Phenytoin: How does it work, what are its side effects, and what is fetal hydantoin syndrome?

How Phenytoin Works

Phenytoin's primary mechanism involves inhibiting voltage-gated sodium channels in neurons. By keeping these channels in an inactive state, it reduces neuronal excitability, preventing seizures. This also explains its use in treating certain cardiac arrhythmias, as electrical hyper-excitability is a common factor in both conditions.

Essentially, it stabilizes the electrical activity in the brain and heart.

Pharmacokinetics: Zero-Order Elimination

One critical aspect of phenytoin is its zero-order elimination. This means that a constant amount of the drug is eliminated per unit time, regardless of the concentration. This can lead to rapid increases in plasma concentration and toxicity with small dose adjustments, making careful monitoring essential.

Phenytoin Side Effects

Phenytoin has a range of potential side effects, some dose-dependent and others not.

Dose-Dependent Side Effects

• Hepatic necrosis: Liver damage due to the drug's metabolism.
• CNS depression: Reduced brain activity, leading to drowsiness and other neurological symptoms.
• Folate and Vitamin D deficiency: Resulting in megaloblastic anemia, neural tube defects, rickets, and osteomalacia.

Non-Dose-Dependent Side Effects

• Lupus-like reaction: Symptoms mimicking lupus.
• Allergic rash.
• Pseudo lymphoma: Lymphadenopathy with fever and rash.
• Gingival hyperplasia: Gum overgrowth.
• Hirsutism: Excessive hair growth.
• Nystagmus: Involuntary eye movements.

The liver metabolizes phenytoin by hydroxylation. Overwhelming the liver with high doses saturates the enzymes, drastically increasing plasma drug levels and the risk of toxicity, including coma, cardiovascular collapse, and respiratory depression.

Fetal Hydantoin Syndrome

Phenytoin is a known teratogen, meaning it can cause birth defects. Fetal hydantoin syndrome is a specific pattern of congenital anomalies associated with prenatal exposure to phenytoin.

Characteristics of Fetal Hydantoin Syndrome

• Microcephaly: Abnormally small head.
• Midfacial hypoplasia: Underdevelopment of the midface.
• Cleft lip and palate.
• Low-set ears.
• Developmental delay and intellectual disability.
• Hypoplasia of nails and distal phalanges.
• Congenital heart defects (e.g., ventricular septal defect, pulmonic stenosis, transposition of great vessels).

It is important to note that other fetal complications can occur, such as intrauterine growth restriction, twin-to-twin transfusion syndrome, and oligohydramnios/polyhydramnios.

Clinical Uses

Despite its potential side effects, phenytoin remains valuable for treating:

• Focal seizures.
• Tonic-clonic seizures.
• Status epilepticus.
• Certain cardiac arrhythmias.