Antiepileptic drugs

ANTIEPILEPTIC DRUGS

Anticonvulsant Therapy

  • Phenobarbital Phenobarbital (PB) remains one of the first-choice drugs for use in dogs with seizures and is also the preferred anticonvulsant drug for cats . The proposed mechanisms of action of PB include increasing neuronal responsiveness to gamma-aminobutyric acid (GABA), antiglutamate effects, and decreasing calcium inflow into neurons. PB is metabolized by hepatic microsomal enzymes, with a serum half-life (t½) of elimination between 40 and 90 hours in the dog, and approximately 40 to 50 hours in the cat after oral administration. It takes approximately 10 to 15 days to reach steady-state kinetics with oral dosing at a maintenance level. PB is a potent inducer of hepatic microsomal enzyme activity (eg, cytochrome P450), The maintenance dose range used by the author for PB in dogs is 3 to 5 mg/kg of body weight administered orally every 12 hours.
  • In cats, a similar dose range is used, but the initial dose is 2.5 mg/kg of body weight administered orally every 12 hours. Commonly reported side effects of PB in dogs and cats include sedation, polyuria/polydipsia (PU/PD), polyphagia (PP) with weight gain, and ataxia. These side effects usually subside dramatically within the first several weeks of treatment.. An uncommon but potentially life-threatening consequence of PB use is hepatic failure. Less commonly reported side effects attributable to PB use in dogs include bone marrow necrosis (with attendant blood dyscrasias) and superficial necrolytic dermatitis.
  • Blood dyscrasias (eg, leukopenia, thrombocytopenia, anemia) are likely to resolve after PB discontinuation. Chronic (>3 weeks) PB administration at standard therapeutic doses has been shown to cause a significant decrease in total (TT4) and free (FT4) serum thyroxine levels. Serum chemistry values should be checked every 6 months in patients receiving PB. Increased serum alkaline phosphatase (ALP) is expected in dogs receiving PB. Increases in serum alanine aminotransferase (ALT) are cause for concern. It is generally thought that serum ALT increases represent hepatocellular damage, whereas serum ALP elevations reflect PB-induced hepatic enzyme production.

Bromide

  • Bromide (Br) is a halide salt that has been used primarily as a second-line (ie, add-on to PB) drug in dogs but is gaining popularity as a first-choice anticonvulsant in this species Br has been shown to be an effective add-on therapy for dogs receiving PB; side effects of Br therapy are similar to those of PB when compared as sole anticonvulsant agents. Br is usually administered as the potassium salt (KBr). The sodium salt form (NaBr) contains more Br per gram of drug; therefore, the dose should be approximately 15% less than that calculated for KBr.
  • The anticonvulsant mechanism of Br is thought to be attributable to its competition with chloride ions; the Br ion is thought to hyperpolarize neuronal membranes after traversing neuronal chloride channels Br is renally excreted, and is thus a good choice for patients with hepatic disease (eg, portosystemic shunt). The t½ of elimination for KBr is 24 days in dogs; initial maintenance dose for oral KBr is 35 mg/kg of body weight divided into two daily doses. A loading dose is often administered over a 5-day period to dogs to attain steady-state kinetics sooner.
  • The loading dose used by the author is 125 mg/kg of body weight divided into two daily doses. Side effects of KBr include pelvic limb stiffness and ataxia, sedation, vomiting, PU/PD, PP with weight gain, hyperactivity, and skin rash. Less commonly, aggressive behavior and pancreatitis have been associated with KBr use Pancreatitis has been suggested to be more likely when KBr is used in conjunction with PB. persistent cough that seemed to be associated with Br therapy.

Benzodiazepines

  • Benzodiazepine drugs used in dogs and cats with seizure disorders include diazepam, clonazepam, clorazepate, midazolam, and lorazepam. Benzodiazepines exert their anticonvulsant effects by enhancing GABA activity in the brain. Diazepam is ineffective as an oral maintenance anticonvulsant in dogs because of its short t½ of elimination (2–4 hours) and the tendency for dogs to develop tolerance to its anticonvulsant effect. In contrast, diazepam is an effective oral anticonvulsant in cats
    Clonazepam is an oral anticonvulsant drug of limited use in dogs because of the rapid development of tolerance to the drug's anticonvulsant effects. Clorazepate has an elimination t½ between 3 and 6 hours in dogs after oral administration, and the dose range is 0.5 to 1 mg/kg of body weight administered every 8 hours.

Felbamate

  • Felbamate is a dicarbamate drug that has demonstrated efficacy for focal (partial) and generalized seizures Proposed mechanisms of action include blocking of N-methyl-D-aspartate (NMDA)–mediated neuronal excitation, potentiation of GABA-mediated neuronal inhibition, and inhibition of voltage-sensitive neuronal sodium and calcium channels Approximately 70% of the orally administered dose of felbamate in dogs is excreted in the urine unchanged; the remainder undergoes hepatic metabolism. For adult dogs, the author recommends an initial felbamate dose regimen of 15 mg/kg of body weight administered every 8 hours.
  • A major advantage of felbamate over more standard anticonvulsant drugs is that it does not cause sedation. Because felbamate does undergo some hepatic metabolism, liver dysfunction is a potential side effect Aplastic anemia (caused by bone marrow suppression) reversible bone marrow suppression mild thrombocytopenia, and mild leukopenia. In dogs with evidence of preexisting hepatic disease, felbamate should be avoided. Because of the potential for hepatoxicity.

Gabapentin

  • Gabapentin, a structural analogue of GABA, has been suspected to exert its antiseizure effects via enhancing the release and action of GABA in the brain as well as by inhibiting neuronal sodium channels. More recent evidence, however, suggests that gabapentin's anticonvulsant activity is due primarily to inhibition of voltage-gated calcium channels in the brain. Despite undergoing some hepatic metabolism in dogs, there is no appreciable induction of hepatic microsomal enzymes in this species.
  • The recommended dose range of gabapentin for dogs is 25 to 60 mg/kg of body weight divided into doses administered every 6 to 8 hours The author recommends an initial dose regimen of 10 mg/kg of body weight administered every 8 hours. dogs experienced mild sedation or mild polyphagia and weight gain associated with gabapentin use, sedation and pelvic limb ataxia.

Levetiracetam

  • Levetiracetam is a new piracetam anticonvulsant drug that has demonstrated efficacy in the treatment of focal and generalized seizure disorders in people as well as in several experimental animal models The mechanism of action for levetiracetam's anticonvulsant effects is unknown; There is some evidence that levetiracetam may inhibit high voltage–activated neuronal calcium currents.
  • It has recently been discovered that the binding site for levetiracetam in the brain is an integral membrane protein called synaptic vesicle protein 2A (SV2A); the interaction of levetiracetam with this protein appears to be associated with the drug's anticonvulsant effect. In dogs, approximately 70% to 90% of the administered dose of levetiracetam is excreted unchanged in the urine; the remainder of the drug is hydrolyzed in the serum and other organs. initial dosing schedule of 20 mg/kg of body weight administered every 8 hours

Zonisamide

  • Zonisamide is a sulfonamide-based anticonvulsant drug efficacy in the treatment of focal and generalized seizures in people, Suspected anticonvulsant mechanisms of action include blockage of T-type calcium and voltage-gated sodium channels in the brain, facilitation of dopaminergic and serotonergic neurotransmission in the central nervous system, scavenging free radical species, enhancing actions of GABA in the brain, inhibition of glutamate-mediated neuronal excitation in the brain, and inhibition of carbonic anhydrase activity. Zonisamide is metabolized primarily by hepatic microsomal enzymes, initial oral zonisamide dose schedule of 10 mg/kg of body weight administered every 12 hours.

Therapy for Cluster Seizures and Status Epilepticus

  • Cluster seizures and status epilepticus hold the unfortunate role of being the most life-threatening and difficult to treat types of seizure activity. Cluster seizures to include two or more discrete seizure events within a 24-hour period. A discrete seizure implies that the patient fully recovers before experiencing a subsequent seizure episode. Status epilepticus is continuous seizure activity lasting more than 5 minutes or recurrent seizures between which the patient does not fully recover.
  • Unabated seizure activity can lead to severe consequences, such as hyperthermia, aspiration pneumonia, disseminated intravascular coagulation, and permanent brain injury It is vitally important in such severe cases to halt seizure activity, treat any seizure-associated problems (eg, brain edema), and provide attentive monitoring and nursing care. many cases of cluster seizures, and most cases of status epilepticus, require measures that produce heavy sedation or anesthesia; these patients typically require tracheal intubation and close monitoring in an intensive care unit setting. Intravenous diazepam (0.5–1.0 mg/kg) is the preferred initial choice to halt seizure activity because of its rapid onset of action and safety.
  • Despite this, diazepam often results in temporary cessation of seizure activity or fails to halt seizure activity entirely. If seizure activity is repeatedly ceased with intravenous diazepam boluses, a diazepam intravenous CRI at a dose of 0.5 to 2.0 mg/kg/h may be successful. Other intravenous benzodiazepine drugs have been suggested for emergency treatment of seizures in dogs and cats,. These drugs include clonazepam, midazolam, and lorazepam Intravenous.
  • Clonazepam 0.05 to 0.2 mg/kg of body weight intravenous Midazolam intravenous or intramuscular administration. 0.066 to 0.22 mg/kg of body weight
  • Lorazepam An intravenous dose of 0.2 mg/kg of body weight
  • Potential disadvantages of intranasal administration of drugs versus intrarectal drug administration include technical factors (eg, drug loss attributable to swallowing or sneezing) and increased risk of an owner being inadvertently bitten by a pet during a seizure episode. Diazepam (0.5 mg/kg of body weight) and lorazepam (0.2 mg/kg of body weight) have been demonstrated to reach serum levels in dogs within the suspected therapeutic range within minutes after intranasal administration
  • Diazepam has been shown to be well absorbed after intrarectal administration in dogs and effective as an at-home treatment of dogs with cluster seizures; the recommended dose range is 1 to 2 mg/kg of body weight
  • Intravenous barbiturate therapy is commonly used when intravenous benzodiazepine therapy fails to terminate seizure activity or if repeated dosing of intravenously administered benzodiazepine is necessary to control seizures. Because of the potential for respiratory and cardiovascular depression with barbiturates, these drugs should be given to effect, with meticulous patient monitoring
  • Pentobarbital is usually successful in abolishing motor manifestations of seizure activity within several minutes of intravenous administration but is not generally considered an anticonvulsant drug. The dose range for intravenous pentobarbital is 2 to 15 mg/kg of body weight. Compared with diazepam, it may require several minutes for pentobarbital to take effect If seizure activity is recurrent, an intravenous pentobarbital CRI can also be administered at a dose range of 0.5 to 4.0 mg/kg/h In addition to lacking anticonvulsant activity, pentobarbital is often associated with paddling activity during recovery; such activity may be confused with continued seizure activity
  • Intravenously administered phenobarbital (2–6 mg/kg of body weight) requires approximately 15 to 20 minutes for clinical effect, so it is important not to give an overdose during this lag period.. For patients not already receiving PB therapy, intermittent bolus injections (eg, 3–6 mg/kg of body weight) can be cautiously administered every 15 to 30 minutes to attain a serum PB level within the therapeutic range Alternatively, an IV CRI of PB (2–4 mg/kg/h) can be instituted.
  • Propofol is a phenolic injectable anesthetic agent that has been demonstrated to have GABA agonistic activity in the brain; propofol also decreases intracranial pressure (ICP) and brain metabolic activity. Propofol has the advantageous properties of being rapidly acting and quickly metabolized Propofol has proven to be useful in the treatment of cluster seizures and status epilepticus in human and small animal patients. A bolus dose of 1 to 6 mg/kg should be administered slowly to effect. Because transient apnea is a commonly reported effect of bolus propofol administration, the clinician should be prepared to intubate the patient and assist with respirations. propofol CRI can be initiated (0.1–0.6 mg/kg/min). Clonic motor activity, similar to that seen with pentobarbital use, can occur with propofol
  • Etomidate is an imidazole injectable anesthetic drug that has GABA-ergic activity in the brain and also decreases brain metabolic activity. Etomidate also may protect neurons from hypoxic damage and decrease ICP. 1 to 3 mg/kg of body weight. transient apnea may occur after injection of etomidate, this drug has minimal effects on the respiratory and cardiovascular systems
  • Fosphenytoin After intravenous or intramuscular injection, fosphenytoin is rapidly converted to phenytoin (the active drug) by serum and tissue phosphatases. Unlike injectable phenytoin, fosphenytoin use is not associated with severe phlebitis and pain at the injection site. An intravenous dose range of approximately 10 to 20 mg/kg of body weight, potential side effects of fosphenytoin use reported in people include hypotension, cardiac arrhythmias, nystagmus, ataxia, and somnolence
    Ineffective and Contraindicated Drugs
  • There are a number of older drugs that are generally ineffective in dogs, primarily because of their extremely short elimination t½ in this species. These drugs are known or suspected to be toxic to cats as well. They include phenytoin, carbamazepine, valproic acid, and ethosuximide. More recently introduced drugs that have been suggested for use in dogs include vigabatrin, lamotrigine, oxcarbazepine, tiagabine, and topiramate. vigabatrin hemolytic anemia
  • Lamotrigine cardiotoxic compound.
  • Tiagabine cause marked sedation and visual impairment
Last modified: Tuesday, 5 June 2012, 2:07 PM