Phenytoin

PHARMACOKINETICS

Absorption
Phenytoin (Phenytoin) is well absorbed after oral administration, but the rate and extent can vary depending on the formulation. Immediate-release tablets or capsules are absorbed relatively quickly, while extended-release formulations provide slower, more prolonged absorption. Peak plasma concentrations are usually reached within 3–12 hours for oral forms. Its absorption can be influenced by food, which may delay the time to peak levels but does not significantly reduce overall bioavailability.

Distribution
Phenytoin (Phenytoin) is widely distributed throughout the body, particularly in muscle and liver tissues, but its penetration into the cerebrospinal fluid (CSF) is limited, usually achieving about 50% of plasma concentrations. It is highly protein-bound (approximately 90% bound to plasma albumin), which means that only the unbound fraction is pharmacologically active.

Metabolism

This non-linear metabolism makes careful therapeutic drug monitoring essential to avoid toxicity. The drug is converted to inactive hydroxylated metabolites, which are then excreted mainly via the kidneys. Liver function, drug interactions, and genetic variations in CYP enzymes can significantly influence phenytoin metabolism.

Elimination

Phenytoin (Phenytoin) is primarily eliminated via hepatic metabolism, with only a small fraction excreted unchanged in the urine. Because its metabolism follows saturation (zero-order) kinetics at higher doses, the half-life is variable, typically ranging from 22 to 36 hours, and can be prolonged in cases of liver impairment or high plasma concentrations. The metabolites formed are largely inactive and renally excreted. This complex elimination pattern requires careful dose titration and monitoring of plasma levels to maintain therapeutic efficacy while avoiding toxicity.

PHARMACODYNAMICS
Phenytoin (Phenytoin) is a neuronal membrane stabilizer that exerts its antiepileptic effects by inhibiting repetitive, high-frequency firing of neurons. It does this primarily by prolonging the inactivated state of voltage-gated sodium channels, which reduces the propagation of abnormal electrical discharges in the brain. This action is time- and voltage-dependent, making phenytoin particularly effective in preventing generalized tonic-clonic seizures and complex partial seizures.

ADMINISTRATION
Phenytoin (Phenytoin) can be administered orally or intravenously, depending on the clinical situation. Oral forms include immediate-release tablets, extended-release capsules, and oral suspensions, which are typically taken once or twice daily depending on the formulation and seizure control needs. For optimal absorption, oral phenytoin should be taken consistently with respect to meals, as food can alter the rate of absorption. Intravenous phenytoin is reserved for acute seizure management, such as status epilepticus, and must be administered slowly with careful monitoring to avoid cardiovascular complications. Dose adjustments and monitoring of plasma levels are essential to maintain therapeutic efficacy and minimize toxicity.

DOSAGE AND STRENGTH
Phenytoin (Phenytoin) is available in immediate-release tablets (100 mg), extended-release capsules (100 mg, 200 mg), chewable tablets (50 mg), and oral suspension (125 mg/5 mL). For adults, the usual starting dose is 100 mg three times daily, with gradual titration based on seizure control and plasma levels, typically aiming for a total daily dose of 300–400 mg. Pediatric dosing is generally 5 mg/kg/day in divided doses, adjusted according to age, weight, and response. In acute settings, intravenous phenytoin can be given, but infusion rates must be carefully controlled to prevent cardiovascular complications.

DRUG INTERACTIONS
Phenytoin (Phenytoin) can interact with various medications, affecting its own levels or the effects of other drugs. Enzyme-inducing drugs such as rifampin or carbamazepine can reduce phenytoin levels, while enzyme inhibitors like valproic acid can increase its plasma concentration, raising the risk of toxicity. Phenytoin may decrease the effectiveness of oral contraceptives. It can also enhance the effects of anticoagulants like warfarin, requiring careful monitoring. Interactions with other antiepileptics, antifungals, and certain antibiotics may necessitate dose adjustments and monitoring to maintain therapeutic efficacy and avoid adverse effects.

FOOD INTERACTIONS
Phenytoin (Phenytoin) absorption can be affected by food. Taking phenytoin with meals may delay the time to reach peak plasma concentrations, although it does not significantly reduce overall bioavailability. For consistent and predictable effects, it is recommended to take phenytoin at the same time each day and maintain a consistent relationship to meals, either always with food or always on an empty stomach, depending on the prescribed regimen. High-fat meals may further slow absorption, so consistency is important to maintain stable therapeutic levels.

CONTRAINDICATIONS
Phenytoin (Phenytoin) is contraindicated in individuals with a known hypersensitivity to phenytoin or other hydantoin derivatives, as administration can trigger severe allergic reactions. It should also be avoided in patients with sinus bradycardia, sinoatrial block, or second- and third-degree atrioventricular block, particularly when administered intravenously, due to the risk of serious cardiac complications.

SIDE EFFECTS

• Nystagmus (early sign of toxicity) 

• Ataxia (unsteady gait) 

• Dizziness 

• Drowsiness or sedation 

• Slurred speech 

• Cognitive impairment or confusion (long-term use) 

• Gingival hyperplasia (gum overgrowth) 

• Hirsutism (excess hair growth) 

• Skin rash (may progress to Stevens-Johnson syndrome in severe cases) 

• Nausea and vomiting 

• Peripheral neuropathy (long-term use) 

• Osteomalacia (with chronic use due to vitamin D metabolism effects) 

• Blood disorders (rare: megaloblastic anemia, leukopenia) 

OVER DOSAGE

Phenytoin overdose is associated with dose-dependent central nervous system and cardiovascular toxicity. Early symptoms include nystagmus, slurred speech, dizziness, ataxia, and confusion. As toxicity worsens, patients may develop lethargy, coma, and seizures paradoxically in severe cases.

TOXICITY

Phenytoin (Phenytoin) has a narrow therapeutic index, meaning the difference between therapeutic and toxic levels is small. Signs of toxicity include nystagmus, ataxia, dizziness, slurred speech, and confusion. Severe toxicity may cause seizures, hypotension, cardiac arrhythmias, or coma, particularly with rapid intravenous administration or overdose. Chronic high plasma levels can also result in gingival hyperplasia, hirsutism, and cerebellar degeneration. Management of toxicity involves discontinuing or reducing the dose, supportive care, and in severe cases, monitoring in a hospital setting to prevent life-threatening complications.