Donepezil. Donepezil, (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one (Aricept), commonly referred to in the literature as E2020, is a reversible inhibitor of AChE. It is indicated for the treatment of symptoms of mild-to-moderate Alzheimer disease. Donepezil is approximately 96% bound to plasma proteins, with an elimination half-life of 70 hours. It is metabolized principally by the 2D6 and 3A4 isozymes of the P450 system.

Edrophonium Chloride, USP. Edrophonium chloride, ethyl(m-hydroxyphenyl)dimethylammonium chloride (Tensilon), is a reversible anticholinesterase agent. It is bitter and very soluble in water and alcohol. Edrophonium chloride injection has a pH of 5.2 to 5.5. On parenteral administration, edrophonium has a more rapid onset and shorter duration of action than neostigmine, pyridostig-mine, or ambenonium. It is a specific anticurare agent and acts within 1 minute to alleviate overdose of d-tubocu-rarine, dimethyl d-tubocurarine, or gallamine triethiodide. The drug is also used to terminate the action of any one of these drugs when the physician so desires. It is of no value, however, in terminating the action of the depolarizing (i.e., noncompetitive) blocking agents, such as decamethonium and succinylcholine. In addition to inhibiting AChE, edro-phonium chloride has a direct cholinomimetic effect on skeletal muscle, which is greater than that of most other anticholinesterase drugs.

Edrophonium chloride is structurally related to neostigmine methylsulfate and has been used as a potential diagnostic agent for myasthenia gravis. This is the only degenerative neuromuscular disease that can be temporarily improved by administration of an anticholinesterase agent. Edrophonium chloride brings about a rapid increase in muscle strength without significant side effects.

Galantamine. Galantamine, 4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H -benzofuro-[3a,3,2,ef][2]-benzazepin-6-ol (Nivalin, Reminyl), is an alkaloid extracted from the tuberous plant Leucojum aestivum (L.) belonging to the Amaryllidaceae family and from the bulbs of the daffodil, Narcissus pseudonarcissus. It is a reversible cholinesterase inhibitor that appears to have no effect on bu-tyrylcholinesterase. In addition, it acts at allosteric nicotinic sites, further enhancing its cholinergic activity. Galantamine undergoes slow and minor biotransformation with approximately 5% to 6% undergoing demethylation. It is primarily excreted in the urine.

Metrifonate. Metrifonate is an organophosphate that was originally developed to treat schistosomiasis under the trade name Bilarcil. It is an irreversible cholinesterase inhibitor with some selectivity for BuChE over AChE. It achieves sustained cholinesterase inhibition by its nonenzy-matic metabolite dichlorvos (DDVP), a long-acting organophosphate. Its use in mild-to-moderate Alzheimer disease was suspended recently because of adverse effects experienced by several patients during the clinical evaluation of this product. Toxicity at the neuromuscular junction is probably attributable to the inhibition by the drug of neu-rotoxic esterase, a common feature of organophosphates.

Rivastigmine. Rivastigmine (Exelon, EA 713) is a pseudoirreversible noncompetitive carbamate inhibitor of AChE. Although the half-life is approximately 2 hours, the inhibitory properties of this agent last for 10 hours because of the slow dissociation of the drug from the enzyme. The Food and Drug Administration (FDA) approved its use in mild-to-moderate Alzheimer disease in April 2000. In July 2007, rivastigmine was granted approval for use in managing mild-to-moderate dementia associated with Parkinson disease.

Tacrine Hydrochloride. Tacrine hydrochloride, 1,2,3,4-tetrahydro-9-aminoacridine hydrochloride (THA, Cognex), is a reversible cholinesterase inhibitor that has been used in the treatment of Alzheimer disease for several years. The drug has been used to increase the levels of ACh in these patients on the basis of observations from autopsies that concentrations of ChAT and AChE are markedly reduced in the brain, whereas the number of muscarinic receptors is almost normal. The use of the drug is not without controversy, as conflicting results on efficacy have been reported.58,59 The drug has been used in mild-to-moderate Alzheimer dementia.

R2 = alkoxyl, alkyl, or tertiary amine X = a good leaving group

Irreversible Inhibitors

Both AChE and BuChE are inhibited irreversibly by a group of phosphate esters that are highly toxic (LD50 for humans is 0.1-0.001 mg/kg). These chemicals are nerve poisons and have been used in warfare, in bioterrorism, and as agricultural insecticides. They permit ACh to accumulate at nerve endings and exacerbate ACh-like actions. The compounds belong to a class of organophosphorous esters. A general formula for such compounds follows:

A is usually oxygen or sulfur but may also be selenium. When A is other than oxygen, biological activation is required before the compound becomes effective as an inhibitor of cholinesterases. Phosphorothionates [^1R2P(S)X] have much poorer electrophilic character than their oxygen analogs and are much weaker hydrogen bond-forming molecules because of the sulfur atom.60 Their anticholinesterase activity is 105-fold weaker than their oxygen analogs. X is the leaving group when the molecule reacts with the enzyme. Typical leaving groups include fluoride, nitrile, and ^-nitrophenoxy. The R groups may be alkyl, alkoxy, aryl, aryloxy, or amino. The R moiety imparts lipophilicity to the molecule and contributes to its absorption through the skin. Inhibition of AChE by organophosphorous compounds takes place in two steps, association of enzyme and inhibitor and the phosphorylation step, completely analogous to acylation by the substrate (Fig. 17.16). Stereospecificity is mainly caused by interactions of enzyme and inhibitor at the esteratic site.

The serine residue at the esteratic site forms a stable phosphoryl ester with the organophosphorous inhibitors. This stability permits labeling studies61 to be carried out on this and other enzymes (e.g., trypsin, chymotrypsin) that have the serine hydroxyl as part of their active site.

Although insecticides and nerve gases are irreversible inhibitors of cholinesterases by forming a phosphorylated serine at the esteratic site of the enzyme, it is possible to reactivate the enzyme if action is taken soon after exposure to

Cholinesterase Reactivations
Figure 17.16 • Phosphorylation and reactivation of cholinesterase. A. Phosphorylation of serine by isofluorphate. B. Phosphorylated serine at the esteratic site. C. Nucleophilic attack on phosphorylated residue by 2-PAM. D. Free enzyme.



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