Phenobarbital metabolism/excretion

Pharmacokinetics PO route onset 20-60 min, peak N/A, duration 6-8 hr. Well absorbed after PO administration. Widely distributed. Metabolized in liver to active metabolite, a form of phenobarbital. Minimally excreted in urine. Removed by hemodialysis. Half-life 34 hr. 

Drugs affecting fiver enzymes may alter phenobarbital metabolism, but phenobarbital clearance is not affected by fiver blood flow. The elimination of phenobarbital is linear. Because tubular reabsorption of phenobarbital is pH dependent, the amount excreted renally can be increased by giving diuretics and urinary alkalinizers." ... 

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. 

Conversely, certain drugs modify the effectiveness or side effects of aspirin. Phenobarbital, occasionally used for seizures, induces liver enzymes that increase the metabolism and excretion of aspirin, (3-adrenoceptorblocking drugs, such as propranolol, and decrease the antiinflammatory effects of aspirin, whereas reserpine decreases its analgesic effects. Antacids decrease the absorption of aspirin. Alcohol consumption in combination with aspirin increases the latter s ulcerogenic effects. 

Phenobarbital is effective orally and is distributed widely throughout the body. It is metabolized by microsomal drug-metabolizing enzymes, but up to 50% of the parent drug is excreted unchanged by the kidneys. Primidone is metabolized to phenobarbital and phenyl-ethylmalonamide. The latter metabolite has anticonvulsant activity, but most of the anticonvulsant efficacy of primidone is due to the phenobarbital that is produced. 

Primidone is metabolized by oxidation to phenobarbital, which accumulates very slowly, and by scission of the heterocyclic ring to form (Figure 24-6). Both primidone and phenobarbital also undergo subsequent conjugation and excretion. 

The inactive metabolites are excreted in the urine. The administration of bicarbonate enhances the urinary excretion of barbiturates that have a pK of 7.4 (phenobarbital and thiopental). This generalization is not true of other barbiturates. The long-term administration of barbiturates activates the cytochrome P-450 drug-metabolizing system. 

Phenobarbital is absorbed rapidly and well after oral administration to horses, with bioavailability approaching 100% (Ravis et al 1987). It is distributed widely into the tissues but, because of its lower lipid solubility, does not distribute into the CNS as rapidly as other barbiturates. After i.v. administration, it may take 15-20 min before therapeutic concentrations of phenobarbital are reached in the CNS. Phenobarbital primarily undergoes hepatic metabolism and only 25% is excreted as unchanged drug. The half-lives reported in horses, around 18-24 h (Duran et al 1987, Knox et al 1982, Ravis et al 1987) and 12 h in foals (Spear et al 1984), are substantially shorter than in other species, meaning that steady-state concentrations can be achieved more rapidly. 

Much of the evidence, however, is based on prolonged plasma half-lives of drugs that are metabolized totally or mainly by hepatic micrasomal enzymes (e.g antipyrine, phenobarbital, acetaminophen). In evaluating the effect of age on drug metabolism, one must differentiate between normal" loss of enzymatic activity with aging and the effect of a disea.sed iiver from hepatitis, cirrhosis, etc., plus decreased renal function, becau.se much of the water-soluble conjugation products are excreted in the liver. 

The majority of a dose is excreted in the urine as PEMA 15% as phenobarbital. The plasma elimination half-lives of primidone, PEMA, and phenobarbital are 8-10, 24-36, and 100 h, respectively. The metabolism of primidone is enhanced with chronic therapy, with a reduced half-life of 4-7 h. An elimination half-life of 6.2 h has been documented following overdose. 

Oxidation of substituents attached to C5 is the most important pathway of metabolism for the barbiturates. The oxidative processes may yield alcohols, ketones, and carboxylic acids. For example, pentobarbital is oxidized to a hydroxy compound and a carboxylic acid (8) as shown in Fig. 5.2. The oxidative process may also yield phenols. If the barbiturate has a phenyl group attached to C5, by far the most important metabolic product is the p-hydroxyphenyl derivative, which has been shown to be formed through the intermediate epoxide (9). For example, phenobarbital is metabolized top-hydroxyphenobarbital (Fig. 5.3). The oxygenated metabolites (alcohols, phenols, ketones, and carboxylic acids) may be excreted in the urine in the free form or conjugated with glucuronic or sulfuric acid. 

Elimination. Barbiturates are eliminated from the body both by hepatic metabolism and by renal excretion. In the liver, phenobarbital is parahydroxylated and subsequently conjugated to glucuronic acid. 

Phenobarbital is metabolized by CyP 2C19 to p-hydroxy-phenobarbital, which is largely excreted as the glucuronide (by UGT). When renal and hepatic function are decreased, patients experience decreased clearance of the drug. Alcohol, carbamazepine, other barbiturates, and rifampin induce oxidative enzymes (CyP 2C19 and 2C9) this induction results in increased metabolism of phenytoin, reduced serum concentration of phenobarbital, and a reduced pharmaco-... 

The barbiturates undergo extensive hepatic metabolism in which the C5 substituents are transformed to alcohols, phenols, ketones, or carboxylic acids these metabolites may be excreted in urine in part as glucuronide conjugates. For some barbiturates (amobarbital and phenobarbital), N-glucosylation is an additional important metabolic trans-... 

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