full agonist

**Definition:** A full agonist is a ligand that binds to a receptor and stabilizes its active conformation. This produces the maximal response the tissue or system can generate. It has high intrinsic activity (efficacy), defined as 1 (100%).

**Key pharmacodynamic concepts** - **Efficacy (Emax):** the maximal effect a drug can produce. Full agonists have the highest efficacy. Partial agonists have lower Emax even at 100% receptor occupancy. - **Potency (EC50):** the concentration that produces 50% of the maximal effect. On a dose-response curve, potency is the horizontal position (left shift = more potent). Efficacy is the height of the plateau. Potency and efficacy are independent. A full agonist can be less potent than a partial agonist but still reach a higher Emax. - **Spare receptors (receptor reserve):** many full agonists reach Emax while occupying only a fraction of the receptors. Partial agonists may act as full agonists in tissues with large receptor reserve.

**Comparison with other ligand types** - **Partial agonist:** lower Emax than a full agonist. In the presence of a full agonist, it competes for receptors and can lower the net response, so it acts as a functional antagonist. Examples: buprenorphine (mu-opioid), aripiprazole (D2), buspirone (5-HT1A), varenicline (nicotinic alpha4beta2), clomiphene and tamoxifen (SERMs, tissue-dependent). - **Competitive antagonist:** binds the same site with no intrinsic activity. It shifts the full agonist's curve to the right (higher EC50) with no change in Emax. This can be overcome with more agonist. Example: naloxone vs. morphine. - **Noncompetitive (irreversible) antagonist:** reduces Emax, with no change in EC50 if there are no spare receptors. Examples: phenoxybenzamine, aspirin (irreversible COX inhibition). - **Inverse agonist:** reduces constitutive receptor activity below baseline. Example: some H1 blockers and beta-blockers in certain systems.

**Clinical pearls (USMLE)** - Giving a partial agonist (buprenorphine) to a patient dependent on a full agonist (heroin, methadone) can precipitate withdrawal. It displaces the full agonist but produces less receptor activation. - Partial agonists have a ceiling effect, which gives a better safety profile. Buprenorphine has less respiratory depression risk than full opioid agonists. - Aripiprazole, a D2 partial agonist, acts as a "dopamine stabilizer": it lowers dopaminergic tone in the mesolimbic pathway and raises it in the mesocortical pathway. - Full agonist examples by receptor: - Opioid: morphine, fentanyl, methadone, heroin - Beta-adrenergic: isoproterenol (beta-1 and beta-2) - Alpha-1: phenylephrine - Muscarinic: bethanechol, carbachol, pilocarpine - Benzodiazepine site on GABA-A: positive allosteric modulators, which are not classic orthosteric agonists - Dose-response graph questions: identify the full agonist as the curve with the highest plateau. Compare potency by horizontal position.

**Mechanism overview:** Agonist binding shifts the receptor equilibrium toward the active state (R*). This triggers downstream signaling, such as G-protein activation (Gs → cAMP, Gq → IP3/DAG/Ca2+, Gi → decreased cAMP), ion channel opening, or enzyme-linked signaling (e.g., insulin receptor tyrosine kinase).