Carbamates

Carbamate anticholinesterase agents are carbamic acid esters that are hydrolyzed by AChE in a manner similar to that of ACh. Carbamates have this general structure:

The clinically useful carbamates generally contain a tertiary or quaternary amine group that can bind non-covalently to the anionic site of the enzyme. The inhibition of AChE by neostigmine (Prostigmin) illustrates the general mechanism. The quaternary ammonium group of neostigmine binds electrostatically to the an-ionic site of the enzyme, thereby orienting the drug. The serine oxygen at the esteratic site of the enzyme then reacts with the carbonyl carbon of neostigmine, just as it did with ACh (Fig. 12.1). However, a carbamylated intermediate is formed instead of an acetylated one, and this carbamylated enzyme undergoes hydrolysis much more slowly. Whereas the acetylated enzyme is hy-drolyzed nearly instantly, the half-life for hydrolysis of this particular carbamylated intermediate is about an hour. The carbamates generally inhibit pseudo-ChE as well as true AChE, and their suicidal degradation by cholinesterases contributes importantly to terminating their duration of effect. Physostigmine (also called eser-ine) (Antilirium) is a tertiary amine that can inhibit

AChE in the CNS, and it can be used in life-threatening cases to treat antimuscarinic poisoning.

Pyridostigmine (Mestinon) is a quaternary ammonium carbamate. Neostigmine and pyridostigmine also have direct agonist activity at nicotinic receptors on skeletal muscle. Rivastigmine (Exelon) is a carbamate cholinesterase inhibitor with good penetration into the brain.

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