Phenobarbital Ethanol

The cytochrome P450 (CYP) system is the group of enzymes of most interest to psychiatrists. These enzymes show considerable genetic variation, and certain isozymes can be induced by specific substrates such as phenobarbital, ethanol, and steroids. They can also be inhibited by various medications that are potent competitive inhibitors of the enzymes (e.g., cimetidine and ketoconazole). 

Animal studies indicate that trichloroethylene can sensitize the heart to epinephrine-induced arrhythmias. Other chemicals can affect these epinephrine-induced cardiac arrhythmias in animals exposed to trichloroethylene. Phenobarbital treatment, which increases the metabolism of trichloroethylene, has been shown to reduce the trichloroethylene-epinephrine-induced arrhythmias in rabbits (White and Carlson 1979), whereas high concentrations of ethanol, which inhibits trichloroethylene metabolism, have been found to potentiate trichloroethylene-epinephrine-induced arrhythmias in rabbits (White and Carlson 1981). These results indicate that trichloroethylene itself and not a metabolite is responsible for the epinephrine-induced arrhythmias. In addition, caffeine has also been found to increase the incidence of epinephrine-induced arrhythmias in rabbits exposed to trichloroethylene (White and Carlson 1982). 

Nakajima T, Wang RS, Murayama N, et al. 1990b. Three forms of trichloroethylene-metabolizing enzymes in rat liver induced by ethanol, phenobarbital, and 3-methylcholanthrene. Toxicol Appl Pharmacol 102 546-552. 

Okino T, Nakajima T, Nakano M. 1991. Morphological and biochemical analyses of trichloroethylene hepatotoxicity Differences in ethanol- and phenobarbital-pretreated rats. Toxicol Appl Pharmacol 108 379-389. 

The hepatic microsomal a-hydroxylase activity for NPYR is inducible in rats by pretreatment with Aroclor, and in hamsters by pretreatment with Aroclor, 3-methylcholanthrene, phenobarbi-tal, and ethanol (10,15,19). In contrast, pretreatment of rats with 3-methylcholanthrene or phenobarbital causes no change or a slight decrease in microsomal NPYR o-hydroxylase activity (19). 

Ethanol increases phenobarbital metabolism, but valproic acid, cimeti-dine, and chloramphenicol inhibit its metabolism. 

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). 

A number of substances including ethanol, isopropyl alcohol, polybrominated biphenyls, phenobarbital, and benzo( )pyrene have been shown to synergistically affect carbon tetrachloride toxicity." Alcohol has been a concomitant factor in many of the human cases of poisoning, especially in cases in which severe liver and kidney damage have occurred. Some substances such as chlordecone greatly potentiate the toxicity of carbon tetrachloride at... 

Long-acting drugs such as chlordiazepoxide and diazepam and, to a lesser extent, phenobarbital are administered in progressively decreasing doses to patients during withdrawal from physiologic dependence on ethanol or other sedative-hypnotics. Parenteral lorazepam is used to suppress the symptoms of delirium tremens. 

Examples of drugs with large volumes of distribution (> 5 L/kg) include antidepressants, antipsychotics, antimalarials, opioids, propranolol, and verapamil. Drugs with a relatively small (< 1 L/kg) include salicylate, ethanol, phenobarbital,... 

In isolated rat hepatocytes obtained from acetone- or phenobarbital-treated rats, the metabolism of toluene at low (below 100 pM) or high (100-500 pM) concentration was increased, in particular after phenobarbital treatment. Ethanol (7 and 60 mM) inhibited the overall metabolism of toluene (sum of benzyl alcohol, benzaldehyde, benzoic acid and hippuric acid), leading to accumulation of benzyl alcohol (Smith-Kielland Ripel, 1993). 

Elovaara, E., Engstrom, K., Hayri, L., Hase, T. Aitio, A. (1989) Metabolism of antipyrine and OT-xylene in rats after prolonged pretreatment with xylene alone or xylene with ethanol, phenobarbital or 3-methylcholanthrene. Xenobiotica, 19, 945-960... 

Rapaport and Solyanik (168) have developed a rapid method of refractometric determination of 23 mixtures containing anesthesin, barbamyl, bromcamphor, bro-misoval, camphor, antipyrine, amidopyrine, acetalsali-cylic acid, barbital, codeine, salol, terpin hydrate, hexamethylenetetramine, and phenobarbital. The method described is suitable for analysis of pharmaceutical mixtures containing compounds which are insoluble in water and soluble in ethanol. A mixture of 2 pharmaceuticals (0.1 g) is dissolved in 1 ml. ethanol and np of this solution is determined. One component is... 

Fusari and coworkers3 have developed a similar method for the assay of phenytoin and phenobarbital in dosage forms. They have used Silanized Celite 545 as the support material, 25% amyl alcohol in chloroform as the stationary phase and 0.05M borate buffer of pH 9.5 as the mobile phase. Phenobarbital was eluted with the mobile phase and phenytoin eluted with absolute ethanol. Ultraviolet absorption was used to quantitate the substances. 

Some toxicants that affect body temperature are shown in Figure 6.11. Among those that increase body temperature are benzadrine, cocaine, sodium fluoroacetate, tricyclic antidepressants, hexachlorobenzene, and salicylates (aspirin). In addition to phenobarbital and ethanol, toxicants that decrease body temperature include phenothiazine, clonidine, glutethimide, and haloperidol. 

Examples of toxicants that affect body temperature. Amphetamine, cocaine, and fluoroacetate increase body temperature phenobarbital and ethanol decrease it. 

Bicchi and Bertolino [193] analyzed a variety of pharmaceuticals for residual solvents. Samples were equilibrated directly or dissolved in a suitable solvent with a boiling point higher than that of the residual solvent to be determined. Equilibration conditions were 90 or 100°C for 20 min. A Perkin-Elmer HS-6 headspace sampler was used. The chromatographic phase chosen was a 6 x Vs in. column packed with Carbopack coated with 0.1% SP 1000. Residual ethanol in phenobarbital sodium was determined by a direct desorption method. An internal standard, /-butanol, was used. Typically, 0.44% of ethanol was detected (compared to a detection limit of 0.02 ppm). The standard deviation of six determinations was 0.026. Pharmaceutical preparations which were analyzed by the solution method included lidocaine hydrochloride, calcium pantothenate, methyl nicotinate, sodium ascorbate, nicotinamide, and phenylbutazone. Acetone, ethanol, and isopropanol were determined with typical concentrations ranging from 14 ppm for ethanol to 0.27% for acetone. Detection limits were as low as 0.03 ppm (methanol in methyl nicotinate). 

D. Phenobarbital induces respiratory depression, which is enhanced by the consumption of ethanol. 

Correct answer = D. Barbiturates and ethanol are a potentially lethal combination. Phenobarbital is unable to alter the pain threshold. 

There is general agreement among various investigators in the field of benzene toxicity that benzene metabolites, rather than benzene, are the primary toxic agents in the induction of hematotoxicity. This agreement has evolved as a result of studies in which agents known to alter benzene metabolism (toluene, phenobarbital, and ethanol) have also altered benzene toxicity (Andrews et al. 1977 Sammett et al. 1979). 

Studies have been conducted on the interaction of benzene with other chemicals, both in vivo and in the environment. Benzene metabolism is complex, and various xenobiotics can induce or inhibit specific routes of detoxification and/or activation in addition to altering the rate of benzene metabolism and clearance from the body. Toluene, Aroclor 1254, phenobarbital, acetone, and ethanol are known to alter the metabolism and toxicity of benzene. 

Hanzlick R. 1995. National association of medical examiners pediatric toxicology (pedtox) registry report 3 case submission summary and data for acetaminophen, benzene, carboxyhemoglobin, dextromethorphan, ethanol, phenobarbital, and pseudoephedrine. American Journal of Forensic Medicine and Pathology 16 (4) 270-277. 

Nakajima T, Okuyama S, Yonekura I, et al. 1985. Effects of ethanol and phenobarbital administration on the metabolism and toxicity of benzene. Chem-Biol Interact 55 23-38. 

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