Synapse cholinergic, inhibitors

Cholinesterases (ChEs), polymorphic carboxyles-terases of broad substrate specificity, terminate neurotransmission at cholinergic synapses and neuromuscular junctions (NMJs). Being sensitive to inhibition by organophosphate (OP) poisons, ChEs belong to the serine hydrolases (B type). ChEs share 65% amino acid sequence homology and have similar molecular forms and active centre structures [1]. Substrate and inhibitor specificities classify ChEs into two subtypes ... 

Acetylcholinesterase is a component of the postsynaptic membrane of cholinergic synapses of the nervous system in both vertebrates and invertebrates. Its structure and function has been described in Chapter 10, Section 10.2.4. Its essential role in the postsynaptic membrane is hydrolysis of the neurotransmitter acetylcholine in order to terminate the stimulation of nicotinic and muscarinic receptors (Figure 16.2). Thus, inhibitors of the enzyme cause a buildup of acetylcholine in the synaptic cleft and consequent overstimulation of the receptors, leading to depolarization of the postsynaptic membrane and synaptic block. 

The discovery of the loss of the cholinergic neurons and acetylcholine in the brain of Alzheimer s disease patients led to the use of drugs that would enhance the actions of acetylcholine in the brain. Therapeutic agents approved for the treatment of Alzheimer s disease are the cholinesterase inhibitors, drugs that block the breakdown of acetylcholine and increase the availability of the neurotransmitter in synapses (see Chapter 12). These drugs are palliative only and do not cure or prevent neurodegeneration. 

Mechanism of Action A cholinesterase inhibitor that inhibits the enzyme acetylcholinesterase, thus increasing the concentration of acetylcholine at cholinergic synapses and enhancing cholinergic function in the CNS. Therapeutic Effect Slows the progression of Alzheimer s disease. 

Figure 30-22 Some inhibitors of cholinergic synapses. The structure of conotoxin GI is from Guddat et al.533 Courtesy of A. B. Admundson.

Unlike the systemic direct-acting cholinergic stimulants (e.g., bethanechol), cholinesterase inhibitors display a relative lack of specificity regarding which cholinergic synapses they stimulate. These drugs tend to inhibit the acetylcholinesterase found at... 

Carbofuran is an inhibitor of acetylcholinesterase. Inhibition of acetylcholinesterase activity leads to an increase in acetylcholine at the nerve synapse resulting in excessive cholinergic stimulation. Following intravenous injection of 50pgkg in rats, blood acetylcholinesterase activity was depressed by 83% within 2 min. With oral exposures, acetylcholinesterase activity was depressed by 37% within 15 min of ingestion. Recovery of acetylcholinesterase activity parallels carbofuran elimination. 

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