Basic Pharmacology

Inhibition of AChE potentiates and prolongs the stimulation of cholinoreceptors resulting from ACh released at cholinergic synapses (Fig. 12.5). These synapses include those found at the skeletal neuromuscular junction, adrenal medulla, autonomic ganglia, cholinergic neuroeffector junctions of the autonomic nervous system, and cholinergic synapses in the CNS. The degree and range of effects observed depend on the inhibitor chosen, the dose employed, and the route of exposure or administration.

Neuromuscular transmission in skeletal muscle is enhanced by low concentrations of anticholinesterase agents, whereas high concentrations result in choliner-gic blockade. This blockade is initially due to a persistent membrane depolarization and inactivation of voltage-gated sodium channels, but if ACh levels remain high, the nicotinic cholinergic receptors can quickly become desensitized. Although anticholinesterase agents will facilitate cholinergic transmission at autonomic ganglia, their action at these sites is less marked than at the neuromuscular junction. See Chapter 28 for further discussion of this topic. Muscarinic receptors do not exhibit comparable desensitization.

Anticholinesterase agents of all classes can initiate antidromic firing of action potentials in motor neurons, possibly due to an activation of prejunctional ACh receptors that are activated by the elevated synaptic ACh. Quaternary ammonium inhibitors can also act as agonists at these receptors. The initiation of antidromic firing may be a mechanism by which cholinesterase inhibitors produce fasciculation of skeletal muscle.

The actions of anticholinesterase agents on the cardiovascular system are complex. The primary effect produced by potentiation of vagal stimulation is brady-cardia with a consequent decrease in cardiac output and blood pressure. However, potentiation of both parasympathetic and sympathetic ganglionic transmis-

A No Drug

A No Drug

choline and acetic acid

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