Metabolism of barbiturates

Additive psychoactive effects sought by users may be achieved by combinations of cannabis and short-acting barbiturates, but at the same time the ability of THC to induce microsomal enzymes will increase the rate of metabolism of barbiturates and so reduce the additive effects (127). 

Valproic acid often causes gastrointestinal distress and is potentially hepatotoxic. The use of this drug in pregnancy has been associated with teratogenicity (neural tube defects). Valproic acid inhibits the metabolism of barbiturates marked CNS depression may result if such drugs are given concomitantly. Peripheral neuropathy, in the form of diminished deep tendon reflexes in the lower extremities, is associated with chronic use of phenytoin. The answer is (C). 

Both alcohol and the barbiturates are CNS depressants, and simple additive CNS depression provides part of the explanation. Acute alcohol ingestion may inhibit the liver enzymes concerned with the metabolism of barbiturates such as phenobarbital and pentobarbital, but chronic exposure to alcohol increases hepatic microsomal enzyme activity and may reduce sedation from barbiturates in patients without liver impairment. - Similarly, chronic exposure to a barbiturate such as phenobarbital may increase alcohol metabolism due to enzyme induction and consequently reduce blood-alcohol levels. ... 

Not known. Animal studies show that MAOIs prolong the activity of barbiturates, and that this is possibly because they inhibit the metabolism of barbiturates by a mechanism independent of MAO inhibition. Whether this occurs in man as well is uncertain. 

Barbiturates structure-activity relationships 60 Metabolism of barbiturates 60... 

Hayaishi O, A Kornberg (1952) Metabolism of cytosine, thymine, uracil and barbituric acid by bacterial enzymes. J Biol Chem 197 717-732. 

The purpose of this paper is to give some of the results obtained in a study of the antidotal action of barbiturates in chlordan poisoning, and of the metabolic fate of chlordan. 

In a number of barbiturates, the 5-alkyl side chain is known to undergo metabolic hydroxylation at C(2 ) and/or C(3 ). Examples include allobarbi-... 

Several animal studies indicate that chloroform interacts with other chemicals within the organism. The lethal and hepatotoxic effects of chloroform were increased by dicophane (DDT) (McLean 1970) and phenobarbital (a long-acting barbiturate) in rats (Ekstrom et al. 1988 McLean 1970 Scholler 1970). Increased hepatotoxic and nephrotoxic effects were observed after interaction with ketonic solvents and ketonic chemicals in rats (Hewitt and Brown 1984 Hewitt et al. 1990) and in mice (Cianflone et al. 1980 Hewitt et al. 1979). The hepatotoxicity of chloroform was also enhanced by co-exposure to carbon tetrachloride in rats (Harris et al. 1982) and by co-exposure to ethanol in mice (Kutob and Plaa 1962). Furthermore, ethanol pretreatment in rats enhanced chloroform-induced hepatotoxicity (Wang et al. 1994) and increased the in vitro metabolism of chloroform (Sato et al. 1981). 

Effects on vitamin D Barbiturates may increase vitamin D requirements, possibly by increasing the metabolism of vitamin D via enzyme induction. 

Pharmacodynamic tolerance, probably on the basis of down-regulation of receptors, develops more rapidly to the effects of barbiturates on mood and sedation than to the anticonvulsant and lethal action. This results in a marked decrease in therapeutic index and the ratio of LD50 and ED50 can approach 1. Furthermore, barbiturates induce P450 enzymes and thus increase their own metabolism resulting in time dependent pharmacokinetic behavior. 

A wide range of drugs can interact with the barbiturates. Additive effects are seen with other sedatives. The metabolism of other drugs can be induced or the metabolism of the barbiturate can be diminished by cytochrome P450 inhibitors. 

Drugs that have been associated with elevations in quinidine concentrations include acetazolamide, the antacids magnesium hydroxide and calcium carbonate, and the H2-receptor antagonist cimetidine. Cimetidine inhibits the hepatic metabolism of quinidine. Phenytoin, rifampin, and barbiturates increase the hepatic metabolism of quinidine and reduce its plasma concentrations. 

Alcohol, nicotine, and most anticonvulsants induce a number of CYP enzymes (39, 40). This mechanism explains why barbiturates and carbamazepine induce the metabolism of other drugs as well as their own (i.e., autoinduction ). Blood levels obtained 3 or 4 days after starting these drugs reflect the rate of elimination at that time however, levels will subsequently fall on the same dose because autoinduction results in faster elimination (i.e., a shorter half-life) as a function of continued drug administration. Therefore, early TDM of carbamazepine will overestimate the eventual concentration reached after several weeks on the drug (see the section Alternatiye T[eatm in Chapter 10). 

Tolerance—decreased responsiveness to a drug following repeated exposure—is a common feature of sedative-hypnotic use. It may result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep. It is important to recognize that partial cross-tolerance occurs between the sedative-hypnotics described here and also with ethanol (see Chapter 23)—a feature of some clinical importance, as explained below. The mechanisms responsible for tolerance to sedative-hypnotics are not well understood. An increase in the rate of drug metabolism (metabolic tolerance) may be partly responsible in the case of chronic administration of barbiturates, but changes in responsiveness of the central nervous system (pharmacodynamic tolerance) are of greater importance for most sedative-hypnotics. In the case of benzodiazepines, the development of tolerance in animals has been associated with down-regulation of brain benzodiazepine receptors. Tolerance has been reported to occur with the extended use of zolpidem. Minimal tolerance was observed with the use of zaleplon over a 5-week period and eszopiclone over a 6-month period. 

Barbiturates [P] Increased metabolism of itraconazole, ketoconazole, voriconazole. 

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