Phenobarbital
T1/2: 2-6 days
Vd: 0.5-0.6 L/kg
Fb: 0.50
pKa: 7.2
Occurrence and Usage. Phenobarbital is a barbiturate derivative that has been used as a daytime sedative and very extensively as an anticonvulsant since 1912. Phenobarbital is an excellent inducer of drug-metabolizing microsomal enzymes and its use often results in the lowering of plasma levels of other drugs. Its low oil/water partition coefficient relative to other barbiturates is the basis for its slow accumulation in brain tissue and its limited metabolism. The drug is available as either the free acid or the sodium salt in an elixir or as tablets of 15-65 mg for oral use or in a 65-130 mg/mL solution for intramuscular or intravenous injection. It is often found in combination with bronchodilators, vasodilators, analgesics, and anticholinergic agents. It is generally administered to epileptic patients in oral doses of 60-200 mg daily, often in combination with other anticonvulsant drugs.
Blood Concentrations. A single 30 mg oral dose given to 3 volunteers produced an average peak serum concentration of about 0.7 mg/L, while the same dose repeated for 21 days resulted in an average peak level of 8.1 mg/L. Rather than inducing its own metabolism, phenobarbital appeared to have a longer half-life after repeated dosing (Viswanathan et al., 1979). Following oral administration of 600 mg of phenobarbital to volunteers, the average peak blood concentration measured 4.5 hours later was 18 mg/L (range 12-26) (Parker et al., 1970).
With chronic administration of 200 mg daily to epileptic patients, blood concentrations averaged 29 mg/L and ranged from 16-48 mg/L (Plaa and Hine, 1960). Plasma concentrations of 10-30 mg/L are generally considered desirable in patients receiving phenobarbital as an anticonvulsant, and it may require 14-21 days to achieve a steady-state level. The compound has an average plasma half-life of approximately 4 days (Kutt and Penry, 1974).
Metabolism and Excretion. Biotransformation of phenobarbital occurs primarily by N-glucoside formation and by oxidation to p-hydroxyphenobarbital, which is consequently conjugated with glucuronic acid. A dihydrodibydroxyphenyl metabolite has also been identified in minor amounts and is thought to arise from an epoxide intermediate (Harvey et al., 1972). From 78%-87% of a single labeled dose is excreted in the urine within 16 days as unchanged drug (25%-33%), N-glucosylphenobarbital (24%-30%), and free or conjugated p-hydroxyphenobarbital (18%-19%) (Tang et al., 1979). In patients on chronic phenobarbital therapy, an average of 25% (range, 12%-55%) of the dose is excreted unchanged in the 24-hour urine; 8% is excreted as free p-hydroxyphenobarbital and 9% as the glucuronide conjugate (Whyte and Dekaban, 1977). In volunteers receiving a single dose of 600 mg of phenobarbital, less than 2% was excreted unchanged in urine during the first 21 hours, and peak urine phenobarbital concentrations ranged from 8-22 mg/L (Parker et al., 1970).
The following concentrations
are indicative of phenobarbital tissue distribution during therapy in an epileptic patient (Sakata et al., 1985):
Toxicity. Toxic reactions to phenobarbital in chronically dosed subjects generally occur when plasma concentrations exceed 40 mg/L. Patients developing coma with reflexes present exhibited plasma concentrations of 65-117 mg/L, while those lacking deep tendon reflexes had concentrations of 100-134 mg/L (Sunshine, 1957). One patient survived overdosage of the drug after achieving a plasma phenobarbital level of 253 mg/L (Costello and Poklis, 1981).
In acute fatalities 
that occurred after ingestion of as little as 6 g of phenobarbital, blood concentrations ranged from 78-116 mg/L and liver concentrations from 89-266 mg/kg (Cravey, 1975). The following body distribution of phenobarbital was observed in the death of an epileptic patient (Bruce and Smith, 1977):
Analysis. The classical approach to measurement of phenobarbital in biological specimens involves ultraviolet spectrophotometry (Goldbaum, 1952); this technique has been modified to allow the simultaneous determination of phenytoin, which otherwise would interfere with the assay (Wallace, 1969). Gas chromatography provides a more specific result and is usually performed with flameionization or nitrogen-selective detection of the free drug (Ritz and Warren, 1975) or its methylated derivative (Kananen et al., 1972; Vandemark and Adams, 1976). Gas chromatographic procedures have been described for determination of p-hydroxyphenobarbital in plasma and urine (Kallberg et al., 1975; Patel et al., 1980). Phenobarbital has been included in a general liquid chromatographic scheme for the common anticonvulsant drugs (Kabra et al., 1978). Reagents are commercially available for determination of the drug by enzyme immunoassay and radioimmunoassay.