Cholinesterase Inhibitors

Mechanism of Action

• Edrophonium - electrostatic attraction and hydrogen bonding; short-lived interaction
• Neostigmine, pyridostigmine - covalent (carbamate) bonds; longer lasting but reversible
• Organophosphates - form stable, irreversible covalent bonds; effect persists long after the drug is cleared from circulation

Morgan and Mikhail's Clinical Anesthesiology, 7e - Fig. 12-4

Classification

1. Reversible ChEIs (Short-acting)

2. Reversible ChEIs (for Dementia)

3. Irreversible ChEIs (Organophosphates & Carbamates)

• Echothiophate - used in glaucoma (ophthalmic)
• Organophosphate pesticides (parathion, malathion) - agricultural; poisoning risk
• Nerve agents (sarin, VX, tabun) - chemical warfare; extremely toxic

Pharmacology of Individual Agents

Neostigmine

• Carbamate moiety + quaternary ammonium group - lipid insoluble, cannot cross BBB
• Dose for reversal: 0.04-0.08 mg/kg (max 5 mg adults)
• Effects apparent in 5 min, peak at 10 min, last >1 hour
• Also inhibits pseudocholinesterase (prolongs succinylcholine)
• Paired with glycopyrrolate (0.2 mg per 1 mg neostigmine) to block muscarinic side effects

Pyridostigmine

• Similar structure and mechanism to neostigmine
• Dose for reversal: 0.1-0.25 mg/kg
• Paired with glycopyrrolate (0.05 mg per mg)
• Used in myasthenia gravis (longer duration than neostigmine)

Edrophonium

• Quaternary ammonium compound; no carbamate - acts by electrostatic interaction only
• Fast onset but shorter duration than neostigmine
• Dose: 0.5-1 mg/kg
• Paired with atropine (0.014 mg per mg)
• Classic use: Tensilon test for myasthenia gravis diagnosis

Physostigmine

• Tertiary amine - crosses the blood-brain barrier (the only reversal-class ChEI that does)
• Used to reverse central anticholinergic syndrome (from atropine, scopolamine overdose)
• Dose: 0.01-0.03 mg/kg
• Not used to reverse neuromuscular blockers
• Unique: causes CNS diffuse excitation (muscarinic + nicotinic CNS stimulation)

Donepezil

• Selectively active within the CNS; minimal peripheral AChE inhibition - favorable GI side-effect profile
• Peak plasma in 3-4 hours; t½ ~70 hours in elderly
• Steady state in ~2 weeks; once-daily dosing
• Metabolized by CYP2D6 and CYP3A4
• Cirrhosis reduces clearance by ~20%

Rivastigmine

• Inhibits both AChE and butyrylcholinesterase (BuChE); BuChE is upregulated in Alzheimer disease brain
• t½ 1 hour but enzyme-bound activity lasts ~10 hours; twice-daily oral or once-daily transdermal patch
• More peripheral activity than donepezil - more GI side effects
• Metabolized by tissue esterases (not CYP - fewer drug-drug interactions)
• FDA-approved for Parkinson's disease dementia (PDD) as well

Galantamine

• AChE inhibition + allosteric modulation of nicotinic receptors (unique dual action)
• Maximum concentrations at 30 min - 2 hours; t½ ~6 hours
• Metabolized by CYP2D6 and CYP3A4
• Extracted from the daffodil Galanthus nivalis

Systemic (Muscarinic) Effects of ChEIs

Clinical Uses

1. Reversal of Neuromuscular Blockade (Anesthesia)

• Neostigmine, pyridostigmine, edrophonium reverse nondepolarizing NMBAs (e.g., rocuronium, vecuronium)
• They prolong depolarizing blockade (succinylcholine) - never use together
• Must co-administer an anticholinergic (glycopyrrolate or atropine) to block muscarinic side effects
• Contraindicated if no twitches are present after 50 Hz tetany for 5 seconds (blockade too deep)
• Note: sugammadex has now replaced ChEIs for reversal of rocuronium/vecuronium in many centers

2. Alzheimer's Disease and Dementia

• First-line symptomatic treatment for mild-to-moderate AD: donepezil, rivastigmine, galantamine
• Donepezil approved for all stages (mild through severe); others mild-moderate only
• Effect: modest ~6-12 month delay in progression; improvement in memory, apathy, behavioral symptoms
• Often combined with memantine (NMDA antagonist) for moderate-severe disease
• Also used in Lewy body dementia, Parkinson's disease dementia, vascular dementia, TBI

3. Myasthenia Gravis

• Pyridostigmine is the drug of choice for symptomatic management
• Increases ACh at the NMJ to compensate for reduced/blocked nicotinic receptors
• Edrophonium (Tensilon test) used diagnostically - brief reversal of weakness confirms MG

4. Glaucoma

• Echothiophate (irreversible) - reduces IOP via pupillary constriction and increased aqueous outflow
• Pilocarpine is the cholinergic agonist typically preferred now

5. Anticholinergic Overdose / Postoperative Cognitive Dysfunction

• Physostigmine reverses central anticholinergic syndrome (confusion, delirium, hyperthermia from atropine/scopolamine)
• Only ChEI that crosses the BBB

Organophosphate Toxicology

• Muscle fasciculations → weakness → respiratory paralysis
• CNS: agitation, confusion, seizures, coma
• Lab: depressed RBC acetylcholinesterase and plasma butyrylcholinesterase

1. Decontaminate (remove clothing, wash skin); protect rescue personnel
2. Atropine IV (0.5-5 mg; repeated until muscarinic signs resolve) - blocks muscarinic effects only; no effect on nicotinic
3. Pralidoxime (2-PAM) - reactivates AChE if given before "aging" occurs; active at both muscarinic and nicotinic sites. Dose: 1-2% solution IV over 15-30 min, then 1% infusion (200-500 mg/h)
4. Respiratory support (2-PAM does not enter CNS; ventilation is often required)
5. Benzodiazepines for seizures

Aging: the organophosphate-AChE complex undergoes a time-dependent stabilization that makes it resistant to 2-PAM reactivation. This is why pralidoxime must be given early.

Adverse Effects Summary

Drug Interactions

• All ChEIs should be used cautiously with anticholinergic drugs (antagonistic) and with drugs that slow the heart (additive bradycardia risk - e.g., beta-blockers, digoxin)
• Donepezil and galantamine: CYP2D6/3A4 inhibitors (ketoconazole, paroxetine) increase plasma levels
• Rivastigmine: metabolized by esterases - fewer CYP-based interactions
• Succinylcholine: markedly prolonged by ChEIs (via both AChE and pseudocholinesterase inhibition)

Recent Evidence

• A 2024 meta-analysis (PMID 38439609) confirmed the safety and efficacy of AChEIs in Alzheimer's disease
• A 2024 Cochrane review of galantamine (PMID 39498781) confirmed modest but consistent cognitive benefits
• A 2024 comparative meta-analysis (PMID 38640313) evaluated the comparative efficacy and safety of AD drugs including ChEIs combined with memantine