Structure and Mechanism of Action

There are several types of esterases in the body, all of which hydrolyze esters such as acetlycholine. Some of those in the plasma are nonspecific and hydrolyze many esters including ACh, whereas acetylcholinesterase, which is found at cholinergic synapses, is more specific for ACh. AChE is also found in erythrocytes, but its function in these cells is poorly understood. Inhibition of the plasma (or erythrocyte) esterase is without known consequence, whereas the inhibition of AChE at cholinergic synapses leads to a spectrum of toxicological effects.

At cholinergic synapses, ACh released from nerve endings by action potentials activates the postjunctional receptors and thereby elicits responses. To prevent it from inappropriately reactivating the receptors, ACh is hydrolyzed to inactive products by the enzyme AChE in the synapse, thus ensuring that one action potential leads to a single response. Interference with the ability of AChE to hydrolyze ACh leads to accumulation of the latter in the synapse, and the excess neurotransmitter is then responsible for both the pharmacological and the toxicological manifestations of AChE inhibition.

The toxicokinetics of PB are complex, and there is incomplete agreement on the fate of an ingested dose (Joiner and Kluwe, 1988; Golomb, 1999). The gastrointestinal tract erratically absorbs PB, leading to considerable variations in plasma concentration (Aquilonius et al., 1980). Absorbed PB is subject to first-pass metabolism by the liver (Barber et al., 1975), but since 60–85 percent of an administered dose is excreted unchanged via the kidney, the fraction of a dose undergoing hepatic biotransformation is not large. Hepatic biotransformation of neostigmine and pyridostigmine apparently gives rise to the metabolites 3-hydroxy-N-methylpyridinium, 3-hydroxyphenyltrimethylammonium, and edrophonium (Hennis et al., 1984); there is no evidence that these metabolites contribute to antagonism of neuromuscular blockade or that they are neurotoxic.

The differences in duration and reversibility of cholinesterase inhibition by PB and organophosphate exposures provide the rationale for battlefield use of PB by the military. Although both PB and the organophosphate (OP) compounds employed as “nerve gases” inhibit AChE by binding to it, the OP–AChE bond is much stronger than the PB–AChE bond, making the former essentially irreversible. The differences in binding of carbamates and organophosphates to AChE have been exploited in the use of a reversible inhibitor of AChE (e.g., PB) to protect it against irreversible inhibitors such as the nerve gases (Gordon et al., 1978; Dirnhuber et al., 1979). In effect, protection results from “preinhibition” of the enzyme with a more readily reversible inhibitor.

As noted, the prophylactic use of PB in military personnel calls for 30 mg to be taken three times a day. Since the plasma half-lives of orally administered PB are 120–195 minutes and the corresponding half-lives for reversal of erythrocyte AChE inhibition are in the same range (Kluwe et al., 1990), 8-hour intervals between doses are adequate to maintain constant levels of AChE inhibition and thus protection. Joiner and Kluwe (1988) found 30 percent inhibition of red blood cell (RBC) AChE in monkeys following oral administration of 0.28 mg/kg



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