Cholinergic and antimuscarinic (anticholinergic) mechanisms and drugs

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Chapter 22 Cholinergic and antimuscarinic (anticholinergic) mechanisms and 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.

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).

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:

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.

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 paracrine5 role 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.