Phenytoin
Phenytoin is an anticonvulsant primarily used to treat epilepsy, particularly generalized tonic-clonic seizures and focal seizures. It is also used to prevent seizures during or after surgery and in the treatment of status epilepticus.
Trade Name
Phenytoin is marketed under several brand names, including Dilantin, Pro epanutin and Phenytek.
Chemical Properties
Chemical structure: Phenytoin is an aromatic hydantoin compound.
Molecular formula: C₁₈H₁₈N₂O₂
Molecular weight: 252.35 g/mol
Solubility: Phenytoin is poorly soluble in water but is usually available in tablet, capsule, and injectable forms for administration.
Biochemical Properties
Mechanism of action: Phenytoin works by stabilizing the neuronal membranes through the inhibition of voltage-gated sodium channels. By reducing the sodium influx during neuronal depolarization, it prevents repetitive firing of neurons, which helps control seizures. It also has some effects on calcium channels and may affect neurotransmitter release, though sodium channel inhibition is its primary action.
Pharmacology
Administration: Phenytoin is administered orally (in tablets or capsules) or intravenously in hospitals for acute seizure control. It has a long duration of action, allowing for less frequent dosing in some patients.
Bioavailability: The bioavailability of phenytoin is around 90%, but it follows nonlinear pharmacokinetics. At higher doses, its absorption can become saturated, leading to unpredictable increases in drug levels.
Metabolism: Phenytoin is primarily metabolized in the liver by the cytochrome P450 enzyme system, mainly CYP2C9 and CYP2C19. It has a relatively slow clearance rate, which is influenced by factors like liver function, age, and concurrent medications.
Half-life: Phenytoin has a long half-life, typically ranging from 22 to 60 hours, allowing for once or twice-daily dosing in most patients.
Clinical Indications
Epilepsy: Phenytoin is effective in the treatment of focal (partial) and generalized tonic-clonic seizures. It can be used as monotherapy or in combination with other anticonvulsants.
Status epilepticus: Phenytoin is commonly used intravenously to manage status epilepticus (prolonged or repeated seizures).
Seizure prevention during surgery: Phenytoin may be used perioperatively to prevent seizures in patients undergoing neurosurgery or those at risk.
Side Effects
Gingival hyperplasia: Overgrowth of the gums is a well-known side effect, particularly with long-term use.
Nystagmus: A rhythmic involuntary eye movement, which is often seen with higher phenytoin levels.
Dizziness and drowsiness: Phenytoin can cause sedation, dizziness, and unsteadiness, especially at higher doses.
Rash: A common side effect, which can range from a mild rash to more serious conditions such as Stevens-Johnson syndrome, a rare but life-threatening skin reaction.
Ataxia and coordination problems: Ataxia (lack of muscle coordination) and gait problems can occur, especially with higher doses. Ataxia can be result of cerebellar atrophy which occur during long time Phenytoin treatment.
Cognitive impairment: Phenytoin can cause cognitive side effects, such as confusion, difficulty concentrating, and memory problems.
Osteomalacia: Chronic use of phenytoin may interfere with vitamin D metabolism, leading to bone softening and increased fracture risk.
Hepatotoxicity: Phenytoin can cause liver toxicity in rare cases, leading to liver dysfunction or failure.
Hypersensitivity reactions: Rarely, phenytoin can cause severe allergic reactions, including fever, rash, and lymphadenopathy (swollen lymph nodes).
Hirsutism: Excessive growth of hair in unusual areas, such as the face, can occur in some women using phenytoin long-term.
Monitoring and Considerations
Therapeutic drug monitoring: Due to its nonlinear pharmacokinetics, phenytoin levels should be closely monitored. Blood levels above 20 mcg/mL are generally considered toxic and can increase the risk of side effects.
Drug interactions: Phenytoin interacts with many other drugs, particularly those metabolized by the cytochrome P450 system. Drugs that either increase or decrease the activity of this enzyme system can significantly alter phenytoin levels, requiring careful monitoring and dose adjustment.
Pregnancy: Phenytoin is classified as a Category D drug during pregnancy, meaning it can cause harm to a fetus. It is teratogenic and can lead to birth defects, particularly facial abnormalities, and cognitive impairments in the newborn. It should only be used during pregnancy if the benefits outweigh the risks, and women of childbearing age should use effective contraception.
Phenytoin is a widely used anticonvulsant, effective for managing both acute and chronic seizures, but it requires careful monitoring due to its potential for significant side effects and drug interactions. Despite its therapeutic benefits, phenytoin's use must be carefully managed, particularly in patients with liver dysfunction or during pregnancy.
