Anti Epileptic Drugs

Antiepileptic drugs:
Types of seizures:
Generalized Seizure: Whole brain is involved in seizure			Partial seizure: Activity of seizure start in one part of brain
Generalized Tonic Clonic Seizure: Ø  Also known as Grand mal epilepsy Ø  Last for 60-120 seconds. Ø  Alternate contraction and relaxation of muscles			Simple partial seizure: Ø  Seizures are located in specific locus of the brain e.g. jerking of thumb (Seizure in motor area of cortex for thumb). Ø  Consciousness preserved. Ø  Seizure lasting up to 20-60 seconds
Absence Seizure: Ø  Also known as Petit mal epilepsy. Ø  Momentary loss of consciousness. Ø  Lasting up to 30 seconds. Ø  Generally occur in children (3-5 years)			Complex partial seizure: Ø  Seizure focus located in temporal area. Ø  Consciousness affected. Ø  Purposeless movement, hallucination (sensory), diarrhoea. Ø  Seizure lasting up to 30-120 seconds.
Atonic Seizure: Ø  Relaxation of all muscles Ø  Person become unconsciousness and fall			Simple or partial seizure with secondary generalised tonic clonic seizure: Ø  Seizure starts in one area of brain but spread to whole brain. Simple or partial seizure converted in to tonic clonic seizure (alternate contraction and relaxation of muscles). Ø  Loss of consciousness Ø  Seizure lasting up to 60-120 seconds.
Myoclonic Seizure: Ø  Shock like contraction of muscles (for a second) Ø  Restricted to a part or involve whole body
Status Epilepticus: Ø  More than two seizures recurs without recovery of 1st seizure
Classification of antiepileptic drugs:
Aliphatic carboxylic acid		Valproic acid Divalproex=valproic acid+sodium valproate(1:1)
Barbiturate		Phenobarbitone
Benzodiazepine		Clobazam Clonazepam Diazepam Lorazepam
Deoxybarbiturate		Primidone
GABA analogue		Gabapentin
Hydantoin		Phenytoin Fosphenytoin  (water soluble prodrug of Phenytoin) Mephenytoin Ethotoin (used for patient sensitive to Phenytoin)
Iminostilbene		Carbamazepine Oxcarbazepine (less toxic than Carbamazepine)
Phenyltriazine		Lamotrigine
Succinimide		Ethosuximide
New drugs		Felbamate Ganaxolone Lacosamide Levetiracetam Retigabine Rufinamide Tiagabine Topiramate Vigabatrin Zonisamide
Others		Magnesium sulphate Trimethadione  Acetazolamide
Phenytoin	v  Major action: delay in recovery of inactivated Na+ channels v  At high dose inhibit excitatory action of glutamate v  At high dose facilitate inhibitory action of GABA v   Inhibit Na+ and Ca2+ Channel influx also.			v  Non sedative v  At low dose follow 1st order kinetics and at high dose follow zero order kinetics v  Teratogenic: Cause fetal hydantoin syndrome (cleft lip and palate, hypoplatic phalanges ) v  Cause Hirsutism, Osteomalacia, Hyperglycemia, Gingival Hyperplasia, Megaloblastic anaemia, Vitamin K and D deficiency, Hypertrophy of gums, Ataxia. v  Cause induction of enzymes (potent enzyme inducer) v  Also used as antiarrythmic v  When phenytoin cause hypersensitivity reaction than we use ethotoin as alternate. v  Not effective in absence seizure
Carbamazepine	v  Delay in recovery of inactivated Na+ channels			v  Cause Sedation v  Teratogenic- cause neural tube defect in foetus v  Cause induction of enzymes (also induce self metabolism). v  Drug of choice for partial seizure (simple as well as complex), trigeminal neuralgia and GTCS. v  Also used for mania and  bipolar disorder v  Cause ataxia, diplopia, aplastic anemia v  Not effective in absence seizure v  Oxcarbazepine less toxic than Carbamazepine.
Lamotrigine	v  Delay in recovery of inactivated Na+ channels v  Inhibit Na+ channels also v  Inhibit release of excitatory neurotransmitter (Glutamate and Aspartate)			v  Cause Sedation v  Broad spectrum antiepileptic ( used for GTCS, partial seizure, absence seizure, myoclonic seizure) v  Cause Steven Johnson syndrome v  Safer in pregnancy v  Effective in absence seizure
Topiramate	v  Delay in recovery of inactivated Na+ channels v  Also inhibit excitatory action of glutamate v  Also facilitate inhibitory action of GABA v  Also activate K+ channels			v  Cause Sedation v  Cause weight loss and renal stone v  Effective in GTCS and partial seizures v  Not effective in absence seizure
Zonisamide	v  Delay in recovery of inactivated Na+ channels v  Also inhibit T type Ca2+ current			v  Cause renal stone
Phenobarbitone	v  Facilitate inhibitory action of GABA neurotransmitter by opening GABA mediated chloride channel  (increase time duration of opening of GABA mediated chloride channels) v  At high dose also have GABAmimetic action v  Also inhibit excitatory action of Glutamate v  Also activate K+ channels			v  Cause Sedation v  Osteomalacia, megaloblastic anemia v  Cause enzyme induction v  Safe in pregnancy
Primidone	v  Facilitate inhibitory action of GABA neurotransmitter by opening GABA mediated chloride channel v  GABAmimetic action also.			v  Cause Sedation
Benzodiazepines	v  Facilitate inhibitory action of GABA neurotransmitter by opening GABA mediated chloride channel  (increase frequency of opening of GABA mediated chloride channels)			v  Cause Sedation v  Diazepam/Lorazepam 1st choice of drug in status epilepticus
Valproic acid	v  Delay in recovery of inactivated Na+ channels v  Also inhibit T type Ca2+ current v  Facilitate inhibitory action of GABA neurotransmitter by opening GABA mediated chloride channel v  Increase GABA level by two ways: v  A. Increase synthesis of GABA neurotransmitter by activating GABA synthetase enzyme v  B. Inhibit GABA transaminase enzyme which metabolise GABA neurotransmitter v  Decrease release of Glutamate			v  Cause little sedation v  Effective in all types of seizures v  Cause induction of enzymes. (potent inducer) v  Teratogenic- cause neural tube defect/spina bifida v  Folic acid added to decrease neural tube defect v  Cause weight gain, alopecia, curling of hair, hepatic necrosis (in children below 2-3 years age), acute pancreatitis, long term use cause menstrual abnormality and polycystic ovarian disease in girls. v  In children age less than 3 years Valproic acid avoided for absence seizure (Ethosuximide preferred) v  Effective in GTCS, partial and absence seizure
Vigabatrine	v  Inhibit GABA transaminase enzyme which metabolise GABA neurotransmitter. S o increase availability of GABA.			v  Drug of choice for infantile spasm v  Cause irrversible visual defects
Gabapentin	v  Increase GABA neurotransmitter release but not act as GABA agonist			v  Sedation v  1st choice of drug in diabetic neuropathy v  Effective in partial and GTCS seizures
Tiagabine	v  Inhibit GABA transporter (GAT). So decrease presynaptic reuptake of GABA and increase availability of GABA at postsynaptic site.			v  Sedation v  Used for treatment of partial seizures
Ethosuximide	v  inhibit T type Ca2+ current			v  Sedation v  Effective only in absence seizure (preferred for absence seizure in children )
Trimethadione	v  Inhibit T type Ca2+ current			v  Effective only in absence seizure
Felbamate	v  Decrease glutamate activity by inhibiting NMDA receptor			v  Cause hepatotoxicity and aplastic anemia
Levetiracetam	v  Affect release of GABA and glutamate			v  Effective in partial seizures
Lacosamide	v  Delay in recovery of inactivated Na+ channels			v  Effective in treatment of partial seizures
Rufinamide	v  Delay in recovery of inactivated Na+ channels
Retigabine	v  Open K+ channel			v  Cause urinary retention
Teratogenic potential: Valproic acid>Phenytoin>Carbamazepine>Newer antiepileptic drugs Drugs used in absence seizure: Ethosuximide, Valproic acid, Lamotrigine Drugs used in myoclonic seizure: Valproic acid, Lamotrigine, Topiramate In case of Partial seizure drug of choice is Carbamazepine Valproic acid cause hepatotoxicity in children Drug of choice in absence seizure is Valproic acid but for children below 3 years choice of drug is ethosuximide. To overcome the neural tube defect due to valproic acid in foetus we use folic acid as supplement. Carbamazepine induce self metabolism due to microsomal enzyme induction (initially t1/2 of Carbamazepine is 30-35 hrs later it reduce to 10-15 hrs) Safest drug in pregnancy: Lamotrigine, Phenobarbitone