Phenobarbital with valproic acid

PROCARBAZINE ANTIEPILEPTICS-CARBAMAZEPINE, PHENOBARBITAL PHENYTOIN, VALPROIC ACID T risk of hypersensitivity reactions in patients with brain tumours Strong correlation between the therapeutic antiepileptic level and the hypersensitivity reactions Consider using non-enzyme-inducing agents... 

A 13-year-old boy with Lesch-Nyhan syndrome who was taking phenobarbital, elonazepam, valproic acid and phenytoin 200 mg daily became somnolent within 7 days of starting to take allopurinol 150 mg daily. TEs serum phenytoin levels were found to have increased from 7.5 to 20.8 micrograms/mL. In another study, 2 patients had a marked increase in phenytoin levels when given allopurinol (150 mg daily in those less than 20 kg, and 300 mg daily for other patients) for 4 months, which in one case led to withdrawal from the study, and in the other to a phenytoin dosage reduction. However, 16 other patients had no change in phenytoin levels while taking this dose of allopurinol. ... 

Anticonvulsant drugs such as carbamazepine, diazepam, valproic acid, and phenobarbital also slightly increased the duration of the initial AD. However, the effects of these drugs on the other associated seizure events were quite different from PCP and ketamine. The effects of carbamazepine and diazepam, typical of the four compounds, are illustrated in figure 4. These compounds either suppressed the rebound spiking (diazepam, valproic acid, and phenobarbital) or lengthened the total seizure duration with no rebound suppression (carbamazepine). 

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. 

The answer is d. (Katzung, pp 411, 1029.) An increased incidence of spina bifida may occur with the use of valproic acid during pregnancy Cardiovascular, orofacial, and digital abnormalities may also occur. The main issue with the use of phenobarbital or primidone (metabolite is phe-nobarbital) for the fetus is neonatal dependence on barbiturates. 

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... 

Valproic acid causes hair loss in about 5% of patients, but this effect is reversible. Transient gastrointestinal effects are common, and some mild behavioral effects have been reported. Metabolic effects, including hyperglycemia, hyperglycinuria, and hyperammonemia, have been reported. An increase in body weight also has been noted. Valproic acid is not a CNS depressant, but its administration may lead to increased depression if it is used in combination with phenobarbital, primidone, benzodiazepines, or other CNS depressant agents. 

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. 

Drug interactions involving AEDs are shown in Table 52-5. Phenobarbital, phoiytom, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP450), epoxide hydrolase, and uridine diphosphate gjucuronosyltransferase enzyme systems. Valproic acid inhibits many hepatic enzjrme systems and displaces some drugs from plasma albumin. Felbamate and topiramate can act as inducers with some isoforms and inhibitors with others. 

Pseudolymphoma and a condition resembling malignant lymphoma occur very rarely with phenytoin (SED-13, 142). There is no evidence of a significant increase in the incidence of other tumors. There have also been reports of pseudolymphoma with other antiepileptic drugs, including carbamazepine (147-149), lamotrigine (150), phenobarbital (151), and valproic acid (151). 

Clinically important, potentially hazardous interactions with carbamazepine, lamotrigine, phenobarbital, primidone, topiramate, valproic acid, vigabatrin... 

The DRESS syndrome is an acronym for Drug Rash with Eosinophilia and Systemic Symptoms. It is also known as the Drug-Induced Pseudolymphoma and Drug Hypersensitivity Syndrome. The symptoms of DRESS syndrome usually begin I to 8 weeks after exposure to the offending drug. Common causes include carbamazepine, phenobarbital, phenytoin, terbinafine, and valproic acid. 

Decreased effect with (P450 3A4 inducers) carbamazepine, phenytoin, and phenobarbital also decreased with verapamil and valproic acid... 

Co-administration of acetazolamide with primidone results in decreased gastrointestinal absorption of primidone and subsequent diminished plasma concentrations. Primidone administered in association with phenytoin produces a modest elevation of the phenobarbital/primidone ratio because phenytoin competes with the hepatic hydroxylating enzymes associated with phenobarbitaFs metabolism. Coadministration of valproic acid, for the same reasons out-fined for phenobarbital, causes a modest increase in both primidone and phenobarbital serum concentrations. 

Valproic add modulates the action of various other common antiepileptic drugs. It inhibits the nonrenal clearance of phenobarbital, resulting in elevated phenobarbital levels. It competes -with phenytoin for protein-binding sites. The free phenytoin concentration remains approximately the same, but the total phenytoin in the plasma decreases. Because the free phenytoin concentration remains unchanged, the pharmacological effect is retained. Other common antiepileptic drugs that induce hepatic oxidative enzymes result in increased valproic acid clearance this increased clearance rate requires a higher dose to maintain effective therapeutic levels. 

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