1. ANTIEPILEPTIC DRUGS Brief History Treatment of seizures started in 1850 with Bromides. Based on a theory that epilepsy was due to an excessive sx drive. Followed by Phenobarbitone in 1910 Phenytoin in 1940 Carbamazepine in 1974 Ethosuximide in 1958 Valproate in 1960 Newer AEDs e.g.. Lamotrigine 1990 onwards

2. EPILEPSY Definition : A chronic disorder characterized by recurrent seizures, often along with unconsciousness & or amnesia It is a disorder of brain function Reasons : Birth traumas, head injury, childhood fevers, brain tumors, meningitis and drug induced

3. A seizure or convulsion is a paroxysmal event due to abnormal, excessive, hyper synchronous discharges from CNS neurons. Epilepsy is a chronic condition in which a person has recurrent seizures. Epilepsy - Recurrent seizures - Antiepileptics Convulsions Non-epileptic conditions - hypoglycemia, fever etc - Anticonvulsants AntiepilepticsAnticonvulsants

4.  Epilepsy affects about 0.5% of people & is the second most common neurological disorder.  Epileptic convulsions are caused by high-frequency discharge from a group of neurons, starting locally and spreading to a varying extent to other parts of the brain.  Partial seizures affect localised brain regions, and the attack may involve mainly motor, sensory or behavioral phenomena.  Generalized seizures affect whole brain. whole brain.

5.  The two most common forms of epilepsy are the tonic- clonic fit (grand mal) & the absence seizure (petit mal).  Status epilepticus is a life-threatening condition in which seizure activity is uninterrupted.  The neurochemical basis of the abnormal discharge may be enhanced excitatory amino acid transmission or impaired inhibitory transmission or abnormal electrical properties of the affected cells.  Repeated epileptic discharge can cause neuronal death (excitotoxicity).  Current drug therapy is effective in 70-80% of patients.

6. TYPES OF SEIZURES TYPES OF SEIZURES  Seizures are 1) PARTIAL 2) GENARILIZED 2) GENARILIZED Partial can be (a) Simple partial No loss of consciousness. Seizures lasting 20 – 60 secs (b) Complex partial Purposeless movements e.g.. Hand wringing, or swallowing – lasts 30 secs – 2 mins Consciousness may be impaired. May – aura.

7. TYPES OF SEIZURES II Generalized Seizures – 40 % Generalized Seizures – 40 % 1. Absence (petit mal) Sudden onset of impaired consciousness associated with staring – lasts 30 secs or less Sudden onset of impaired consciousness associated with staring – lasts 30 secs or less 2. Myoclonic seizures Sudden brief, shock like contraction of muscles – part or full body Sudden brief, shock like contraction of muscles – part or full body 3. Atonic seizures Sudden loss of postural tone with head drop Sudden loss of postural tone with head drop 4. Tonic – clonic (grand mal) Sudden loss of consciousness followed by sustained contraction of muscles – all body (tonic phase) -1 min then series of jerks (contractions) then clonic phase of relaxation – 2 – 4 mins. CNS is depressed. Person sleeps and there may be injuries during the seizure. Sudden loss of consciousness followed by sustained contraction of muscles – all body (tonic phase) -1 min then series of jerks (contractions) then clonic phase of relaxation – 2 – 4 mins. CNS is depressed. Person sleeps and there may be injuries during the seizure. 5. Status Epilepticus Recurrent seizures without recovery of consciousness between Recurrent seizures without recovery of consciousness between attacks attacks 6. Febrile seizures in children

8. Tonic-clonic seizure: Tonic phase for 1 minute during which strong contraction of the whole musculature occurs causing a rigid extensor spasm. Respiration stops and defecation, micturition and salivation often occur. Clonic phase consisting of a series of violent, synchronous jerks, which gradually dies out in 2-4 minutes. The patient stays unconscious for a few more minutes and then gradually recovers, feeling ill and confused. The EEG shows generalized continuous high-frequency activity in the tonic phase, and an intermittent discharge in the clonic phase.

9. CLASSIFICATION 1. Hydantoins e.g. Phenytoin, Mephenytoin 2. Barbiturates e.g. Pheno & Mephobarbitone 3. Deoxybarbiturate e.g. Primidone 4. Iminostilbene e.g. Carbamazepine 5. Succinimides e.g. Ethosuximide 6. GABA transaminase Inhibitors e.g. Valproic acid and Vigabatrin Valproic acid and Vigabatrin 7. Benzodiazepines e.g. Diazepam, Clonazepam, Lorazepam, Clorazepate 8. Misc e.g. Gabapentin, Lamotrigine, Acetazolimide, Amphetamine

10. Clinical classification of antiepileptic drugs  Tonic-clonic (grand mal) seizures:  Carbamazepine, Phenytoin, Valproate, Phenobarbitone  Newer agents: Lamotrigine, Gabapentin  Partial (focal) seizures (Psychomotor epilepsy or temporal lobe epilepsy): Carbamazepine, Phenytoin, Primidone, Valproate  Absence seizures (petit mal): Ethosuximide, Clonazepam  Petitmal + Grandmal: Valproate  Status epilepticus: Lorazepam, Diazepam, Phenytoin, Phenobarbitol, General anesthesia  Febrile seizures: Diazepam, Phenobarbitone

11. Mechanism of Action I

12. Mechanism of Action II

13. Mechanism of Action III

14. Mechanism of Action IV

15. Mechanism of Action V

16. Mechanism of Action VI

17. Structures involved in development of seizure Structures involved in development of seizure Neurons Neurons Ion channels Ion channels Receptors Receptors Glia Glia Inhibitory synapses Inhibitory synapses Excitatory synapses Excitatory synapses

18. Grouping of drugs by Mechanism of action Sodium Channel Blockers : Sodium Channel Blockers : Carbamazepine (CBZ), Phenytoin (PHT), Fosphenytoin, Oxycarbazepine (OXC), Lamotrigine (LTG), Zonisamide (ZNS), Topiramate Carbamazepine (CBZ), Phenytoin (PHT), Fosphenytoin, Oxycarbazepine (OXC), Lamotrigine (LTG), Zonisamide (ZNS), Topiramate Calcium Channel Inhibitors Calcium Channel Inhibitors PHT, Fosphenytoin, ZNS PHT, Fosphenytoin, ZNS GABA Receptor Agonists GABA Receptor Agonists Clobazam, Clonazepam, Phenobarbitone -(PHB), Primidone, Tiagabine (TGB) Clobazam, Clonazepam, Phenobarbitone -(PHB), Primidone, Tiagabine (TGB) GABA Transaminase Inhibitor GABA Transaminase Inhibitor Vigabatrin Vigabatrin GABA like Action GABA like Action Gabapentin (GBP), Valproate (VPA), Gabapentin (GBP), Valproate (VPA), Glutamate Blockers Glutamate Blockers Felbamate, Topiramate Felbamate, Topiramate Others mechanisms Others mechanisms Levetiracetam(LEV), Progesterone Levetiracetam(LEV), Progesterone

19. Salient Features of Phenytoin Salient Features of Phenytoin  Depresses CNS  Blocks Sodium Channels  Stabilizes neuronal membrane  Depresses Post Tetanic Potential (PTP)  Inhibits generation of repetitive action potentials  90 % protein bound  Is an enzyme inducer  Also called Diphenylhydantoin

20. Phenytoin - ADRs Phenytoin - ADRs  Nausea, vomiting, stomach pain, anorexia  Nystagmus, diplopia, ataxia  Gingival hyperplasia ( children on prolonged use)  Peripheral neuropathy  Endocrinal: (a) Hirsutism, acne, coarsening of facial features (b) Hyperglycemia (by inhibition of insulin) (b) Hyperglycemia (by inhibition of insulin) (c) Decreased released of ADH (c) Decreased released of ADH (d) Osteomalacia (d) Osteomalacia  Hypersensitivity – rashes, SLE, hepatic neurosis, neutropenia, lymphadenopathy  Megaloblastic anemia because of decreased absorption & increased excretion of folates  Teratogenicity – Fetal Hydantoin Syndrome – Hypo plastic phalanges, cleft palate, harelip,microencaphaly

22. Phenytoin - Toxicity Phenytoin - Toxicity  Cerebellar and vestibular effects  Drowsiness  Delirium  Confusion  Hallucinations  Altered behavior  Coma

23. Phenytoin - Uses Generalized Seizures Status Epilepticus Trigeminal Neuralgia Cardiac arrhythmias

24. Drug Interactions Enzyme induction Carbamazepine & Phenytoin alter each others metabolism Valproate displaces phenytoin from its protein binding Cimetidine, Chloramphenicol inhibit metabolism of phenytoin Antacids decrease absorption of phenytoin

25. Phenytoin & Other Drugs Plasma Levels Phenytoin on Plasma Levels Other Drugs on Phenytoin of Other Drugs Plasma Levels Increase Decrease Increase Decrease Ac alcohol intake Carbamazepine carbamazepine corticosteroids Amiodarone reserpine coumarin Chlramphenicol sucralfate anticoagulants Chlordiazepoxide molindone hydrochloride digitoxin Dicoumarol chr alcohol intake doxycycline Disulfiram estrogens Estrogens felbamate Felbamate furesomide H 2 Antagonists lamotrigine Halothane O C Ps INH quinidine Methylphenidate rifampicin Phenothiazines theophylline Phenylbutazone vigabatrin Salicylates vitamin D SuccinimidesSulfonamidesTolbutamideTrazodone

26. Carbamazepine Efficacy: similar to phenytoin and is particularly more effective in psychomotor epilepsy. Mechanism of action: similar to phenytoin ADME: orally absorbed. It is a microsomal enzyme inducer. ADR: drowsiness, dizziness, ataxia, water retention, GI & CV side-effects, Renal and hepatic function to be monitored during therapy. Teratogenic

27. Drug interactions:  Carbamazepine is a microsomal enzyme inducer.  the metabolism of antiepileptics, oral contraceptives, warfarin, corticosteroids  Drugs which  concentration of carbamazepine: Erythromycin Megaloblastic anemia (decreased absorption of folic acid), Osteomalacia, Vit. K deficiency (due to  metabolism of vit.) Precautions: Do not stop the drug abruptly. Uses: Psychomotor epilepsy - drug of choice Grandmal epilepsy Nonepileptic Uses – Trigeminal neuralgias, Mood stabilizer in bipolar depression

28. Hypersensitivity - carbamazepine

29. Phenobarbitone Efficacy: Antiepileptic & also anticonvulsant Exerts maximal antiepileptic activity in subhypnotic doses. Mechanism of action: unknown, but may involve potentiation of inhibitory effects of (GABA)- mediated neurons.  seizure threshold & limits spread Causes sedation & tolerance develops to sedation gradually. ADME: Oral. IV in status epilepticus. Microsomal enzyme inducer – drug interactions.

30. ADR: Sedation, ataxia, nystagmus, vertigo, acute, psychotic reaction, nausea and vomiting, rash, irritability hyperactivity in children, agitation and confusion in the elderly. Megaloblastic anemia (decreased absorption of folic acid), osteomalacia, vit. K deficiency (due to  metabolism of vit.) Precautions: Rebound seizures if stopped abruptly. Uses:Grand mal, Temporal lobe epilepsy Status epilepticus Febrile fits Primidone: metabolized to phenobarbitone in the body & has similar actions.

31. Valproic acid (Sodium valproate) Efficacy: Broad spectrum, one of the few drugs effective against both grandmal and petitmal. Mechanism of action:  Prevents GABA degradation by inhibiting the degrading enzymes, GABA transaminase and succinic semialdehyde dehydrogenase.  Enhances the action of GABA by postsynaptic action.  Blocks sodium channels & calcium channels ADME: orally absorbed. -  se Plasma concentration of phenytoin, phenobarbitone etc.

32. ADR: GI upset, ataxia, tremor, alopecia, thrombocytopenia fulminant hepatitis – monitor LFT Pregnancy - definite teratogen, causes spina bifida & CV abnormalities. Uses: Petit mal Grand mal Petitmal and grandmal Mood stabilizer in bipolar depression, Migraine prophylaxis

33. Ethosuximide Efficacy: Absence seizures or petit mal Mechanism of action: inhibition of T-type calcium channels, which may play a role in generating the 3/sec spike & wave pattern in thalamic relay neurons. ADME: oral ADR: Well tolerated and relatively safe drug. GI upset, mood changes, drowsiness, rashes. Very rarely it can cause severe hypersensitivity reactions. Use: Only petit mal

34. Clonazepam Efficacy: Effective in petit mal, but tolerance develops very fast. Mechanism: Belongs to benzodiazepine group (diazepam like drug). The benzodiazepine receptor is an integral part of the GABA receptor. Potentiates GABA activity. ADR: Sedation & dullness Use - petit mal

35. Diazepam Efficacy: Anticonvulsant benzodiazepine. Not an antiepileptic. Being replaced by longer acting lorazepam. Mechanism of action: Potentiates GABA activity by acting on benzodiazepine receptor which is an integral part of the GABA receptor. ADR: Sedation & tolerance Route: IV as an anticonvulsant. Uses:Status epilepticus,Tetanus Eclampsia, Convulsant drug poisoning Eclampsia, Convulsant drug poisoning PremedicationAnxiety neurosis

36. Gabapentin Amino acid related to GABA. Exact mechanism not known. Safe and relatively free of side effects. Uses: Adjunct in resistant cases of grandmal & partial seizures. Neuropathic pain such as postherpetic neuralgia. Lamotrigine Inhibits glutamate release Skin rashes broad therapeutic profile – partial seizures and petitmal.

37. Benzodiazepines Pharmacokinetic Parameters Specific Specific Drug Drug On P O On P O Time to Time to peak peak ( plasma ( plasma level) level)Elimination Half life Half life (hr) (hr) Protein Protein Binding Binding (%) (%) Active Active Metabolite Metabolite Diazepam 1 - 2 1 - 2 20 - 60 20 - 60 >90 >90Nordiazepam (T 1/2 30 – 90 hrs) Clorazepate 1 39 – 90 39 – 90 (Nordiazepam ) 99 99 ( Nordiazepam ) Nordiazepam Clonazepam 1 - 2 1 - 2 24 - 48 24 - 48 86 86 None None Lorazepam 2 12 12 16 (im/iv) 16 (im/iv) 85 85 None None Clobazam 1 - 4 1 - 4 18 18 90 90Norclobazam(weak Active T 1/2 42 hrs) Nitrazepam 1 24 – 31 24 – 31 86 86 None None

38. Carbamazepine - Interactions Carbamazepine on Plasma Other Drugs on Levels of Other Drugs Carbamazepine Plasma Levels Plasma Levels Decrease Increase Decrease Increase Clobazam phenytoin phenytoin erythromycin Clonazepam lithium primidone INH Primidone imipramine phenobarbital meconazole Phenobarbital felbamate verapamil Valproate cisplatin diltiazem Ethosuximide viloxazine Haloperidol cimetidine OCPsTheophylineCyclosporin Doxycycline

39. AEDs – With Relatively Infrequent Usage Drug Drug Chemical Chemical Class Class Indication Indication Comments Comments MephobarbitalPentobarbitone Barbiturate Barbiturate Tonic clonic Absence In emergency control of Status & other acute convulsions Prodrug for phenobarbital,induces enzymes, controlled substance,Fetal abnormalities, sedative hypnotic, withdrawal may Status Epilepticus Av as inj. AED only at anaes dose. Controlled subs. Synergism + MephentoinEthotoin Hydantoin Hydantoin Refractory cases of tonic-clonic, focal, Jacksonian & complex partial Tonic – clonic, complex partial Close supervision, serious ADRs e.g. blood dyscrasias, fatal dermatological reactions, CNS effects, hepatitis & nephrosis Possible neonatal coag deffects Some lymphadenopathy & SLE ParamethodioneOxazalidenedione Refractory Absence Foetal malformations, Mysthenia gr, Hepatitis, fatal nephrosis, exfoliative Dermatitis (see next slide)

40. AEDS – WRIU continues D CC CC I C MethosuccimidePhensuximidePhenacemide Succinimide Succinimide Substituted acetyl-urea Refractory Absence Absence seizures Severe refractory complex partial seizures Severe ADRS e.g. blood dyscrasias, SLE, neuro & psychological disturbances. Use in Hepatic & renal pts with extreme caution As monotherapy may increase frequency of tonic – clonic seizures, Severe ADRs as above Potentially fatal effects incl hepatotoxicity, aplastic anemia. Birth defects. Personality changes – suicidal, allergic reactions

41. Principles of treatment of epilepsy Aim: To prevent seizures  Treat primary cause if any.  Therapy initiated with low doses.  Patient compliance is vital.  Monotherapy is advisable to avoid drug interactions & if no response, alternate drugs are tried & then only polytherapy to be prescribed.  Treatment to continue till a minimum ?2 yr seizure free period.  Drug withdrawal should be gradual over a period of months to avoid rebound epilepsy & status epilepticus.  Phenytoin dose to be regulated by therapeutic drug monitoring. (TDM)  If women on antiepileptics conceive (pill failure), therapy is continued at minimal doses. Change from valproate, to a relatively safer drug like carbamazepine.

42. Status epilepticus Is a condition where seizures are continuous without recovery of consciousness. It is a medical emergency with a mortality of about 10 – 15%. Management: IV 10 ml 10% dextrose stat then AEDs:- 1.Lorazepam i.v. 4 mg or Diazepam 10 mg iv. 2.Reinstate previous anticonvulsant drugs. 3.If seizures continue, i.v. phenytoin is given. 4.If seizures continue, slowly phenobarbital 10 mg/kg is given. 5.If, despite these measures, status persists > 90 minutes, thiopental or propofol anaesthesia with assisted ventilation. 6.General management of the patient

43. Must Know Must Know  Classification of anti epileptic drugs  Mechanism of actions of AEDs  ADRs and interactions of AEDs  Therapeutic indications of AEDs  Status Epilepticus & its treatment  Varieties of epilepsy and specific drugs used in their treatment