Neuropharmacology IIIWhat are seizures?Seizures are episodes of neurologic dysfunction arising fromAlterations of consciousness and abnormal motor activity areEpilepsy (recurring seizures without a clear precipitant) isPharmacological treatment is very successful in the majorityClassification of seizures:Partial seizures (focal onset)Simple partial seizures most common; “Jacksonian march” someComplex partial: impairment of consciousness, with or withouEither simple or complex partial seizures may become secondaPrimary generalized seizures - bilateral onsetTypified by absence (“petit mal”) seizures, which can be recStrategies for the discovery of anticonvulsant drugs:“Traditional” – screening of compounds in animals models of “Rational” – based on presumed mechanism of seizure initiatiInhibit repetitive activity – e.g., blockade of voltage-depeIncrease inhibitory input – e.g., GABA enhancersReduce excitatory input – e.g., glutamate antagonistsDrugs for treatment of partial seizures or generalized tonicphenytoinOne of the oldest and most widely used anticonvulsants.Mechanism uncertain, but probably related to effect on Na+ cMay be administered orally or IV.Pharmacokinetics are complex:oral absorption is good but rate is variable.highly protein-bound - important to note that usual laboratometabolism is primarily hepatic. Exhibits saturation kinetichalf-life averages 22 hours but highly variable; bid dosing induces hepatic metabolism of other anticonvulsants as well Acute toxicity of oral form is usually nystagmus, ataxia andChronic administration causes hirsuitism, gingival hyperplasHypersensitivity with fever, rash which may progress to exfoFosphenytoin (Cerebyx) a “prodrug”fosphenytoin is rapidly metabolized to phenytoinfosphenytoin is water soluble; allows IM administration, and1200 mg phenytoin = $1.50; fosphenytoin = $119.00CarbamazepineStructural features similar to phenytoin; mechanism of actioAvailable in oral form only; rate of absorption variable.Protein binding less than that of phenytoin.Metabolism is primarily hepatic; induces own metabolism, as Half-life is 10-20 hours; tid dosing usually satisfactory, aSeveral active metabolites, including a 10,11 epoxide, contrMost common effects of toxicity are ataxia and diplopia, sedAplastic anemia may occur and can be fatal. This is rare (6-Oxcarbazepine – a derivative, does not form epoxide metaboliBarbituratesFamily of drugs used for hypnotic, anesthetic and anticonvulMechanism probably related to increased GABA-mediated chloriTwo members of class commonly used as anticonvulsants:PhenobarbitalMay be administered PO, IM or IVLong half-life (about 100 hours), hepatic metabolism. StrongFrequently used in infants; less commonly used in adults becPrimidoneParent drug has anticonvulsant properties, but is metabolizeToxicity similar to that of phenobarbitalValproic acidCarboxylic acid, structurally distinct from other current clMechanism uncertain - effective against both partial and priOral or IV administrationHepatic metabolism, with half life 8-12 hours. Induces metabCommon adverse effects are tremor, weight gain, nausea.Most significant risk is hepatotoxicity, which may be fatal.Drugs for primary generalized epilepsyEthosuccimidedrug of choice for treatment of absence seizure. Also effectValproic acideffective in generalized as well as focal epilepsy; particulNew anticonvulsantsBecause they are new, the clinical indications for these ageFelbamate was approved by the FDA in early 1994 and was the Lamotrigine was approved in late 1994. It is thought to act Gabapentin is approved for use as an “add-on” medication forTopiramate approved in 1997; unknown mechanism, possibly acTiagabin - an inhibitor of GABA reuptake, approved in 1997 aLevetiracetam – analog of piracetam, mechanism uncertain, apVigabatrin - an inhibitor of GABA transaminase, the degradatZonisamide, a sulfonamide derivative approved for partial seBenzodiazepines:An important anticonvulsant use of benzodiazepines is in setNote that although biological half-life of diazepam is long,Oral benzodiazepines are not frequently used alone in primarPrinciples for the Management of epilepsyAttempt to classify, localize and investigate underlying etiNot every seizure is an indication for anticonvulsant therapIn general, monotherapy is preferred to the use of multiple Serum drug levels are a guide to therapy, but you should trRoughly 80% of patients with epilepsy can achieve good contrIn refractory epilepsy, surgical treatment may be appropriatPregnancy and the use of anticonvulsant drugsAll of the anticonvulsant drugs have been reported to have tAlso important to recognize that uncontrolled seizures have In general, the best approach is to keep the number of drugsValproic acid should probably be avoided if at all possible,Abrupt discontinuation of anticonvulsants during pregnancy iEmergency medicine: treatment of status epilepticusDefinition and identificationStatus epilepticus is a state of repeated or continuous seizOften defined operationally as a single seizure lasting moreProlonged status epilepticus leads to irreversible brain injManagementABC’s - Airway, Breathing, CirculationIV access - obtain initial labs (electrolytes, ABG, CBC, toxAdminister glucose (50g IV) and thiamin (100mg IV)Initial treatment: - lorazepam, 1-2 mg IV, repeat at 3-5 minAdminister a long acting agent - phenytoin or fosphenytoin -If seizures persist, next agent is phenobarbital. Initial doSeizures which are refractory to these measures require urgeStandaert 1 March 2005 Neuropharmacology III Anticonvulsants What are seizures? • Seizures are episodes of neurologic dysfunction arising from abnormal synchronous activity of neurons. • Alterations of consciousness and abnormal motor activity are the most common manifestations • Epilepsy (recurring seizures without a clear precipitant) is common, affecting about 1% of the population • Pharmacological treatment is very successful in the majority of cases, but requires accurate diagnosis and classification of seizures Classification of seizures: • Partial seizures (focal onset) ¾ Simple partial seizures most common; “Jacksonian march” sometimes observed. May also affect sensory and autonomic systems ¾ Complex partial: impairment of consciousness, with or without motor or other signs ¾ Either simple or complex partial seizures may become secondarily generalized, producing a tonic-clonic seizure.