PHARMACOLOGY---- Student Notes

PHARMACOLOGY LECTURE 1
INTRODUCTION
a xenobiotic is a drug that is not synthesied within the body
pharmacodynamics is the effect of the drug on the body (effect of drug at
receptor site)
pharmacokinetics is the effect of the body on the drug (absorption, distribution
and elimation of drug)
toxicology deals with the side effects of drugs
the therapeutic index ratio is the minimum dose that produces toxicity divided
by the minimum dose that produces the therapeutic response (therefore you want
a high therapeutic index)
PHARMACOLOGY LECTURE 2
RECEPTORS 1 - TARGETS FOR DRUG ACTION
affinity constant = K(D) - a low KD = a high affinity
o a K(D) of 10E-6 or more is considered too weak
drugs act at the following sites:
o cell surface receptors
o ion channels
o carrier pumps
e.g. some diurectics act on the Na+/Cl- cotransporter in the distal
tubules
e.g. some diurectics act on the Na+/K+ antiporter in the collecting
ducts
e.g. some antiulcer/reflux drugs work on the H+/K+ antiporter
o enzymes
e.g. NSAIDs inhibit cyclo-oxygenase which blocks prostaglandin
production
e.g. ACE inhibitors inhibit angiotensin converting enzyme to
decrease blood pressure
e.g. HMGCoA reductase inhibitors inhibit this to reduce lipid
concentration
o nuclear receptors/RNA/DNA
o intracellular structural proteins
Question: Aspirin and ibuprofen are NSAIDs that inhibit cyclo-oxygenase in
platelets (ibuprofen - competitive; aspirin - irreversible). What are the
clinical consequences of this difference in inhibition?
o Aspirin will be longer acting. Hence, people undergoing surgery must stop
taking aspirin 1 week before so clotting can occur during. whereas people
must only stop taking ibuprofen 1 day before surgery
inhibition constant = K(I) - measures degree of inhibition of an enzyme
therapeutics: treatment of disease can be by different targets:
o e.g. to treat gastric hyperacidity:
neutralising drug (NaHCO3)
proton pump inhibitor (omeprazole)
histamine 2 receptor blocker (ranitidine)
o some drugs act on more than one target, e.g. caffeine
levels of mecahnisms of action of drugs
o e.g. propranolol:
-1. molecular: is a competitive inhibitor by binding to beta 1
receptors
-1. cellular: prevents increase in cAMP, protein phosphorylation
-1. physiological: reduces cardiac heart rate and contractile force
-1. therapeutic: used to treat angina

PHARMACOLOGY LECTURE 3
RECEPTORS 2 - INTRACELLULAR MECHANISMS
(PHARMACODYNAMICS)
there are 4 basic mechanisms for transmembrane signalling
0. ligand gated channels
1. G protein-coupled receptors/second messengers
2. intracellular receptors
3. ligand-regulated transmembrane enzymes
1. ligand gated channels:
o example: nicotinic acetylcholine receptor
where: found on skeletal muscle
function: when activated causes contraction
structure: pentamer crossing lipid bilayer
mechanism of action: acetycholine binds to alpha subunit -->
conformational change --> trransient opening of central aqueous
channel --> Na+ flows down concentration gradient -->
depolarisation --> contraction
2. G protein-coupled receptors/second messengers
o signalling system involves:
0. extracellular drug binds to cell surface receptor
1. receptor triggers activation of a G protein on cytoplasmic face of
plasma membrane
2. activated G protein alters activity of an effector element (e.g.
enzyme or ion channel)
3. effector element changes concentration of intracellular second
messenger
o G protein structure:
contains alpha, beta and gamma subunits
the beta-gamma anchors the G protein to the membrane
the G protein is not normally bound to the receptor but is free
floating in the cell membrane (cytoplasmic side
o how G proteins work: see Alberts Molecular Biology of the Cell, Figure
15-23
0. when the receptor is not occupied by a drug: the G protein is in a
resting state, where beta-gamma anchors G protein to membrane,
and GDP occupies site on alpha subunit
1. the ligand binds to the receptor, which alters the conformation of
the receptor, exposing the binding site for G protein
2. the G protein binds to the receptor, greatly weakening the affinity
of the G protein for GDP
3. GDP dissociates, allowing GTP to bind to the alpha subunit
4. this causes the alpha subunit to change conformation, it now
dissociates from the receptor and the beta and gamma subunits
5. the free alpha subunit now changes conformation so that it can
bind with its target enzyme
6. this target enzyme acts, e.g. converts ATP-->cAMP, ion channel
etc.
7. hydrolysis of the GTP by the alpha subunit returns the subunit to
its original conformation, causing it to dissociate from the target
enzyme and reassociate with the beta and gamma subunits
o Gs is a G protein that acts on adenyl cyclase, hence converts ATP--
>cAMP
o Gi is a G protein that inhibits adenyl cyclase, hence prevents ATP--
>cAMP
o note that the slower the hydrolysis of the GTP (step 8), the longer for
which the G protein will act
o SECOND MESSENGERS - commonly used second messenger systems in
the body include:
0. cAMP
many drugs/hormones act by increasing or decreasing the
adenyl cyclase which in turn increases or decreases cAMP
1. calcium-phosphoinositide pathway (IP3/DAG)
mechanims of this pathway:
1. Gs stimulates phospholipase C (a membrane
enzyme) -->
2. hydrolysis of IP2 into DAG (diacyclglycerol) and
IP3 (inositol-1,4,5-triphosphate)
DAG activates protein kinase C -->
phosphorylates intracellular proteins -->
altered cellular function (e.g. contraction of
smooth muscle)
IP3 triggers release of Ca++ from storage
vesicles (in smooth muscle this will increase
contraction)
3. these signals are terminated by the following:
0. dephosphorylation of IP3
1. phosphorylating DAG to arachidonic acid
2. actively removing the Ca++
o How does ACh affect the ion channels in the heart?
the vagus nerve releases ACh --> binds to receptor in cardiac
muscle --> enhances K+ permeability --> hyperpolarisation -->
decreases activity
3. intracellular receptors - regulate gene expression
o ligands for intracellular receptors include: steroids, vitamin D, thyroid
hormone
o mechanism:
-1. ligand is lipid soluble, hence can cross plasma membrane
-1. binds with intracellular receptor
-1. intracellular receptors increases gene transcription by directly or
indirectly acting on promoter region
o drugs that act on intracellular receptors are slow acting because gene
transcription takes time, but endure hours after the drug has been
eliminated from the body
4. ligand-regulated transmembrane enzymes (protein tyrosine kinases)
o mechanism:
-1. ligand (includes insulin, growth factors) binds to receptor
-1. enzymes (tyrosine kinases) located in the cytoplasmic domains
(receptors have large extracellular and intracellular domains) are
activated and cause phosphorylation of certain targets
-1. these targets are activated or inactivated by this

SPECIFIC EXAMPLES DISCUSSED IN LECTURES, NOT ALLUDED TO ON HANDOUT
2. SURGERY
o during surgery, give curare to block nicotinic receptors (found on skeletal
muscle)
o therefore, surgeon can cut through muscle (it is relaxed)
o now, the curare stops breathing, therefore, must respirate patient
o after operation, give acetylcholinesterase inhibitor (stops
acetylcholinesterase from breaking down ACh in the synaptic clefts from
being broken down) which will increase the amount of ACh in the
synaptic clefts which is now in a great enough concentration to overcome
the curare, and hence, breathing will return quickly
2. CHOLERA
o is caused by a bacterium - cholerae
o bacterium secretes a toxin
o toxin enters intestinal cells
o toxin prevents GTP hydrolysing to GDP
o this prevents G stimulatory protein from shutting itself off
o therefore, intestinal cells accumate cAMP
o this leads to a Cl-/Na+ imbalance (more Cl- and Na+ in the lumen)
o hence, water is lost to the lumen
o this results in diarrhoea
2. CAFFEINE
o this inhibits phosphoresterase
o normally phosphoresterase hydrolases cAMP, which decreases cAMP
o hence, caffeine causes the following effect: increased cellular cAMP in
smooth muscle --> vasodilatation in kidney --> increases GFR --> diuresis

PHARMACOLOGY LECTURE 4
PHARMAKINETICS - GENERAL PRINCIPLES
pharmacokinetics is the characterisation of the time course of drug/metabolite
concentrations in the body
clinical pharmacokinetics is the application of pharmacokinetic principles to the
therapeutic management of patients
disposition
o is defined as those pharmacokinetc processes that occur after absorption of
the drug into the body (i.e. dristribution and elimination, and includes:
0. movement of drug from the site of administration to site of action
0. movement of drug to other organs
0. excretion of drug
absorption: most drugs are administered orally, and the gastrointestinal
absorption of drugs is a function of its physico-chemical properties (pKa,
lipophilicty, molecular weight) and the physiology of the gastrointestinal tract
(pH, gastric emptyimg)
distribution: is a function of:
o affinity of drug for tissue and plasma
o blood flow rates to organs
o drug's physico-chemical properties
elimination: is a function of
o biotransformation in the liver to metabolites
o excretion of the drug by the kidney
various parameters:
o bioavailability = F
o volume of distribution = V
o half-life = T(1/2)
o clearance = CL
first order kinetics = the rate of absorption, distribution and elimination is
directly proportional to the concentration
zeroth order kinetics = the rate of absorption, distribution and elimination are
independent of the concetration
the therapeutic window = the range of concentrations that give both adequate
therapy without unacceptable toxicity

PHARMACOLOGY LECTURE 5
PHARMACOKINETIC CONCEPTS
the two basic processes that modify pharmacokinetics (how the body deals with a
drug) are:
0. clearance
0. volume of distribution
CLEARANCE = CL
INTRODUCTION
o CL = rate of elimination/concentration (mg/h)
o elimination of drug can occur at:
CL(renal) = rate of elimination at kidneys / C
CL(liver) = rate of elimination at liver / C
CL(other) = rate of elimination not at the kidney or liver / C
CL(total) = CL(renal) + CL (liver) + CL (other)
o first order elimination (constant CL)
for most drugs the rate of elimination is directly proportional to the
concentration, and so clearance is constant
o zeroth order elimination (variable CL) - capacity limited elimination
some durgs do not have a constant clearance; these are capacity
limited drugs (e.g. ethanol)
for these drugs, an increase in concentration, does not see a
corresponding increase in elimination because the pathways of
elimination are saturated
note: actually, most drug elimination pathways will become
saturated if the concentration is high enough, and so eventually, at
a high enough concentration, all drugs will become capacity
limited BUT most drugs are given at concentrations that aren't
nearly high enough for this
a formula describing rate of elimination is:
rate of elimination = (Vmax + C) / (Km + C)
o flow dependent elimination: for drugs that are cleared very readily,
elimination is dependent on blood flow
MEASUREMENT OF TOTAL BODY CLEARANCE:
o area under concentration curve = AUC (this is the total area under the
blood/plasma concentration time curve) - see handout for diagram
o F = bioavailabilty (how much drug reaches the circulation after ingestion)
o Css = steady state concentration
o tau = the AUC within the dosing interval divided by the dosing interval
o single dose:
IV: CL = dose / AUC
oral: CL = dose x F / AUC
o chronic dosing:
IV constant infusion into body: CL = dose rate / Css
IV giving at separate intervals: CL = dose / (tau x Css)
oral taken at separate intervals: CL = F x dose / (tau x Css)
CLINICAL RELEVANCE
o clearance is the parameter which determines the maintenance of dose rate
required
o rearrangement of the IV constant infusion into body formula gives:
maintenance dose rate = desired concentration x clearance (i.e.
dose rate = Css x CL)
o clearance is an independent pharmacokinetic parameter
VOLUME OF DISTRIBUTION (V)
INTRODUCTION
o V = amount of drug in body / concentration in plasma
o example: a high V --> a low blood concentration, and therefore a high
drug concentration in extravascular tissue
MEASUREMENT OF V
o V = dose/C(0) = dose/(AUC x terminal slope)
o C(0) = plasma concentration at time 0
o C(0) can be determined by drawing a log plasma concentration vs. time
and extending the line to time 0; note that this is most accurate using log
paper since the line will probably be straight with log papers
CLINICAL RELEVANCE
o in some clinical settings, it is important to achieve the target concentration
instantly, rather than waiting for some time - the following formula can be
used
loading dose = Css x V
o volume of distribution is an independent pharmacokinetic parameter
HALF LIFE (t(1/2))
is the time taken for the blood concentration to fall by 50%
clearly, half life will be constant for first order drugs
MEASUREMENT OF HALF LIFE
o look at the concentration vs. time graph
o OR calculate using:
half life = ln2 x V / CL
half life is a dependent pharmacokinetic parameter derived from the
indepdent parameters CL and V
CLINICAL RELEVANCE
o for continuous dosing, steady state is said to be achieved after 5 half lives
BIOAVAILABILITY (F)
is defined as the frction of drug dose reaching the systemic circulation following
administration by any route
o F = 1 for IV administration
o 0 < F < 1 for oral administration
obviously therefore, F = (AUC[oral] / AUC[iv]) x (dose[iv] / dose[oral])
estimation of area under curve: bloody obvious

PHARMACOLOGY LECTURE 6
ADVERSE DRUG REACTIONS (ADR)

Adverse drug reaction: noxious and unintended effect of drug, occurring at doses used for
prophylaxis, diagnosis or therapy.
CLASSIFICATION: note that it is assumed drug dosage is within therapeutic window
Type A - explainable
type A ADR is the result of an exaggerated, but otherwise expected
pharmacological effect of drug
are predictable and dose dependent
examples:
o antihypertensive drugs - postural hypotension
o morphine - constipation
o caffeine - palpitations
o anti-epileptic drugs - sedation
some causes:
-1. pharmacokinetic (what body does to drug) - common
due to variability between patients in: bioavailability, first pass
effect, metabolism and renal excretion
predisposing factors:
age
pregnancy
diseases affecting pharacokinetics (e.g. kidney disease)
and/or pharmacodynamics, and pharmacogenetics
(oxidation, acetylation)
dose reduction will avoid ADR
-1. pharmacodynamic (what drug does to body)
result from
altered end-organ sensitivity (e.g. changes in receptors)
predisposing factors:
eldery (impaired homeostasis; e.g. postural hypotension
with diuretics)
drug interactions
unavoidable toxicity (e.g. cancer chemotherapeutic drugs
causes bone marrow depression)
-1. pharmaceutical formulation - not common
changes in the way the drug is distributed to the body can increase
concentration (e.g. by increasing bioavailability), so that the
concentration is at toxic levels
example: in 1968, changes with phenytoin increased bioavailability
leading to toxicity
Type B - unexplainable
type B ADR is not expected from known pharmacological action of drug
example:
o skin rash - penicillin
o haemolysis - antimalarials
some causes:
-1. pharmaceutical
due to in vitro degradation of products or additives
-1. pharmacokinetic
due to formation of electrophilic drug metabolite binding
covalently to tissue macromolecules
exmple: sulphonamides - major route of metabolism is n-
acetylation (non-toxic), but minor route is via cytochrome P450
metabolism (forms a reactive metabolite which binds covalently to
tissue and causes cellular toxicity)
-1. pharmacodynamic
example: haemolysis with sulphonamides in patients with red
blood cell glucose-6-phosphate dehydrogenase deficiency
Comparison between A and B
feature = type A / type B
pharmacology = augmented / bizarre
predictable = yes / no
dose dependent = yes / no
morbidity = high / low
mortality = low / high
Other
6. teratogenic, e.g. warfarin
6. carcinogenic, e.g. diethylstilboestrol
6. drug allergy
o previous exposure - sensitisation
o antigen can be drugs, drugs + protein, metabolites, impurities
o 4 posible mechanisms
0. immediate anaphylactic
0. antibody dependent cytotoxicity
0. antigen-antibody complexing
0. cell-mediated
EPIDEMIOLOGY
accurate informatino hard to get
o 5-35% of hospital admissions involve ADR
o 5% of hospital admissions are primarily due to ADR
o 10-20% of inpatients suffer ADR
o 0.1% of deaths on wards directly caused by ADR
o communicty prevalence unknown
FACTORS PREDISPOSING TO ADR
1. presence of severe disease, especially renal, hepatic and heart
1. polypharmacy and prolonged treatment
1. extremes og age
1. previous ADR
1. gender: females more susceptible than males
1. atopic history (more likely to have an allergic reaction)
1. genetic polymorphism
ADVERSE DRUG REACTION MONITORING - may be drug-oriented, disease
oriented, complication oriented
Methods
7. spontaneous - case reports (only a small proportion are reported)
7. intensive hospital monitoring - research based (high costs, limited numbers of
patients)
7. record linkage - collection of medical records of patients (confidentiality is a
major issue in Australia)
7. mandatory/compulsory - must report by law (e.g. in Sweden) or to gain
accreditation (e.g. Canada)
7. regulatory - manufacturer must keep record of all ADRs reported to it by doctor
or pharmacist
ADRs and Australia (spontaneous reporting)
Adverse Drug Reaction Advisory Committe set up by Australian Drug Evaluation
Committee
ADRAC regularly reviews all Australian reports of suspected ADRs (5000 each
year) and publishes cases and sends them to WHO Collaborating Centre for
International Drug Monitorings
ADRAC reports on suspected adverse drug reactions are sent free to all docts,
dentists and pharmacists
What to report? Anything, no matter how trivial, particularly for
3. new drugs
3. suspected drug interactions
3. reactions signifantly affecting patient management (death, life in danger, hospital
admission or prolongation, birth defect)
Note that premarketing clinical trials provide no guarantee that all relatively common
adverse effects will be adequately domcumated (e.g. persistent cough in 1 in 100 ACE
inhibitor users)

PHARMACOLOGY LECTURE 7
DRUG ABSORPTION

drug absorption = the process by which drug proceeds from the site of
administration to the site of measurement (blood stream) within the body
absorption occurs for the following drug fomrulations:
0. oral
1. sublingual (will avoid breakdown in stomach and liver)
2. transdermal (e.g. niotine) (very slow absorption)
3. rectal (use when patient is vomiting)
4. intramuscular injection
5. subcutaneous injection
6. miscellaneous - inhalation, intranasal, eye, nose, ear drops
gastrointestinal absorption = extent to which drug is absorbed from gut lumen
into portal circulation
drug absorption occurs by following 2 mechanisms:
0. passive diffusion
rate of transfer across membrane = concentration difference x
surface area x permeability constant
permeability constant = diffusion coefficient x partition coefficient
/ membrane thickness
diffusion coefficient = k / Sqrt (molecular weight)
molecular weight: this is realtively constant for most drugs because
molecular weights usually vary between about 100 and 500
membrane thickness: this is relatively constant
partition coefficient:
this is a marjor source of variation in drug diffusion
drugs which are lipophilic have high partition coefficients,
and drugs which are lipophobic have low partition
coefficients
a value above 5 indicates high lipid solubility
degree of ionisation:
only a non-ionised nonpolar drug diffuses across the
membrane, hence this is an important factor
degree of ionisation depends on pKa of drug (and pH of
body fluid)
1. carrier mediated transport
unlike passive diffusion, this exhibits saturability, specificity,
competition, requires energy, and involves movement against a
concentration gradient
for GI absorption - facilitated diffusion
is important for a few drugs based on endogenous compounds (e.g.
levo-dopa, which is used for Parkinson's disease) and vitamins
physiological factors influencing gastrointestinal absorption
0. blood flow
the blood flow is responsible for removal of drug from the other
side of the membrane
for some very lipophilic drugs, the limiting factor in
gastrointestinal absorption is rate of blood flow (e.g. ethanol)
1. surface areas/blood flow
the surface area of intestine is 1000 x greater than stomach
blood flow of intestine is 8 x greater than stomach
hence, although physico-chemical properties would dictate that
weak acids are absorbed in stomach, and weak bases in intestine,
in reality, most drugs are absorbed across intestinal wall
2. gastric emptying
affects the rate of drug absorption (i.e. decreased gastric emptying
slows down absorption)
gastric emptying can be decreased by drugs (opioids), disease
(migraine, shock) and food
solid oral dosage forms
o for tablets/capsules to be absorbed, they must undergo:
0. distintegration to form granules
1. dissolution in gastrintestinal fluids
2. absorption into body
o some special formulas are:
enteric coated tablets:
contain a coat over the tablet preventing breakdown in acid
overcome
local side effects (e.g. coated aspirin will not cause
gastritic bleeding)
degradation (e.g. coated penicillin will not undergo
acid hydrolysis)
sustained release tablets:
are formulated to decrease rate of dissolution --> decrease
rate of absorption
are used to reduce the frequency of dosing (e.g. morphine)
o hence, formulation factors can affect drug absorption
o therapeutic failures have occurred when one manufacturer's brand has
been substituted by another
o the principal mechanism affecting drug absorption is dissolution - which
can be influenced by
particle size
solubility
fluid pH
gastric emptying
pharmacokinetic measurement of absorption:
o bioavailability (F) = amount of (oral) dosewhich reaches the systemic
circulation (between 0% and 100%)
reasons why some drugs do not have bioavailability of 100%
-1. insufficient time for absorption
-1. decomposition in gut wall and lumen
examples include:
acid hydrolysis (penicillin)
complexation (tetracycline with Ca++)
metabolism by gut microflora
metabolism in gut wall (oral contraceptive)
-1. liver and the first pass effect = when drug is absorbed, it
must first pass through portal circulation and liver
i.e. drug absorbed across GI tract --> portal
circulation --> systemic circulation
hence, in liver there may be metabolism of drug
before it can enter the systemic circulation (e.g.
morphine)
the major determinant of oral bioavailability of high
extraction drug is hepatic enzyme activity
some drugs have low extraction (e.g. caffein), and
hence high bioavailability
some drugs have high extraction (e.g. morphine)
note: F = fraction absorbed x (1-E) [E = extraction
ratio]

PHARMACOLOGY LECTURE 8
DRUG DISTRIBUTION

general concepts of distribution:
o distribution = process of reversible transfer of trug to and from
circulation
o distribution rate and extent is determined by:
delivery of drug to tissue
ability of drug to pass through tissue membranes
binding of drug to plasma and tissue components
o perfusion rate limitations
occur when the tissue membranes are not a barrier to distribution
of a drug
hence well perfused tissues take up the drug more rapidly than
poorly perfused tissues (e.g. lungs, kidneys > brain, muscle > fat,
bone)
the time to convey to the tissue the amount of drug at equilibrium
depends on:
1. Kp - the equilibrium ratio (Kp = equilibrium concentration
of tissue / equilibrium concentration of venous blood)
2. perfusion rate
o permeability rate limitations
occur when the tissue membranes act as a barrier to distribution of
a drug
factors that act as barriers to distribution include:
1. tight capillaries (e.g. in brain)
most capillaries are relatively leaky, and permeable
all except very large molecules, e.g. proteins and
protein bound drugs
however, in the brain the endothelial cells have no
fenestrae and are attached by tight junctions
2. cell membranes
physico-chemical properties (molecular weight and
solubility) determine rate at which drug penetrates
cell membranes since they determine a moluecles
ability to pass through:
1. lipid matrix of membrane
2. membrane pores
3. affinity for active transport carriers
o distribution equilibrium = unbound concentrations of drug in tissue and
plasma are equal
the exception to this will be if tissue is involved in excretion or
metabolism or where there is active transport out of the tissue
plasma protein binding is an important factor in determining a drug's volume of
distribution because only drugs not pound can be distributed outside the
circulation
o affinity of protein for a drug:
[unbound drug] + [protein] <--> [drug-protein complex]
k1 is the rate constant of the reaction (drug + protein --> drug-
protein)
k2 is the rate constant of the reverse reaction (drug-protein -->
drug + protein)
Ka = k1 / k2 = association constant (a measure of affinity of the
protein for the drug)
o drugs bind predominantly to two proteins:
0. albumin
comprsises 60% of total plasma proteins
acts as a transporting protein for numerous endogenous
substances
binds various anions, cations, steroids, bilirubin, many
drugs (especially those which are acids)
the drug-albumin complex usually consists of one or two
high affinity binding sites, and many low affinity binding
sites
the 2 high affinity bindings sites are:
0. bilirubin binding site (drugs such as warfarin and
sulphonamides bind)
1. benzodiazepine binding site (drugs such as
benzodiazapines, tryptophan and medium change
fatty acids bind)
knowledge of which site on albumin a drug binds enables
the prediction of drug-drug and drug-endogenous ligand
displacement interactions
displacement interactions and reduction in albumin
concentrations may may make interpretation of total
(unbound + bound) concentrations difficult in therapeutic
drug monitoring
1. alpha1-acid glycoprotein
is only in small concentrations in plasma, but does bind to
many drugs (e.g. propranolol, lignocaine, imipramine)
is an acute phase protein, and so in inflammatory diseases
(including MI and cancer) its concentration may increase
several fold
binding to this protein usually occurs at one site of high
affinity
o other proteins which bind drugs are:
lipoproteins (bind triglycerides, phospholipids, cholesterol, some
drugs)
transcortin (binds steroids)
thyroxine binding globulin
retinol binding globulin
other structures (e.g. white cells bind some antimalarial drugs)
tissue binding
o tissue binding occurs at following sites:
tissue proteins
DNA (e.g. antimalarials)
lipids (e.g. fat soluble drugs and environmental pollutants)
skin/ocular melanin (e.g. quinacrine)
kinetics of protein binding
o fu = unbound fraction of drug in plasma = 1 / (1 + (Ka x Pu))
Ka = association constant
Pu = [unbound protein concentration] = Pt - DP
Pt = [total protein]
DP = [drug-protein]
(note: fu is normally constant, i.e. independent of drug
concentration (because only a small fraction of available binding
sites are occupied))
o fu is affected by:
0. effect of drug concentration
if concentration of drug is so high that almost all drug
binding sites are filled, then a further increase in
concentration will not cause more drug-protein complexes
to form, hence fu will increase (i.e. fu will no longer be
constant)
(in other words, as DP approaches Pt, fu will become
variable, i.e. concentration dependent)
this is uncommon for albumin because [albumin] is high
and so large concentrations of drug are required to
saturated the binding sites
this is more common for alpha1-glycoprotein because
[alph1-glycoprotein] is low and so lower concentrations of
drug are required to saturated the binding sites
1. effect of protein concentration
if total protein concentration decreases, then fu increases
albumin may decrease in nephrotic syndrome or severe
liver cirrhosis (increase fu)
alpha1-acid glycoprotein may increase in many diseases
(e.g. rheumatoid arthritis) (reudce fu)
2. effect of binding affinity:
a decrease in affinity will increase fu
this may occur because of:
disease states
displacement by endogenous ligands or other drugs
binding and drug disposition
o knowledge of degree of drug-plasma binding is important because:
0. only unbound drug is pharmacologically active
1. is a determinant of drug's volume and distribution
2. assists in elucidating clearance mechanisms
o volume of distribution (V) = amount of drug in body (A) / plasma
concentration (C)
a large volume of distribution indicates extensive tissue binding
a simple model is:
V = Vp + (fu x Vt / fut)
Vp = plasma volume (about 3L)
fu = drug's unbound fraction in plasma
Vt = tissue volume
fut = unbount fraction in tissue
Vt can be extracellular water (15 L) or total body
water (45 L)
if a drug is polar and does not penetrate
membrane easily, then Vt will be 15 L
if a drug is lipophilic then it will distribute
into total body water, (Vt = 45 L)







PHARMACOLOGY LECTURE 9
DRUG CLEARANCE - HEPATIC METABOLISM

Introduction
a major route of drug clearance involves the metabolism of lipophilic drugs to
hydrophilic derivatives that can be eliminated by the kidneys
this process is called biotransformation
Tissues invovled in drug metabolism
most drug metabolism invovles enzymes in the liver, many of which are
associated with the smooth endoplasmic reticulum of hepatocytes
metabolism of drugs by liver directly after absorption into the portal system prior
to reaching circulation is refered to as first pass metabolism
other tissues that play a role in drug metabolism include:
o gastrointestinal tract (contributes to first pass clearance)
o kidneys
o skins (relevenat following topical applications of drugs)
Classification of drug metabolism pathways
phase I reactions
o (functionalisation = introduction of a new functional group)
o phase I reactions are functionalisation reactions, frequently adding a new
oxygen atom (e.g. -OH group) or exposing an existing functional group
(e.g. hydrolysis of ester linkage)
o are usually catalsed by oxidases located in endoplasmic reticulum, mainly
cytochome P450 enzymes
o CYP450s are mainly in hepatocytes, but also cells of the kidney, lung,
intestine, skin, testis, brain
o each CYP450 oxidises many substrates (with some selectivity for classes
of chemicals)
o nomenclature of CYP450s:
example P4502E1
first number (i.e. "2") refers to CYP family (>40%
homology)
capital letter (i.e. "E") refers to subfamilies (>60%
homology)
second number (i.e. "1") refers to a particular P450 isoform
o major human cytochrom P40s (also called hepatic mono-oxygenases)
CYP1A2
is expressed universally in liver tissue
is further induced by smoking, ingestion of grilled meats
metabolises drugs such as: caffeine, theophylline,
phenacetin by dealkylations
also activates aromatic amino procarcinomages
CYP2C9/10 and CYP2C18/19 (important)
collectively, the 2C family is very important in drug
metabolism, e.g. taxol, phenytoin, diclofenac, piroxicam,
diazepam, cycloguanil, imipramine
a genetic deficeincy (polymorphism) for CYP2C9 was
identified with tolbutamide
a genetic polymorphism for CYP2C19 was identified with
mephenytoin
CYP2D6 (important)
expressed mainly in liver
important in drug metabolism, e.g. codein, debrisoquine,
propranolol, captopril, dextromethorphan, nortryptiline
a genetic polymorphism (identified with sparteine) affects
10% of Caucasions, 2% of Mongoloids and Negroes
CYP2E1
expressed mainly in liver, and also peripheral lymphocytes
induced by ethanol (major role in ethanol metabolism in
alcoholics)
minor role in drug metabolism, e.g. paracetamol,
chlorzoxazone
important in metabolism of a range of industrial chemicals,
e.g. benzene, styrene, vinyl chloride, carbon tetrachloride,
chloroform, ethyl carbamate
CYP3A4 (important)
most abundant human isoform (liver, intestine)
induced by barbiturates, rifampicin, glucocorticoids
most important CYP450 in drug metabolism, e.g.
nifedipine, quinidine, taxol, erythromycin, contraceptives,
warfarin, cyclosporin, midazolam, lidnocaine
phase II reactions
o phase II reactions are biosynthetic reactions (conjugation reactions)
o involve conjugation of a hydrophilic endogenou cofactor with a drug
o the conjugate is usually more polar than metabolites formed via phase I
oxidation, thus phase II conjugates are readily cleared by kidney or bile
o major phase II reactions include (primarily occur in liver)
glucuronidation - transfer of glucuronic acid to drug
enzyme involved: UDP-glucuronosyl transferase
cofacter required: UDP-glucuronic acid
functional group required in drug: -OH, -COOH, -NH2, -
NH, -SH
sulphation - transfer SO3- to drug
enzyme involved: sulfotransferase
cofacter required: PAP-sulphate
functional group required in drug: aromatic -OH or -NH2
acetylation (transfer of acetyl group to drug)
enzymes involved: N-acetyltransferase
cofacter required: acetyl CoA
functional group required in drug: aromatic or aliphatic -
NH2
glutathione conjugation (add glutathione to drug)
enzyme involved: glutathione-S-transferase
cofacter required: glutathione
functional group required in drug: epoxides, organic
halides
Integration of drug metabolism
for a drug to be metabolised by phase II conjugation it requires an appropriate
function group
such functional groups may have been introduced by a phase I enzyme
thus, phase I and phase II reactions are tightly integrated:
o drug in plasma --> oxidised metabolite --> conjugated metabolite
o either the product of the phase I reaction (oxidised metabolite) or of the
phase II reaction (conjugated metabolite) may be excreted via urine or bile
Pharmacological implcations of drug metabolism
modification by phase I and phase II reactions usually alters the pharmacological
properties of the agent
pharmacological deactivation
o most drug metabolites exhibit less affinity for relevant receptors, thus
biotransformation usually implies pharmacological deactivation
o biotransformation also typically generates metabolites that are more easily
cleared from the body, further dimishing the duration of a drug's action
o example: amphetmine
is a CNS stimulant, reversing fatigue symptoms
inactivated by CYP450-catalysed oxidation (deamination)
o example: diazepam
is a hypnosedative used in control of anxiety, insomnia
undergoes oxidation by CYP2C19 to an inactive metabolite (N-
demethylation)
pharmacological activation
o for a few drugs, inactive prodrugs undergo metabolism within the body to
active drugs
o example: sulindac
is a NSAID used in treatment of rheumatoid arthritis, gout and
moderate pain
converted to an active silphide metabolite by reductive phase I
metabolism occurring in the gut (catalysed by bacterial reductases
in gut contents, not gut wall)
resulting metabolite is 500 times more potent inhibitor of
cyclooxygenase than parent
o example: codeine
is an inactive prodrug that required CYP2D6-catalysed O-
demethylation to form morphine, which is much more active a mu
opioid receptors
in a subsequent reaction, morphine is converted to a potent
analgesic (morphine-6-glucuronide) via glucuronidation (note that
it is unusual for phase II metabolites to be active)
Role of drug metabolism in drug interactions
knowing the metabolic fate of drug is important because:
3. it can help avoid adverse effects due to drug interactions during tretment
with 2 or more drugs
example: ketoconazole is metabolised by a specific CYP450 (3A4)
and can inhibit the clearance of terfenadine which is a substrate for
the same CYP450 (hence cardiac toxicity)
3. prolonged exposure to some drugs can cause overexpression of CYP450s
(induction) causing a loss of potency of other drugs that are metabolised
via that isoform
example: barbiturates induce specific CYP, and eththinylestradiol
(contraceptive) is metabolised by this CYP, and so is metabolised
too quickly (therefore ineffective) if patient is taking barbiturates






PHARMACOLOGY LECTURE 10
RENAL EXCRETION

Introduction
renal excretion is the final step in most drug pathways (water-soluble xenobiotics
and lipophilic compounds converted to water soluble metabolites are excreted)
fraction excreted unchanges = fe = amount in urine / dosage = renal clearance /
total clearance
CL(total) = CL(renal) + CL (hepatic) + CL (other) {assume that CL (other) is
minimal}
thus, if drug's total clearnace and fe are known, renal and hepatic clearances can
be calculated
for 70% of drugs, CL(renal) < CL(nonrenal)
Mechanisms
1. filtration
o 20% of renal flow forms glomerular filtrate (typically, GFR = 120 ml/min)
o protein binding of a drug allows only unbount portion (fu) to filter
o rate of filtration of a drug from plasma is related directly to plasma
concentration (C)
o equation: rate at which drug is filtered at glomerulus = C x
CL(glomerular) = C x fu x GFR
2. active transport in the proximal tubule
o reabsorption:
the proximal tubule performs active reabsorption of glucose and
amino acids, but drugs are not carried by these transporters
o secretion:
the proximal tubule has 2 active transport excretory systems
(accepting organic cations and anions respectively) which are non-
selective and excrete a wide variety of xenobiotics and endogenous
substrates
these systems:
are energy dependent
can be saturated at high concentrations (hence substances
handled have a tubular maximum secretion rate [Tm])
show competition between drugs for the same transporter
natural substrates for these transporters include metabolites
conjugated with sulphage, glucuronide and glycine, and metabolic
products such as creatinine (which is also filtered)
3. distal tubule and collecting duct
o as the tubular concentration of drug rises progressively along the nephron
due to reabsorption of water, hence a concentration gradient develops
which favours the passive diffusion of drug from the tubule into the
peritubular capillary
o reabsorption varies from negligible to compelte, denedning on the
physico-chemical properties of drug (molecular weight, pKa, lipophilicity)
o two physiological variables are important in this process
-1. urine flow rate
this influences the drug concentration concentration
gradient
low tubular flwo rate will be accompanied by a higher drug
concentration in distal tubular fluid, and more complete
reabsorption of a lipid-soluble drug
-1. distal tubular pH
varies between 4.5 and 8
changes within this range alter degree of ionisation of a
weak acid or base
since non-ionic form only will be reabsorbed, a chnage in
urine pH can alter tubular reabsorption
example: urate excretion can be enhanced by alkalinising
the tubular fluid (uric acid is a weak acid) since there will
be more ionised urate
overall: CL (renal) = CL(GFR) + CL (secretion) + CL (reabsorption) {note that
CL (reabsorption) < 0}
Significance
renal disease:
o renal disease alters all forms of renal excretion
o renal clearance, tubular secertion etc. are reduced in direct proportion to
the reduction in GFR
o this will be clinically relevant if the major pathway of excretion is renal
o example:
lipiophobic beta-blocker atenolol has > 90% renal excretion and an
intermediate therapeutic index
in renal failure, toxicity is common unless dose is reduced
estimating drug excretion:
o normal renal function varies widely with age, body weight etc.
o plasma creatinine is not sufficiently reliable
o 24 hour urine collections to directly measure creatinine clearance is
impractical
o if a high degree of precision is needed, creatining clearance (GFR) is
estimated from plasma creatinine, body weight, age, and sex
a good method is the Cockkroft and Gout formula
estimated creatinine clearance (ml/min) = (140-age) x
weight / (serum creatine (mmol/L) x 815)
multiply this value by 0.85 for females
other estimation formulae exist
these methods are not valid if renal function is not stable, or on
extremely high or low protein diets, or at extremes of age
o for the few drugs which have a narrow therapeutic index and are mainly
excreted renally (e.g. aminoglycosides and digoxin), individual GFR
should be estimated and then the individual's total clearance for the drug
derived; from this the correct dosage (loading and maintenance and
timing) can be calculated; therapeutic drug monitoring should also occur
o example:
for digoxin, total clearance in normal man is 130 mil/min, fe = 0.6
by how much should the normal maintenance dose rate (250
micrograms/day) be altered to achieve the same Css in a patient
with a GFR of 30 ml/min?
you know that F x dose rate = CL x Css
therefore, to keep Css constant, need to adjust dose rate in direct
proportion to Cl
CL(nonrenal) = 130 x (1 - fe) = 130 x 0.4 = 50 ml/min (for normal
man and patient since this involves liver)
in normal man, CL(renal) = 130 x 0.6 = 80 ml/min
in patient, CL(renal) = 30 x 0.6 = 20 ml/min
therefore in patient, CL(total) = CL(nonrenal) + CL (renal) = 50 +
20 = 70 ml/min
hence, need to reduce maintenance dose to 70/130 = 55% of
normal (125 micrograms/day)
altered tubular secretion - potential drug interaction
o anion pathway:
handles many drugs such as penicillins, cephalosporins,
probenecid, salicylates, diuretics
(PAH (para-amino-hipppurate) is transported avidly, and clearance
by the healthy kidney > 90% of total renal plasma flow (600
ml/min) - hence can be used to determine renal blood flow;
fortunately most drugs aren't transported so efficiently)
o cation pathway:
handles drugs such as cimetidine, procainamide, amiloride,
pindolol, ranitidine
o drugs compete for transport, thus introducing one can reduce the renal
clearnace of another
example: probenecid has been used to reduce excretion of
penicillin, and thus reduce the dose required (by up to 80%)
example: cimetidine can produce a significant rise in plasma
procainamide due to competition for common transport mechanism
o note: in neonates, tubular secretory function is very poor, but develops
after birth - caution is needed in drug treatment
distal tubule
o effect of urine volume
drug nephrotoxicity can be worse when urine volume is low (e.g.
gentamicin toxicity)
in drug overdoses: high fluid intake and therefore urine output
often aids recovery
o effect of urine pH
for drugs that are weak acids (pKa 3-7) or weak bases (pKa 6-12),
the degree of ionisation in tubular fluid is dependent upon pH
example: methamphetamine
is a weak base (pKa = 10)
renal excretion is 4 x faster in an acid than an alkaline urine
(because obviously a lower pH means lower ionisation and
hence less reabsorption and hence greater excretion)
example: phenobarbital
is a weak acid (pKa = 7.4)
renal excretion is 7 x faster in alkaline urine (however renal
clearance is still only a small fraction of total clearance)
clinically important example: salicylic acid
is a weak acid (pKa = 3.5)
at physiologic pH it is mainly ionised
at pH of 5.0, the amount of non-ionised form is 25 x that
present at pH of 7.4
in serious aspirin overdose, a systemic and tubular acidosis
occurs, which enhances tubular reabsorption (and therefore
prolongs half life of elimination)
this can be reversed by giving systemic alkali and fluids
and producing an alkaline pH urine with high flow
(note that haemodialysis is actually used in life-threatening
poisoning)
renal handling of drug metabolites
o for a few drugs, the metabolite is toxic or active, examples include:
clofibrate
is a cholesterol lowering drug
is metabolised in liver to clofibric acid glucuronide which
is excreted renally
however, in renal failure, clofibrate treatment produced an
unexpected syndrome of muscle pain and inflammation
it turned out that clofibric acid is a selective muscle toxin at
the plasma levels reached in renal failure
morphine
in renal failure, morphine has much longer duration of
action than plasma half life (the plasma half lfie is not
prolonged in renal failre)
morphine is metabolised in part to morphine-6-glucuronide
which is renally excreted
M-6-g has opioid properties, and elevated levels of m-6-g
account for this difference in renal failure
hence give morphine in less frequent doses in patients with
failure
procainamide
dose of procainamide should be reduced in renal failure
because its excretion is reduced, and the major metabolite
N-acetyl-procainamide (renally excreted) is antiarrhythmic
it is usual to use TDM and measure procainamide and N-
acetyl-procainamide levels to control treatment
drugs acting on kidneys
o some drugs depend on concentration mechanisms in renal tubule for their
therapeutic effect and selectivity action
o examples:
urinary tract antibiotics (nitrofurantoi, nalidixic acid) are present in
urine at 100 x the plasma concentration
loop acting (freusemide) and distal vonvoluted tubule acting
(thiazides) diuretics depend on tubular concentration for their
selective effects on the luminal surface of the tubular cells
o these drugs become less effective when the tubular concentrating process
is impaired in renal disease

PHARMACOLOGY LECTURE 11
INTERRELATIONS
Diagrams on handout are useful

Introduction
usually, there is a functional and reversible relationship between the concentration
of a drug at its site of action and the intensity and duration of response produced
because it's impossible to measure concentration of drug at site of action and
response at site of action, inferences have to be made by studying plasma drug
concentrations and clinical responses
Concentration and response
response increases with increasing concentration (see diagrams - note that the
shapes of 1a and 1b are different because 1a has a linear x axis scale, and 1b has a
logarithmic x axis scale) - note that this is not a linear relationship (i.e. doubling
the dose does not double the effect)
Hill equation:
o intensity of effect = (Emax x c^n) / (EC50^n + c^n)
o Emax = maximum effect
o EC50 = concnetration needed to produce 50% of Emax
o c = concentration of drug in plasma
o n = shape (also called slope) factor that accommodates the shape of the
curve
a higher n defines a steeper curve
example: if n = 1 then EC20 = 0.25EC50 and EC80 = 4EC50
example: if n = 2 then EC20 = 0.5EC50 and EC80 = 2EC50
most drugs have an n value between 1 and 3
examination of 1b shows that: between about 20% and 80% of maximum effect,
response is approximately directly proportional to the logarithm of the
concentration
Time delays
drug effect often lags behind plasma concentrations
example: digoxin
o used for treatment of heart failure and some arrhythmias
o has a positive inotropic effect (i.e. it increases force of heart muscle
contraction)
o the effect lags behind plasma concentrations by several hours after dosing
o this delay is related to the time taken for the drug concentration to
equilibriate between the plasma and the site of action (myocardium)
o hence TDM during the distribution phase is highly misleading
see figure 2
o the diagram is divided into 4 parts:
1. large increase in concentration, small increase in effect
2. small increase in concentration, large increase in effect
3. small decrease in concentration, no change in effect
4. decrease in concentration, decrease in effect
causes for the time delay in effect following concentration include:
0. time taken for drug concentration to equilibriate between plasma and site
of action
1. drug produces active metabolite(s)
2. observed effect is indirect measure of true effect
example: allopurinol
used to prevent gout
acts to inhibit xanthine oxidase (the enzyme that catalyses
the formation of uric acid)
2. drug reduces the concentration of an endogenous substance, whose
concentration must fall below a critical value to produce observed
response
example: warfarin
is an anticoagulant
inhibits formation of several clotting factors
2. drug acts irreversibly at site of action
example: aspirin
inhibits enzyme cyclooxygenase
Onset-duration-intensity relationships
following asumptions are made:
o response can be characterised by Hill equation
o only the drug acts to produce response and does not have active
metabolites
o the drug does not influence its own kinetics (for example, by altering liver
blood flow or fu or CL)
onset (see figure 3)
o onset occurs when concentration at site of action reaches critical value
(Cmin = minimum concentration at site of action, Amin = minimum
amount in the body needed to achieve effect)
o onset is governed by factors such as:
dosage form (e.g. rapid release or slow release tablets)
dose size
route of administration
absorption rate
distribution kinetics
concentration-response relationships (EC50, n)
duration (see figure 3)
o duration of effect will last as long as Cmin is exceeded at site of action
o is a function of dose and rate of removal (elimination or redistribution)
o if a drug is eliminated by first order kinetics: doubling a single dose, will
obviously increase the duration of effect by one half life
o there is a limit to how many dose doublings can be achieved because of
toxicity
o hence multiple dosings are usually essentially
Integration of concentration-time-intensity relationships
see sheet; it is very basic and obvious, and hence not worth writing about










PHARMACOLOGY LECTURE 12 AND 13
VARIABILITYIN DRUG RESPONSES

Description of variability
dose(min) - dose effective at the 5 centile (of the population)
dose(max) - dose effective at the 95 centile
typically, dose(min):dose(max) = 1:4
o example: penicillin is effective for 5% of population at dose z, and is
effective for 95% of population as dose 2z, hence dose(min):dose(max) =
1:2
sources of variability are:
o genetic
o drug interactions
o food interactions
o drug formulation and route
o age, weight and gender
o disease
o environmental factors
o in practice, behavioural factors are common (non compliance and dosing
errors)
Classification of variability in response
pharmacokinetic factors
o absorption
0. formulation of drug
this determines rate and extent of dissolution
an unreliable oral formulation can lead to incomplete and
variable absorption
examples where this especially a problem: digoxin,
phenytoin, cyclosporin
1. route of administration
patient response varies with route
example: lignocaine
is an antiarrhythmic
well absorbed orally, but because of high
presystemic metabolism, therapeutic plasma levels
are not reached, hence has to be given intravenously
also has a neurotoxic metabolite, methylxylidide
2. other drugs: may interfer with absorption
3. food may alter absorption, examples include:
fat delays gastric emptying and therefore prolongs the T1/2
of absorption - this may delay Tmax but does not usually
affect bioavailability (although a poorly absorbed drug such
as griseofulvin (antifungal) has a higher F after food)
dietary Ca++ forms non-absorbed chelates with
tetracycline (these should therefore be taken on an empty
stomach)
absorption of L-dopa is less reliable after food because of
competition for its active transport system (in gut wall and
blood-brain barrier) by amines in food
o bioavailability
for lipid soluble (well absorbed) drugs, F is mainly determined by
degree of presystemic hepatic metabolism (F = 1 - E(H))
E(H) is dependent on hepatic enzymes and shows marked
interindividual variation
clearly, for drugs with a large E(H), only a small variation in E(H)
will lead to a large change in F
example: propranolol
has an average E(H) = 70%, therefore average F =
30%
a subject showing a 50% reduction in Vmax will
half E(H), hence F will become 65% and less than
one half the average oral dose will be required
this is not true for the majority of drugs that have a
negligble first pass effect (E(H))
o volume of distribution
for a given drug, V(D) is mainly proportional to body weight
(although for non-fat soluble drugs, lean body weight is a better
predictor) (not true for neonates)
V(D) determines the loading dose, so body weight is necessary in
calculating loading doses for drugs with narrow TIs
example: loading dose of gentamicin and tobramicin is 2 mg/kg
BW
o clearance
-1. renal excretion
renal clearance correlates directly with GFR
renal function is proportional to body surface area - weight
relates closely to this
for the few drugs with a narrow therapeutic range and
predominantlly renal excretion, maintenance dose is
calculated from body weight (unless renal disease is
present)
example: usual adult dose of gentamicin is 1 mg/kg BW (8-
hourly) for adults, 1.5 mg/kg BW for children (reflects
higher body surface area)
-1. hepatic metabolism
is major cause of variation in clearance of most drugs and
is hard to predict, but associated with:
genetic traits (most unknown and polygenic)
smoking (enhance clearance of diazepam,
chlorpromazine, theophylline)
chronic alcohol intake (induces CYP450s and
increases clearnaces of diazepam, phenytoin)
acute alcohol intake (acts as a transient phase I
enzyme inhibitor)
living in a city or rurual area (city dwellers have
higher hepatic clearance, ascribed to enzyme
induction from environment exposure to chemicals)
example: theophylline (see figure c)
shows wide and unpredictable variation between
individuals (T1/2 between 4 and 14 hours)
is due to difference in hepatic clearance (but F does
not alter (low E(H)))
example: propranolol (see figure a and b)
shows wide variation between individuals (T1/2
between 2 and 6 hours)
E(H) varies in parallel (so a subject with impaired
hepatic metabolism on propranolol will show both
increased bioavailability and reduced drug
clearance)
2 non-linear kinetic examples: phenytoin and theophylline
Km is close to therapeutic levels, hence a small
change in either enzyme activity or dosage will lead
to a large change in plasma steady state levels
note: these have very high 1st pass CL
Ca++ channel blockers
beta blockers
tetracyclic (?) antidepressants
Pharmacodynamic factors
poorly understood, although many drugs have a greater dynamic than kinetic
variability
monitoring drug plasma levels of these drugs will not be useful in predicting
response
for drugs that compete at site of action with endogenous ligands, plasma
concentration of ligand may determine drug response:
o example: hypotensive effect of ACE inhibitors correlates with plasma
angiotensin levels; hence may cause severe hypotension in dehydration
o example: anticoagulant effect of warfarin is partly determined by vitamin
K intake (broccoli)
or, the pathophysiologic state may determine response
o example: BP fall after nifedipine is proportional to original blood pressure
Clinical importance of variability
5. standard dose forms
o example: theoretical drug
T1/2 = 12 hours
dose(min) = 50 mg (12 hourly)
dose(min) : dose(max) = 1 : 4
if the drug was marketed in 50mg, 100mg and 200mg tablets then
90% of population could take a 100 mg tablet, twice a day
the 10%:
low clearance group take the 50 mg daily (T1/2 will
be longer)
high clearance group take the 200 mg, 3 times a day
(T1/2 will be shorter)
6. starting treatment
-1. CL determines maintenance dose
-1. for drugs that have common dose-related side effects, treatment is started
with dose(min) (with or without a loading dose)
-1. in a few subjects, an altered response can be predicted and starting must be
modified
-1. dose-escalation is then performed as appropriate - genearlly by allowing
concentrations to reach steady state before assessing response (although
the time to response for some drugs differs from the T1/2)
-1. for drugs that have minimal dose-related side effects, or treatment is
urgent, the dose(max) is generally used for simplicity (although cost
implications)
Predicting drug responses in special population groups
in people who need treatment, pharmacokinetics/dynamics often differ greatly
from that seen in normal (because of age and disease)
example:
o peak incidence of heart failure is age > 70
o drug absorption, distribution and effects differ with old age and with heart
failure
the young
o in kids, adjustment of dose for body weight/body surface area is usually
adequate
o however, in neonates (especially premature), drug absorpiton, distributio
and clearance differ
o premature infants:
85% of body weight is water (adult 55%) and body fat is 1% or
less: a lipid-soluble drug will need a lower loading dose (per kg
BW compared with adults)
hepatic metabolic pathways and renal excretion are immature (30-
50% of adult values on a BW basis), maintenance drug dosage is
reduced accordingly
o examples:
chloramphenicol (antibiotic) caused cardiovascular collapse - the
'grey' baby syndrome in neonates when give in standard dosage;
the drug accumulated due to reduced hepatic clearance
penicillin: active renal tubular secretion is absent at birth, the
clearance/BW of penicillin is 20% of adult values (but can be
induced by drug exposure)
phenobarbitone: is an effectve (but out-dated) treatment when
given to near-term women to reduce foetal haemolytic jaundice; it
crosses the placenta and induces foetal hepatic enzymes which
have low activity normally; this increases conjugation and
excretion of bilirubin
the elderly
o renal function:
age-related reduction in GFR and renal blood flow is universal
toxicity from standard dose of drugs eliminated mainly by kidney
(especially digoxin and gentamicin) would be expected
estimation of GFR and dose adjustement is necessary (GFR varies
positively with 140 - age)
o hepatic function:
hepatic clearance declines (especially phase I metabolism) - but
cannot be assessed clinically
hence, T1/2 for many drugs increases with age (e.g. for diazepam)
cautious drug sue, smaller doses and longer inter-dosing intervals
are recommended
o pharmacodynamic factors: elderly appear to be more sensitive to sedative
effects of diazepam even when differences in clearance have been
accounted for
pregnancy
o drug use must be minimised because of risk to foetus
o drug distribution changes by 14th week because plasma and ECF volumes
increase by 30%, and plasma proteins, including albumin, fall by 20%
o also, GFR increases and some hepatic phase I metabolism is increases
(probably induced by high levels of progesterone)
o problems arise when treatment is essential, example: phenytoin (for
epilepsy contorl)
increased metabolism, hence phenytoin levels fall
but, fall in albumin means that f(u) of this highly protein-bound
drug is greater
since TDM measures total drug concentrations, increasing dose to
reach a plasma level that is in the (non-pregnant) therapeutic range
will result in toxicity due to high concentrations of unbound drug
instead, a lower therapeutc range is desirable, and regular TDM is
necessary
after delivery, the dose needs to be rapidly reduced to avoid
toxicity
disease
o low cardiac output
in general:
in shock and severe left heart failure, blood flow to most
organs is decreased
intestinal, subcutaneous and intramuscular drug absorption
is slow and unreliable in shock therefore
example: diabetics with hypotensive shock
when given subcutaneous insulin, often do not respond
until the circulation improves, when delayed
hypoglycaemia may occur
it is necessary to give insulin intravenously to ensure a
prompt response
toxicity in brain and heart:
blood flow to brain and heart is better maintained than to
other organs in shock
therefore, a rapid intravenous bolus will produce very high
peak local concentrations and increased risk of toxicity in
these organs
example: there is an increased risk of cardiac arrhythmias
with intravenous digoxin in heart failure
this is minimised by giving drugs by slow intravenous
infusion of minutes
impaired renal and hepatic function due to cardiac disease is
discussed below
o renal disease
for a drug with mainyl renal excretion, clearance will be prolonged
in renal disease
example (taken from renal clearance lecture)
for digoxin, total clearance in normal man is 130 mil/min,
fe = 0.6
by how much should the normal maintenance dose rate
(250 micrograms/day) be altered to achieve the same Css
in a patient with a GFR of 30 ml/min?
you know that F x dose rate = CL x Css
therefore, to keep Css constant, need to adjust dose rate in
direct proportion to Cl
CL(nonrenal) = 130 x (1 - fe) = 130 x 0.4 = 50 ml/min (for
normal man and patient since this involves liver)
in normal man, CL(renal) = 130 x 0.6 = 80 ml/min
in patient, CL(renal) = 30 x 0.6 = 20 ml/min
therefore in patient, CL(total) = CL(nonrenal) + CL (renal)
= 50 + 20 = 70 ml/min
hence, need to reduce maintenance dose to 70/130 = 55%
of normal (125 micrograms/day)
note:
if there are active metaabolites which are renally excreted,
these may accumulate
example: morphine-6-glucuronide
Vd is sometimes lower in renal failure
example: for digoxin
non-renal clearance may vary in renal failure
pharmacodynamics may differ
despite the above points, a general rule of thumb is that if Fe <
30% (i.e. renal clearance is less than 30%) then no dose reduction
is needed even in severe renal disease
o liver disease
bioavailability of drugs with high hepatic extraction is increased in
severe liver enzyme because either:
depressed gepatic enzymes
or
shunting of blood from portal to systemic venous
circulations
many drugs, particularly those invovled with phase I clearance,
have decreased clearance in liver disease (but the relationship with
severity of liver disease is poor)
drugs that undergo mainly phase II metabolism do not show
impaired clearance unless liver failure is extreme
also, Vd may be increased for drugs with low Fu when albumin
levels are low
specific examples: see handout for more details
o hepatic disease
cirrhosis
theophylline (bronchodilator) - reduced CL (slower fall in
plasma concentration)
propranolol (beta blocker) - F increased (higher peak
plasma concentration)
viral hepatitis
warfarin (anticoagulant) - CL reduced (excessive response)
o cardiovascular disease
congestive cardiac failure
lignocaine (anti-arrhythmic) - CL and V reduced (elevated
plasma concentration)
o renal disease
uraemia
gentamicin (antibiotic) - reduced CL
thiopental (anaesthetic) - prolonged anaesthesia (unknown
reason)
o gastrointestinal disease
coeliac disease
ferrous sulphate (haematinic) - absorption reduced
(anaemia does not respond)
Crohn's disease
propranolol (beta blocker) - increased plasma binding:
elevated alpha1-acid glycoprotein
o respiratory disease
emphysema
morphine (analgesic) - increased sensitivity to respiratory
depression (unknown reason)
chest infection
theophylline (bronchodilator) - metabolic CL decreased
(elevated plasma concentrations)
o endocrine disease
thyroid disease
digoxin (cardioactive agent) - altered pharmacodynamics
(dimished response in hyperthyroidism; increased response
in myxoedema)
o fever
quinine (antimalarial) - impaired metabolism (plasma
concentration elevated)





















PHARMACOLOGY LECTURE 14
THERAPEUTIC DRUG MONITORING

What is therapeutic drug monitoring (TDM)?
= measurement of drug in plasma to assist in indivualising dosage regimen for a
particular patient (especially when therapeutic effect is not easily measured)
What is the theoretical basis for TDM?
major assumption is that there is a direct and predicatble relationship between:
o concentration of drug in plasma
o unbound concentration of drug in plasma
o tissue concentration of drug (inc. concentration at site(s) of action)
o pharmacological effect, either efficacy and toxicity
What is the therapeutic concentration rage?
= range of concentrations associated with a high degree of efficacy and a low risk
of dose related predictable toxicity derived from populations of patients
note: a small proportion of patients will show excellent responses be;pw the lower
limit of the range, and others will derive benefit only a concentration above the
range
When is TDM useful?
TDM is only useful when there is a known relationship between plasma drug
concentration and pharacological response
for some drugs, the therapeutic response is difficult to measure (e.g. prophylactic
agents such as anticonvulstants, cardiac anti-arrhythmic agents)
some drugs have unpredictable relations between dose and plasma concentration
(e.g. dose dependnet or "non linear" kinetic drugs such as phenytoin)
some drugs have very narrow therapeutic index (e.g. digoxin, aminoglycosides,
anticonvulsants, anti-arrhytmic agents, theophylline, lithium, salicylic acid)
where poor patient compliance is suspected
for some drugs, adverse effects of drug may mimic disease state (e.g. digoxin can
cause arrhythmias, cyclosporin)
when there is suspected toxicity
when there is reason to suspect there has been a change in pharmacokinetics
(renal function, hepatic function etc.)
What do you need to know to intrepret the TDM results?
exact knowledge of sampling time of plasma in relation to time of dose
administered; in general, it is bets to take a pre-dose (trough) sample, because this
is the most easily predictable part of the concentration-time curve (i.e. you know
that this will be the minimum value)
knowledge of the sampling time in relation to "steady state" (how many half lives
have elapsed since the dose was started or changed)
an understanding of the drug's (and the formulation) plasma concentraion versus
time profile (e.g. immediate or slow release)
knowledge of any possible non-linear kinetics of the drug
o example: protein binding - valproate, salicylate
o example: clearance - phenytoin
knowledge of patient specific changes, examples include
o pregnancy
o extremes of age
o genetics
o renal, hepatic, cardiac disease
o hypoalbuminaemia
o concomitant drug therapy
What is the proper clinical role of TDM?
plasma drug concentrations must always be seen in a clinical context
CASE 1
20 year old has had epilepsy since age 12, but been seizure free since age 14
over this 6 year period, he has taken phenytoin (260 mh daily) and
carrbamazepine (400 mg daily)
he attended his family doctor, who ordered TDM of both drugs, giving these
values:
o plasma phenytoin concentration = 24 umol/L (therapeutic range 40-80)
o plasma carbamazepine concentration = 12 umol/L (therapeutic range 20-
50 umol/L)
on the basis of these, doctor increased dose of phenytoin to 400 mg daily and
carbamazepine to 800 mg daily
one week later, the patient required admission to hospital because of marked
drowsiness, ataxia, vomiting, nystagmus
plasma concentrations were:
o phenytoin = 130 umol/L
o carbamazepine = 24 umol/L
COMMENTS
o phenytoin- nonlinear kinetics
o carbamazepine - linear kinetics
o there was no need to increase dosage because he was seizure free; if
anything, the dose should have been reduced because the doctor should
have considered that the epilepsy may have left
o note, even if the doses should have been increased, phenytoin dose should
have only been increased slightly, because of its non-linear kinetics
CASE 2
66 year old man admitted to hospital due to severe breathlessness and swollen
ankles over past week
has been heavy smoker and has ischaemic herat disease and COAD
at time of admission, there is evidence of congestive heart failure, and his airways
disease appears to be no worse than usual
he has been on theophylline at home, receiving 800 mg daily
on admission, he complains of severe nausea, and shakes
plasma theophylline concentration is 39 mg/L (therapeutic range 10-20 mg/L)
his heart failure is treated and he improves
dose of theophylline is reduced to 400 mg daily
on 5th day he becomes breathless, and is found to have extensive bronchospasm,
but no evidence of heart failure
his plasma theophylline concentration is now 6 mh/L
COMMENTS
o theophylline has linear kinetics in this range
o hence, halving dose normally would have plasma levels
o but perhaps - congestive heart failure --> decreased liver function
(reduced liver flow and liver congestion) --> decreased theophylline
clearance --> theophylline rises during CCF
o also, smoking induces P450s (maybe he recently began smoking)
CASE 3
74 year old woman, admitted for inguinal hernia repair
found to have atrial fibrillation (ventricular rate at rest of 105 beats/minute)
digoxin is started at a dose of 125 micron daily (with no loading dose)
a very conscientious intern orders a serum digoxin concentration on the next day
the result if 0.4 nmol/L (therapeutic range 0.6 - 2.3 nmol)
COMMENTS
o should have given loading dose (because her surgery will be soon and
there will not be enough time to give for 5 half-lives)
o not until 1 week will steady state be reached (half life = 24 hours for
digoxin)
o note: 0.4 is a trough level after 1 half life, therefore is too high, therefore
should decrease dosage






PHARMACOLOGY LECTURE 15
INTEGRATION OF PHYSIOLOGICAL CONCEPTS
AND PHARMACOKINETICS

"~" means approximately
CLEARANCE BY THE LIVER
hepatic extraction ratio (E)
o = fraction of dose entering liver from blood which is irreversibly
eliminated (metabolised) during one pass through the liver
o rate of entry = flow x concentration in = Q x C(in)
o rate of exit = flow x concentration out = Q x C(out)
o rate of elimination = rate of entry - rate of exit = Q(Cin - Cout)
o extraction ratio = E = (how much is extracted / how much goes in)
= (Cin - Cout) / Cin
o i.e. E = 1 --> complete extraction, whereas E = 0 --> no extraction
o note also, for CL
rate of elimination = CL x Cin
CL = rate of elimination / Cin
CL = Q(Cin - Cout) / Cin
CL = Q x E
(i.e. clearnance is a function of blood flow rate and extraction ratio
- this applies to any organ)
o the hepatic extraction ratio can also be described physiologically by:
E = (fu x CLint) / (Q + (fu x CLint))
fu = unbound fraction in blood (since only unbound can diffuse
into liver cells; there are exceptions)
CLint = intrinsic clearance of liver (the ability of liver to
metabolise the drug in the absence of restrictions imposed by blood
flow or binding)
o note: F = 1 - E
o i.e. F = Q / (Q + (fu x CLint)
o hence, it can be seen that hepatic clearance and bioavailability are
described in terms of:
Q
fu
CLint
o there are two limiting cases:
low hepatic extraction ratio drugs - when Q >>> fu x CLint
i.e. the unbound fraction x the intrinsic clearance is very
small (therefore, using logic, bioavailability is very high)
i.e. F ~ Q / (Q + 0)
i.e. F ~ 1
by the same logic, hepatic CL will be very low, regardless
of flow rate
the clearance of such drugs depends directly on the degree
of binding and the activity of the drug's metabolising
enzymes
these drugs have a very low first pass, and bioavailability
will be close to 100%
examples:
caffeine
ibuprofen
increasing or decreasing rate of supply by altering Q will
make very little difference to hepatic clearance
also called capacity limited drugs
summary: these drugs will have a high bioavailability, and
clearance will vary depending on hepatic enzyme activity
and plasma binding
high hepatic extraction ratio drugs - when Q <<< fu x CLint
i.e. the unbound fraction x the intrinsic clearance is very
high (therefore, using logic, bioavailability is very low)
i.e. F ~ Q / (0 + (CLint x fu))
i.e. F ~ Q / (CLint x fu)
by the same logic, hepatic CL will be very high, regardless
of changes of CLint x fu
the clearance of such drugs depends directly on the hepatic
flow rate
these drugs have a very high first pass, and bioavailability
will be close to 0%
examples:
morphine
lignocaine
also called flow limited drugs
summary: these drugs will have a low bioavailability, and
clearance will vary depending on flow rate
most hepatically cleared drugs can be classified as either low
extraction or high extraction
by classifying a drug in this way, one can determine the critical
physiological factors which determine hepatic clerance and
bioavailability, and therefore the plasma concentrations and
response to the drug after oral and intravenous administrations


SUMMARY: bioavailability and first pass effect
o F = fraction absorbed x (1 - E)
o some drugs have low E (e.g. caffeine) --> high F (a change in E therefore
has a minor effect on F)
o some drugs have high E (e.g. morphine) --> low F (a change in E therefore
has a major effect on F)
o the major determinant of oral bioavailability of high extraction drugs is
hepatic enzyme activity
EXERCISE: determine for some low and high extraction drugs, the effect of
changes in drug binding on
o clearance
o volume of distribution
o half life
o bioavailability
o unbound stead state plasma concentrations on chronic dosing (IV and oral)
APPENDIX
o variability in response - for high extraction drugs, a small change in E will
lead to a large change in F, leading to more variability in plasma
concentrations after oral vs IV doses
o dosage (oral vs. IV) - for a drug with high hepatic extraction, an oral dose
will need to be much higher than an IV dose to elicit the plasma
concentrations
o other routes - to avoid some first pass effect, use sublingual, transdermal,
inhalation, rectal
o drug interactions - other drugs may induce or inhibit hepatic enzymes, and
so for high extraction drugs, this can lead to significant changes in
bioavailability
o liver disease - if shunts exist because of liver disease, bioavailability will
increase because blood flow through liver will be less; therefore, for high
extraction drugs given to patients with liver disease, there is the potenital
for increases adverse effects












PHARMACOLOGY LECTURE 16
PHARMACOGENETICS

genetic polymorphism: trait determined by a single gene, occurring in normal
population in a least two phenotypes, neither of which is rare (i.e. at least 1%)
extensive metabolisers - these people metabolise the drug normally
poor metabolisers - these people do not metabolise the drug at the same rate as
extensive metabolisers
GENETICALLY DETERMINED VARIATION IN PHARMACOKINETICS
Debrisoquine-type polymorphism of oxidative metabolism
4. History
o was observed that excretion of unchanged debrisoquine in urine was very
variable
o extensive metabolisers could be heterzygos or homozygous for the normal
allele
o poor metaboliser phenotype occurs in 10% of Caucastion population;
lower frequency in other populations
5. Metabolic defect
o impaired drug hydroxylation by CYP 2D6
o no enzyme protein is detectable in homozygotes
o detection:
phenotype - enzyme function tested by ratio of parent drug to
hydroxylated metabolite in urine after standard dose of drug
genotype - gene sequences
6. Clinical relevance
o poor metabolisers have impaired metabolism of a number of drugs,
therefore:
0. more prone to adverse drug reactions if given standard doses
1. reduces drug effect if metabolite is active (e.g. codeine -->
morphine)
o there seems to be a possible link with other diseases
poor metabolisers have lower rate of cancers of lung, liver and
gastrointestinal tract
poor metabolisers may have a higher rate of Parkinson's disease
6. Other drugs of clinical relevance (common examples only; there are > 50)
o beta-adrenoceptor antagonists, e.g. metoprolol
o tricyclic antidepressants, e.g. amitriptyline
o anti-anginal vasodilator - perhexiline (can have bery severe adverse effects
including irreversible peripheral neuropathy)
Polymorphism of drug acetylation
2. History
o observed bimodal distribution of plasma concentration after standard dose
of isoniazid (used to treat TB) --> higher risk of peripheral neuropathy
o slow acetylators are homozygous for mutant allele
2. Metabolic defect
o reduced activity of hepatic N-acetyltransferase
o detection:
phenytype by measuring plasma concentration of isoniazid or
caffeine after standard dose (slow acetylators have higher
concentration)
frequency in different populations varies widely: about 10% in
Eskimos, 20% in Asians, 50% in Caucasions, 80% in Egyptians
2. Clinical relevance
o reduced clearance and increased risk of adverse effects from drugs which
are usually acetylated
o epidemiological associated with other diseases:
slow acetylators - bladder cancer, Gilbert's disease (gemetic
problem in liver), SLE (autoimmune against various organs)
fast acetylators - breast cancer, diabetes mellitus
2. Some examples of drugs of clinical relevance (slow acetylators at ncreased risk of
ADR)
o vasodilators - hydralazine --> lupus-like syndrome (auto-immune disease)
o anti-arrhythmic - procainamide --> lupus-like syndrome
o some benzodiazepines - e.g. nitrazepam --> sedation
Atypical plasma pseudocholinesterase (a rare genetic trait)
4. Metabolic defect
o there are many variants of plasma pseudocholinesterase (each under
separate genetic control)
these have much lower than normal affinity for succinylcholine
(muscle relaxant used in general anaesthesia)
people with variant enzyme have much longer duration of action
following usual doses (50-100 mg) of the drug (hours vs. minutes)
o enzyme activity can be tested in vitro, but in practice, most cases are
detected following anaesthetia
o incidence in Caucasians is about 0.05%; not found in Japanese, Eskimos
or South American Indians
4. Clinical relevance
o succinylcholine produces muscle paralysis (including respiratory muscles)
and is often used during induction of anaesthesia to allow tracheal
intubation
o effect usually lasts only a few minutes, but may last for hours in patients
with atypical cholinesterase - these patients wake up paralysed and require
prolonged mechanical ventilation
GENETICALLY DETERMINED VARIATION IN PHARMACODYNAMICS
Drug induced haemolytic anaemia (glucose-6-phosphate dehydrogenase deficiency)
2. Clinical problem
o sometimes there is an unexpected occurrence of haemolytic anaemia after
treatment with oxidant drugs
o such drugs can produce haemolytic crises in about 20% of males in some
populations
2. Mechanism
o normally, glutathione is involved in the mopping up of free radicals (it can
chemically detoxify H2O2)
o in this disorder, haemolysis caused because there is less reduced
glutathione (G-SH) within red cell due to a deficiency of enzyme G6PD
o lack of reduced glutathione makes cell vulnerable to oxidation, with
damage to cell membrane and lysis; therefore drugs that in someway
increase this oxidation can lead to haemolytic anaemias
o G6PD occurs in many different abnormal variants and genetic
transmission is X-linked
o (note heterozygotes are more resistant to malaria than homozygotes of
normal allele)
o about 200 million people are affected world-wide
2. Some drugs involved (should be avoided in people with G6PD deficiency)
o urinary antiseptic - nitrofurantoin
o anti-malarial drugs - primaquine, chloroquine
o analgesics - aspirin















PHARMACOLOGY LECTURE 17
INTRODUCTION TO TOXICOLOGY

BIOACTIVATION OF FOREIGN COMPOUNDS TO TOXIC METABOLITES
normally, phase I and II reactions dimish biological properties
but, sometimes bioactivation occurs and products are more toxic
toxic metabolites cause cellular dysfunction by reacting with components such as
DNA or proteins
note that toxicity only occurs in organs that possess the necessary enzymes that
cause the bioactivation (unless the metabolites are stable enough to migrate to
other organs via the blood)
hence most toxic drugs tend to preferentially affect a limited numbers of organs
if the metabolite causes DNA damage, then the patient is at a greater risk of
cancer
general outcomes:
o cleared via urine/bile <-- non-toxic metabolite <-- (detoxification) <--
drug/foreign chemical --> (bioactivation) --> chemically reactive
metabolite -->
DNA damage --> cancer
protein and cell damage --> organ pathology
CHEMICALLY INDUCED ORGAN DAMAGE: THE LIVER AS A TARGET
liver is vulnerable to damage by ingested chemicals because:
o of its close proximity to blood supply from digestive dract
o it actively concentrates foreign chemicals
o it plays a major role in biotransformation
a number of toxic responses are known within the liver, including hypersensitivity
reactions (e.g. drug induced hepatitis), cirrhosis, intrahepatic cholestasis and
necrosis
PARACETAMOL-INDUCED HEPATOTOXICITY
o is an intrinsic hepatotoxicant, i.e. produces a predictable, dose-dependent
toxic response
o is very safe at therapeutic doses
o normally:
90% is metabolised via phase II pathways (sulphation and
glucuronidation)
10% is oxidised via phase I (hepatic CYP2E1, CYP1A2, CYP3A4)
to a chemically reactive quinoneimine toxic metabolite (NAPQI),
which reacts with glutathione to form a non-toxic metabolite which
is excreted in the urine
o biochemistry under overdose conditions:
conjugative phase II metabolism is saturated and used up, and
therefore NAPQI overproduction occurs
this results in depletion of glutathione
in absence of glutathione, NAPQI reacts with nucleophilic sites on
critical cellular proteins, interfering with cell function and
initiating hepatocellular necrosis
o symptoms, signs, tests and treatment of paracetamol-induced
hepatotoxicity:
symptoms:
early symptoms of poisoning include nausea and vomiting
(requires 10-30 g in adults)
some patients progress to fulminant hepatic necrosis,
involving progressive jaundice with hepatic
encephalopathy (headache, drowsiness, confusion are early
signs of the rapid onset of cerebral oedema [which requires
CNS monitoring])
signs:
liver tenderness may appear afer 12 hours, and may persist
for up to 72 hours
serum enzymes:
hepatic necrosis is evident after 3 days when huge (up to
500 fold) elevations in serum hepatic enzymes occur (e.g.
aspartate and alanine transaminases)
serum enzymes peak on day 3, and return to normal after 7-
21 days in survivors
clotting:
liver toxicity is accompanied by impaired hepatic
production of clotting factors (esp. III, V, VII), increasing
the prothrombin time and prothrombin time ratio
treatment:
thiol therapy (oral or IV N-acetylcysteine [NAC])
ameliorates toxicity by replenishing hepatic glutathione
stores, facilitating NAPQI detoxification
NAC therapy is most effective if administered within 8 10
hours of ingestion
effective management requires knowledge of plasma
paracetamol concentrations
note that anaphylaxis occurs in 5% of IV NAC recipients
o see diagram on sheet
CHEMICALLY INDUCED ORGAN DAMAGE: THE BRAIN AS A TARGET
blod brain barrier protects brain against toxic ionised and bulky water soluble
agents
but, some toxicants can penetrate CNS, and can lead to diffuse encephalopathy
with global or dysfunction or a localised encephalopathy
MTTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
o in California in 1983, unusual motor defecits resembling Parkinson's
disease were seen in drug addicts using MPPP, a designer drug analogue
of meperidine opioid
o symptoms:
developed within hours to days
included difficulty in initiating and terminating movement, resting
tremors, rigidity (which sometimes progressed to immobility)
o biochemistry
toxicity was due to a synthetic by-product in the drug, MPTP
0. MPTP crosses blood brain barrier
0. is activated by monoamine oxidase B in astrocytes to
MPP+ which is a toxic metabolite (note that MPP+ couldn't
enter CNS, and therefore only the MPP+ produced in the
CNS caused symptoms)
0. MPP+ is a substrate for dopaminergic re-uptake pathwyas,
and therefore accumulates within dopaminergic neurons in
the substantia nigra
0. within the neurons, MPP+ is actively accumulated within
the mitochondria
0. MPP+ interferes with electron transport chain at NADH
dehydrogen
0. hence oxidative phosphorylation is impaired, and ATP is
not produced
0. cell death ensues
o later it was observed that in individuals exposed to low levels of MPTP
that didn't initially develop Parkinsons, the disease did manifest some
years later - this suggested that idiopathic Parkinson's is due to exposure to
MPTP like xenobiotics; two classes of endogenous analogues present in
foodstuffs and also human tissue (beta carbolines and isoquinolines) have
been suggested to play a role in idiopathic Parkinson's, although they are
much less potent neurotoxins than MPTP
CHEMICALLY INDUCED DNA DAMAGE: CANCER AS A TOXIC OUTCOME
genotoxic = a substance that has the ability to damage DNA
DNA possesses nucleophilic atoms (e.g. oxygen) that react with electrophilic
metabolites
DNA adducts = the products of reactions between toxic metabolites and a purine
or pyrimidine
DNA adducts promote misreplication (mutations) during DNA synthesis
hence, if mutations in oncogenes or tumour suppressor genes occur, the cell
becomes one step closer to a neoplastic state
often carcinogens are produced by cytochrome P450s making reactive metabolites
(e.g. benzene)
note that cytotoxic anticancer drugs are often drugs that cause DNA damage
TAMOXIFEN
o is very effective in treatment of oestrogen receptor positive breast cancer;
may also decrease risk of developing a second primary tumour
o mechanism of therapeutic action:
blocks effects of oestrogen by binding to oestrogen receptor
blockage of growth promoting effects of oestrogen suppresses
breast tumour growth
o adverse reactions: drug is generally well tolerated, with hot flushes and
menstrual disorders most problematic
o study was done to test effectiveness of tamoxifen as a chemopreventive
agent:
1992: clinical trial of 16,000 women in US commenced; results
promised for 1998
1995: trial was temporarily halted, when it seemed drug may
double risk of endometrial cancer in women who received more
than 20 mg/day for > 2 years
1996: tamoxifen was shown to cause liver cancer in rats (not
known whether this was relevant to human endometrial cancer)
recently: tamoxifen has been shown to undergo bioactivation to a
genotoxic metabolite that forms up to 12 different DNA adducts in
rodent liver
see diagram on sheet






















PHARMACOLOGY LECTURE 18
DRUG TOLERANCE AND DEPENDENCE

Introduction
tolerance and physical dependence often develop together, but although the
mechanisms are similar, they are not identical
Tolerance
= decreased responsiveness to drug resulting from its administration
acute tolerance (densensitisation, tachyphylaxis) = tolerance that develops by a
single administration
cross tolerance (i.e. tolerance of oen drug leads to tolerance of another drug)
occurs due to similar mechanisms of action
mechanisms of tolerance action:
0. dispositional (pharmacokinetic, metabolic) tolerance = decreased drug
effect due to reduced drug concentration at site of action (e.g. due to
increased metabolism)
0. pharmacodynamic tolerance = decreased responsiveness at site of action
due to:
for agonists:
reduction in number of receptors
uncoupling of receptor and G protein
decreased sensitivity of second messenger system
decreased production and release of endogenous ligand
for antagonists: the opposite (i.e. increased receptors, increased
sensitivity of second messenger system and increased production
and release of endogenous ligand)
Physical dependence
= altered physiological state resulting from repeated or prolonged drug
administration; cessation of administration results in a withdrawal syndrome
withdrawal syndrome depends on pharmacological action of drug taken - many
symptoms/signs are opposite to direct effect of drug
examples:
0. opioids
opioid symptom/sign : withdrawal symptom/sigh
sedation : restlessness and insomnia
analgesia : joint and bone pain
constipation : diarrhoea
pupil constriction : pupil dilation
reduced BP, temp : increased BP, temp
both drug and withdrawal of drug cause vomiting and nausea
1. sedatives
sedative symptom/sign : withdrawal symptom : sign
reduced anxiety : increased anxiety
sedation : restlessness
decreased seizures : increased seizures
muscle relaxation : tremor
withdrawal of drug causes hallucinations
withdrawal symptoms bary depending:
o dose change
o duration of use
o rate of decrease in drug concentration





PHARMACOLOGY LECTURE 19
DRUG-DRUG INTERACTIONS

Introduction
drug-drug interaction = dose-response relation of one drug is altered by another
drug
synergism = enahnces therapeutic efficacy
antagonism = reduces therapeutic efficacy
risk ADR is increased with multiple drug regimes
a drug-drug interaction (DI) is likely to have therapeutic consequences (TDI) if it
alters the
3. concentration of a drug with a steep dose-response relationship
3. drug response for a condition which unstable (e.g. cardiac arrhytmias,
epilepsy)
drugs usually involved in TDIs include anticoagulatns, cardiac glycosides, anti-
arrhythmics, sympathomimetic amines, antihypertensives, anticonvulsants, oral
hypoglycaemics, cytotoxics
revision: phase I enzymes are cytochrome P450s, phase II enzymes are
conjugative enzymes
Major mechanisms of drug interaction
8. pharmacokinetic
1. absorption
1. interference with gut absorption:
0. complex formation in gut
example: cholestyramine binds many drugs
example: Ca++/Mg++ antacids complex with iron,
tetracycline, quinolones
1. delayed/accelerated gut emptying
example: anticholinergics delay gastric emptying
and therefore delay drug absorption
2. changes in gut flora
example: antibiotics interrupt enterohepatic
recycling of the oestrogen component of oral
contraceptives, causing contraceptive failure
example: erythromycin prevents bacterial
inactivation of digoxin in the gut, increases
bioavailability, plasma digoxin levels rise 50%
2. alteration in first pass metabolism
(note: high clearance drug have > 30% extraction from
hepatic blood (F < 0.7))
a drug that inhibits hepatic metabolism will increase
bioavailability of high clearance drug (provided it is
metabolised by the enzyme(s) inhibited) and vice-versa
examples:
cimetidine inhibits CYP450s, therefore doubles oral
propranolol bioavailability
phenytoin induces enzymes, therefore decreases
felodipine bioavailability
acute alcohol intake inhibits a CYP, therefore
amitrptiline bioavailability is higher
2. distribution
1. drug-protein binding displacement
0. in plasma
the drug displaces another drug from a binding site
on plasma proteins leading to:
0. transient rise in f(u) (unbound
concentration) of displaced drug
1. compensatory rise in drug clearance
therefore a new steady state f(u) is reached that is
similar to the initial level - therefore this is usually
clinically unimportant (unless the transient rise in
f(u) is toxic)
example of clinical importance
99% of warfarin binds to albumin
NSAIDs bind to same site, and therefore
displace albumin, causing a transient rise in
warfarin, which can be dangerous while it
lasts
1. in tissue
example:
digoxin binds to intracellular sites in muscle
qiunidine displaces digoxin from tissue sites,
leading to an 80% rise in plasma dioxin
levels
3. elimination
1. enzyme induction
if this metabolic route is a major pathway of elimination,
drug kinetics will change (reduce Css and T(1/2)) and
therefore drug response will change
enzyme induction takes about 2 weeks to develop, and on
cessation of inducer, about 2 weeks to revert to normal
examples
smoking causes 100% increase in clearance of
theophylline
phenoobarbital and rifampicin cause 200% increase
in clearance of warfarin
carbamazepine causes 200% increase in clearance
of clonazepam
chronic alcohol
2. enzyme inhibition
(drugs that reduce hepatic blood flow also inhibit
metabolism of high clearance drugs)
if this metabolic route is a major pathway of elimination,
drug kinetics will change (increase Css and T(1/2)) and
therefore drug response will change
enzyme inhibition is immediate, and on cessation of
inhibitor, reversion to normal is immediate
examples:
metronidazole decreases clearance of warfarin by
40%
cimetidine decreases clearance of phenytoin by 35%
propranolo decreases clearance of lignocaine by
50% (by reducing hepatic blood flow)
omeprazole decreases clearance of warfarin
3. examples with regards to enzymes other than cytochrome P450s
example 1: allopurinol
is a xanthine oxidase inhibitor (used as an anti-gout
agent)
also inhibits metabolism of cytotoxic agent 6-
mercaptopurine (6-MP)
therefore concurrent use of allopurinol and 6-MP
leads to elevated plasma levels of 6-MP and toxicity
example 2: disulfiram
inhibits aldehyde dehydrogenase
therefore is used to give alcoholics a nasty
"aldehyde reaction" when they take alcohol
4. alteration of liver blood flow:
for high first pass clearance drugs only, a fall in liver blood
flow will cause a clear reduction in systemic clearance
example: lignocaine toxicity can occur when patients are
given a beta-blocker which reduces liver blood flow
5. interference with renal excretion
intereference can occur if there is competition for tubular
secretion; this will only be clinically significant if drug has
a narrow therapeutic ratio and a large fraction is excreted
unchanged
(note also sometimes interactions with tubular
reabsorption)
example 1: penicillin
probenicid is a competitive inhibitor for tubular
secretion
once (years ago when penicillin was not readily
available) probenecid was used to reduce dose
requirements by 80%
example: procainamide
procainamide competes with cimetidine for renal
tubular excretion through the organic cation
transporter
using both at once may result in procainamide
toxicity
example: lithium
diuretics and NSAIDs both enhance proximal
tubular reabsorption of Na+ and Li+
therefore these elevate Li+ levels
9. pharmacodynamic (may occur at receptor, cell or physiological level)\
o synergistic effects
commonly used therapetucally; examples of synergy used
therapeutically:
Parkinson's disease: L-dopa + monoamine oxidase B
inhibitor
hypertension: vasodilator + negative inotrope
problems can occur, the following show synergy:
CNS sedatives - e.g. alcohol + barbiturates
hypertension - monoamine oxidase A inhibitor +
sympathomimetic
digoxin toxicity - diurectics that cause hypokalaemia +
digoxin
o antagonistic effects
occasionally used therapeutically to reduce a side-effect; example:
benzhexol (anticholinergic) used to treat Parkinsonism
induced by chlorpromazine (tranquiliser)
problems can occur:
NSAIDs reduce antihypertensive efficacy (reduce renal
sodium excretion)
Clinical approach to drug-drug interactions
predict and avoid if possible, that is
o become familar with drug TDIs
o take full drug history (including alcohol, smoking)
o avoid multiple drug use when possible
o if multiple drugs need to be used, select drugs to avoid TDIs
if unavoidable, carefully monitor drug response


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