ANTICONVULSANTS/ ANTISEIZURE Agents EPILEPSY: Disorder of Brain function (a disease) characterized by periodic and unpredictable occurrence of seizures associated with 1. Loss or disturbance of consciousness 2. Characteristic body movements 3. CNS hyperactivity 4. Abnormal or Excessive EEG Discharge

PATHOPHYSIOLOGY Etiological Factors: Congenital problem Infectious or non- infectious inflam.dis. Metabolic disorders Toxins Drugs Hereditary Trauma Nutritional Neoplasms Vascular disorders

PATHOPHYSIOLOGY Neurophysiological Mechanisms : Neuronal hyperexcitability Paroxysmal Depolarizing Shift(PDS) Abnormal neuronal membrane Loss of inhibitory input Synchronous discharge of other cells in the same column

EPILEPSY:

EPILEPSY SEIZURE: refers to a transient alteration of behavior due to the disordered, synchronous, and rhythmic firing of populations of neurons

TYPES of SEIZURES Site of origin: Cerebral Cortex Partial Seizures: begins focally in a cortical site Generalized seizures: involve both cerebral hemispheres, & brain stem Absence: Myoclonic: Tonic-Clonic or Grand mal:

ions The Synapse The Ion Channels/Receptors The Brain Neuronal Substrates of Epilepsy

STATUS EPILEPTICUS Is a neurological emergency characterized by a series of convulsions, rapidly repeated without intervals of consciousness if untreated may lead to coma and death.

PHASES of SEIZURES Preictal Phase: Period just before seizure- Aura, Restlessness, Nervousness, Wandering, Ictal Phase: Seizure period - a few seconds to minutes Postictal Phase: Period after seizure- Disorientation, Confusion, Salivation, Unresponsiveness, Transient blindness

Classification of anticonvulsants 1. Barbiturates: Phenobarbital 2. Deoxybarbiturates: Primidone 3. Hydantoins: Diphenylhydantoin or Phenytoin 4. Benzodiazepines: Diazepam, Clonazepam 5. Tricyclic compounds: Carbamazepine 6. Valproic acid

Neurophysiological Mechanisms of Actions 1. Reduction in Post tetanic Potentiation (PTP) 2. Elevation of Excitatory Synaptic Threshold 3. Potentiation of presynaptic and postsynaptic inhibition 4. Prolongation of Refractory Period

Mechanisms of Actions Block the initiation of the electrical discharge from the focal area. Prevent the spread of the abnormal electrical discharge to adjacent brain cases.

General principals of antiepilepsic drugs The first choice of drugs Several drugs,effectively ;toxicity,major consideration Monotherapy,at first ; never be terminated abruptly;second drug may be added.

phenytoin Mode of action Inhibit the influx of Na+,Ca 2+ Actions Reduces the propagation of abnormal impulse in the brain Depression of CNS

Actions of Phenytoin on Na + Channels A. Resting State B. Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in. C. Refractory State, Inactivation Na + Sustain channel in this conformation

Therapeutic uses All partial seizures Tonic-clonic seizures Status epilepticus(iv) Not effective in absense seizures Antiarrhythmic drugs

Main adverse effect Depression CNS:nystagmus,ataxia GI problems Gingival hyperplasia Megaloblastic anemia occur Behavioral changes Teratogenic effect

carbamazepine Mode of action Inhibit the influx of Na+, Inhibit the generation of repetitive action potentials in the epileptic focus Actions Reduces the propagation of abnormal impulse in the brain

Therapeutic uses All partial seizures(first choice) Tonic-clonic seizures Trigeminal neuralgia

Main adverse effect Depression CNS:stupor,coma,respiratory depression Stimulate GI : nausea,vomitting Serious liver toxicity

Phenobarbital Sodium Mode of action Increases the seizure threshold Decreases the spread of seizure Potentiates GABA mediated inhibitions

Phenobarbital Sodium Therapeutic uses Febrile seizure (first choice) Simple partial seizure

Phenobarbital Sodium Heavily metabolized by the liver to hydroxy-phenobarbital Potent inducer of hepatic drug metabolizing enzymes!

Phenobarbital Sodium Toxic/Side/Adverse Effects: Depression CNS Agitation and confusion occurred at high dose Primidone(alternative choice ) All partial seizures (first choice) Tonic-clonic seizures; smaller doses of other drugs

Valproic acid Actions reduces the spread of seizure Potentiates GABA mediated inhibitions uses Myoclonic seizures Reduces the incidences and severity of tonic- clonic seizures

Ethosuxiomde reduces the propagation of abnormal electrical activity First choice of absence seizures

Diazepam The drug of choice for status epilepticus Administered intravenously Second choice for chronic epilepsy non- responsive to phenobarbital Well absorbed orally/rectally Metabolites are biologically active Sedation/ataxia/hyperactivity/

Clorazepam absence and myoclonic seizures Clorazepate Partial seizures