Phenobarbital bioavailability

When utilized as sedative hypnotics, barbiturates are administered orally. They are rapidly and completely absorbed by this route with nearly 100% bioavailability and an onset of action ranging from 10 to 60 min.3 Sodium salts are more rapidly absorbed than free acids. Intramuscular injections of sodium salts should be made deep into the muscle to prevent pain and tissue damage. Some barbiturates are also administered rectally barbiturates utilized for the induction and maintenance of anesthesia (thiopental) or for treating status epilepticus (phenobarbital) are administered intravenously. 

CALCIUM CHANNEL BLOCKERS BARBITURATES L plasma concentrations of felodipine, nifedipine, nimodipine, nisoldipine and verapamil with phenobarbital Phenobarbital induces CYP3A4, which metabolizes calcium channel blockers. It also induces intestinal P-gp, which may 1 the bioavailability of verapamil Monitor PR and BP closely watch for Tbp... 

Elixirs are sweetened hydroalcoholic oral solutions that are specially formulated for oral use in infants and children. Digoxin, a non-ionizable cardiotonic glycoside, is practically insoluble in water and is solubilized in propylene glycol, 10% ethanol, flavor, sweetener, preservative, and buffers to 50pg/ml in Lanoxin Elixir Pediatric from which the oral bioavailability of digoxin is 70-85%. Phenobarbital, an anticonvulsant and sedative with an intrinsic water solubility of 1 mg/ml, is solubilized in water, 23% ethanol, glucose, sodium saccharin, and flavors to 3.5 mg/ml in Donnatal Elixir. 

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. 

Peak plasma levels occur 1-4 h for capsules and syrup and 3 h for delayed-release capsules and tablets. Absorption is delayed but not diminished in the presence of food. Bioavailability appears to be complete. The majority of a dose undergoes hepatic glucuro-nidation or oxidation. At least two metabolites, 2-propyl-2-pentenoic acid and 2-propyl-4-pentenoic acid, have anticonvulsant activity. Biotransformation can be enhanced by enzyme-inducing drugs (e.g., primadone, carbamazine, phenobarbital, and... 

Unfortunately, only relatively few of the many papers published on povidone deal with its influence on bioavailability in vivo. However, where results are available, they almost always show an improvement in bioavailability. Figs. 49 to 51 show the effect of coprecipitation with povidone on the bioavailability of different active substances administered by different routes. Fig. 49 shows, as a typical example, the oral bioavailability of a nifedipine coprecipitate in the rat, Fig. 50 shows the rectal bioavailability of a phenobarbital coprecipitate in rabbits, while Fig. 51 shows the effect of a hydrocortisone coprecipitate on the human skin after percutaneous administration. In all three cases, the same dose of the pure active substance without povidone was applied for reference. 

A 40-year-old man was brought to the ER after ingesting an unknown quantity of phe-nobarbital, the plasma level of which was 50 mg/L on admission. Pharmacokinetic parameters for phenobarbital are Vd = 40 L, CL = 6 L/day, half-life - 4 days, oral bioavailability f = 1, The quantity of the drug that the patient ingested must have been close to... 

Aluminum salts, cholestyramine, and colestipol may decrease absorption of /3 blockers. Pheny-toin, rifampin, and phenobarbital, as well as smoking, induce hepatic biotransformation enzymes and may decrease plasma concentrations of /3 receptor antagonists that are metabolized extensively (e.g., propranolol). Cimetidine and hydralazine may increase bioavailability of propranolol and metoprolol by affecting hepatic blood flow, fi Receptor antagonists can impair the clearance o/lidocaine. 

Chlorpromazine and tricyclic antidepressants increase the respiratory-depressant and sedative effects of meperidine. Increased respiratory depression is not seen with concomitant use of diazepam. Treatment with phenobarbital or phenytoin increases systemic clearance and decreases oral bioavailability of meperidine this is associated with an elevation of the plasma concentration of normeperidine. Concomitant administration of amphetamine has been reported to enhance the analgesic effects of meperidine and its congeners while counteracting sedation. 

Inducers of hepatic CYPs such as carbamazepine and phenobarbital reduce the bioavaUabihty of praziquantel. Dexamethasone reduces the bioavailability of praziquantel, but the mechanism is not understood. Under certain conditions, praziquantel may increase the bioavailability of albendazole. 

Four hours after ingestion of an unknown quantity of phenobarbital, a patient was hospitalized and the drug concentration in the plasma was found to be 50 mg/L. Assume that in this patient pharmacokinetic parameters for phenobarbital are as follows oral bioavailability = 100% V j = 40 L CL = 6 L/d half-life = 4 days. Estimate the dose of phenobarbital ingested. The Skill Keeper Answer appears at the end of the chapter. 

Phenytoin The oral bioavailability of phenytoin is variable because of differences in first-j>ass metabolism. Phenytoin metabolism is nonlinear elimination kinetics shift from first-order to zero-order at moderate to high dose levels. The drug binds extensively to plasma proteins (97-98%), and free (unbound) phenytoin levels in plasma are increased transiently by drugs that compete for binding (eg, sulfonamides, valproic acid). The metabolism of phen)Toin is enhanced in the presence of inducers of liver metabolism (eg, phenobarbital, rifampin) and inhibited by other drugs (eg, cimetidine, isoniazid). Fos-phenytoin is a water-soluble prodrug form of phen)Toin that is used parenterally. 

A >. (X Eh X o (X e Eh o PO. 50% bioavailability, >90% plasma protein bound, half-life = 2-3 hrs, eliminated as unchanged drug and as metabolites. Phenobarbital shortens its half-life. Enhances actions of other antihypertensives, may produce severe hypotension. Because of severe ortho -static hypotension, patients should be lying down and observed for at least two hours after initial doses. 

Valproate increases the bioavailability of zidovudine, and one case of severe anaemia was attributed to the interaction. A case of liver toxicity with combined use has also been reported. Phenytoin and phenobarbital are predicted to slightly decrease abacavir levels. 

The evidence indicates that the metabolism (glucuronidation) of zidovudine is inhibited by valproate so that its bioavailability is increased. It was suggested that this caused zidovudine haematological toxicity in the case reported. The glucuronidation of abacavir is predicted to be increased by drugs that can induce UDP-glucuronyltransferase, such as phenobarbital and phenytoin. ... 

After taking felodipine 10 mg daily for 4 days, 10 epileptics (including one who was taking phenobarbital) had markedly reduced plasma felodipine levels (peak levels of 1.6nanomol/L compared with 8.9 nanomol/L in 12 control subjects). The felodipine bioavailability was reduced to 6.6%. ... 

A study in 7 healthy subjects found phenobarbital 100 mg daily for 3 weeks increased the clearance of verapamil 80 mg every 6 hours four-fold and reduced the bioavailability fivefold." ... 

Deferasirox did not alter the pharmacokinetics of digoxin. Food increases the bioavailability of deferasirox, and it should be taken on an empty stomach. The use of deferasirox with aluminium antacids is not recommended. Rifampicin, phenobarbital and pheny-toin are predicted to increase the metabolism of deferasirox, and, until more is known, concurrent use should be monitored. Based on in vitro data, deferasirox might inhibit the metabolism of CYP2C8 substrates like paclitaxel and repaglinide. Hydroxycar-bamide does not alter deferasirox metabolism. 

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