1. ANTI-EPILEPTIC DRUGS 1

2. INTRODUCTION Is a family of different recurrent seizure disorders characterized by sudden, excessive and synchronous discharge of cerebral neurons. Is a family of different recurrent seizure disorders characterized by sudden, excessive and synchronous discharge of cerebral neurons. This results in abnormal movements or perception that are of short duration and tend to recur. This results in abnormal movements or perception that are of short duration and tend to recur. The site of electric discharge determines the symptoms that are produced. The site of electric discharge determines the symptoms that are produced. The goal of drug management is restoration of normal patterns of electrical activity The goal of drug management is restoration of normal patterns of electrical activity 2

3. 3 TYPES OF EPILEPSY PRIMARY or IDIOPATHIC SECONDARY KNOWN CAUSES: HEAD INJURY HEAD INJURY TUMORS TUMORS MENINGITIS MENINGITIS HYPOGLYCEMIA HYPOGLYCEMIA DRUG WITH DRAWAL DRUG WITH DRAWAL

4. 4 CLASSIFICATION Seizures PARTIAL / FOCAL PARTIAL / FOCAL SIMPLESIMPLE COMPLEXCOMPLEX GENERALIZED GENERALIZED GRAND MAL ( tonic clonic)GRAND MAL ( tonic clonic) PETIT MAL ( Absence)PETIT MAL ( Absence) MYOCLONICMYOCLONIC FEBRILEFEBRILE STATUS EPILEPTICUSSTATUS EPILEPTICUS

5. 5 The two main categories of seizures include The two main categories of seizures include Partial seizures – no loss of consciousness Partial seizures – no loss of consciousness and and Generalized seizures – loss of consciousness Generalized seizures – loss of consciousness A partial seizure can evolve to a generalized tonic-clonic seizure. A partial seizure can evolve to a generalized tonic-clonic seizure.

6. 6 Partial Seizures Symptoms depend on the site of neuronal discharge Partial Seizures Symptoms depend on the site of neuronal discharge The two most common types of partial seizure are The two most common types of partial seizure are Simple partial and Simple partial and Complex partial. Complex partial.

7. 7 Simple Partial These produce symptoms associated with the area of abnormal neural activity in the brain confined to single locus: These produce symptoms associated with the area of abnormal neural activity in the brain confined to single locus: The electrical discharge does not spread The electrical discharge does not spread Can occur at any age Can occur at any age There is no impairment of consciousness in simple partial seizures. There is no impairment of consciousness in simple partial seizures.

8. 8 Complex Partial Impairment(altered) of consciousness, characteristic of complex partial seizures (CPS) Impairment(altered) of consciousness, characteristic of complex partial seizures (CPS) results in the inability to respond to or carry out simple commands or to execute willed movement, and a lack of awareness of one’s surroundings and events, hallucination. results in the inability to respond to or carry out simple commands or to execute willed movement, and a lack of awareness of one’s surroundings and events, hallucination. Experience initial seizure before age of 20 yrs Experience initial seizure before age of 20 yrs

9. 9 Generalized Seizures Begin locally and rapidly spread to both the hemispheres. Begin locally and rapidly spread to both the hemispheres. Loss of consciousness Loss of consciousness Seizures can be convulsive or nonconvulsive. Seizures can be convulsive or nonconvulsive. The two most common types are tonic- clonic (grand mal) and The two most common types are tonic- clonic (grand mal) and Absence (Petit mal). Absence (Petit mal).

10. 10 Tonic-clonic (grand mal). Most common Tonic-clonic (grand mal). Most common There is loss of consciousness during the seizure. There is loss of consciousness during the seizure. The tonic phase, consisting of continuous muscle contraction (rigidity), is followed by the clonic phase, which involves jerking of the extremities. The tonic phase, consisting of continuous muscle contraction (rigidity), is followed by the clonic phase, which involves jerking of the extremities. Followed by confusion and exhaustion post-ictally. Followed by confusion and exhaustion post-ictally.

11. 11 Absence (petit mal) This type occurs most often in children, usually beginning between the ages of 3 to 5 years lasting until puberty. Absence (petit mal) This type occurs most often in children, usually beginning between the ages of 3 to 5 years lasting until puberty. This seizure involves a brief, abrupt and self- limiting loss of consciousness last 10 seconds or less. This seizure involves a brief, abrupt and self- limiting loss of consciousness last 10 seconds or less. The patient stares and exhibits rapid eye- blinking which lasts for 3 to 5 secs The patient stares and exhibits rapid eye- blinking which lasts for 3 to 5 secs There is no postictal state, but the person usually lacks awareness of what occurs during the seizure. There is no postictal state, but the person usually lacks awareness of what occurs during the seizure.

12. 12 Myoclonic seizures are rapid, brief contractions of bodily muscles, sudden jerks or clumsiness. Myoclonic seizures are rapid, brief contractions of bodily muscles, sudden jerks or clumsiness. Infantile Spasms sudden spasm or bending (flexion) of the body either at the waist or neck. Infantile Spasms sudden spasm or bending (flexion) of the body either at the waist or neck.

13. 13 Status Epilepticus is defined as 30 minutes of continuous seizure activity or a series of seizures without return to full consciousness between the seizures Status Epilepticus is defined as 30 minutes of continuous seizure activity or a series of seizures without return to full consciousness between the seizures Febrile seizures are convulsions brought on by a fever in infants or small children. Febrile seizures are convulsions brought on by a fever in infants or small children.

14. 14 ANTIEPILEPTIC DRUGS ANTIEPILEPTIC DRUGS PHENYTOIN PHENYTOIN CARBAMAZEPINE CARBAMAZEPINE VALPROIC ACID VALPROIC ACID ETHOSUXIMIDE ETHOSUXIMIDE BENZODIAZEPINES BENZODIAZEPINES BARBITURATES BARBITURATES LAMOTRIGINE - NEWER AGENTS LAMOTRIGINE - NEWER AGENTS GABAPENTIN - NEWER AGENTS GABAPENTIN - NEWER AGENTS TIAGABINE - NEWER AGENTS TIAGABINE - NEWER AGENTS TOPIRAMATE - NEWER AGENTS TOPIRAMATE - NEWER AGENTS VIGABATRIN - NEWER AGENTS VIGABATRIN - NEWER AGENTS

15. 15 ANTI EPILEPTIC DRUGS - MECH Preventing the influx of Na⁺ through fast Na channels: carbamazepine, phenytoin Preventing the influx of Na⁺ through fast Na channels: carbamazepine, phenytoin Facilitation of the effect of GABA resulting in hyperpolarization: barbiturate & benzodiazepine Facilitation of the effect of GABA resulting in hyperpolarization: barbiturate & benzodiazepine ↓ presynaptic calcium influx through the T-type calcium channel: ethosuximide, valproic acid, phenytoin ↓ presynaptic calcium influx through the T-type calcium channel: ethosuximide, valproic acid, phenytoin ↓ excitatory effect of glutamic acid: Lamotrigine, topiramate & felbamate ↓ excitatory effect of glutamic acid: Lamotrigine, topiramate & felbamate

16. 16 PHENYTOIN MECH: DECREASES Na INFLUX DECREASES Na INFLUX DECREASES INFLUX OF Ca DECREASES INFLUX OF Ca

17. 17 USES: MAINLY in USES: MAINLY in Partial Partial generalized generalized status epilepticus status epilepticus OTHERS: treatment of arrhythmia OTHERS: treatment of arrhythmia

18. 18 Undergoes zero-order kinetics of elimination Undergoes zero-order kinetics of elimination An inducer of cyt P450 KINETICS : ROUTE – ORAL, IV – ST. EPILEPTICUS ROUTE – ORAL, IV – ST. EPILEPTICUS MET : LIVER via cyt P450 MET : LIVER via cyt P450 EXCRETION : URINE. EXCRETION : URINE.

19. 19 Drug interactions: Phenytoin Induces P 450 : Induces P 450 : ↓ effectiveness of : OCP, ANTI COAGULANT, QUINIDINE. ↓ effectiveness of : OCP, ANTI COAGULANT, QUINIDINE. DRUGS INCREASING PHENYTOIN LEVELS: INH, CIMETIDINE, SULFONAMIDES INH, CIMETIDINE, SULFONAMIDES

20. 20 PHENYTOIN - SE CNS depression: causing sedation & drowsiness CNS depression: causing sedation & drowsiness NYSTAGMUS, ATAXIA NYSTAGMUS, ATAXIA GINGIVAL HYPERPLASIA GINGIVAL HYPERPLASIA FACIAL FEATURES – COARSE FACIAL FEATURES – COARSE Inhibition of ADH and INSULIN release Inhibition of ADH and INSULIN release MEGALOBLASTIC ANEMIA MEGALOBLASTIC ANEMIA Aplastic anemia Aplastic anemia

21. 21

22. 22 FETAL HYDANTOIN SYNDROME FETAL HYDANTOIN SYNDROME IF GIVEN IN PREGNANCY IF GIVEN IN PREGNANCY CLEFT LIP, CLEFT PALATE CLEFT LIP, CLEFT PALATE GROWTH RETARDATION GROWTH RETARDATION LOW IQ LOW IQ CONGENITAL HEART DEFECT CONGENITAL HEART DEFECT TERATOGENIC EFFECT

23. 23 CARBAMAZEPINE MECH : BLOCKS Na CHANNELS MECH : BLOCKS Na CHANNELS USED MAINLY -All partial, grand mal epilepsy USED MAINLY -All partial, grand mal epilepsy Drug of choice for Trigeminal neuralgia and mania Drug of choice for Trigeminal neuralgia and mania ORAL ROUTE ORAL ROUTE

24. 24 SE : CNS depression resulting in sedation and drowsiness CNS depression resulting in sedation and drowsiness Megaloblastic anemia Megaloblastic anemia Aplastic anemia Aplastic anemia Exfoliative dermatitis Exfoliative dermatitis ↑ADH secretion causing dilutional hyponatremia ↑ADH secretion causing dilutional hyponatremia

25. 25

26. 26 DRUG INTERACTIONS Induces cyt P450 Increase in metabolism of other drugs, ↓ing their effectiveness OCP OCP ORAL ANTI COAGULANTS ORAL ANTI COAGULANTS PHENYTOIN PHENYTOIN INH (Isoniazid) INH (Isoniazid) CIMETIDINE CIMETIDINE STEROIDS STEROIDS

27. 27 BARBITURATES PHENOBARBITAL PHENOBARBITAL PRIMIDONE PRIMIDONE MECH OF ACTION MECH OF ACTION due to Facilitation of the effect of GABA due to Facilitation of the effect of GABA USES ; FEBRILE CONVULSIONS, CAN ALSO BE USED FOR SIMPLE PARTIAL & GRAND MAL EPILEPSY USES ; FEBRILE CONVULSIONS, CAN ALSO BE USED FOR SIMPLE PARTIAL & GRAND MAL EPILEPSY Not effective in complex partial Not effective in complex partial SE : SEDATION, ATAXIA, NYSTAGMUS, VERTIGO, morbiliform rash SE : SEDATION, ATAXIA, NYSTAGMUS, VERTIGO, morbiliform rash Rebound seizures occur on discontinuance Rebound seizures occur on discontinuance DOC: for seizure in pregnancy DOC: for seizure in pregnancy

28. 28

29. 29 PRIMIDONE PRIMIDONE Metabolized to phenobarbital Metabolized to phenobarbital effective in complex partial effective in complex partial Mechanism of action & side effect: Mechanism of action & side effect: Same as phenobarbital Same as phenobarbital

30. 30 BENZODIAZEPINES DIAZEPAM, LORAZEPAM, CLONAZEPAM, CLORAZEPATE DIAZEPAM, LORAZEPAM, CLONAZEPAM, CLORAZEPATE Diazepam, lorazepam - Slow I. V. – Status Epilepticus Diazepam, lorazepam - Slow I. V. – Status Epilepticus SE : Resp depression, CVS depression with i.v. administration of high doses SE : Resp depression, CVS depression with i.v. administration of high doses

31. 31 CLONAZEPAM, CLORAZEPATE CLONAZEPAM, CLORAZEPATE For Chronic treatment For Chronic treatment DIAZEPAM, LORAZEPAM DIAZEPAM, LORAZEPAM For acute conditions of Status Epilepticus For acute conditions of Status Epilepticus Lorazepam longer duration than diazepam Lorazepam longer duration than diazepam

32. 32 VALPROIC ACID(Divalproex) VALPROIC ACID(Divalproex) MOA : enhances the effect of GABA MOA : enhances the effect of GABA Blocks Na Channels Blocks Na Channels USES : MYOCLONIC SEIZURES USES : MYOCLONIC SEIZURES Absent seizures – 2 nd drug of choice. Absent seizures – 2 nd drug of choice. mania mania SE : GIT, TREMOR, ATAXIA,SEDATION GIT, TREMOR, ATAXIA,SEDATION THROMBOCYTOPENIA, hepatotoxic THROMBOCYTOPENIA, hepatotoxic CI : LIVER FAILURE CI : LIVER FAILURE

33. 33 ETHOSUXIMIDE Mech: Reduces propagation of abnormal electrical activity in the brain by inhibiting T-type Calcium channels Mech: Reduces propagation of abnormal electrical activity in the brain by inhibiting T-type Calcium channels USES: ABSENCE SEIZURES USES: ABSENCE SEIZURESSE: MC : GIT MC : GIT CONFUSION, CONFUSION, LACK OF CONCENTRATION LACK OF CONCENTRATION STEVEN JOHNSON SYNDROME. STEVEN JOHNSON SYNDROME. APLASTIC ANEMIA, APLASTIC ANEMIA, THROMBOCYTOPENIA. THROMBOCYTOPENIA.

34. 34

35. 35 Adjunct Antiepileptic drugs

36. 36 LAMOTRIGINE Broad spectrum Broad spectrum IHIBITS GLUTAMATE, ASPARTATE IHIBITS GLUTAMATE, ASPARTATE Blocks Na channels and high voltage ca channels Blocks Na channels and high voltage ca channels Can be used for partial and GTCS. Can be used for partial and GTCS. Lennox-Gastaut syndrome Lennox-Gastaut syndrome SE : RASH, Drowsiness, ataxia, confusion, blood dyscrasias SE : RASH, Drowsiness, ataxia, confusion, blood dyscrasias

37. 37 GABAPENTIN. Analogue of GABA Analogue of GABA Mech – Not known Mech – Not known May interfere with ca channels May interfere with ca channels Can be used for partial seizures Can be used for partial seizures SE; Drowsiness, ataxia.. SE; Drowsiness, ataxia..

38. 38 TIAGABINE TIAGABINE Blocks GABA uptake into presynaptic neurons Blocks GABA uptake into presynaptic neurons Making GABA available for receptor binding, thereby enhancing the effect of GABA Making GABA available for receptor binding, thereby enhancing the effect of GABA Exe: BILE ( Major), small amt in Urine Exe: BILE ( Major), small amt in Urine Can be used for Partial and GTCS Seizures in refractory patients Can be used for Partial and GTCS Seizures in refractory patients SE: Drowsiness, ataxia, tremor, SE: Drowsiness, ataxia, tremor, GI upset dizziness GI upset dizziness

39. 39 TOPIRAMATE Many actions, Broad spectrum Many actions, Broad spectrum Blocks Na channels Blocks Na channels Increases GABA activity Increases GABA activity Block T-type Ca channels Block T-type Ca channels Can be used for Partial and GTCS Can be used for Partial and GTCS Exe: Urine Exe: Urine SE: Drowsiness, ataxia, Nephrolithiasis, taste alteration, confusion SE: Drowsiness, ataxia, Nephrolithiasis, taste alteration, confusion

40. 40 VIGABATRIN Inhibit enzyme GABA transaminase Inhibit enzyme GABA transaminase Increases GABA levels Increases GABA levels Can be used for Partial, GTCS & sometimes for Infantile spasms Can be used for Partial, GTCS & sometimes for Infantile spasms Exe: Urine Exe: Urine Adv: very less drug interactions Adv: very less drug interactions SE: Aggression, Alopecia, Skin rash, drowsiness. SE: Aggression, Alopecia, Skin rash, drowsiness.