Phenobarbital mechanism

Aryl halides react too slowly to undergo substitution by the Sn2 mechanism with the sodium salt of diethyl malonate and so the phenyl substituent of phenobarbital cannot be introduced in the way that alkyl substituents can... 

The results demonstrate anticonvulsant properties of PCP and ketamine in two quite different seizure models. On the one hand, ketamine was effective in antagonizing several components of PTZ activity. Others have previously reported anti-PTZ effects of ketamine. However, the present results demonstrate that the anticonvulsant effects of ketamine against PTZ seizures closely resembled the effects of phenobarbital in that both compounds delayed clonic convulsions and prevented tonic extension. Moreover, a low dose of ketamine, which alone showed no anticonvulsant effect or overt behavioral changes, potentiated the anti-PTZ effects of phenobarbita 1. These findings suggest that ketamine possesses selective anticonvulsant properties. The anticonvulsant mechanism of action for phenobarbital is not known. However, the similarities between ketamine and phenobarbital, and the interaction between the two compounds, suggest a common mechanism or site of acti on. 

Many experts would mechanically intubate the patient if a loading dose of phenobarbital is required... 

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. 

Metofluthrin (I) The committee determined that the new data were sufficient to support a mitogenic mode of action for the development of liver tumors in rats exposed to metofluthrin in the carcinogenicity study. The report summarized mode of action study data that characterized effects such as increased P450 enzyme levels, increased smooth endoplasmic reticulum, hepatocellular hypertrophy, hepatocellular proliferation, and inhibition of intracellular communication, which were described as steps leading to tumor development via a nongenotoxic mechanism (i.e., mitogenicity). Some of these studies used sodium phenobarbital as a positive control,... 

Pyrethrins (I) Pyrethrins induce the formation of liver and thyroid tumors by mechanisms that appear to be similar to those of other non-genotoxic, mitogenic substances, e.g., phenobarbital, which produce tumors in rodents, and these tumors are not predictive of hazard in humans at relevant exposures [99]... 

Sladek, N.E. and Mannering, G.J. (1969) Induction of drug metabolism. I. Differences in the mechanisms by which polycyclic hydrocarbons and phenobarbital produce their inductive effects on microsomal N-demethylating systems. Molecular Pharmacology, 5 (2), 174-185. 

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. 

Pharmacology Primidone s mechanism of antiepileptic action is not known. Primidone and its 2 metabolites, phenobarbital and phenylethylmalonamide (PEMA) have anticonvulsant activity. 

Two main effects occur here. First, change in the pH of urine—weak bases, such as pethidine, are more easily excreted in an acid urine while alkalinisation promotes excretion of weak acids, such as salicylates and phenobarbital. Second, drugs that compete for an active excretion mechanism will reduce each other s elimination—probenecid was used in the early days of penicillin to conserve the drug, while less desirable interactions also occur, e.g. chlorpropamide and phenylbutazone interact to give increased levels of chlorpropamide and a danger of hypoglycaemia. 

Although primidone is converted to phenobarbital, the mechanism of action of primidone itself may be more like that of phenytoin. 

Figure 5.34 Mechanism of induction of CYP2B6 by a chemical such as the drug phenobarbital. This drug activates a nuclear receptor (CAR).This combines with the retinoid X receptor and binds to PBREM, as specific section of the CYP gene, which stimulates the production of CYP2B6 mRNA leading to the production of CYP2B6 protein and enzyme. Abbreviations CAR, constitutive androstane receptor RXR retinoid X receptor PBREM, phenobarbital-responsive enhancer module.

Furthermore, initiation of this repair process by prior treatment of an animal with a small sub-toxic dose will afford protection against a second, larger dose. This may be part of the mechanism underlying the tolerance to the hepa to toxicity of carbon tetrachloride as well as the destruction of cytochrome P-450 (see chap. 7). Effects on tissue repair may also be important in interactions between compounds. Thus, exposure to another agent such as phenobarbital may stimulate tissue repair and decrease the eventual toxicity of carbon tetrachloride. 

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