Barbiturate metabolism

Barbiturates metabolic demand dose as 500 mg IV bolus CPP >60 using hypotension. 

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). 

The benzodiazepines, one of the most widely prescribed groups of drugs, undergo extensive metabolism by routes already described for the barbiturates, namely 7V-dealkylation and hydroxylation. However, unlike the barbiturates, metabolic conversion yields derivatives which have similar pharmacological activities and potencies to those of the parent compounds. For example, the three major metabolites of diazepam are desmethyl-diazepam (nordazepam), 3 -hydroxydiazepam (temazepam), and desmethyl-3-hydroxydiazepam... 

Barbiturate metabolism apparently follows four different routes ... 

Early work with human hepatocjdes showed induction of P450 2C9 by barbiturates and rifampicin , consistent with earlier in vivo work on the induction of barbiturate metabolism . Subsequent studies have shown that P450 2C9 is the only P450 2C subfamily enzyme expressed at a significant level in untreated hepatoc5des and that expression is induced by rifampicin, dexam-ethasone, and phenobarbital - . The induction involves a glucocorticoid receptor, CAR, and PXR, with CAR and PXR apparently competing at the same site . 

A study in 532 healthy patients, aged from 20 to over 80 years, found that those who normally drank aleohol (more than 40 g weekly, roughly 400 mL of wine) needed more thiopental to aehieve anaesthesia than non-drinkers. After adjusting for differenees in age and weight distribution, men and women who were heavy drinkers (more than 40 g aleohol daily) needed 33% and 44% more thiopental, respeetively, for induetion than non-drinkers. Chronie aleohol intake is known to inerease barbiturate metabolism by eytoehrome P450 enzymes. ... 

A water-soluble fraction was shown to have an antianxiety effect in animals comparable to diazepam and to inhibit hepatic enzymes responsible for barbiturate metabolism, and hence may prolong pentobarbitone-induced sleep.The same effect was exhibited by the methanolic and ethyl acetate extracts as well as by asiaticoside in a number of rat behavioral models. ... 

Maintenance doses widely vary among patients (e.g., from 1 to 20 mg/day for warfarin), and are influenced by diet (variable vitamin K intake) and medications that affect coumarin metabolism (decreased drug clearance e.g., cotrimoxazole, amiodarone, erythromycin increased clearance e.g., barbiturates, carbamaze-pine, rifampin). Thus, regular monitoring is needed... 

The most common unwanted effects of the barbiturates are oversedation and psychomotot impaitment, which may petsist well into the next day following a hypnotic dose. Patadoxical excitement, hypersensitivity reactions, and muscle or joint pain may occur in rare cases. Drug-drug interactions occur with the CNS sedatives, and a number of drugs have enhanced metabolism when co-administered with barbiturates (Barnhill et al. 1989). 

Table VI lists several drugs Inducing hepatic microsomal enzymes (5). These enzymes can metabolize the drug as well as other substrates. Barbiturates, grlseofulvln, and glutethlmlde Induce enzymes which metabolize coumarln and phenlndlone derivatives and thus reduce their anticoagulant activity. Dlphenylhydantoln and phenylbutazone stimulate cortisol hydroxylase activity and Increase the urinary excretion of B-hydroxy cortisol and decrease the concentration of cortisol In the plasma.

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. 

Might antagonize verapamil Might induce hypercalcemia with thiazide diuretics Fiber laxatives (variable), oxalates, phytates, and sulfates can decrease calcium absorption if given concomitantiy Phenytoin, barbiturates, carbamazepine, rifampin increase vitamin D metabolism... 

Zolpidem, chemically unrelated to benzodiazepines or barbiturates, acts selectively at the y-aminobutyric acidA (GABAA)-receptor and has minimal anxiolytic and no muscle relaxant or anticonvulsant effects. It is comparable in effectiveness to benzodiazepine hypnotics, and it has little effect on sleep stages. Its duration is approximately 6 to 8 hours, and it is metabolized to inactive metabolites. Common side effects are drowsiness, amnesia, dizziness, headache, and GI complaints. Rebound effects when discontinued and tolerance with prolonged use are minimal, but theoretical concerns about abuse exist. It appears to have minimal effects on next-day psychomotor performance. The usual dose is 10 mg (5 mg in the elderly or those with liver impairment), which can be increased up to 20 mg nightly. Cases of psychotic reactions and sleep-eating have been reported. 

However, metabolic cleavage represents only a very minor pathway for barbiturates, and it has been questioned whether the ring-opened products are really metabolites or artifacts resulting from workup procedures. The most important metabolic pathway for barbiturates is oxidation of the 5-substituent. 

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). 

When used for detoxification, phenobarbital is given in equal doses four times a day. The maximum daily dose of phenobarbital is 600 mg, but much lower doses are usually sufficient. The phenobarbital dose is lowered (i.e., tapered) by about 20% per day. If the patient is too drowsy, then a dose should be skipped. If breakthrough withdrawal symptoms continue to occur, then the pace of the detoxification should be slowed. Before using phenobarbital, liver function tests should be obtained. All barbiturates depend greatly on the liver to be metabolized. Alcoholics with cirrhosis or other forms of liver impairment may have difficulty clearing phenobarbital. Phenobarbital should not be used in patients with poor liver function. In addition, the barbiturates can worsen a medical condition known as porphyria and should be avoided in those with this disorder. Phenobarbital, as noted, is seldom used today for alcohol detoxification. 

The pharmacological activity of a series of 3,5,6-trialkyluracils was studied, considering them as analogues ofbarbitone, and it was found that they did possess sedative action. The 3,5-dibutyl-6-methyl derivative (XLVlll) was reported to be a comparatively potent sedative agent [372]. Partition coefficient and metabolic studies would be of interest in comparing such compounds with the barbiturates. 

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

Hepatic function impairment Barbiturates are metabolized primarily by hepatic microsomal enzymes. Administer with caution and initially in reduced doses. 

Rifampin is known to induce the hepatic microsomal enzymes that metabolize various drugs such as acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta blockers, chloramphenicol, clofibrate, oral contraceptives, corticosteroids, cyclosporine, disopyramide, estrogens, hydantoins, mexiletine, quinidine, sulfones, sulfonylureas, theophyllines, tocainide, verapamil, digoxin, enalapril, morphine, nifedipine, ondansetron, progestins, protease inhibitors, buspirone, delavirdine, doxycycline, fluoroquinolones, losartan, macrolides, sulfonylureas, tacrolimus, thyroid hormones, TCAs, zolpidem, zidovudine, and ketoconazole. The therapeutic effects of these drugs may be decreased. 

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