Autonomics

Direct muscarinic agonists and acetylcholinesterase inhibitors. M1/M3 receptors signal through Gq and calcium, M2 through Gi; the inhibitors split into reversible carbamates and irreversible organophosphates, whose enzyme “ages” beyond the reach of pralidoxime.

Competitive, surmountable antagonists of acetylcholine at muscarinic receptors: M2 block speeds the SA node, M3 block dries glands and relaxes gut and bladder, and CNS block confuses. Whether a drug is a tertiary amine that enters the brain or a quaternary one that stays out decides its CNS effects.

Two ways to quiet the detrusor: antimuscarinics block the Gq-coupled M3 receptor through which acetylcholine contracts it, and the β3 agonists mirabegron and vibegron stimulate the Gs-coupled β3 receptor that relaxes it during storage. Among the antimuscarinics, M3 selectivity (darifenacin), quaternary structure (trospium) and the shared active metabolite 5-HMT (tolterodine, fesoterodine) set their differences.

Drugs at the nicotinic receptor of the motor end plate. Succinylcholine depolarizes and holds the end plate (phase I, then phase II); the nondepolarizers compete with acetylcholine. Neostigmine (with an antimuscarinic) outcompetes them, and sugammadex encapsulates rocuronium and vecuronium.

Each pressor or inotrope is a receptor recipe: α1 and V1 receptors signal through Gq (IP3, calcium) to constrict vessels, β1 through Gs and cAMP to speed and strengthen the heart, β2 through cAMP to relax smooth muscle. Milrinone reaches the same cAMP by blocking PDE3, and oral midodrine is a prodrug of an α1 agonist. Baroreceptor reflexes decide what happens to heart rate. (on the Cardiovascular pages)

Antagonists of Gq-coupled α1 receptors (vascular and prostatic smooth muscle) and, for the nonselective agents, of the Gi-coupled α2 brake on norepinephrine release. Selectivity decides the reflex tachycardia; the α1A preference of tamsulosin and silodosin targets the prostate. Metyrosine instead blocks catecholamine synthesis at tyrosine hydroxylase.

Four ways around the first-line drugs: alpha-1 blockers relax arterioles and the prostate; clonidine and methyldopa (via a false transmitter) cut sympathetic outflow from the brainstem; hydralazine, minoxidil and nitroprusside relax vascular smooth muscle directly and provoke a reflex response; aliskiren inhibits renin itself. (on the Cardiovascular pages)

Competitive β-adrenergic antagonists that blunt Gs–cAMP signalling in the heart and kidney. β1 selectivity, partial agonism (ISA), α1 or nitric-oxide vasodilation and the route of elimination tell the ten drugs apart. (on the Cardiovascular pages)