Phenobarbital, effect

Elskus, A.A. and J.J. Stegeman. Further consideration of phenobarbital effects on cytochrome P-450 activity in the killifish, Fundulus heteroclitus. Comp. Biochem. Physiol. 92C 223-230, 1989. 

Battino D, Avanzini G, Bossi L, Croci D, Cusi C, Gomeni C, Moise A. Plasma levels of primidone and its metabolite phenobarbital effect of age and associated tiierapy. TherDn Monit (1983) 5, 73-9. 

Primidone [125-33-7] C22H24N2O2 (39) is an analogue of phenobarbital that is used for the treatment of generalized tonic-clonic seizures. It is metabolized in humans to phenobarbital (6) and phenylethyLmalondiamide [7206-76-0J, C22H24N2O2 (40) and these metaboUtes are probably responsible for its anticonvulsant actions. Primidone has many of the side effect HabiUties seen with phenobarbital. 

Kodama S, Negishi M (2006) Phenobarbital confers its diverse effects by activating the orphan nuclear receptor CAR. Drug Metab Rev 38 75-87... 

The metabolism of metronidazole may decrease when administered widi cimetidine When administered widi phenobarbital, die effectiveness of metronidazole may decrease When metronidazole is administered widi warfarin, die effectiveness of die warfarin is increased. 

When metronidazole is administered with cimeti-dine, the metabolism of metronidazole is decreased when it is administered with phenobarbital, the metabolism is increased, possibly causing a decrease in the effectiveness of metronidazole Metronidazole increases the effects of warfarin. 

Occasionally, status epilepticus (an emergency situation characterized by continual seizure activity with no interruptions) can occur. Diazepam (Valium) is most often the initial drug prescribed for this condition. However, because the effects of diazepam last less than 1 hour, a longer-lasting anticonvulsant, such as phenytoin or phenobarbital, also must be given to control the seizure activity. 

The most common adverse reaction associated with phenobarbital is sedation, which can range from mild sleepiness or drowsiness to somnolence. These dru > may also cause nausea, vomiting, constipation, bradycardia, hypoventilation, skin rash, headache fever, and diarrhea Agitation, rather than sedation, may occur in some patients. Some of these adverse effects may be reduced or eliminated as therapy continues. Occasionally, a slight dosage reduction, without reducing the ability of the drug to control the seizures, will reduce or eliminate some of these adverse reactions. 

The barbiturates are contraindicated in patients with known hypersensitivity to the drugs. The barbiturates are used cautiously in patients with liver or kidney disease and those with neurological disorders. The barbiturates (eg, phenobarbital) are used with caution in patients with pulmonary disease and in hyperactive children. When barbiturates are used with other CNS depressants (eg, alcohol, narcotic analgesics, and antidepressants), an additive CNS depressant effect may occur. See Chapter 26 for additional information on the barbiturates. 

NSAIDs or phenobarbital, their antihypertensive effects may be decreased. 

Long-acting barbiturates used as sedative-hypnotics and also for their anticonvulsant effects include phenobarbital (Luminal) and mephobarbital (Mebaral). 

Compounds that affect activities of hepatic microsomal enzymes can antagonize the effects of methyl parathion, presumably by decreasing metabolism of methyl parathion to methyl paraoxon or enhancing degradation to relatively nontoxic metabolites. For example, pretreatment with phenobarbital protected rats from methyl parathion s cholinergic effects (Murphy 1980) and reduced inhibition of acetylcholinesterase activity in the rat brain (Tvede et al. 1989). Phenobarbital pretreatment prevented lethality from methyl parathion in mice compared to saline-pretreated controls (Sultatos 1987). Pretreatment of rats with two other pesticides, chlordecone or mirex, also reduced inhibition of brain acetylcholinesterase activity in rats dosed with methyl parathion (2.5 mg/kg intraperitoneally), while pretreatment with the herbicide linuron decreased acetylcholine brain levels below those found with methyl parathion treatment alone (Tvede et al. 1989). 

Type I Crigler-Najjar syndrome is a rare autosomal recessive disorder. It is characterized by severe congenital jaundice (serum bilirubin usually exceeds 20 mg/dL) due to mutations in the gene encoding bilirubin-UGT activity in hepatic tissues. The disease is often fatal within the first 15 months of life. Children with this condition have been treated with phototherapy, resulting in some reduction in plasma bilirubin levels. Phenobarbital has no effect on the formation of bilirubin glucuronides in patients with type I Crigler-Najjar syndrome. A liver transplant may be curative. 

A variety of drugs have been developed that act as sedatives, antidepressants, or stimulants some of these are effective in treating psychiatric disorders. Many of these drugs are weak bases. Examples are barbiturates such as phenobarbital, tranquilizers like diazepam (Valium), and amphetamines derived from phenylethylamine. 

In this study, potential oscillation was measured in the presence of lOOmM sodium salts of barbital, allobarbital, phenobarbital, and amobarbital in phase wl [19]. Their chemical structures are shown in Fig. 15. Amplitude and the oscillatory and induction periods were noted to depend on the particular hypnotic used. Amplitude decreased in the order, barbital > allobarbital > phenobarbital > amobarbital. The oscillatory period increased in the order, barbital < allobarbital < phenobarbital < amobarbital. Induction period increased in the order, barbital < allobarbital < phenobarbital < amobarbital. These parameters changed depending on drug concentration. Hypnotics at less than 5 mM had virtually no effect on the oscillation mode. 

The profiles of anticonvulsant effects for phenobarbital, pheny-toin, and trimethadione were also determined in the PTZ model. 

Phenobarbital closely resembled ketamine, but was more effective in delaying clonic and tonic convulsions (figure 1). In contrast, phenytoin was effective only in preventing tonic extension convulsions and delaying lethality (figure 2). Trimethadione delayed the clonic and tonic endpoints but did not prevent tonic extension convulsions or the lethal effect of the tonic convulsion (figure 2). 

FIGURE 1. Effect of phenobarbital and ketamine on pentylenetetrazol convulsions... 

The interaction of ketamine with each of the three anticonvulsant compounds was also tested. Ketamine, 15 mg/kg, a dose showing no anti-PTZ effect and causing no overt behavioral changes, potentiated the effect of phenobarbital (20 mg/kg) in delaying the clonic and tonic convulsive responses and lethality (figure 3). Ketamine also potentiated the ability of phenytoin (20 mg/kg) to delay... 

Anticonvulsant drugs such as carbamazepine, diazepam, valproic acid, and phenobarbital also slightly increased the duration of the initial AD. However, the effects of these drugs on the other associated seizure events were quite different from PCP and ketamine. The effects of carbamazepine and diazepam, typical of the four compounds, are illustrated in figure 4. These compounds either suppressed the rebound spiking (diazepam, valproic acid, and phenobarbital) or lengthened the total seizure duration with no rebound suppression (carbamazepine). 

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. 

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