Chloral hydrate liver

Chloral hydrate (Noctec, Somnos) was developed in the late 1800s and is still used as a sedative-hypnotic agent. It is a hydrated aldehyde with a disagreeable smell and taste that is rapidly reduced in vivo to trichloroethanol, which is considered to be the active metabohte. It produces a high incidence of gastric irritation and allergic responses, occasionally causes cardiac arrhythmias, and is unreliable in patients with liver damage. 

Pharmacokinetics Rapidly, completely absorbed from G1 tract rectal absorption variable. Widely distributed to most body tissues. Acetaminophen is metabolized in liver excreted in urine. Dichloralphenazone is hydrolyzed to active compounds chloral hydrate and antipyrine. Chloral hydrate is metabolized in the liver and erythrocytes to the active metabolite trichloroethanol, which maybe further metabolized to inactive metabolite. It is also metabolized in the liver and kidneys to inactive metabolites. The pharmacokinetics of isometheptene is not reported. Removed by hemodialysis. Half-life Acetaminophen 1-4 hr (half-life is increased in those with liver disease, elderly, neonates decreased in children). 

The biotransformation of TCE in humans is carried out by the liver microsomal enzymes, hence requires NADPH and oxygen. Oxidation products found were chloral hydrate, trichloroacetic acid and trichloroethanol. The acid is excreted unchanged in the urine the ethanol is first converted to the glucuronate (ref. 65a). 

Haloaldehydes and haloketones have received very little attention. Members of this class have been identified as key metabolites of chemicals such as TCE, vinyl chloride, and dibromochloropropane. Trichloroacetaldehyde and chloral hydrate are important compounds of this group. Chloral hydrate is primarily known for its depressant effects on the central nervous system and doses of 500-2000 mg produce central nervous system depression in humans. It is also known to cause liver damage. This compound is classified as group 3 by lARC. TCA and DCA are major metabolites of chloral hydrate. 

Other adverse effects Barbiturates and carbamates (but not benzodiazepines, buspirone, zolpidem, or zaleplon) induce the formation of the liver microsomal enzymes that metabolize dmgs. This enzyme induction may lead to multiple drug interactions. Barbiturates may also precipitate acute intermittent porphyria in susceptible patients. Chloral hydrate may displace coumarins from plasma protein binding sites and increase anticoagulant effects. 

A variable proportion of chloral hydrate is oxidized in the liver and kidney by a DPN-depen-dent enzyme to give a CNS-inactive metabolite, trichloroacetic acid287. This is the main urinary metabolite found in man, but is minor to trichloroethanol (free plus conjugated) in the dog and ratl 5. 

Cetyl alcohol Cetyl esters Chloral hydrate Chloroacetamide Chloroacetic acid Chlorobenzene Chloroform Chromium nitrate Chromium potassium sulfate Cl 77000 Cobalt acetate (ous) Coconut acid Coconut (Cocos nucifera) oil Cod liver oil Copal resin Corn (Zea mays) oil Corn (Zea mays) starch Cottonseed (Gossypium) oil Coumarone/indene resin C10-12 pareth-3 C10-12 pareth-6 C10-12 pareth-8 C12-14 pareth-1 C12-14 pareth-3 C12-14 pareth-4 C12-14 pareth-7 C12-14 pareth-8 C12-14 pareth-11 p-Cresol/dicyclopentadiene butylated reaction product Cumene hydroperoxide... 

The toxieity of triehloroethylene is dependent upon metabolism and induction of cytochrome P450. Triehloroethylene is metabolized through chloral hydrate to compounds including trichloroacetic acid and dichloroacetic acid which alter intercellular communication, induce peroxisome proliferation and may promote tumor production. Significant variability in trichloroethylene metabolism in 23 human haptic microsomal samples was reported by Lipscomb et al. It was also demonstrated that the trichloroethylene metabolism is dependent on enzymatic activities of the cytochrome system, and they conclude that their data indicates that humans are not uniform in their capacity for CPY dependent metabolism of trichloroethylene and increased activity may increase susceptibility to trichloroethylene induced toxicity in humans. These observations are compatible with the variability reaction which is depending on nutritional factors, enzyme induction factors, hormonal factors and interaction with other environmental chemicals, prescription medications and general health conditions, and explains the variable reports as far as trichloroethylene and level of liver toxicity in the various individuals studied. 

CgHnCbOy 325.529 Synth, from trichloroethanol by rat liver microsomal fraction in the presence of UDP-glucuronic acid. Chloral hydrate and trichloroethanol metab. 

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