Zenaida N. Maglaya,MD,FPSECP Department of Pharmacology ANTISEIZURE DRUGS Zenaida N. Maglaya,MD,FPSECP Department of Pharmacology

SEIZURE Is a finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons. PRIMARY SEIZURES SECONDARY SEIZURES

CLASSIFICATION OF SEIZURE TYPES PARTIAL SEIZURES Simple partial seizures Complex partial seizures Partial seizures secondarily generalized

CLASSIFICATION OF SEIZURE TYPES GENERALIZED SEIZURES Generalized tonic-clonic (grand mal) Sz Absence (petit mal) seizures Tonic/ Atonic Seizures Clonic & myoclonic seizures Infantile Spasms Febrile Seizures Status Epilepticus

PRIMARY DRUGS CARBAMAZEPINE PHENYTOIN VALPROIC ACID PHENOBARBITAL PRIMIDONE DIAZEPAM /LORAZEPAM CLONAZEPAM ETHOSUXIMIDE

ADJUNCTIVE DRUGS FELBAMATE GABAPENTIN LAMOTRIGINE TIAGABINE TOPIRAMATE VIGABATRIN LEVETIRACETAM ZONISAMIDE

ANTISEIZURES CLASSIFICATION I. TONIC-CLONIC & PARTIAL SEIZURES Carbamazepine. Phenytoin, valproic acid II.ABSENCE SEIZURES Ethosuximide, valproic acid, clonazepam III MYOCLONIC SEIZURES Valproic acid, clonazepam IV. ADJUNCT/NEWER ANTICONVULSANTS

MECHANISM OF ACTION Inhibition of sodium channels function: phenytoin, carbamazepine, lamotrigine Inhibition of calcium channel function: ethosuximde Enhancement of GABA action: benzodiazepines,phenobarbital gabapentin,vigabatrin, tiagabine Multiple & Complex Mechanism: Valproic Acid

PHENYTOIN BLOCK SODIUM CHANNELS USE: partial seizures; generalized tonic-clonic seizures, Antiarrhymic drug0 Oral, IV highly bound to plasma proteins T ½ 12 -36 hrs Metabolized, dose dependent elimination Fosphophytoin, mephenytoin, ethotoin. phenacemide

Phenytoin Adverse Effects nystagmus, diplopia, ataxia, sedation, gingival hyperplasia & hirsutism, coarsening of facial features, mild peripheral neuropathy, megaloblastic anemia fever, skin rash, fetal hydantoin syndrome

PHENYTOIN DRUG INTERACTIONS Sulfonamides, valproate & phenylbutazone: displace phenytoin from binding sites Cimetidine, disulfiram, doxycycline, isoniazid, phenylbutazone, sulfas, warfarin, chloramphenicol: inhibits phenytoin metabolism

PHENYTOIN DRUG INTERACTIONS 3.Barbiturates & carbamazepine, pyridoxine, theophylline: enhance phenytoin metabolism 4.PHENYTOIN decreases serum levels of: carbamazepine, chloramphenicol, corticosteroids, haloperidol, quinidine, theophylline, oral contraceptives, warfarin

CARBAMAZEPINE BLOCK SODIUM CHANNELS DOC for partial seizures Generalized tonic-clonic seizures Trigeminal neuralgia Mania:bipolar disorders Orally absorbed with slow distribution Completely metabolized CAUSE: diplopia & ataxia, idiosyncratic blood dyscrasias, aplastic anemia & agranulocytosis, leukopenia

CARBAMAZEPINE DRUG INTERACTIONS 1. Increase carbamazepine levels via metabolism: cimetidine, erythromycin, isoniazid 2. Decrease carbamazepine levels via increase metabolism: phenytoin, valproic acid 3. Carbamazepine decreases drug levels :warfarin, oral contraceptives, doxycycline, phenytoin, haloperidol 4. Carbamazepine increases drug levels : cimetidine, isoniazid 5. Lithium induces carbamazepine toxicity.

PHENOBARBITAL Enhancement of inhibitory process Dimimution of excitatory transmission USE: partial seizures, generalized tonic-clonic seizures May cause: CNS depression Tolerance & dependence CI in porphyria disorders

PHENOBARBITAL DRUG INTERACTIONS Increase phenobarbital levels via metabolism; acute ethanol ingestion, chloramphenicol, valproic acid Decrease phenobarbital levels via increase metabolism, chronic alcohol ingestion, pyridoxine, rifampin Barbiturates decrease serum levels: tricyclics, warfarin, beta blockers, oral contraceptives, digitoxin, doxycycline, metronidazole, theophyllline

PRIMIDONE Metabolized to: PHENOBARBITAL PHENYLETHYLMALONAMIDE(PEMA) Mechanism of action similar to phenytoin May cause sedation, ataxia, vertigo, GIT upset, megaloblastic anemia CI: porphyria, hypersensitivity

VIGABATRIN Inhibits GABA transaminase Partial seizures & ‘WEST syndrome In patients unresponsive to conventional drugs Rapid absorption T ½ 6 -8 hrs CAUSES: drowsiness, behavioral & mood changes, weight gain, visual field defect

LAMOTRIGINE Inhibits sodium channels Partial seizures Absense seizures Completely absorbed T ½ of 24 hours Broad therapeutic profile CAUSES: hypersensitivity rxns, diplopia, ataxia, headache, dizziness, life threatening skin disorders, hematotoxicity

FELBAMATE MOA is unknown For partial seizures Broad therapeutic profile For intractable cases T ½ is 20 hrs CAUSES: severe hypersensitivity rxs aplastic anemia, hepatotoxicity Increase plasma phenytoin & valproic acid Decrease carbamazepine levels

GABAPENTIN MOA: alters GABA metabolism, its nonsynaptic release or its reuptake by GABA transporters Also binds to the α2δ subunit of voltage sensitive calcium channels FOR PARTIAL & GENERALIZED SEIZURES SATURABLE ABSORPTION CAUSE: somnolence, dizziness, ataxia, headache & tremor

TOPIRAMATE Complex action: GABA effect, blocks voltage dependent sodium channels Similar to phenytoin with lower side effects & simpler pharmacokinetics Risk of teratogenesis Sedation, mental dulling, renal stones, weight loss

TIAGABINE Nicotinic acid derivative GABA uptake inhibitor in both neurons & glia Partial seizures Dizziness, tremor, difficulty in concentration, psychosis

ETHOSUXIMIDE DOC for absense seizures Effect on calcium channels( reduce low threshold (T type) currents Inhibits NA/K/ ATPase, depresses the cerebral metabolic rate & inhibits GABA aminotransferase Absorption is complete Completely metabolized CAUSES; gastric distress, lethargy & headache DI: valproic acid inhibits its metabolixm

VALPROIC ACID On partial seizures sodium channel effects Increased levels of GABA inhibits GABA transaminase & succinic semialdehyde dehydrogenase Sodium channel blockade

VALPROIC ACID CLINICAL USES: 1. ABSENCE SEIZURES 2. MYOCLONIC SEIZURES 3. GENERALIZED TONIC-CLONIC TYPE OF SEIZURES 4. ATONIC ATTACKS 5. PARTIAL SEIZURES 6. MIGRAINE PROPHYLAXIS 7. BIPOLAR DISORDER

VALPROIC ACID Well absorbed; ppc within 2 hrs Bioavailability > 80% T ½ is 9 -18 hrs CAUSES: nausea, vomiting, pain & heart burn, sedation uncommon, fine tremors, weight gain, increase in appetite & hair loss, hepatotoxicity, thrombocytopenia, SPINA BIFIDA

VALPROIC DRUG INTERACTIONS Decrease valproic acid levels from increase metabolism with carbamazepine Increase valproic acid levels with antacid (increase absorption) salicylates (displacements from binding sites) When used with clonazepam may precipitate absence status

BENZODIAZEPINES Diazepam, lorazepam, clonazepam, clorazepate, Nitrazepam, clobazam Well absorbed, widely distributed Extensively metabolized with many active metabolites May cause sedation, tolerance DIAZEPAM: DOC for status epilepticus

STATUS EPILPETICUS DIAZEPAM LORAZEPAM PHENYTOIN PHENOBARBITAL

EFFECTIVE PLASMA LEVELS DRUG Effective Level(ug/m TOXIC LEVEL (ug/mL) Carbamzepine 4 - 12 > 8 Phenytoin 10 - 20 >20 Phenobarbital 10 - 40 > 40 Ethosuximide 50 -100 > 100 Valproic Acid 50 - 100

Thank You!!! And we know that all things work together for good to those who love God, to those who who are called according to His purpose. ROMANS 8: 28