2. Epilepsy and Anticonvulsants Patty Ghazvini, PharmD., CGP Associate Professor of Pharmacy Practice FAMU College of Pharmacy

3. Seizures Epilepsy Video

4. Case Presentation J.H. is a 42-year-old man with complex partial seizures for which he was prescribed topiramate. He has been increasing the dose of topiramate every other day according to instructions from his primary care provider. He comes to your clinic for a follow-up a few weeks later but seems a little confused and has difficulty finding the words to have a conversation with you. Which one of the following is the best assessment of J.H.’s condition?

5. Case Presentation A. Discontinue topiramate; he is having an allergic reaction. B. Increase his topiramate dose; he is having partial seizures. C. Slow the rate of topiramate titration; he is having psychomotor slowing. D. Get a topiramate serum concentration; he is likely supratherapeutic. A. Discontinue topiramate; he is having an allergic reaction. B. Increase his topiramate dose; he is having partial seizures. C. Slow the rate of topiramate titration; he is having psychomotor slowing. D. Get a topiramate serum concentration; he is likely supratherapeutic.

6. Case Presentation B.V. is a 28-year-old woman brought to your emergency department for treatment of status epilepticus. She receives lorazepam 4 mg intravenously with subsequent seizure cessation. Which one of the following medications is the best next treatment step for B.V.?

7. Case Presentation A. Topiramate. B. Phenytoin. C. Zonisamide. D. Diazepam. A. Topiramate. B. Phenytoin. C. Zonisamide. D. Diazepam.

8. Classification of Seizures Generalized seizures (absence, myoclonic, generalized tonic-clonic) - widespread regions of the brain Partial (focal) seizures - originate in a localized area of the cerebral cortex Further, seizures can be divided into simple or complex seizure depending on whether consciousness is altered

9. Epidemiology 1. Ten percent of the population will have a seizure. 2. About 50 million people worldwide have epilepsy. 3. About 50% of patients with a new diagnosis become seizure free on their first treatment, with up to 70% becoming seizure free after treatment adjustment.

10. Pathophysiology Initially a small number of neurons will fire abnormally, however, there is a break down of normal membrane conductance and inhibitory mechanisms which leads to the spread of the excitability either to a local area or widespread generalized area. Dramatic increase in metabolic needs. The brain will consume more oxygen than the vasculature can supply which can lead to brain damage.

11. Factors Leading to Membrane Instability Ion channel abnormalities Increase in Neurotransmitters that enhance excitability Deficiency in Inhibitory Neurotransmitters Abnormalities in serum pH can lead to seizures due to the fact that normal neuronal activity depends on adequate supplies of glucose, electrolytes, oxygen and amino acids.

12. Classification of Seizures Focal seizures begin in one hemisphere of the brain. - A. Without impairment of consciousness/responsiveness (replaces the term simple partial seizure) - With observable motor or autonomic components - Involving subjective sensory (e.g., visual, auditory, olfactory, gustatory sensations) - B. With impairment of consciousness/responsiveness (replaces the term complex partial seizure)

13. Classification of Seizures Generalized seizures begin in both hemispheres of the brain: A. Absence: B. Myoclonic: C. Tonic-clonic – 5 Phases: - Flexion - Extension - Tremor - Clonic - Postictal D. Clonic E. Tonic F. Atonic

14. Lennox-Gestaut Syndrome Presents in preschool age children Mixture of seizure types ◦Myoclonic, generalized, tonic-clonic, absence, partial, atonic High seizure frequency Difficult to control High incidence of status epilepticus 40-80 % will be severely mentally retarded.

15. Diagnosis Physical Examination/neurologic Laboratory tests EEG MRI

16. Anticonvulsants First generation- - Phenytoin (Dilantin) - Carbamazepine (Tegretol) - Valproic Acid (Depakote) - Phenobarbital - Ethosuximide (Zarontin) - Benzodiazepines (Clonazepam, Lorazepam, Diazepam, Clorazepate

17. Overview Older AED’s such as carbamazepine, valproic acid, and phenytoin remain the first line therapy in most seizure types. Exception is absence seizures ◦is the drug of choice ???? New AED are generally used as add on therapy for children who have refractory seizures. Dosages are adjusted according to patient response and/or serum concentrations Older AED’s such as carbamazepine, valproic acid, and phenytoin remain the first line therapy in most seizure types. Exception is absence seizures ◦is the drug of choice ???? New AED are generally used as add on therapy for children who have refractory seizures. Dosages are adjusted according to patient response and/or serum concentrations

18. Overview Anticonvulsants are thought to carry an increased risk of suicidal ideation and behavior Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior.

19. Differences between the Generations First generation – Second generation

20. Limitations with 1st Generation Anticonvulsants Enzyme Induction/Inhibition Cognitive impairment Metabolic Products ◦ CBZ-epoxide, hyperammonemia Hematological Disorders ◦ bone marrow depression, thrombocytopenia

21. 2nd Generation Anticonvulsants No required therapeutic monitoring Fewer Drug Interactions Adjunct therapy & monotherapy; Indicated for partial seizures with or without generalization Orally administered Not used for Status Epilepticus Used “Outside of the Box”

22. Partial Seizures First Line Therapy Second Line Therapy Adjunct Therapy

23. Absence Seizures First Line Therapy Second line therapy

24. Myoclonic Seizures First Line Therapy Second Line Therapy Third Line Therapy Adjunct Therapy

25. Tonic-Clonic, Atonic Seizures First Line Agents ◦Carbamazepine, Valproic Acid, Oxcarbazepine Second Line Agent ◦Phenytoin Third Line Agents ◦Lamotrigine, Topiramate Atonic Seizures ◦Valproic Acid or Clonazepam

26. Pharmacotherapy

27. Phenobarbital (Luminal®) Drowsiness Confusion Agitation Elevated hepatic enzymes Anxiety Constipation

28. Carbamazepine ( Tegretol ®) MOA: limits the influx of sodium ions Therapeutic Serum Concentrations 4-12 mg/L Administration ◦The solution should be given 3-4 times a day ◦Tablets may be given 2-4 times a day ◦Do not mix the solution with other medications it may decrease the effect. ◦Suspension will produce a higher peak level than tablets at the same dose  Start suspensions at the lower dosage range and titrate slowly to avoid ADE. Side Effects

29. Oxcarbazepine ( Trileptal ®) MOA: B lock Na+ channels inhibiting repetitive neuronal firing and stabilizing neuronal membranes Cross hypersensitivity can occur with carbamazepine ( 20-35%) Monitor sodium levels in person who receive other medications that also alter sodium levels. Suspension is stable for 7 weeks after opening the bottle Side Effects ◦Sedation, ataxia, nausea, hyponatremia

30. Valproic Acid ( Depakote ®) MOA: increases GABA availability and action Therapeutic Serum Concentrations??? Should not be used in children < 2 years. ◦Increased risk of developing fatal hepatotoxicity Do not substitute Depakote ER for Depakote ◦May take with food. Do not administer with carbonated drinks ◦Do not give the tablet with milk ◦Depakote Sprinkles may be sprinkled on food and swallowed immediately. Do not chew or crush. Side Effects????

31. Phenytoin ( Dilantin ®) MOA: Increases efflux or decreases the influx of sodium across the cell membrane. Therapeutic Serum Concentrations ◦Neonates 8-15 mg/L ◦Children 10-20 mg/L Use with caution in neonates ◦Capsules and suspension contain Sodium Benzoate and may cause gasping syndrome. Food may affect absorption depending on formulation. ◦High fat meals decrease the rate of absorption of Dilantin Kapseals and decreases the bioavailability of generic extended release phenytoin sodium. ◦Administer at the same time with regard to meals Separate the doses of other medications or tube feedings by 2 hours. Side Effects ◦Ataxia, sedation, cognitive impairment, visual disturbances,hirsutism

32. Gabapentin ( Neurontin ® ) MOA: GABA agonist activity Neuropsychiatric ADE’s have occurred in pediatric population ◦ Hostility, aggressive behaviors ◦Do not discontinue abruptly; taper over at least one week Oral Solution must be refrigerated Side Effects ◦Somnolence, ataxia, dizziness, weight gain

33. Zonisamide (Zonegran®) Approved for adjunctive treatment of partial seizures in adults with epilepsy Blocks sodium channels, thereby stabilizing neuronal membranes Used “off-label” in children Adverse effects:???????

34. Topiramate ( Topamax ® ) MOA: Thought to block sodium channels, potentiate GABA and inhibit the activation of glutamate. May cause an ocular syndrome characterized by acute angle closure glaucoma ◦Typically occurs within 1 month of initiation of therapy. ◦Advise patients to report any blurred vision to physician immediately May cause kidney stones ◦Parents should report any pain upon urination Tablets may be crushed, mixed with water and administered immediately Sprinkle capsules should not be chewed.

35. Felbamate ( Felbatol ® ) MOA: regulates Na, enhances GABA Associated with ? and ?. Currently FDA recommends that it only be used in patients who have failed therapy with all other AED’s and who have such severe epilepsy that the benefits outweigh the risk. Weekly or biweekly monitoring of CBC and Liver Function tests are recommended with use.

36. Tiagabine (Gabitril®) Indicated for the adjunctive treatment of partial seizures Inhibits the reuptake of GABA, the major inhibitory neurotransmitter in the CNS. Side Effects: mostly GI (diarrhea, nausea, abdominal pain)

37. Levetiracetam (Keppra®) FDA-approved as adjunctive therapy for adults and children 4 years of age and older with partial seizures FDA-approved for adults and children 6 years of age and older with primary generalized tonic-clonic seizures FDA-approved for adults and adolescents greater than 12 years of age with myoclonic seizures.

38. Vigabatrin (Sabril®) Structural analog of GABA and was designed to inhibit the metabolism of GABA First drug to be FDA approved for the treatment of infantile spasms Also FDA-approved for adjunctive therapy in the treatment of adults with refractory complex partial seizures. Due to the risk of ?????????, vigabatrin is only available through a restricted distribution program called SHARE.

39. Pregabalin (Lyrica®) Binds to voltage-gated calcium channel and results in a decrease in the release of several excitatory neurotransmitters More potent than gabapentin Minimal CNS side effects; no drug interactions May cause weight gain and edema FDA approved for ????????

40. Lamotrigine ( Lamictal ® ) MOA: affects voltage regulated sodium channels and inhibits the presynaptic release of glutamate and aspartate Potential to cause ???????????; risk factors are ◦Young age, concurrent VPA therapy, high initial dose, rapid titration ◦Occurs as a result of a toxic arene oxide intermediate metabolite which is produced through the P450 pathway

41. Newer Agents Lacosamide (Vimpat®) – - MOA: Slow sodium channel blocker - FDA approval: Oral or IV use as add-on in adults with partial-onset seizures - Maximal dose of 300mg/d with CrCl of 30mL/min or less or hepatic impairment -SE:????????? - Controlled substance schedule V:???? - Parenteral formulation: FDA indication only for replacement of oral formulation

42. New Agents Rufinamide (Banzel®) - MOA: inhibition of sodium-dependent action potential - FDA-approved for ????????????? - Absorption is increased by food - Decreases concentration of ethinyl estradiol and northindrone - Slightly shortens QT interval

43. New Agents Clobazam (Onfi®) - Oral benzodiazepine - Approved for ????????????? - Inhibitor of 2D6; drugs metabolized by 2D6 (fluoxetine, paroxetine, etc>) - Metabolized through ???????; Diflucan and Prilosec can increase serum concentrations of the metabolite

44. New Agent Ezogabine (Potiga®) - Approved for ????????????? - MOA: potassium channel facilitator; reduces the degree of depolarization needed to pen the channel which opens faster and stays open longer, slowing repetitive firing in the brain - Dose-related mean weight increases of 1.2- 2.7 kg - Urinary retention requiring catheterization has been reported; psychotic symptoms (dose – related) has occurred. - Schedule V due ??????? - QT prolongation has been reported

45. Status Epilepticus Continuous or intermittent seizures lasting more than 30 minutes, without full recovery of consciousness between seizures. Therapeutic principles: time is brain If a treatment fails, there should be no interval between the end of a failed protocol and the initiation of next therapy

46. First-Line Therapies Benzodiazepines – IV diazepam (0.2 mg/Kg given at 5mg/min) and lorazepam (0.1 mg/kg given at 2 mg/min) Phenytoin – limitation is the rate at which it can be delivered Fosphenytoin – prodrug of phenytoin; can be infused at rates faster than phenytoin; less vascular irritation; can be given IM

47. Other First-Line Therapies Valproate Phenobarbital – Works on the GABA receptors; causes profound respiratory depression and hypotension

48. Refractory Status Epilepticus Failure of adequate amounts of two IV drugs to stop seizures. Add enough anticonvulsant to reach a high therapeutic or low toxic serum anticonvulsant concentration Should be no hesitation to depress respiration and intubate, but severe arterial hypotension should be avoided since it will curtail cerebral blood flow.

49. Refractory Status Epilepticus Midazolam – continuous infusion due to short duration of action; less hypotension Propofol – ?????????? Anesthetic Barbiturates – Pentobarbital and thiopental

50. Elderly Pharmacokinetic changes may affect antiepileptic medications: - Carbamazepine: - Phenytoin: - Valproic acid : - Diazepam: - Lamotrigine:

51. Role of the Pharmacist Improve compliance - Education - Refer to patient support groups - Reinforce importance of treatment - Provide written instructions