Cholinesterases half-life

Aspirin is rapidly absorbed in the stomach and quickly degraded by plasma cholinesterases (half-life, 15-20 min). A once-daily dose of 160 mg of aspirin, which is much lower than dosages needed for its anti-inflammatory/analgesic actions, is sufficient to completely inactivate platelet COX-1 irreversibly (90). Higher doses of aspirin only contribute to its side effects, especially internal bleeding and upper gastrointestinal irritations. 

Carbamates are used as insecticides, nematocides, fungicides, and herbicides the toxicity of carbamate insecticides is similar to that of OP compounds and is based on the inhibition of ACHE. Also, carbamate metabolites may inhibit ACHE but are usually weaker inhibitors than the unchanged compound. Cholinesterase inhibition caused by carbamates is labile, of short duration, and rapidly reversible in fact, the half-life of the inhibited enzymes ranges between some minutes and 2 to 3 hours for RBC-ACHE and is on the order of some minutes for PCHE. Accumulation of cholinesterase activity on repeated exposures, as observed with OP compounds, does not occur with... 

Photolytic. Based on data for phenol, a structurally related compound, an aqueous solution containing 1-naphthoxide ion (3 x 10 M) in room light would be expected to photooxidize to give 2-hydroxy-1,4-naphthoquinone (Tomkiewicz et al., 1971). 1-Naphthol, methyl isocyanate, and other unidentified cholinesterase inhibitors were reported as products formed from the direct photolysis of carbaryl by sunlight (Wolfe et al., 1976). In an aqueous solution at 25 °C, the photolysis half-life of carbaryl by natural sunlight or UV light (X = 313 nm) is 6.6 d (Wolfe et al, 1978a). 

Chloroprocaine hydrochloride (Nesacaine) is obtained from addition of a chlorine atom to procaine, which results in a compound of greater potency and less toxicity than procaine itself. This local anesthetic is hydrolyzed very rapidly by cholinesterase and therefore has a short plasma half-life. Because it is broken down rapidly, chloroprocaine is commonly used in obstetrics. It is believed that the small amount that might get to the fetus continues to be rapidly hydrolyzed, so there may be no residual effects on the neonate. 

Mechanism of Action A benzimidazole carbamate anthelmintic that degrades parasite cytoplasmic microtubules, irreversibly blocks cholinesterase secretion, glucose uptake in helminth and larvae (depletes glycogen, decreases ATP production, depletes energy). Vermicidal. Therapeutic Effect Immobilizes and kills worms. Pharmacokinetics Poorly and variably absorbed from GI tract. Widely distributed, cyst fluid and including cerebrospinal fluid (CSF). Protein binding 70%. Extensively metabolized in liver. Primarily excreted in urine and bile. Not removed by hemodialysis. Half-life 8-12 hr. 

Pharmacokinetics Penetrates blood-brain barrier. Rapidly hydrolyzed by cholinesterases. Small amount eliminated in urine largely destroyed in body by hydrolysis. Half-life Unknown. 

Appendix B reviews some important animal studies of cholinesterase reactivator chemicals. The extensive literature reviewed offers little definitive information with which to project possible long-term effects or delayed sequelae in human subjects tested at Edgewood. These compounds have a short biologic half-life of 1 to 3 h. However, no chronic studies were found. Consequently, the carcinogenic potential of cholinesterase reactivators remains... 

Mivacurium is a mixture of three stereoisomers, the two short-acting cis-trans and trans-trans isomers comprising about 94% of the mixture. Both have very short half-lives of about 2 minutes, while the much less potent c/s-c/s isomer has about one-tenth the neuromuscular blocking potency of the other two isomers. The c/s-c/s isomer undergoes some renal excretion as well as being broken down by plasma cholinesterase with a half-life of about 50 minutes (Table 6.4). The short-acting isomers are broken down almost entirely by plasma cholinesterase with a high rate of clearance and a short duration of action. The duration of action of mivacurium is increased when there is a reduction in plasma cholinesterase activity as in patients with marked renal and hepatic disease. The same is true for elderly patients. 

Thus, the inhibition of cholinesterase enzymes by organophosphorus compounds may last for several days or weeks, and repeated dosing at shorter intervals than the half-life of regeneration of the enzyme leads to accumulation of the inhibition until the toxic threshold of around 50% is reached. 

Tacrine was the first cholinesterase inhibitor approved for the enhancement of memory associated with Alzheimer s disease in the United States. Because of its short half-life, drug interactions, and hepatic toxicity, it is currently considered second-line therapy for patients who fail to respond to donepezil. Its psychophar-... 

After release from the presynaptic terminal, acetylcholine molecules may bind to and activate an acetylcholine receptor (cholinoceptor). Eventually (and usually very rapidly), all of the acetylcholine released will diffuse within range of an acetylcholinesterase (AChE) molecule. AChE very efficiently splits acetylcholine into choline and acetate, neither of which has significant transmitter effect, and thereby terminates the action of the transmitter (Figure 6-3). Most cholinergic synapses are richly supplied with acetylcholinesterase the half-life of acetylcholine in the synapse is therefore very short. Acetylcholinesterase is also found in other tissues, eg, red blood cells. (Another cholinesterase with a lower specificity for acetylcholine, butyrylcholinesterase [pseudocholinesterase], is found in blood plasma, liver, glia, and many other tissues.)... 

Rivastigmine is a pseudo-irreversible inhibitor of both acetyl and butyryl cholinesterases. Thus although the drug initially blocks the enzymes, it is metabolized by them thereby giving the drug a relatively short half-life. The top dose is often necessary to achieve therapeutic efficacy, at which dose the central and peripheral cholinergic side effects become apparent. 

In the clinic, esmolol s distribution half-life is 2 min and its elimination half-life is 9 min. Esmolol hydrochloride is rapidly metabolized by hydrolysis of the ester linkage, chiefly by esterases in the cytosol of red blood cells and not by plasma cholinesterases or red cell membrane acetylcholinesterase [22]. Its volume of distribution is 3.4 L kg-1, and its total clearance is 285 mL kg-1 min-1, "... which is greater than cardiac output thus the metabolism ofesmolol is not limited by the rate of blood flow to metabolizing tissues such as the liver or affected by hepatic or renal blood flout [22]. As expected from such a "... high rate of blood-based metabolism, less than 2% of the drug is excreted unchanged in the wind [22]. Within 24 h after infusion, approximately... 

The carbamates, like the organophosphorus insecticides, are cholinesterase inhibitors. However, the reaction is rapidly reversible. Carbaryl has a half life in the soil of about 8 days and is decomposed by ultraviolet light. The carbamates metabolize rapidly in animals and show little, if any, propensity for storage in animal tissues. Additional properties and reactions of carbamates are discussed in the section on fungicides. 

DONEPEZIL SUXAMETHONIUM Possible t efficacy of suxamethonium Suxamethonium is metabolized by cholinesterase parasympatho-mimetics inhibit cholinesterase and so prolong the action of suxamethonium Avoid co-administration. Ensure that the effects of suxamethonium have worn off before administering a parasympathomimetic to reverse non-depolarizing muscle relaxants. A careful risk-benefit analysis should be made before considering the use of suxamethonium for emergency anaesthesia in patients taking parasympathomimetics. The short half-life of edrophonium means that it can be used to diagnose suspected dual block with suxamethonium... 

Kinetic analysis of hydrolysis revealed a half-life of 2 min for MIC in aqueous solution, which is much slower than that for aryl isocyanates (Brown et al, 1987). Interaction of isocyanates with cholinesterases is reversible and MIC is far less potent than aryl isocyanates in this respect (Brown et al, 1987). At the same time MIC can act as a hapten leading to generation of antibodies in both animals and humans, although it results in low titers (Karol and Kamat, 1988 Karol et al, 1987). 

The covalent bond between OP and the active site serine of intact cholinesterase is stable, but not irreversible. Hydrolysis can occur with a half-life of between 10 and 35,000 min, depending on the enzyme, OP, temperature, pH, and buffer composition. The adduct becomes irreversibly bound to the enzyme after one of the alkyl groups on the OP is lost in a step called aging (Benschop and Keijer, 1966 Michel et al., 1967). The dealkylated OP makes a stable salt bridge with the protonated histidine of the catalytic triad, so that histidine is no longer available for the dephosphorylation step that would otherwise have restored the enzyme to an uninhibited state. Hundreds of scientists have contributed to this understanding... 

Cholinesterase During the further course of disease, chohn-esterase decreases in relation to its longer half-life and likewise allows a reliable assessment to be made of the remaining liver function. (s. p. 103)... 

Mivacurium chloride is a non-depolarizing muscle relaxant, a benzylisoquinolinium diester compound with a duration of approximately twice that of suxamethonium. In vitro (1), it is metabolized to a significant extent by plasma cholinesterase, and minimally by acetylcholinesterase. The rate of metabolism in vitro is directly related to plasma cholinesterase activity. In pooled human plasma the rate of hydrolysis of mivacurium was 70% that of suxamethonium. Its half-life is 5-10 minutes compared with 2-5 minutes for suxamethonium. The in vitro hydrolysis of mivacurium by purified human plasma cholinesterase occurs at 88% of the rate for suxamethonium (2). There was a poor correlation between the duration of action of bolus doses of mivacurium and the plasma cholinesterase activity in individual patients (2), a finding that has also been reported by others (3). However, the average infusion rate to maintain around 95 % blockade in individual patients correlated significantly with the patients plasma cholinesterase activities (4). While metabolites have been detected in both urine and bile, mivacurium seems to depend principally on ester hydrolysis for its plasma clearance, so that reduced activity of plasma cholinesterase is likely to result in a prolonged duration of action. 

Indications Motion sickness, dizziness, nausea, vomiting Category Cholinesterase absorption inhibitor Half-life N/A... 

Indications Mild dementia of the Alzheimer s type Category Cholinesterase inhibitor Half-life 50-70 hours... 

Trade names Enlon (Baxter) Tensilon (Valeant) Indications Myasthenia gravis diagnosis Category Anesthetic Cholinesterase inhibitor Half-life 1.8 hours... 

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