ANTISEIZURE DRUGS Medical Pharmacology Randal A Skidgel Ph D Dept of Pharmacology 412 CSN 6 9179 I HISTORY Ancient Times epilepsy was called the Asacred disease due to presumed cause by a deity or demon The term Aseizure may have originated from the belief that epileptics were Aseized by the devil The word Aepilepsy is derived from the Greek Aepilambanein meaning Ato seize or attack 1850 Bromides discovered to be effective use of bromides persisted into the mid 1900s 1870 John Hughlings Jackson proposed that seizures were caused by Aoccasional sudden excessive rapid and local discharges of gray matter 1912 The first clinical use of phenobarbital to treat epilepsy was reported 1929 1938 Hans Berger discovered the EEG and showed the relationship between discharges in the brain and the clinical manifestations of epileptic seizures 1938 Merritt and Putnam systematically studied 746 compounds in a cat model of epilepsy and discovered phenytoin Introduced the new concept that antiseizure drugs did not have to be sedatives Phenytoin is still widely used today II INTRODUCTION A Seizures result from abnormal neuronal discharge in the central nervous system produced by either focal or generalized disturbances of brain tissue B Causes a wide variety of disorders can result in seizures head trauma birth and perinatal injuries congenital malformations metabolic disturbances blood sodium glucose calcium urea drugs or alcohol drug withdrawal vascular insults anoxia infections neoplasia genetic defects fever C Seizures can take many form such as motor convulsions abnormal sensory perceptions abnormal emotional responses abnormal pain trigeminal neuralgia All people are capable of experiencing a seizure given the appropriate conditions In many cases e g metabolic disturbances if the condition is corrected seizures do not recur 1 D Epilepsy the most common chronic seizure disorders seizures of a particular pattern characterized by recurrent There are between 1 in 100 and 1 in 300 epileptic patients in the general population E Definition of epilepsy chronic central nervous system CNS disorder having in common the occurrence of sudden and transitory episodes seizures of abnormal phenomena of motor convulsion sensory autonomic or psychic origin The seizures are nearly always correlated with abnormal and excessive EEG discharges F Epileptic Syndromes A cluster of symptoms frequently occurring together including seizure types see below etiology age of onset etc More than 40 syndromes have been identified Primarily useful in clinical assessment and management Choice of drug dependent on particular seizure type see below G Etiology Epileptic seizures are caused by hyperexcitable neurons 1 2 3 Seizures usually originate at a site of damage called an epileptogenic focus The manifestations of the seizure depend on the location of the focus The abnormal electrical discharge of the focus can spread to normal neuronal tissue during a seizure causing generalized symptoms H Mechanisms hyperexcitability of neurons can be caused by 1 2 3 4 Increased activity of voltage gated ion channels e g Na Ca channels Decreased inhibitory i e GABA neurotransmission Increased excitatory neurotransmission i e glutamate receptors Alteration of extracellular ion concentration e g potassium calcium III CLASSIFICATION OF SEIZURES The classification of seizures is based on the degree of central nervous system involvement and is divided into two main groups partial and generalized See Table 2 Classification of Seizures Frequency Loss of Consciousness Simple partial 10 No Complex partial 35 Partial with secondarily generalized tonicclonic seizure Seizure Type PARTIAL FOCAL Duration Features 20 60 sec Focal motor specific muscle groups sensory e g tingling hot or cold sensations or speech disturbances Impaired 30 sec to 2 min Complex symptoms confused behavior dreamy state amnesia often associated with automatisms purposeless movements 10 Yes 1 2 min Simple or complex partial seizure evolves into loss of consciousness rigid extension of trunk and limbs tonic then rhythmic contraction of arms and legs clonic Tonic Clonic grand mal 30 Yes 1 5 min Loss of consciousness massive contraction of skeletal muscle rigid extension of trunk and limbs tonic posture called opisthotonos then rhythmic contraction of arms and legs clonic Absence petit mal 10 Impaired 30 sec Abrupt brief onset of impaired consciousness cessation of activities and staring Characteristic 3 per second spike and wave pattern on EEG Commonly in children 3 15 years old Myoclonic 3 No 1 5 sec Brief shocklike contraction of muscles may be restricted to part of extremity or may be generalized Can occur in clusters for several min Atonic Akinetic 2 Yes 5 sec mins Sudden loss of postural tone leading to sagging of the head or falling Sudden freezing of motion called akinetic 7 Yes 5 min A state of continuous generalized tonic clonic seizure of 5 min or 2 or more discrete seizures between which baseline consciousness is not regained This is a medical emergency that can be fatal up to 35 of the time GENERALIZED Status Epilepticus 3 Figure 1 Pathways of seizure spread A Focal seizure with spread to adjacent and contralateral cortical regions B Focal seizure with secondary generalization Seizure discharge activates subcortical centers A which then activate entire cortex B C Primary generalized absence seizure in which thalamocortical relays are believed to act on a diffusely hyperexcitable cortex Figure 2 Cellular and synaptic mechanisms of seizures A seizure can be divided into three phases 1 focal epileptogenesis initiation 2 synchronization of the surrounding neurons and 3 propagation of the seizure discharge to other areas of the brain Arrows indicate where each of the mechanisms on the left participates in the three phases involved in seizure generation 4 Figure 3 Relationship between cortical EEG extracellular and intracellular recordings in a seizure focus A Seizure was induced by local application of a convulsant agent The extracellular recording was made through a high pass filter Note the high frequency firing of the neuron evident in both extracellular and intracellular recording during the paroxysmal depolarization shift PDS This seizure would is representative of a partial with secondarily generalized tonic clonic seizure B Recording during an absence seizure demonstrating the characteristic generalized spike and wave discharges at a frequency of 3 per second IV DRUG
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