Drug Receptors&

Pharmacodynamics

By

M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science

Drug Receptors & Pharmacodynamics

Receptors

Receptor Regulation

Coupling

Antagonists

Signaling Mechanisms

Dose – Response Relationship

Receptors

Receptors determine the quantitative relations between concentration of drug and its effects.

Receptors are responsible for selectivity of drug action.

Receptors mediate the actions of both agonists and antagonists.

Receptors (Cont’d)

Drug receptors include:

Enzymes, which may be inhibited (or, less commonly, activated) by binding a drug.

Transport proteins (eg, Na+/K+ ATPase)

Structural proteins (eg, tubulin, the receptor for colchicine).

Receptor Regulation

Sometimes the response diminishes even in the continued presence of the agonist.

This "desensitization" is reversible.

A second exposure to agonist can elicit the response.

Coupling

Coupling: The process that links occupancy of receptors to pharmacologic response.

Sometimes the effect of the drug is linearly related to the number of receptors. (ion channels).

Antagonists

Some antagonists (so-called "inverse agonists") reduce receptor activity.

Antagonists are divided into: Competitive or reversible Non competitive or irreversible Other antagonists

Competitive Antagonists

Inhibition by a competitive antagonist depends on its concentration.

Clinical response to a competitive antagonist depends on the concentration of agonist.

Irreversible Antagonists

The effect of irreversible antagonists depends on the turnover of its receptor (not the antagonist).

In overdose a real problem may arise.

Excess of these drugs must be antagonized "physiologically”.

Other Antagonists

Some antagonists do not involve a receptor: Chemical antagonist: one drug inhibits the other by

ionic binding (protamine).

Physiologic antagonism: is between pathways mediated by different receptors.

Physiologic antagonists are less specific and less easy to control than receptor-specific antagonism.

Signaling Mechanisms

They include: Receptors

Enzymes

Second messengers (postreceptor signaling)

Signaling mechanisms (Cont’d)

There are five signaling mechanisms: A ligand crosses the membrane and acts on an

intracellular receptor. Transmembrane receptors with enzymatic activity:

The receptor has direct enzymatic activity The receptor stimulates a protein tyrosine kinase.

A transmembrane ion channel which is ligand gated. A transmembrane receptor that stimulates a “G

protein” which produces a second messenger.

Intracellular Receptors

Ligands which act on intracellular receptors include: Steroids (corticosteroids, mineralocorticoids, sex

steroids, vitamin D) Thyroid hormone Many of the target DNA sequences (response

elements)

Intracellular Receptors (Cont’d)

This mechanism (which regulates genes) has important consequences: The effect begins after 30 minutes to several hours

(required for the synthesis of new proteins). They are not suitable in emergency. Their effects persist even for days after the agonist

has metabolized (slow turnover of proteins). Their beneficial (or toxic) effects will decrease

slowly after stoping the drug.

Transmembrane Enzymes They mediate signaling for:

Insulin Epidermal growth factor (EGF) Platelet-derived growth factor (PDGF) Atrial natriuretic peptide (ANP) Transforming growth factor-β (TGF-β) Cytokine receptors

The action of these agents are limited by down-regulation.

• Growth hormone• Erythropoietin • Several kinds of

interferon

Ligand-Gated Ion Channels

Many drugs mimick or block the actions of endogenous ligands on the ion channels.

The time between the binding of the agonist and the response is within milliseconds.

Ligand-gated ion channels can be regulated by phosphorylation and endocytosis.

G Proteins & Second Messengers

They use a signaling system with separate steps: The ligand is detected by a receptor.

The receptor activates a G protein.

The G protein changes the activity of an enzyme or ion channel.

This element then changes the concentration of a second messenger.

G Proteins & Second Messengers (Cont’d)

The second messengers may be: Cyclic adenosine monophosphate (CAMP)

Cyclic guanosine monophosphate (CGMP)

Calcium and phosphoinositides

G Proteins & Second Messengers (Cont’d)

Such receptors include: β-adrenoceptors Glucagon receptors Thyrotropin receptors Certain subtypes of dopamine and serotonin

receptors

Dose – Response Relationship

The two factors that determine the dose-response relationship include: Potency

Maximal Efficacy

Potency

Potency is the dose of a drug that produces 50% of the maximal effect (EC50 or ED50).

Potency is inferred from dose axis and determines the dose of the drug.

Potency depends on: The efficiency with which drug-receptor interaction is coupled to response.

The affinity (Kd) of receptors for binding the drug.

Kd (the equilibrium dissociation constant) is the drug concentration at which half-maximal binding is observed.

Potency (Cont’d)

The dose required to produce a toxic effect in 50% of animals is the median toxic dose (TD50).

If the toxic effect is death, a median lethal dose (LD50) is defined.

Therapeutic index is the ratio of the TD50 to the ED50.

The acceptable risk of toxicity depends on the severity of the disease being treated.

Maximal Efficacy

Maximal efficacy reflects the limit of the dose-response relation on the response axis.

The maximal efficacy is crucial for clinical decisions when a large response is needed.

Maximal Efficacy (Cont’d)

Idiosyncratic drug response: one that is infrequently observed in most patients.

A patient may be hypo- or hyperreactive to a drug compared to most individuals.

Tolerance: when the intensity of response to a drug decreases by continued administration.

Tachyphylaxis: when responsiveness diminishes rapidly after administration of a drug.

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40 Km.

Thank youAny question?

mh_farjoo@yahoo.com