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8 Autonomic drugs acting at cholinergic synapses

Acetylcholine released from the terminals of postganglionic parasympathetic nerves (left, ) produces its actions on various effector organs by activating muscarinic receptors (). The effects of acetylcholine are usually excitatory, but an important exception is the heart, which receives inhibitory cholinergic fibres from the vagus (Chapter 17). Drugs that mimic the effects of acetylcholine are called cholinomimetics and can be divided into two groups:

 drugs that act directly on receptors (nicotinic and muscarinic agonists); and

 anticholinesterases, which inhibit acetylcholinesterase and so act indirectly by allowing acetylcholine to accumulate in the synapse and produce its effects.

Muscarinic agonists (top left) have few uses, but pilocarpine (as eyedrops) is sometimes used to reduce intraocular pressure in patients with glaucoma (Chapter 10). Bethanechol was used to stimulate the bladder in urinary retention, but it has been superseded by catheterization.

Anticholinesterases (bottom left) have relatively little effect at ganglia and are used mainly for their nicotinic effects on the neuromuscular junction. They are used in the treatment of myasthenia gravis and to reverse the effects of competitive muscle relaxants used during surgery (Chapter 6).

Muscarinic antagonists (bottom middle) block the effects of acetylcholine released from postganglionic parasympathetic nerve terminals. Their effects can, in general, be worked out by examination of the figure in Chapter 7. However, parasympathetic effector organs vary in their sensitivity to the blocking effect of antagonists. Secretions of the salivary, bronchial and sweat glands are most sensitive to blockade. Higher doses of antagonist dilate the pupils, paralyze accommodation and produce tachycardia by blocking vagal tone in the heart. Still higher doses inhibit parasympathetic control of the gastrointestinal tract and bladder. Gastric acid secretion is most resistant to blockade (Chapter 12).

Atropine, hyoscine (scopolamine) or other antagonists are used:

1 in anaesthesia to block vagal slowing of the heart and to inhibit bronchial secretion;

2 to reduce intestinal spasm in, for example, irritable bowel syndrome (Chapter 13);

3 in Parkinson’s disease (e.g. benzatropine, Chapter 26);

4 to prevent motion sickness (hyoscine, Chapter 30);

5 to dilate the pupil for ophthalmological examination (e.g. tropicamide) or to paralyse the ciliary muscle (Chapter 10);

6 as a bronchodilator in asthma (ipratropium, Chapter 11) and

7 in urinary incontinence antimuscarinic drugs e.g. solfenacin, darifenacin reduce detrusor muscle overactivity.

Transmission at autonomic ganglia () can be stimulated by nicotinic agonists (top middle) or blocked by drugs that act specifically on the ganglionic neurone nicotinic receptor/ionophore (middle). Nicotinic agonists are of no clinical use and ganglion blocking drugs, e.g. hexamethonium, are only of historical interest.

Cholinergic nerve terminals in the autonomic nervous system synthesize, store and release acetylcholine in essentially the same way as at the neuromuscular junction (Chapter 6). Acetylcholinesterase is bound to both the pre‐ and postsynaptic membranes.

Cholinomimetics

Muscarinic agonists

These directly activate muscarinic receptors, usually producing excitatory effects. An important exception is the heart, where activation of the predominantly M₂‐receptors has inhibitory effects on the rate and force of (atrial) contraction. The M₂‐receptors are negatively coupled by a G‐protein (G₁) to adenylyl cyclase, which explains the negative inotropic effect of acetylcholine. Subunits (βγ)) of G₁ directly increase K⁺ conductances in the heart causing hyperpolarization and bradycardia (Chapter 17). Acetylcholine stimulates glandular secretion and causes contraction of smooth muscle by activating M₃‐receptors, which are coupled to the formation of inositol‐1,4,5‐trisphosphate (InsP₃) and diacylglycerol (Chapter 1). InsP₃ increases cytosolic Ca²⁺, thus triggering muscle contraction or glandular secretion. An intravenous injection of acetylcholine causes vasodilatation indirectly by releasing nitric oxide (NO) from vascular endothelial cells (Chapter 16). However, most blood vessels have no parasympathetic innervation and so the physiological function of vascular muscarinic receptors is uncertain.

Choline esters

Bethanechol is a quaternary compound that does not penetrate the blood–brain barrier. Its actions are much more prolonged than those of acetylcholine, because it is not hydrolyzed by cholinesterase.

Pilocarpine possesses a tertiary N atom, which confers increased lipid solubility. This enables the drug to penetrate the cornea readily when applied locally, and enter the brain when given systemically.

Anticholinesterases

These are indirectly acting cholinomimetics. The commonly used anticholinesterase drugs are quaternary compounds that do not pass the blood–brain barrier and have negligible central effects. They are poorly absorbed orally. Physostigmine (eserine) is much more lipid soluble. It is well absorbed after oral or local administration (e.g. as eyedrops) and passes into the brain.

Mechanism of action

Initially, acetylcholine binds to the active site of the esterase and is hydrolyzed, producing free choline and acetylated enzyme. In a second step, the covalent acetyl–enzyme bond is split with the addition of water. Edrophonium is the main example of a reversible anticholinesterase. It binds by electrostatic forces to the active site of the enzyme. It does not form covalent bonds with the enzyme and so is very short acting (2–10 min). The carbamate esters (e.g. neostigmine, pyridostigmine) undergo the same two‐step process as acetylcholine, except that the breakdown of the carbamylated enzyme is much slower (30 min to 6 h). Organophosphorus agents result in a phosphorylated enzyme active site. The covalent phosphorus–enzyme bond is very stable and the enzyme is inactivated for hundreds of hours. For this reason, the organophosphorus compounds are referred to as irreversible anticholinesterases. They are extremely toxic and are used as insecticides (parathion, malathion) and chemical warfare agents (e.g. sarin). Malathion is used topically in the treatment of scabies and head lice.

The effects of anticholinesterases are generally similar to those produced by the directly acting muscarinic agonists, but, in addition, transmission at the neuromuscular junction is potentiated. The cholinesterase inhibitors produce less vasodilatation than the directly acting agonists because they can only act on the (few) vessels possessing cholinergic innervation. Also, stimulation of sympathetic ganglia may oppose the vasodilator effects of the drug. Only large toxic doses of anticholinesterase produce marked bradycardia and hypotension.

Toxic doses initially cause signs of extreme muscarinic stimulation: miosis, salivation, sweating, bronchial constriction, bronchosecretion, vomiting and diarrhoea. Excessive stimulation of nicotinic receptors may cause depolarizing neuromuscular blockade. If the drug is lipid soluble (e.g. organophosphorus compounds, except ecothiopate), convulsions, coma and respiratory arrest may occur. Strong nucleophiles (e.g. pralidoxime) can split the phosphorus–enzyme bond initially formed by organophosphorus compounds and ‘regenerate’ the enzyme. Later, this becomes impossible because a process of ‘ageing’ strengthens the phosphorus–enzyme bond.

Muscarinic antagonists (antimuscarinics)

Atropine occurs in deadly nightshade (Atropa belladonna). It is a weak central stimulant, especially on the vagal nucleus, and low doses often cause bradycardia. Higher doses cause tachycardia. Hyoscine (scopolamine) is more sedative than atropine and often produces drowsiness and amnesia. Toxic doses of both drugs cause excitement, agitation, hallucination and coma. The effects of muscarinic antagonists can be worked out by studying the figure in Chapter 7. The student should understand why these drugs produce dilated pupils, blurred vision, dry mouth, constipation and difficulty with micturition. The latter effect, although usually unwanted, is useful in patients with overactive bladder associated with urinary incontinence. Antimuscarinic drugs (e.g. solfenacin, darifenacin) reduce detrusor muscle overactivity probably by an action on M3‐receptors.