1. Explain the PD princpiles?

2. Know what are receptors ??

3. Understand Ligands- receptors interaction
4. Know major receptor families
5. Understand
 Dose-response curve,
 Agonist & Antagonist (types)
 Potency & Efficacy
 Therapeutic index & Therapeutic range
 Desensitization, Tachyphylaxis, & Tolerance
 The biochemical and physiologic mechanisms
of drug action
 A drug alters the physiology of the cell

 These process include uptake, movement,

binding and interactions of pharmacologically
active molecules at their tissue site of action.

The effects of What the drug

does when it gets the body.
 PD deals with
 Interaction of drugs with receptors and understanding
the molecular mechanisms by which a drug acts
 Relationship between drug concentration and
magnitude of the response
 Why we study it ??
 To understand how the drugs produce its therapeutic and
toxic effects.
 PD answer many questions. For instances:
 Why do some drugs produce effects that persist for
minutes, or even days after the drug is no longer
present?
 Why do responses to other drugs diminish rapidly with
prolonged or repeated administration?
 Lock and key mechanism

Agonist Receptor

Agonist-Receptor
Interaction
 Receptors are biological macromolecules to which a
ligand can bind and produce a measurable response.
They include :-
 Regulatory proteins, which mediate the actions of
endogenous chemical signals such as
neurotransmitters
 Enzymes, which may be inhibited by binding a drug
(e.g., Dihydrofolate reductase, the receptor for the
antineoplastic drug methotrexate)
 Transport proteins (e.g., Na+/K+ ATPase, the
membrane receptor for cardioactive digitalis-
glycosides)
 Structural proteins (e.g., tubulin, the receptor for
colchicine, an anti-inflammatory agent).
 They largely determine the quantitative relations
between dose of drug and pharmacologic effects.
 They are responsible for selectivity of drug action.
 They mediate the actions of both pharmacologic
agonists and antagonist
 Many toxic chemicals produce their effect by
interaction with receptors.
 Drugs only modify an already existing biochemical
processes.
 Involve formation of chemical bonds
- Hydrogen bonding other weak electrostatic interaction
- Usually interaction is reversible
- Few cases , strong covalent bonds are formed (Toxic
substances )
 Drug–receptor interaction initiates the action of the drug.
 Drug + Receptor D-R complex

biological response
 The formation of D-R complex depends on drug affinity for
the receptors
 However, the Pharmacological response depends on
intrinsic activity
1. Ligand – gated ion channels
2. G-Protein coupled receptors
3. Enzyme –linked receptors*
4. Intracellular receptors

*at least 6 types , they include

 Tyrosine –linked R & Cytokine R
 are another type of Receptor, which poses enzymatic
activity.
 Theintensity and duration of a drug’s effects are a
function of drug concentration at the effect site

Two types of Dose-response relationship

 Graded : Relates dose to intensity of effect

e.g., blood pressure, hemoglobulin,
bronchodilation

 Quantal : % population responding to drug

 Frequencyof distribution of % population
responding to drug A
% population responding

1 10 20 30 40 50 60 70 80 90 100

Dose (mg/kg)
 Affinity & intrinsic activity

 Are the two factors that determine the effect of a drug

on physiologic processes

A-Affinity is a measure of the tightness that a drug

binds to the receptor.
B-Intrinsic activity is a measure of the ability of a drug
once bound to the receptor to generate an effect
activating stimulus and producing a change in
cellular activity.
 Agonist:
• A drug which binds to a receptor and activates it,
producing pharmacological response (contraction,
relaxation, secretion, enzyme activation, etc.).
• A drug is said to be an agonist when it binds to a receptor
and causes a response or effect.
• Intrinsic activity =1

---
++ ++-
+
+++
--- +--

Depolarization
 A drug which binds to a receptor and activates it,
producing a pharmacological response but less than
full agonist.
 Intrinsic activity <1 but not zero (0<IA<1)

Fuall agonis t vs par tial agonis t

1.2
% of maximal responses

1 full agonis t

0.8
0.6
0.4
par tial
0.2 agonis t

0
1.00 1000.00
log Conce ntr ation
A drug binds to a receptor and prevents
(blocks or inhibits) a natural compound or a
drug to have an effect on the receptor.

 An antagonist has NO activity.

 Its intrinsic activity is = 0

A drug which binds to the receptors in common

with an agonist, without causing their
activating;
 A-PHARMACOLOGICAL ANTAGONISTS

1. Competitive
They compete for the binding site
• Reversible
• Irreversible

2. Non-competitve
Bind elsewhere in the receptor (Channel Blockers).
Non competitive Competitive

Bind irreversibly to the Bind reversibly to the receptors

receptors.

Their effect Can’t be Their effect Can be overcome by

overcome by increasing the increasing the concentration of
concentration of agonist agonist

Calcium channel blockers Example atropine is a competitive

agonist for acetylcholine
 Dos e re s pons e curve of agonis t alone (A)
and in pre s e nce of com m e ttive
antagonis ( B)
1.20
% of maximal responses

1.00 A
0.80
0.60
0.40
0.20 B
0.00
1.00 1000.00

log Conce ntration

•Their effect can’t be
overcome by adding Dose response curve of agonist alone (A)
and in presence of non commettive
more agonist antagonis( B)
•They causes downward 1.20

% of maximal responses
shift of the Emax. 1.00 A
 e.g.: 0.80
organophosphorus 0.60
compounds 0.40
0.20
B
0.00
0.10 100.00

log Concentration
FUNCTIONAL ANTAGONISTS

1. Physiologic Antagonists

2. Chemical Antagonist
 Physiologic ANTAGONIST

 A drug that binds to a non-related receptor, producing

an effect opposite to that produced by the drug of
interest.

 Its intrinsic activity is = 1, but on another receptor.

Glucocorticoid Hormones  Blood Sugar

Insulin  Blood Sugar
 Chemical ANTAGONIST

 A chelator (sequester) of similar agent that interacts

directly with the drug being antagonized to remove it or
prevent it from binding its receptor.
 A chemical antagonist does not depend on interaction
with the agonist’s receptor (although such interaction may
occur).
 Heparin, an anticoagulant, acidic
 If there is too much  bleeding and
haemorrhaging
 Protamine sulfate is a base. It forms a stable
inactive complex with heparin and inactivates
it.
 Synergism
 Thecombined effect of two drugs is higher
than the sum of their individual effects.

 Additivity
 The combined effect of two drugs is equal
to the sum of their individual effects.
Potency
 is related to the amount of drug needed to
produce a given effect.
 In graded dose-response potency of drugs are compared
using EC50 (The dose producing 50 % of the maximum effect )

Efficacy
 Is the maximum effect an agonist can
produce (Emax)
 Its More clinically important than potency .
 Potency
 amount of drug required A B
to produce an effect
 More potent drug is theEffect Therapeutic
one that requires lower Effect
dose to cause same
effect

Which drug is more potent? Dose

Why?
Potency and efficacy…cont’d

Maximal Effect

EFFICACY
POTENCY

ED50

Log [Dose]
Potency and efficacy…

A C

B
D

RANK ORDER OF POTENCY: A > B > C > D

RANK ORDER OF EFFICACY: A = C > B > D
 drug A or B are
more potent than
drug C. 8 Drug A
Drug C

% Response
 Drug A has 6
higher efficacy Drug B
than drug B 4
2
Quiz : Compare A
&C? 0
0 10 20 30
Ln concenteration
 Is the ratio of the LD50 (Lethal dose that kills 50
% of animals tested) to the ED50 (is the amount
of drug that produces a therapeutic response in
50% of the people taking it)

 Itrepresents an estimate of relative safety of the

drug.
 For example, penicillin has a high therapeutic
index as compared to digoxin which have a low
therapeutic index
 Therapeutic range is clinically more important
 Effective dose 50
Maximal Effect

50% Effect
Effect or

ED50
 Some drug when given continuously or repeatedly
their effect are gradually decreases.
 If decrease of drug effect develops in very short
time we call it tachyphylaxis or desensitization
 If decrease of effect occurs during several days
or weeks we call it Tolerance
 Many different mechanisms can give rise to this
type of phenomenon.
 E.g. Change in receptors; Loss of receptors; Exhaustion of
mediators; Increased metabolic degradation; Physiological
adaptation