Short note on phenytoin for University exam

Reading File

Finding Sources

Reading File

Finding Sources

Reading File

I now have comprehensive content from multiple authoritative sources. Let me compile a well-structured university exam note on phenytoin.

Phenytoin - Short Note

Introduction

Phenytoin (diphenylhydantoin) is the oldest non-sedating antiseizure drug, first identified in 1938. It belongs to the hydantoin class and remains widely used despite being displaced from first-line status due to its complex pharmacokinetics and adverse effect profile.

Chemistry

Phenytoin is the 5,5-diphenyl substituted analog of hydantoin - a five-membered ring compound structurally similar to barbiturates (six-membered ring). Its free base is poorly water-soluble (pKa 8.06-8.33), while the sodium salt dissolves in water at 17 mg/mL. Fosphenytoin is a water-soluble phosphate ester prodrug rapidly converted to phenytoin in plasma, used for IV/IM administration.

Mechanism of Action

Phenytoin acts by blocking voltage-gated sodium (Na+) channels. It slows the rate of recovery of these channels from inactivation, acting in a:

Voltage-dependent manner (greater effect when membrane is depolarized)
Use-dependent manner (greater effect on rapidly firing neurons)

This selectively suppresses repetitive high-frequency neuronal firing without affecting normal neuronal activity. At therapeutic concentrations, effects are limited to Na+ channels. At 5-10x higher concentrations, it also reduces spontaneous activity and enhances GABA responses (contributing to toxicity).

Clinical Uses / Indications

Focal (partial) seizures - drug of choice historically
Generalized tonic-clonic seizures (focal-to-bilateral and primary)
Status epilepticus - IV administration (fosphenytoin preferred)
Trigeminal neuralgia (second-line)
Cardiac arrhythmias - particularly digitalis-induced arrhythmias (used less now)

Does NOT work for: Absence seizures, juvenile myoclonic epilepsy, Dravet syndrome - may actually worsen these.

Pharmacokinetics

Parameter	Detail
Absorption	Nearly complete orally; peak at 3-12 hours (formulation-dependent)
Protein binding	~90% bound to albumin
Distribution	Wide; crosses blood-brain barrier and placenta
Metabolism	Hepatic - CYP2C9 and CYP2C19 (hydroxylation)
Elimination	Zero-order (saturation) kinetics at therapeutic doses
Half-life	~22 hours (variable; longer in slow metabolizers)

Key Pharmacokinetic Features:

Zero-order (Michaelis-Menten) kinetics: At therapeutic levels, the metabolizing enzymes are near saturation. Small dose increases cause disproportionately large rises in plasma levels - this makes dosing tricky and toxicity easy to precipitate.
Narrow therapeutic index: Therapeutic range = 10-20 mg/L (total); 1-2 mg/L (free)
Low albumin (liver disease, nephrotic syndrome, pregnancy) increases free drug and risk of toxicity
Intramuscular absorption is erratic - not recommended

Drug Interactions

Phenytoin is a potent inducer of CYP enzymes (CYP1A2, CYP2C, CYP3A4) - it accelerates metabolism of many drugs.

Drugs that increase phenytoin levels (toxicity risk):

Valproate (displaces from albumin AND inhibits metabolism)
Isoniazid, fluconazole, amiodarone, chloramphenicol, cimetidine

Drugs that decrease phenytoin levels (loss of seizure control):

Carbamazepine, rifampicin, phenobarbitone, antacids (reduce absorption)

Phenytoin reduces levels of:

Warfarin, oral contraceptives, corticosteroids, cyclosporine, lamotrigine, theophylline, vitamin D

Adverse Effects

Dose-Related (concentration-dependent):

Plasma Level	Effects
>20 mg/L	Nystagmus (first sign - on lateral gaze)
>30 mg/L	Ataxia, diplopia, dysarthria
>40 mg/L	Confusion, mental deterioration
Very high	Coma, seizures (paradoxical), respiratory depression

Chronic Long-Term Effects (not dose-dependent):

Gingival hyperplasia (20-30% of patients; especially children) - due to altered collagen metabolism
Hirsutism (coarsening of facial features, acne)
Peripheral neuropathy - loss of deep tendon reflexes
Folate deficiency - megaloblastic anaemia (phenytoin interferes with folate absorption)
Osteomalacia - induces CYP enzymes which increase vitamin D catabolism
Cerebellar atrophy - with long-term use
Coarsening of facial features

Idiosyncratic/Hypersensitivity (weeks 1-6):

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
Rash (can progress to Stevens-Johnson Syndrome / TEN)
Pseudolymphoma
Lupus-like syndrome
Hepatotoxicity

Teratogenicity:

Fetal hydantoin syndrome: cleft palate, congenital heart defects, digital/nail hypoplasia, craniofacial abnormalities, cognitive impairment
Causes hemorrhagic disease of the newborn (inhibits vitamin K-dependent clotting factors)

IV Administration:

"Purple glove syndrome" - purplish discoloration + edema distal to injection site
Hypotension, bradycardia, cardiac arrhythmias, AV block - administer at no more than 50 mg/min IV
Fosphenytoin is preferred for IV use (less cardiovascular toxicity, no propylene glycol vehicle)

Preparations & Dosing

Oral: Extended-release capsule (phenytoin sodium) - once daily possible; prompt-release tablets/suspension for more frequent dosing
IV: Phenytoin sodium injection (propylene glycol-based, pH 12) or fosphenytoin (preferred, water-soluble)
Typical dose: 300-400 mg/day orally; loading dose 15-20 mg/kg IV for status epilepticus

Summary Table

Feature	Detail
Class	Hydantoin
Mechanism	Na+ channel blocker (use- and voltage-dependent)
Uses	Focal seizures, tonic-clonic, status epilepticus
Kinetics	Zero-order at therapeutic levels; 90% protein-bound
Therapeutic range	10-20 mg/L
Unique ADRs	Gingival hyperplasia, hirsutism, folate deficiency, fetal hydantoin syndrome
Enzyme effect	CYP inducer
Pregnancy	Category D - teratogenic

Sources: Katzung's Basic & Clinical Pharmacology, 16th Ed. | Goodman & Gilman's Pharmacological Basis of Therapeutics | Tintinalli's Emergency Medicine | Lippincott Illustrated Reviews: Pharmacology

This is a shared conversation. Sign in to Orris to start your own chat.