What is the role of phenytoin (PHT) in the treatment of epilepsy?

Updated: Jan 28, 2020
  • Author: Juan G Ochoa, MD; Chief Editor: Selim R Benbadis, MD  more...
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Since 1938, phenytoin (PHT) has been a major first-line AED in the treatment of partial and secondary generalized seizures in the United States. It blocks movements of ions through sodium channels during propagation of the action potential and thus blocks and prevents posttetanic potentiation, limits development of maximal seizure activity, and reduces the spread of seizures. It also has an inhibiting effect on calcium channels and the sequestration of calcium ions in nerve terminals, thereby inhibiting voltage-dependent neurotransmission at the level of the synapse.

In addition, PHT has an antiepileptic effect on calmodulin and other secondary messenger systems, the mechanisms of which are unclear. The adverse-effect profile (eg, gingival hyperplasia and coarsening of the facial features in women) makes its use less desirable than CBZ in some patients.

PHT is a lipid-soluble crystalline powder that is a weak acid and has a pKa in the range of 8.3-9.2, which makes it soluble in alkaline solutions. Usually, it is administered to patients as a sodium salt. It is not absorbed in the stomach because of the low pH of the gastric juices but is absorbed rather slowly in the small intestines, the juices of which have a higher pH. Food and diseases of the small intestines alter PHT absorption.

Oral bioavailability is approximately 95%, and peak level after oral administration is reached in approximately 4-12 hours. It is 70-95% bound to plasma protein, and the volume of distribution is 0.5-0.8 L/kg. The brain-plasma ratio is between 1 and 2. PHT is metabolized in the liver by the hepatic P-450 mixed oxidase system and follows zero-order kinetics. A number of minor metabolites are formed, but none of them are active (ie, they have no antiepileptic properties). Excretion is through the kidneys. Elimination half-life is 7-42 hours.

The drug is available as capsules (25 mg, 50 mg, 100 mg, 200 mg), chewable tablets (50 mg), suspension (30 mg/5 mL, 125 mg/5 mL), and injection (250 mg/5 mL). Administration frequency is 1-2 times a day.

PHT is one of the most commonly used first-line or adjunctive treatments for partial and generalized seizures, Lennox-Gastaut syndrome, status epilepticus, and childhood epileptic syndromes. It is not indicated for myoclonus and absence seizures. This drug is highly effective and economical for the patient; however, tolerability of the drug is still in dispute.

One disadvantage of PHT is that it causes central nervous system (CNS) and systemic adverse effects. Long-term use of PHT has been associated with osteoporosis; therefore, this agent must be used with caution in susceptible populations, and routine screening must be performed to detect the condition early. CNS effects occur particularly in the cerebellum and the vestibular system, causing ataxia and nystagmus. PHT is not a generalized CNS depressant; however, some degree of drowsiness and lethargy is present, without progressing to hypnosis.

Nausea and vomiting, rash, blood dyscrasias, headaches, vitamin K and folate deficiencies, loss of libido, hormonal dysfunction, and bone marrow hypoplasia are among the most common adverse effects. When given during pregnancy, PHT, like other AEDs, can cause cleft palate, cleft lip, congenital heart disease, slowed growth rate, and mental deficiency in the offspring.

Among all AEDs, PHT has one of the most problematic drug interaction profiles. The 2 major reasons are its highly protein-bound (>90%) nature and its use of the P-450 enzymes for metabolism. CBZ and PHB have variable and unpredictable effects (ie, increase or decrease) on PHT levels, in that they both induce and compete for hepatic enzymes. Valproate (VPA) raises levels of PHT by displacing PHT from its protein-binding site and inhibiting its metabolism.

Other drugs that significantly increase PHT levels are isoniazid, cimetidine, chloramphenicol, dicumarol, and sulfonamides. Drugs that lower PHT levels are vigabatrin (VGB) and amiodarone.

PHT itself is a strong inducer of hepatic enzymes and alters levels of other drugs. It decreases levels of CBZ, ethosuximide, felbamate, primidone, tiagabine (TGB), and PHB. It inhibits dicumarol, warfarin, and corticosteroids; clotting factors and immunosuppression must be monitored and doses adjusted accordingly. Other drugs whose levels are reduced by PHT and require monitoring and adjustment include furosemide, cyclosporin, folate, and praziquantel. levels of chloramphenicol and quinidine are elevated by PHT.

Because of PHT’s poor adverse-effect profile, epileptologists generally try to avoid prescribing it. Despite the difficult pharmacokinetics and the adverse effects, this drug is still used widely. The once-daily dosing, the good efficacy, the extensive experience amassed, the possibility of monitoring the plasma levels, and the availability of a parenteral preparation make PHT suitable for use by the primary care physician.

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