Phenytoin half-life

The apparent effectiveness of charcoal hemoperfusion has been reported in a 19-year-old woman who took about 5 g of phenytoin (68). The plasma concentrations of total and unbound phenjdoin fell rapidly, from 160 and 14 pmol/l to 65 and 6 pmol/l respectively, after 3 hours of hemoperfusion. The total phenytoin half-life was 3.9 hours. The protein-bound fraction was constant (91%) throughout. 

In a group of 15 drinkers (consuming a minimum of200 g of ethanol daily for at least 3 months) phenytoin levels measured 24 hours after the last dose of phenytoin were approximately half those of 76 non-drinkers. The phenytoin half-life was reduced by 30%. ... 

This interaction has been described in a number of other reports. " One study found that intravenous chloramphenicol more than doubled the half-life of phenytoin. The AUC of phenytoin after a single intravenous dose of fosphenytoin was 23% higher (not significant) in children also given intravenous chloramphenicol when compared with those given intravenous cefotaxime. In addition, the phenytoin half-life was significantly prolonged by chloramphenicol (23.7 hours versus 15.5 hours). - ... 

A study in 4 patients taking phenytoin 300 mg daily found that when they were given phenprocoumon their serum phenytoin levels rose from about 10 micrograms/mL to 14 micrograms/mL over 7 days. The phenytoin half-life increased from 9.9 to 14 hours. 

A review of the drug interactions of sulfinpyrazone identified two studies that found interactions with phenytoin. In the first, the serum phenytoin levels of 2 out of 5 patients taking phenytoin 250 to 350 mg daily were doubled from about 10 to 20 micrograms/mL within 11 days of starting to take sulfinpyrazone 800 mg daily. One of the remaining patients had a small increase in phenytoin levels, but the other two had no changes at all. When the sulfinpyrazone was withdrawn, the serum phenytoin concentrations fell to their former levels. The second study was a clinical study in epileptic patients that found that sulfinpyrazone 800 mg daily for a week increased the phenytoin half-life from 10 to 16.5 hours and reduced the metabolic clearance from 59 to 32 mL/minute. 

A child who was stable taking phenytoin and sultiame developed phenytoin toxicity within 48 hours of starting co-trimoxazole. Toxicity resolved when the antibacterial was changed to amoxicillin. A clinical study found that co-trimoxazole and trimethoprim can increase the phenytoin half-life by 39% and 51%, respectively, and decrease the mean metabolic clearance by 27% and 30%, respectively. Sulfamethoxazole alone had only a small effect on the half-life and did not affect the clearance of phenytoin. A case report describes fatal acute hepatic failure in a 60-year-old woman 10 days after starting co-trimoxazole and 14 days after starting phenytoin. This patient was also given cimetidine, which may raise phenytoin levels (see Phenytoin + H2-receptor antagonists , p.559). 

Phenytoin s absorption is slow and variable yet almost complete absorption eventually occurs after po dosing. More than 90% of the dmg is bound to plasma protein. Peak plasma concentrations are achieved in 1.5—3 h. Therapeutic plasma concentrations are 10—20 lg/mL but using fixed po doses, steady-state levels are achieved in 7—10 days. Phenytoin is metabolized in the fiver to inactive metabolites. The plasma half-life is approximately 22 h. Phenytoin is excreted primarily in the urine as inactive metabolites and <5% as unchanged dmg. It is also eliminated in the feces and in breast milk (1,2). Prolonged po use of phenytoin may result in hirsutism, gingival hyperplasia, and hypersensitivity reactions evidenced by skin rashes, blood dyscrasias, etc... 

When a preparation of phenytoin was administered to a patient, the volume of distribution was found to be 70 liters, and the half-life of elimination was 1.5 hours. What is the total clearance of phenytoin ... 

Theophylline is a narrow therapeutic index drug with significant difference in bioavailability following oral administration. The half-life of the drug is increased by heart failure, cirrhosis and viral infections, in elderly patients, and by certain drugs, such as cimetidine, ciprofloxacin, oral contraceptives and fluvoxamine. The half-life is decreased in smokers, chronic alcoholism, and by certain drugs, such as phenytoin, rifampicin and carbamazepine. 

Phenytoin has a long half-life, 18-24 hours, after oral administration (G9), which may be prolonged further at high dosages (VI). Twice daily prescriptions of phenytoin should result in relatively constant blood concentrations once steady-state conditions have been achieved, a process taking 6-15 days (K21). A limited amount of experimental data supports this prediction (B30, Cl, D5, Hll). 

Primidone has a comparatively short half-life of 10-12 hours (B17). Therefore, the time relationships between blood sampling and dose regimes acquire greater importance when interpreting the results than with either phenobarbitone or phenytoin. 

Metabolism/Excretion - Phenytoin is metabolized in the liver and excreted in the urine. The metabolism of phenytoin is capacity-limited and shows saturability. Elimination is exponential (first-order) at plasma concentrations less than 10 mcg/mL, and plasma half-life ranges from 6 to 24 hours. 

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. 

II.e. 5.2. Interactions between first and second generation AEDs. Felbamate raises plasma concentrations of phenytoin, valproic acid and carbamazepine. Clearance of tiagabine, topiramate and zon-isamide is increased in the presence of an enzyme inducer. Vigabatrin reduces phenytoin concentrations after 4-5 weeks of comedication (via an unknown mechanism). For tiagabine, the elimination half-life may be reduced by 2-3 hours in the presence of an enzyme-induction AED. Lamotrigine elimination is slower if given with valproic acid. Topiramate reduces elimination of phenytoin. 

Completely absorbed after IM administration. Protein binding 95%-99%. After IM or IV administration, rapidly and completely hydrolyzed to phenytoin. Time of complete conversion to phenytoin IM 4 hr after injection IV 2 hr after the end of infusion. Half-life for conversion to phenytoin 8-15 min. 

In this example, the increased unbound phenytoin concentration resulted in a larger volume of distribution (more free drug distributed to the tissues), increased clearance (more free drug available for metabolism), but no change in the drug s half-life. The paradox in this case is that the increased clearance caused the total phenytoin blood concentration to go down, while the free concentration was elevated and led to clinical toxicity. Moreover, the unchanged half-life would not have clarified the cause of the subther-apeutic phenytoin level. 

Substances which have a long half-life when present in large amounts Theophylline, aspirin, alcohol, phenytoin, chloral hydrate, acetaminophen. 

The elimination of phenytoin is dose-dependent. At very low blood levels, phenytoin metabolism follows first-order kinetics. However, as blood levels rise within the therapeutic range, the maximum capacity of the liver to metabolize phenytoin is approached. Further increases in dosage, though relatively small, may produce very large changes in phenytoin concentrations (Figure 24-5). In such cases, the half-life of the drug increases markedly, steady state is not achieved in routine fashion (since the plasma level continues to rise), and patients quickly develop symptoms of toxicity. 

The half-life of phenytoin varies from 12 to 36 hours, with an average of 24 hours for most patients in the low to mid therapeutic range. Much longer half-lives are observed at higher concentrations. At low blood levels, it takes 5-7 days to reach steady-state blood levels after every dosage change at higher levels, it may be 4-6 weeks before blood levels are stable. 

Felbamate appears to have multiple mechanisms of action. It produces a use-dependent block of the NMDA receptor, with selectivity for the NR1-2B sub-type. It also potentiates GABAa receptor responses. Felbamate has a half-life of 20 hours (somewhat shorter when administered with either phenytoin or carbamazepine) and is metabolized by hydroxylation and conjugation a significant percentage of the drug is excreted unchanged in the urine. When added to treatment with other antiseizure drugs, felbamate increases plasma phenytoin and valproic acid levels but decreases levels of carbamazepine. 

Isoniazid Inhibits synthesis of mycolic acids, an essential component of mycobacterial cell walls Bactericidal activity against susceptible strains of M tuberculosis First-line agent for tuberculosis treatment of latent infection less active against other mycobacteria Oral, IV hepatic clearance (half-life 1 h) reduces levels of phenytoin Toxicity Flepatotoxic, peripheral neuropathy (give pyridoxine to prevent)... 

Praziquantel is a synthetic isoquinoline-pyrazine derivative. It is rapidly absorbed, with a bioavailability of about 80% after oral administration. Peak serum concentrations are reached 1-3 hours after a therapeutic dose. Cerebrospinal fluid concentrations of praziquantel reach 14-20% of the drug s plasma concentration. About 80% of the drug is bound to plasma proteins. Most of the drug is rapidly metabolized to inactive mono- and polyhydroxylated products after a first pass in the liver. The half-life is 0.8-1.5 hours. Excretion is mainly via the kidneys (60-80%) and bile (15-35%). Plasma concentrations of praziquantel increase when the drug is taken with a high-carbohydrate meal or with cimetidine bioavailability is markedly reduced with some antiepileptics (phenytoin, carbamazepine) or with corticosteroids. 

An interesting example of racial differences in drug conversion is seen in the metabolism of the antitubercular, isoniazid. It is inactivated by an acetylation reaction. Slow acetylation leads to toxicity (lupus, drowsiness, nausea, cyanosis). Free isoniazid also inhibits the action of phenytoin (an anticonvulsive) and results in phenytoin toxicity. Normal acetylation has a half-life of 45-80 minutes while a "slow acetylator" shows a 140-200 min half-life. The U.S. population shows a 50/50 distribution of "slow" versus "fast" acetylators. 44-55% of American Causasians and blacks are "slow". 

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

Melting Point (1C) Phenytoin Equivalent Solubility in Water (mg/mL) Hydrolysis Half-Life in Human Plasma (min)... 

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