Pharmacodynamics

Pharmacodynamics: What the drug does to the body

Actions of drugs on target organs.

A response may result when a drug or endogenous ligand (hormone or neurotransmitter) binds to a receptor

The drug–receptor complex initiates alterations in biochemical and/or molecular activity of a cell by a process called signal transduction.

Drugs act as signals and their receptors act as signal detectors

The magnitude of the response is proportional to the number of drug-receptor complexes

Receptor (or signal detector)

any biologic molecule to which a drug binds and produces a measurable response

Regulatory proteins

Enzymes

Transport proteins

Structural proteins

richest source of pharmacologic receptors

Proteins that transduce extra-cellular signals into intracellular responses are the richest source of pharmacologic receptors.

Major Receptor Families

Ligand-gated ion channels

G protein–coupled receptors

Enzyme-linked receptors

Intracellular receptors

Dose-Response Relationships

The magnitude of the drug effect depends on the drug concentration at the receptor site.

As the concentration of a drug increases, its pharmacologic effect also gradually increases until all the receptors are occupied which would then produce the maximum effect.

Potency

a measure of the amount of drug necessary to produce an effect of a given magnitude

Clinically, a drug that produces the same measured effect at a lower dose would be more potent

Efficacy

the magnitude of response a drug causes when it interacts with a receptor (e.g., the ability of a drug to lower blood pressure).

dependent on the number of drug–receptor complexes formed and the intrinsic activity of the drug

Maximal efficacy of a drug (Emax) assumes that all receptors are occupied by the drug, and no increase in response is observed if a higher concentration of drug is obtained

maximal response differs between full and partial agonists

For antagonists, even though an antagonist occupies 100% of the receptor sites, no receptor activation results.

Efficacy is a more clinically useful characteristic than is drug potency, since a drug with greater efficacy is more therapeutically beneficial than is one that is more potent

Affinity

how strongly a drug molecule binds to a binding site

The dissociation constant (Kd) describes the degree of a drug’s affinity for the receptor site.

The higher the Kd value, the weaker the interaction and the lower the affinity.

High affinity drug molecules have a low dissociation constant (Kd) and are less likely to become dissociated from their binding sites than low affinity molecules

Types of Agonists and Antagonists

Agonists

• Full agonists

• Partial agonists

• Inverse agonists

Antagonists

• Competitive antagonists

• Irreversible antagonists (Non-Competitive)

• Allosteric antagonists (Non-Competitive)

Drug-Receptor Interactions – Agonists

An agonist binds to a receptor and produces a biologic response.

The biologic response seen is based on the concentration of the agonist and the fraction of activated receptors.

The intrinsic activity of a drug determines its ability to fully or partially activate the receptors.

Full Agonist

produces a maximal response when binding to a receptor (intrinsic activity = 1 or 100%)

Partial Agonist

produces a less than maximal response when binding to a receptor (intrinsic activity = > 0, < 1)

When a receptor is exposed to both a partial agonist and a full agonist, the partial agonist may act as an antagonist of the full agonist

Inverse Agonist

Decreases the number of activated receptors to below that observed in the absence of drug, (e.g., produce a response below the base-line response measured in the absence of drug (intrinsic activity < 0)

reverse the activity of receptors and exert the opposite pharmacological effect of agonists.

Drug-Receptor Interactions – Antagonists

An antagonist binds to a receptor with high affinity but possesses zero intrinsic activity.

An antagonist has no effect in the absence of an agonist but can decrease the effect of an agonist when present.

Antagonism may occur either by:

-blocking the drug’s ability to bind to the receptor

-blocking its ability to activate the receptor (e.g., allosteric antagonists)

Competitive antagonists

When the antagonist and the agonist bind to the same site on the receptor in a reversible manner.

This inhibition can be overcome by increasing the concentration of agonist relative to antagonist.

Competitive antagonists reduce potency.

Irreversible (Non-Competitive) antagonists

Reduce the number of receptors available to the agonist by binding covalently to the active site of the receptor.

The effect of irreversible antagonists cannot be overcome by adding more agonist.

Irreversible antagonists reduce efficacy.

Allosteric (Non-Competitive) antagonists

Bind to a site (“allosteric site”) other than the agonist-binding site and prevents the receptor from being activated by the agonist

Quantal Dose-Response Relationships

A quantal-dose response relationship is a dose–response relationship that is between the dose of the drug and the proportion of a population that responds to it.

Therapeutic Index (TI)

Therapeutic Index (TI) is the ratio of the dose of a drug that produces toxicity

The TI is a measure of a drug’s safety, because a larger value indicates a wide margin between doses that are effective and doses that are toxic.

Example of a drug with a narrow therapeutic index: Warfarin

an oral anticoagulant which has a risk of bleeding

Example of a drug with a wide therapeutic index: Penicillin Class Antibiotics

an antimicrobial (antibiotic class)