Enzyme induction barbiturates

Enzyme induction Barbiturates induce P-450 microsomal enzymes in the liver (see p. 14). Therefore, chronic barbiturate administration diminishes the action of many drugs that are dependent on P-450 metabolism to reduce their concentration. 

CYP450 enzyme induction from phenytoin, fosphenytoin, or barbiturates may decrease effect... 

Urinary D-glucaric acid levels have been shown to be a sensitive indicator of microsomal enzyme induction in workers exposed to chlordecone (Guzelian 1985). However, other substances such as barbiturates, phenytoin, chlorbutanol, aminopyrine, phenylbutazone, and contraceptive steroids as well as other organochlorinated pesticides also cause microsomal enzyme induction and cause changes in urinary D-glucaric acid (Morgan and Roan 1974). 

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

Taken with alcohol they potentiate the sedative effects and impairment of psychomotor performance. Hepatic enzyme induction by barbiturates or nicotine may reduce plasma levels. Cimetidine may increase levels by enzyme inhi bition. Some antipsychotic drugs may compete for similar metabolic pathways. 

During the acute phase of thyrotoxicosis, B-adrenoceptor blocking agents without intrinsic sympathomimetic activity are extremely helpful. Propranolol, 20-40 mg orally every 6 hours, will control tachycardia, hypertension, and atrial fibrillation. Propranolol is gradually withdrawn as serum thyroxine levels return to normal. Diltiazem, 90-120 mg three or four times daily, can be used to control tachycardia in patients in whom blockers are contraindicated, eg, those with asthma. Other calcium channel blockers may not be as effective as diltiazem. Adequate nutrition and vitamin supplements are essential. Barbiturates accelerate T4 breakdown (by hepatic enzyme induction) and may be helpful both as sedatives and to lower T4... 

Tricyclic antidepressants + barbiturates, carbamazepine —> increased metabolism of the tricyclic due to enzyme induction leading to a reduced antidepressant effect. 

Barbiturates + phenytoin —> decreased anticonvulsant effect due to hepatic enzyme induction enhanced phenytoin toxicity on abruptly stopping barbiturate. 

Barbiturates + oral anticoagulants —> decreased anticoagulant effects due to hepatic enzyme induction. 

Being one of the long-time standards in basic psychopharmacology, there are few major variants to the procedure apart from the kind of barbiturate employed. Several barbiturates undergo clear hepatic metabolism, for example pentobarbital and phenobarbital, thereby confounding interpretations because of pharmacokinetic and metabolic factors. Indeed, one modification of the method has been specifically employed to estimate enzyme induction in the liver as indicated by more rapid barbiturate metabolism. Animals given a pre-exposure to a test substance are then exposed to a standard dose of phenobarbital (80 mg/kg i.p.) 24 hours later and assessed for sleep duration. The presence or absence of a decrease in sleep duration is taken as an index of the hepatic enzyme induction produced by the test substance (Kushikata et al. 2003). 

Induction of cytochrome P450 enzymes by barbiturates and other anticonvulsants can result in increased catabolism of calcidiol, and hence secondary. 

The phenomenon of barbiturate-like enzyme induction is still an issue in drug development, however. The point is not only drug interactions, but particularly the prospect of tumor promotion in rodent cancer bioassays, which is probably unrelated to the P450 induction... 

In hepatic studies, plasma GGT can be used as an indicator of cholestasis, even in rats where plasma GGT levels are normally very low (often less than 2 lU/L). The use of GGT as a marker of enzyme induction and in the presence of hepatic tumors is less predictive in laboratory animals compared with data from human studies (Braun et al. 1987 Batt et al. 1992). GGT synthesis is induced in the liver by some xenobi-otics (e.g., barbiturate) and by compounds that act via the thyroid on the liver (e.g., propylthiouracil and some glucocorticoids) (Sulakhe, Tran, and Pulga 1990). 

Drug Interactions Barbiturates combine with other CNS depressants to cause severe depression ethanol is the most frequent offender, and interactions with first-generation antihistamines also are common. Isoniazid, methylphenidate, and monoamine oxidase inhibitors also increase the CNS-depressant effects. Other prominent drag interactions occin as a result of the induction of hepatic drug-metabolizing enzymes by barbiturates see above). 

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. 

Barbiturates, especially phenobarbital Azoles, calcium channel blockers, propranolol, quinidine, steroids, wailarin, and many other drugs metabolized in the liver Increased deararx of the affected drugs due to enzyme induction, possibly leading to decreases in drug effectiveness... 

Furthermore, nonester-type drugs, especially lidocaine derivatives, also are known to be more prone to enzyme induction or inhibition of other medications (e.g., cimetidine and barbiturates). 

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. ... 

Phase I reactions can be enhanced by enzyme induction. The MFO systems stimulated to increased activity by previcxjs exposure to the same or to a similar foreign compound, which in turn generally increases the biotransfonnJion of these compounds. Barbiturates, halogena hydrocarbons and endogenexjs steroids are examples of MFO enzyme inducers. 

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