Paraldehyde toxicity

Methanol toxicity Uremia of renal failure Ketoacidoses Diabetes meUitus Ethyl alcohol toxicity Starvation Paraldehyde toxicity Isoniazid or iron toxicity, also ischemia Lactic acidosis Ethylene glycol toxicity... 

Paraldehyde toxicity may develop after chronic paraldehyde ingestion. The pathogenesis is poorly defined, but the acidosis may actually be a ketosis (nitroprusside negative) with P-hydroxybutyric acid as the main acidic product. Patients with paraldehyde toxicity have a pungent, apple-like odor to their breath. 

The oldest anti-anxiety agent is undoubtedly alcohol and it is certain that this drug is still routinely self-administered for this purpose. Towards the end of the eighteenth century, bromide salts were used to relieve conditions akin to anxiety despite the risk of a characteristic toxic delirium, known as bromism . Alternative treatments, such as paraldehyde and chloral hydrate, were also widely used but these too had adverse effects the former can cause psychosis but the latter is still used as a sedative and anaesthetic agent. 

Historically the first sedative hypnotics to be introduced were the bromides in the mid 19th century, shortly followed by chloral hydrate, paraldehyde and urethane. It was not until the early years of this century that the first barbiturate, sodium barbitone, was developed and this was shortly followed by over 50 analogues, all with essentially similar pharmacological properties. The major breakthrough in the development of selective, relatively non-toxic sedative hypnotics followed the introduction of chlordiazepoxide in 1961. Most of the benzodiazepines in current use have been selected for their high anxiolytic potency relative to their central depressant effects. Because of their considerable safety, the benzodiazepines have now largely replaced the barbiturates and the alcohols, such as chloral hydrate and trichloroethanol, as the drugs of choice in the treatment of insomnia. 

Toxicity. The minimum lethal dose has been estimated as 25 ml orally and 12 ml rectally, although recovery has occurred after the ingestion of 125 ml. Toxic effects have been associated with blood concentrations of 200 to 400 pg/ml. Blood concentrations of about 500 pg/ml, or less if alcohol has also been ingested, may be lethal. On storage, paraldehyde may depolymerise to acetaldehyde and acetic acid severe acidosis and fatalities may follow the use of partly depolymerised material. 

Paraldehyde is metabolized in the liver to acetaldehyde (22), and the metabohsm of aldehyde by aldehyde dehydrogenase is inhibited by disulfiram, causing aldehyde toxicity. The adverse effects of this have been shown in experimental animals (23) and there have been reports of confusional psychosis in patients given disulfiram and paraldehyde (24). 

Thiram and other dithiocarbamates are metabolic poisons. The acute effects of thiram are very similar to that of carbon disulfide, supporting the notion that the common metabolite of this compound is responsible for its toxic effects. The exact mechanism of toxicity is still unclear, however it has been postulated that the intracellular action of thiram involves metabolites of carbon disulfide, causing microsome injury and cytochrome P450 disruption, leading to increased heme-oxygenase activity. The intracellular mechanism of toxicity of thiram may include inhibition of monoamine oxidase, altered vitamin Bg and tryptophan metabolism, and cellular deprivation of zinc and copper. It induces accumulation of acetaldehyde in the bloodstream following ethanol or paraldehyde treatment. Thiram inhibits the in vitro conversion of dopamine to noradrenalin in cardiac and adrenal medulla cell preparations. It depresses some hepatic microsomal demethylation reactions, microsomal cytochrome P450 content and the synthesis of phospholipids. Thiram has also been shown to have moderate inhibitory action on decarboxylases and, in fish, on muscle acetylcholinesterases. 

The first lipophilicity-activity relationship was published by Charles Richet in 1893, exactly 100 years ago. From his quantitative investigations of the toxicities of ethanol, diethyl ether, urethane, paraldehyde, amyl alcohol, acetophenone, and essence of absinthe ( ) he concluded plus Us sont solubles, mains Us sont toxiques (the more they are soluble, the less toxic they are). One year later Emil Fischer derived the lock and key model of ligand-enzyme interactions from his results on the stereospecificity of the enzymatic cleavage of anomeric glycosides. 

A. The mechanism of toxicity is not well understood. Metaldehyde, like paraldehyde, is a polymer of acetaldehyde, and depolymerization to form acetaldehyde may account for some of its toxic effects. Further metabolism to acetone bodies may contribute to metabolic acidosis. 

The EPA defines hazardous wastes in the RCRA. This waste also includes pharmaceutical wastes that contain toxic chemicals or exhibit properties that make them hazardous to the environment and/or humans. RCRA wastes include broken or spilled vials, partial vials, expired products, and patient s personal medications. EPA limits hazardous waste maximum storage time to 90 or 180 days based on generator status. All wastes must be stored in a separate and locked area clearly marked so that it cannot become a food source or breeding place for insects or animals. Like infectious wastes, there is no time limit to fill the container. Not all states mandate the same storage requirements. Contact local and state authorities for additional information. EPA s P-listed chemicals (40 CFR 261.33) include such pharmaceuticals as epinephrine, nicotine, chloroform, and warfarin over 0.3%. The U-listed chemicals (40 CFR 261.33) include many used in chemotherapy, such as paraldehyde, mercury, phenol, and warfarin under 0.3%. 

Coniine, 2-propylpiperidine the most important of the Conium alkaloids (see), and the toxic principle of the poison hemlock, Conium maculatum, which was used in ancient Athens to put Socrates to death. The lethal dose of C. in humans is 0.5-1 g. The largest quantities of C. are found in the unripe seeds The synthesis of C. from a-picoline and paraldehyde by Ladenburg in 1886 was the first laboratory synthesis of any alkaloid. M, 127.22, m.p. -2.5 C, b.p. 166 C, [a] 7 16°. 

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