Category:Antimuscarinics

An antimuscarinic is a medicine that blocks the muscarinic receptors for acetylcholine. The category covers a heterogeneous set of clinical indications, unified by their shared pharmacology: the relief of bronchoconstriction in asthma and chronic obstructive pulmonary disease, the symptomatic treatment of overactive bladder, the management of intestinal smooth-muscle spasm in irritable bowel syndrome and biliary or renal colic, the prevention of motion sickness, the dilation of the pupil for ophthalmologic examination, the reduction of salivary and bronchial secretions before anaesthesia, the reversal of organophosphate poisoning, and the management of certain extrapyramidal and movement disorders. The five known muscarinic receptor subtypes (M1 through M5) are differentially distributed across these tissues, and the antimuscarinic medicines vary in selectivity for each.

The natural prototype of the class, atropine, comes from the nightshade family of plants, principally Atropa belladonna (deadly nightshade), Hyoscyamus niger (henbane), Datura stramonium (jimson weed), and Mandragora officinarum (mandrake). These plants were known in classical antiquity for the dilated pupils they produced when their juice was dropped into the eye, a cosmetic use among Renaissance Venetian women that gave the genus its species name bella donna (beautiful lady), and for the delirium, tachycardia, urinary retention, and hot dry flushed skin of their accidental ingestion, the toxidrome remembered by the mnemonic blind as a bat, mad as a hatter, red as a beet, hot as a hare, dry as a bone. The German pharmacist Heinrich Mein in 1831 isolated the active alkaloid as a pure crystalline substance, naming it atropine for the eldest of the three Greek Fates, Atropos, who cuts the thread of life.^[1] The closely related hyoscyamine was isolated from Hyoscyamus and characterised as the levorotatory enantiomer of atropine; scopolamine (hyoscine), the second principal nightshade alkaloid, differs from atropine only in an epoxide ring across the tropane skeleton and exerts greater central-nervous-system effect.

The pharmacological framework was assembled in the early twentieth century. The Cambridge pharmacologist Henry Dale established in 1914 that acetylcholine, isolated from ergot and from ox spleen, mimicked the response of parasympathetic nerve stimulation and that this response was selectively blocked by atropine, in contrast to the response of certain other tissues to acetylcholine that was instead blocked by curare and nicotine. The two acetylcholine-responsive populations were named the muscarinic (after the action of muscarine, the alkaloid of Amanita muscaria) and the nicotinic. Dale shared the 1936 Nobel Prize with Otto Loewi for the discovery of chemical neurotransmission. The molecular biology of the muscarinic receptors was completed in the 1980s by the cloning of the M1, M2, M3, M4, and M5 subtypes by Tom Bonner and Mark Brann at the National Institute of Mental Health.^[2]

The clinical pharmacology has expanded along subtype-selectivity lines. The synthesis of quaternary-amine derivatives of atropine, which carry a permanent positive charge that prevents the molecule from crossing the blood-brain barrier, gave the inhaled bronchodilators ipratropium (Boehringer Ingelheim, 1976) and the long-acting tiotropium (Boehringer Ingelheim, 2002), used as inhalation medicines in COPD and asthma without the cognitive side effects of central muscarinic blockade. The bladder-selective short-acting oxybutynin (Marion Laboratories, 1975) and the longer-acting M3-selective solifenacin (Yamanouchi, 2004), tolterodine (Pharmacia, 1998), and darifenacin (Pfizer, 2004) treat the urgency, frequency, and incontinence of overactive bladder by reducing M3-receptor-mediated detrusor contractions. The intestinal-smooth-muscle agent dicyclomine (1947) remains in use for irritable bowel syndrome despite an unfavourable adverse-effect profile that includes the entire antimuscarinic toxidrome at higher doses.

Several of the older central-effect antimuscarinics retain specific clinical niches. Scopolamine, available as a transdermal patch, is the standard prevention of motion sickness; atropine, by injection, is the agent of choice for both organophosphate-pesticide poisoning (where it reverses muscarinic features pending the regeneration of acetylcholinesterase by pralidoxime) and for symptomatic bradycardia. Glycopyrrolate (a synthetic quaternary muscarinic blocker) is used by anaesthetists to dry secretions before intubation and to counter the muscarinic effects of the cholinesterase inhibitors given to reverse neuromuscular blockade. Benztropine and trihexyphenidyl block central M1 receptors in the basal ganglia and reduce the parkinsonism produced by neuroleptic medicines, although their cognitive cost has progressively narrowed their indication. The selective M3-receptor antagonists used in ophthalmology (homatropine, cyclopentolate, tropicamide) produce pupillary dilation for refraction and fundoscopic examination.

The therapeutic role of an antimuscarinic carries a corresponding profile of adverse effect. The non-selective agents produce, in dose-dependent fashion, dry mouth (M1 and M3 on salivary acini), blurred vision (M3 on ciliary muscle and iris sphincter), constipation (M3 on intestinal smooth muscle and glands), urinary retention (M3 on detrusor with reciprocal action on the bladder neck), tachycardia (M2 on the sinus node), and (for centrally penetrating agents) cognitive impairment that includes confusion, hallucination, and frank delirium, particularly in elderly patients. The cumulative anticholinergic burden of multiple concurrent medicines is an increasingly recognised contributor to falls, delirium, and cognitive decline in older adults, and prescribing tools such as the Anticholinergic Cognitive Burden Scale and the Drug Burden Index have been developed to quantify it.

By principal indication:

• Inhaled antimuscarinics for COPD and asthma (also indexed under short-acting and long-acting muscarinic antagonists): ipratropium (short-acting), tiotropium (long-acting), aclidinium, umeclidinium, glycopyrronium
• Bladder-selective antimuscarinics for overactive bladder: oxybutynin, solifenacin, tolterodine, darifenacin, fesoterodine, trospium
• Gastrointestinal antispasmodics (also indexed under antispasmodics): dicyclomine, hyoscyamine, propantheline, glycopyrrolate
• Ophthalmic mydriatics and cycloplegics: homatropine, cyclopentolate, tropicamide
• Antiemetic and motion-sickness: scopolamine (hyoscine), transdermal
• Central antimuscarinics for parkinsonism and dystonic reactions: benztropine, trihexyphenidyl
• Anaesthetic adjuncts and antidotes: atropine (organophosphate poisoning, symptomatic bradycardia, premedication), glycopyrrolate

The boundary of this category is "medicine whose principal mechanism is competitive antagonism at muscarinic acetylcholine receptors." The closely related nicotinic antagonists (curare-type neuromuscular blockers, ganglion blockers) are not antimuscarinics and are collected under anesthetics and their procedural-medicine categories. The acetylcholinesterase inhibitors used in Alzheimer's disease (donepezil, rivastigmine, galantamine) and in myasthenia gravis (pyridostigmine, neostigmine) work on the opposite side of cholinergic transmission and are collected separately. Tricyclic antidepressants, several first-generation antihistamines, and the older neuroleptics also block muscarinic receptors and produce the corresponding adverse effects, but are categorised under their primary class because their muscarinic action is incidental rather than therapeutic.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.