Chemistry - A hydantoin-derivative, phenytoin sodium occurs as a white, hygroscopic powder which is freely soluble in water and warm propylene glycol, and soluble in alcohol.
Because phenytoin sodium slowly undergoes partial hydrolysis in aqueous solutions to phenytoin (base) with the resultant solution becoming turbid, the commercial injection contains 40% propylene glycol and 10% alcohol. The pH of the injectable solution is approximately 12.
Phenytoin sodium is used in the commercially available capsules (both extended and prompt) and the injectable preparations. Phenytoin (base) is used in the oral tablets and suspensions. Each 100 mg of phenytoin sodium contains 92 mg of the base.
Storage/Stability/Compatibility - Store capsules at room temperature (below 86°F) and protect from light and moisture. Store phenytoin sodium injection at room temperature and protect from freezing. If injection is frozen or refrigerated, a precipitate may form which should resolubilize when warmed. A slight yellowish color will not affect either potency or efficacy, but do not use precipitated solutions. Injectable solutions at less than a pH of 11.5 will precipitate. No problems with adsorption to plastic have been detected thus far.
Phenytoin sodium injection is generally incompatible with most IV solutions (upon standing) and drugs. It has been successfully mixed with sodium bicarbonate and verapamil HCl.
Because an infusion of phenytoin sodium is sometimes desirable, several studies have been performed to determine whether such a procedure can be safely done. The general conclusions and recommendations of these studies are: 1) use either normal saline or lactated Ringer’s; 2) a concentration of 1 mg/ml phenytoin be used; 3) start infusion immediately and complete in a relatively short time; 4) use a 0.22 µm in-line IV filter; 5) watch the admixture carefully.
Pharmacology - The anticonvulsant actions of phenytoin are thought to be caused by the promotion of sodium efflux from neurons, thereby inhibiting the spread of seizure activity in the motor cortex. It is believed that excessive stimulation or environmental changes can alter the sodium gradient which may lower the threshold for seizure spread. Hydantoins tend to stabilize this threshold and limit seizure propagation from epileptogenic foci.
The cardiac electrophysiologic effects of phenytoin are similar (not identical) to that of lidocaine (Group 1B). It depresses phase O slightly and can shorten the action potential. Its principle cardiac use is in the treatment of digitalis-induced ventricular arrhythmias.
Phenytoin can inhibit insulin and vasopressin (ADH) secretion.
Uses/Indications - Because of its undesirable pharmacokinetic profiles in dogs and cats, the use of phenytoin as an anticonvulsant for long term treatment of epilepsy has diminished over the years. It remains however, as an alternative or adjunctive therapy in dogs who have not responded to, or have developed severe adverse reactions from either phenobarbital or primidone. Prerequisites for successful therapy include: a motivated client who will be compliant with multiple daily dosing and who is willing to assume the financial burden of high dose phenytoin therapy and therapeutic drug monitoring expenses.
Although not commonly used, phenytoin has been employed as an oral or IV antiarrhythmic agent in both dogs and cats. It has been described as the drug of choice for digitalis-induced ventricular arrhythmias in dogs.
It has been suggested that phenytoin be used as adjunctive treatment of hypoglycemia secondary to hyperinsulinism, but apparently little clinical benefit has resulted from this therapy.
Pharmacokinetics - After oral administration, phenytoin is nearly completely absorbed in humans, but in dogs, bioavailabilities may only be about 40%. Phenytoin is well distributed throughout the body and is about 78% bound to plasma proteins in dogs (vs. 95% in humans). Protein binding may be reduced in uremic patients. Small amounts of phenytoin may be excreted into the milk and it readily crosses the placenta.
The drug is metabolized in the liver and with much of the drug conjugated to a glucuronide form and then excreted by the kidneys. Phenytoin will induce hepatic microsomal enzymes which may enhance the metabolism of itself and other drugs. The serum half-life (elimination) differences between various species are striking. Phenytoin has reported half-lives of 2-8 hours in dogs, 8 hours in horses, 15-24 hours in humans, and 42-108 hours in cats. Because of the pronounced induction of hepatic enzymes in dogs, phenytoin metabolism is increased with shorter half-lives within 7-9 days after starting treatment. Puppies have a smaller volumes of distribution and shorter elimination half-lives (1.6 hours) than adult dogs.
Contraindications/Precautions - Some data suggest that additive hepatotoxicity may result if phenytoin is used with either primidone or phenobarbital. Weigh the potential risks versus the benefits before adding phenytoin to either of these drugs in dogs.
Phenytoin is contraindicated in patients known to be hypersensitive to it or other hydantoins. Intravenous use of the drug is contraindicated in patients with 2nd or 3rd degree heart block, sinoatrial block, Adams-Stokes syndrome, or sinus bradycardia. Safe use of this drug has not been established during pregnancy; weigh risks versus benefits.
Adverse Effects/Warnings - Adverse effects in dogs associated with high serum levels include anorexia and vomiting, ataxia, and sedation. Liver function tests should be monitored in patients on chronic therapy as hepatotoxicity (elevated serum ALT, decreased serum albumin, hepatocellular hypertrophy and necrosis, hepatic lipidosis, and extramedullary hematopoiesis) has been reported. Gingival hyperplasia has been reported in dogs receiving chronic therapy.
Oral absorption may be enhanced and GI upset decreased if given with food.
Cats exhibit ataxia, sedation, and anorexia secondary to accumulation of phenytoin and high serum levels. Cats have also been reported to develop a dermal atrophy syndrome secondary to phenytoin.
Overdosage - Symptoms of overdosage may include sedation, anorexia, and ataxia at lower levels, and coma, hypotension and respiratory depression at higher levels. Treatment of overdose symptoms in dogs is dependent on the severity of the symptoms since dogs so rapidly clear the drug. Severe intoxications should be handled supportively.
Drug Interactions - A case report of chloramphenicol increasing the serum half-life of phenytoin from 3 to 15 hours in a dogs has been reported. Note: the following interactions are from the human literature, because of the significant differences in pharmacokinetics in dogs and cats their veterinary significance will be variable. This list includes only agents used commonly in small animal medicine, many more agents have been implicated in the human literature: The following agents may increase the effects of phenytoin: allopurinol, cimetidine, chloramphenicol, diazepam, ethanol, isoniazid, phenylbutazone, sulfonamides, trimethoprim, valproic acid, salicylates, and chlorpheniramine. The following agents may decrease the pharmacologic activity of phenytoin: barbiturates, diazoxide, folic acid, theophylline, antacids, antineoplastics, calcium (dietary and gluconate), enteral feedings, nitrofurantoin, and pyridoxine. Phenytoin may decrease the pharmacologic activity of the following agents: corticosteroids, disopyramide, doxycycline, estrogens, quinidine, dopamine, and furosemide. Phenytoin may decrease the analgesic properties meperidine, but enhance its toxic effects. The toxicity of lithium may be enhanced. The pharmacologic effects of primidone may be altered. Some data suggest that additive hepatotoxicity may result if phenytoin is used with either primidone or phenobarbital. Weigh the potential risks versus the benefits before adding phenytoin to either of these drugs in dogs. Pyridoxine (Vitamin B6) may reduce the serum levels of phenytoin.
a) 2.83 - 16.43 mg/kg PO q8h to obtain serum levels from 5 - 10 micrograms/ml. Suggest monitoring serum levels to adjust dosage. (Kowalczyk and Beech 1983)
Monitoring Parameters -
1) Level of seizure control; sedation/ataxia
2) Body weight (anorexia)
3) Liver enzymes (if chronic therapy) & serum albumin
4) Serum drug levels if signs of toxicity or lack of seizure control
Client Information - Notify veterinarian if dog becomes anorexic, lethargic, ataxic, or if seizures are not adequately controlled. The importance of regular dosing is imperative for successful therapy.
Dosage Forms/Preparations -
Extended Phenytoin Sodium Capsules, USP® (Fort Dodge) (Rx) 100 mg tablets. Approved for use in dogs.Note: This product may no longer be marketed.
Phenytoin Sodium, Extended Oral Capsules 30 mg, 100 mg; Dilantin® Kapseals® (Parke-Davis); generic, (Rx)
Phenytoin Oral Suspension 25 mg/ml in 8 oz. bottles; Dilantin-125® (Parke-Davis) (Rx)
Phenytoin Oral Tablets 50 mg; Dilantin® Infa-Tabs® (Parke-Davis) (Rx)
Phenytoin Sodium for Injection 50 mg/ml (46 mg/ml phenytoin) in 2 ml and 5 ml amps, syringes and vials; 150 mg (100 mg phenytoin sodium) in 2 ml vials; 750 mg (500 mg phenytoin sodium) in 10 ml vials (Rx)
Phenytoin may also be called diphenylhydantoin or DPH .
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