noncompetitive antagonist

**Mechanism** - Binds an allosteric (separate) site on the receptor, causing a conformational change that prevents activation, OR binds the active site irreversibly (covalently), functionally acting the same way. - Because the antagonist is not displaced by agonist, increasing the agonist dose cannot restore the full response. The number of functional receptors is effectively reduced.

**Effect on dose-response curve** - Emax (efficacy): decreased. - EC50 (potency of the agonist): unchanged for a pure allosteric noncompetitive antagonist (classically). Irreversible competitive antagonists may also lower Emax once spare receptors are exhausted. - Curve: downward shift (flattening), not a parallel rightward shift. - On a Lineweaver-Burk plot (enzyme analogy): Vmax decreases, Km unchanged.

**Contrast with competitive antagonist** - Competitive: binds the same (active) site reversibly; Emax unchanged, EC50 increased (potency decreased); parallel rightward shift; overcome with more agonist. - Noncompetitive: Emax decreased, EC50 unchanged; cannot be overcome by more agonist. - Spare receptors: with spare receptors, a low dose of an irreversible antagonist may shift the curve rightward first (looks competitive) before Emax falls.

**Clinical examples (high-yield)** - Phenoxybenzamine: irreversible alpha-blocker (covalent binding) used in pheochromocytoma; acts as a noncompetitive (irreversible) antagonist, and its effect can't be overcome by catecholamine surge. - Ketamine and memantine: noncompetitive NMDA receptor antagonists (bind inside the channel pore, a PCP site). - Aspirin: irreversible COX inhibitor (enzyme analog). - Picrotoxin: noncompetitive GABA-A channel blocker. - Diazepam is not an antagonist (it is a positive allosteric modulator), a common distractor. - Contrast: Naloxone, atropine, propranolol, and flumazenil are competitive (reversible) antagonists.

**Clinical significance** - Duration of action of irreversible antagonists depends on synthesis of new receptors/enzymes, not on drug half-life. - Overdose cannot be reversed by simply giving more agonist, so management is supportive or relies on removing the drug.

**Board pearls** - "Noncompetitive = lower Emax, same EC50 (downward shift)." - "Competitive = same Emax, higher EC50 (rightward shift)." - Noncompetitive antagonists lower efficacy, not potency of the agonist.