Cholinesterase Inhibitors

Cholinesterase inhibitors block acetylcholinesterase, so acetylcholine accumulates at muscarinic receptors, the neuromuscular junction and autonomic ganglia. They treat myasthenia gravis, reverse non-depolarising neuromuscular blockade, slow symptom progression in dementia and reverse anticholinergic delirium. The same pharmacology underlies organophosphate and carbamate poisoning.

Classification. Reversible carbamates: neostigmine, pyridostigmine, physostigmine, rivastigmine. Reversible non-carbamate: edrophonium (very short acting), donepezil and galantamine. Irreversible organophosphates: echothiophate (topical), plus pesticides and nerve agents.

Mechanism. The drug binds the enzyme's active site. Carbamates carbamoylate the serine residue, and the enzyme recovers over hours. Organophosphates phosphorylate it, and the complex ages within hours, after which the enzyme cannot be reactivated by oximes. Enzyme inhibition raises acetylcholine at all cholinergic synapses, producing both muscarinic and nicotinic effects.

Central versus peripheral action. Quaternary agents (neostigmine, pyridostigmine, edrophonium) do not enter the brain. Tertiary agents (physostigmine, donepezil, rivastigmine, galantamine) do, which explains their use in dementia and anticholinergic delirium.

Pharmacokinetics. Pyridostigmine has poor oral bioavailability and acts for 3 to 6 hours. Neostigmine acts within minutes intravenously for about 1 to 2 hours. Donepezil has a half-life of about 70 hours. Rivastigmine is cleared by cholinesterase hydrolysis rather than the liver. Galantamine is metabolised by CYP2D6 and CYP3A4.

Organophosphate poisoning burden. Agricultural pesticide self-poisoning causes substantial mortality in many low and middle income regions, including East Africa, so recognition of cholinergic crisis is clinically important.

• Pyridostigmine: oral long-term symptomatic therapy in myasthenia gravis. Also used for neurogenic orthostatic hypotension and constipation off label.
• Neostigmine: parenteral for reversal of non-depolarising blockade, and for myasthenic crisis support, paralytic ileus and acute colonic pseudo-obstruction.
• Physostigmine: crosses the blood-brain barrier; used for anticholinergic toxicity.
• Edrophonium: diagnostic for myasthenia gravis and for distinguishing cholinergic from myasthenic crisis; now rarely available or used because antibody testing and electrophysiology are preferred.
• Donepezil: once-daily oral; mild to severe Alzheimer disease. Longest half-life.
• Rivastigmine: oral or transdermal; Alzheimer disease and Parkinson disease dementia. Patch lowers nausea and vomiting.
• Galantamine: oral; also weakly modulates nicotinic receptors.
• Echothiophate: topical irreversible agent for glaucoma, rarely used now.

• Myasthenia gravis: pyridostigmine 30 to 60 mg orally 3 to 4 times daily, titrated to benefit and cholinergic effects, usually given 30 to 60 minutes before meals. Total daily doses over 960 mg seldom add benefit. It is a symptomatic first step, usually combined with immunosuppression when disease is more than mild.
• Reversal of non-depolarising blockade: neostigmine 0.05 mg/kg intravenously to a maximum of 5 mg, with glycopyrronium 0.2 mg for each 1 mg of neostigmine (or atropine) to prevent bradycardia and secretions. Give only when some spontaneous recovery has occurred (at least 2 twitches on train-of-four). Sugammadex 2 mg/kg is an alternative for rocuronium or vecuronium block at moderate depth.
• Anticholinergic delirium: physostigmine 0.5 to 2 mg intravenously, given slowly over at least 5 minutes with atropine ready. Avoid with tricyclic antidepressant co-ingestion, QRS prolongation, or seizures.
• Alzheimer disease: donepezil 5 mg at night, raised to 10 mg after 4 to 6 weeks. Rivastigmine 1.5 mg twice daily with food, increased by 1.5 mg twice daily every 2 weeks to a maximum of 6 mg twice daily, or patch 4.6 mg/24 hours increased to 9.5 mg/24 hours. Galantamine 4 mg twice daily increased to 8 then 12 mg twice daily at 4-week intervals.
• Organophosphate poisoning: atropine 1 to 2 mg intravenously, doubled every 5 minutes until the chest is clear, heart rate over 80 beats/minute and systolic pressure over 80 mmHg. Pralidoxime 30 mg/kg intravenously over 30 minutes, then 8 mg/kg/hour. Benefit of oximes is contested. Benzodiazepines for seizures and early airway protection.

Contraindications and cautions. Bradycardia, atrioventricular block, sick sinus syndrome, mechanical gastrointestinal or urinary obstruction, active peptic ulcer, asthma or COPD, seizure disorder, and QT prolongation (donepezil carries a torsades risk). Neostigmine is contraindicated if peritonitis or obstruction is present.

Adverse effects. Nausea, vomiting, diarrhoea, abdominal cramps, anorexia and weight loss, sweating, salivation, bronchial secretions, bradycardia, syncope, muscle cramps and fasciculations, vivid dreams and insomnia (donepezil), and weakness at high doses.

Cholinergic crisis versus myasthenic crisis. Cholinergic crisis follows excess drug and combines weakness with muscarinic signs (salivation, sweating, miosis, diarrhoea, bradycardia). Myasthenic crisis follows disease worsening and lacks these signs. Treatment of either is airway support in critical care, with temporary withdrawal of the inhibitor in suspected cholinergic crisis.

Interactions. Prolong succinylcholine block. Antimuscarinics oppose their effect. Additive bradycardia with beta blockers, digoxin, verapamil, diltiazem and amiodarone. CYP2D6 and CYP3A4 inhibitors raise donepezil and galantamine levels. Aminoglycosides, magnesium and some other drugs worsen myasthenia.

Monitoring. Heart rate and rhythm, weight and gastrointestinal tolerance in dementia therapy. In myasthenia, strength and bulbar function. Neuromuscular monitoring during reversal.

Referral and escalation. Suspected crisis, respiratory compromise, or poisoning needs urgent critical care and toxicology input.

Special groups. Pregnancy: neostigmine and pyridostigmine are used when needed; neonatal myasthenia needs paediatric review. Renal impairment: reduce pyridostigmine and neostigmine doses because of renal elimination. Older adults: higher bradycardia, syncope and fall risk.