nicotinic antagonist

**Receptor basics** - Nicotinic ACh receptors (nAChR) are ligand-gated pentameric ion channels (Na+/K+ influx causes depolarization). - Nm (muscle type, at the NMJ): (α1)2β1δε in adults. Nn (neuronal type, in autonomic ganglia, adrenal medulla, and CNS): α3β4 at ganglia. - Both ganglia (sympathetic and parasympathetic) and the NMJ use nicotinic receptors. Preganglionic neurons release ACh at nicotinic receptors in both divisions.

**1. Neuromuscular blockers (Nm antagonists)** - *Non-depolarizing (competitive antagonists)*: tubocurarine, atracurium, cisatracurium, rocuronium, vecuronium, pancuronium, mivacurium. - Compete with ACh at the Nm receptor. Effects can be overcome by increasing ACh in the cleft, so they are **reversed by acetylcholinesterase inhibitors** (neostigmine, edrophonium, pyridostigmine), usually given with an antimuscarinic (glycopyrrolate or atropine) to prevent muscarinic effects. **Sugammadex** reversibly encapsulates rocuronium and vecuronium. - Order of paralysis: small, rapidly moving muscles first (extraocular, face, fingers), then limbs, trunk, and finally the diaphragm. Recovery occurs in reverse order. - Tubocurarine causes histamine release, leading to hypotension and bronchospasm. Pancuronium is vagolytic (tachycardia, hypertension). Atracurium and cisatracurium undergo **Hofmann elimination** (spontaneous, organ-independent degradation), so they are preferred in renal or hepatic failure. Cisatracurium produces less laudanosine and less histamine release than atracurium. - Rocuronium has a rapid onset and is an alternative for rapid-sequence intubation when succinylcholine is contraindicated. - *Depolarizing (agonist-like, "Phase I/II block")*: **succinylcholine**. - It is an nAChR agonist that is not degraded by acetylcholinesterase, so it causes persistent depolarization and receptor desensitization. Fasciculations occur first, then flaccid paralysis. - Phase I block is *not* reversed (and is potentiated) by anticholinesterases. Phase II block (after prolonged exposure) may be partially reversed by anticholinesterases. - Metabolized by plasma pseudocholinesterase (butyrylcholinesterase). Prolonged paralysis occurs with atypical pseudocholinesterase variants or deficiency. - Adverse effects: **hyperkalemia** (especially with burns, crush injury, denervation, upper motor neuron lesions, or prolonged immobilization because of upregulated extrajunctional receptors), **malignant hyperthermia** (with volatile anesthetics; treat with dantrolene), bradycardia, increased intraocular and intragastric pressure, and myalgias.

**2. Ganglionic blockers (Nn antagonists)** - Examples: hexamethonium, mecamylamine, trimethaphan. - They block both sympathetic and parasympathetic ganglia, so the net effect depends on the dominant tone in each organ: - Blood vessels (sympathetic dominant): vasodilation, hypotension, orthostasis. - Heart (parasympathetic dominant at rest): tachycardia. - GI tract and bladder (parasympathetic dominant): constipation, urinary retention. - Eye: mydriasis and cycloplegia. - Others: dry mouth (xerostomia) and sexual dysfunction. - Rarely used now (previously used for hypertensive emergencies). Mecamylamine has been studied for smoking cessation.

**Other clinical points** - Dantrolene (a ryanodine receptor antagonist) is *not* a nicotinic antagonist. It treats malignant hyperthermia and neuroleptic malignant syndrome. - Botulinum toxin blocks presynaptic ACh release (cleaves SNARE proteins) and is not a receptor antagonist. - Myasthenia gravis (anti-nAChR antibodies) makes patients **very sensitive to non-depolarizing blockers** (use lower doses) and relatively **resistant to succinylcholine**. Lambert-Eaton syndrome patients are sensitive to both types. - Monitoring is by **train-of-four** stimulation. Non-depolarizing blockers show fade; a Phase I depolarizing block shows no fade. - Drugs that potentiate non-depolarizing blockade include volatile anesthetics, aminoglycosides, magnesium, calcium channel blockers, and clindamycin. - Nicotinic receptor-targeting toxins: α-bungarotoxin (snake venom) and curare are competitive antagonists at the Nm receptor.

**High-yield mnemonics/pearls** - "Competitive blockers are reversed by neostigmine; depolarizing blockers are not." - Succinylcholine = fasciculations → paralysis → hyperkalemia/malignant hyperthermia risk. - Cisatracurium = Hofmann elimination (organ-independent).