Pharmacology of phenytoin | phenytoin mechanism of action

 Pharmacology of phenytoin 

Phenytoin is a medication used to treat epilepsy and other seizure disorders. It is also used to prevent seizures during neurosurgery. This article provides an overview of the pharmacokinetics and pharmacodynamics of phenytoin, including its absorption, distribution, metabolism, excretion, mechanism of action, dosage, adverse effects, contraindications, and interactions.

1. Pharmacokinetics

a. Absorption mechanism

Phenytoin is well absorbed after oral administration, but the rate and extent of absorption can vary depending on the formulation and the presence of food in the stomach. Peak plasma concentrations are reached within 1-4 hours of ingestion. Phenytoin is also available in other forms such as intravenous injections and capsules.

b. Distribution in body

Phenytoin is distributed throughout the body after absorption. The drug is highly protein-bound (about 90%), primarily to albumin. Phenytoin is distributed into most body tissues, including the brain, where it has a long half-life. The concentration of phenytoin in the body may be affected by factors such as age, pregnancy, liver disease, and drug interactions.

c. Metabolism mechanism

Phenytoin is primarily metabolized in the liver, mainly by the cytochrome P450 system, particularly CYP2C9 and CYP2C19. The major metabolic pathway leads to the formation of inactive metabolites that are excreted in the urine. A small fraction of phenytoin is metabolized via the CYP3A4 system to form a toxic metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH), which can cause liver damage if it accumulates in high concentrations.

d. Excretion mechanism

Phenytoin and its metabolites are eliminated mainly by the kidney. The half-life of phenytoin is about 22 hours in adults, but may be longer in neonates and in patients with liver or kidney disease. The drug is excreted primarily in the urine as glucuronide and sulfate conjugates, and a small amount is excreted unchanged.

2. Pharmacodynamics 

a. Mechanism of action

Phenytoin's mechanism of action is not fully understood, but it is believed to involve the inhibition of sodium channels in neuronal membranes, particularly those that are rapidly firing during seizures. This reduces the influx of sodium ions into the cell, which stabilizes the neuronal membrane and prevents the spread of seizures.

b. Dose required

The recommended dose of phenytoin for adults is usually started at 100-300 mg per day, divided into two or three doses. The dose may be adjusted based on the individual's response and plasma concentration of phenytoin, which is monitored regularly. The recommended dose for children is based on their weight and age, with a maximum dose of 5 mg/kg per day.

c. Adverse effects

The most common adverse effects of phenytoin are dizziness, drowsiness, and ataxia. These side effects are generally mild and transient. Rare but serious adverse effects include liver damage, particularly in overdose or in patients with liver disease, and allergic reactions such as skin rash, hives, and swelling of the face, lips, tongue, or throat.

d. Contraindications

Phenytoin is contraindicated in patients with a known allergy to the drug or other hydantoins. It should be used with caution in patients with liver or kidney disease, and in patients who consume alcohol regularly. Phenytoin is also contraindicated in patients with a history of bone marrow depression, and in patients with a genetic predisposition to Stevens