PHENYTOIN SODIUM
Chemistry - A hydantoin-derivative, phenytoin sodium occurs as a white, hygroscopic powderwhich 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) andthe injectable preparations. Phenytoin (base) is used in the oral tablets and suspensions. Each 100mg of phenytoin sodium contains 92 mg of the base.
Phenytoin sodium injection is generally incompatible with most IV solutions (upon standing) anddrugs. 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 andrecommendations 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 relativelyshort time; 4) use a 0.22 µm in-line IV filter; 5) watch the admixture carefully.
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 cardiacuse 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 ofphenytoin as an anticonvulsant for long term treatment of epilepsy has diminished over the years. Itremains however, as an alternative or adjunctive therapy in dogs who have not responded to, or havedeveloped severe adverse reactions from either phenobarbital or primidone. Prerequisites forsuccessful therapy include: a motivated client who will be compliant with multiple daily dosing andwho is willing to assume the financial burden of high dose phenytoin therapy and therapeutic drugmonitoring expenses.
Although not commonly used, phenytoin has been employed as an oral or IV antiarrhythmic agentin both dogs and cats. It has been described as the drug of choice for digitalis-induced ventriculararrhythmias in dogs.
It has been suggested that phenytoin be used as adjunctive treatment of hypoglycemia secondaryto hyperinsulinism, but apparently little clinical benefit has resulted from this therapy.
The drug is metabolized in the liver and with much of the drug conjugated to a glucuronide formand then excreted by the kidneys. Phenytoin will induce hepatic microsomal enzymes which mayenhance the metabolism of itself and other drugs. The serum half-life (elimination) differencesbetween various species are striking. Phenytoin has reported half-lives of 2-8 hours in dogs, 8hours in horses, 15-24 hours in humans, and 42-108 hours in cats. Because of the pronouncedinduction of hepatic enzymes in dogs, phenytoin metabolism is increased with shorter half-liveswithin 7-9 days after starting treatment. Puppies have a smaller volumes of distribution and shorterelimination half-lives (1.6 hours) than adult dogs.
Contraindications/Precautions - Some data suggest that additive hepatotoxicity may result ifphenytoin is used with either primidone or phenobarbital. Weigh the potential risks versus thebenefits 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 beenestablished during pregnancy; weigh risks versus benefits.
Gingival hyperplasia has been reported in dogs receiving chronic therapy. Oral absorption may beenhanced and GI upset decreased if given with food.
Cats exhibit ataxia, sedation, and anorexia secondary to accumulation of phenytoin and high serumlevels. 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 overdosesymptoms in dogs is dependent on the severity of the symptoms since dogs so rapidly clear thedrug. Severe intoxications should be handled supportively.
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 listincludes only agents used commonly in small animal medicine, many more agents have beenimplicated 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 andgluconate), 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 thepotential risks versus the benefits before adding phenytoin to either of these drugs in dogs.
Pyridoxine (Vitamin B6) may reduce the serum levels of phenytoin.
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) andthe injectable preparations. Phenytoin (base) is used in the oral tablets and suspensions. Each 100mg of phenytoin sodium contains 92 mg of the base.
Storage, Stability, Compatibility
Store capsules at room temperature (below 86°F) and protectfrom light and moisture. Store phenytoin sodium injection at room temperature and protect fromfreezing. If injection is frozen or refrigerated, a precipitate may form which should resolubilizewhen warmed. A slight yellowish color will not affect either potency or efficacy, but do not useprecipitated solutions. Injectable solutions at less than a pH of 11.5 will precipitate. No problemswith adsorption to plastic have been detected thus far.Phenytoin sodium injection is generally incompatible with most IV solutions (upon standing) anddrugs. 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 andrecommendations 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 relativelyshort time; 4) use a 0.22 µm in-line IV filter; 5) watch the admixture carefully.
Pharmacology - PHENYTOIN SODIUM
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 motorcortex. It is believed that excessive stimulation or environmental changes can alter the sodiumgradient which may lower the threshold for seizure spread. Hydantoins tend to stabilize thisthreshold 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 cardiacuse 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 ofphenytoin as an anticonvulsant for long term treatment of epilepsy has diminished over the years. Itremains however, as an alternative or adjunctive therapy in dogs who have not responded to, or havedeveloped severe adverse reactions from either phenobarbital or primidone. Prerequisites forsuccessful therapy include: a motivated client who will be compliant with multiple daily dosing andwho is willing to assume the financial burden of high dose phenytoin therapy and therapeutic drugmonitoring expenses.
Although not commonly used, phenytoin has been employed as an oral or IV antiarrhythmic agentin both dogs and cats. It has been described as the drug of choice for digitalis-induced ventriculararrhythmias in dogs.
It has been suggested that phenytoin be used as adjunctive treatment of hypoglycemia secondaryto hyperinsulinism, but apparently little clinical benefit has resulted from this therapy.
Pharmacokinetics - PHENYTOIN SODIUM
After oral administration, phenytoin is nearly completely absorbed in humans, but in dogs, bioavailabilities may only be about 40%. Phenytoin is well distributed throughout thebody and is about 78% bound to plasma proteins in dogs (vs. 95% in humans). Protein bindingmay be reduced in uremic patients. Small amounts of phenytoin may be excreted into the milk andit readily crosses the placenta.The drug is metabolized in the liver and with much of the drug conjugated to a glucuronide formand then excreted by the kidneys. Phenytoin will induce hepatic microsomal enzymes which mayenhance the metabolism of itself and other drugs. The serum half-life (elimination) differencesbetween various species are striking. Phenytoin has reported half-lives of 2-8 hours in dogs, 8hours in horses, 15-24 hours in humans, and 42-108 hours in cats. Because of the pronouncedinduction of hepatic enzymes in dogs, phenytoin metabolism is increased with shorter half-liveswithin 7-9 days after starting treatment. Puppies have a smaller volumes of distribution and shorterelimination half-lives (1.6 hours) than adult dogs.
Contraindications/Precautions - Some data suggest that additive hepatotoxicity may result ifphenytoin is used with either primidone or phenobarbital. Weigh the potential risks versus thebenefits 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 beenestablished during pregnancy; weigh risks versus benefits.
Adverse Effects, Warnings
Adverse effects in dogs associated with high serum levels includeanorexia and vomiting, ataxia, and sedation. Liver function tests should be monitored in patients onchronic therapy as hepatotoxicity (elevated serum ALT, decreased serum albumin, hepatocellularhypertrophy and necrosis, hepatic lipidosis, and extramedullary hematopoiesis) has been reported.Gingival hyperplasia has been reported in dogs receiving chronic therapy. Oral absorption may beenhanced and GI upset decreased if given with food.
Cats exhibit ataxia, sedation, and anorexia secondary to accumulation of phenytoin and high serumlevels. 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 overdosesymptoms in dogs is dependent on the severity of the symptoms since dogs so rapidly clear thedrug. 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 listincludes only agents used commonly in small animal medicine, many more agents have beenimplicated 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 andgluconate), 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 thepotential risks versus the benefits before adding phenytoin to either of these drugs in dogs.
Pyridoxine (Vitamin B6) may reduce the serum levels of phenytoin.