Anticholinesterases in Pharmacology

Mechanism of Action of Anticholinesterases

• Anticholinesterases (AchE) inhibit the breakdown of acetylcholine (ACh) in the synaptic space, leading to an increase in ACh levels.
• Reversible AchE inhibitors, such as physostigmine and neostigmine, have a similar structure to ACh and bind to the enzyme, temporarily inhibiting it.
• This indirect mechanism allows ACh to accumulate in the synaptic space, leading to a cholinergic effect.

Physostigmine vs Neostigmine

• Physostigmine:
• Natural alkaloid
• Tertiary amine structure
• Highly lipid soluble, allowing it to cross the blood-brain barrier
• Can cause convulsions at high doses
• Neostigmine:
• Synthetic derivative
• Quaternary amine structure
• Not lipid soluble, unable to cross the blood-brain barrier
• Less likely to cause convulsions even at high doses

Therapeutic Uses of Reversible Anticholinesterases

• Alzheimer's disease: Galantamine, Tacrine, Donepezil, Rivastigmine
• Myasthenia gravis: Neostigmine, Pyridostigmine
• Post-operative reversal of muscle relaxation: Neostigmine
• Atropine poisoning: Physostigmine

Uses of Cholinomimetics

• Edrophonium: Short-acting, diagnosis of myasthenia gravis
• Physostigmine: Intermediate-acting, treatment of glaucoma and atropine poisoning
• Neostigmine: Intermediate-acting, treatment of paralytic ileus, urinary retention, myasthenia gravis, and reversal of non-depolarizing neuromuscular blockers
• Donepezil: Lipid soluble, treatment of Alzheimer's disease
• Organophosphates: Irreversible inhibitors, used as insecticides and nerve gas

Adverse Effects of Cholinomimetics

• SLUDGE syndrome: Salivation, lacrimation, urination, defecation, gastrointestinal upset, and emesis
• CNS stimulation
• Miosis and spasm of accommodation
• Bronchoconstriction and tracheobronchial secretions
• AV block

Organophosphate Poisoning and Management

• Muscarinic symptoms: Diarrhea, urination, miosis, bronchospasm, bradycardia, lacrimation, emesis, and sweating
• Nicotinic symptoms: Muscle fatigue and weakness, twitching, fasciculation, tremors, muscle paralysis
• CNS symptoms: Ataxia, confusion, convulsions, depressed respiration, and cardiovascular function
• Initial treatment: Rapid decontamination, maintaining respiration, suction of bronchial secretions, catheterization of the urinary bladder, and control of convulsions
• Atropine: Antimuscarinic agent, blocks all actions of ACh on muscarinic receptors
• Oximes: Cholinesterase reactivators, reactivate AchE inhibited by organophosphates

Reactivation of AchE by Oximes

• Golden period: Within 2 hours of exposure, oximes can prevent aging and reactivate AchE

Drugs Used in Glaucoma

• Parasympathetic agents: Pilocarpine, physostigmine, dipivefrin, apraclonidine, and brimonidine
• Adrenergic agonists: Timolol, levobunolol, carteolol
• Beta blockers: Timolol, levobunolol, carteolol
• Carbonic anhydrase inhibitors: Acetazolamide, dorzolamide
• Prostaglandin analogs: Latanoprost, travoprost
• Osmotic agents: Mannitol, glycerin