Pharmacodynamics

Receptors, agonists, and the dose-response curve

Pharmacodynamics. What the drug does to the body: the relationship between drug concentration and effect, usually mediated by receptor binding. It complements pharmacokinetics (what the body does to the drug). Dose-response curves summarize a drug's potency, efficacy, and susceptibility to antagonism; plotted against log dose, a graded response traces a sigmoid curve.

Affinity vs intrinsic activity. Affinity is how tightly a drug binds its receptor; intrinsic activity is how strongly it activates the receptor once bound. An agonist has both. An antagonist has affinity but no intrinsic activity, so it simply occupies the receptor and blocks agonists.

Full agonist. Binds and produces the maximal tissue response (full Emax).

Partial agonist. Produces a lower maximal effect (lower Emax) than a full agonist even at 100% receptor occupancy. Alone it gives some activation; alongside a full agonist it acts as a net antagonist, because it occupies receptors while activating them weakly. Examples: buprenorphine (opioid), buspirone (serotonin), pindolol (β-adrenergic), varenicline (nicotinic), aripiprazole (dopamine).

Inverse agonist. Binds a receptor that has baseline (constitutive) activity and reduces that activity below baseline, producing the opposite effect of an agonist.

Potency vs efficacy

Potency. The amount of drug needed for a given effect, indexed by EC50, the concentration producing 50% of the maximal response. The farther LEFT the curve (lower EC50), the more potent the drug. Potency largely reflects receptor affinity and is mainly a dosing convenience, not clinical superiority: fentanyl is far more potent than morphine, yet both are full μ agonists.

Efficacy. The maximal effect a drug can produce (Emax), the height of the curve's plateau. It is clinically more important than potency because it sets the ceiling of benefit. Full agonists have high efficacy; partial agonists have lower efficacy no matter the dose.

Spare (reserve) receptors. When a tissue has more receptors than it needs, a full agonist can produce its maximal effect while occupying only a fraction of them, so half-maximal response is reached at well under half occupancy. Response is therefore not proportional to the number of receptors bound, and partial occupancy can still give a full response.

Antagonists

Competitive (reversible) antagonist. Binds the same site as the agonist and can be outcompeted: adding more agonist overcomes it (surmountable). The curve shifts RIGHT (higher EC50, decreased potency) but Emax is UNCHANGED. Naloxone at opioid receptors is the model: very high opioid levels can partially overcome it.

Noncompetitive antagonist. Binds a different (allosteric) site or binds the receptor irreversibly. Adding agonist cannot restore the response (insurmountable), so Emax is DECREASED. Phenoxybenzamine irreversibly blocks α receptors and is used before surgery for pheochromocytoma; because the block is covalent, recovery requires synthesis of new receptors.

Antagonism without a shared receptor. A physiologic antagonist acts on a different receptor to produce the opposite effect (epinephrine reversing histamine-driven bronchoconstriction and hypotension in anaphylaxis). A chemical antagonist binds the drug itself (protamine neutralizing heparin).

Right shift with the same ceiling = competitive (surmountable). Lower ceiling = noncompetitive or irreversible (insurmountable). A partial agonist given with a full agonist competes for the same site, shifting the full agonist curve to the right; enough full agonist still reaches the full Emax (surmountable).

Safety: quantal curves and therapeutic index

Graded vs quantal curves. A graded dose-response curve plots the magnitude of a continuous effect in a single subject or tissue and yields EC50 and Emax. A quantal curve plots the fraction of a population reaching an all-or-none endpoint (effect, toxicity, death) and yields ED50, TD50, and LD50, the inputs for therapeutic index.

Therapeutic index (TI). A high TI means a wide margin between effective and toxic doses. A low (narrow) TI means small changes in level cause toxicity, so these drugs need therapeutic drug monitoring. Classic low-TI drugs: warfarin (followed by INR), theophylline, digoxin, and lithium (followed by serum levels). Mnemonic: Warning! These Drugs are Lethal.

Therapeutic window. The clinically useful range between the minimum effective concentration and the concentration at which toxicity appears; narrow-TI drugs have a narrow window.

Loading doses and loss of response

Loading dose. To reach a target plasma concentration quickly, loading dose = V_d × target concentration, divided by bioavailability (F) for non-IV routes. Because it depends on volume of distribution and not clearance, it is unchanged in renal or hepatic impairment; only the maintenance dose is reduced.

Tachyphylaxis. A rapid decline in response after repeated doses over a short time, from receptor desensitization or downregulation or from depleted mediators. Classic examples: nitrates (nitrate tolerance, prevented by a daily nitrate-free interval) and indirect sympathomimetics such as amphetamine and ephedrine, which lose effect as releasable norepinephrine stores are depleted.

Tolerance. A slower loss of response over days to weeks of continued use, requiring higher doses for the same effect (e.g., opioids).