Phenobarbital half-life

Rats pretreated with xylene or phenobarbital and then exposed to -hexane by inhalation exhibited a markedly increased peak serum concentration of 2,5-hexanedione (Toftgard et al. 1983). Peak serum concentrations were approximately 4 g/mL in control rats, 11 g/mL in xylene-induced rats, and 13 g/mL in phenobarbital-induced rats. Peaks were reached in 1-2 hours. The half-life for elimination from serum was approximately one hour for both pretreated and untreated rats. The high serum 2,5-hexanedione concentrations were correlated with an induction of liver microsomal P-450 content (0.56 nmol/mg protein in control rats, 1.03 nmol/mg in xylene-induced rats, and 1.7 nmol/mg protein in phenobarbital-induced rats, respectively). 

CYP 450 Drugs that induce liver enzymes (eg, phenytoin, carbamazepine, phenobarbital) increase the metabolism and clearance of zonisamide and decrease its half-life. Concurrent medication with drugs that induce or inhibit CYP3A4 would be expected to alter serum concentrations of zonisamide. Zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by cytochrome P450 isozymes. 

Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine discontinuing valproate should shorten the half-life of lamotrigine. 

With some drugs, particularly those with a long half life, a loading dose may be useful in order to achieve a therapeutic level more rapidly. For example, the half-life of phenobarbital in the neonate is long, approximately 120 hours, with steady-state concentrations achieved in two to three weeks. A slowly-infused loading dose can be efficacious in achieving seizure control within minutes, typically followed by maintenance infusion and subsequent transition to oral therapy daily. 

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. 

Primidone has a larger clearance than most other antiseizure drugs (2 L/kg/d), corresponding to a half-life of 6-8 hours. clearance is approximately half that of primidone, but phenobarbital has a very low clearance. The appearance of phenobarbital corresponds to the disappearance of primidone. Phenobarbital therefore accumulates very slowly but eventually reaches therapeutic concentrations in most patients when therapeutic doses of primidone are administered. During chronic therapy, phenobarbital levels derived from primidone are usually two to three times higher than primidone levels. 

Pentobarbital is 65% plasma protein bound with a volume of distribution of 0.5 to 1.0 L/kg.6 After intravenous administration, estimates of the plasma half-life have averaged between 20 and 30 h. Amobarbital is similar to pentobarbital in the degree of plasma protein binding (59%) with a slightly larger volume of distribution (0.9 to 1.4 L/kg). The plasma half-life, however, is dose dependent, with a range of 15 to 40 h.6 Phenobarbital is approximately 50% plasma protein bound... 

Phenobarbital increases the metabolism of glucocorticoids, reducing the half-life by some 50% (496). 

Numerous drugs are able to either enhance or inhibit the excretion of other drugs. For example, sodium bicarbonate enhances the excretion of phenobarbital. Probenecid interferes with the active secretion of penicillin and hence prolongs its half-life. Probenecid s uricosuric effects are counteracted by acetylsalicylic acid, which also possesses a uricosuric effect. When given concomitantly, both are excreted (see Chapter 24). 

VINCA ALKALOIDS - VINBLASTINE, VINCRISTINE 1. ANTIBIOTICS-rifampicin 2. ANTICANCER AND IMMUNOMODULATING DRUGS - dexamethasone 3. ANTIDEPRESSANTS-St John s wort 4. ANTI EPILEPTICS -carbamazepine, phenobarbital, phenytoin 1 of plasma concentrations of vinblastine and vincristine, with risk of inadequate therapeutic response. Reports of 1 AUC by 40% and elimination half life by 35%, and t clearance by 63%, in patients with brain tumours taking vincristine, which could lead to dangerously inadequate therapeutic responses Due to induction of CYP3A4-mediated metabolism Monitor for clinical efficacy, and t dose of vinblastine and vincristine as clinically indicated in the latter case, monitor clinically and radiologically for clinical efficacy in patients with brain tumours and t dose to obtain desired response... 

Elimination half-life in patients receiving concomitant enzyme-inducing antiepileptic drugs (such as carbamazepine, phenobarbital, phenytoin, and primidone) approximately 14 hours after a single dose of lamotrigine... 

Because the half-life of the epoxide intermediate is short, immediate rearrangement or reaction may lead to a single metabolite or a variety of substituted metabolites. The intermediacy of an epoxide intermediate can be inferred by the identification of para-and meta-hydroxylated and dihydrodiol metabolites, although their relative abundances will vary with substitution and steric considerations. Acetanilide, like phenobarbital discussed previously, exemplifies the aromatic compounds that rearrange rapidly following CYP-mediated arene epoxide formation leading to a single metabolite, as shown in Scheme 11.10. 

Phenobarbital stimulates the microsomal enzymes in the liver. This results in increases in liver enzyme concentrations and more rapid metabolism of not only phenobarbital but also other concurrently administered drugs. In the horse, it has been shown that the half-life of phenobarbital decreases (to around 11 h) following repeated oral dosing (Knox et al 1982). Dosage adjustments of phenobarbital may be required to maintain plasma concentrations within the therapeutic window and can be made using the equation ... 

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. 

Remacemide, which chemically is ( )-2-aini-no-iV-( 1-methyl- l,2-diphenylethyl)acetamide (58), and its principal active desglycinyl metabolite (58a), are low-affinity, noncompetitive NMDA receptor blockers and Na+ fast-channel blockers (242). Remacemide is rapidly absorbed on oral administration and achieves a peak plasma level in 1 h, whereas the active metabolite (58a) takes 2-3 h. The parent has a half-life of 3-4 h, compared to 12-15 h for the active metabolite (243). Comedication with enzyme-inducing anticonvulsants (i.e., phe-nytoin, carbamazepine, and phenobarbital) induces the metabolism of both remacemide and (68a), thus reducing their plasma concentration. The agent has been studied for its anticonvulsant effect, and because of its neuro-... 

Absorption of oral phenobarbital is slow but complete. The time at which peak plasma concentrations are reached is widely variable and ranges from 4 to 10 hours after the dose. Phenobarbital is 40% to 60% bound to plasma proteins. CyP 2C19 is the primary hepatic enzyme involved in metabolism, producing an elimination half-life of 70 to 100 hours metabolism is age dependent (children average 70 hours, geriatric patients 100 hours). Because hepatic metabolism is the primary organ of elimmation, reduced liver function results in prolonged half-life. 

Primidone is rapidly and completely absorbed after oral administration. Once absorbed, it is not highly protein bound and it has a half-life of approximately 10 hours. Disposition of the drug is known to be affected by the drugs that alter CyP 2C19 and 2C9 metabolism arid by diseases that alter phenobarbital disposition. 

Tiagabine has an elimination half-Ufe of 7 to 9 hours. In patients receiving CyP 3A4 inducing anti-epileptic drugs (AEDs), the elimination half-life decreases to 4 to 7 hours. Phenytoin, phenobarbital, and carbamazepine are CyP 3A4 inducers. Valproic acid and gabapentin are not. Tiagabine is not considered to be a CyP 3A4 inducer. ... 

Pharmacokinetics. Phenobarbital is absorbed rapidly and completely regardless of whether it is given orally, intramuscularly, or rectally." Phenobarbital penetrates the brain at a rate comparable with that of phenytoin, and peak concentrations are achieved 3 to 20 minutes after an intravenous dose. Phenobarbital is about 50% bound to plasma proteins, and it has a very long half-life. 

I Dosing and Administration, in nonacute situations, phenobarbital should be started in low doses and titrated upward. The dose-concentration relationship is linear. Because the half-life of phenobarbital is long, doses can be given once daily. Bedtime dosing may... 

Valproic acid is an enzyme inhibitor that can inhibit specific cytochrome P450 isozymes, epoxide hydrolase, and UGT isozymes. The addition of valproic acid to phenobarbital results in a 30% to 50% decrease in the clearance of phenobarbital and potential toxicity if the dose of phenobarbital is not reduced. Valproic acid may increase concentrations of 10,11-carbamazepine epoxide without affecting concentrations of the parent drug via inhibition of epoxide hydrolase. Valproic acid is also a potent inhibitor of lamotrigine, via inhibition of UGT enzymes, and can result in a doubling of the half-life of lamotrigine. ... 

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