Overview
Acetylcholinesterase (AChE) is an enzyme responsible for breaking down acetylcholine (Ach) into acetate and choline, terminating its action. Located both pre- and postsynaptically in the nerve terminal, AChE is membrane-bound. Inhibiting AChE (using anticholinesterase agents or cholinesterase inhibitors) indirectly enhances cholinergic action by preventing Ach degradation, leading to its accumulation in the synaptic space. Consequently, these drugs can activate all cholinoceptors, including muscarinic and nicotinic receptors in the autonomic nervous system (ANS), neuromuscular junction (NMJ), and brain. Reversible AChE inhibitors are classified as either short-acting or intermediate-acting.
A. Edrophonium
Edrophonium, a short-acting AChE inhibitor, reversibly binds to the active center of AChE, blocking Ach hydrolysis. It has a brief duration of action (10-20 minutes) due to rapid renal elimination. Being a quaternary amine, its effects are peripheral. Edrophonium is primarily used to diagnose myasthenia gravis, an autoimmune disease characterized by antibodies against NMJ nicotinic receptors, reducing receptor availability for Ach. Intravenous edrophonium rapidly boosts muscle strength in these patients. Overdosage may cause a cholinergic crisis, treatable with atropine. Edrophonium is also used to evaluate cholinesterase inhibitor therapy, differentiate between cholinergic and myasthenic crises, and reverse nondepolarizing neuromuscular blocker effects post-surgery. Its use has decreased due to alternative agents.
B. Physostigmine
Physostigmine, a naturally occurring nitrogenous carbamic acid ester and tertiary amine, acts as a substrate for AChE, forming a stable carbamoylated intermediate that inactivates the enzyme reversibly, enhancing cholinergic activity throughout the body.
- Actions: Physostigmine affects both muscarinic and nicotinic receptors of the ANS, as well as NMJ nicotinic receptors. It can induce GI smooth muscle contraction, miosis, bradycardia, and hypotension, as well as skeletal muscle twitches and paralysis at high doses. It acts for about 30 minutes to 2 hours and can cross into the CNS, stimulating cholinergic sites.
- Therapeutic uses: Physostigmine treats overdoses of anticholinergic drugs (e.g., atropine) and reverses the effects of neuromuscular blockers.
- Adverse effects: High doses may cause convulsions, bradycardia, and decreased cardiac output. Prolonged AChE inhibition at the NMJ can lead to skeletal muscle paralysis due to continuous depolarization, though therapeutic doses rarely produce these effects.
C. Neostigmine
Neostigmine, a synthetic carbamic acid ester, reversibly inhibits AChE similarly to physostigmine but with a quaternary nitrogen, making it more polar and poorly absorbed from the GI tract. It does not cross into the CNS but has a more substantial effect on skeletal muscle, stimulating contractility before inducing paralysis. Its duration of action is 30 minutes to 2 hours.
- Actions: Neostigmine does not cross the blood-brain barrier and strongly affects skeletal muscles.
- Therapeutic uses: It is used to stimulate the bladder and GI tract and as an antidote for competitive neuromuscular-blocking agents. It also manages myasthenia gravis symptoms.
- Adverse effects: These include generalized cholinergic stimulation such as salivation, flushing, low blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm. It is contraindicated in cases of intestinal or urinary obstruction and does not treat antimuscarinic agent toxicity.
D. Pyridostigmine
Pyridostigmine, another cholinesterase inhibitor, is used for chronic management of myasthenia gravis. It has an intermediate duration of action (3 to 6 hours), longer than neostigmine. Its adverse effects are similar to those of neostigmine.
Indirect-Acting Cholinergic Agonists: Anticholinesterase Agents (Irreversible)
Overview
Certain synthetic organophosphate compounds can irreversibly bind to AChE, leading to prolonged increases in Ach levels. Many of these substances are highly toxic and have been developed as nerve agents, with related compounds used as insecticides.
A. Echothiophate
- Mechanism of action: Echothiophate is an organophosphate that covalently binds to AChE’s active site, permanently inactivating the enzyme. Restoring AChE activity requires new enzyme synthesis. Following covalent modification, the phosphorylated enzyme slowly loses an ethyl group, a process called aging, which prevents chemical reactivators like pralidoxime from detaching the drug from the enzyme.
- Actions: Echothiophate causes generalized cholinergic stimulation, motor function paralysis (affecting breathing), and convulsions. It induces intense miosis and reduces intraocular pressure by facilitating aqueous humor outflow. High-dose atropine can reverse many peripheral and some central muscarinic effects.
- Therapeutic uses: It is available as a topical ophthalmic solution for treating open-angle glaucoma but is rarely used due to the risk of cataracts and other side effects.
This summary outlines the functions, therapeutic uses, and adverse effects of several reversible and irreversible anticholinesterase agents, highlighting their applications in various medical conditions and treatments.
