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.

Classification

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

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).³ Treatment is much more likely to be successful if it is used as an aid to, not a substitute for, continued counselling. Bupropion is 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 Inocybe contain 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.