Antimuscarinic Drugs

Atropine is the prototype drug of this group and will be described first. Other named agents will be mentioned only in so far as they differ from atropine. All act as non-selective and competitive antagonists of the various muscarinic receptor subtypes (Ml-3). Atropine is a simple tertiary amine; certain others (see Summary) are quaternary nitrogen compounds, a modification that is important as it intensifies antimuscarinic potency in the gut, imparts ganglion-blocking effects and reduces CNS penetration.

Atropine

Atropine is an alkaloid from the deadly nightshade (Atropa belladonna).11 In general, the effects of

11 The first name commemorates its success as a homicidal poison, for it is derived from the senior of three legendary Fates, Atropos, who cuts with shears the web of life spun and woven by her sisters Clothos and Lachesis (there is a minor synthetic atropine-like drug called lachesine). The term belladonna (Italian: beautiful woman) refers to the once fashionable female practice of using an extract of the plant to dilate the pupils (incidentally blocking ocular accommodation) as part of the process of making herself attractive.

• For their central actions, some [benzhexol (trihexyphenidyl) and orphenadrine] are used against the rigidity and tremor of parkinsonism, especially drug-induced parkinsonism, where doses higher than the usual therapeutic amounts are often needed and tolerated.

They are used as antiemetics (principally hyoscine, promethazine).Their sedative action is used in anaesthetic premedication (hyoscine).

• For their peripheral actions, atropine, homatropine and cyclopentolate are used in ophthalmology to dilate the pupil and to paralyse ocular accommodation. Patients should be warned of a transient, but unpleasant stinging sensation, and that they cannot read or drive {at least without dark glasses) for at least 3^4 hours.Tropicamide is the shortest acting of the mydriatics. If it is desired to dilate the pupil and to spare accommodation,a sympathomimetic, e.g. phenylephrine, is useful.

In onoestftesic premedication, atropine, arid hyoscine* block the vagus and reduce mucosal secretions; hyoscine also has useful sedative effects. Glycopyrronium* is frequently used during anaesthetic recovery to block the muscarinic effects of neostigmine given to reverse a nondepolarising neuromuscular blockade.

In the respiratory tract, ipratropium* is a useful bronchodilator in chronic obstructive pulmonary disease and acute asthma.

• For their actions on the gut, against muscle spasm and hypermotility, e.g against colic (pain due to spasm of smooth muscle) and to reduce morphine-induced smooth muscle spasm when the analgesic is used against acute colic.

• In the urinary tract, flavoxate.oxybutynin, propiverine, tolterodine, trospium and propantheline'' are used to relieve muscle spasm accompanying infection in cystitis, and for detrusor instability.

• In disorders of the cardiovascular system, atropine is useful in bradycardia following myocardial infarction.

• In cholinergic poisoning, atropine is an important antagonist of both central nervous, parasympathomimetic and vasodilator effects, though it has no effect at the neuromuscular junction and will not prevent voluntary muscle paralysis It is also used to block muscarinic effects when cholinergic drugs, such as neostigmine, are used for their effect on the neuromuscular junction in myasthenia gravis.

Disadvantages of the antimuscarinics include glaucoma, and urinary retention where there is prostatic hypertrophy.

'Quaternary ammonium compounds (see text).

atropine are inhibitory but in large doses it stimulates the CNS (see poisoning, below). Atropine also blocks the muscarinic effects of injected cholinergic drugs both peripherally and on the central nervous system. The clinically important actions of atropine at parasympathetic postganglionic nerve endings are listed below; they are mostly the opposite of the activating effects on the parasympathetic system produced by cholinergic drugs.

Exocrine glands. All secretions except milk are diminished. Dry mouth and dry eye are common. Gastric acid secretion is reduced but so also is the total volume of gastric secretion so that pH may be little altered. Sweating is inhibited (sympathetic innervation but releasing acetylcholine). Bronchial secretions are reduced and may become viscid, which can be a disadvantage, as removal of secretion by cough and ciliary action is rendered less effective.

Smooth muscle is relaxed. In the gastrointestinal tract there is reduction of tone and peristalsis. Muscle spasm of the intestinal tract induced by morphine is reduced, but such spasm in the biliary tract is not significantly affected. Atropine relaxes bronchial muscle, an effect that is useful in some asthmatics. Micturition is slowed and urinary retention may be induced especially when there is pre-existing prostatic enlargement.

Ocular effects. Mydriasis occurs with a rise in intraocular pressure in eyes predisposed to narrowangle glaucoma. This is due to the dilated iris blocking drainage of the intraocular fluids from the angle of the anterior chamber. An attack of glaucoma may be induced. There is no significant effect on pressure in normal eyes. The ciliary muscle is paralysed and so the eye is accommodated for distant vision. After atropinisation, normal pupillary reflexes may not be regained for 2 weeks. Atropine use is a cause of unequal sized and unresponsive pupils.12

Cardiovascular system. Atropine reduces vagal tone thus increasing the heart rate, and enhancing conduction in the bundle of His, effects that are less marked in the elderly in whom vagal tone is low. Full atropinisation may increase rate by 30 beats /min in the young, but has little effect in the old.

Transient vagal stimulation, probably in the CNS, may cause bradycardia, e.g. if atropine is given i.v. with neostigmine and the effects of the two drugs summate.

Atropine has no significant effect on peripheral blood vessels in therapeutic doses but, in poisoning, there is marked vasodilatation.

Central nervous system. Atropine is effective against both tremor and rigidity of parkinsonism. It prevents or abates motion sickness.

Antagonism to cholinergic drugs. Atropine opposes the effects of all cholinergic drugs on the CNS, at postganglionic cholinergic nerve endings and on the peripheral blood vessels. It does not oppose cholinergic effects at the neuromuscular junction or significantly at the autonomic ganglia, i.e. atropine opposes the muscarine-like but not the nicotine-like effects of acetylcholine.

Pharmacokinetics. Atropine is readily absorbed from the gastrointestinal tract and may also be injected by the usual routes. The occasional cases of atropine poisoning following use of eye drops are due to the solution running down the lacrimal ducts into the nose and being swallowed. Atropine is in part destroyed in the liver and in part excreted unchanged by the kidney (t l/2 2 h).

Dose. 0.6-1.2 mg by mouth at night or 0.6 mg i.v. and repeated as necessary to a maximum of 3 mg per day; for chronic use it has largely been replaced by other antimuscarinic drugs.

Poisoning with atropine (and other antimuscarinic drugs) presents with the more obvious peripheral

12 A doctor, after working in his garden greenhouse, was alarmed to find that the vision in his left eye was blurred and the pupil was grossly dilated. Physical examination failed to reveal a cause and the pupil gradually and spontaneously returned to normal, suggesting that the explanation was exposure to some exogenous agent. The doctor then recalled that his greenhouse contained flowering plants called 'angels' trumpet' (sp. Brugmansia, of the nightshade family), and he may have brushed against them. Angels' trumpet is noted for its content of scopolamine (hyoscine), and is very toxic if ingested. The plant is evidently less angelic than the name suggests. Merrick J, Barnett S 2000 British Medical Journal 321:219.

effects: dry mouth (with dysphagia), mydriasis, blurred vision, hot, flushed, dry skin, and, in addition, hyperthermia (CNS action plus absence of sweating), restlessness, anxiety, excitement, hallucinations, delirium, mania. The cerebral excitation is followed by depression and coma or, as it has been described with characteristic American verbal felicity, 'hot as a hare, blind as a bat, dry as a bone, red as a beet and mad as a hen'.13 It may occur in children who have eaten berries of solanaceous plants, e.g. deadly nightshade and henbane. When the diagnosis is doubtful, it is said to be worth putting a drop of the patient's urine in one eye of a cat. Mydriasis, if it results, confirms the diagnosis, but absence of effect proves nothing. Treatment involves giving activated charcoal to adsorb the drug, and diazepam for excitement.

Other antimuscarinic drugs

In the following accounts of drugs, the principal peripheral atropine-like effects of the drugs may be assumed; differences from atropine are described.

Atropine is also a racemate (dl-hyoscyamine), and almost all of its antimuscarinic effects are attributable to the 1-isomer alone. It is, however, more stable chemically as the racemate which is the preferred formulation.

Hyoscine (scopolamine) is structurally related to atropine. It differs chiefly in being a central nervous system depressant, although it may sometimes cause excitement. Elderly patients are often confused by hyoscine and so it is avoided in their anaesthetic premedication. Mydriasis is also briefer than with atropine.

Hyoscine butylbromide (strictly N-butylhyoscine bromide, Buscopan) also blocks autonomic ganglia. If injected, it is an effective relaxant of smooth muscle, including the cardia in achalasia, the pyloric antral region and the colon, which properties are utilised by radiologists and endoscopists. It may sometimes be useful for colic.

Homatropine is used for its ocular effects (1% and 2% solutions as eye drops). Its action is shorter than atropine and therefore less likely to cause serious rises of intraocular pressure; the effect wears off in a

13 Cohen H L et al 1944 Archives of Neurology and Psychiatry 51:171.

day or two. Complete cycloplegia cannot always be obtained unless repeated instillations are made every 15 min for 1-2 h. It is especially unreliable in children, in whom cyclopentolate or atropine is preferred. The pupillary dilation may be reversed by physostigmine eyedrops.

Tropicamide (Mydriacyl) and cyclopentolate (Myd-rilate) are useful (as 0.5% or 1% solutions) for mydriasis and cycloplegia. They are quicker and shorter-acting than homatropine. Both cause mydriasis in 10-20 min and cycloplegia shortly after. The duration of action is 4-12 h.

Ipratropium (Atrovent) is used by inhalation as a bronchodilator, and can be useful when cough is a pronounced symptom in an asthmatic patient.

Flavoxate (Urispas) is used for urinary frequency, tenesmus and urgency incontinence because it increases bladder capacity and reduces unstable detrusor contractions (see p. 543).

Oxybutynin is also used for detrusor instability, but antimuscarinic adverse effects may limit its value.

Glycopyrronium is used in anaesthetic premedication to reduce salivary secretion; given i.v. it causes less tachycardia than does atropine.

Propantheline (Pro-Banthine) also has ganglion-blocking properties. It may be used as a smooth

• Acetylcholine is the most important receptor agonist neurotransmitter in both the brain and peripheral nervous system.

• It acts on neurons in the CNS and at autonomic ganglia.on skeletal muscle at the neuromuscular junction, and at a variety of other effector cell types, mainly glandular or smooth muscle.

• The effector response is rapidly terminated through enzymatic destruction by acetylcholinesterase.

• Outside the CNS, acetylcholine has two main classes of receptor: those on autonomic ganglia and skeletal muscle responding to stimulation by nicotine arid the rest that respond to stimulation by muscarine

• Drugs that mimic or oppose acetylcholine have a wide variety of uses. For instance, the muscarinic agonist pilocarpine lowers intraocular pressure and antagonist atropine reverses vagal slowing of the heart.

• The main use of drugs at the neuromuscular junction is to relax muscle in anaesthesia, or to inhibit acetylcholinesterase in diseases where nicotinic receptor activation is reduced.e.g. myasthenia gravis.

muscle relaxant, e.g. for irritable bowel syndrome and diagnostic procedures.

Dicyclomine (Merbentyl) is an alternative.

Benzhexol (trihexyphenidyl) and orphenadrine: see parkinsonism.

Promethazine: see p. 555.

Propiverine, tolterodine and trospium diminish unstable detrusor contractions and are used to reduce urinary frequency, urgency and incontinence.

Oral antimuscarinics have occasional use in the treatment of hyperhidrosis.

Cohen H L et al 1944 Acetylcholine treatment of schizophrenia. Archives of Neurology and Psychiatry 51:171 Hawkins J R et al 1956 Intravenous acetylcholine therapy in neurosis. A controlled trial (p. 43);

Carbon dioxide inhalation therapy in neurosis. A controlled clinical trial (p. 52); The placebo response (p. 60). Journal of Mental Science 102:43 HMSO 1987 Medical manual of defence against chemical agents. (No. 0117725692) JSP: 312 Lambert D 1981 (personal paper) Myasthenia gravis. Lancet 1:937

Morita H et al 1996 Sarin poisoning in Matsumoto,

Japan. Lancet 346: 290-293 Morton H G et al 1939 Atropine intoxication. Journal of Pediatrics 14: 755 Report 1998 Organophosphate sheep dip. Clinical aspects of long-term low-dose exposure. Royal College of Physicians (London) and Royal College of Psychiatrists Steenland K 1996 Chronic neurological effects of organophosphate pesticides. British Medical Journal 312:1312-1313 Vincent A et al 2001 Myasthenia gravis. Lancet 357: 2122-2128

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