Lecture #20: Pharmacology: Cholinesterase Inhibitors

What are indirect-acting cholinomimetics?

Indirect-acting cholinomimetics are drugs that increase acetylcholine levels by inhibiting acetylcholinesterase, thereby amplifying endogenous acetylcholine effects at muscarinic and nicotinic receptors.

Why are cholinesterase inhibitors called indirect-acting cholinomimetics?

They do not activate receptors directly; instead, they inhibit acetylcholine breakdown, increasing acetylcholine concentration and duration of action at synapses.

What enzyme do cholinesterase inhibitors block?

They block acetylcholinesterase, the enzyme responsible for rapid hydrolysis and termination of acetylcholine signaling.

What is the physiologic role of acetylcholinesterase?

Acetylcholinesterase rapidly hydrolyzes acetylcholine into choline and acetate, terminating neurotransmission within microseconds.

What is butyrylcholinesterase and why is it inhibited?

Butyrylcholinesterase is a nonspecific plasma enzyme that hydrolyzes choline esters; inhibition contributes to drug effects and toxicity but is not essential for normal synaptic termination.

How does acetylcholinesterase normally hydrolyze acetylcholine?

Acetylcholine binds the anionic site and esteratic site of acetylcholinesterase, allowing enzymatic cleavage into choline and acetate.

How does edrophonium inhibit acetylcholinesterase?

Edrophonium reversibly binds the anionic site of acetylcholinesterase via electrostatic interactions, preventing acetylcholine access for minutes.

What is the duration of action of edrophonium?

Edrophonium has a very short duration of action lasting only minutes.

How do carbamate cholinesterase inhibitors work?

They carbamoylate the esteratic site of acetylcholinesterase, forming a reversible but more stable enzyme–inhibitor complex.

Why do carbamate inhibitors have longer duration than edrophonium?

The carbamoylated enzyme is resistant to hydrolysis, prolonging inhibition for several hours.

Which carbamate cholinesterase inhibitors do not cross the blood–brain barrier?

Neostigmine and pyridostigmine are quaternary ammonium compounds that poorly cross the blood–brain barrier.

Which carbamate inhibitor crosses the blood–brain barrier?

Physostigmine is a tertiary amine with sufficient lipid solubility to enter the CNS.

How do organophosphate cholinesterase inhibitors differ mechanistically?

They irreversibly phosphorylate acetylcholinesterase, forming an extremely stable enzyme–inhibitor complex.

What is enzyme aging in organophosphate toxicity?

Aging is the chemical strengthening of the phosphate–enzyme bond, making inhibition irreversible and resistant to reactivation.

Why are organophosphates particularly dangerous?

They cause prolonged acetylcholine accumulation at synapses, leading to severe muscarinic, nicotinic, and CNS toxicity.

What are the primary therapeutic uses of carbamate cholinesterase inhibitors?

They are used to treat myasthenia gravis and to reverse nondepolarizing neuromuscular blockade after surgery.

How do cholinesterase inhibitors improve myasthenia gravis symptoms?

By increasing acetylcholine concentration at the neuromuscular junction, they improve activation of the reduced number of nicotinic receptors.

Which drug is commonly used for chronic management of myasthenia gravis?

Pyridostigmine is the drug of choice due to oral availability and longer duration.

How do cholinesterase inhibitors reverse nondepolarizing neuromuscular blockade?

Increased acetylcholine outcompetes the neuromuscular blocker at nicotinic receptors, restoring muscle contraction.

Why is edrophonium no longer used diagnostically?

Safer diagnostic methods exist, and the risk of adverse effects outweighs its brief benefit.

What is a cholinergic crisis?

A life-threatening condition caused by excessive cholinesterase inhibition leading to depolarizing neuromuscular blockade and respiratory failure.

How does a cholinergic crisis differ from a myasthenic crisis?

Cholinergic crisis results from excess acetylcholine, while myasthenic crisis results from insufficient neuromuscular transmission.

What are the classic muscarinic signs of cholinergic toxicity?

Diarrhea, urination, miosis, bronchoconstriction, bronchorrhea, bradycardia, emesis, lacrimation, salivation, and sweating.

What nicotinic effects occur in cholinergic toxicity?

Muscle fasciculations, weakness, paralysis, hypertension, and tachycardia followed by hypotension.

What CNS effects occur in severe cholinesterase inhibitor poisoning?

Seizures, coma, respiratory depression, and death.

What is the primary cause of death in organophosphate poisoning?

Respiratory failure due to central depression, bronchoconstriction, secretions, and paralysis of respiratory muscles.

What is atropine’s role in cholinesterase inhibitor toxicity?

Atropine blocks muscarinic receptors, reducing life-threatening parasympathetic overstimulation.

What symptoms does atropine treat in toxicity?

Bronchorrhea, bronchoconstriction, bradycardia, hypotension, and excessive secretions.

What is pralidoxime’s mechanism of action?

Pralidoxime is a strong nucleophile that removes organophosphate groups from acetylcholinesterase before aging occurs.

Why must pralidoxime be given early?

Once aging occurs, the phosphorylated enzyme cannot be regenerated.

Does pralidoxime cross the blood–brain barrier?

No, pralidoxime acts only in the peripheral nervous system.

Why are atropine and pralidoxime used together?

Atropine treats muscarinic symptoms, while pralidoxime reverses nicotinic neuromuscular dysfunction.

What drug class treats Alzheimer disease via cholinesterase inhibition?

Centrally acting cholinesterase inhibitors enhance cortical acetylcholine to improve cognition.

Why are cholinesterase inhibitors useful in Alzheimer disease?

They compensate for loss of cholinergic neurons involved in attention, learning, and memory.

Which pharmacokinetic feature makes donepezil convenient?

Its long half-life allows once-daily dosing with reliable blood levels.

What adverse effects limit cholinesterase inhibitor use in dementia?

Bradycardia, hypotension, syncope, gastrointestinal distress, weight loss, and sleep disturbances.

Why must cholinesterase inhibitors be used cautiously in cardiac disease?

M2 receptor stimulation can cause bradycardia, AV block, and hypotension.

Which organ systems are most affected by cholinesterase inhibitors?

Cardiovascular, gastrointestinal, ocular, respiratory, and skeletal muscle systems.

What is the unifying mechanism behind cholinesterase inhibitor adverse effects?

Excessive stimulation of muscarinic and nicotinic receptors throughout the body.

What is the overall therapeutic goal of indirect-acting cholinomimetics?

To enhance endogenous acetylcholine signaling in a controlled manner while avoiding toxic overstimulation.