Anticonvulsants

Chapter 31 Anticonvulsants





Anticonvulsants are used for the treatment of seizure disorders in animals.18 Numerous anticonvulsants have been used for treatment of seizures in animals, with some being more commonly used in the modern era, and others having been used historically and are less commonly used today. Additionally, newer anticonvulsants are constantly being identified for use in human seizure disorders.9 These newer anticonvulsants invariably are administered to animals, usually when standard anticonvulsants are ineffective or are associated with side effects. Although these newer anticonvulsants often have theoretical benefits, much less toxicological data exist for these drugs in the clinical setting. In rare instances, animals may ingest anticonvulsants that are intended for the owner or another family member.


Therapeutic anticonvulsants are primarily administered either to acutely terminate seizures, such as in an emergency setting, or are administered more chronically as a maintenance medication to reduce or eliminate overall seizure frequency or severity. For rapid termination of seizure activity, such as in the emergency setting, diazepam is most commonly administered. The two most commonly used maintenance anticonvulsants in animals in the current era are phenobarbital and potassium bromide. Historically, anticonvulsants, such as primidone and phenytoin, were used in some dogs, but are infrequently administered in the modern era. Newer maintenance anticonvulsants include drugs, such as gabapentin (Neurontin), lamotrigine (Lamictal), zonisamide (Zonegran), and levetiracetam (Keppra).



PHENOBARBITAL




Toxicokinetics


Bioavailability of oral phenobarbi tal is between 88% and 95%. The serum half-life (T½) is approximately 47 to 74 hours in most mongrel dogs. The T½ in beagles is 25 to 38 hours. The T½ is approximately 34 to 43 hours in cats.10 When phenobarbital is administered chronically, such as a maintenance anticonvulsant, half-lives will decline as a result of autoinduction of the drug’s own metabolism. Maximum concentrations are observed 4 to 8 hours after oral administration, although food may delay peak concentrations by an additional 2 to 4 hours.1811


Phenobarbital is primarily metabolized via hepatic microsomal enzymes, although up to 25% of the unchanged drug is eliminated by pH-dependent renal excretion.18 Glucuronidation is not an important mechanism of elimination, and therefore cats do not appear to metabolize this drug differently from dogs. Metabolism increases with use because of hepatic enzyme induction.



Mechanism of toxicity and clinical signs


Doses of phenobarbital that are associated with both efficacy and toxicity may vary between individual animals. Serum concentrations have been more closely correlated with therapeutic benefit than the administered dose. Therapeutic levels of 20 to 40 μg/mL have been suggested to maximize seizure control while minimizing side effects.1811 Trough levels historically correlate better with therapeutic outcome than with peak levels; however, this may not be as significant as initially thought.


Side effects associated with phenobarbital administration include sedation, ataxia, polyuria, polydipsia, polyphagia, nystagmus, restlessness or hyperexcitability, drug rash, hyperprothrombinemia, blood dyscrasias, and osteomalacia.18 Polyuria is thought to be caused by central inhibition of aldosterone release, whereas polyphagia is believed to result from suppression of the satiety center in the ventromedial hypothalamus. Phenobarbital has been shown to induce coagulation defects in cats by reducing vitamin K–dependent clotting factors (II, VII, IX, and X). Phenobarbital, displaced by sulfonamides and salicylates, may lead to an increase in the metabolism of other co-administered drugs. Phenobarbital may decrease measured serum T4 levels caused by increased biliary excretion and possibly an increase in deiodination of T4.18, 1214 Importantly, phenobarbital administration may induce the production of some commonly measured serum indicators of liver dysfunction, such as alkaline phosphatase (AP) and alanine transaminase (ALT).18, 1517 Liver enzyme elevations may take anywhere from 5 weeks up to 7 months to return to normal after discontinuing the drug.


Toxicity with phenobarbital administration includes those clinical signs associated with acute barbiturate overdose, but may also result in liver failure and cirrhosis. Common clinical signs of acute phenobarbital overdose include sedation (which may progress to coma), respiratory depression, ataxia, paresis, and possibly death. Co-administered drugs, such as chloramphenicol, decrease the metabolism of phenobarbital, and this can cause severe depression, sedation, and coma.18


Clinical signs of phenobarbital-associated liver disease are similar to signs of liver disease in general. General ill thrift, polyuria, gastrointestinal abnormalities (vomiting and diarrhea), abdominal enlargement, and icterus are possible. Increases in liver-associated enzymes (ALT, AP) and liver function tests (bile acids) and decreases in albumin, glucose, and cholesterol may be observed.18, 1518





POTASSIUM BROMIDE



Sources


Potassium bromide (KBr) is actually a chemical product, not a drug formulation.13,58,1923 Potassium bromide has reasonable efficacy for treatment of seizures in dogs and may be used as a monotherapy or in combination with other anticonvulsants. This chemical was historically difficult to obtain in formulations for administration to dogs, but this is less of a problem currently because there are a number of veterinary compounding laboratories that provide therapeutic distribution of the drug.



Toxicokinetics


Potassium bromide has a relatively long serum half-life (∼24 days in dogs and 10 days in cats) and therefore requires a significant amount of time to reach a steady state (up to 4 months in dogs and 6 weeks in cats).13,58,1923 In an effort to increase the therapeutic drug level of potassium bromide sooner, a loading dose of potassium bromide can be given at the initiation of treatment. The normal maintenance dosage of potassium bromide is between 20 and 60 mg/kg/day. If sodium bromide is used, the dosage is slightly reduced to 17 to 30 mg/kg/day. If more rapid seizure control is necessary, an initial dose of 400 to 600 mg/kg, usually divided over a 2- to 3-day period, can be administered. Potassium bromide, when administered in increased concentrations in a single dosing period, is often irritating to the stomach and results in vomiting. To prevent this problem, the loading dose is administered in multiple, smaller doses over the 2- to 3-day period. It often helps when using the loading dose to first calculate the maintenance dose expected. This will most likely be the capsule size that can be formulated by a compounding laboratory. During the loading period, the total loading dose is given over 48 to 72 hours by giving multiple doses of the maintenance dose of the medication.



Clinical signs


Potassium bromide is reasonably safe, but has some side effects. The bromide component is toxic to humans who can exhibit headaches, skin rashes, tremors, and gastrointestinal disturbances following administration of the chemical.13,58,1922,24 Owners should be careful therefore in handling the medication and not expose themselves to the chemical. This may require placing the medication in the food, wearing gloves when pilling, and washing hands after touching the capsule. Diets with relatively high chloride (sodium chloride) content may increase bromide elimination because bromide competes with chloride for elimination. Renal disease may decrease elimination of bromide, requiring decreases in the dose of bromide up to 50% of normal levels to prevent toxicity.1924


The most common side effects of potassium bromide administration in dogs include sedation and ataxia. Pancreatitis is associated with the use of this drug, but the actual cause and effect relationship is not clear.26 With some doses, vomiting may occur because of the local irritant effects on the stomach. Diet, alterations in fluid intake, or dehydration may alter the therapeutic KBr levels in the blood. Rarely, skin irritation, itchiness, or rashes may be noted. Importantly in cats, KBr can result in a fatal asthmatic condition.5 Caution should be exercised when using this drug in cats, and if any respiratory signs are noted, the drug should be stopped immediately. Rarely, dogs may become aggressive while receiving bromide therapy. When performing routine serum chemistry evaluations, measured serum chloride concentrations will appear to be increased because some analytical methods may measure the serum bromide as chloride.


Sep 11, 2016 | Posted by in SMALL ANIMAL | Comments Off on Anticonvulsants
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