Cholinergic drugs

Cholinergic receptors and where they sit

Acetylcholine (ACh) is the transmitter at every autonomic ganglion, at all parasympathetic postganglionic endings, at the neuromuscular junction and at a few sympathetic cholinergic endings: eccrine sweat glands (muscarinic) and, in some species, skeletal muscle vasodilator fibres. That is why antimuscarinics stop sweating and cause hyperthermia even though sweating is a "sympathetic" function.

• ACh has a negative inotropic effect on the atria (M2 shortens the action potential) and a negative chronotropic and dromotropic effect on the nodes. Ventricular force is affected little.
• In the eye, M3 contracts the sphincter pupillae (miosis) and the ciliary muscle (accommodation for near, and opening of the trabecular meshwork). Pilocarpine on the sphincter is the mirror image of adrenaline (α1) on the dilator pupillae: both produce their pupil change by contracting a muscle.

Quaternary versus tertiary: the key to CNS and systemic effects

A quaternary ammonium compound carries a permanent positive charge. It is poorly absorbed from the gut or the airway mucosa and does not cross the blood–brain barrier. A tertiary amine is lipid-soluble, is well absorbed and enters the CNS.

• Ipratropium is inhaled and quaternary, so very little is absorbed from the bronchi: it blocks airway M3 receptors locally with few systemic anticholinergic effects (some dry mouth, rarely urinary retention or angle closure if sprayed into the eye).
• Physostigmine treats central anticholinergic poisoning because it crosses the BBB; neostigmine cannot.

Direct-acting muscarinic agonists

• Pilocarpine: glaucoma (contracts the ciliary muscle and pulls open the trabecular meshwork, increasing outflow through the canal of Schlemm); dry mouth in Sjögren syndrome.
• Bethanechol: postoperative non-obstructive urinary retention and atonic bowel; resistant to cholinesterase. Never use it when the outlet is mechanically obstructed.
• Oral pilocarpine stimulates residual salivary gland function in Sjögren syndrome.
• Carbachol: intraocular use; methacholine: bronchial provocation test for asthma.
• Effects of any muscarinic agonist: bradycardia, vasodilatation with fall in blood pressure, bronchoconstriction, salivation, sweating, miosis, increased gut motility and voiding.

Anticholinesterases

• Pyridostigmine side effects are muscarinic: abdominal cramps, diarrhoea, salivation, sweating, bradycardia. Aminoglycosides, magnesium, β-blockers and quinine can worsen myasthenia.
• Neostigmine improves weakness in myasthenia (postsynaptic receptor loss) but not in Lambert–Eaton syndrome, where antibodies against presynaptic voltage-gated calcium channels reduce ACh release; strength there improves with repeated effort.

Cholinergic crisis versus myasthenic crisis

A myasthenic patient whose dose of pyridostigmine keeps rising can reach a point where excess ACh causes a depolarising block at the endplate. Weakness then worsens because of overtreatment, not undertreatment.

Remember Weak plus wet, small pupils and twitching means cholinergic crisis: stop the pyridostigmine.

Organophosphate poisoning

Organophosphates phosphorylate the serine site of acetylcholinesterase, so ACh accumulates at every cholinergic synapse. Common in Pakistan from farm insecticide spraying and ingestion.

• Muscarinic: diarrhoea, urination, miosis, bronchorrhoea and bronchospasm, bradycardia, emesis, lacrimation, salivation, sweating (DUMBELS).
• Nicotinic: fasciculations, weakness, paralysis; tachycardia and hypertension from ganglionic stimulation (so heart rate can go either way).
• CNS: confusion, seizures, coma, central respiratory depression.
• Cause of death: respiratory failure, from bronchorrhoea and bronchospasm, respiratory muscle paralysis and central depression together.
• Diagnosis is clinical; a low red cell (true) acetylcholinesterase confirms; plasma (pseudo)cholinesterase also falls.

Treatment

• Decontaminate (remove clothing, wash skin; staff wear gloves), airway, oxygen.
• Atropine in doubling doses until atropinised: clear chest on auscultation, heart rate above 80, systolic pressure above 80 mmHg, dry axillae. Pupil size is not an endpoint. Atropine blocks only muscarinic effects; it does nothing for muscle weakness.
• Pralidoxime (an oxime) pulls the phosphate group off the enzyme and reactivates acetylcholinesterase, so it helps the nicotinic weakness. It must be given early, because the phosphorylated enzyme undergoes ageing (loss of an alkyl group), after which the bond is permanent and no oxime can reverse it. Recovery then needs new enzyme synthesis.
• Benzodiazepines for seizures.
• Intermediate syndrome (24–96 hours): proximal limb, neck flexor, cranial nerve and respiratory muscle weakness. Organophosphate-induced delayed polyneuropathy (2–3 weeks): distal sensorimotor neuropathy.

Exam trap Pralidoxime does not replace atropine. Atropine treats the muscarinic features; pralidoxime treats the enzyme and the nicotinic features; both are used.

Muscarinic antagonists

• Atropine relaxes gut and bronchial smooth muscle but tends to contract GI sphincters; it causes bronchodilation and reduces secretions.
• Phenylephrine (α1 agonist) dilates the pupil without cycloplegia, because accommodation is purely parasympathetic.
• Scopolamine (hyoscine) is the drug whose actions most resemble atropine. The hydrobromide patch behind the ear, applied hours before travel, prevents motion sickness by blocking vestibular–vomiting centre muscarinic pathways; the butylbromide barely enters the brain and is useless for this.
• Low-dose atropine (below 0.5 mg in an adult) can cause paradoxical bradycardia, by blocking presynaptic M1 autoreceptors or by a central vagal effect, before the peripheral M2 block takes over. Atropine has no effect on a denervated transplanted heart.
• Antimuscarinics prevent new secretions but do not clear secretions already present, so start them early for a death rattle.
• Nebulised ipratropium leaking from a loose mask can reach the eye and precipitate acute angle-closure glaucoma in an older patient.

Anticholinergic toxidrome

Caused by atropine, Datura (dhatura) seeds, antihistamines, tricyclics and antipsychotics.

• The fever comes from blocked muscarinic receptors on sweat glands: the body cannot lose heat. Children are especially prone.
• Treat supportively (cooling, benzodiazepines); physostigmine is the specific antidote when central features are severe (for example a child who ate Datura or belladonna berries).

Contraindications to antimuscarinics

• Angle-closure glaucoma (mydriasis crowds the angle), prostatic enlargement and urinary retention, paralytic ileus, tachyarrhythmias, myasthenia (relative).
• Elderly patients are prone to confusion from cumulative anticholinergic burden.

Exam trap Antimuscarinic eye drops can precipitate acute angle-closure glaucoma in a patient with a shallow anterior chamber.

Nicotinic drugs

• Ganglion blockers (hexamethonium, trimetaphan) are historical.
• Varenicline: partial agonist at α4β2 nicotinic receptors, for smoking cessation.
• Neuromuscular blockers are covered with anaesthetic drugs.

How FCPS asks about this

• Antidote for a farmer poisoned while spraying insecticide: atropine until the chest is dry, plus early pralidoxime.
• Why pralidoxime must be given early: the phosphorylated enzyme ages and becomes permanently inactive.
• Cause of death in organophosphate poisoning: respiratory failure.
• Myasthenic on rising pyridostigmine with sweating, miosis and fasciculations: cholinergic crisis.
• Why ipratropium has few systemic effects: quaternary, poorly absorbed from the airway.
• Neostigmine versus physostigmine: only physostigmine (tertiary) crosses the BBB.
• Mydriasis without cycloplegia: phenylephrine; shortest-acting antimuscarinic mydriatic is tropicamide.