Pentobarbital
T 1/2: 20-30 hours
Vd: 0.5-1.0 L/kg
Fb: 0.65
pKa: 7.9
Occurrence and Usage. Pentobarbital (pentobarbitone, Nembutal) is a very popular short-acting barbiturate derivative first prepared in 1930. The drug is available alone and in combination with other agents in amounts of 15-200 mg for oral, intramuscular, or rectal administration. It is supplied as the racemic mixture in the form of both the free acid and the sodium salt, the latter being strongly alkaline in aqueous solution.
Blood Concentrations. After a 5-minute intravenous infusion of 50 mg, plasma concentrations in 5 subjects averaged 1.18 mg/L (range, 1.05-1.33) at 0.08 hours, declining to 0.54 mg/L by 1 hour and 0.27 mg/L by 24 hours (Smith et al., 1973). Plasma concentrations averaged 3 mg/L at 6 minutes after intravenous injection of 100 mg of pentobarbital to 7 volunteers and fell to 1.6 mg/L by 1 hour, when they began to decline with a half-life of 22 hours (Ehrnebo, 1974). A single oral dose of 100 mg produced peak serum pentobarbital concentrations of 1.2-3.1 mg/L at 0.5-2.0 hours after administration; these levels diminished slowly, and after 48 hours an average serum concentration of 0.3 mg/L was found (Sun and Chun, 1977). Estimates of the plasma half-life of pentobarbital have ranged from 15-48 hours, with the average between 20 and 30 hours (Breimer, 1977). The oral administration of 600 mg of the drug over a 3-hour period produced a maximal average blood concentration of 3.0 mg/L (range, 1.8-4.7) in 5 subjects by 0.5 hours after the last dose; this level remained unchanged by 4.5 hours and declined to 1.5 mg/L (range, 1.2-1.7) after 18 hours (Parker et al., 1970).
Repeated intravenous doses of pentobarbital, usually 100-200 mg every 30-60 minutes, have been used to reduce intracranial pressure and lower cerebral oxygen demand in patients with severe head trauma, Reye’s syndrome, or anoxic brain damage. The doses are adjusted to maintain the plasma drug level at 25-40 mg/L, and therapy may continue for up to several weeks (Marshall et al., 1978, 1979). The plasma 3′-hydroxypentobarbital concentrations in such patients are generally less than 10% those of the parent drug levels (Cary and Pape, 1983).
Metabolism and Excretion. The biotransformation of pentobarbital proceeds primarily via oxidation of the penultimate carbon of the methylbutyl side-chain with formation of a diastereoisomeric mixture of alcohols, and secondarily by N-hydroxylation (Maynert, 1965; Tang et al., 1977). Unlike hydroxyamobarbital, the alcoholic metabolites of pentobarbital are pharmacologically inactive (Maynert and Dawson, 1952). The existence of a carboxylic acid metabolite resulting from the oxidation of the terminal methylbutyl side-chain carbon atom has also been suggested (Algeri and McBay, 1953; Titus and Weiss, 1955). The oral bioavailability of pentobarbital is 100% (Doluisio et al., 1978).
As much as 86% of a radioactive dose of pentobarbital is excreted in the urine in 6 days; about 1% is present as unchanged drug, up to 73% as the levorotatory and dextrorotatory diastereoisomers of 3′-hydroxypentobarbital (in a 5.4 to 1 ratio), and up to 15% as N-hydroxypentobarbital (Maynert, 1965; Tang et al., 1977). None of the metabolites was found to be eliminated in a conjugated form. Parker et al. (1970) found urine pentobarbital concentrations of only 0.7-1.8 mg/L throughout the 21-hour period after a 600 mg oral dose of the drug, representing less than 0.2% of the total dose.
Toxicity. Although the frequency of pentobarbital involvement in poisoning episodes has declined in recent years, much data has been accumulated on the tissue levels of the drug following overdosage. A plasma concentration of 28 mg/L was achieved by a comatose patient who regained consciousness when the level fell to 13 mg/L after 24 hours (Prescott et al., 1973).
In 61 fatalities attributed to pentobarbital, postmortem blood concentrations ranging from 12-112 mg/L (average, 40) were determined (Rehling, 1967). In another 55 cases, blood concentrations averaged 30 mg/L (range, 5-169) and liver concentrations averaged 130 mg/kg (range, 23-550) (Baselt and Cravey, 1977).
The estimated lethal dose as established by investigation of these cases has ranged from 2-10 g (Cravey et al., 1977). In three fatal overdoses in which pentobarbital and 3′-hydroxypentobarbital concentrations were measured by gas chromatography, the following tissue distribution was observed (Robinson and McDowall, 1979):
Analysis. Analytical methods for the determination of barbiturate derivatives are discussed in the section on amobarbital.