Pharmacodynamics

Drug Receptor Interactions

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

KD: units of concentration (like mol/L)

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

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

Dose Response Relationships

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

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

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

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

Synergy

Additive effect: overall effect is sum of individual drug effects

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

Desensitization/Tachyphylaxis

Gradual diminishing of response to drug (tolerance)

Changes in receptors (conformation/ uncoupled signaling molecules)

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

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

Therapeutic index: The 50% lethal dose of a drug

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

Receptor Theory

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

Receptor: Drug target

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

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

Drug-receptor binding

Agonist-->Response

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

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

Antagonist-->No response

Reversible antagonist: functionally decreases potency of an agonist drug

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

Occupation:Affinity

Activation: Efficacy

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

Floating topic