Phenytoin plasma half-life

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... 

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. 

Plasma half life varies considerably and is in the approximate range of 7 to 40 hours at doses above 100 mg, the half life is dose dependent. Phenytoin is widely and rapidly distributed throughout the body it is secreted in the milk, accumulates in red blood cells and amounts secreted in saliva show a linear relationship to non-protein bound concentrations in serum. 

Piperonyl butoxide, isoniazid, and SKF 525A and related chemicals are inhibitors of various xenobiot-ic-metabolizing enzymes. For instance, piperonyl butoxide increases the toxicity of pyrethrum (an insecticide) by inhibiting MFO activity in insects that detoxifies this agent. Isoniazid, when taken along with phenytoin, lengthens the plasma half-life of the antiepileptic drug and increases its toxicity. Iproniazid inhibits monoamine oxidase and increases the cardiovascular effects of tyramine, which is found in cheese and which is normally readily metabolized by the oxidase. 

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. 

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. 

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. 

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. 

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

Albumin Maintains plasma oncotic pressure. Transports fat-soluble substances, e.g. bilirubin, drugs Reduced levels Low levels cause ascites and increase free plasma concentration of albumin-bound drugs, e.g. oestradiol, phenytoin Albumin is a useful clinical indicator of the liver s synthetic function. The liver produces and exports up to 12 g of albumin per day. Low levels are also seen in malnutrition, hypercatabolism and nephrotic syndrome. Half-life of 20 days, therefore indicator of chronic liver disease... 

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... 

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. 

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. 

Mephenytoin is demethylated to 5-ethyl-5-phenylhydantoin (Nirvanol), which is an active anticonvulsant. Mephenytoin binds to plasma protein to the extent of 40%, with an elimination half-life of 7 hours. Mephenytoin causes sedation, whereas phenytoin does not. The incidence of dose- and time-dependent side effects of mephenytoin is lower than that seen with phenytoin. On the other hand, the incidence of severe and fatal hypersensitivity reactions is far higher than that reported for phenytoin. Therefore, mephenytoin is not the first drug of choice. It is used for the treatment of tonic-clonic, simple partial, and complex partial seizures... 

Omeprazole increases the half-life of diazepam by inhibiting its metabolism and reduces the plasma clearance of phenytoin and warfarin. 

Oral Dose of Plasma Level of Phenytoin (mg/kg) Phenytoin (pg/mL) Half-Life (hour)... 

Tiagabine is rapidly absorbed after oral administration, extensively bound to serum or plasma proteins, and metabolized mainly in the liver, predominantly by CYP3A. Its half-life of about 8 hours is shortened by 2 to 3 hours when coadministered with hepatic enzyme-inducing drugs such as phenobarbital, phenytoin, or carbamazepine. 

Fosphenytoin sodium (Fig. 20.5) is a soluble pro-drug disodium phosphate ester of phenytoin (142 mg/mL) that was developed as a replacement for parenteral phenytoin sodium to circumvent the pH and solubility problems associated with parenteral phenytoin sodium formulations (36,37). Unlike phenytoin, fosphenytoin is freely soluble in aqueous solutions and is rapidly absorbed by the IM route. It is rapidly metabolized (conversion half-life, 8-15 minutes) to phenytoin by in vivo phosphatases. Therapeutic free (unbound) and total plasma phenytoin concentrations are consistently attained following IM or IV administration of fosphenytoin (26). It is administered IV following benzodiazepines for control of status epilepticus or whenever there is a need to rapidly achieve therapeutic plasma concentrations. Severe bradycardiac adverse events to fosphenytoin, including some fatalities, have been reported (38). A dose reduction in patients who are elderly or have renal or hepatic impairment has been suggested. 

Phenytoin may be administered either orally or intravenously and is absorbed slowly after oral administration, with peak plasma levels achieved after 3 to 12 hours. It is extensively plasma protein bound ( 90%), and the elimination half-life is between 15 and 30 hours. These large ranges reflect the considerable variability observed from patient to patient. Parenteral administration of phenytoin is usually limited to the intravenous route. Phenytoin for injection is dissolved in a highly alkaline vehicle (pFI 12). This alkaline vehicle is required because phenytoin is weakly acidic and has very poor solubility in its un-ionized form. Reportedly, however, its phosphate ester fosphenytoin has water solubility advantages over phenytoin for injection. Intramuscular phenytoin generally is avoided, because it results in tissue necrosis at the site of injection and erratic absorption because of high alkalinity. In addition, intermittent intravenous infusion is required to reduce the incidence of severe phlebitis. 

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