Cholinesterase inhibitors

Overview
Cholinesterase inhibitors are drugs that block the activity of cholinesterase enzymes, thereby increasing the concentration and duration of action of acetylcholine (ACh) at synaptic junctions. They enhance cholinergic neurotransmission in both the peripheral and central nervous systems. Clinically, they are used in the management of neurodegenerative disorders such as Alzheimer’s disease, in the treatment of myasthenia gravis, in reversing non-depolarizing neuromuscular blockade after surgery, and as part of the treatment for certain types of glaucoma. Some cholinesterase inhibitors are also toxic (e.g., organophosphates used as pesticides and nerve agents).

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Mechanism of Action

• Acetylcholine is broken down in the synaptic cleft by acetylcholinesterase (AChE) and butyrylcholinesterase (BChE).

• Cholinesterase inhibitors bind to these enzymes, preventing ACh hydrolysis.

• Increased ACh levels enhance stimulation of muscarinic and nicotinic receptors, affecting both autonomic and somatic nervous systems, and in some cases the CNS.

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Classification

1. Reversible inhibitors – Bind non-covalently or form a reversible covalent bond; effects last hours

   • Examples: Donepezil, Rivastigmine, Galantamine (Alzheimer’s disease); Neostigmine, Pyridostigmine (myasthenia gravis, reversal of non-depolarizing neuromuscular block); Physostigmine (anticholinergic toxicity)

2. Pseudo-irreversible inhibitors – Carbamates that bind covalently but hydrolyze slowly (hours to days)

   • Examples: Rivastigmine (also listed above), Echothiophate (ophthalmic use for glaucoma)

3. Irreversible inhibitors – Organophosphates that phosphorylate the enzyme, leading to long-lasting inactivation unless treated quickly; effects last days to weeks

   • Examples: Isoflurophate (ophthalmic), insecticides (parathion, malathion), nerve agents (sarin, VX)

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Therapeutic Uses

• Neurodegenerative diseases:

  • Alzheimer’s disease – Donepezil, Rivastigmine, Galantamine improve cognitive symptoms modestly by increasing central cholinergic activity

• Neuromuscular disorders:

  • Myasthenia gravis – Neostigmine, Pyridostigmine improve neuromuscular transmission

• Postoperative care:

  • Reversal of non-depolarizing neuromuscular blockade – Neostigmine, Edrophonium (diagnostic use)

• Ophthalmic:

  • Echothiophate – Chronic glaucoma treatment (rarely used now due to systemic effects)

• Anticholinergic toxicity:

  • Physostigmine – Antidote for atropine or other antimuscarinic poisoning

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Contraindications (general)

• Mechanical obstruction of the GI or urinary tract

• Asthma or COPD exacerbations (risk of bronchoconstriction)

• Bradycardia or significant AV conduction block

• Known hypersensitivity to the drug

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Precautions

• Monitor for signs of cholinergic excess (“SLUDGE” – salivation, lacrimation, urination, diarrhea, GI cramping, emesis)

• Dose adjustments in renal or hepatic impairment for certain agents

• Use with caution in seizure disorders (can lower seizure threshold)

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Adverse Effects

• Muscarinic: Nausea, vomiting, diarrhea, abdominal cramps, increased salivation, sweating, bradycardia, hypotension, miosis, bronchoconstriction

• Nicotinic: Muscle cramps, fasciculations, weakness (with excessive dosing)

• CNS: Dizziness, headache, insomnia, vivid dreams (donepezil)

• Serious: Bradyarrhythmias, syncope, seizures (rare), cholinergic crisis (with overdosage in myasthenia gravis)

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Drug Interactions

• Additive cholinergic effects with other cholinergic agents (e.g., bethanechol)

• Antagonism by anticholinergics (e.g., atropine, tricyclic antidepressants)

• Increased bradycardia risk with beta-blockers or digoxin

• Neuromuscular blockade prolongation or antagonism with concurrent use of certain muscle relaxants (depends on type)