Pharmacodynamics

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Receptor Theory

Pharmacology: Protein or complex of protein that recognize and respond to endogenous chemical signals

Receptor: Drug target

Drug-receptor binding

Activation: Efficacy

Occupation:Affinity

Antagonist-->No response

Irreversible antagonist: Binds to receptor and remains there (usually covalent). Will reduce potency, but primarily affects efficacy

Allosteric antagonism, pharmacokinetic antagonism, signaling blockade, physiological antagonism, chemical antagonism

Reversible antagonist: functionally decreases potency of an agonist drug

Agonist-->Response

Inverse agonists: binds to constitutively active receptor causing a reduction in that constitutive activity

Partial agonist: Low efficacy due to lower ability to elicit signaling response while binding the same number of receptors

Examples: Membrane receptors, ion channels, carriers/transporter molecules, enzymes (also gene therapy)

Drug specificity: High structural conservation (ligand specificity) and site specificity

Drugs aren't magical entities, require direct interaction with tissue, won't work unless bound

Pharmacodynamics

Therapeutic index: The 50% lethal dose of a drug

Certain safety factor (CSF): LD/ED (LD: lethal dose and ED: effective dose)

Quantal response: number of patients in which a measured dose elicits a response

Desensitization/Tachyphylaxis

Translocation of receptors, exhaustion of mediators, altered drug metabolism, physiological adaptation

Changes in receptors (conformation/ uncoupled signaling molecules)

Gradual diminishing of response to drug (tolerance)

Synergy

Synergistic/potentiating effect: Overall effect is greater than the sum of individual effects. Many variations can cause this.

Additive effect: overall effect is sum of individual drug effects

Spare receptors: Unbound receptors

Both % receptor occupancy and dose responsiveness increase with drug concentration, but rarely equivalent. Many full agonists can elicit maximal response with low levels of receptor binding

Dose Response Relationships

Efficacy: An agonist has the ability to stimulate a signal response from a receptor (AKA intrinsic activity)

Potency: dose of drug required to achieve 50% of maximal effect

Must know true receptor binding capacities, that percentage drug bound to receptor may not equal real tissue response, and that KD is functionally replaced by ED50 (effective dose) or EC50 (effective concentration) for comparison

Drug Receptor Interactions

K(+1) [A][R]=K(-1)[AR]

([A][R])/[AR]=(K(-1))/(K(+1))=KD

Equilibrium dissociation constant (KD): Contentration of drug required to occupy 50% of receptors

KD: units of concentration (like mol/L)