Phenytoin with valproic acid

Epilepsy is a clinical disorder characterized by spontaneous, recurrent seizures arising from excessive electrical activity in certain parts of the brain [51]. Currently available drugs, such as phenytoin, carbamazepine, valproic acid, lamotrigine, and topiramate (for molecular structures see Fig. 6), provide symptomatic seizure suppression in only 60-70% of those receiving treatment [52-54]. These drugs are also associated with unwanted side... 

Assess the AED serum concentration and adjust therapy as needed for agents with a defined therapeutic range (e.g., phenytoin, carbamazepine, valproic acid, and phenobarbital). Drug levels can also be used to determine adherence to medication regimens for agents that do not have defined ranges. 

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 antiseizure drugs exhibit many similar pharmacokinetic properties—even those whose structural and chemical properties are quite diverse— because most have been selected for oral activity and all must enter the central nervous system. Although many of these compounds are only slightly soluble, absorption is usually good, with 80-100% of the dose reaching the circulation. Most antiseizure drugs (other than phenytoin and valproic acid) are not highly bound to plasma proteins. 

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. 

Co-admuiistration of erythromycin, phenytoin, or valproic acid increases the rate of metabolism of carbamazepine, reducing the blood concentration. Itraconazole and grapefruit juice interfere with CyP 3A4, increasing carbamazepine levels. 

I Advantages. The efficacy of oxcarbazepine is comparable with that of carbamazepine, phenytoin, and valproic acid. It has been approved in 50 conntries, and thns broad international experience has been gained. 

Oxcarbazepine (Trileptal) (10,ll-dihydro-10-oxocar-bamazepine) is a keto analog of carbamazepine. Oxcarbazepine functions as a prodrug, in that it is almost immediately converted to its main active metabolite, a 10-monohydroxy derivative, which is inactivated by glucuronide conjugation and eliminated by renal excretion. Its mechanism of action is similar to that of carbamazepine. Oxcarbazepine is a less potent enzyme inducer than is carbamazepine, and substitution of oxcarbazepine for carbamazepine is associated with increased levels of phenytoin and valproic acid, presumably because of reduced induction of hepatic enzymes. Oxcarbazepine does not induce the hepatic enzymes involved in its own degradation. Although oxcarbazepine does not appear to... 

Haidukewych, D., Rodin, E. A., and Zielinski, J. J., Derivation and evaluation of an equation for prediction of free phenytoin concentrations in patients co-medicated with valproic acid, Ther. Drug Monit., 11 134-139, 1989. 

In 12 adults with status epilepticus, intravenous levetiracetam 2500 mg was added as soon as possible to a standardized regimen of intravenous clonazepam and/or rectal diazepam as needed followed by phenytoin or valproic acid no serious adverse effects could be related directly to the administration of levetiracetam [208 ]. 

The following drugp have a decreased pharmacologic effect when administered with an antacid corticosteroids, digoxin, chlorpromazine, oral iron products, isoniazid, phenothiazines, ranitidine, phenytoin, valproic acid, and the tetracyclines. 

Phenobarbitone was the first AED and was introduced in 1912. It was largely replaced in 1932 by phenytoin for the management of tonic-xilonic seizures and partial and secondary epilepsy. Carbamazepine followed, then ethosuximide for absence seizures and valproic acid. These remained, apart from the introduction of the benzodiazepines, the mainstay of therapy until the last decade. They were introduced solely on their ability to control experimentally induced seizures. Their mechanisms of action were unknown and no thought was given to the possibility of NT modification and in fact subsequent research has shown that with the exception of the benzodiazepines none of them work primarily through NT manipulation. They act directly on neuronal excitability. 

Studies suggest that as monotherapy for partial seizures, lamotrigine is as effective as carbamazepine and phenytoin lamotrigine may be better tolerated. Clinical data suggest that oxcarbazepine is as effective as phenytoin, valproic acid, and immediate-release carbamazepine, with perhaps fewer side effects. 

Phenytoin, carbamazepine, phenobarbital, oxcarbazepine, and valproic acid may interfere with vitamin D metabolism, causing asymptomatic high-turnover bone disease with normal bone density or decreased bone mineral... 

Distribution - Valproic acid is rapidly distributed. Volume of distribution of total or free valproic acid is 11 or 92 L/1.73 m, respectively. Valproic acid has been detected in CSF (approximately 10% of total concentrations) and milk (about 1% to 10% of serum concentrations). Therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate. The plasma protein binding of valproate is concentration-dependent. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (eg, aspirin). Conversely, valproate may displace certain protein-bound drugs (eg, phenytoin, carbamazepine, warfarin, tolbutamide). 

Convulsions associated with fever often occur in children 3 months to 5 years of age. Epilepsy later develops in approximately 2 to 3% of children who exhibit one or more such febrile seizures. Most authorities now recommend prophylactic treatment with anticonvulsant drugs only to patients at highest risk for development of epilepsy and for those who have multiple recurrent febrile seizures. Phenobarbital is the usual drug, although diazepam is also effective. Phenytoin and carba-mazepine are ineffective, and valproic acid may cause hepatotoxicity in very young patients. 

Levodopa or dopamine agonists produce diverse dyskinesias as a dose-related phenomenon in patients with Parkinson s disease dose reduction reverses them. Chorea may also develop in patients receiving phenytoin, carbamazepine, amphetamines, lithium, and oral contraceptives, and it resolves with discontinuance of the offending medication. Dystonia has resulted from administration of dopaminergic agents, lithium, serotonin reuptake inhibitors, carbamazepine, and metoclopramide and postural tremor from theophylline, caffeine, lithium, valproic acid, thyroid hormone, tricyclic antidepressants, and isoproterenol. 

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