Escolar Documentos
Profissional Documentos
Cultura Documentos
Pharmacology: Areas of
Study
Medical Pharmacology
science of substances used to
prevent, diagnose & treat disease
Toxicology
deals with undesirable effects of
chemicals on living systems
(cells to ecosystems)
- Poisons & Organ toxicity
Pharmacology: Areas of
Study
2 MAIN SUBDIVISIONS:
Pharmacology: Areas of
Study
Pharmacotherapeutics use of drugs
in the treatment of disease
Pharmacogenomics study of genetic
variations that cause differences in
drug response
Nature of Drugs
DRUG
- natural product, chemical
substance, or pharmaceutical
preparation for administration to
diagnose or treat a disease
- any substance that brings about a
change in biologic functions
through its chemical actions
Nature of Drugs
Synthetic
1. Aspirin
2. Barbiturates
3. Local anesthetics
Xenobiotics:
chemicals not synthesized in the
body
Nature of Drugs
isolated from
natural sources
or synthesized in
the laboratory
drugs intended
for
administration to
Nature of Drugs
Pharmaceutical Preparations
1.
2.
3.
4.
5.
Nature of Drugs
Routes of Administration
1. Topical Administration
2. Systemic Administration
A. Enteral
Administration
3. Oral
4. Rectal
5. Sublingual
6. Buccal
C. Transdermal
Administration
D. Inhalation
Administration
B. Parenteral
Administration
1.
Intravenous
2.
Intramuscular
3.
Subcutaneous
4.
Intrathecal
5.
Intra-articular
6.
Intra-dermal
7.
Epidural
Nature of Drugs
Drug Size
MW: 7 (Lithium)
59,050 (altepase)
Intravenous
or Intraarterial
MW 100-1000
drugs must be able to move from site
of administration to site of action
Nature of Drugs
Drug Reactivity & Drug-Receptor Bonds
1. Covalent very strong
e.g. ASA + cyclooxygenase
2. Electrostatic more common; relatively
strong (ionic bonds), weak (hydrogen
bonds), very weak (van der Waals forces)
3. Hydrophobic weak; interaction of lipidsoluble drugs with cell membrane
Nature of Drugs
Drug Reactivity & DrugReceptor Bonds
Drugs that form weak bonds with
receptors are more selective.
Nature of Drugs
Drug Shape
Complementary to its receptor as a
key to a lock
Stereoisomerism
*one enantiomer may be more potent than
the other
* one enantiomer more susceptible to drugmetabolizing enzymes (duration of action)
Me-too drug
structurally very similar to already known
drugs, with only minor differences.
genericdrugwith an identical formulation
and stated indications as adrugpreviously
approved by the FDA
chemically related to the prototype, or other
chemical compounds which have an identical
mechanism of action
Nature of Drugs
Side Effects
nuisance; tolerated to gain benefit of therapeutic effect
e.g. dry mouth & sedation of antihistamine
Adverse Effects
undesired and may be harmful
e.g. persistent diarrhea
Toxic Effects
Poisoning, extremely harmful & may be life-threatening
PHARMACOKINETIC
PRINCIPLES
Processes:
Absorption entrance of a drug
into the bloodstream
Distribution various tissues &
organs
Metabolism biotransformation
Elimination excretion of drug
(renal, intestinal, respiratory)
PHARMACOKINETIC
PRINCIPLES
Absorption
Permeation
-Movement through barriers separating
compartments
-Oral drug intestinal wall capillary wall
BBB walls of capillaries perfusing the
brain
PHARMACOKINETIC
PRINCIPLES
Mechanisms of Permeation
1. Aqueous diffusion drugs diffuse through
aqueous channels
large aqueous compartments (interstitial
space, cytosol)
epithelial membrane tight junctions &
endothelial pores
(MW 20,000-30,000)
PHARMACOKINETIC
PRINCIPLES
Mechanisms of Permeation
2. Lipid diffusion most important limiting factor in
permeation
- lipid:aqueous partition coefficient determines how
readily drug moves between aqueous & lipid media
- Ability of weak acid & weak base to move from
aqueous to lipid media or vice versa varies with the
pH of the medium
PHARMACOKINETIC
PRINCIPLES
Mechanisms of Permeation
Electrostatic charge of ionized molecule attracts water
dipoles polar, water-soluble & lipid-insoluble complex
Weak acid neutral molecule that can reversibly
dissociate into an anion & proton
C8H7O2COOH C8H7O2COO- + H+
Neutral ASA
ASA anion
Neutral Pyrimethanine
PHARMACOKINETIC
PRINCIPLES
Mechanisms of Permeation
ACID
Neutral ASA
BASE
ASA anion
C12H11O2CIN3NH3+
Pyrimethanine cation
C8H7O2COO- + H+
C12H11O2CIN3NH2 + H+
Neutral Pyrimethanine
PHARMACOKINETIC
PRINCIPLES
Mechanisms of Permeation
3. Special Carriers for molecules that are
too large or too insoluble to lipid
(peptides, AA, glucose)
- facilitated diffusion & active transport
- selective, saturable , inhibitable
PHARMACOKINETIC
PRINCIPLES
Mechanisms of Permeation
3. Special Carriers
ABC ATP- binding cassette family
- Less selective & expel foreign
molecules
1. P-glycoprotein or MDR1 (multi-
PHARMACOKINETIC
PRINCIPLES
Mechanisms of Permeation
3. Special Carriers
2. MDRP (MDR protein) transporters
- for excretion of drugs & metabolites in
urine & bile
- plays a role in resistance of tumors to
chemotherapeutic drugs
PHARMACOKINETIC
PRINCIPLES
Mechanisms of Permeation
3. Special Carriers
SLC (Solute carrier) family
- important in uptake of Neurotransmitters
NET (Norepinephrine transporter)
SERT (Serotonin transporter)
VMAT (Vesicular monoamine transporter)
PHARMACOKINETIC
PRINCIPLES
Mechanisms of Permeation
4. Endocytosis/Exocytosis for molecules
that are too large & impermeant
e.g. B12 (intrinsic factor)
Fe (transferrin)
Neurotransmitters
PHARMACOKINETIC
PRINCIPLES
Absorption
Bioavailability fraction of unchanged
drug reaching systemic circulation following
administration
IV 100%
IM, SC, Transdermal - < 100%
Oral, Rectal - < 100%
PHARMACOKINETIC
PRINCIPLES
Factors affecting Bioavailability
A. Extent of Absorption
Incomplete Low Bioavailability
Oral administration incompletely absorbed in the
gut
Hydrophilic drug cannot cross CM
Hydrophobic drug cant cross water layer adjacent
to cell
Reverse transporter P-glycoprotein
pumps drug out of gut wall back into
PHARMACOKINETIC
PRINCIPLES
Factors affecting
Bioavailability
B. First-Pass Effect
- portal blood delivers drug to the
liver prior to entry in systemic
circulation
Direct access to systemic veins
Alternative Routes
Sublingual
Transdermal
PHARMACOKINETIC
PRINCIPLES
Summary
Factors controlling Rate of
absorption:
1.Degree of ionization
2.Surface Area
3.Blood flow
4.Gastric emptying time & GI
motility
PHARMACOKINETIC
PRINCIPLES
Distribution
Volume of Distribution (V)
- Defined with respect to blood, plasma, or water
- An apparent volume necessary to contain the
amount of drug homogenously found in blood,
plasma, or water
- Can vastly exceed physical volume of the body
0.4 L/kg
0.04 L/kg
0.6 L/kg
0.2L/kg
PHARMACOKINETIC
PRINCIPLES
Distribution
Volume of Distribution
V = Amount of drug (dose)
C plasma conc.
= 500 mg
0.01 mg/ml
= 50000 ml or 50L
e.g. A 500 mg New drug was administered . The
plasma concentration is 0.01mg/ml. What is the V?
PHARMACOKINETIC
PRINCIPLES
Distribution
COMPARTMENT
Total body water
Extracellular
water
Blood
Fat
Bone
EXAMPLE OF DRUGS
Ethanol: Small water
soluble
Gentamicin: Large water
soluble
Heparin: Strongly plasma
protein-bound large
molecules
DDT : highly lipid soluble
Lead, Fluoride: ions
PHARMACOKINETIC
PRINCIPLES
Distribution
PHARMACOKINETIC
PRINCIPLES
Distribution
Binding to Plasma Proteins
1. Albumin most important; high affinity to drugs
2. Glycoproteins
3. Lipoprotein
4. Globulins
PHARMACOKINETIC
PRINCIPLES
Distribution
Factors Affecting Rate of Distribution:
1. Extent of binding free drug (unbound) able to distribute
2. Ability to diffuse through CM lipophilic
3. Degree of perfusion higher perfusion, faster equilibrium
Lung - 10 Kidney - 4
Heart
- 0.6 Brain - 0.5
Muscle 0.025 Fat - 0.003
PHARMACOKINETIC
PRINCIPLES
Distribution
Factors Affecting Rate of Distribution:
4. Properties of tissue membrane
Blood Brain Barrier tightly joined capillaries covered by
foot-like processes of astrocytes
Placental Barrier
separates fetal & maternal blood
- lipid-soluble drugs diffuse easily; water-soluble
drugs diffuse poorly
PHARMACOKINETIC
PRINCIPLES
Drug Biotransformation
Why is this necessary?
PHARMACOKINETIC
PRINCIPLES
Drug Biotransformation
Site:
Kidneys
Brain
Skin
GI tract
Gastric acid - penicillin
Digestive enzymes insulin
Enzymes in intestinal wall
PHARMACOKINETIC
PRINCIPLES
Drug Biotransformation
Site:
Plasma
hydrolyzed by
e.g. succinylcholine
pseudocholinesterase
lidocaine
Lungs
e.g. converts Angiotensin I to
Angiotensin II
PHARMACOKINETIC
PRINCIPLES
Drug Biotransformation
Major Categories
Phase I Reactions
- convert parent drug to a more polar metabolite by
introducing or unmasking a functional group
(-OH, -NH2, -SH) to be readily excreted
Oxidations Deamination
Desulfuration Reductions
Hydrolyses
e.g. Isoniazid N-acetyl conjugate hydrolyzed to
isonicotinic acid
PHARMACOKINETIC
PRINCIPLES
Drug Biotransformation
Major Categories
Phase II Reactions
PHARMACOKINETIC
PRINCIPLES
Drug Biotransformation
Phase II Reactions
- relatively faster
- previously terminal inactivation events or true
detoxification
- May precede Phase I reaction
Conjugates
- Polar molecules readily excreted & often
inactive
- Involves high-energy intermediates & specific
transfer enzymes
PHARMACOKINETIC
PRINCIPLES
Drug Biotransformation
Subcellular Site:
Endoplasmic reticulum
Mitochondria
Cytosol
Lysosomes
Plasma membrane
Microsomes lamellar membranes of
ER reform into vesicles after
PHARMACOKINETIC
PRINCIPLES
Drug Biotransformation
PHARMACOKINETIC
PRINCIPLES
Drug Biotransformation
Transferases
3.GSH (glutathione) transferase
- GSH conjugation
4. N-acetyl transferase
e.g. Isoniazid N-acetyl conjugate
- acetylation
5. Methyltransferase
- transmethylases methylation
Epoxide Hydrolases water conjugation
Absorptio
n
Metabolism
Phase I
Drug
Drug
Elimination
Phase II
Conjugate
Drug
metabolite
with modified
activity
Inactive drug
metabolite
Conjugate
Conjugate
Drug
Lipophilic
Hydrophilic
PHARMACOKINETIC
PRINCIPLES
Drug Biotransformation
PHARMACOKINETIC
PRINCIPLES
Drug Biotransformation
Acetaminophen
Glucuronidation
CYP1 CYP3A4
Sulfation
Sulfate
(N-acetylbenzoiminoquinone)
+
GSH
Neucleophillic
conjugation
cellular proteins
Mercapturic Acid
conjugate
PHARMACOKINETIC
PRINCIPLES
PHARMACOKINETIC
PRINCIPLES
PHARMACOKINETIC
PRINCIPLES
PHARMACOKINETIC
PRINCIPLES
PHARMACOKINETIC
PRINCIPLES
inducers
inducers
PHARMACOKINETIC
PRINCIPLES
Drug Excretion
Common Pathways:
Sweat
Saliva
Milk
Respiratory - role not significant in excretion
- when drugs are metabolized into
products that can be exchanged
from blood into respiratory system
- excreted by lungs
PHARMACOKINETIC
PRINCIPLES
Drug Excretion
Common Pathways:
PHARMACOKINETIC
PRINCIPLES
Drug Excretion
Common Pathways:
Renal
Fruits
Protein rich
Vegetables
food
Na2HCO3
Probiotics
PHARMACOKINETIC
PRINCIPLES
Drug Excretion
PHARMACOKINETIC
PRINCIPLES
Drug Excretion
kidney
kidney
+ CL liver + CL other
PHARMACOKINETIC
PRINCIPLES
Drug Excretion
First-order elimination
: constant over concentration
range
: elimination is not saturable
: rate of drug elimination is directly
proportional to concentration
Drug Concentration
(%max)
100
80
-
60
-
40
Time
20
0
Drug Concentration
(%max)
100 .0
10.0
1.0 -
Time
0.1
PHARMACOKINETIC
PRINCIPLES
Drug Excretion
Zero-order elimination
Capacity-limited elimination
Mixed-order, saturable, dose or
concentration dependent
Nonlinear or Michealis-Menten
elimination
Drug Concentration
(%max)
60
40
20
Time
Drug Concentration
(%max)
100
-
80
100
10
Time
PHARMACOKINETIC
PRINCIPLES
100
75
50
Plasma Concentration
(%of steady state)
Drug Excretion
25
1
7
2 3 4
8Time
PHARMACOKINETIC
PRINCIPLES
Drug Excretion
PHARMACOKINETIC
PRINCIPLES
Drug Excretion
Half life
Time required to change the amount
of drug in the body by during
elimination or constant infusion
Time course will depend on V & CL
t1/2 = 0.7 x V
CL
Elimination can be
described by exponential
process, time taken for 2fold decrease is
proportional to log 2 (0.7)
PHARMACOKINETIC
PRINCIPLES
Drug Excretion
100
75
50
Drug
accumulation
in constant rate
of infusion
Plasma Concentration
(%of steady state)
Half life
Indicates time required to attain 50% steady state
or to decay 50% from steady state
25
1
7
2 3 4 5 6
8Time (half lives)
Drug elimination
after constant
rate of infusion
reached steady
state
PHARMACOKINETIC
PRINCIPLES
Drug Accumulation
PHARMACOKINETIC
PRINCIPLES
Drug Excretion
100
75
50
Peak
Css
Trough
Plasma Concentration
(%of steady state)
25
1
7
2 3 4
8Time
PHARMACODYNAMIC PRINICPLES:
Objectives:
1. Identify the different target proteins and discuss their
mechanisms of drug-receptor interactions
2. Discuss the concepts of affinity, intrinsic activity,
selectivity and specificity
3. Describe signal transduction mechanisms, the
different types of G-proteins, and second messenger
system
4. State the occupancy theory and receptor inactivation
theories
5. Describe the different dose-response curves and the