Kevin M. O'Shaughnessy
Synopsis
Acetylcholine is a widespread chemotransmitter in the body, mediating a broad range of physiological effects. The two classes of receptor for acetylcholine are defined on the basis of their preferential activation by the alkaloids nicotine and muscarine.
Cholinergic drugs (acetylcholine receptor agonists) mimic acetylcholine at all sites, although the balance of nicotinic and muscarinic effects is variable.
Acetylcholine antagonists that block the nicotine-like effects (neuromuscular blockers and autonomic ganglion blockers) are described elsewhere (Ch. 19).
Acetylcholine antagonists that block the muscarine-like effects, e.g. atropine, are often imprecisely called anticholinergics. The more specific term ‘antimuscarinic’ is preferred here.
• Cholinergic drugs.
Classification
Sites of action
Pharmacology
Choline esters
Alkaloids with cholinergic effects
Anticholinesterases; organophosphate poisoning
Disorders of neuromuscular transmission: myasthenia gravis.
• Drugs that oppose acetylcholine action.
Antimuscarinic drugs.
Cholinergic drugs (cholinomimetics)
These drugs act on post-synaptic acetylcholine receptors (cholinoceptors) at all sites in the body where acetylcholine is the effective neurotransmitter. They initially stimulate and usually later block transmission. In addition, like acetylcholine, they act on the non-innervated receptors that relax peripheral blood vessels.
Uses of cholinergic drugs
• For myasthenia gravis, both to diagnose (edrophonium) and to treat symptoms (neostigmine, pyridostigmine, distigmine).
• To lower intraocular pressure in chronic simple glaucoma (pilocarpine).
• To bronchodilate patients with airflow obstruction (ipratropium, tiotropium).
• To improve cognitive function in Alzheimer's disease (rivastigmine, donepezil).
Classification
Direct-acting (receptor agonists)
• Choline esters (bethanechol, carbachol), which act at all sites, like acetylcholine, but are resistant to degradation by acetylcholinesterases (AChE; see Fig. 22.1). Muscarinic effects are much more prominent than nicotinic (see p. 373).
• Alkaloids (pilocarpine, muscarine) act selectively on end-organs of postganglionic, cholinergic neurones. Effects are exclusively muscarinic.
Fig. 22.1 The different origins of acetylcholine (ACh) activating nicotinic (N) versus muscarinic (M) cholinergic receptors. The three sites (numbered 1–3) are referred to in the text.
Indirect-acting
Cholinesterase inhibitors, or anticholinesterases (physostigmine, neostigmine, pyridostigmine, distigmine, galantamine, rivastigmine, donepezil), block acetylcholinesterase (AChE), the enzyme that destroys acetylcholine, allowing endogenous acetylcholine to persist and produce intensified effects.
Sites of action (Fig. 22.1)
• Autonomic nervous system (Fig. 22.1, sites 1 and 2).
• Neuromuscular junction (Fig. 22.1, site 1).
• Central nervous system (CNS).
• Non-innervated sites: blood vessels, chiefly arterioles (Fig. 22.1, site 3).
Acetylcholine is released from nerve terminals to activate a post-synaptic receptor, except on blood vessels, where the action of cholinergic drugs is unrelated to cholinergic ‘vasodilator’ nerves. It is also produced in tissues unrelated to nerve endings, e.g. placenta and ciliated epithelial cells, where it acts as a local hormone (autacoid) on local receptors.
A list of principal effects is given below. Not all occur with every drug and not all are noticeable at therapeutic doses. For example, CNS effects of cholinergic drugs are best seen in cases of anticholinesterase poisoning. Atropine antagonises all the effects of cholinergic drugs except nicotinic actions on autonomic ganglia and the neuromuscular junction, i.e. it has antimuscarinic but not antinicotinic effects (see below).
Pharmacology
Autonomic nervous system
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 toxic mushroom, Amanita muscaria).
It was Henry Dale who, in 1914, first made this functional division, which remains a robust and useful way of classifying cholinergic drug effects. He noted that the actions of acetylcholine and substances acting like it at autonomic ganglia and the neuromuscular junction mimic the stimulant effects of nicotine (hence nicotinic). In contrast, the actions at postganglionic cholinergic endings (parasympathetic endings plus the cholinergic sympathetic nerves to the sweat glands) and non-innervated receptors on blood vessels resembled the alkaloid, muscarine (hence muscarinic).
Parasympathetic division
Stimulation of cholinoceptors in autonomic ganglia and at postganglionic endings affects chiefly the following organs:
• Eye: miosis and spasm of the ciliary muscle occur so that the eye is accommodated for near vision. Intraocular pressure falls.
• Exocrine glands: there is increased secretion most noticeably from salivary, lachrymal, bronchial and sweat glands. The last are cholinergic, but anatomically part of the sympathetic system; some sweat glands, e.g. axillary, may be adrenergic.
• Heart: bradycardia occurs with atrioventricular block, and eventually cardiac arrest.
• Bronchi: there is bronchoconstriction and mucosal hypersecretion that may be clinically serious in asthmatic subjects, in whom cholinergic drugs should be avoided if possible.
• Gut: motor activity is increased and may cause colicky pain. Exocrine secretion is also increased. Tone in sphincters falls, which may cause defaecation (anal sphincter) or acid reflux/regurgitation (oesophageal sphincter).
• Urinary bladder and ureters contract and the drugs promote micturition.
Sympathetic division
Only the ganglia are stimulated and cholinergic nerves to the adrenal medulla. These effects are overshadowed by effects on the parasympathetic system and are usually seen only if atropine has been given to block the latter, when tachycardia, vasoconstriction and hypertension occur.
Neuromuscular (voluntary) junction
The neuromuscular junction has cholinergic nerve endings and so is activated when anticholinesterases allow acetylcholine to persist, causing muscle fasciculation. Prolonged activation leads to a secondary depolarising neuromuscular block.
Central nervous system
There is usually stimulation followed by depression but considerable variation between drugs is observed, possibly due to differences in CNS penetration. In overdose, mental excitement occurs, with confusion and restlessness, insomnia (with nightmares during sleep), tremors and dysarthria, and sometimes even convulsions and coma. Nicotinic receptor activation in the CNS is also thought to be important for cognitive processing, which appears to be impaired in schizophrenic subjects.
Blood vessels
There is stimulation of cholinergic vasodilator nerve endings in addition to the more important dilating action on arterioles and capillaries mediated through non-innervated muscarinic receptors. Activation of these receptors stimulates nitric oxide production from the vascular endothelium that relaxes the underlying smooth muscle.
Choline esters
Acetylcholine
As acetylcholine has such importance in the body it is not surprising that attempts have been made to use it therapeutically. But a substance with such a huge variety of effects and rapid destruction in the body is unlikely to be useful when given systemically, as its use in psychiatry illustrates.
Acetylcholine was first injected intravenously as a therapeutic convulsant in 1939, in the reasonable expectation that the fits would be less liable to cause fractures than those following therapeutic leptazol (pentylenetetrazole) convulsions. Recovery rates of up to 80% were claimed in various psychotic conditions. Enthusiasm began to wane, however, when it was shown that the fits were due to anoxia resulting from cardiac arrest and not to pharmacological effects on the brain.1
The following description is typical:
A few seconds after the injection (which was given as rapidly as possible, to avoid total destruction in the blood) the patient sat up ‘with knees drawn up to the chest, the arms flexed and the head bent forward. There were repeated violent coughs, sometimes with flushing. Forced swallowing and loud peristaltic rumblings could be heard’. Respiration was laboured and irregular. ‘The coughing abated as the patient sank back in the bed. Forty seconds after the injection the radial and apical pulse were zero and the patient became comatose.’ The pupils dilated, and deep reflexes were hyperactive. In 45 seconds the patient went into opisthotonos with brief apnoea.
Lachrymation, sweating and borborygmi were prominent. The deep reflexes became diminished. The patient then relaxed and ‘lay quietly in bed – cold moist and gray. In about 90 seconds, flushing of the face marked the return of the pulse’. The respiratory rate rose and consciousness returned in about 125 seconds. The patients sometimes micturated but did not defaecate. They ‘tended to lie quietly in bed after the treatment’. ‘Most of the patients were reluctant to be retreated.’2
Other choline esters
Carbachol is not destroyed by cholinesterase; its actions are most pronounced on the bladder and gastrointestinal tract, so that the drug was used to stimulate these organs, e.g. after surgery. These uses are now virtually obsolete, e.g. catheterisation is preferred for bladder atony. It is occasionally applied topically (3% solution) to the eye as a miotic.
Bethanechol resembles carbachol in its actions but is some 10-fold less potent (it differs by a single β-methyl group) and has no significant nicotinic effects at clinical doses.
Alkaloids with cholinergic effects
Nicotine
(see also p. 151) is a social drug that lends its medicinal use as an adjunct to stopping its own abuse as tobacco. It is available as gum to chew, dermal patches, a nasal spray or an inhalator. These deliver a lower dose of nicotine than cigarettes and appear to be safe in patients with ischaemic heart disease. The patches are slightly better tolerated than the gum, which releases nicotine in a more variable fashion depending on the rate at which it is chewed and the salivary pH, which is influenced by drinking coffee and carbonated drinks. Nicotine treatment is reported to be nearly twice as effective as placebo in achieving sustained withdrawal from smoking (18% versus 11% in one review).3Treatment is much more likely to be successful if it is used as an aid to, not a substitute for, continued counselling. Bupropionis possibly more effective than the nicotine patch4 (see also p. 152) and the partial nicotinic agonist, varenicline, slightly more effective still. The efficacy of varenicline is tempered by its ability to cause suicidal ideation and behaviour.
Pilocarpine,
from a South American plant (Pilocarpus spp.), acts directly on muscarinic receptors (see Fig. 22.1); it also stimulates and then depresses the CNS. The chief clinical use of pilocarpine is to lower intraocular pressure in primary open-angle glaucoma (also called chronic simple or wide-angle glaucoma), as an adjunct to a topical β-blocker; it produces miosis, opens drainage channels in the trabecular network and improves the outflow of aqueous humour. Oral pilocarpine is available for the treatment of xerostomia (dry mouth) in Sjögren's syndrome, or following irradiation of head and neck tumours. The commonest adverse effect is sweating, an effect actually exploited in a diagnostic test for cystic fibrosis.
Arecoline
is an alkaloid in the betel nut, which is chewed extensively throughout India and South-East Asia. Presumably the lime mix in the ‘chews’ provides the necessary alkaline pH to maximise its buccal absorption. It produces a mild euphoric effect, like many cholinomimetic alkaloids.
Muscarine
is of no therapeutic use but it has pharmacological interest. It is present in small amounts in the fungus Amanita muscaria (fly agaric), named after its capacity to kill the domestic fly (Musca domestica); muscarine was so named because it was thought to be the insecticidal principle, but it is relatively non-toxic to flies (orally administered). The fungus may contain other antimuscarinic substances and γ-aminobutyric acid (GABA) receptor agonists (such as muscimol) in amounts sufficient to be psychoactive in humans. The antimuscarinic components may explain why the dried fungus was used previously to treat excessive sweating, especially in patients with tuberculosis.
Poisoning with these fungi may present with antimuscarinic, cholinergic or GABAergic effects. All have CNS actions. Happily, poisoning by Amanita muscaria is seldom serious, but species of Inocybecontain substantially larger amounts of muscarine (see Ch. 10). The lengths to which humans are prepared to go in taking ‘chemical vacations’ when life is hard are shown by the inhabitants of eastern Siberia, who used Amanita muscaria recreationally for its cerebral stimulant effects. They were apparently prepared to put up with the autonomic actions to escape briefly from reality – so much so that when the fungus was scarce in winter they were even prepared to drink their own urine to prolong the experience. Sometimes, in generous mood, they would even offer their urine to others as a treat.
Anticholinesterases
At cholinergic nerve endings and in erythrocytes there is a specific enzyme that destroys acetylcholine, true cholinesterase or acetylcholinesterase. In various tissues, especially plasma, there are other esterases that are not specific for acetylcholine but that also destroy other esters, e.g. suxamethonium, procaine (and cocaine) and bambuterol (a prodrug that is hydrolysed to terbutaline). Hence, they are called pseudocholinesterases. Chemicals that inactivate these esterases (anticholinesterases) are used in medicine and in agriculture as pesticides. They act by allowing naturally synthesised acetylcholine to accumulate instead of being destroyed. Their effects are explained by this accumulation in the CNS, neuromuscular junction, autonomic ganglia, postganglionic cholinergic nerve endings (which are principally in the parasympathetic nervous system) and in the walls of blood vessels, where acetylcholine has a paracrine5role not necessarily associated with nerve endings. Some of these effects oppose one another, e.g. the effect of anticholinesterase on the heart will be the result of stimulation at sympathetic ganglia and the opposing effect of stimulation at parasympathetic (vagal) ganglia and at postganglionic nerve endings.
Physostigmine
is an alkaloid, obtained from the seeds of the West African Calabar bean (spp. Physostigma), which has had long use both as a weapon and as an ordeal poison.6 It acts for a few hours. It has been shown to have some efficacy in improving cognitive function in Alzheimer-type dementia.
Neostigmine
(t½ 2 h) is a synthetic reversible anticholinesterase whose actions are more prominent on the neuromuscular junction and the alimentary tract than on the cardiovascular system and eye. It is therefore used principally in myasthenia gravis and as an antidote to competitive neuromuscular blocking agents; its use to stimulate the bowels or bladder after surgery is now obsolete. Neostigmine is effective orally, and by injection (usually subcutaneous). But higher doses may be used in myasthenia gravis, often combined with atropine to reduce the unwanted muscarinic effects.
Pyridostigmine
is similar to neostigmine but has a less powerful action that is slower in onset and slightly longer in duration, and perhaps with fewer visceral effects. It is used in myasthenia gravis.
Distigmine
is a variant of pyridostigmine (two linked molecules as the name implies).
Edrophonium
is structurally related to neostigmine but its action is brief and autonomic effects are minimal except at high doses. The drug is used to diagnose myasthenia gravis and to differentiate a myasthenic crisis (weakness due to inadequate anticholinesterase treatment or severe disease) from a cholinergic crisis (weakness caused by over-treatment with an anticholinesterase). Myasthenic weakness is substantially improved by edrophonium whereas cholinergic weakness is aggravated but the effect is transient; the action of 3 mg i.v. is lost in 5 min.
Carbaryl
(carbaril) is another reversible carbamoylating anticholinesterase that closely resembles physostigmine in its actions. It is used widely as a garden insecticide and, clinically, to kill head and body lice. Sensitive insects lack cholinesterase-rich erythrocytes and succumb to the accumulation of acetylcholine in the synaptic junctions of their nervous system. Effective and safe use in humans is also probably due to the very limited absorption of carbaryl after topical application. The anticholinesterase malathion is effective against scabies, head and crab lice.
A more recent use of anticholinesterase drugs has been to improve cognitive function in patients with Alzheimer's disease (see p. 344), where both the degree of dementia and amyloid plaque density correlate with the impairment of brain cholinergic function. Donepezil, galantamine (which has additional nicotinic agonist properties) and rivastigmine are licensed in the UK for this indication. They are all reversible inhibitors that are orally active and cross the blood–brain barrier readily (see p. 81).
Anticholinesterase poisoning
The anticholinesterases used in therapeutics are generally of the carbamate type that reversibly inactivates cholinesterase only for a few hours. This contrasts markedly with the very long-lived inhibition caused by inhibitors of the organophosphate (OP) type. In practice, the inhibition is so long that clinical recovery from organophosphate exposure is usually dependent on synthesis of new enzyme. This process may take weeks to complete, although clinical recovery is usually evident in days. Cases of acute poisoning are usually met outside therapeutic practice, e.g. after agricultural, industrial or transport accidents.
Substances of this type have also been developed and used in war, especially the three G agents: GA (tabun), GB (sarin) and GD (soman). Although called nerve ‘gas’, they are actually volatile liquids, which facilitates their use.7 Where there is known risk of exposure, prior use of pyridostigmine, which occupies cholinesterases reversibly for a few hours (the lesser evil), competitively protects them from access by the irreversible warfare agent (the greater evil); soldiers during the Gulf Wars expecting attack were provided with preloaded syringes (of the same design as the Epipen) for delivering adrenaline/epinephrine as antidote therapy (see below). Organophosphate agents are absorbed through the skin, the gastrointestinal tract and by inhalation. Diagnosis depends on observing a substantial part of the list of actions below.
Typical features
of acute poisoning involve the gastrointestinal tract (salivation, vomiting, abdominal cramps, diarrhoea, involuntary defaecation), the respiratory system (bronchorrhoea, bronchoconstriction, cough, wheezing, dyspnoea), the cardiovascular system (bradycardia), the genitourinary system (involuntary micturition), the skin (sweating), the skeletal system (muscle weakness, twitching) and the nervous system (miosis, anxiety, headache, convulsions, respiratory failure). Death is due to a combination of the actions in the CNS, to paralysis of the respiratory muscles by peripheral depolarising neuromuscular block, and to excessive bronchial secretions and constriction causing respiratory failure. At autopsy, ileal intussusceptions are commonly found.
Quite frequently and typically 1–4 days after resolution of symptoms of acute exposure, the intermediate syndrome may develop, characterised by a proximal flaccid limb paralysis that may reflect muscle necrosis. Even later, after a gap of 2–4 weeks, some exposed persons exhibit delayed polyneuropathy, with sensory and motor impairment usually of the lower limbs. Claims of chronic effects (subtle cognitive defects, peripheral neuropathy) following recurrent, low-dose exposure, as with organophosphate used as sheep dip, continue to be the subject of investigation but, as yet, there is no conclusive proof.
Treatment
As the most common circumstance of accidental poisoning is exposure to pesticide spray or spillage, contaminated clothing should be removed and the skin washed. Attendants should take care to ensure that they themselves do not become contaminated.
• Atropine is the mainstay of treatment; 2 mg is given i.m. or i.v. as soon as possible and repeated every 15–60 min until dryness of the mouth and a heart rate exceeding 70 beats per minute indicate that its effect is adequate. A poisoned patient may require 100 mg or more for a single episode. Atropine antagonises the muscarinic parasympathomimetic effects of the poison, i.e. due to the accumulated acetylcholine stimulating postganglionic nerve endings (excessive secretion and vasodilatation), but has no effect on the neuromuscular block, which is nicotinic.
• Mechanical ventilation may therefore be needed to assist the respiratory muscles; special attention to the airway is vital because of bronchial constriction and excessive secretion.
• Diazepam may be needed for convulsions.
• Atropine eye drops may relieve the headache caused by miosis.
• Enzyme reactivation. The organophosphate (OP) pesticides inactivate cholinesterase by irreversibly phosphorylating the active centre of the enzyme. Substances that reactivate the enzyme hasten the destruction of the accumulated acetylcholine and, unlike atropine, they have both antinicotinic and antimuscarinic effects. The principal agent is pralidoxime, which should be given by slow intravenous injection (diluted) over 5–10 min, initially 30 mg/kg repeated every 4–6 h or by intravenous infusion, 8 mg/kg/h; usual maximum 12 g in 24 h. Its efficacy is greatest if administered within 12 h of poisoning, then falls off steadily as the phosphorylated enzyme is further stabilised by ‘ageing’. If significant reactivation occurs, muscle power improves within 30 min.
Poisoning
with reversible anticholinesterases is appropriately treated by atropine and the necessary general support; it lasts only hours.
In poisoning with irreversible agents, erythrocyte or plasma cholinesterase content should be measured if possible, both for diagnosis and to determine when a poisoned worker may return to the task (should he or she be willing to do so). Return should not be allowed until the cholinesterase exceeds 70% of normal, which may take several weeks. Recovery from the intermediate syndrome and delayed polyneuropathy is slow and is dependent on muscle and nerve regeneration.
Disorders of neuromuscular transmission
Myasthenia gravis
In myasthenia gravis synaptic transmission at the neuromuscular junction is impaired; most cases have an autoimmune basis and some 85% of patients have a raised titre of autoantibodies to the muscle acetylcholine receptor. The condition is probably heterogeneous, as about 15% do not have receptor antibodies, or have antibodies to another neuromuscular junction protein (muscle specific kinase, MuSK) and, rarely, it occurs with D-penicillamine used for rheumatoid arthritis.
Neostigmine was introduced in 1931 for its stimulant effects on intestinal activity. In 1934 it occurred to Dr Mary Walker that, as the paralysis of myasthenia had been (erroneously) attributed to a curare-like substance in the blood, physostigmine (eserine), an anticholinesterase drug known to antagonise curare, might be beneficial. It was, and she reported this important observation in a short letter.8 Soon after this she used neostigmine by mouth, with greater benefit. The sudden appearance of an effective treatment for a hitherto untreatable chronic disease must always be a dramatic event for its victims. One patient described the impact of the discovery of the action of neostigmine, as follows:
My myasthenia started in 1925, when I was 18. For several months it consisted of double vision and fatigue … An ophthalmic surgeon … prescribed glasses with a prism. However, soon more alarming symptoms began. [Her limbs became weak and she] was sent to an eminent neurologist. This was a horrible experience. He … could find no physical signs … declared me to be suffering from hysteria and asked me what was on my mind. When I answered truthfully, that nothing except anxiety over my symptoms, he replied ‘my dear child, I am not a perfect fool …’, and showed me out. [She became worse and at times she was unable to turn over in bed. Eating and even speaking were difficult. Eventually, her fiancé, a medical student, read about myasthenia gravis and she was correctly diagnosed in 1927.] There was at that time no known treatment and therefore many things to try. [She had gold injections, thyroid, suprarenal extract, lecithin, glycine and ephedrine. The last had a slight effect.] Then in February 1935, came the day that I shall always remember. I was living alone with a nurse … It was one of my better days, and I was lying on the sofa after tea … My fiancé came in rather late saying that he had something new for me to try. My first thought was ‘Oh bother! Another injection, and another false hope’. I submitted to the injection with complete indifference and within a few minutes began to feel very strange … when I lifted my arms, exerting the effort to which I had become accustomed, they shot into the air, every movement I attempted was grotesquely magnified until I learnt to make less effort … it was strange, wonderful and at first, very frightening … we danced twice round the carpet. That was my first meeting with neostigmine, and we have never since been separated.9
Pathogenesis
The clinical features of myasthenia gravis are caused by specific autoantibodies to the nicotinic acetylcholine receptor. These antibodies accelerate receptor turnover, shortening their typical lifetime in the skeletal muscle membrane from around 7 days, to 1 day in a myasthenic. This process results in marked depletion of receptors from myasthenic skeletal muscle (about 90%), explaining its fatigability. The frequent finding of a specific human leucocyte antigen (HLA) haplotype (A1-B8-Dw3) in myasthenics and concurrent hyperplasia or tumours of the thymus support the autoimmune basis for the disease.
Diagnosis
Edrophonium dramatically and transiently (5 min) relieves myasthenic muscular weakness. A syringe is loaded with edrophonium 10 mg; 2 mg is given i.v. and if there is no improvement in weakness in 30 s the remaining 8 mg is injected. Adults without suitable veins may receive 10 mg by i.m. injection. Atropine should be at hand to block severe cholinergic autonomic (muscarinic) effects, e.g. bradycardia, should they occur.
Titres of acetylcholine receptor antibodies should also be measured to confirm the diagnosis.
Treatment
involves immunosuppression, thymectomy (unless contraindicated) and symptom relief with drugs:
• Immunosuppressive treatment is directed at eliminating the acetylcholine receptor autoantibody. Prednisolone induces improvement or remission in 80% of cases. The dose should be increased slowly using an alternate-day regimen until the minimum effective amount is attained; an immunosuppressive improvement may take several weeks. Azathioprine may be used as a steroid-sparing agent. Prednisolone is effective for ocular myasthenia, which is fortunate, for this variant of the disease responds poorly to thymectomy or anticholinesterase drugs. Some acute and severe cases respond poorly to prednisolone with azathioprine and, for these, intermittent plasmapheresis or immunoglobulin i.v. (to remove circulating anti-receptor antibody) can provide dramatic short-term relief.
• Thymectomy should be offered to those with generalised myasthenia gravis under 40 years of age, once the clinical state allows and unless there are powerful contraindications to surgery. Most cases benefit and about 25% can discontinue drug treatment. Thymectomy should also be undertaken in all myasthenic patients who have a thymoma, but the main reason is to prevent local infiltration, as the procedure is less likely to relieve the myasthenia.
• Symptomatic drug treatment is decreasingly used. Its aim is to increase the concentration of acetylcholine at the neuromuscular junction with anticholinesterase drugs. The mainstay is usually pyridostigmine,starting with 60 mg by mouth 4-hourly. It is preferred because its action is smoother than that of neostigmine, but the latter is more rapid in onset and can with advantage be given in the mornings to get the patient mobile. Either drug can be given parenterally if bulbar paralysis makes swallowing difficult. An antimuscarinic drug, e.g. propantheline (15–30 mg t.i.d.), should be added if muscarinic effects are troublesome.
Excessive dosing
with an anticholinesterase can actually worsen the muscle weakness in myasthenics if the accumulation of acetylcholine at the neuromuscular junction is sufficient to cause depolarising blockade (cholinergic crisis). It is important to distinguish this type of muscle weakness from an exacerbation of the disease itself (myasthenic crisis). The dilemma can be resolved with a test dose of edrophonium 2 mg i.v. (best before next dose of anticholinesterase), which relieves a myasthenic crisis but worsens a cholinergic one. The latter may be severe enough to precipitate respiratory failure and should be attempted only with full resuscitation facilities, including mechanical ventilation, at hand.
A cholinergic crisis should be treated by withdrawing all anticholinesterase medication, mechanical ventilation if required, and atropine i.v. for muscarinic effects of the overdose. The neuromuscular block is a nicotinic effect and will be unchanged by atropine. A resistant myasthenic crisis may be treated by withdrawal of drugs and mechanical ventilation for a few days. Plasmapheresis or immunoglobulin i.v. may be beneficial by removing anti-receptor antibodies (see above).
Lambert–Eaton syndrome
Separate from myasthenia gravis is the Lambert–Eaton syndrome, in which symptoms similar to those of myasthenia gravis occur in association with a carcinoma; in 60% of patients this is a small-cell lung cancer. The defect here is pre-synaptic with a deficiency of acetylcholine release due to an autoantibody directed against L-type voltage-gated calcium channels.
Patients with the Lambert–Eaton syndrome do not usually respond well to anticholinesterases. The drug 3,4-diaminopyridine (3,4-DAP) increases neurotransmitter release and also the action potential (by blocking potassium conductance), producing a non-specific enhancement of cholinergic neurotransmission. It should be taken orally, four or five times a day. Adverse effects due to CNS excitation (insomnia, seizures) can occur. An example of an orphan drug without a product licence, 3,4-DAP is available in the UK on a ‘named patient’ basis.
Drug-induced disorders of neuromuscular transmission
Quite apart from the neuromuscular blocking agents used in anaesthesia, a number of drugs possess actions that impair neuromuscular transmission and, in appropriate circumstances, give rise to:
• Postoperative respiratory depression in people with otherwise normal neuromuscular transmission.
• Aggravation or unmasking of myasthenia gravis.
• A drug-induced myasthenic syndrome.
These drugs include:
Antimicrobials
Aminoglycosides (neomycin, streptomycin, gentamicin), polypeptides (colistimethate sodium, polymyxin B) and perhaps the quinolones (e.g. ciprofloxacin) may cause postoperative breathing difficulty if they are instilled into the peritoneal or pleural cavity. It appears that the antibiotics both interfere with the release of acetylcholine and also have a competitive curare-like effect on the acetylcholine receptor.
Cardiovascular drugs
Those that possess local anaesthetic properties (quinidine, procainamide, lidocaine) and certain β-blockers (propranolol, oxprenolol) interfere with acetylcholine release and may aggravate or reveal myasthenia gravis.
Other drugs
Penicillamine causes some patients, especially those with rheumatoid arthritis, to form antibodies to the acetylcholine receptor and a syndrome indistinguishable from myasthenia gravis results. Spontaneous recovery occurs in about two-thirds of cases when penicillamine is withdrawn. Phenytoin may rarely induce or aggravate myasthenia gravis, or induce a myasthenic syndrome, possibly by depressing release of acetylcholine. Lithium may impair pre-synaptic neurotransmission by substituting for sodium ions in the nerve terminal.
Drugs that oppose acetylcholine
These may be divided into:
• Antimuscarinic drugs, which act principally at postganglionic cholinergic (parasympathetic) nerve endings, i.e. atropine-related drugs (see Fig. 22.1). Muscarinic receptors can be subdivided according to their principal sites, namely in the brain (M1), heart (M2) and glandular, gastric parietal cells and smooth muscle cells (M3). As with many receptors, the molecular basis of the subtypes has been defined together with two further cloned subtypes M4 and M5, the precise functional roles of which remain to be clarified.
• Antinicotinic drugs:
ganglion-blocking drugs (see Ch. 24)
neuromuscular blocking drugs (see Fig. 22.1 and Ch. 19).
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 (above). Atropine is a simple tertiary amine; certain others (see Summary) are quaternary nitrogen compounds, a modification that increases antimuscarinic potency in the gut, imparts ganglion-blocking effects and reduces CNS penetration.
Atropine
Atropine is an alkaloid from the deadly nightshade, Atropa belladonna.10 It is a racemate (DL-hyoscyamine), and almost all of its antimuscarinic effects are attributable to the L-isomer alone. Atropine is more stable chemically as the racemate, which is the preferred formulation. In general, the effects of 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 CNS. 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 due to the dilated iris blocking drainage of the intraocular fluid from the angle of the anterior chamber. An attack of glaucoma may be induced in eyes predisposed to primary angle (also called acute closed-angle or narrow-angle) closure and is a medical emergency. 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 unequally sized and unresponsive pupils.11
Cardiovascular system
Atropine reduces vagal tone, thus increasing the heart rate and enhancing conduction in the bundle of His. As efficacy depends on the level of vagal tone, full atropinisation may increase heart rate by 30 beats/min in a young subject, but has little effect in the elderly.
Atropine has no significant effect on peripheral blood vessels in therapeutic doses but in overdose there is marked vasodilatation.
Central nervous system
Atropine is effective against both the tremor and rigidity of parkinsonism. It prevents or abates motion sickness.
Antagonism to cholinergic drugs
Atropine opposes the effects of muscarinic agonists on the CNS, at postganglionic cholinergic nerve endings and on peripheral blood vessels. It does not block 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, including intratracheal instillation in an emergency setting. The occasional cases of atropine poisoning following use of eye drops are due to the solution running down the lachrymal ducts into the nose and being swallowed. Atropine is in part destroyed in the liver and in part excreted unchanged by the kidney (t½ 2 h).
Dose
0.6–1.2 mg by mouth at night or 0.6 mg i.v., repeated as necessary to a maximum of 3 mg per day; for chronic use atropine has largely been replaced by other antimuscarinic drugs.
Poisoning
with atropine (and other antimuscarinic drugs) presents with the more obvious peripheral 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’.12 Poisoning is typically seen (especially in children) following ingestion of the rather attractive berries of solanaceous plants, e.g. deadly nightshade and henbane. Treatment involves activated charcoal to adsorb the drug, sponging to cool the patient and diazepam for the central excitement.
Other antimuscarinic drugs
In the following accounts, the peripheral atropine-like effects of the drugs may be assumed; only differences from atropine are described.
Uses of antimuscarinic drugs
• For their central actions – some (trihexyphenidyl (benzhexol) 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 h. 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 non-depolarising 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).
Hyoscine
(scopolamine) is structurally a close relative of atropine. It differs chiefly in being a CNS 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, properties 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 that of atropine, and it is therefore less likely to cause serious increases in intraocular pressure; the effect wears off in a day or two. Complete cycloplegia cannot always be obtained unless repeated instillations are made every 15 min for 1–2 h. Its effects are especially unreliable in children, in whom cyclopentolate or atropine is preferred. The pupillary dilatation may be reversed by physostigmine eye drops.
Tropicamide
(Mydriacyl) and cyclopentolate (Mydrilate) 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 thereafter. The duration of action is 4–12 h.
Ipratropium
(Atrovent) is used as an inhaled bronchodilator for both acute asthma and chronic obstructive pulmonary disease (COPD), and in chronic COPD. It has very limited efficacy in most chronic asthmatics.
Tiotropium
(Spiriva) is a long-acting (> 24 h) alternative to ipratropium, but only for patients with chronic COPD. It is not licensed for acute bronchoconstriction because of its slow onset of action.
Flavoxate
(Urispas) is used for urinary frequency, tenesmus and urgency incontinence because it increases bladder capacity and reduces unstable detrusor contractions (see p. 400).
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 intravenously it causes less tachycardia than atropine.
Propantheline
(Pro-Banthine) also has ganglion-blocking properties. It may be used as a smooth muscle relaxant, e.g. for irritable bowel syndrome and diagnostic procedures.
Dicyclomine
(Merbentyl) is an alternative.
Benzhexol
(trihexyphenidyl) and orphenadrine: see parkinsonism (p. 359).
Promethazine
See p. 342.
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.
Summary
• Acetylcholine is the most important receptor agonist neurotransmitter in both the brain and the peripheral nervous system.
• It acts on neurones 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 terminated rapidly 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, and the rest which 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.
Guide to further reading
Cohen L.H., Thale T., Tissenbaum M.J. Acetylcholine treatment of schizophrenia. Arch. Neurol. Psychiatry. 1944;51:171–175.
Costa L.G. Current issues in organophosphate toxicology. Clin. Chim. Acta. 2006;366:1–13.
Hawkins J.R., Tibbetts R.W. Intravenous acetylcholine therapy in neurosis. A controlled clinical trial. J.Ment. Sci.. 1956;102:43–51. (In the same issue see also: Carbon dioxide inhalation therapy in neurosis. A controlled clinical trial (p. 52); The placebo response (p. 60))
Medical Manual of Defence Against Chemical Agents. (no. 0117725692) (JSP 312). London:HMSO; 1987.
Meriggioli M.N., Sanders D.B. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol.. 2009;8:475–490.
Morita H., Yanigasawa T., Shimizu M., et al. Sarin poisoning in Matsumoto, Japan. Lancet. 1995;346:290–293.
Morton H.G. Atropine intoxication: its manifestation in infants and children. J. Pediatr.. 1939;14(6):755–760.
Weitz G. Love and death in Wagner's Tristan und Isolde – an epic anticholinergic crisis. Br. Med. J. 2003;327:1469–1471. (and the Commentary by Jeff Aronson, pp. 1471–1472)
1 Harris M et al 1943 Archives of Neurology and Psychiatry 50:304.
2 Cohen L H et al 1944 Archives of Neurology and Psychiatry 51:171.
3 Drug and Therapeutics Bulletin 1999; 37 (July issue).
4 Jorenby D E, Leischow S J, Nides M A et al 1999 A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. New England Journal of Medicine 340:685–692.
5 A hormone function that is restricted to the local environment.
6 To demonstrate guilt or innocence according to whether the accused died or lived after the judicial dose. The practice had the advantage that the demonstration of guilt provided simultaneous punishment.
7 In recent times, there have been major instances of use against populations by both military and terrorist bodies (in the field and in an underground transport system).
8 Walker M B 1934 Lancet i:1200.
9 Disabilities and How to Live with Them. (1952) Lancet Publications, London.
10 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 thread of life spun out by her sister Clothos, of a length determined by her other sister, 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 improving attractiveness.
11 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 angel's trumpet (sp. Brugmansia, syn. Datura, of the nightshade family), and he may have brushed against them. Angel's 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).
12 Cohen H L et al 1944 Archives of Neurology and Psychiatry 51:171.