Which of the following enzymes is irreversibly inhibited by organophosphate compounds, leading to accumulation of acetylcholine at the neuromuscular junction?

Explanation

## Mechanism of Organophosphate Toxicity ### Target Enzyme **Key Point:** Organophosphates irreversibly phosphorylate the serine residue at the active site of acetylcholinesterase (AChE), preventing hydrolysis of acetylcholine. ### Pathophysiology 1. Organophosphate compound binds to AChE active site 2. Phosphorylation of serine hydroxyl group occurs 3. Normal hydrolysis of acetylcholine is blocked 4. Acetylcholine accumulates at synapses and neuromuscular junction 5. Continuous stimulation of cholinergic receptors ensues ### Clinical Consequence **High-Yield:** The accumulation of acetylcholine leads to a cholinergic crisis characterized by: - Muscarinic effects: miosis, bronchospasm, bradycardia, salivation, lacrimation, urination, defecation - Nicotinic effects: fasciculations, paralysis, muscle weakness - CNS effects: anxiety, tremor, seizures, coma ### Why Other Enzymes Are Not Targets - **Monoamine oxidase:** Metabolizes monoamines; not the primary target in organophosphate poisoning - **Butyrylcholinesterase:** A plasma enzyme that is also inhibited but plays a secondary role; AChE at the neuromuscular junction is the critical target - **Catechol-O-methyltransferase:** Involved in catecholamine metabolism; not inhibited by organophosphates **Clinical Pearl:** The degree of AChE inhibition correlates with severity of poisoning. Levels >50% inhibition typically produce symptoms.