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Pharmacotherapy of epilepsy
This document discusses the pharmacotherapy of epilepsy. It begins with definitions of epilepsy and seizures, then provides a brief history of views and treatments of epilepsy from the Christian middle ages through the 20th century. The remainder of the document focuses on classification of seizures, mechanisms and types of antiepileptic drugs, characteristics and side effects of various older and newer antiepileptic medications, and treatment algorithms.
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Pharmacotherapy of epilepsy
- 1. Pharmacotherapy of Epilepsy Presenter: Dr Swaroop H S Swaroop: Antiepileptic drugs, 27/12/12 1
- 2. Epilepsy: Definition o Seizures: oParoxysmalevent oAbnormal excessive or synchronous neuronal activity in the brain o Epilepsy: o o o Recurrent seizures Cause: Chronic, underlying condition. Epidemiological definition: At least 2 unprovoked seizures Swaroop: Antiepileptic drugs, 27/12/12 2
- 3. Seizure activity Swaroop: Antiepilepticdrugs, 27/12/12 3
- 4. History: Christian middleages 14th century Epilepsy came from demons, and was thought to be contagious Swaroop: Antiepileptic drugs, 27/12/12 4
- 5. Christian middle ages 14thcentury Falling sickness: praying to virgina marry for votive tablets Swaroop: Antiepileptic drugs, 27/12/12 5
- 6. History: Renaissance th TO17th century 14 Quacks surgery Swaroop: Antiepileptic drugs, 27/12/12 6
- 7. Euthanasia operation T4 'Tiergartenstrasse4’ Physicians killed thousands of people who were "judged incurably sick, by critical medical examination" Swaroop: Antiepileptic drugs, 27/12/12 7
- 8. History:1990-1999 It took 12years for Dr. K. S. Mani to persuade Parliament to delete a clause in the Indian Marriage Act that ◦ Disqualified people with epilepsy from legally marrying. The battle was finally won in December 1999 Dr. K. S. Mani Swaroop: Antiepileptic drugs, 27/12/12 8
- 9. Epilepsy: Classification Focal Seizures Epilepsy Generalized Seizures Focal Seizurewithout dyscognitive features Focal Seizures with dyscognitve features Typical Absence Seizures Atypical Tonic Clonic Tonic Atonic Myoclonic May be focal, generalized, or unclear epileptic spasms Swaroop: Antiepileptic drugs, 27/12/12 9
- 10. Epilepsy: Simple focalseizures Swaroop: Antiepileptic drugs, 27/12/12 10
- 11. Epilepsy: Complex focalseizures Swaroop: Antiepileptic drugs, 27/12/12 11
- 12. Generalised tonic clonicseizures Main seizure type: In ~10% epileptics Tonic phase: ◦ Stiff, crying out, tongue bite, apnea, cyanosed ◦ Increase heart rate, blood pressure ◦ Fall, labored breathing, salivation Clonic phase: ◦ Intermittent clonic movements of muscles ◦ Brief relaxations, involves all limbs ◦ Incontinence at the end of clonic phase, lasts for few minutes Post-ictal period: Drowsiness, confusion, headache, deep sleep Swaroop: Antiepileptic drugs, 27/12/12 12
- 13. Generalized tonic clonicseizures Swaroop: Antiepileptic drugs, 27/12/12 13
- 14. Absence seizures Swaroop: Antiepilepticdrugs, 27/12/12 14
- 15. Mesial Temporal LobeEpilepsy Syndrome (MTLE) Most common syndrome associated with focal seizures with dyscognitive features Detection: ◦ High-resolution MRI to identify the ◦ Pathophysiology: Hippocampal sclerosis Swaroop: Antiepileptic drugs, 27/12/12 15
- 16. Causes of Epilepsy Idiopathic:72% Can be determined: 28% case Determined causes: Inherited genetic: Acquired : Trauma, Neuro surgery, Inflammatory, Metabolic, Infections, Tumor, Toxic disorders, drugs Congenital: Inborn error of metabolism. Withdrawal of drugs: Alcohol Barbiturates Anti-Epileptics Benzodiazepines Swaroop: Antiepileptic drugs, 27/12/12 16
- 17. Management First priorities: ◦Attention to vital signs ◦ Respiratory and cardiovascular support ◦ Treatment of seizures if they resume To be followed by: Management of life-threatening conditions CNS infection, metabolic derangement and drug toxicity When the patient is not acutely ill: Evaluation should initially focus on whether there is a history of earlier seizures Swaroop: Antiepileptic drugs, 27/12/12 17
- 18. Epilepsy: Treatment algorithm Swaroop:Antiepileptic drugs, 27/12/12 18
- 19. Antiepileptic drug therapy Mainstayof treatment: Most epileptics The overall goal: ◦ ◦ ◦ ◦ Completely prevent seizures Without causing any untoward side effects Preferably a single medication Dosing schedule: Easy for the patient to follow Seizure classification: An important element in designing the treatment plan, since some antiepileptic drugs have different activities against various seizure types Swaroop: Antiepileptic drugs, 27/12/12 19
- 20. Anti Epileptic Drugs(AED): Classification Older AEDs: ◦ Phenobarbital, Phenytoin, Primidone ◦ Ethosuximide , Carbamazepine , Valporate Newer AEDs: ◦ ◦ ◦ ◦ Lamotrigine, Topiramate, Tiagabine Oxcarbazepine, Zonisamide, Levetiracetam Vigabatrin, Felbamate, Pregabalin Rufinamide, Lacosamide, Stiripentol, Clobazam ◦ Eslicarbazepine, Ezogabine, Perampanel Swaroop: Antiepileptic drugs, 27/12/12 20
- 21. Seizure: Types andChoice of AEDs Swaroop: Antiepileptic drugs, 27/12/12 21
- 22. Mechanism of action:Older AED’s Action of phenytoin on A. Channel Na+ Resting State B. Na+ Arrival of AP Na+ Depolarization Channel opens Sodium flows in C. Na+ Refractory State Inactivation Swaroop: Antiepileptic drugs, 27/12/12 22
- 23. Facilitation of GABAmediated Chloride channel opening • • • • • Drugs acting through this mechanism are Barbiturate Benzodiazepine Vigabatrin Valproate Gabapentin Swaroop: Antiepileptic drugs, 27/12/12 23
- 24. Glutaminergic synapse Type: Excitatory Permeableto: Na+ Ca2+ Na+, Ca2+ and K+ Blocked by: Magnesium ions in resting state GLU GLY Enhancement: Glycine (GLY) binding enhances the ability of GLU or NMDA to open the channel AGONISTS Mg++ Agonists: NMDA, AMPA, Kianate K+ Swaroop: Antiepileptic drugs, 27/12/12 24
- 25. Phenobarbitone Discovery: 1912: First efficaciousAED, it raised seizure threshold as well as limits spread, suppresses kindled seizures with wide spectrum, one of the safest drugs Pharmacokinetics: ◦ Slow oral absorption, long plasma t1/2 (80-120 hours), 40-60% bound to plasma proteins ◦ Metabolism: liver , excreted unchanged by kidney Disadvantage: ◦ Sedation, nystagmus, ataxia, hyperactivity in children and confusion in the elderly Dose: Adult: 60mg OD to tds, children: 3-6mg/kg/day Swaroop: Antiepileptic drugs, 27/12/12 25
- 26. Phenytoin Synthesis 1908 : Germanchemist Sir Heinrich Blitz Advantage: ◦ Oldest non-sedative AED First clinical use 1937 : Meritt and Putnam Swaroop: Antiepileptic drugs, 27/12/12 26
- 27. Phenytoin Pharmacokinetics: ◦ Extensively bound(~90%) to serum proteins ◦ Plasma t1/2 : 6 and 24 hours at plasma conc. 10 g/mL but with higher conc. ◦ Metabolism: hepatic CYP2C9/10, CYP2C19 ◦ Excretion: Bile and urine • Dose: • Adult: 300mg/day • Children: 5mg/kg/day Swaroop: Antiepileptic drugs, 27/12/12 27
- 28. Adverse reactions ofPhenytoin • • • • • • Stevens-Johnson syndrome Toxic epidermal necrolysis Systemic lupus erythematosus Fatal hepatic necrosis Neutropenia Leukopenia Gingival hyperplasia Fetal hydantoin syndrome Swaroop: Antiepileptic drugs, 27/12/12 28
- 29. Fosphenytoin Type of drug: Prodrugof phenytoin Advantage: Water-soluble Conversion: Phosphatases in liver and red blood cells Pharmacokinetics: ◦ Plasma t1/2 : 8-15 minutes ◦ Extensively bound (95-99%) to human plasma proteins Formulations: IV and IM Swaroop: Antiepileptic drugs, 27/12/12 29
- 30. Carbamazepine • • • Approval: U.S. in1974 Derivative:Iminostilbene with a carbamyl group at the 5th position Pharmacokinetics: • Peak concentrations in plasma usually are observed 4-8 hours after oral ingestion • 75% of binds to plasma proteins • Metabolism: Hepatic CYP3A4 Swaroop: Antiepileptic drugs, 27/12/12 30
- 31. Carbamazepine Adverse reactions: Acuteintoxication ◦ Stupor or coma, hyper-irritability, convulsions, and respiratory depression, drowsiness, vertigo, ataxia, diplopia, and blurred vision ◦ Aplastic anemia, agranulocytosis Interactions: Phenobarbital, phenytoin, and valproate: induction of CYP3A4 CBZ Dose: ◦ Adult: 200 to 400mg TDS ◦ Children: 15 to 30mg/kg/day Swaroop: Antiepileptic drugs, 27/12/12 31
- 32. Valproic acid Spectrum: Broad Mechanism of action: ◦ Frequency dependent prolongation of sodium channel inactivation ◦ Attenuation of calcium mediated T current ◦ Augmentation of release of inhibitory transmitter GABA by inhibiting its degradation Swaroop: Antiepileptic drugs, 27/12/12 32
- 33. Valproic acid Pharmacokinetics: ◦ Plasmaprotein binding: 90% ◦ Plasma t1/2: 10 -15 hours ◦ Metabolism: Liver Oxidation and glucuronide conj. Adverse reactions: ◦ Alopecia, Curling of hair, increased blood ammonia, PCOD, Fulminant hepatitis, neural tube defects ◦ Rashes and thromobocytopenia Dose: ◦ Adult: 200 – 800mg TDS ◦ Children: 15-30mg/kg/day Swaroop: Antiepileptic drugs, 27/12/12 33
- 34. Fetal Valproate Syndrome Fetal Valproate Syndrome Childwith facial features of FVS: Trigonocephaly which has been surgically repaired, broad forehead, thin arched eyebrows, flat nasal bridge, infraorbital grooves, short anteverted nose, long and smooth philtrum and thin upper lip. Swaroop: Antiepileptic drugs, 27/12/12 34
- 35. Ethosuximide • Mechanism of action: •It has an important effect on Ca 2+ currents, reducing the low-threshold (T-type) current. • Pharmacokinetics: • t1/2 : 40 hours • Metabolism: Hydroxylation • inactive products Adverse reactions: • Gastric distress including pain, nausea, and vomiting • Dose: 20-30mg/kg/day Swaroop: Antiepileptic drugs, 27/12/12 35
- 36. Levitracetam Mechanism of action: ◦It inhibits partial and secondarily generalized tonic-clonic seizures in the kindling model ◦ Inhibits synaptic vesicle protein (SV2A) Pharmacokinetics: ◦ Oral absorption: Nearly complete, rapid and unaffected by food ◦ Plasma half-life: 6–8 hours ◦ Two thirds of the drug is excreted unchanged in the urine Swaroop: Antiepileptic drugs, 27/12/12 36
- 37. Levitracetam Advantage: Well tolerated. Adverse drug reactions: ◦ Somnolence, asthenia, and dizziness ◦ Behavioral problems, Psychosis and depression Dose: Adult: 500-3000mg/day Swaroop: Antiepileptic drugs, 27/12/12 37
- 38. Oxcarbazepine It is aprodrug of carbamazepine Mechanism of action: Similar to that of carbamazepine. Half-life: 1–2 hours Advantage: ◦ Less potent enzyme inducer than carbamazepine Most common AE: Hyponatremia, Dizziness, nausea, vomiting, abdominal pain, headache, somnolence, diplopia, fatigue, imbalance and tremor Swaroop: Antiepileptic drugs, 27/12/12 38
- 39. Esclicarbazepine Type of drug:Prodrug Advantage: Once daily dosing Half-life: 9-11 hours Approved in Europe as adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization Dose: 400–1200 mg/d Swaroop: Antiepileptic drugs, 27/12/12 39
- 40. Lacosamide Functionalized amino acid Mechanismof action: ◦ Lacosamide facilitates slow inactivation of voltage gated sodium ion channels ◦ Binds to a collapsin response mediator protein-2 ◦ This protein performs important roles like cytoskeletal, vesicle, and synaptic functions in the developing brain Swaroop: Antiepileptic drugs, 27/12/12 40
- 41. Lacosamide Pharmakokinetics: ◦ Metabolism: CYP2C19by demethylation ◦ No significant induction/inhibition or interaction Adverse drug reactions: Dizziness, headache, nausea, and diplopia Use: Adjunctive therapy in the treatment of partial-onset seizures Dose: ◦ Adult: 50 mg twice daily; may be increased at weekly intervals by 100 mg/day ◦ Maintenance dose: 200-400 mg/day Swaroop: Antiepileptic drugs, 27/12/12 41
- 42. Rufinamide • Mechanism of action: Itslows sodium ion channel recovery from the inactivated state & limits repetitive neuronal firing • Plasma half life: 6-10 hours • Most common AE: Dizziness, fatigue, somnolence, nausea, headache • Use: In the treatment of generalized seizures of Lennox-Gastaut syndrome (LGS) Swaroop: Antiepileptic drugs, 27/12/12 42
- 43. Vigabatrin Mechanism of action: Itirreversibly inhibits the major degradative enzyme for GABA Use: ◦ Adjunctive treatment for infantile spasms and adult refractory complex partial seizure ◦ Good 1st choice for infantile spasms from tuberous sclerosis (TS) Reserve drug: Due to progressive and permanent bilateral vision loss, must be reserved for patients who have failed several alternative therapies Swaroop: Antiepileptic drugs, 27/12/12 43
- 44. Perampanel • • • Mechanism of action: Targetsthe AMPA component Pharmacokinetics: 95% bound to plasma proteins Metabolized by CYP3A4 Adverse reactions: Dizziness, Somnolence, fatigue and headache • Use: Approved for refractory partial onset seizures in Oct 2012 Swaroop: Antiepileptic drugs, 27/12/12 44
- 45. Ezogabine • Approved in 2011 •Mechanism of action: K+ opener • Adverse reactions: • Dizziness, somnolence, fatigue, urinary retention, ataxia, blurred vision. • Use: • For refractory partial onset seizures for patients ≥ 18years, with Seizure ≥ 4 /month • In clinical trial, Ezogabine reduced seizure frequency by 44.3% vs 17.5% for placebo Swaroop: Antiepileptic drugs, 27/12/12 45
- 46. References Goodman and Gilman‟s:The Pharmacological basis of Therapeutics 12th edition, Laurence L Bruton, 2010, USA Katzung „s “ Basic and Clinical Pharmacology”: 12th edition, Bertram G Katzung. Antiepileptic drugs by Martha I. Dávila-García, Ph.D. Howard University, available on www.medscape.com accessed on 21/12/2012 Essentials of Medical pharmacology by KD Tripathi 6th edition, 2008, Jaypee brothers, New Dehli. Text book of Internal Medicine by Harrisons 16th edition. Magiorkinis E, Sidiropoulou K and Diamantis A. Hallmarks in the history of epilepsy: from antiquity till the twentieth century. Available from: http://cdn.intechopen.com/pdfs/21744/InTechHallmarks_in_the_history_of_epilepsy_from_antiquity_till_the_twe ntieth_century.pdf, accessed on 25th October, 2012. Swaroop: Antiepileptic drugs, 27/12/12 46
- 47. Thank You Swaroop: Antiepilepticdrugs, 27/12/12 47
Editor's Notes
- #3 Simplified using bullets, try to manage to speak out the deleted stuff
- #4 Included ‘Title’ in the slide. Start the next slide stating ‘Any new discovery stands on the shoulder of existing ones. So let us quickly walk through the history briefly’….
- #5 Please check if the caption is correct.
- #6 ‘Falling sickness: Saints and relics for cures’ is correct
- #8 Check the caption
- #16 Comment: Do we need to include this slide can you not men while presenting the classification slide?Recognition of this syndrome is especially important because it tends to be refractory to treatment with anticonvulsants but responds extremely well to surgical intervention
- #19 Can you open it in pdfseperately or with a link …font size was very small, I have further made it small to fit into the slide to appreciate or draw the same in black board asthis is a very important slide
- #21 Try to mention the traditional classification along with this slide in black board, also include one or two other 4th generation drugs
- #23 Pheytoin, CBZ, Valproate, Lamotrgine
- #25 Ethosuximide, Trimethadione,Valproate
- #28 Clonic phase will be exaggregated. Conversely, the degradation rate of other drugs that are substrates for these enzymes can be inhibited by phenytoin; one such drug is warfarin, and addition of phenytoin to a patient receiving warfarin can lead to bleeding disorders
- #29 About one third of children whose mothers are taking this drug during pregnancy typically have intrauterine growth restriction with microcephaly and develop minor dysmorphic craniofacial features and limb defects including hypoplastic nails and distal phalanges (birth defects). A smaller population will have growth problems and developmental delay, or mental retardation
- #36 Is it same in both adults and children?
- #37 levetiracetam modifies the synaptic release of glutamateand GABA through an action on vesicular function
- #38 Include more ADRS
- #39 Include more adrs
- #44 GABA-transaminase, thereby leading to increased concentrations of GABA in the brain
- #45 See my note and include few more points
- #46 Brivaracetam, Retigabine
- #47 Include other references