CLINICAL PHARMACOLOGY 2003 (PART 23)

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Acetylcholine is a widespread chemotransmitter in the body, mediating a broad range of physiological effects.There are two distinct classes of receptor for acetylcholine defined on the basis of their preferential activation by the alkaloids, nicotine (from tobacco) and muscarine (from a fungus, Amanita muscaria). Cholinergic drugs (acetylcholine agonists) mimic acetylcholine at all sites although the balance of nicotinic and muscarinic effects is variable. Acetylcholine antagonists (blockers) that block the nicotine-like effects (neuromuscular blockers and autonomic ganglion blockers) are described elsewhere (see Ch. 18). ...

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SECTION 5 CARDIO RESPIRATORY AND RENAL SYSTEMS
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21 Cholinergic and antimuscarinic (anticholinergic) mechanismsand drugs SYNOPSIS Cholinergic drugs Acetylcholine is a widespread chemotransmitter in the body, mediating a broad range of (cholinomimetics) physiological effects.There are two distinct classes of receptor for acetylcholine defined on These drugs act on postsynaptic acetylcholine the basis of their preferential activation by the receptors (cholinoceptors) at all the sites in the body alkaloids, nicotine (from tobacco) and where acetylcholine is the effective neurotransmitter. muscarine (from a fungus, Amanita muscaria). They initially stimulate and usually later block Cholinergic drugs (acetylcholine agonists) transmission. In addition, like acetylcholine, they mimic acetylcholine at all sites although the act on the noninnervated receptors that relax vas- balance of nicotinic and muscarinic effects is cular smooth muscle in peripheral blood vessels. variable. Acetylcholine antagonists (blockers) that block the nicotine-like effects (neuromuscular • For myasthenia gravis, both to diagnose (edrophonium) blockers and autonomic ganglion blockers) are and to treat (neostigmine, pyridostigmine, distigmine) described elsewhere (see Ch. 18). • To stimulate the bladder and bowel after surgery (bethanechol, carbachol, distigmine) Acetylcholine antagonists that block the • To lower intraocular pressure in chronic simple muscarine-like effects, e.g. atropine, are often glaucoma (pilocarpine) imprecisely called anticholinergics.The more • To bronchodilate patients with airflow obstruction precise term antimuscarinic is preferred here. (ipratropium, oxitropium) • Cholinergic drugs • To improve cognitive function in Alzheimer's disease (rivastigmine, donepezil) — Classification — Sites of action — Pharmacology — Choline esters CLASSIFICATION — Alkaloids with cholinergic effects — Anticholinesterases; organophosphate Direct-acting (receptor agonists) poisoning • Choline esters (carbachol, bethanechol) which — Disorders of neuromuscular act at all sites like acetylcholine. They are transmission: myasthenia gravis resistant to degradation by cholinesterases. • Drugs which oppose acetylcholine Muscarinic effects are much more prominent — Antimuscarinic drugs than nicotinic (see p. 435). 433
11 C H O L I N E R G I C AND A N T I M U SC A RI N I C M E C H A N I S M S • Alkaloids (pilocarpine, muscarine) which act ganglionic endings affects chiefly the following selectively on end-organs of postganglionic, organs: cholinergic neurons. Eye: miosis and spasm of the ciliary muscle occur so that the eye is accommodated for near vision. Indirect-acting Intraocular pressure falls due, perhaps, to dilation • Cholinesterase inhibitors, or of vessels at the point where intraocular fluids pass anticholinesterases (physostigmine, into the blood. neostigmine, pyridostigmine, distigmine, Exocrine glands: there is increased secretion most rivastigmine, donepezil), which inhibit the noticeably of the salivary, lachrymal, bronchial and enzyme that destroys acetylcholine, allowing sweat glands. The last are cholinergic, although the endogenous transmitter to persist and anatomically part of the sympathetic system; some produce intensified effects. sweat glands, e.g. axillary, may be adrenergic. Heart: bradycardia occurs with atrioventricular block and eventually cardiac arrest. SITES OF ACTION Bronchi: there is bronchoconstriction and mucosal • Autonomic nervous system hypersecretion that may be clinically serious in (1) Parasympathetic division: ganglia; asthmatic subjects, in whom cholinergic drugs postganglionic endings (all) should be avoided, as far as possible. (2) Sympathetic division: ganglia; a minority of Gut: motor activity is increased and may cause postganglionic endings, e.g. sweat glands colicky pain. Exocrine secretion is also increased. • Neuromuscular junction Tone in sphincters falls which may cause defaecation • Central nervous system (anal sphincter) or acid reflux/regurgitation (oeso- • Noninnervated sites: blood vessels, chiefly phageal sphincter). arterioles. Bladder and ureters contract and the drugs pro- mote micturition. Acetylcholine is the neurotransmitter at all these sites, acting on a postsynaptic receptor, except on Sympathetic division. The ganglia only are stimu- most blood vessels in which the action of cholinergic lated, also the cholinergic nerves to the adrenal drugs is unrelated to cholinergic Vasodilator' medulla. These effects are overshadowed by effects nerves. It is also produced in tissues unrelated to on the parasympathetic system and are commonly nerve endings, e.g. placenta and ciliated epithelial evident only if atropine has been given to block cells, where it acts as a local hormone (autacoid) on the latter, when tachycardia, vasoconstriction and local receptors. hypertension occur. A list of principal effects is given below. Not all occur with every drug and not all are noticeable at therapeutic doses. For example, central nervous Neuromuscular (voluntary) junction system effects of cholinergic drugs are best seen The neuromuscular junction has a cholinergic nerve in cases of anticholinesterase poisoning. Atropine ending and so is activated by anticholinesterases antagonises all the effects of cholinergic drugs which allow acetylcholine to persist, causing muscle except nicotinic actions on autonomic ganglia and fasciculation. Prolonged activation leads to a the neuromuscular junction; i.e. it has antimuscarinic secondary depolarising neuromuscular block. but not antinicotinic effects (see below). Central nervous system PHARMACOLOGY There is usually stimulation followed by depression Autonomic nervous system but variation between drugs is great, possibly due to differences in CNS penetration. In overdose, Parasympathetic division. Stimulation of cholino- mental excitement occurs, with confusion and rest- ceptors in autonomic ganglia and at the post- lessness, insomnia (with nightmares when sleep 434
CHOLINERGIC D R U G S ( C H O L I N O M I M ET I C S) 21 does come), tremors and dysarthria and sometimes The following description is illustrative: even convulsions and coma. A few seconds after the injection (which was given as rapidly as possible, to avoid total destruction in Blood vessels the blood) the patient sat up 'with knees drawn up to the chest, the arms flexed and the head bent There is stimulation of cholinergic vasodilator forward. There were repeated violent coughs, nerve endings in addition to the more important sometimes with flushing. Forced swallowing and dilating action on arterioles and capillaries mediated loud peristaltic rumblings could be heard'. through noninnervated receptors. Anticholinester- Respiration was laboured and irregular. The ases potentiate acetylcholine that exists in the vessel coughing abated as the patient sank back in the walls independently of nerves. bed. Forty seconds after the injection the radial and apical pulse were zero and the patient became Nicotinic and muscarinic effects comatose.' The pupils dilated, and deep reflexes were hyperactive. In 45 seconds the patient went It was Henry Dale, in 1914, who first made this into opisthotonos with brief apnoea. functional division which remains a robust and Lachrymation, sweating and borborygmi were useful way of classifying cholinergic drug effects. prominent. The deep reflexes became diminished. He noted that the actions of acetylcholine and The patient then relaxed and 'lay quietly in bed substances acting like it at autonomic ganglia and — cold moist and gray. In about 90 seconds, the neuromuscular junction (i.e. at the end of flushing of the face marked the return of the cholinergic nerves arising within the central pulse'. The respiratory rate rose and nervous system) mimic the stimulant effects of consciousness returned in about 125 seconds. The nicotine (hence nicotinic). In contrast, the actions patients sometimes micturated but did not at postganglionic cholinergic endings (parasym- defaecate. They 'tended to lie quietly in bed after pathetic endings plus the cholinergic sympathetic the treatment'. 'Most of the patients were nerves to the sweat glands) and noninnervated reluctant to be retreated'.2 receptors on blood vessels resembled the alkaloid, muscarine (hence muscarinic). OTHER CHOLINE ESTERS CHOLINE ESTERS Carbachol is not destroyed by cholinesterase, its actions are most pronounced on the bladder and Acetylcholine gastrointestinal tract, so that the drug has been used Since acetylcholine has such great importance in the to stimulate these organs, e.g. after surgery. This body it is not surprising that attempts have been use (also of bethanecol, below) is now much made to use it in therapeutics. But a substance with diminished and, for example, catheterisation is such a huge variety of effects and so rapidly preferred for bladder atony. Carbachol is stable in destroyed in the body is unlikely to be useful when the gut, hence it can be given orally; it is extremely given systemically, as its history in psychiatry dangerous if given i.v, but can be safely admin- illustrates. istered s.c. Acetylcholine was first injected intravenously as Bethanechol resembles carbachol in its actions but a therapeutic convulsant in 1939, in the justified is some 10-fold less potent (it differs by a single (3- expectation that the fits would be less liable to cause methyl group) and has no significant nicotinic fractures than those following therapeutic leptazol effects at clinical doses. convulsions. Recovery rates of up to 80% were claimed in various psychotic conditions. Enthusiasm 1 Harris M et al 1943 Archives of Neurology and Psychiatry began to wane however when it was shown that the 50: 304. fits were due to anoxia resulting from cardiac arrest 2 Cohen L H et al 1944 Archives of Neurology and and not to pharmacological effects on the brain.1 Psychiatry 51: 171. 435
21 CHOLINERGIC AND ANTIMUSCARINIC MECHANISMS ALKALOIDS WITH CHOLINERGIC Muscarine is of no therapeutic use but it has EFFECTS pharmacological interest. It is present in small amounts in the fungus Amanita muscaria (Fly Nicotine (see also p. 173) is a social drug that lends agaric), named after its capacity to kill the domestic its medicinal use as an adjunct to stopping its own fly (Musca domestica); muscarine was so named abuse as tobacco. It is available as either gum to because it was thought to be the insecticidal chew, as dermal patches or as an inhalation. These principle, but it is relatively nontoxic to flies (orally deliver a lower dose of nicotine than cigarettes and administered). The fungus may contain other anti- appear to be safe in patients with ischaemic heart muscarinic substances and GABA-receptor agonists disease. The patches are slightly better tolerated (such as muscimol) in amounts sufficient to be than the gum, which releases nicotine in a more psychoactive in man. variable fashion depending on the rate at which it is Poisoning with these fungi may present with chewed and the salivary pH, which is influenced by antimuscarinic, with cholinergic or with GABAergic drinking coffee and carbonated drinks. Nicotine effects. All have CNS actions. Happily, poisoning treatment is reported to be nearly twice as effective by Amanita muscaria is seldom serious. Species as placebo in achieving sustained withdrawal from of Inocybe contain substantially larger amounts of smoking (18% vs. 11% in one review).3 Treatment is muscarine (see Ch. 9). The lengths to which man is much more likely to be successful if it is used as an prepared to go in taking 'chemical vacations' when aid to, not a substitute for, continued counselling. life is hard, are shown by the inhabitants of Eastern Bupropion is possibly more effective than the nic- Siberia who used Amanita muscaria recreationally, otine patch4 (see also p. 177). for its cerebral stimulant effects. They were appar- ently prepared to put up with the autonomic actions Pilocarpine, from a South American plant (Pilo- to escape briefly from reality. The fungus was scarce carpus spp.), acts directly on end-organs innervated in winter and the frugal devotees discovered that by postganglionic nerves (parasympathetic system by drinking their own urine they could prolong plus sweat glands); it also stimulates and then the intoxication. Sometimes, in generous mood, the depresses the central nervous system. The chief intoxicated person would offer his urine to others clinical use of pilocarpine is to lower intraocular as a treat. pressure in chronic simple glaucoma, as an adjunct to a topical beta-blocker; it produces miosis, opens ANTICHOLINESTERASES drainage channels in the trabecular network and improves the outflow of aqueous humour. Oral At cholinergic nerve endings and in erythrocytes pilocarpine is available for the treatment of xero- there is an enzyme that specifically destroys acetyl- stomia (dry mouth) in Sjogren's syndrome, or choline, true cholinesterase or acetylcholinesterase. following irradiation of head and neck tumours. In various tissues, especially plasma, there are other The commonest adverse effect is sweating; adverse esterases which are not specific for acetylcholine cardiac effects have not been reported. but which also destroy other esters, e.g. suxametho- nium, procaine (and cocaine) and bambuterol (a Arecoline is an alkaloid in the betel nut, which is pro-drug that is hydrolysed to terbutaline). These chewed extensively throughout India and south- are called nonspecific or pseudocholinesterases. Chemi- east Asia. Presumably the lime mix in the 'chews' cals which inactivate these esterases (anticholin- provides the necessary alkaline pH to maximise esterases) are used in medicine and in agriculture its buccal absorption. It produces a mild euphoric as pesticides. They act by allowing naturally effect like many cholinomimetic alkaloids. synthesised acetylcholine to accumulate instead of being destroyed. Their effects are almost entirely due to this accumulation in the central nervous 3 Drug and Therapeutics Bulletin 1999; 37 (July issue). system, neuromuscular junction, autonomic ganglia, 4 Jorenby D E et al 1999 New England Journal of Medicine postganglionic cholinergic nerve endings (which 340: 685-692. are principally in the parasympathetic nervous 436
C H O L I N E R G I C D R U G S ( C H O L I N O M I M ET I C S) 21 system) and in the walls of blood vessels, where myasthenic crisis (weakness due to inadequate acetylcholine has a paracrine role not necessarily anticholinesterase treatment or severe disease) from associated with nerve endings. Some of these effects a cholinergic crisis (weakness caused by over- oppose each other, e.g. the effect of anticholines- treatment with an anticholinesterase). Myasthenic terase on the heart will be the resultant of stimu- weakness is substantially improved by edropho- lation at sympathetic ganglia and the opposing nium whereas cholinergic weakness is aggravated effect of stimulation at parasympathetic (vagal) but the effect is transient; the action of 3 mg i.v. is ganglia and at postganglionic nerve endings. lost in 5 minutes. Physostigmine is an alkaloid, obtained from the Carbaryl (carbaril) is another reversible carbamoy- seeds of the West African Calabar bean (spp. lating anticholinesterase that closely resembles Physostigma), which has long been used both as a physostigmine in its actions. It is widely used as a weapon and as an ordeal poison.5 It acts for a few garden insecticide and, clinically, to kill head and hours. Physostigmine is used synergistically with body lice. Sensitive insects lack cholinesterase-rich pilocarpine to reduce intraocular pressure. It has erythrocytes and succumb to the accumulation of been shown to have some efficacy in improving acetylcholine in the synaptic junctions of their cognitive function in Alzheimer-type dementia. nervous system. Effective and safe use in humans is possible because we possess cholinesterase, and Neostigmine (tl/2 2 h) is a synthetic reversible anti- absorption of carbaryl is very limited after topical cholinesterase whose actions are more prominent application. The anticholinesterase malathion is on the neuromuscular junction and the alimentary effective against scabies, head and crab lice. tract on the cardiovascular system and eye. It is A more recent use of anticholinesterase drugs therefore principally used in myasthenia gravis, to has been to improve cognitive function in patients stimulate the bowels and bladder after surgery,6 with Alzheimer's disease, where both the degree of and as an antidote to competitive neuromuscular dementia and amyloid plaque density correlate blocking agents. Neostigmine is effective orally, and with the impairment of brain cholinergic function. by injection (usually s.c.). But higher doses may be Donepezil and rivastigmine7 are licensed in the UK used in myasthenia gravis, often combined with for this indication. Both are orally active and cross atropine to reduce the unwanted muscarinic effects. the blood-brain barrier readily (see p. 408). Pyridostigmine is similar to neostigmine but has Anticholinesterase poisoning a less powerful action that is slower in onset and slightly longer in duration, and perhaps fewer The anticholinesterases used in therapeutics are visceral effects. It is used in myasthenia gravis. generally of the carbamate type that reversibly inactivate cholinesterase only for a few hours. This Distigmine is a variant of pyridostigmine (two contrasts markedly with the very long-lived inhi- linked molecules as the name implies). bition caused by inhibitors of the organophosphate (OP) type. In practice, the inhibition is so long that Edrophonium is structurally related to neostigmine clinical recovery from organophosphate exposure is but its action is brief and autonomic effects are usually dependent on synthesis of new enzyme. minimal except at high doses. The drug is used to This process may take weeks to complete although diagnose myasthenia gravis and to differentiate a clinical recovery is usually evident in days. Cases of acute poisoning are usually met outside therapeutic practice, e.g. after agricultural, industrial or trans- 5 To demonstrate guilt or innocence according to whether the port accidents. Substances of this type have also accused died or lived after the judicial dose. The practice had been developed and used in war, especially the the advantage that the demonstration of guilt provided simultaneous punishment. 6 Ponec R J et al 1999 New England Journal of Medicine 341: 7 137-141. Report. Drug and Therapeutics Bulletin 1998 38:15-16. 437
21 CHOLINERGIC AND ANTIMUSCARINIC MECHANISMS three G agents, GA (tabun), GB (sarin) and GD Treatment. Since the most common circumstance (soman). Although called nerve 'gas', they are of accidental poisoning is exposure to pesticide actually volatile liquids, which facilitates their use.8 spray or spillage, contaminated clothing should be Where there is known risk of exposure, prior use of removed and the skin washed. Gastric lavage is pyridostigmine, which occupies cholinesterases needed if any of the substance has been ingested. reversibly for a few hours (the lesser evil), com- Attendants should take care to ensure that they petitively protects them from access by the irre- themselves do not become contaminated. versible warfare agent (the greater evil); soldiers • Atropine is the mainstay of treatment; 2 mg is expecting attack have been provided with preloaded given i.m. or i.v. as soon as possible and repeated syringes (of the same design as the Epipen for every 15-60 min until dryness of the mouth and delivering adrenaline) as antidote therapy (see a heart rate in excess of 70 beats per minute below). Organophosphate agents are absorbed indicate that its effect is adequate. A poisoned through the skin, the gastrointestinal tract and by patient may require 100 mg or more for a single inhalation. Diagnosis depends on observing a sub- episode. Atropine antagonises the muscarinic stantial part of the list of actions below. parasympathomimetic effects of the poison, i.e. due to the accumulated acetylcholine Typical features of acute poisoning involve the stimulating postganglionic nerve endings gastrointestinal tract (salivation, vomiting, abdomi- (excessive secretion and vasodilatation), but has nal cramps, diarrhoea, involuntary defaecation), the no effect on the neuromuscular block, which is respiratory system (bronchorrhoea, bronchocon- nicotinic. striction, cough, wheezing, dyspnoea), the cardio- • Mechanical ventilation may therefore be needed to vascular system (bradycardia), the genitourinary assist the respiratory muscles; special attention system (involuntary micturition), the skin (sweating), to the airway is vital because of bronchial the skeletal system (muscle weakness, twitching) constriction and excessive secretion. and the nervous system (miosis, anxiety, headache, • Diazepam may be needed for convulsions. convulsions, respiratory failure). Death is due to a • Atropine eyedrops may relieve the headache combination of the actions in the central nervous caused by miosis. system, to paralysis of the respiratory muscles by • Enzyme reactivation. The organophosphate (OP) peripheral depolarising neuromuscular block, and pesticides inactivate cholinesterase by to excessive bronchial secretions and constriction irreversibly phosphorylating the active centre of causing respiratory failure. At autopsy, ileal intus- the enzyme. Substances that reactivate the susceptions are commonly found. enzyme hasten the destruction of the Quite frequently, and typically 1-4 days after accumulated acetylcholine and, unlike atropine, resolution of symptoms of acute exposure, the inter- they have both antinicotimc and antimuscarinic mediate syndrome may develop, characterised by a effects. The principal agent is pralidoxime, 1 g of proximal flaccid limb paralysis which may reflect which should be given 4-hourly i.m. or (diluted) muscle necrosis. Even later, after a gap of 2-4 by slow i.v. infusion, as indicated by the patient's weeks, some exposed persons exhibit the delayed condition; its efficacy is greatest if administered polyneuropathy, with sensory and motor impairment within 12 hours of poisoning then falls of usually of the lower limbs. Claims of chronic effects steadily as the phosphorylated enzyme is further (subtle cognitive defects, peripheral neuropathy) stabilised by 'aging'. If significant reactivation following recurrent, low-dose exposure, as with occurs, muscle power improves within 30 min. organophosphate used as sheep dip, continues to be the subject of investigation but, as yet, no con- Poisoning with reversible anticholinesterases is app- clusive proof. ropriately treated by atropine and the necessary general support; it lasts only hours. 8 In recent times, there have been major instances of use In poisoning with irreversible agents, erythrocyte against populations by both military and terrorist bodies (in or plasma cholinesterase content should be the field and in an underground transport system). measured if possible, both for diagnosis and to 438
C H O L I N E R G I C D R U G S ( C H O L I N O M I M ET I C S) 21 determine when a poisoned worker may return to When I answered truthfully, that nothing except the task (should he or she be willing to do so). anxiety over my symptoms, he replied 'my dear Return should not be allowed until the cholin- child, I am not a perfect fool...', and showed me esterase exceeds 70% of normal, which may take out. [She became worse and at times she was several weeks. Recovery from the intermediate unable to turn over in bed. Eating and even syndrome and delayed polyneuropathy is slow and speaking were difficult. Eventually, her fiance, a is dependent on muscle and nerve regeneration. medical student, read about myasthenia gravis and she was correctly diagnosed in 1927.] There was at that time no known treatment and therefore many DISORDERS OF NEUROMUSCULAR things to try. [She had gold injections, thyroid, TRANSMISSION suprarenal extract, lecithin, glycine and ephedrine. The last had a slight effect.] Then in February 1935, Myasthenia gravis came the day that I shall always remember. I was In myasthenia gravis synaptic transmission at the living alone with a nurse ... It was one of my better neuromuscular junction is impaired; most cases days, and I was lying on the sofa after tea ... My have an autoimmune basis and some 85% of fiance came in rather late saying that he had patients have a raised titre of autoantibodies to the something new for me to try. My first thought was muscle acetylcholine receptor. The condition is 'Oh bother! Another injection, and another false probably heterogeneous, however, as about 15% do hope'. I submitted to the injection with complete not have receptor antibodies, or have antibodies to indifference and within a few minutes began to feel another neuromuscular junction protein (muscle very strange ... when I lifted my arms, exerting the specific kinase) and rarely it occurs with penicil- effort to which I had become accustomed, they shot lamine used for rheumatoid arthritis. into the air, every movement I attempted was Neostigmine was introduced in 1931 for its grotesquely magnified until I learnt to make less stimulant effects on intestinal activity. In 1934 it effort... it was strange, wonderful and at first, very occurred to Dr Mary Walker that since the paralysis frightening ... we danced twice round the carpet. of myasthenia had been (erroneously) attributed to That was my first meeting with neostigmine, and a curare-like substance in the blood, physostigmine we have never since been separated.10 (eserine), an anticholinesterase drug known to antagonise curare, might be beneficial. It was, and Pathogenesis. The clinical features of myasthenia she reported this important observation in a short gravis are caused by specific autoantibodies to the letter.9 Soon after this she used neostigmine by nicotinic acetylcholine receptor. These antibodies mouth with greater benefit. The sudden appearance accelerate receptor turnover shortening their typical of an effective treatment for an hitherto untreatable lifetime in the skeletal muscle membrane from chronic disease must always be a dramatic event for around 7 days to 1 day in a myasthenic. This process its victims. One patient described the impact of the results in marked depletion of receptors from discovery of the action of neostigmine, as follows. myasthenic skeletal muscle (about 90%) explaining My myasthenia started in 1925, when I was 18. For its fatigability. The frequent finding of a specific several months it consisted of double vision and haplotype (Al-B8-Dw3 HLA) in myasthenics and fatigue ... An ophthalmic surgeon ... prescribed concurrent hyperplasia or tumours of the thymus glasses with a prism. However, soon more support the autoimmune basis for the disease. alarming symptoms began. [Her limbs became weak and she] 'was sent to an eminent neurologist. Diagnosis. Edrophonium dramatically and tran- This was a horrible experience. He ... could find no siently (5 min) relieves myasthenic muscular weak- physical signs ... declared me to be suffering from ness. A syringe is loaded with edrophonium 10 mg; hysteria and asked me what was on my mind. 10 Disabilities and how to live with them. Lancet Publications 9 Walker M B 1934 Lancet 1:1200. (1952), London. 439
21 C H O L I N E R G I C AND A N T I M U SC A RI N I C M E C H A N I S M S 2 mg are given i.v. and if there is no improvement in Either drug can be given parenterally if bulbar weakness in 30 s the remaining 8 mg are injected. paralysis makes swallowing difficult. An A syringe loaded with atropine should be at hand antimuscarinic drug, e.g. propantheline (15-30 to block severe cholinergic autonomic (muscarinic) mg tid), should be added if muscarinic effects are effects, e.g. bradycardia, should they occur. Acetyl- troublesome. choline receptor antibodies should also be measured Excessive dosing with an anticholinesterase can in the plasma, for an elevated titre confirms the actually worsen the muscle weakness in myasthenics diagnosis. if the accumulation of acetylcholine at the neuro- muscular junction is sufficient to cause depolarising Treatment involves immunosuppression, thymec- blockade (cholinergic crisis). It is important to tomy (unless contraindicated) and symptom relief distinguish this type of muscle weakness from an with drugs. exacerbation of the disease itself (myasthenic crisis). • Immunosuppressive treatment is directed at The dilemma can be resolved with a test dose of eliminating the acetylcholine receptor edrophonium, which relieves a myasthenic crisis autoantibody. Prednisolone induces but worsens a cholinergic one. The latter may be improvement or remission in 80% of cases. The severe enough to precipitate respiratory failure dose should be increased slowly using an and should be attempted only with full resuscita- alternate day regimen until the minimum tion facilities, including mechanical ventilation, at effective amount is attained; an hand. immunosuppressive improvement may take A cholinergic crisis should be treated by with- several weeks. Azathioprine may be used as a drawing all anticholinesterase medication, mech- steroid-sparing agent. Prednisolone is effective anical ventilation if required, and atropine i.v. for for ocular myasthenia, which is fortunate, for muscarinic effects of the overdose. The neuro- this variant of the disease responds poorly to muscular block is a nicotinic effect and will be thymectomy or anticholinesterase drugs. Some unchanged by atropine. A resistant myasthenic crisis acute and severe cases respond poorly to may be treated by withdrawal of drugs and mech- prednisolone with azathioprine and, for these, anical ventilation for a few days. Plasmapheresis or intermittent plasmapheresis or immunoglobulin immunoglobulin i.v. may be beneficial by removing i.v. (to remove circulating antireceptor antibody) antireceptor antibodies (see above). can provide dramatic short-term relief. • Thymectomy should be offered to those with generalised myasthenia gravis under 40 years of Lambert-Eaton syndrome age, once the clinical state allows and unless there are powerful contraindications to surgery. Separate from myasthenia gravis is the Lambert- Most cases benefit and about 25% can Eaton syndrome, where symptoms similar to those discontinue drug treatment. Thymectomy in myasthenia gravis occur in association with a should also be undertaken in all myasthenic carcinoma; in 60% of patients this is a small-cell patients who have a thymoma, but the main lung cancer. The defect here is presynaptic with a reason is to prevent local infiltration for the deficiency of acetylcholine release due to an auto- procedure is less likely to relieve the myasthenia. antibody directed against L-type voltage-gated • Symptomatic drug treatment is decreasingly used. calcium channels. Its aim is to increase the concentration of Patients with the Lambert-Eaton syndrome do acetylcholine at the neuromuscular junction with not usually respond well to anticholinesterases. anticholinesterase drugs. The mainstay is usually The drug 3,4-diaminopyridine (3,4-DAP) increases pyridostigmine, starting with 60 mg by mouth 4- neurotransmitter release and also the action poten- hourly. It is preferred because its action is tial (by blocking potassium conductance); these smoother than that of neostigmine, but the latter actions lead to a nonspecific excitatory effect on the is more rapid in onset and can with advantage be cholinergic system, and provide benefit. It should given in the mornings to get the patient mobile. be taken orally, 4-5 times per day. Adverse effects 440
D R U G S W H I C H O P P O S E A C ET Y L C H O L I N E 21 due to CNS excitation (insomnia, seizures) can occur. 3,4-DAP is an example of an orphan drug without Drugs which oppose product licence, available in the UK for 'named patient' use from specialist pharmacies. acetylcholine These may be divided into: Drug-induced disorders of neuromuscular transmission Antimuscarinic drugs which act principally at postganglionic cholinergic (parasympathetic) nerve Quite apart from the neuromuscular blocking agents endings, i.e. atropine-related drugs (see Fig. 21.1, used in anaesthesia, a number of drugs possess site 2). Muscarinic receptors can be subdivided actions that impair neuromuscular transmission according to their principal sites, namely in the and, in appropriate circumstances, give rise to: brain and gastric parietal cells (Mj), heart (M2) and • Postoperative respiratory depression in people glandular and smooth muscle cells (M3). As with whose neuromuscular transmission is otherwise many receptors, the molecular basis of the subtypes normal has been defined together with two further cloned • Aggravation or unmasking of myasthenia gravis subtypes (M4 and M5) for which no functional • A drug-induced myasthenic syndrome. counterpart has yet been described. These drugs include: Antinicotinic drugs Ganglion-blocking drugs (Fig. 21.1, site 1) (see Antimicrobials. Aminoglycosides (neomycin, strep- Ch. 24). tomycin, gentamicin), polypeptides (colistimethate Neuromuscular blocking drugs (Fig. 21.1, site 5) sodium, polymyxin B) and perhaps the quinolones (see Ch. 18). (e.g. ciprofloxacin) may cause postoperative breathing difficulty if they are instilled into the ANTIMUSCARINIC DRUGS peritoneal or pleural cavities. It appears that the Atropine is the prototype drug of this group and will antibiotics both interfere with the release of be described first. Other named agents will be acetylcholine and also have a competitive curare- mentioned only in so far as they differ from atropine. like effect on the acetylcholine receptor. All act as non-selective and competitive antagonists of the various muscarinic receptor subtypes (Ml-3). Cardiovascular drugs. Those that possess local Atropine is a simple tertiary amine; certain others anaesthetic properties [quinidine, procainamide, (see Summary) are quaternary nitrogen compounds, lignocaine (lidocaine)] and certain fi-blockers a modification that is important as it intensifies (propranolol, oxprenolol) interfere with acetylcholine antimuscarinic potency in the gut, imparts ganglion- release and may aggravate or reveal myasthenia blocking effects and reduces CNS penetration. gravis. Atropine Other drugs. Penicillamine causes some patients, especially those with rheumatoid arthritis, to form Atropine is an alkaloid from the deadly nightshade antibodies to the acetylcholine receptor and a syn- (Atropa belladonna).11 In general, the effects of drome indistinguishable from myasthenia gravis results. Spontaneous recovery occurs in about two- 11 The first name commemorates its success as a homicidal thirds of cases when penicillamine is withdrawn. poison, for it is derived from the senior of three legendary Phenytoin may rarely induce or aggravate myas- Fates, Atropos, who cuts with shears the web of life spun and thenia gravis, or induce a myasthenic syndrome, woven by her sisters Clothos and Lachesis (there is a minor possibly by depressing release of acetylcholine. synthetic atropine-like drug called lachesine). The term belladonna (Italian: beautiful woman) refers to the once Lithium may impair presynaptic neurotransmission fashionable female practice of using an extract of the plant to by substituting for sodium ions in the nerve dilate the pupils (incidentally blocking ocular accommodation) terminal. as part of the process of making herself attractive. 441
21 CHOLINERGIC AND ANTIMUSCARINIC MECHANISMS • 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 anaesthesic premedication, atropine, and 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, para- sympathomimetic 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). 442
D R U G S W H I C H O P P O S E A C ET Y L C H O L I N E 21 atropine are inhibitory but in large doses it stimu- Transient vagal stimulation, probably in the CNS, lates the CNS (see poisoning, below). Atropine also may cause bradycardia, e.g. if atropine is given i.v. blocks the muscarinic effects of injected cholinergic with neostigmine and the effects of the two drugs drugs both peripherally and on the central nervous summate. system. The clinically important actions of atropine Atropine has no significant effect on peripheral at parasympathetic postganglionic nerve endings blood vessels in therapeutic doses but, in poisoning, are listed below; they are mostly the opposite of the there is marked vasodilatation. activating effects on the parasympathetic system produced by cholinergic drugs. Central nervous system. Atropine is effective against both tremor and rigidity of parkinsonism. Exocrine glands. All secretions except milk are It prevents or abates motion sickness. diminished. Dry mouth and dry eye are common. Gastric acid secretion is reduced but so also is the Antagonism to cholinergic drugs. Atropine opposes total volume of gastric secretion so that pH may be the effects of all cholinergic drugs on the CNS, at little altered. Sweating is inhibited (sympathetic postganglionic cholinergic nerve endings and on innervation but releasing acetylcholine). Bronchial the peripheral blood vessels. It does not oppose secretions are reduced and may become viscid, which cholinergic effects at the neuromuscular junction or can be a disadvantage, as removal of secretion by significantly at the autonomic ganglia, i.e. atropine cough and ciliary action is rendered less effective. opposes the muscarine-like but not the nicotine-like effects of acetylcholine. Smooth muscle is relaxed. In the gastrointestinal tract there is reduction of tone and peristalsis. Pharmacokinetics. Atropine is readily absorbed Muscle spasm of the intestinal tract induced by from the gastrointestinal tract and may also be morphine is reduced, but such spasm in the biliary injected by the usual routes. The occasional cases of tract is not significantly affected. Atropine relaxes atropine poisoning following use of eye drops are bronchial muscle, an effect that is useful in some due to the solution running down the lacrimal asthmatics. Micturition is slowed and urinary ducts into the nose and being swallowed. Atropine retention may be induced especially when there is is in part destroyed in the liver and in part excreted pre-existing prostatic enlargement. unchanged by the kidney (t \ 2 h). Ocular effects. Mydriasis occurs with a rise in Dose. 0.6-1.2 mg by mouth at night or 0.6mg i.v. intraocular pressure in eyes predisposed to narrow- and repeated as necessary to a maximum of 3 mg angle glaucoma. This is due to the dilated iris per day; for chronic use it has largely been replaced blocking drainage of the intraocular fluids from the by other antimuscarinic drugs. angle of the anterior chamber. An attack of glau- coma may be induced. There is no significant effect Poisoning with atropine (and other antimuscarinic on pressure in normal eyes. The ciliary muscle is drugs) presents with the more obvious peripheral paralysed and so the eye is accommodated for 12 distant vision. After atropinisation, normal pupillary A doctor, after working in his garden greenhouse, was reflexes may not be regained for 2 weeks. Atropine alarmed to find that the vision in his left eye was blurred and the pupil was grossly dilated. Physical examination failed to use is a cause of unequal sized and unresponsive reveal a cause and the pupil gradually and spontaneously pupils.12 returned to normal, suggesting that the explanation was exposure to some exogenous agent. The doctor then recalled Cardiovascular system. Atropine reduces vagal that his greenhouse contained flowering plants called tone thus increasing the heart rate, and enhancing 'angels' trumpet' (sp. Brugmansia, of the nightshade family), and he may have brushed against them. Angels' trumpet is conduction in the bundle of His, effects that are less noted for its content of scopolamine (hyoscine), and is very marked in the elderly in whom vagal tone is low. toxic if ingested. The plant is evidently less angelic than the Full atropinisation may increase rate by 30 beats/min name suggests. Merrick J, Barnett S 2000 British Medical in the young, but has little effect in the old. Journal 321: 219. 443
21 C H O L I N E R G I C AND A N T I M U SC A R I N I C M E C H A N I S M S effects: dry mouth (with dysphagia), mydriasis, day or two. Complete cycloplegia cannot always be blurred vision, hot, flushed, dry skin, and, in obtained unless repeated instillations are made addition, hyperthermia (CNS action plus absence of every 15 min for 1-2 h. It is especially unreliable in sweating), restlessness, anxiety, excitement, halluci- children, in whom cyclopentolate or atropine is nations, delirium, mania. The cerebral excitation is preferred. The pupillary dilation may be reversed followed by depression and coma or, as it has been by physostigmine eyedrops. described with characteristic American verbal Tropicamide (Mydriacyl) and cyclopentolate (Myd- felicity, 'hot as a hare, blind as a bat, dry as a bone, rilate) are useful (as 0.5% or 1% solutions) for red as a beet and mad as a hen'.13 It may occur in mydriasis and cycloplegia. They are quicker and children who have eaten berries of solanaceous shorter-acting than homatropine. Both cause myd- plants, e.g. deadly nightshade and henbane. When riasis in 10-20 min and cycloplegia shortly after. the diagnosis is doubtful, it is said to be worth The duration of action is 4-12 h. putting a drop of the patient's urine in one eye of a Ipratropium (Atrovent) is used by inhalation as a cat. Mydriasis, if it results, confirms the diagnosis, bronchodilator, and can be useful when cough is a but absence of effect proves nothing. Treatment pronounced symptom in an asthmatic patient. involves giving activated charcoal to adsorb the Flavoxate (Urispas) is used for urinary frequency, drug, and diazepam for excitement. tenesmus and urgency incontinence because it increases bladder capacity and reduces unstable detrusor contractions (see p. 543). Other antimuscarinic drugs Oxybutynin is also used for detrusor instability, In the following accounts of drugs, the principal but antimuscarinic adverse effects may limit its peripheral atropine-like effects of the drugs may be value. assumed; differences from atropine are described. Glycopyrronium is used in anaesthetic pre- Atropine is also a racemate (dl-hyoscyamine), medication to reduce salivary secretion; given i.v. it and almost all of its antimuscarinic effects are causes less tachycardia than does atropine. attributable to the 1-isomer alone. It is, however, Propantheline (Pro-Banthine) also has ganglion- more stable chemically as the racemate which is the blocking properties. It may be used as a smooth preferred formulation. Hyoscine (scopolamine) is structurally related to atropine. It differs chiefly in being a central nervous • Acetylcholine is the most important receptor agonist system depressant, although it may sometimes cause neurotransmitter in both the brain and peripheral excitement. Elderly patients are often confused by nervous system. hyoscine and so it is avoided in their anaesthetic • It acts on neurons in the CNS and at autonomic premedication. Mydriasis is also briefer than with ganglia, on skeletal muscle at the neuromuscular atropine. junction, and at a variety of other effector cell types, Hyoscine butylbromide (strictly N-butylhyoscine mainly glandular or smooth muscle. • The effector response is rapidly terminated through bromide, Buscopan) also blocks autonomic ganglia. enzymatic destruction by acetylcholinesterase. If injected, it is an effective relaxant of smooth • Outside the CNS, acetylcholine has two main classes muscle, including the cardia in achalasia, the pyloric of receptor: those on autonomic ganglia and skeletal antral region and the colon, which properties are muscle responding to stimulation by nicotine and the utilised by radiologists and endoscopists. It may rest that respond to stimulation by muscarine. sometimes be useful for colic. • Drugs that mimic or oppose acetylcholine have a wide Homatropine is used for its ocular effects (1% and variety of uses. For instance, the muscarinic agonist pilocarpine lowers intraocular pressure and antagonist 2% solutions as eye drops). Its action is shorter than atropine reverses vagal slowing of the heart. atropine and therefore less likely to cause serious • The main use of drugs at the neuromuscular junction rises of intraocular pressure; the effect wears off in a is to relax muscle in anaesthesia, or to inhibit acetylcholinesterase in diseases where nicotinic 13 receptor activation is reduced, e.g. myasthenia gravis. Cohen H L et al 1944 Archives of Neurology and Psychiatry 51:171, 444
D R U G S W H I C H O P P O S E A C ET Y L C H O L I NE 21 muscle relaxant, e.g. for irritable bowel syndrome Carbon dioxide inhalation therapy in neurosis. and diagnostic procedures. A controlled clinical trial (p. 52); The placebo Dicyclomine (Merbentyl) is an alternative. response (p. 60). Journal of Mental Science 102: 43 Benzhexol (trihexyphenidyl) and orphenadrine: see HMSO 1987 Medical manual of defence against parkinsonism. chemical agents. (No. 0117725692) JSP: 312 Promethazine: see p. 555. Lambert D 1981 (personal paper) Myasthenia gravis. Propiverine, tolterodine and trospium diminish un- Lancet 1:937 stable detrusor contractions and are used to reduce Morita H et al 1996 Sarin poisoning in Matsumoto, urinary frequency, urgency and incontinence. Japan. Lancet 346: 290-293 Oral antimuscarinics have occasional use in the Morton H G et al 1939 Atropine intoxication. Journal treatment of hyperhidrosis. 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 GUIDETO FURTHER READING of Psychiatrists Cohen H L et al 1944 Acetylcholine treatment of Steenland K 1996 Chronic neurological effects of schizophrenia. Archives of Neurology and Organophosphate pesticides. British Medical Psychiatry 51:171 Journal 312:1312-1313 Hawkins J R et al 1956 Intravenous acetylcholine Vincent A et al 2001 Myasthenia gravis. Lancet 357: therapy in neurosis. A controlled trial (p. 43); 2122-2128 445