Anti-Epileptic drugs

Anticonvulsants are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder and borderline personality disorder, since many seem to act as mood stabilizers, and for the treatment of neuropathic pain.

1. Presented By: Mr Vijay Salvekar Associate Professor Dept. of Pharmacology GRY Institute of Pharmacy,Borawan

2. Seizure:- paroxysmal event due to abnormal excessive or synchronous neuronal activity in the brain A Seizure Latin word meaning " To take possession of” ) Epilepsy is a disorders of brain function characterized by paroxysmal cerebral dysrhythmia . In this condition a person has recurrent seizures due to a chronic {old} , underlying process. Patients who have two or more seizures (within 6-12 month) are considered to have epilepsy

3. History:- Hippocrates called “ Epilepsy” as ‘ Sacred disease ’ Christian middle age (14 th century)-epilepsy came from “ demons” & it was thought to be contagious.

4. Sei z u r es F o c a l Generalized Simple Partial Complex Partial Secondarily G enerali z ed Absence Myoclonic clo n ic T o n ic Tonic-Clonic/GTCS ILAE – International League Against Epilepsy ILAE Classification of Seizures Classification based on history ,clinical finding ,EEG recording & imaging studies by ILAE

5. distributed across both cerebral hemispheres. They may result from cellular, biochemical or structural abnormalities that have a more widespread distribution. Several types of generalized seizures have features that place them in distinctive categories 1.GTCS:- Generalised tonic-Clonic seizures also called Grand mal Main seizure type in 10% of all persons Initial phase of the seizure is usually tonic contraction of muscles throughout the body

6. Other feature include- Tonic phase- Stiff , crying out, tongue bite, Apnea- contraction of laryngeal muscle ↑ HR, ↓ BP, Salivation , Clonic Phase- Intermittent clonic movement of muscle Brief relaxation involves all limbs Repetitive bilateral muscle jerking Recovery:- coma last for 30 min Post ictal Phase:- Drowsiness, confusion, headache ,deep sleep

7. Absence seizures (Petit mal ):- No aura {spirit} , No loss of consciousness Sudden onset of staring, Bilateral motor symptoms-rapid blinking of eyelide Children-more experience Myoclonic seizures:- Single or multiple sudden brief shock like contractions of skeletal muscles. sudden jerking movement observed while falling asleep

8. SIMPLE PARTIAL limited to one cerebral hemisphere (80% pt) Usually associated with structural abnormalities of the brain Accompanied by transient impairment of the patient's ability to maintain normal contact with the environment Simple Focal seizures (SFS)/cortical focal epilepsy :- The manifestations depend on the region of the cortex involved:- no loss of consciousness focal motor symptoms (convulsions) sensory symptoms ( variety of subjective symptoms ) -symptom Not observe by other person

9. Complex Focal seizures:- (CFS, Temporal lobe Ep. Psychomotor Ep.) Usually originate in the temporal lobe & are accompanied by partial loss of consciousness A ura – A mnesia – A bnormal behavior – A utomatism

10. Infancy and childhood Prenatal or birth injury Inborn error of metabolism Congenital malformation Childhood and adolescence Idiopathic/genetic syndrome CNS infection Adolescence and young adult Head trauma Drug intoxication and withdrawal Trauma Older adult Stroke Brain tumor Acute metabolic disturbances Neurodegenerative Etiology of Seizures and Epilepsy

11. Seizure Precipitants:- Stimulants/Other Pro-convulsant Intoxication I.v. drug use Cocaine Ephedrine Other herbal remedies Alcohol withdrawal

12. A n tidepressant s :- Bupropion Tricyclics Neuroleptics:- Phenothi a zin e s Clozapine Theophylline Antimalarials:- chloroquine,mefloquine Cardiac anti arrythmics:- lidocaine,disopyramide Isoniazid Penicillins, fluoroquinolones,metronidazole Cyclosporin Radiographic contrast Seizure Precipitants (cont.)

13. Excitation (too much) :- Ionic—inward Na + , Ca ++ currents Neurotransmitter—glutamate, aspartate Inhibition (too little):- Ionic—inward CI - , outward K + currents Neurotransmitter—GABA Cellular Mechanisms of Seizure Generation

14. Antiepileptic Drug Drug Treats ↓ frequency/severity of seizures symptom of seizures, underlying epileptic condition Goal—maximize quality of life by minimizing seizures and adverse drug effects Currently no “anti-epileptogenic” drugs available

15. Clinical Classification of Antiepileptic Drugs Seizure type Preferred drugs Alternat ive drugs GT C S Carbamazepine Sodium valproate Phenytoin Phenobarbitone La m otrigine Topiramate Primidone Simple focal seizure C a r b a m azepine Phenytoin Sod.valproate Gabapentin,Lamotrigine,T opiramate,Tiagabine Zonisamide Complex focal seizure Carbamazepine Phenytoin Sod.valp r oate Gabapen t in , L a m otr i gin e , T opi ramate,Tiagabine Zonisamide Absence seizure Sod.valproate Ethosuximide Clonazepam Lamotrigine Myoclonic seizure Sodium valproate Clon a z e pam L a m otr i gine Topiramate

16. Chemical Classification:- Hydantoins: Phenytoin,fosphenytoin Barbiturates: Phenobarbitone, Mephobarbitone Iminostilbenes: Carbamazepine,oxcarbazepine Succinimides: Ethosuximide BZDs: Clonazepam,Diazepam,lorazepam,Clobazam, Aliphatic carboxylic acid derivative: Valproic acid Deoxybarbiturates: Primidone 8. Phenyltriazine :- Lamotrigine, Gabapentin, Vigabatrin 9. Cyclic GABA analogue:- Gabapentin, pregabalin Newer drugs:- Top i ra m ate , Zon i sa m i d e , L e veti r a c eta m ,Ti a gab i ne,L a cosa m i de

17. Mechanism of action of different anti-epileptics Prolongation of Na+ channel inactivation Phenytoin Carb a m a z ep i ne Valproate Lamotrigine Topiramate Zonisamide Lacosamide Rufinamide Cl - channel Opening Barbiturate Benzodiazepine Vigabatin Gabapentin Tigabine Facilitation of Inhibition of T- GABA mediated type Ca ++ channel E thosuximide T rimeth a dione V alproate Decrease of Excitatory Ne u r otran s mitt er Lamotrigine Felbamate Topiramate Hormone ACTH Others o L e ve t ir a c e t a m o Pregabalin o MgS0 4 o Ace t a zo l amide o Ketogenic diet o Vagal nerve stimulation

18. 1840 1860 1880 1900 1920 1940 1960 1980 2000 5 10 15 20 B r omide Phenytoin Phenobarbital Primidone Ethosuximide C a rbam a z epine Benzodiazepines Vigabatrin Z onis a mide Sodium valproate L a motrigine G a bap e n t in Felbamate Fosphenytoin Oxcarbazepine Ti a gabine Topiramate Levetiracetam M o r e Y ear AEDs Antiepileptic drug development

19. Hydantoin derivative One of the most commonly used drug Does not produce significant Drowsiness Effective against all types of Partial and Tonic clonic seizures but not absence seizures Mechanism:- Phenytoin P h enytoin Bind to voltage dependent Na + channels (Prolongs the inactivated state) and prevent further entry of Na + ions into the neuron. (Stabilize neuronal membrane ) Inhibit the generation of repetitive action potentials Therefore, prevent /reduce the spread of seizure discharges

20. Other mechanism :- At high conc. Phenytoin reduce Ca 2+ influx(during depolarization) into the neurons Suppresses repetitive firing of neurons & NT Reduces glutamate levels increases GABA responses Pharmacokinetics:- Absorption- slowly after oral administration H ighly bound to plasma proteins Metabolism- by H ydroxylation(CYP2C9,CYP2C19) and glucuronide conjugation, Repeated doses cause enzyme induction

21. Exhibits dose dependent elimination through saliva Phenytoin At low doses, follow first order kinetics As the plasma conc. increases Elimination processes get saturated Plasma conc. Should be monitored in neonates and in pt suffering with uremia, liver disease ,hypoprotenaemia On I.M. administration-get ppt in muscle cause pain Upon I.V. administration-thrombophlebitis

22. Therapeutic Uses Epileptic uses:- Effective drugs for all focal seizures(simple & complex) First choice of seizure prophylaxis in head injury First choice for Tonic-clonic seizure Status epilepticus May even worsen absence & myoclonic seizures Non-Epileptics:- Trigeminal neuralgia To treat ventricular arrhythmias due to digitalis toxicity To enhance wound healing ↑platelet derived growth factors-B & its mRNA from enhance wound healing, promote local Phenytoin m ac r ophages angiogenesis

23. Fosp h enytoin Water soluble Prodrug of phenytoin (Diphosphate -ester) Active metabolite is phenytoin It is available for IM & IV administration Antiepileptic effect=phenytoin Advantages:- Less irritating to vein Less cardiotoxic Safer & better tolerated-infuse 3 times faster than I.V. phenytoin Disadvantage:- Expensive

24. Chemically related to tri carboxylic acid MOA:- Same as phenytoin but claim to cause less cognitive impairment Pharmacokinetics:- Unstable substance (protect from hot/humid condition) High lipid solubility-enters brain rapidly Therapeutic blood level:-4-12µg/ml Induces its own hepatic metabolism(auto induction) USES:- 1. All focal seizures Tonic-clonic seizures(not effective for absence & myoclonic seizures) trigeminal neuralgia Occasionally used in manic depressive pt. Carb a mazep i ne

25. Benzodiazepines Ba r bit u r a te Safest & all most free from Severe side effects of all Antiepileptic Chronic treatment:- Clonazepam, Clobazam, Clorazepate In status epilepticus:- Diazepam , Lorazepam Very potent anticonvulsant Significant ADR Chronic treatment:- Used as 2 nd line drugs Pheno b arbi t one :- In Pregnancy Recurrent febrile seizures in children

26. Tiagabine:- Reversibly inhibits GABA reuptake Transporter-1 ( GAT- 1 ) Second line adjunctive therapy in refractory partial or secondarily generalized seizures Can worsen absence epilepsy

27. Vig a batrin : - Uses:- Infantile spasms Refractory Complex Partial seizure Adverse Effects :- Visual toxicity due to retinal atrophy and Neuropsychiatric Symptoms 3-6 days Resynthesize

28. -:Valproate:- Broad spectrum anti-epileptics Mechanism:- Blockade of sodium channel ↑GABA activity by inhibiting GABA transminases Inhibition of T-type Ca ++ channel ↓ release of glutamate in brain Therapeutic Uses:- Epileptic uses:- All types of Generalized & focal seizures DOC in idiopathic generalized epilepsy DOC myoclonic seizures DOC in absence seizures in (adult)-children ethosuximide is DOC because of hepatotoxic potential of valproate DOC in tonic-clonic seizure

29. First line drug in photosensitive epilepsy Non-Epileptic uses:- DOC in bipolar disorder with rapid cyclers Prophylaxis of migraine Pharmacokinetics:- Absorption :- Orally rapid Plasma protein binding:- Highly (conc. Dependent & nonlinear) Metabolism:- liver Therapeutic blood levels- 50-150mg/ml Adverse Effects:- Idiosyncratic,genetically determined hepatic toxicity Nausea & vomiting

30. ↑ appetite leading to weight gain Rash Alopecia Thrombocytopenia Endocrine effect- insulin resistance, anovulatory cycles, amenorrhea, polycystic ovary syndrome Bone marrow suppression- rare Fatal acute pancreatitis Teratogenic effects especially neural tube defects Gabapentin :- ↑GABA level (brain) ↓Glutamate level (brain) Only modest efficacy in partial & secondary generalized tonic-clonic seizures Has analgesic properties

31. Ethos u ximi d e Block T-type Ca ++ channels First choice in Absence seizure –children (below 3yr.) Not use in other seizures T1/2-60 hrs No drug interaction Sedation common side effects Characterized side effects- hemeralopia (Photophobia) Therapeutic Blood level-40-100 µg/ml

32. Very effective ,broad spectrum & well tolerated DOC- focal seizure in elderly Less incidence of congenital malformation( preferred during pregnancy ) Use in manic depressive psychosis Side effect-rash (rarely cause SJ-syndrome) Zonisamide T-type Ca++ channel blocked also process weak CA-inhibiting property Neuroprotective action Juveniles myoclonic epilepsy Main side effects- sedation, metabolic acidosis, renal stone Lamotrigine

33. Glutamate Receptor blockers Felbamate:- o potent ,very effective against all seizures Blocks NMDA receptors & voltage gated Ca++ channels No effects on GABA receptors Has neuroprotective effect on hypoxic-ischemic injuries uses:- secondary generalized seizure Topiramate Very potent, chemical relatives of fructose has several action Blocked of glutamate receptors Blocked of voltage gated Na+ channels ↑ GABA activity at GABA A receptors

34. Therapeutic uses:- Partial onset & secondarily generalized tonic clonic seizures Primary GTCS SE:- nausea, appetite subpression –weight loss Renal stone-due to CA-Inhibition. RX- drink plenty of fluids Others:- ACTH:- acts by modulating GABA receptors (open Cl- channels ) Levetiracetam- inhibit Ca++ release Pregabalin- GABA analogue.( anticonvulsant+ analgesic +anxiolytics )

35. Acetazolamide:- CA-I (use:- epileptic women who experience seizures exacerbation at the time of menses ) MgS04 - DOC in controlling Seizure in eclampsia Newer drugs :- Retigabine:- ( K+ channel facilitator ) Partial onset seizures in adult

36. I.V.- Lorazepam (0.1-0.15mg/Kg ) over 1-2 min(repeat if no Fosphenytoin 20mg/kg I.V. at 150 mg/min Or Phenytoin 20mg/Kg IV.slow Status Epilepticus response after 5 min) Seizure Continue If Seizure Stop R x - No further treatment Seizure Continue Repeat at low dose Phenytoin 7-10mg/Kg I.V. 50mg/min No further treatment No further treatment Admit to ICU IV anesthesia with propofol /midazolam/Phenobarbital Phenobarbital 20mg/Kg IV.60mg/min Seizure continue Phenobabital 10mg/kg IV 60mg/min Seizure Continue Sodium valproate 25mg/kg IV No immediate access to ICU