DXGC 6180

Pharmacology: General
Principles of Pharmacology

By:
Dr Ajantha Sinniah
Department of Pharmacology
University Malaya
[email protected]
LECTURE OBJECTIVES
Review of the four important processes that drugs
undergo in a body, namely absorption, distribution,
metabolism and excretion.

The concept of plasma half-life, volume of

distribution, clearance, bioavailability and plasma
steady-state concentration.

The various molecular mechanisms of drug action.

Review of the various pharmacodynamic concepts

such as dose-response relationships, drug specificity,
margin of safety and drug antagonism
Pharmacokinetics and Pharmacodynamics
 PHARMACOKINETICS
‘What body does to drug?’
• Absorption: from the site of
administration permits entry of
the therapeutic agent into plasma.
• Distribution: drugs reversibly
leave the bloodstream and
distribute into the interstitial and
intracellular fluids.
• Metabolism: drugs
biotransformed by metabolism by
the liver, or other tissues.
• Elimination: drug and its
metabolites are eliminated from
the body in urine, bile, or feces.
Routes of administrations

Lippincott, 6th Ed
Lippincott, 6th Ed
 I) Drug absorption
Factors that affect drug absorption:
1) Drug form and formulations

absorption of drug is easier if the drug is formulated in solution > suspension > capsules > tablets

2) Lipid solubility
• Hydrophobic drugs are absorbed well when given orally
• Highly polar drugs are poorly absorbed
e.g. gentamicin, suxamethonium
 I) Drug absorption
Factors that affect drug absorption:
3) Drug ionization
• Unionized drugs are absorbed well
• Degree of ionisation may vary according to the pH at different levels of
GIT
– Weak acid drug are absorbed well at stomach (pH 1-3)
– Weak base drug are absorbed well at small intestine (pH 5-8)

4) Gastric emptying rate

• The rate of the stomach emptying may affect the time for drug to reach small
intestine - affect absorption rate
 I) Drug absorption
Factors that affect drug absorption:
5) Mucosal surface area
Small intestine is the optimal site of absorption due
to the villi and microvilli – increased absorptive
surface area

6) First pass metabolism / “pre-systemic elimination”:

Degradation of drug by
– GIT secretion (acid, enzymes)
– GIT microflora,
– GIT mucosa
– Liver
 I) Drug absorption
Factors that affect drug absorption:
7) Complex formation with gut contents
• Drug form complex with gut content - reduces absorption
e.g. tetracycline complexes with Ca2+, Mg2+, Fe2+

8) Splanchnic (GIT) blood flow

greatly reduced in shock → slow absorption

9) Disease state
Reduced absorption of drugs in Crohn’s disease (inflammatory disease of the
intestines) and Chronic heart failure (CHF)
Achlorhydria (low / absent of acid production in stomach) : ↓ aspirin absorption

Factors affecting the absorption: other routes (rectal, sublingual, inhalation)

• absorption depends mainly on:
– physico-chemical properties of drug
– formulation
– area of absorption surface
– regional blood flow
– ventilation rate (inhalation route)
 Mechanism of absorption of drugs
from the GI tract
1. Passive diffusion: Drug moves from high to lower
concentration; does not involve a carrier. Water-soluble
drugs penetrate the cell membrane through aqueous
channels or pores, whereas lipid-soluble drugs readily
move across membrane lipid bilayers
2. Facilitated diffusion: Other agents can enter the cell
through specialized transmembrane carrier proteins
that facilitate the passage of large molecules.
3. Active transport: moving drugs against a concentration
gradient, from low to higher drug concentration. Are
selective and may be competitively inhibited by other
co-transported substances.
4. Endocytosis: transport drugs of exceptionally large size
across the cell membrane. Endocytosis involves
engulfment of a drug molecule by the cell membrane
and transport into the cell.

Lippincott, 6th Ed
 Bioavailability
Fraction of administered drug that reaches the systemic circulation

• For example, if 100 mg of a drug are administered orally, and

80 mg of this drug are absorbed unchanged, the bioavailability
is 80%!
• ** Determining bioavailability is important for calculating drug
dosages for non-intravenous routes of administration.
Factors that influence bioavailability:
a) First pass metabolism: occurs when the concentration of a drug, specifically when
administered orally, is greatly before it reaches the systemic circulation.
b) Solubility of drugs: Very hydrophilic drugs are absorbed because of their inability
to cross lipid bilayer cell membrane.
c) Chemical instability: Some drugs (Eg: penicillin G are unstable in the pH of the
gastric contents; insulin easily destroyed by degradative enzymes in the GI tract).
d) Nature of drug formulation: particle size, salt form, crystal polymorphism, enteric
coatings, and the presence of excipients (such as binders and dispersing agents) might
influence the ease of dissolution and, therefore, alter the rate of absorption.
 First pass metabolism

• Metabolism / degradation of drug by tissue / organ that is

found along the journey when the drug travels from the point
it is administered till it reaches the systemic circulation
Location Agent
Stomach Acid
GIT Enzyme + microflora
GIT mucosa Enzyme
Liver Enzyme

** Once the drug reaches systemic circulation, the subsequent

degradation of drug that occurs if the drug passes by the same
organ / tissue again is not counted as first pass metabolism
 II) Drug Distribution

• Movement of a drug from one location to another in the body

• generally occur in a rapid manner
• Rate and pattern of drug distribution depends mainly on:
• tissue blood perfusion
• drug molecular size
• drug lipid solubility
• drug plasma protein binding
• Once entering the systemic circulation, drug may redistribute itself
rapidly among the following locations:
• Plasma protein (as bound drugs)
• Body fluids / plasma
• Storage tissue (adipose tissue)
• Site of action
• Site of elimination (liver/ kidney)
 II) Drug Distribution

• Binding of drug to plasma protein:

• reduces drug’s pharmacological activity
• affects drug’s renal excretion
(Glomerular filtration rate reduced directly in proportion to the
fraction that is bound)
• Drug bound to plasma protein can be displaced by another
compound / drug that can bind to the same binding site on
the plasma protein
• Competition of 2 drugs for the same binding sites causes increase in
free conc. of one of the drugs in plasma
• ↑ effect / toxicity (or increased rate of elimination) e.g. :
phenylbutazone displaces warfarin
• Drug-drug interaction at plasma protein may be clinically important
for
• highly bound drugs (e.g. warfarin (99% bound) )
• Drugs with low therapeutic index (e.g. digoxin)
 II) Drug Distribution
• Volume of distribution (Vd)
• A theoretical values that relates the amount of drug in the body to the
concentration of drug in blood
• The volume that is needed to house all the drugs administered into the
body, if it is estimated based on the drug concentration in the plasma

E.g.
Amount of drug that is given to patient = 20g
• If plasma concentration = 0.01g/L
• Vd = volume to accommodate all the drug
• 0.01 g = 1 L
• 10g = 1000 L
• Hence: the Vd is 2000 L
Main
Main area
area of
of accumulation
accumulation == cell
cell or
or tissue
tissue
plasma
plasma conc.
conc. (Cp)
(Cp) ↓
↓
Vd=C0
Vd=C0 /Cp↓
/Cp↓ == large
large Vd
Vd value
value
Main area of stay = plasma
plasma conc. (Cp) ↑
Vd=C0 /Cp↑ = small Vd value
Drugs with small Vd value:
• Hydrophilic
• Do not distribute extensively into body tissue
Drugs with large Vd value:
• Hydrophobic
• Distribute extensively into body tissue (e.g. adipose tissue), or bind to receptors
or ion channels of cell
 III) Drug Metabolism

• Conversion of drugs into another chemical species by body

enzymes (multiple substrates)
• To inactivate drug (detoxification / remove drug’s therapeutic
effects)
• Location: Mainly in liver cells (smooth endoplasmic reticulum,
sER)
• General direction for conversion:
• inactivate the drug and make the drug more polar / hydrophilic
(for hepatic/renal excretion) via Phase I & Phase II metabolisms -
transport drug out of the cells
 III) Drug Metabolism

Lippincott, 6th Ed
• Phase 1: oxidation, reduction and hydrolysis.
• usually form more chemically reactive products, which can be
pharmacologically active, toxic or carcinogenic.
• often involve a monooxygenase system in which cytochrome P450
plays a key role.
• Phase 2 reactions involve conjugation (e.g. glucuronidation) of a reactive
group (often inserted during phase 1 reaction) and usually lead to inactive
and polar products that are readily excreted in urine.
Examples of drugs inducing / inhibiting enzyme action

Rang and Dale, 9th Ed

 IV) Drug Elimination

• Routes:
• Renal: small polar drugs/metabolites
• Biliary Route: large polar drugs / metabolites
• Pulmonary: gaseous/volatile agents
• (e.g. alcohol, * police’s breathalyzer test: measure
pulmonary excretion of ethanol)
• Other routes : sweat, saliva, tears and milk
• (e.g. rifampicin (for TB treatment) → orange-colour
metabolite in urine, sweat & tears)

* Drugs can be excreted either as its original form or

metabolites through the above routes
CLEARANCE
 Clearance

• Total clearance (CLtot) of a drug : the rate of elimination

equals CLtot multiplied by plasma concentration.
• CLtot determines steady-state plasma concentration (CSS):
• CSS = rate of drug administration/CLtot.
• Elimination half-life (t1/2) is directly proportional to Vd and
inversely proportional to CLtot.
• Half-life (t1/2): time taken by the plasma concentration to
reduce by half.
• With repeated dosage or sustained delivery of a drug, the
plasma concentration approaches a steady value within three to
five plasma half-lives.
• In urgent situations, a loading dose may be needed to achieve
therapeutic concentration rapidly.
 PHARMACODYNAMICS
WHAT THE DRUG DOES TO THE BODY???
 PHARMACODYNAMICS
• Study of biochemical and
physiological effects of drugs and
DEFINITION
their mechanisms of action

• Actions of a drug on the body and the

influence of drug concentrations on the
magnitude of the response (either
beneficial or harmful).
• Most drugs interacts with receptors
OVERVIEW present on the cell surface or
intracellular.
• The drug–receptor complex initiates
alterations in biochemical and/or
molecular activity of a cell by a process
called signal transduction.
 MECHANISM OF DRUG ACTIONS

Effects of most drugs

Interaction with macromolecular

components of the organism

Alter the function of the pertinent

component

Biochemical and physiological

changes

Response to the drug.

1. Receptors 2. Ion channels

TARGET FOR DRUG

ACTIONS

3. Enzymes 4. Transporters

Rang and Dale, 9th Ed.

RECEPTORS

Rang and Dale, 9th Ed.

 1. Receptors
2. Ion Characterized by:
channels 1. Selectivity for
particular ion
species, size of
TARGET FOR DRUG
pore, nature of its
ACTIONS lining.
2. Gating properties
3. Molecular
3. Enzymes 4. Transporters
architecture

Ion channels are essentially gateways

in cell membranes, which selectively
allow the passage of particular ions,
and which are induced to open or
close by a variety of mechanisms.
2. ION CHANNELS

Ligand-gated Voltage-gated
channels channels
Open only when one or Are gated by changes in the
more agonist molecules transmembrane potential
are bound rather than by agonist binding

Classified as receptors, since Channel opening induced by

agonist binding is needed to membrane depolarization is
activate short lasting

Fast neurotransmitters, such as

Selective to sodium, potassium
glutamate, acethylcholine,
or calcium channels
GABA, 5-HT & ATP
 2. ION CHANNELS (cont.)

Ion channels Modulators Blockers

Voltage-gated Na+ channels Veratridine Tetrodotoxin Local anaesthetics

Renal tubule Na+ channels Aldosterone Amiloride

Voltage-gated Ca2+ channels Dihydropyridines Divalent cations (e.g. Cd 2+)

ATP-sensitive K+ channels Sulphonylureas

ATP

GABA-gated Cl- channels Benzodiazepines Picrotoxin

3. ENZYMES

1. Receptors 2. Ion channels

TARGET FOR DRUG

ACTIONS

3. Enzymes 4. Transporters
 3. ENZYMES

• Often, the drug molecule is a substrate analogue that acts as a

competitive inhibitor of the enzyme
• e.g. captopril, acting on angiotensin-converting enzyme
(ACE)
• In other cases, the binding is irreversible and non-competitive
• e.g. aspirin, acting on cyclo-oxygenase (COX).
• Drugs may also act as false substrates for the enzymes.
• The anticancer drug fluorouracil, which replaces uracil as an
intermediate in purine biosynthesis but cannot be converted
into thymidylate, thus blocking DNA synthesis and cell
division.
• Prodrugs require enzymic degradation for its conversion to
active form.
Enzymes Inhibitors

Acetylcholinesterase Neostigmine

Cyclo-oxygenase Aspirin
Angiotensin-converting enzyme Captopril
HMG-CoA reductase Simvastatin

Monoamine oxidase-A Iproniazid

Phosphodiesterase type V Sildenafil (VIAGRA®)
Dihydrofolate reductase Trimethoprim

Methotrexate

Thymidine kinase Aciclovir

HIV protease Saquinavir
4. TRANSPORTERS

1. Receptors 2. Ion channels

TARGET FOR DRUG

ACTIONS

3. Enzymes
4.
Transporters
 4. TRANSPORTERS
• The movement of ions and small organic molecules across cell
membranes generally occurs either through channels, or a
transport protein, because the permeating molecules are often
too polar (i.e. insufficiently lipid soluble) to penetrate lipid
membranes on their own.

• Examples of transporters

• For the transport of ions and many organic molecules across

the renal tubule, the intestinal epithelium and the blood-
brain barrier.
• the transport of Na+ and Ca2+ out of cells, and the uptake of
neurotransmitter precursors (such as choline) or of
neurotransmitters themselves (such as noradrenaline, 5-
hydroxytryptamine [5-HT], glutamate and peptides) by nerve
terminals.
• the transport of drug molecules and their metabolites across
cell membranes and epithelial barriers.
 Carriers / transporter Inhibitors
Noradrenaline transporter Tricyclic
antidepressants
Dopamine transporter Cocaine
Weak acid carrier (renal tubule) Probenecid
Na+/K+/2Cl- co-transporter (loop of Loop diuretics
Henle)
Proton pump (gastric mucosa) Omeprazole
Receptor-related cell activities that affects drug pharmacodynamics

RESPONSE RESPONSE
Tolerance Up-regulation
Tachyphylaxis Supersensitivity
Down-regulation
Desensitization

Tolerance Tachyphylaxis Down-regulation Desensitization

Drug
Decrease in
induced,
Reduction in no. of After initial
developed
responsiveness receptors: response, effect
over long
as a result of increased diminishes over
period of
continuous receptor seconds or min
time (long
drug internalizatio even in presence
term /
administration n and of agonist
delayed drug
degradation
response):
Important concepts in drug – receptor interaction
Affinity:
• the strength of drug binding to receptor
Efficacy/intrinsic activity:
• the ability of the drug to induce a response in the receptor post-
binding (i.e. through a conformational change in the receptor)
Potency:
• the powerfulness of a drug, depending on its affinity and efficacy
Full agonist:
• an agonist which has the ability to induce a max response in tissue
post-binding
Partial agonist:
• an agonist which can only produce a partial response in tissue, and in
conjunction with a full agonist may act with antagonistic activity
Selectivity:
• the preference of a drug for a receptor (this is not specificity;
specific suggests one drug one receptor. In fact the adverse
effects of many drugs are caused by the binding to their non-
preferred receptors)
 POTENCY

• measurement of the amount of drug necessary to produce an effect of a

given magnitude.
• The concentration of drug producing an effect that is 50 percent of the
maximum is used to determine potency and is commonly designated as the
EC50.
• EC50 for Drugs A and B are indicated. Drug A is more potent than Drug B,
because a lesser amount of Drug A is needed when compared to Drug B to
obtain 50-percent effect. Thus, therapeutic preparations of drugs will
reflect the potency. (E.g.: candesartan (Drug A) and irbesartan (Drug B)
are angiotensin-receptor blockers that are used alone or in combination
with other drugs to treat hypertension.
AFFINITY
• Drugs of high potency will generally have a high affinity for the
receptors
• Drugs with higher affinity: occupy a significant proportion of the
receptors even at low concentrations.
• The lower the potency of a drug:
àthe higher the dose needed to give a response
àthe more likely the drug may act significantly on additional target /
receptor
à more likely side effects may occur

Affinity: The tendency of a drug to bind to a receptor

Affinity Potency

Receptor Effect /
L response
 EFFICACY

• Capability of a ligand / drug in activating a

receptor to give maximal tissue response
(effect) upon binding to receptor
• Intrinsic activity: the capability of a ligand-
receptor complex in evoking tissue response
(effect) upon binding to receptor
• A drug with high efficacy (e = 1) : full agonist
• drug binds and activate some / all receptors on
cell and cause cell to give maximum response
(e.g. morphine)
• A drug with medium efficacy (0 < e < 1) : partial
agonist
• drug that can only cause cell to generate medium
response even if they bind to all the
receptors on cell (e.g.: norclozapine)
• A drug with zero efficacy / zero intrinsic
activity (e = 0) : antagonist
• drug that causes no cell response even if they bind
to all the receptors on cell (e.g. prazosin)
POTENT DRUG IS NOT NECESSARILY EFFICACIOUS!!!

C D
100
B
tissue response (%)

A Drug A

Drug B

Drug C

Drug D

0
Log10 [Drug]

A = partial agonist (0 < e < 1) Drug of high potency (strong affinity to

receptor) may occupy a large number of
B, C, D = full agonist (e = 1) receptor on cell/tissue at low concentration,
but it may not be able to evoke maximum
Efficacy : A<B=C=D
level of cell/tissue response even when it
Potency : A>B>C>D
occupies 100% of the receptors of the cell
FULL AGONIST
• DEFINITION: a drug binds to a receptor and produces a maximal
biologic response that mimics the response to the endogenous
ligand.
• Receptors exist in active or inactive conformational states that are
in reversible equilibrium with one another.
• For example, phenylephrine is an agonist at α1-adrenoceptors,
because it produces effects that resemble the action of the
endogenous ligand, noradrenaline.
• Upon binding to α1-adrenoceptors on the membranes of
vascular smooth muscle, phenylephrine stabilizes the receptor in
its active state.
• This leads to the mobilization of intracellular Ca2+, causing
interaction of the smooth muscle actin and myosin filaments.
• The shortening of the muscle cells decreases the diameter of
the arteriole (vasoconstriction) and ↑Blood pressure.
• In general, a full agonist has a strong affinity for its receptor and
good efficacy.
PARTIAL AGONIST
• Have efficacies (intrinsic activities) greater than zero
but less than that of a full agonist
• Even if all the receptors are occupied, partial agonists
cannot produce an Emax of as great a magnitude as
that of a full agonist.
• However, a partial agonist may have an affinity that is
greater than, less than, or equivalent to that of a full
agonist.
• A partial agonist may act as an antagonist of a full
agonist.
• As the number of receptors occupied by the partial
agonist increases, the Emax would decrease until it
reached the Emax of the partial agonist.
• This potential of partial agonists to act both as an
agonist and antagonist may be therapeutically
exploited.
• For example, aripiprazole, an atypical neuroleptic
agent, is a partial agonist at selected dopamine Rc.
INVERSE AGONIST
• Unbound receptors are inactive and require interaction with an agonist to assume an
active conformation.
• Some receptors show a spontaneous conversion from R to R* in the absence of
agonist (that is, they can be active without the presence of agonist).
• These receptors, thus, show a constitutive activity that is part of the baseline
response measured in the absence of drug.
• Inverse agonists, unlike full agonists, stabilize the inactive R form. All of the
constitutively active receptors are forced into the inactive state by the inverse
agonist.
• This decreases the number of activated receptors to below that observed in the
absence of drug.
• Thus, inverse agonists reverse the constitutive activity of receptors and exert the
opposite pharmacological effect of receptor agonists.
REVERSIBLE COMPETITIVE ANTAGONISM
• Antagonist shares chemical structure similarity with the agonist
• Cellular response triggered by agonist decreases.
• Due to antagonist competes with agonist for receptor binding site
• The binding of the antagonist to the receptor is reversible
• Lower agonist’s binding to receptor à decreased cellular response
• Antagonists bind receptor via weak non-covalent interactions (ionic
bonds, hydrophobic interactions, and hydrogen bonds)
• Binding of antagonist to receptor is reversible
• Blocking effect of antagonist: removed by increasing agonist
concentration (surmountable antagonism)
• e.g. reversible antagonist:
• propranolol à compete with noradrenaline for β adrenoceptor
• phentolamineà compete with epinephrine for α adrenoceptor
Reversible competitive antagonism
In the presence of the antagonist, the log dose-response curve for the
agonist will be shifted to the right, without any change in slope or level of
maximum response (Emax)

agonist
antagonist

Agonist + antagonist

Agonist only

Agonist only

0 1 10 100 Antagonist’s
conc.

Agonist concentration (mol/l)

IRREVERSIBLE / NON-EQUILIBRIUM COMPETITIVE ANTAGONISM
• Cellular response triggered by lower agonist concentration.
• Due to antagonist competes with agonist for receptor binding site.
• Binding of the antagonist to the receptor is not reversible.
• Antagonist has some chemical structure similarity with the agonist
• Lower agonist’s binding to receptor à decreased cellular response
• Irreversible competitive antagonist forms covalent bonds with receptor
• dissociate slowly / not dissociate from receptor after binding
• Also known as insurmountable antagonism:
• Whereby its antagonistic effects could NOT be overcome by increasing agonist
concentration
• Used as experimental tools for investigating receptor function, and few
are used clinically (e.g)
• Candesartan, an angiotensin II receptor antagonists, treats
hypertension.
• Phenoxybenzamine: compete with epinephrine for α adrenoceptor
• Irreversible enzyme inhibitors that act similarly are used clinically,
• e.g. aspirin, omeprazole and monoamine oxidase inhibitors (MAO)
 Irreversible/non-equilibrium competitive antagonism

In the presence of the antagonist, the log concentration-effect curve for

the agonist will NOT be shifted to the right, but change in slope and level
of maximum response (Emax) will be seen, but not EC50

Emax

More receptors
are blocked
permanently
EC50

EC50
 Example of reversible / irreversible
antagonist acting on the same receptor

• Receptor :
α1-adrenergic receptor on the blood vessel wall
• cause vasoconstriction (blood vessel wall smooth
muscle contraction) when activated
• Agonist
• phenylephrine, epinephrine
• Reversible antagonist
• phentolamine
• Irreversible antagonist
• phenoxybenzamine

** Important difference :
reversible competitive antagonist graph: EC50 change, Emax same
irreversible competitive antagonist graph: EC50 same, Emax change
Non-competitive antagonism
agonist
• Whereby the antagonist blocks at some
point the chain of events that leads to the

Tissue response
production of a response by the agonist. Agonist
+
• verapamil and nifedipine prevent the Non-competitive
antagonist
influx of Ca2+ through cell membrane: block
non-specifically the contraction of smooth Log dose drug

muscle produced by other drugs.

• May also refer to antagonism where the
antagonist binds to an allosteric site on the
Dru
receptor g Na+

• decreased affinity of an agonist for that Receptor

receptor / prevent conformational changes X X

in the receptor required for receptor Receptor X
allosteric
activation after the agonist binds. site X
• In the presence of the antagonist, the slope G protein
Chemical mediators of the 2nd
and maximum of the agonist log messenger system

concentration-response curve will be

reduced, some degree of curve rightward
shift may also occur
GENERAL METHODS TO ASSESS
THE EFFECTIVENESS OF DRUG:

GRADED AND QUANTAL DOSE

RESPONSE CURVES
A graded dose–response
• a sigmoidal dose response curve studying a physiological
or a biochemical response.
• THRESHOLD DOSE: The first point along the graph where
a response above zero (or above the control response) is
reached.
• Most beneficial drugs: desired effects are found at doses
slightly greater than the threshold dose.
• EC50 / ED50: Concentration/dose required to produce
50% of max response
• Emax: maximum response that can be triggered by drug
(100% receptor occupancy)
• The more potent the drug, the more steep the curve will
be.
• Slope: Response proportional to dose (linear portion)
• A steep slope indicates that a moderate increase in
dose will indicate marked increase in the response.
• A flatter slope implies that a small increase will occur
over a wide dose range.
 GRADED DOSE RESPONSE
Dose – response curve or Log dose response curve
(hyperbolic curve) (sigmoid curve)

E E
% tissue response

% tissue response
max
max

Threshold
EC50 conc.
EC50

[Drug] Log10 [Drug]

Limitation of dose – response curve / log dose response curve:

• cannot be used to measure the affinity of agonist / drugs for

their receptors, because the physiological response produced
is normally not directly proportional to receptor occupancy.
• cannot be used to estimate the concentration of drug at the
receptor site, as drug may undergo diffusion, cellular uptake &
enzymatic degradation before reaching to receptor site.
QUANTAL DOSE RESPONSE
• Not always possible to construct graded dose-response curves if the
pharmacological response is an either-or (quantal) event!: prevention
of convulsions, arrhythmia or death.
• One solution is to determine the quantity of drug required to produce a
specific magnitude of effect in a large number of patients (or animals).
• The cumulative frequency distribution of response is then plotted
versus log dose.
• May be chosen on the basis of clinical relevance
• (e.g. relief of headache),
• preservation of safety of subjects (low dose of cardiac stimulant
producing an increase in heart rate of 20 beats/min)
• may be an inherently quantal event (death).
 Quantal dose reponse

• “All or none” type drug effect

(e.g. sleep, convulsion, death )
that is triggered when the
cells / tissue / individual is
exposed to a certain threshold
concentration / dose of drug .
• Quantal - dose effect curve
shows cumulative frequency
distribution of responders vs.
log dose
 Quantal Dose response
100
Cumulative no. (frequency) of individual
giving response

50

ED50 TD50 LD50

0
0 50 100 150 200 250 300
dose

therapeutic effect Toxic effect Death

Median effective dose (ED50)

• Drug dose required to produce therapeutic effect in 50% of the test
subject population
Median toxic dose (TD50)
• Drug dose required to produce toxic effect in 50% of the test subject
population
Median lethal dose (LD50)
• Drug dose required to cause death in 50% of the test subject
population
Difference between graded and quantal dose
responses

Graded dose Quantal dose

response curve effect curve

How much How many

response will subject will
be obtained give a response
with these with these
doses? doses?
• Graded dose response:
• Study the changes in the drug response as the drug concentration
increases
• E.g.:
Amount of Drug A % of weight loss in 1 patient
within 1 month
1 tablet 20
2 tablets 30
3 tablets 40

• Quantal dose response:

• Study the changes in the number of people giving a preselected response
as the drug concentration increases
• E.g.:
Amount of Drug A % of patient having 30% weight
loss within 1 month
1 tablet 0
2 tablets 60
3 tablets 100
Quantal Dose reponse
Individual Drug dose 7

No. (frequency) of individual

that trigger Drug dose Number Cumulated 6
response that trigger (frequency) number 5

giving response
(mg/kg) response of (frequency) 4
A 10 (mg/kg) individual of individual
3
giving giving
B 70 response response 2

C 30 1
0
D 20 10 1 1
0 20 40 60 80
E 30 20 2 3 dose

F 20 30 4 7
25

Cumulative no. (frequency) of

G 30 40 6 13

individual giving response

20
H 50 50 4 17
15
I 40 60 2 19
70 1 20 10
J 40
5
K 50
L 40 0
0 20 40 60 80
M 50 dose
N 60 120
% individual giving response

O 40 100 Change cumulated

80 frequency into %
P 60
Q 40 60 F x 100 / 20

R 30 40

20
S 50
Can change the ”dose” to
0
T 40 0 20 40 60 80 “log dose” if necessary
dose
 Therapeutic index
• The therapeutic index (TI) of a drug is the ratio of the
dose that produces toxicity to the dose that produces a
clinically desired or effective response in a population of
individuals:

Therapeutic index = TD50/ED50

TD50 = the drug dose that produces a toxic effect in half the
population, and
ED50 = the drug dose that produces a therapeutic or desired
response in half the population.

• The therapeutic index : measure of a drug’s safety,

because a larger value indicates a wide margin between
doses that are effective and doses that are toxic.
THERAPEUTIC INDEX
• Determined by measuring the frequency of desired
response and toxic response at various doses of drug.
• By convention, the doses that produce the
therapeutic effect (ED50) and the toxic effect (TD50)
in 50 percent of the population are used.
• In humans, the therapeutic index of a drug is
determined using drug trials and accumulated clinical
experience.
• These usually reveal a range of effective doses and a
different (sometimes overlapping) range of toxic
doses.
Narrow TI: relatively NOT safe
• E.g: Digoxin (TI: 2-3), morphine, warfarin,
phenobarbitone, phenotoin, lithium, imipramine
Wider TI: relatively safe
• Diazepam (TI: 100), propranolol, penicillin, fluoxetine
• large TI drugs: relatively safe to be used
e.g. Diazepam (TI = 100) propranolol atenolol
penicillin fluoxetine diltiazem
remifentanyl (33k) tetrahydrocannabinol (1000)
aspirin* morphine* (TI=70) carvedilol*
cephalosporin erythromycin
* Not a good example

• small TI drug: relatively unsafe

e.g. Digoxin (TI = 2-3) cocaine (15) paracetamol?
warfarin phenobarbitone dimercaprol
phenytoin refampicin gentamycin
lithium heparin vancomycin
imipramine atropine amphotericin B
theophyline ethanol (10) polymyxin B
pentobarbitone Levothyroxine Carbmazepine
heroin (3) chloramphenicol quinidine
aminoglycosides tetracyclines
 Clinical usefulness of therapeutic index
Warfarin (narrow TI)
• As the dose of warfarin is increased, a
greater fraction of the patients respond
(for this drug, the desired response is a
two- to threefold increase in the
international normalized ratio [INR])
until, eventually, all patients respond
• But at higher doses of warfarin, higher
degree of anticoagulation that results in
hemorrhage occurs.
Penicillin (wider TI)
• For drugs such as penicillin, it is safe and
common to give doses in excess (often
about tenfold excess) of that which is
minimally required to achieve a desired
response.
• Bioavailability does not critically alter the
therapeutic or clinical effects.
 REFERENCES

• Rang and Dale’s PHARMACOLOGY (Rang, Dale,

Ritter & Flower, 9th edition), p. 6-49 and 117-150 .
• BASIC & CLINICAL PHARMACOLOGY (Katzung,
13th edition), p. 20-73 .
• Lippincott’s Illustrated Reviews: PHARMACOLOGY
(Harvey RA, series editors, 6th edition), p. 1-37 .
• Dr Kiew Lik Voon’s (Department of Pharmacology)
lecture notes (PK)