Phenytoin Sodium

Anticonvulsant Hydantoin derivative

Dosage & Administration Guidelines

Species Route Dose Frequency Duration & Clinical Notes
Dog PO 20-35 mg/kg q8h (every 8 hours) Duration: Chronic therapy; adjust based on serum levels
Notes: Start at lower end and titrate to effect. Monitor serum phenytoin concentrations (target 5-15 μg/mL). Due to short half-life, dosing three times daily is often required. Oral absorption is erratic; consider using a reliable formulation.
Dog IV 10-20 mg/kg Slow IV infusion (max rate 50 mg/min) Duration: For status epilepticus; may repeat after 20-30 min if needed
Notes: Use with caution; monitor ECG and blood pressure. Phenytoin sodium injection is not compatible with many IV fluids; flush line with saline before and after.
Cat PO 2-5 mg/kg q12h (every 12 hours) Duration: Chronic therapy; adjust based on serum levels
Notes: Cats have a longer half-life, so twice-daily dosing is possible. However, cats are more prone to toxicity; start at low dose and monitor for adverse effects. Not recommended as first-line.
Horse PO 10-20 mg/kg q8-12h Duration: Not well established
Notes: Oral absorption is poor; IV administration may be used but is not practical for chronic therapy. Not recommended due to lack of efficacy.
Cattle PO 10-20 mg/kg q8-12h Duration: Not well established
Notes: Limited data; not recommended for routine use.

Clinical Indications & Species Uses

General Indications
  • Phenytoin is primarily used in dogs for seizure control, but its use has declined due to the availability of better anticonvulsants (e.g., phenobarbital, levetiracetam). It is not recommended as a first-line agent in any species.
Dog (Canine)
  • Treatment of generalized tonic-clonic seizures
  • Adjunct therapy for refractory epilepsy
  • Treatment of status epilepticus (IV, when other drugs are unavailable)
Cat (Feline)
  • Treatment of seizures (though not first-line due to toxicity and long half-life)
  • Adjunct therapy for refractory epilepsy
Horse (Equine)
  • May be used experimentally for seizures
Cattle (Bovine)
  • May be used for seizures in calves

Pharmacology & Mechanism of Action

Drug Class: Anticonvulsant | Pharmacological Group: Hydantoin derivative

Mechanism of Action: Phenytoin exerts its anticonvulsant effect primarily by blocking voltage-gated sodium channels in neurons. It binds to the inactivated state of the sodium channel, prolonging the inactivation and thereby reducing the high-frequency repetitive firing of action potentials that occurs during seizures. This stabilizes the neuronal membrane and decreases excitability. Phenytoin also affects calcium channels and neurotransmitter release, but the sodium channel blockade is the primary mechanism.

Pharmacodynamics: Phenytoin reduces seizure activity without causing generalized central nervous system depression at therapeutic doses. It has a narrow therapeutic index, and its effects are dose-dependent. In addition to anticonvulsant effects, phenytoin may have antiarrhythmic properties (class IB) and can affect cardiac conduction, particularly at high concentrations. It also has effects on vitamin D metabolism and folate absorption with chronic use.

⚡ Pharmacokinetics Summary

Absorption: Phenytoin is absorbed from the gastrointestinal tract, but absorption is highly variable and can be erratic, especially in dogs. Oral bioavailability may be incomplete and is influenced by the formulation. In dogs, absorption is slow and variable; in horses, oral absorption is poor. In cats, absorption is also variable. Intravenous administration provides immediate and complete bioavailability.
Distribution: Phenytoin is widely distributed throughout the body. It crosses the blood-brain barrier and the placenta. It is highly bound to plasma proteins, primarily albumin. In dogs, protein binding is approximately 70-80%, but in cats it is lower (around 60%). The volume of distribution is approximately 0.5-1.0 L/kg in dogs.
Metabolism: Phenytoin is extensively metabolized in the liver, primarily by cytochrome P450 enzymes (CYP2C and CYP3A in humans; in dogs, CYP2B11 and others). The major metabolite is 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH), which is then glucuronidated and excreted. Metabolism is saturable, leading to nonlinear pharmacokinetics at higher doses. In dogs, the half-life is relatively short (about 4-6 hours) compared to humans, and there is significant interindividual variation.
Excretion: Phenytoin and its metabolites are excreted primarily in the urine, with a small amount in bile and feces. In dogs, the majority of the dose is excreted in urine as metabolites. The elimination half-life in dogs is approximately 4-6 hours, but can be prolonged with chronic dosing due to saturation of metabolism. In cats, the half-life is longer, around 24-48 hours, making it more suitable for twice-daily dosing.
Half-Life: Dog: 4-6 hours; Cat: 24-48 hours; Horse: 6-8 hours (but oral absorption is poor); Cattle: 4-6 hours (limited data)
Bioavailability: Oral: variable, approximately 50-70% in dogs; in cats, oral bioavailability is around 50-80%; in horses, oral bioavailability is very low (<20%).
Protein Binding: Dog: 70-80%; Cat: 60%; Horse: 80% (estimated); Cattle: 70% (estimated)

Available Formulations & Strengths

Oral Tablet 50 mg, 100 mg (PO)
Oral Capsule 30 mg, 100 mg (PO)
Oral Suspension 125 mg/5 mL (PO)
Injectable Solution 50 mg/mL (IV)

Contraindications & Clinical Warnings

Contraindications:
  • Hypersensitivity to phenytoin or other hydantoins
  • Sinus bradycardia, sinoatrial block, second- and third-degree AV block
  • Use in animals with known hepatic disease (severe)
  • Use in pregnant animals (teratogenic effects)
  • Concurrent use with delavirdine (in humans; not relevant in veterinary but caution)
Warnings & Clinical Precautions:
  • Narrow therapeutic index; monitor serum concentrations and adjust dose accordingly.
  • Oral absorption is erratic; use a consistent brand and formulation.
  • Abrupt withdrawal may precipitate seizures; taper dose gradually.
  • May cause hepatotoxicity; monitor liver enzymes periodically.
  • May cause blood dyscrasias (e.g., neutropenia, thrombocytopenia); monitor CBC.
  • Use with caution in animals with cardiac disease, hypotension, or hypoproteinemia.
  • In cats, phenytoin is poorly metabolized and can accumulate; use with extreme caution.
  • Phenytoin may interfere with vitamin D metabolism and folate absorption; consider supplementation with long-term use.
  • IV administration may cause hypotension, arrhythmias, and tissue necrosis if extravasation occurs.

Adverse Effects & Reactions

Common:

  • Ataxia
  • Sedation
  • Gingival hyperplasia (with chronic use)
  • Vomiting
  • Anorexia
  • Nystagmus

Serious / Severe:

  • Hepatotoxicity
  • Blood dyscrasias (neutropenia, thrombocytopenia, aplastic anemia)
  • Stevens-Johnson syndrome (rare)
  • Cardiac arrhythmias (with rapid IV administration)
  • Hypotension
  • Cerebellar degeneration (with chronic high doses)

Rare:

  • Lupus-like syndrome
  • Lymphadenopathy
  • Peripheral neuropathy
  • Osteomalacia
  • Hyperglycemia

Key Drug Interactions

Interacting Drug / Class Clinical Effect & Mechanism Severity
Phenobarbital Phenobarbital induces hepatic enzymes, increasing phenytoin metabolism and decreasing phenytoin serum levels. Conversely, phenytoin may increase phenobarbital levels. Monitor both drugs. High
Cimetidine Cimetidine inhibits hepatic metabolism of phenytoin, increasing phenytoin levels and risk of toxicity. High
Chloramphenicol Chloramphenicol inhibits hepatic enzymes, increasing phenytoin levels. High
Sulfonamides Sulfonamides may displace phenytoin from protein binding sites, increasing free phenytoin levels. Moderate
Antacids (calcium, magnesium, aluminum) Antacids may reduce phenytoin absorption; separate administration by 2-3 hours. Moderate
Isoniazid Isoniazid inhibits phenytoin metabolism, increasing phenytoin levels. High
Diazepam Phenytoin may increase diazepam levels; additive CNS depression. Moderate

Overdose & Toxicity Management

Signs of Toxicity:

  • Nystagmus
  • Ataxia
  • Dysarthria
  • Lethargy
  • Coma
  • Respiratory depression
  • Hypotension
  • Cardiac arrhythmias
  • Seizures (paradoxical)

Emergency Treatment Protocol: Treatment is primarily supportive. Induce vomiting if recent oral ingestion and animal is conscious. Administer activated charcoal to reduce absorption. Provide IV fluids for hypotension. Monitor ECG and vital signs. In severe cases, consider hemodialysis or hemoperfusion (though rarely available in veterinary practice). There is no specific antidote. Supportive care may include oxygen, mechanical ventilation, and anticonvulsants (e.g., diazepam) for seizures if they occur.

Food Animal Withdrawal Times

Phenytoin is not approved for use in food animals in the United States. If used off-label in food animals, a prolonged withdrawal period should be considered, but no official withdrawal times are established. It is not recommended for use in food animals due to lack of residue data.

Storage, Handling & Regulatory Information

Storage Temperature: Store at room temperature (20-25°C, 68-77°F). Protect from moisture.

Handling & Special Conditions: Keep in a tightly closed container. Injectable solution should be stored at room temperature and protected from freezing. Do not use if solution is discolored or contains precipitate.

Dispensing Status: Prescription Required (Rx Only)

Approval Status: Not approved for veterinary use in the United States. Approved for human use.

Extra-Label (Off-Label) Use: In the United States, phenytoin is not FDA-approved for veterinary use. Its use in animals is extra-label (off-label) and must comply with AMDUCA regulations. For food animals, extra-label use is prohibited if an approved animal drug exists that is effective and available, and if the drug is not approved for use in food animals. Phenytoin is not approved for food animals, so its use in food animals is not permitted under AMDUCA unless a valid veterinarian-client-patient relationship exists and a withdrawal time is established by the veterinarian.

Clinical Pearls & Practice Notes

💡 Clinical Insights: Phenytoin is an older anticonvulsant that is rarely used in veterinary medicine today due to its unpredictable pharmacokinetics, narrow therapeutic index, and the availability of safer and more effective drugs such as phenobarbital, levetiracetam, and zonisamide. In dogs, its short half-life necessitates dosing three times daily, and oral absorption is erratic, making therapeutic monitoring essential. In cats, the long half-life and risk of toxicity limit its use. Phenytoin is not recommended as a first-line agent for any species. If used, it should be reserved for cases where other anticonvulsants have failed or are contraindicated. Clinicians should be aware of the potential for drug interactions and adverse effects, and should monitor serum phenytoin levels, liver function, and blood counts regularly. Due to the lack of veterinary approval and limited safety data, informed owner consent should be obtained before use.

References & Literature

  • 📚 Plumb's Veterinary Drug Handbook
  • 📚 Papich Veterinary Pharmacology and Therapeutics
  • 📚 Compendium of Veterinary Products (CVP)