Pharmacodynamics

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 Drugs:
 Chemical agents that interact with components of a
biological system to alter the organism’s function.

 Examples of such components (sites of drug action) are:

 Enzymes
 Ion channels
 Neurotransmitter transport systems
 Nucleic acids
 Receptors

 Many drugs act by mimicking or inhibiting the interactions of

endogenous mediators with their receptors

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 Receptors:
Regulatory proteins that interact with drugs or
hormones and initiate a cellular response

4 types of receptors:
1. Ion channels (Ligand-gated Ion Channels)
2. G-protein coupled receptors
3. Receptor-enzymes
4. Cytosolic-nuclear receptors

Act as transducer proteins

Receptor-effector signal transduction
Post-receptor signal transduction provides for
amplification of the signal

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 1. Ligand-gated Ion Channels

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 2. G-protein coupled
receptors

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3. Enzyme-linked receptors:

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 4. Intracellular Receptors

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 Properties of drugs
Affinity: the chemical forces that cause the drug to
associate with the receptor.

Efficacy: the ability of a drug to elicit a response

when it interacts with a receptor.

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 Graded dose–response Relations

Potency: the amount of drug necessary to

produce an effect of a given magnitude.

Dependent upon receptor density, efficiency of the

stimulus-response mechanism, affinity and efficacy.

Efficacy (Magnitude of effect): maximal response

Solely dependent upon intrinsic efficacy.

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 A drug with greater efficacy is more therapeutically
beneficial than one that is more potent.

Maximal efficacy of a drug assumes that all receptors

are occupied by the drug, and no increase in response
will be observed if more drugs are added.

This concept holds true only if there are no "spare

receptors" present.

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 Concepts to remember!
Threshold: Dose that produces a just-noticeable
effect.

ED50: Dose that produces a 50% of maximum

response.

EC50: refers to the concentration of a drug which

induces a response halfway between the baseline and
maximum after a specified exposure time.

Ceiling: Lowest dose that produces a maximal effect.

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 Dose-response curve
100
Ceiling
80

60
Response

ED50
40

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Threshold

0
0.1 1 10 100 1000 10000

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Dose
 Important parameters:
Onset: The time it takes for the drug to elicit a
therapeutic response.

Peak: The time it takes for a drug to reach its

maximum therapeutic response.

Duration: The time a drug concentration is sufficient

to elicit a therapeutic response

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 Spare receptors
 only a fraction of the total receptors for a specific ligand may need
to be occupied to elicit a maximal response from a cell.
 Systems that exhibit this behavior are said to have spare
receptors.
 Spare receptors are exhibited by:
 insulin receptors: 99 percent of the receptors are “spare.”
 β-adrenoceptors in the heart: 5 to 10 percent of the total β-
adrenoceptors are spare.

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 Desensitization and down-regulation of receptors:

Repeated or continuous administration of an agonist

(or an antagonist) may lead to changes in the
responsiveness of the receptor.
When repeated administration of a drug results in a
diminished effect, the phenomenon is called
tachyphylaxis.
The receptor becomes desensitized to the action of
the drug.
In this phenomenon, the receptors are still present
on the cell surface but are unresponsive to the
ligand.
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 Receptors can also be down-regulated in the presence
of continual stimulation.
Binding of the agonist results in molecular changes in
the membrane-bound receptors, such that the receptor
undergoes endocytosis and is sequestered within the
cell, unavailable for further agonist interaction.

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 Classification of a drug based on drug-
receptor interactions
1. Agonist: If a drug binds to a receptor and produces
a maximal biologic response that mimics the response
to the endogenous ligand, it is known as a full agonist.
e.g. phenylephrine is an agonist at α1-adrenoceptors,
because it produces effects that resemble the action of
the endogenous ligand, norepinephrine.

In general, a full agonist has a strong affinity for its

receptor and good efficacy

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 cont.
2. Partial agonists:
 Drug that, no matter how high the dose, cannot produce a
full response.
 Partial agonists have efficacies (intrinsic activities) greater
than zero but less than that of a full agonist.
 Affinity of a partial agonist may be greater than, less than,
or equivalent to that of a full agonist.
 Under appropriate conditions, a partial agonist may act as
an antagonist of a full agonist. (i.e. Partial agonists have
both agonist and antagonist properties)

 Example, aripiprazole, an atypical neuroleptic agent, is a

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partial agonist at selected dopamine receptors.
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 3. Inverse agonist:
Drug that binds to a receptor to produce an effect
opposite that of an agonist.
Stabilizes receptors in the inactive state.

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 4. Antagonists
 Antagonist: drug that binds to receptors but cannot initiate a
cellular response, but prevent agonists from producing a
response; affinity, but no efficacy. Antagonists maintain the
active-inactive equilibrium. Antagonists mgit be competitive
or non-competitive;
1. Competitive Antagonists: Antagonist binds to same site
as agonist in a reversible manner.
2. Noncompetitive Antagonists: Antagonist binds to the
same site as agonist irreversibly.
 Physiologic Antagonists: Two drugs have opposite effects
through differing mechanisms
 Allosteric: Antagonist and agonist bind to different site on
same receptor
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 Allosteric Antagonism

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 Allosteric Antagonism

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 Allosteric Antagonism

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 Allosteric Antagonism

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 Chemical Antagonism
Simple chemical reaction.
No receptor.

Examples:

Heparin & proteamine sulfate

Iron & Deferoxamine.

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 Physiological Antagonism
Physiological effect is antagonized.
Drugs acting on different receptors:

Examples:
 Norepinephrine → Vasoconstriction → ↑ BP.
 Histamine → Relax vascular smooth muscle→ ↓BP

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 Desired vs undesired effects: therapeutic Index ,
index of drug safety… tolerability profile

ED50 - Median Effective Dose 50 ; the dose at which

50% of the population or sample manifests a given
effect.

TD50 - Median Toxic Dose 50 - dose at which 50% of

the population manifests a given toxic effect

LD50 - Median lethal Dose 50 - dose which kills 50% of

the subjects
Therapeutic Index = TD50 or LD50/ ED50
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 Unusual Responses:
Definitions:

1. Idiosyncratic response: unusual response

2. Hyporeactive: less than normal response
3. Hyperreactive: more than normal response
4. Hypersensitivity: allergic or other immunological
reaction.
5. Tolerance: decreased response with continued
administration
6. Tachyphylaxis: rapidly developing tolerance

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