Anticonvulsants

Chapter 186 Anticonvulsants



Manuel Boller, Dr. med vet., DACVECC, Deborah Silverstein, DVM, DACVECC



KEY POINTS



• The first-line drug for control of status epilepticus is diazepam. In animals refractory to this drug, a midazolam or propofol bolus and infusion are administered.

• Oral phenobarbital (PB), the first-line antiepileptic drug (AED) for chronic seizure control in dogs and cats, is typically titrated to clinical effect and therapeutic serum levels (20 to 40 μg/ml in dogs; 10 to 20 μg/ml in cats).

• PB administration induces hepatic microsomal enzymes and may lead to drug-drug interactions.

• Potassium bromide is an effective second-line AED in dogs and cats, although its use is limited in cats because of the risk of inducing severe lower airway disease in this species.

• In contrast to its effect in dogs, oral diazepam is effective for long-term control of seizures in cats. However, the risk for liver failure after oral, but not intravenous, administration restricts its use in cats.

• Newer AEDs exert pharmacokinetic properties associated with little or no drug-drug interaction. Limited clinical data suggest potential benefit as add-ons or monotherapy in small animals.

• The most common side effects of antiepileptic therapy include sedation and ataxia. Abrupt withdrawal of any of the short-acting AEDs can induce seizure activity.


INTRODUCTION


The emergency and critical care veterinarian often is presented with small animal patients that have:


• New-onset seizures

• Cluster seizures: multiple seizures in a 24-hour period

• Status epilepticus: a continuous, generalized, convulsive seizure lasting more than 5 minutes, or two or more seizures between which no normalization of mental status occurs

• Refractory status epilepticus: seizures lasting more than 2 hours or more than two seizures per hour without normalization of mental status, despite standard antiepileptic treatment1 (see Chapter 98, Seizures and Status Epilepticus)

Although antiepileptic drugs (AEDs) are an essential, although not solitary, part of patient management in all of the above scenarios, the side effects of these medications may be responsible for considerable morbidity that necessitates a high level of medical care. Furthermore, the pharmacokinetic behavior of many AEDs is influenced not only by concurrently administered medications and vice versa, but also by dysfunction of the organs most involved in their elimination, such as the liver and kidneys. To consider the pharmacologic characteristics of AEDs in the assessment and management of critically ill patients is thus of particular importance.



PHENOBARBITAL


Phenobarbital (PB) is a long-acting barbiturate that exerts its anticonvulsive effects by enhancing the postsynaptic effect of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) on the GABAA receptor, thus leading to increased influx of chloride anions into the cytoplasm. This leads to hyperpolarization of the postsynaptic membrane (i.e., a more negative resting membrane potential). Furthermore, PB inhibits the activity of the excitatory neurotransmitter glutamate and limits calcium passage across the neuronal membrane.2 The net result of the above mechanisms is an increase in the seizure threshold, along with a reduction in the spread of a focal discharge to surrounding areas. The drug’s multiple mechanisms of action make it an effective anticonvulsive medication for most types of epileptic seizures.


PB is a weak acid (pKa 7.3) with high oral bioavailability, despite a relatively slow increase in plasma concentration (which peaks after 4 to 8 hours).2 Approximately 50% of the drug is bound to plasma proteins.3 Up to 25% of PB is eliminated unchanged by renal excretion, a mechanism that is pH dependent; alkaline urine accelerates excretion by increasing the ionized fraction of the drug.2 Most of the drug is inactivated by hepatic microsomal enzymes (P-450 enzymes), some of which are induced by PB, thereby leading to a shorter elimination half-life (by 50% after 90 days).2


Generally PB is well tolerated by dogs at therapeutic levels (20 to 40 μg/ml).4 Fast development of tolerance leads to disappearance of initial behavioral abnormalities like sedation, fatigue, restlessness, or hyperexcitability that commonly occur within the first 7 days of administration.4 Long-term administration of PB has been associated with hepatic injury, which is more likely to occur with high plasma levels (above 35 μg/ml).5 Animals that were euthanized because of liver failure secondary to long-term PB administration were found to have hepatic cirrhosis on necroscopic histopathologic examination. There is evidence that alkaline phosphatase and alanine transaminase can be elevated as a result of enzyme induction in dogs treated with PB,6 although this has been questioned.7 The clinician must determine whether elevations of these enzymes in clinically normal dogs is due to enzyme induction or to subclinical hepatocellular damage.


In contrast, alterations in serum aspartate transaminase, fasting and postprandial bile acid levels, total bilirubin values, and the ultrasonic appearance of the liver may be more helpful to confirm hepatic disease.6 Microsomal enzyme induction associated with PB therapy decreases serum free and total thyroxin but not triiodothyronine concentrations and may increase thyroid-stimulating hormone.8-10 There is no apparent influence on adrenal axis function (e.g., adrenocorticotropic hormone stimulation test).4 A potentially life-threatening idiosyncratic reaction to PB in the form of neutropenia, thrombocytopenia, and anemia is described in the literature.11 Superficial necrolytic dermatitis was reported in 11 dogs after long-term treatment with PB.12 These side effects warrant vigilant monitoring of biochemical, hematologic, and clinical parameters every 6 months during long-term treatment.


Oral PB therapy is started at a dosage of 2.5 mg/kg q12h. Because of the long elimination half-life, steady state concentrations will be reached after 2 weeks, when the first serum PB level should be measured. Trough levels of 20 to 25 μg/ml are the initial therapeutic target. Trough serum levels should be determined 2 weeks after each dosage adjustment, when considered clinically effective, and after 45, 90, 180, and 360 days and twice a year thereafter in a consistent manner (e.g., before administration). This is essential because serum PB levels can vary considerably among dogs receiving an identical oral dose.13 A sudden drop in plasma PB levels can induce withdrawal seizures, so a loading dose of another AED, such as potassium bromide, should be administered concurrently to prevent this.


In patients that are already receiving PB, adjustments are made to reach a clinically effective dosage that can vary widely among animals:



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Animals with severe or refractory seizures may benefit from rapid intravenous loading with a total of 12 to 20 mg/kg as a slow bolus or divided and administered q4-6h over 24 hours to achieve a serum concentration of 20 to 40 μg/ml. More pronounced sedation, hypotension, and hypoventilation should be anticipated in patients treated with this regimen.


PB is also the recommended first-line AED in cats. When compared with use in dogs, the elimination half-life is longer and does not change over time.14 An initial administration of 1 to 2 mg/kg PO q24h can be altered to 1 to 3 mg/kg q12h as needed, according to clinical effect and serum levels; 3 mg/kg q12h is often necessary. The target concentration in cats is 10 to 20 μg/ml.4 This is important, because drug elimination and therefore serum concentrations appear to vary among feline populations.14 Polyphagia, polydipsia, and polyuria frequently accompany PB administration in the cat, and sedation can be problematic at higher dosages. Hepatotoxicity has not been reported as a complication in cats.


In animals with renal failure, a reduction in the PB dosage may be necessary, although the contrary is true during peritoneal dialysis or hemodialysis, as directed by serum trough levels after a dialysis treatment. Low albumin levels, a frequently occurring abnormality in the critically ill patient, will increase the free serum PB concentration, and a decrease in dosage may be required.


Because of the significant and broad-spectrum hepatic enzyme–inducer properties of PB, drug-drug interactions have to be expected.15,16 Although this is important in the intensive care setting in which patients receive a large number of medications, reports for the relevance of individual interactions are scarce in the veterinary literature.



PHENYTOIN


The hydantoin derivative phenytoin (diphenylhydantoin) is very effective against all types of seizures. Its mechanism of action is distinctively different from that of PB in that it arrests voltage-activated sodium channels in their inactivated, closed conformation.3 Bioavailability of the oral formulation is only around 40% in the dog, and it is highly bound to plasma proteins.2 In this species, phenytoin potently induces hepatic microsomal enzymes, shortening not only the effect of other AEDs like PB, but also reducing its own elimination half-life by 75% after 9 days.17,18 This, along with the low bioavailability, makes it difficult to achieve and maintain effective plasma levels with the oral formulation in dogs. However, phenytoin is available for intravenous injection and can be used for termination of status epilepticus, but this often causes marked hypotension in dogs. Hepatotoxicity is a major side effect of phenytoin, especially when administered in combination with primidone or PB. In contrast to that in dogs, the phenytoin elimination half-life in cats is very long. The risk for accumulation with subsequent intoxication appears to be high and its use in this species is therefore not recommended.



BROMIDE


Potassium bromide (KBr) frequently is used either as an add-on AED in dogs with seizures refractory to PB or for monotherapy, especially in cases with PB-associated hepatotoxicity. Although its precise mechanism of action is unknown, its preferential movement through GABA-activated chloride channels may lead to hyperpolarization of neuronal cell membranes.2 Oral bioavailability is 47% in dogs receiving KBr solution.19


Bromide is only minimally bound to plasma protein and is eliminated unchanged by renal excretion. Characteristically, bromide has a very long elimination half-life in dogs (varying from 15 to 69 days).20,21 Because approximately 5 times the elimination half-life must elapse until steady-state conditions exist, this may take up to 4 to 5 months in dogs. On the flip side, the long half-life of the drug prevents a significant impact on serum drug concentrations when several days of administration are missed. An increase in chloride intake accelerates bromide elimination by reducing its renal tubular reabsorption, and this mechanism is considered the major contributor to the wide variability in the bromide elimination half-life.20 For this reason, variations in dietary chloride intake may significantly change bromide plasma concentrations. Intravenous sodium chloride administration can be used to treat animals with bromide intoxication.


Generally KBr is well tolerated in dogs. Orally administered bromide can lead to gastric irritation, especially with use of capsules that localize a high concentration in a small area of gastric mucosa. In contrast to PB, hepatotoxicity is not a concern with administration of KBr, but pancreatitis has been reported when used in combination with PB in dogs.22 Signs of neurotoxicity (bromism) can occur at serum bromide concentrations within the target range (1.5 to 3 mg/ml), but they are seen more commonly when concentrations reach higher levels.4 Signs consist of ataxia, progressive quadriplegia with normal reflexes, and hind limb weakness, stiffness, or swelling. Lethargy and sedation, progressing to stupor and coma, have also been described.23,24


If intravenous sodium chloride administration is considered for the treatment of bromism, caution should be used because the fast drop of the bromide concentration could trigger recurrence of seizures.24 Some precautions should also be considered in animals with comorbidities. Renal failure likely reduces bromide clearance, and dosage adjustments according to bromide serum concentrations are needed to avoid bromism.24 In animals with diseases affecting potassium regulation, such as hypoadrenocorticism, KBr should be used carefully and sodium bromide (NaBr) should be considered to prevent worsening a hyperkalemic state. Animals with congestive heart failure or hypertension might not tolerate the amount of sodium associated with NaBr management, especially when used for initial loading. Serum chloride concentration may be falsely elevated because some laboratory equipment does not distinguish between bromide and chloride.


A serum bromide concentration of 0.8 to 3 mg/ml is targeted for treatment of seizures in dogs, depending on the level of seizure control achieved and whether KBr is used as monotherapy or in combination with PB.2,4,25 An oral KBr dosage of 15 to 30 mg/kg/day as an add-on drug and 30 to 50 mg/kg/day as monotherapy is usually sufficient. Serum bromide concentrations should be determined after 1 and 3 months of treatment. To reach effective serum concentrations more rapidly, a loading dose of KBr (400 to 600 mg/kg) can be divided into 4 equal doses over 24 to 48 hours. This will lead to a serum bromide concentration of 1 to 1.5 mg/ml quickly, but can cause significant gastric irritation. Also, this protocol is not applicable to animals unable to tolerate oral nutrition, as is frequently the case in the intensive care setting.


Rectal bioavailability of bromide is close to 100%, and loading by this route should be considered in patients with refractory status epilepticus. The loading dose of KBr or NaBr can be administered rectally divided in 4 equal doses distributed over a 24-hour period.26 The solution should be diluted to prevent colitis.


Potassium and sodium bromide have different molecular weights: KBr and NaBr contain 67% and 77% bromide, respectively, per unit weight, and it is recommended to decrease the dosage by 15% to account for the higher bromide content of the sodium salt.27 Alternatively, NaBr can be administered intravenously. A loading dose of 600 to 1200 mg/kg NaBr given by continuous infusion over q8-24h hours will result in a median peak serum bromide concentration of 2.5 mg/ml.19,28


KBr has been effective in the control of seizures in cats, although to a lesser extent than in dogs. Administration of 15 to 25 mg/kg KBr resulted in serum bromide levels of 1 to 1.6 mg/ml, which was sufficient to control seizures in 7 out of 15 cats evaluated in one study.29 One third of the cats developed asthma-like respiratory tract changes, however, manifesting as a nonproductive cough and leading to euthanasia of one of the cats.29 This is supported by additional reports in the literature.30,31 Routine administration of KBr in cats for treatment of seizures can therefore not be recommended.

Related posts:

  1. Deteriorating Mental Status
  2. Hyperthermia and Fever
  3. Ventilator-Associated Lung Injury
  4. Allergic Airway Disease in Dogs and Cats and Feline Bronchopulmonary Disease

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Sep 10, 2016 | Posted by in SMALL ANIMAL | Comments Off on Anticonvulsants

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