Mechanism Ofaction Of AchE Inhibitors

AChE inhibitors may be divided into three groups: noncovalent or "reversible" inhibitors, car-bamoylating inhibitors, and organophosphorus compounds. The mechanisms of the action of compounds that typify these three classes of anti-ChE agents are shown in Figure 8-1. Three distinct domains on AChE constitute binding sites for inhibitory ligands and form the basis for specificity differences between AChE and butyrylcholinesterase: the acyl pocket of the active center, the choline subsite of the active center, and the peripheral anionic site. Reversible inhibitors (e.g., edrophonium, tacrine) bind to the choline subsite. Edrophonium has a brief duration of action because it binds reversibly and its quaternary structure facilitates renal elimination. Additional reversible inhibitors, such as donepezil, bind with higher affinity to the active center. Other reversible inhibitors (e.g., propidium and the snake peptidic toxin fasciculin) bind to the peripheral anionic site on AChE.

Drugs that have a carbamoyl ester linkage (e.g., physostigmine and neostigmine) are hydrolyzed by AChE (much more slowly than is ACh), generating a carbamoylated enzyme (Figure 8—1C). In contrast to the acetyl enzyme, methylcarbamoyl AChE and dimethylcarbamoyl AChE are far more stable (the t1/2for hydrolysis of the dimethylcarbamoyl enzyme is 15-30 minutes), precluding enzyme-catalyzed hydrolysis of ACh for extended periods of time. In vivo, the duration of inhibition by the carbamoylating agents is 3-4 hours.

The organophosphorus inhibitors (e.g., DFP), form stable conjugates with AChE, with the active center serine phosphorylated or phosphonylated (Figure 8-1D). If the alkyl groups in the phosphorylated enzyme are ethyl or methyl, spontaneous regeneration of active enzyme requires several hours. Secondary (as in DFP) or tertiary alkyl groups further enhance the stability of the phosphorylated enzyme, and significant regeneration of active enzyme usually does not occur. Hence, the return of AChE activity depends on synthesis of a new enzyme. The stability of the phosphorylated enzyme is enhanced through "aging," which results from the loss of one of the alkyl groups.

Thus, the terms reversible and irreversible as applied to the carbamoyl ester and organophos-phorate anti-ChE agents, respectively, reflect only quantitative differences in rates of decarbamoy-lation or dephosphorylation of the conjugated enzyme. Both chemical classes react covalently with the enzyme serine in essentially the same manner as does ACh.

Action at Effector Organs The characteristic pharmacological effects of the anti-ChE agents are due primarily to the accumulation of ACh at sites of cholinergic transmission. Virtually all acute effects of moderate doses of organophosphates are attributable to this action. The consequences of enhanced concentrations of ACh at motor endplates are unique to these sites and are discussed below. The tertiary amine and particularly the quaternary ammonium anti-ChE compounds may have additional direct actions at certain cholinergic receptor sites (e.g., effects of neostigmine on the spinal cord and neuromuscular junction reflect anti-ChE activity and direct cholinergic stimulation).

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