Phenobarbital toxicity

In 114 patients, of whom 72% took phenobarbital, one had ataxia due to phenobarbital toxicity (4). 

Phenobarbital is absorbed from the small intestine. As much as 50% binds to albumin, and it is metabolized in the liver to hydroxyphenobarbital. Approximately 20 to 25% of phenobarbital is excreted in the urine unchanged. It has a very long elimination half-life of up to 140 hours. Therefore, it is administered orally in a dose of 2 to 3 mg/kg once a day. The renal excretion of phenobarbital is enhanced by the alkalinization of urine, which favors its ionization and excretion. NaHC03 has been used in the management of phenobarbital toxicity. 

Felbamate causes a moderate increase in plasma phenobarbital levels (including those derived from primidone), which has resulted in phenobarbital toxicity. 

Primidone-derived serum phenobarbital levels are increased by phenytoin. This is normally an advantageous interaction, but phenobarbital toxicity occasionally occurs. 

Death from overdose of barbiturates may occur and is more likely when more than 10 times the hypnotic dose is ingested. The barbiturates with high lipid solubility and short half-lives are the most toxic. Thus the lethal dose of phenobarbital is 6—10 g, whereas that of secobarbital, pentobarbital, or amo-barbital is 2-3 g. Symptoms of barbiturate poisoning include CNS depression, coma, depressed reflex activity, a positive Babinski reflex, contracted pupils (with hypoxia there may be paralytic dilation), altered respiration, hypothermia, depressed cardiac function, hypotension, shock, pulmonary complications, and renal failure. 

XenobioticX CAR RXR(DRS) Androstanes Phenobarbital Protection against certain drugs, toxic... 

Acrylonitrile alone has little tendency to produce duodenal ulcers in animals, but pretreatment with phenobarbital or Aroclor results in a marked increase in the incidence of such ulcers (Szabo et al. 1983, 1984). Although the mechanism of the ulcerogenic effect is not obvious, these data indicate that agents which enhanced mixed-function oxidase activity may also increase the toxicity of acrylonitrile. 

In mammals, phenobarbital and phenytoin increase serum ceruloplasmin concentrations (Aaseth and Norseth 1986). Chronic copper poisoning in sheep is exacerbated when diets contain heliotrope plants (Heliotropium sp., Echium spp., Senecio sp.). Aggravated effects of the heliotrope plants include reduced survival and a twofold to threefold increase in liver and kidney copper concentrations when compared to control animals fed copper without heliotropes (Howell et al. 1991). Rats given acutely toxic doses of 2,3,7,8-tetrachlorodibenzo-para-dioxin had elevated concentrations of copper in liver and kidney because of impaired biliary excretion of copper (Elsenhans et al. 1991). Morphine increases copper concentrations in the central nervous system of rats, and dithiocarbam-ates inhibit biliary excretion (Aaseth and Norseth 1986). In human patients, urinary excretion of copper is increased after treatment with D-penicillamine, calcium disodium EDTA, or calcium trisodium diethylenetriamine penta acetic acid (Flora 1991). 

Environmental agents that influence microsomal reactions will influence hexachloroethane toxicity. The production of tetrachloroethene as a metabolite is increased by agents like phenobarbital that induce certain cytochrome P-450 isozymes (Nastainczyk et al. 1982a Thompson et al. 1984). Exposure to food material or other xenobiotics that influence the availability of mixed function oxidase enzymes and/or cofactors will change the reaction rate and end products of hexachloroethane metabolism and thus influence its toxicity. 

Strictly speaking, an acute toxicity study is conducted to examine the effect of a single dose of a single compound. In designing specific toxicity screens, however, deviation from this principle is permissible if it increases screen sensitivity. For example, the sensitivity of mice to many indirect hepatotoxins will be enhanced by prior treatment with phenobarbital. Hence, the sensitivity of a hepatotoxicity screen will be enhanced if the mice are pretreated for three days with phenobarbital. 

Mehendale HM, Ray SD, Cai Z. 1991. Paradoxical toxicity of carbon tetrachloride in isolated hepatocytes from chlordecone, phenobarbital and mirex pretreated rats. In Vitro Toxicology 4(3) 187-196. 

DuBois KP, Kinoshita FK. 1968. Influence of induction of hepatic microsomal enzymes by phenobarbital on toxicity of organic phosphate insecticides. Proc Soc Exp Biol Med 129 699-702. 

Fawade MM, Pawar SS. 1980. Effect of phenobarbital pretreatment on mixed function oxidase and lipid peroxidation during thiodemeton toxicity. Indian J Exp Biol 18 645-647. 

The mechanism of toxification of isoniazid was investigated in rats pretreated with inducers or inhibitors of microsomal enzymes or an inhibitor of acylamidases. In animals pretreated with the acylamidase inhibitor bis(4-nitrophenyl) phosphate, isoniazid and acetylisoniazid produced less liver necrosis than in control animals. The treatment had no effect on the necrosis due to acetylhydrazine [173], In animals pretreated with inducers of microsomal cytochrome P450 such as phenobarbital, acetylisoniazid, and acetylhydrazine caused markedly increased necrosis, while pretreatment with cytochrome P450 inhibitors decreased necrosis. In contrast, the toxicity of isoniazid and hydrazine was not modified by phenobarbital pretreatment. From these observations, Trimbell et al. [173] concluded that the hydrolysis of acetylisoniazid is a prerequisite for hepatotoxicity, and that microsomal enzymes transform acetylhydrazine, the product of hydrolysis, to a toxic species. 

Bailie MB, Smith JH, Newton JF, et al. 1984. Mechanism of chloroform nephrotoxicity. IV. Phenobarbital potentiation of in vitro chloroform metabolism and toxicity in rabbit kidneys. Toxicol Appl Pharmacol 74 285-292. 

Drew, R.T. and Fonts, J.R. The lack of effects of pretreatment with phenobarbital and chlorpromazine on the acute toxicity of benzene in rats, Toxicol. Appl. Pharmacol, 27 1) 183-19Z, 1974. 

Barbiturates. The hrst barbiturate, barbital, was introduced in 1903 and was followed a few years later by phenobarbital. The barbiturates effectively relieve anxiety, but they are never used as anxiolytics today due to toxicity and abuse concerns. However, several barbiturates, including phenobarbital (Luminal), secobarbital (Seconal), and pentobarbital (Nembutal), remain available and are occasionally used to treat epilepsy and rarely to manage acute alcohol withdrawal. 

Figure 4. Toxic and mutagenic response of diploid human lymphoblast line MIT-2 to aflatoxin B,. Open symbols afatoxin + phenobarbital-induced rat liver postmitochondrial supernatant (PMS) closed symbols effect of treatment with either aflatoxin or FMS alone.

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... 

---