ANTICONVULSANTS SAMUEL AGUAZIM (MD) 1

What is a Epilepsy? Epilepsy is a chronic disorder characterized by recurrent episodes in which the brain is subject to abnormal excessive discharges (seizures) synchronized throughout a population of neurons. Epilepsy is a chronic disorder characterized by recurrent episodes in which the brain is subject to abnormal excessive discharges (seizures) synchronized throughout a population of neurons. 2

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

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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 seizure. A partial seizure can evolve to a generalized seizure.

6 Partial Seizures The site of origin is a localized or discreet area in one hemisphere of the brain. Partial Seizures The site of origin is a localized or discreet area in one hemisphere of the brain. Symptoms depend on the site of neuronal discharge 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 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 motor signs, sensory symptoms, autonomic signs and symptoms motor signs, sensory symptoms, autonomic signs and symptoms There is no impairment of consciousness in simple partial seizures. There is no impairment of consciousness in simple partial seizures.

8 Complex Partial Impairment of consciousness, characteristic of complex partial seizures (CPS) Impairment 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. 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. Exhibit complex sensory hallucinations, mental distortion and motor dysfunction Exhibit complex sensory hallucinations, mental distortion and motor dysfunction Experience initial seizures before age of 20 yrs Experience initial seizures before age of 20 yrs

9 Generalized Seizures At the onset, seizure activity occurs simultaneously in large areas of the brain, often in both hemispheres. At the onset, seizure activity occurs simultaneously in large areas of the brain, often in both hemispheres. 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 non- convulsive. Seizures can be convulsive or non- convulsive. The two most common types are tonic- clonic (grand mal) and Absence (Petit mal). The two most common types are tonic- clonic (grand mal) and Absence (Petit mal).

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 increased muscle tone (rigidity), is followed by The Clonic phase, which involves jerking of the extremities. The tonic phase, consisting of increased muscle tone (rigidity), is followed by The Clonic phase, which involves jerking of the extremities. Followed by confusion and exhaustion. Followed by confusion and exhaustion.

11 Absence (petit mal) This type occurs most often in children, usually beginning between the ages of 5 and 12 years and often stopping spontaneously in the teens. Absence (petit mal) This type occurs most often in children, usually beginning between the ages of 5 and 12 years and often stopping spontaneously in the teens. The loss of consciousness is so brief that the child usually does not even change position. The loss of consciousness is so brief that the child usually does not even change position. Typically described as a blank stare and often misinterpreted as daydreaming. Typically described as a blank stare and often misinterpreted as daydreaming. Most absence seizures last 10 seconds or less. Most absence seizures last 10 seconds or less.

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 a.k.a West Syndrome sudden spasm or bending (flexion) of the body either at the waist or neck. Infantile Spasms a.k.a West Syndrome sudden spasm or bending (flexion) of the body either at the waist or neck.

13 Status Epilepticus was defined as 30 minutes of continuous seizure activity or a series of seizures without return to full consciousness between the seizures Status Epilepticus was 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 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

15 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

16 BARBITURATES - PHENOBARBITAL BARBITURATES - PHENOBARBITAL PRIMIDONE PRIMIDONE BENZODAIZEPINES - DIAZEPAM BENZODAIZEPINES - DIAZEPAM CLONAZEPAM, CLORAZEPATE CLONAZEPAM, CLORAZEPATE

17 ANTI EPILEPTIC DRUGS - MECH INHIBIT ELECTRICAL DISCHARGE INHIBIT ELECTRICAL DISCHARGE INHIBIT SPREAD OF DISCHARGE INHIBIT SPREAD OF DISCHARGE

18 PHENYTOIN MECH: DECREASES Na INFLUX DECREASES Na INFLUX STABILIZES CELL MEMBRANE STABILIZES CELL MEMBRANE DECREASES INFLUX OF Ca DECREASES INFLUX OF Ca DECREASES FIRING RATE DECREASES FIRING RATE

19 ACTION : DECREASES PROPAGATION OF ABNORMAL IMPULSES DECREASES PROPAGATION OF ABNORMAL IMPULSES USES: USES: First line treatment for tonic-clonic seizures First line treatment for tonic-clonic seizures First line prophylaxis for status epilepticus First line prophylaxis for status epilepticus Treatment for simple and complex seizures. Treatment for simple and complex seizures. Drug of choice for initial therapy in adults Drug of choice for initial therapy in adults

20 DROWSINESS – LITTLE DROWSINESS – LITTLE HYPNOSIS – NO HYPNOSIS – NO KINETICS : ROUTE – ORAL, IV – ST. EPILEPTICUS ROUTE – ORAL, IV – ST. EPILEPTICUS MET : LIVER, EASILY SATURATED MET : LIVER, EASILY SATURATED EXCRETION : URINE. EXCRETION : URINE.

21 PHENYTOIN - SE Side effects of phenytoin include: Side effects of phenytoin include: CNS Depression CNS Depression Gingival hyperplasia Gingival hyperplasia Hirsutism Hirsutism Osteomalacia from decreased vitamin D Osteomalacia from decreased vitamin D Megaloblastic anemia from decreased folate (decreased GI absorption from inhibition of conjugases) Megaloblastic anemia from decreased folate (decreased GI absorption from inhibition of conjugases) Aplastic anemia Aplastic anemia Stevens-Johnson syndrome Stevens-Johnson syndrome Nystagmus Nystagmus Yellow-browning of skin Yellow-browning of skin Neuropathy (vertigo, ataxia, headache) Neuropathy (vertigo, ataxia, headache) SLE-like syndrome SLE-like syndrome

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23 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 DISEASES CONGENITAL HEART DISEASES TERATOGENIC EFFECT

Phenytoin's teratogenic effects usually result in cleft lip and palate. 24

25 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 in Trigeminal neuralgia Drug of choice in Trigeminal neuralgia ORAL ROUTE ORAL ROUTE

26 SE : MC : GIT MC : GIT Chronic use can cause : STUPOR, RESP DEPRESSION, COMA STUPOR, RESP DEPRESSION, COMA APLASTIC ANEMIA, THROMBOCYTOPENIA, AGRANULOCYTOSIS, APLASTIC ANEMIA, THROMBOCYTOPENIA, AGRANULOCYTOSIS, LIVER FAILURE LIVER FAILURE Steven-Johnson syndrome Steven-Johnson syndrome Teratogenicity Teratogenicity Cleft lip and palate Cleft lip and palate Spina bifida Spina bifida

Steven-Johnson syndrome 27

Carbamazepine's teratogenic effects usually result in cleft lip, cleft palate, and spina bifida. 28

29 BARBITURATES PHENOBARBITAL PHENOBARBITAL PRIMIDONE PRIMIDONE MECH MECH May be due to GABA activation May be due to GABA activation USES ; FEBRILE CONVULSIONS, CAN ALSO BE USED FOR SIMPLE & GRAND MAL EPILEPSY USES ; FEBRILE CONVULSIONS, CAN ALSO BE USED FOR SIMPLE & GRAND MAL EPILEPSY Not effective in complex partial Not effective in complex partial Induced CYP450 Induced CYP450 SE : SEDATION, ATAXIA, NYSTAGMUS, VERTIGO SE : SEDATION, ATAXIA, NYSTAGMUS, VERTIGO CHR: PSYCHOSIS. CHR: PSYCHOSIS. Rebound seizures occur on discontinuance Rebound seizures occur on discontinuance

30 PRIMIDONE PRIMIDONE Also effective in complex partial Also effective in complex partial SE SE Same as phenobarbital Same as phenobarbital

31 BENZODIAZEPINES DIAZEPAM, CLONAZEPAM, CLORAZEPATE DIAZEPAM, CLONAZEPAM, CLORAZEPATE SAFEST DRUGS OF ALL THE ANTIEPILETPTIC DRUGS SAFEST DRUGS OF ALL THE ANTIEPILETPTIC DRUGS Diazepam - Slow I. V. – Status Epilepticus Diazepam - 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

32 CLONAZEPAM, CLORAZEPATE CLONAZEPAM, CLORAZEPATE For Chronic treatment For Chronic treatment DIAZEPAM, LORAZEPAM DIAZEPAM, LORAZEPAM For acute conditions Status EPI For acute conditions Status EPI Lorazepam longer duration than diazepam Lorazepam longer duration than diazepam

33 VALPROIC ACID(Divalproex) VALPROIC ACID(Divalproex) MECH : GABA action increased MECH : GABA action increased Blocks Na Channels Blocks Na Channels Broad spectrum antiepileptic drug Broad spectrum antiepileptic drug Inhibitor of CYP45O Inhibitor of CYP45O USES : MYOCLONIC SEIZURES and Bipolar disorder USES : MYOCLONIC SEIZURES and Bipolar disorder Absent seizures – 2 nd drug of choice. (hepatotoxicity) Absent seizures – 2 nd drug of choice. (hepatotoxicity) SE : hepatotoxicity GIT, TREMOR, ATAXIA,SEDATION GIT, TREMOR, ATAXIA,SEDATION THROMBOCYTOPENIA THROMBOCYTOPENIA CI : LIVER FAILURE CI : LIVER FAILURE

34 ETHOSUXIMIDE ( zarontin) Mech: Reduces propagation of abnormal electrical activity in the brain by inhibiting Calcium channels Mech: Reduces propagation of abnormal electrical activity in the brain by inhibiting Calcium channels USES: Drug of choice for ABSENCE SEIZURES USES: Drug of choice for ABSENCE SEIZURESSE: MC : GIT distress MC : GIT distress CONFUSION, CONFUSION, LACK OF CONCENTRATION LACK OF CONCENTRATION STEVEN JOHNSON SYNDROME.( skin reaction) STEVEN JOHNSON SYNDROME.( skin reaction) Headache, Headache, Itching Itching Fatigue Fatigue

35 Adjunct Antiepileptic drugs

36 LAMOTRIGINE ( lamictal) 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 Prevents firing Prevents firing Can be tonic-clonic, simple partial, complex partial and absence seizures and Lennox-Gastaut Syndrome Can be tonic-clonic, simple partial, complex partial and absence seizures and Lennox-Gastaut Syndrome SE : RASH, Drowsiness, ataxia, confusion, blood dyscrasias SE : RASH, Drowsiness, ataxia, confusion, blood dyscrasias

Lennox-Gastaut syndrome (LGS), or childhood epileptic encephalopathy, is a pediatric epilepsy syndrome characterized by multiple seizure types; mental retardation or regression; and abnormal findings on electroencephalography (EEG). Lennox-Gastaut syndrome (LGS), or childhood epileptic encephalopathy, is a pediatric epilepsy syndrome characterized by multiple seizure types; mental retardation or regression; and abnormal findings on electroencephalography (EEG). 37

38 GABAPENTIN.( neurontin) 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 Simple and partial seizures, peripheral neuropathy and Postherpetic neuralgia Can be used for Simple and partial seizures, peripheral neuropathy and Postherpetic neuralgia SE; Sedation, Ataxia, Drowsiness, ataxia, fatigue SE; Sedation, Ataxia, Drowsiness, ataxia, fatigue

39 TIAGABINE TIAGABINE Blocks GABA uptake into presynaptic neurons Blocks GABA uptake into presynaptic neurons More GABA for receptor binding More GABA for receptor binding Exe: BILE ( Major), small amt in Urine Exe: BILE ( Major), small amt in Urine It is effective in decreasing the number of seizures in patients with partial onset epilepsy. It is effective in decreasing the number of seizures in patients with partial onset epilepsy. SE: Drowsiness, ataxia, tremor, SE: Drowsiness, ataxia, tremor, GI upset dizziness GI upset dizziness

40TOPIRAMATE Many actions, Broad spectrum Many actions, Broad spectrum Blocks Na channels Blocks Na channels Increases GABA activity Increases GABA activity Block Ca channels Block Ca channels Prevent Phosporylation of proteins Prevent Phosporylation of proteins Has shown reduction in seizures in refractory cases when used with other Anti-epileptic drugs. Has shown reduction in seizures in refractory cases when used with other Anti-epileptic drugs. Can be used tonic-clonic, simple and complex seizures as well as for migraine prophylaxis.. Can be used tonic-clonic, simple and complex seizures as well as for migraine prophylaxis.. Exe: Urine Exe: Urine SE: Drowsiness, ataxia, Nephrolithiasis, taste alteration, confusion SE: Drowsiness, ataxia, Nephrolithiasis, taste alteration, confusion

41 VIGABATRIN Inhibit enzyme GABA transaminase Inhibit enzyme GABA transaminase Increases the GABA levels Increases the GABA levels Can be used for Partial, General tonic clonic seizures & sometimes for Infantile spasms Can be used for Partial, General tonic clonic seizures & 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.