Phenobarbital + Phenytoin

Oral
Grand mal seizures, Complex partial seizures

Hypersensitivity; acute intermittent porphyria; severe renal and hepatic disorders; severe myocardial damage, AV block; respiratory depression.

Elderly; seriously ill patients; patients doing work requiring mental alertness and unimpaired reflexes; lactation, pregnancy; children; history of alcohol or drug abuse; hepatic and renal impairment; depression and suicidal tendencies. Patients and carers should be counselled how to recognise symptoms of blood or skin disorders and to seek medical attention. Normal therapeutic levels of phenytoin: 20-40 mcg/ml. Phenobarbital and phenytoin may increase vitamin D requirements.

Sedation, depression, irritation, aggressiveness, confusion, paradoxical excitation in children, rash, dyskinesia, macrocytic anaemia, thyroiditis, vertigo, nystagmus, ataxia, diplopia and gingival hypertrophy.
Potentially Fatal: Agranulocytosis, aplastic anaemia, exfoliative dermatitis (Stevens Johnson syndrome), severe hepatitis and leucopenia.

Phenobarbital is moderately dialysable (20-50%). Symptoms of phenobarbital overdose: Slowness, ataxia and coma. Toxic phenobarbital levels: >40 mcg/ml. Clinical symptoms are used to diagnose phenytoin toxicity as some patients require higher than usual therapeutic levels. Symptoms: Nystagmus, diplopia, slurred speech, ataxia, confusion and hyperglycaemia. Lethal phenytoin levels: >40 mcg/ml.

Phenytoin and phenobarbital may alter each other's metabolism. Both reduce levels of abacavir, amprenavir, TCAs, aprepitant, apripiprazole, carbamazepine (phenytoin levels reduced), valproate, clonazepam, lamotrigine, tacrolimus (phenytoin levels may increase) and theophylline. Phenytoin and phenobarbital may decrease effects of systemic corticosteroids, ciclosporin, coumarins, digitoxin, oestrogens and progestogens. Valporate may increase levels of phenobarbitone and phenytoin (levels may conversely increase). Antipsychotics, TCAs, SSRIs and TCA related antidepressants may antagonise effects of phenytoin and phenobarbital. Phenytoin reduces levels and effects of bupropion, busulfan, caspofungin, digoxin, disopyramide, eplerenone, imatinib, levodopa, mirtazapine and furosemide. Levels of phenytoin may be reduced by antacids (separate doses by a couple of hr), sucralfate, carbamazepine and theophylline. Phenytoin levels may be affected by benzodiazepines and ciprofloxacin. Levels of phenytoin may be increased by cimetidine, clarithromycin, diazepam, fluoxetine, fluconazole, fluvoxamine, itraconazole, ketoconazole, metronidazole, sulphonamide, topiramate (may reduce topiramate levels), trimethoprim (antifolate effect) and amiodarone (interaction may continue for wk or mth. Phenytoin effects may be enhanced by influenza vaccine, esomeprazole and NSAIDs. Increased risk of withdrawal symptoms when phenytoin is used with methadone. Pyrimethamine may antagonise phenytoin effects. Phenytoin may increase antifolate effect of methotrexate. Concomitant use of phenobarbital and carbonic anhydrase inhibitors may increase risk of osteomalacia. Chlorpromazine and phenobarbital levels may be reduced when given together. Phenobarbital reduces effects of dihydropyridine calcium channel blockers, diltiazem, felodipine, nelfinavir, verapamil, griseofulvin, doxycycline, disopyramide, thyroid hormones, tibolone, haloperidol and mianserin. Phenobarbital reduces levels of chloramphenicol, indinavir, rifampicin, telithromycin (avoid 2 wk before or after phenobarbital), ethosuximide, itraconazole and voriconazole (avoid concomitant use). Folates may decrease phenobarbital levels. Methylphenidate may increase phenobarbital levels.
Potentially Fatal: Lithium toxicity may occur when used with phenytoin (even without increased lithium levels). Concomitant use of phenytoin with chloramphenicol or voriconazole may lead to increased, possibly, toxic levels of phenytoin (and reduced voriconazole levels).

Avoid: Valerian, St John's wort, kava kava, gotu kola (may increase CNS dpression) and evening primose (may reduce seizure threshold).

Phenobarbital interferes with the assay for lactate dehydrogenase.

Description: Phenytoin and phenobarbital both depress the motor cortex, raise the seizure threshold and reduce spread of seizure. Phenytoin stabilises neuronal membrane, inhibiting movement of sodium and calcium ions during the nerve impulse. Phenobarbital aids gamma-aminobutyric acid (GABA)-mediated inhibition of nerve cells.
Pharmacokinetics:
Absorption: Phenytoin: Slowly but almost completely absorbed from GI tract.
Distribution: Phenobarbital: 45-60% bound to plasma proteins. Phenytoin: About 90% bound to plasma proteins.
Metabolism: Phenytoin: Largely metabolised hepatically to inactive metabolites.
Excretion: Phenobarbital: About 25% of a dose is excreted in urine unchanged; plasma half-life: About 75-120 hr in adults. Phenytoin: Mean half-life: About 22 hr at steady state.

Anticonvulsants