Noncovalent Inhibitors. While these agents interact by reversible and noncovalent association with the active site in AChE, they differ in their disposition in the body and their affinity for the enzyme. Edrophonium, a quaternary drug whose activity is limited to peripheral nervous system synapses, has a moderate affinity for AChE. Its volume of distribution is limited and renal elimination is rapid, accounting for its short duration of action. By contrast, tacrine and donepezil (Figure 10–3) have higher affinities for AChE, are more hydrophobic, and readily cross the blood-brain barrier to inhibit AChE in the CNS. Their partitioning into lipid and their higher affinities for AChE account for their longer durations of action.
"Reversible" Carbamate Inhibitors. Drugs of this class that are of therapeutic interest are shown in Figure 10–3. Early studies showed that the essential moiety of the physostigmine molecule was the methylcarbmate of an amine-substituted phenol. The quaternary ammonium derivative neostigmine is a compound of equal or greater potency. Pyridostigmine is a close congener that also is used to treat myasthenia gravis.
An increase in anti-ChE potency and duration of action can result from the linking of two quaternary ammonium moieties. One such example is the miotic agent demecarium, which consists of two neostigmine molecules connected by a series of ten methylene groups. The second quaternary group confers additional stability to the interaction by associating with a negatively charged amino side chain, Asn74, near the rim of the gorge. Carbamoylating inhibitors with high lipid solubilities (e.g., rivastigmine), which readily cross the blood-brain barrier and have longer durations of action, are approved or in clinical trial for the treatment of Alzheimer's disease (Cummings, 2004; Giacobini, 2000) (Chapter 22).
The carbamate insecticides carbaryl (sevin), propoxur (baygon), and aldicarb (temik), which are used extensively as garden insecticides, inhibit ChE in a fashion identical with other carbamoylating inhibitors. The symptoms of poisoning closely resemble those of the organophosphates (Baron, 1991; Ecobichon, 2000). Carbaryl has a particularly low toxicity from dermal absorption. It is used topically for control of head lice in some countries. Not all carbamates in garden formulations are ChE inhibitors; the dithiocarbamates are fungicidal.
Organophosphorus Compounds. The general formula for this class of ChE inhibitors is presented in Table 10–1. A great variety of substituents is possible: R1 and R2 may be alkyl, alkoxy, aryloxy, amido, mercaptan, or other groups; and X, the leaving group, typically a conjugate base of a weak acid, is a halide, cyanide, thiocyanate, phenoxy, thiophenoxy, phosphate, thiocholine, or carboxylate group. For a compilation of the organophosphorus compounds and their toxicity, see Gallo and Lawryk (1991).
DFP produces virtually irreversible inactivation of AChE and other esterases by alkylphosphorylation. Its high lipid solubility, low molecular weight, and volatility facilitate inhalation, transdermal absorption, and penetration into the CNS. After desulfuration, the insecticides in current use form the dimethoxy or diethoxyphosphoryl enzyme.
The "nerve gases"—tabun, sarin, and soman—are among the most potent synthetic toxins known; they are lethal to laboratory animals in nanogram doses. Insidious employment of these agents has occurred in warfare and terrorism attacks (Nozaki and Aikawa, 1995).
Because of their low volatility and stability in aqueous solution, parathion and methylparathion were widely used as insecticides. Acute and chronic toxicity has limited their use, and potentially less hazardous compounds have replaced them for home and garden use, now largely throughout the world. These compounds are inactive in inhibiting AChE in vitro; paraoxon is the active metabolite. The phosphoryl oxygen for sulfur substitution is carried out predominantly by hepatic CYPs. This reaction also occurs in the insect, typically with more efficiency. Other insecticides possessing the phosphorothioate structure have been widely employed for home, garden, and agricultural use. These include diazinon (spectracide, others) and chlorpyrifos (dursban, lorsban). Both of these agents have been placed under restricted use because of evidence of chronic toxicity in the newborn animal. They have been banned from indoor and outdoor residential use since 2005.
Malathion (chemathion, mala-spray) also requires replacement of a sulfur atom with oxygen in vivo, conferring resistance to mammalian species. Also, this insecticide can be detoxified by hydrolysis of the carboxyl ester linkage by plasma carboxylesterases, and plasma carboxylesterase activity dictates species resistance to malathion. The detoxification reaction is much more rapid in mammals and birds than in insects (Costa et al., 2003). In recent years, malathion has been employed in aerial spraying of relatively populous areas for control of citrus orchard-destructive Mediterranean fruit flies and mosquitoes that harbor and transmit viruses harmful to human beings, such as the West Nile encephalitis virus.
Evidence of acute toxicity from malathion arises only with suicide attempts or deliberate poisoning. The lethal dose in mammals is ∼1 g/kg. Exposure to the skin results in a small fraction (<10%) of systemic absorption. Malathion is used topically in the treatment of pediculosis (lice) infestations.
Among the quaternary ammonium organophosphorus compounds (group D in Table 10–1), only echothiophate is useful clinically and is limited to ophthalmic administration. Being positively charged, it is not volatile and does not readily penetrate the skin.
Metrifonate is a low-molecular-weight organophosphate that is spontaneously converted to the active phosphoryl ester, dimethyl 2,2-dichlorovinyl phosphate (DDVP, dichlorvos). Both metrifonate and DDVP readily cross the blood-brain barrier to inhibit AChE in the CNS. Metrifonate originally was developed for the treatment of schistosomiasis (Chapter 51). Its capacity to inhibit AChE in the CNS and its reported low toxicity led to its clinical trial in treatment of Alzheimer's disease (Cummings, 2004); a low incidence of skeletal muscle paralysis has limited its acceptance.