Pharmacodynamics

Study of the biochemical and physiologic

effects of drugs and their mechanisms of
action.

Deals with the effect of drugs on biological

systems
• The principle of PD applies to all biological

systems, from isolated receptors in the test

tube to patients with specific diseases
 The main ways by which drugs act are via
interaction with cell proteins

 In addition, drugs can work by themselves

mechanically or chemically.

 Its useful to know what are the basic principles

of drug action.
How drugs act.
• A drug is a chemical that affects physiological
function in a specific way.
• Drug molecules must exert some chemical
influence in one or more cell constituents to
produce a pharmacological response.
• Drugs must get so close to these constituents
cellular molecules such that the fxn of the
latter is altered.
• If drug is evenly distributed the chance of
interacting with the molecules are reduced
 Bse the cellular molecules greatly outnumber
the drug molecules.
 Pharmacological effects there4 require the
non-uniform distribution of drugs
 Drugs must be bound to a particular
constituent of cells and tissues in order to
produce an effect.
Protein targets
 Four kinds of regulatory proteins
-enzymes
-carrier molecules
-ion channels
-receptors
Structural proteins e.g. tubulin.
Exceptions
 Antimicrobial
 Antitumour

 Mutagenic

 Carcinogenic

These interact directly with DNA rather than

proteins.
NB: in the absence of an agonist, a receptor is
functionally silent.
Principles of Drug action

 Stimulation: Enhancement of the level of a

specific biological activity (usually already
ongoing physiological process). E.g.
adrenaline stimulates heart rate.

 Depression: Diminution of the level of a

specific biological activity (usually already
ongoing physiological process). E.g.
barbiturate depress the CNS.
Cont’d

 Replacement: Replacement of the natural

hormones or enzymes (any substance) which
are deficient in our body. E.g. insulin for treating
diabetes.

 Cytotoxic action: Toxic effects on invading

micro organisms or cancer cells.
How does all these happen?
 A drug can produce all the said effects by virtue
of any of the following action
1. Through enzymes: a drug can act by either
stimulating or inhibiting an enzyme
2. Through receptors: this is when a drug produces
its response by attaching itself to a protein
called as receptor which in turn regulates the cell
function.
How does all these happen?
Receptor action is the most commonest
way of producing action.
3. Physical action: The physical property is
responsible for drug action. E.g.
radioisotope I131 and other radioisotopes.
3. Chemical action: The drug reacts
extracellularly according to simple
chemical equations. E.g. antacids
neutralising the gastric acid.
Receptors
 Are specific molecules within the biological
system with which drugs interact to produce in
the function of the system.
 They must be selective in their ligand-binding x-
tics
 They must be modifiable when they bind drug
 The receptor site(recognition site) of the drug
is the specific binding region of the receptor
 Has a relative and selective affinity for the drug
molecule.
Drug specificity
• For a drug to be used as a therapeutic agent, it
must act selectively on particular cells and
tissues.
• Individual classes of drugs bind only to certain
targets and individual targets recognize only
certain classes of drugs- reciprocal specificity.
• How ever, not all drugs are specific in their
actions. In many cases ↑sing the dose will
cause it to affect more targets other than the
principle one-side effects.
Effectors
 An effector is a component of the biological
system that accomplishes the biological effect
after the receptor is activated by an agonist.
 Usually a channel or an enzyme molecule.
Drug- receptor interactions
 Occupation of a receptor by a drug molecule
may or may not elicit a tissue response
(activation).
 Binding and activation-agonist
 Binding of the receptor with no activation and
prevention of agonist from binding- antagonist.
Affinity and intrinsic activity
 Affinity: It is the ability of a drug to bind to the
receptor (just bind)
 Intrinsic activity: It is the ability of a drug to
activate a receptor following receptor
occupation.
Binding of drugs to receptors
• Obeys the law of mass action
• At eq=m, receptor occupancy is related to
[drug]
• The higher the affinity of the drug for the
receptor, the lower the [] at which it produces a
given level of occupancy.
• When two or more drugs compete for the
same receptors, each has the effect of
reducing the apparent affinity of the other.
Agonists
 A drug that activates it receptor upon binding.
 A receptor exists in 2 forms, an active and an
inactive state.
 In the absence of a ligand, a receptor may be
fully active or completely inactive.
 An equilibrium state must exist with some
receptors in either state.
 Activity of a receptor in the absence of a ligand
is called constitutive activity.
Agonists
 Agonists are the chemicals that interact with a
receptor, thereby initiate a chemical reaction in
the cell and produces effect .
 Example—ACh is agonist at muscarinic
receptor in heart cell.
 Will have both Affinity and maximal Intrinsic
activity
So, what is a receptor “agonist”?

 Any drug that binds to a receptor and stimulates

the functional activities
 e.g.: Ach

Receptor
Some Effect

Acetylcholine

A Cell
Full agonist
 A dug capable of fully activating the effector
system when it binds receptor
 It has a high affinity for the activated receptor
conformation.
 Sufficiently higher concentrations will achieve
the activated state
Partial Agonist
 A drug that binds to its receptor but produces a
smaller effect than a full agonist.
 Intermediate levels of efficacy, such that even
when 100% receptor occupancy, tissue
response is submaximal.
Partial agonist
 Partial agonist activates receptor to produce
an effect. Less response than a full agonist .
 Partial agonist blocks the agonist action.
 Will have Affinity but sub maximal Intrinsic
activity
 Partial agonist
 Produces a submaximal response

Partial agonist
Submaximal
Oh!!!, I should effect
Have been here

True agonist
 Full and partial agonist occupancy and response
relationship
100

Response
(full agonist) Occupancy
(both)
Response(%)

50

Response
(partial Agonist)

0.0
0.01 0.1 1.0 10.0
Concentration (umol/l)
Inverse agonists
 Inverse Agonists are the chemicals that
interact with a receptor, but produces opposite
effect of the well recognized agonist for that
receptor
 Will have Affinity and negative Intrinsic
activity
 Example: Flumazenil is an inverse agonist of
Benzodiazepine
Inverse agonist

 Any drug that binds to a receptor and

produces an opposite effect as that of an
agonist

Receptor
Effect opposite to
that of
the true agonist

Inverse agonist

A Cell
Antagonists
 A drug that binds to the receptor and blocks
the effect of an agonist for that receptor
 Atropine is antagonist of ACh at Muscarinic
receptors.
 Will have only Affinity but no Intrinsic activity
 So, what is a receptor “antagonist”
?
 Any drug that prevents the binding of an
agonist
 eg: Atropine (an anticholinergic drug)

Atropine
Dude, you’re
in my way!

Acetylcholine
Types of Antagonists
 Competitive antagonism
 Non – competitive antagonism
Competitive antagonism
• Describes a situation where a drug binds
selectively to a particular type of receptor
without activating it, but in such a way as to
prevent the binding of an agonist.
• At a given antagonist [], the agonist occupancy
will be reduced in the presence of the
antagonist.
• Bse the two are in competition, raising the
[agonist] can restore the tissue occupancy.
• The antagonism is therefore surmountable.
contd
 In the presence of the a fixe[] of the antagonist,
the log-conc curve for the agonist will be
shifted to the right.
 The shift is expressed as a dose ratio
 The ratio by which the [agonist] has to be
increased in the presence of an agonist in
order to restore a given level of response.
Competitive Antagonism Shifts The
Agonist D-R Curve (Potency)

AG + ANT
% Max Response

AG alone

EC50 EC50

Drug Concentration (log

scale)
Non competitive antagonism
 Antagonist block at some point the chain of
events that leads to the pdn of a response by
the agonist.
 E.g Ca2+ blockers prevent the influx of Ca2+
through the cell membrane and thus block non
specifically the contraction of smooth muscle
produced by other drugs.
Noncompetitive Antagonism Decreases
Agonist Efficacy

AG alone

AG + NC ANT
% Max response

AG + higher dose
NC ANT

Log Drug Concentration

Antagonism by receptor block
(irreversible competitive
antagonism)
 Competitive antagonism occurs when the
antagonist dissociates very slowly or not at all.
 No change in the antagonist occupancy takes
place when the agonist is applied.
 Occurs with drugs that possess reactive
groups which form covalent bonds with the
receptors.
Drug Antagonism

Propranolol &
Pharmacologic norepinephrine

Dimercaprol &
Chemical heavy metals

Pharmacokinetic
Phenobarbital &
warfarine

Physiologic
Epinephrine &
histamine
Physiological antagonism
 Interaction of two drugs whose opposing
actions tend to cancel each other.
 E.g. several catabolic actions of
glucocorticoids hormones lead to ↑sed blood
sugar, an effect that is physiologically opposed
by insulin.
Pharmacokinetic antagonism
 The antagonist effectively reduces the
concentration of the active drug at its site of
action.
 One drug affecting the absorption, distribution,
metabolism or excretion of the other.
 Important in the clinical setting.
Chemical antagonism
 two substances combine in solution and as a
result, the effect of the active drug is lost.
 E.g. use of chelating agents that bind to heavy
metals and thus reduce their toxicity.
 Protamine, a protein that is positively charged
at physiological PH, can be used clinically to
counteract the effects of heparin, an
anticoagulant that is negatively charged.
Efficacy
 The maximum effect that can be achieved with
a particular drug, regardless of the dose.
 Mainly determined by

-nature of the drug

-receptor
-associated effector system.
 Measured with a graded dose response curve.

 Partial agonists have lower maximal efficacy

than full agonists.
 Agonist posses high efficacy whereas
antagonists posses zero efficacy.
Potency
 Amount of the drug needed to produce a given
effect.
 High potent drugs- have high affinity and thus
occupy a significant proportion of the receptor
even at low concentrations.
 Determined by:

-affinity of the receptor for the drug

-number of receptors available.
Full Agonists (i.e., equal efficacies) that
Differ In Potency:

A
B C
% Max Response

Compare the EC50s

Drug Concentration (log scale)

Agonists That Differ in Efficacy

A
B
% Max response

Log Drug Concentration

 
Thank You!