115. Pharmacology | Pharmacodynamics Part 2: Quantifying Agonism and Antagonism and Pharmacodynamic Variability in Individuals and Populations

What is the defining mechanism of a full agonist in the two-state model?

High affinity for the active (Ra) conformation; shifts most receptors to the active state, producing maximal response.

What does a partial agonist do in the two-state receptor model?

Binds both Ra and Ri, with slightly higher affinity for Ra; produces a submaximal response.

What characterizes a neutral antagonist in the two-state model?

Equal affinity for Ra and Ri; maintains basal activity and blocks agonists from binding. No intrinsic activity

How does an inverse agonist affect receptor activity?

Prefers Ri conformation, reduces basal (constitutive) activity by stabilizing inactive receptors. Negative efficacy

How does a competitive antagonist affect the dose-response curve?

Shifts the curve right (‚Üë EC50); Emax unchanged as effect can be overcome by more agonist.

How does a noncompetitive antagonist affect dose-response?

Reduces Emax regardless of agonist concentration; EC50 may be unchanged.

What is a physiologic antagonist?

A drug that produces opposing effects via different receptors and pathways.

Give two examples of physiologic antagonism.

Insulin vs. Glucagon; Methacholine vs. Albuterol.

What is a chemical antagonist?

A substance that binds or sequesters an agonist, preventing receptor binding.

Give examples of chemical antagonism.

Protamine binding to Heparin; Antacids chelating Tetracycline; Cholestyramine sequesters drugs.

What is tachyphylaxis?

An acute, rapid decrease in drug response after repeated dosing.

Define receptor desensitization.

Decrease in receptor coupling efficiency, often due to phosphorylation or arrestin binding.

What is receptor downregulation?

Decrease in receptor number via internalization and degradation.

Define receptor resensitization.

Restoration of responsiveness after drug withdrawal and receptor recycling.

What is receptor supersensitivity?

Increased receptor expression after chronic antagonist use; leads to exaggerated response when antagonist is withdrawn.

What is the therapeutic index (TI)?

TI = LD50 / ED50 or TD50 / ED50; estimates drug safety.

What is the therapeutic window?

Dose range where efficacy is likely and adverse effects are low.

What does a quantal dose-response curve show?

Population-based all-or-none responses to increasing drug doses.

What does the ED50 represent?

Dose at which 50% of the population shows the desired effect.

What is the function of spare receptors?

Allow maximal response at less than 100% receptor occupancy.

What is the classical receptor occupancy model?

Receptors are inactive unless bound by a ligand; agonists have affinity and intrinsic activity, antagonists block agonists but have no intrinsic activity.

How are competitive antagonists defined in the classical model?

They reversibly bind to the same site as the agonist and are surmountable with high agonist concentrations.

How do irreversible antagonists work?

They bind covalently or with very high affinity to the active site, permanently blocking agonist action and reducing Emax.

What is a positive allosteric modulator (PAM)?

A molecule that binds to a different site on the receptor and increases the affinity or efficacy of the agonist.

What is a negative allosteric modulator (NAM)?

A molecule that binds to a different site on the receptor and decreases the affinity or efficacy of the agonist.

What defines a drug's potency?

The concentration (EC50) needed to achieve 50% of the drug’s maximal effect.

What defines a drug’s efficacy?

The maximal effect (Emax) a drug can produce, regardless of dose.

How does the two-state model explain basal activity?

Receptors exist in equilibrium between active and inactive states even without ligand; some basal signaling occurs.

Why are quantal dose-response curves useful clinically?

They help determine the safe and effective dose range across a population, including ED50, TD50, LD50.

What is the clinical implication of a narrow therapeutic window?

Small changes in drug concentration can lead to toxicity; requires close monitoring.

A 33-year-old woman is taking propranolol for essential tremor. Over several months, she discontinues the drug abruptly and presents to the ER with severe hypertension and tachycardia. Which of the following best explains this phenomenon?

A. Desensitization
B. Tachyphylaxis
C. Receptor downregulation
D. Receptor supersensitivity
E. Neutral antagonism

D

Receptor supersensitivity results from chronic antagonist exposure (e.g., propranolol), which leads to upregulation of β-receptors. Abrupt withdrawal allows endogenous catecholamines to bind excess receptors → hypertensive crisis.

Tachyphylaxis is rapid tolerance due to agonist overuse, not antagonist withdrawal.

An experimental antiplatelet agent irreversibly binds to a non-active site on COX-1, preventing thromboxane A2 production. The effect cannot be reversed with additional substrate. Which of the following best describes the mechanism of this drug?

A. Competitive antagonist
B. Positive allosteric modulator
C. Negative allosteric modulator
D. Irreversible active-site antagonist
E. Noncompetitive antagonist

E

The drug irreversibly binds to a non-active (allosteric) site on COX-1. It prevents receptor activation, and additional substrate has no effect, matching the definition of a noncompetitive antagonist (often irreversible or allosteric binding) rather than a negative allosteric modulator (which reduces affinity or efficacy but can often be overcome).