when: cost of product is
large part of total cost, differences among products, comparisons are easy, con
sumers can judge quality, switching costs are small, commodity. Image: consumers
can select based on perceptions of pharmacy image. Image is affected by: prices
, size, location, services offered, personnel, promotions, etc Price as a signal
of quality: more likely when consumers cannot judge quality, more for services
than products. Penetration pricing: price to sales volume. Loss leader pricing:
Rx prices to OTC sales. Price skimming: price for superior service.
Basic Management
Management components: self, controllable surroundings, uncontrollable surroundi
ngs, external environment. Management activities: satisfy various entities, deal
with emergencies, purchasing, recruiting, accounting, training, planning, negot
iating, sales, dealing with regulatory officials. Management actions: identify t
asks, organize resources, monitor performance / task completion, plan for future
requirements, deal with problems. Functions of management actions: target setti
ng, problem solving, leadership, team building, dealing with emergencies. Manage
ment functions: controlling, directing, organizing, planning, staffing

Controlling: establish standards based on objectives, measure / report performan

ce, take corrective / preventative actions. Directing: motivation, communication
, performance appraisal, discipline, conflict resolution. Organizing: division o
f labor, delegation of authority, departmentalization, span of control, coordina
tion. Planning: vision, mission, objectives, coals Staffing: recruiting, selecti
ng, hiring, training, retaining Know self, who we are, what we aspire to become,
new info, what we need to know, who else need to work with us, etc. Managers ski
lls: intellectual, technical, ethical, interactive, emotional. Intellectual skil
ls: logical thinking, problem solving Ethical skills: define right from wrong In
teractive skills: communicate intelligently and create an atmosphere that facili
tates communication. Most problematic issues: poor communication, developing peo
ple, empowerment, lack of alignment, entitlement, balancing work / personal life
, confronting poor performance, coaching senior management, cross-functional str
ife, fascination with programs. Decision making: identify objectives, analyze re
levant factors, consider all alternatives, selection best option, implement the
decision, evaluate the results Management style: depends on organization, situat
ion, personal values, personality, chance. Self-development methods: observation
, reflection, guided readings, attachments / visits, seeking feedback, seeking c
hallenges. Strategic planning: must complement strategic thinking / acting. Incl
udes where we are going (mission) and how we get there (strategy). SWOT analysis
: strengths, weaknesses, opportunities, threats. Vision of success: mission, bas
ic philosophy, core values, goals, strategies, performance criteria, decision ru
les, ethical standards. Environment: stability, complexity, market diversity, ho
stility, competition Cascade of information: should flow not only downward, but
also upward Project management failures: lack of focus / attention, inability to
cope with different project characteristics, feeling being used / exploited, la
ck of experience Project management process: develop ideas and proposals, approv
e the project, project kick-off / start, monitoring / reporting / managing, term
ination. Project management 10 commandments: concentrate on interfacing, organiz
e project team, plan strategically / technically, remember Murphys law, identify
stakeholders, manage conflict, expect the unexpected, listen to intuition, apply
behavioral skills, take corrective actions. Project management functions: scope
/ quality / time / cost management PDCA Cycle: Plan, DO, Check, Act Problem sol
identify the criteria
weight importance of criteria
gen
ving: define the problem
erate alternatives rate alternatives on each criterion
compute the optimal decis
ion Continuous Quality Improvement (CQI): philosophical / structural / healthcar
e-specific elements. Use PDCA cycle. Philosophical elements: strategic focus (mi
ssion, values, objectives), customer focus (patient, provider, payer), systems f
ocus. Structural elements: process improvement teams, top management commitment,
statistical analysis, customer satisfaction measures, benchmarking, seven tools
(flow charts cause/effect diagrams, check sheets, histograms, etc). Healthcare
specific elements: epidemiological studies, governance processes (QA, committees
, peer review), risk-adjusted outcome measures, cost-effectiveness analysis. Bar
rier to quality transformation: lack of constancy of purpose, emphasis on shortterm profits, personal view system, management mobility, using only visible figu
res, cost of employee healthcare, cost of warranty / insurance.

5. Extemporaneous Prescription Compounding 18. Nuclear Pharmacy 19. Pharmaceutic

al Care and Disease Management 21. Adverse Reactions and Post Market Surveillanc
e 34. Clinical PK and Therapeutic Drug Monitroing 53. Renal Failure 57. Immunosu
ppressants in organ transplantation 58. Outcomes Research and Pharmacoeconomics
Health care system
Preferred Provider Organization (PPO): Broad network of providers available, gen
erally management is less strict. 52% Point of Service (POS): HMO plan with the
option of going outside the narrow provider network if willing to pay higher cos
t-sharing. 18% HMO: Narrow choice of providers, tighter management. 26% Types of
outcomes: Humanistic outcomes: Health Related Quality of Life, Patient Satisfac
tion, Caregiver Impact, Patient Preferences, Functional Status Economic: Cost An
alysis, Cost-of-Illness, Cost-Minimization, Cost-Benefit, Cost-Effectiveness, Co
stUtility Clinical: Efficacy, Safety, Impact of therapy on natural history of the
disease Methods for setting health insurance rates Experience rating: everyone i
n a specific area is charged the same premium based on the average cost of provi
ding health services to all people in the area Community rating: premium adjuste
d individually according to a persons or groups average health history, risk, and
past claim experience