1. 1 Drugs for Epilepsy Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

2. 2 Epilepsy: new definition as of 2014 Diagnosis of epilepsy: a person is considered to have epilepsy if he or she meets any of the following conditions: At least two unprovoked (or reflex) seizures occurring greater than 24 hours apart. One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years. Diagnosis of an epilepsy syndrome –Epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy syndrome but are now past the applicable age, or those who have remained seizure-free for the last 10 years, with no seizure medicines for the last 5 years. Fisher RS et al. A practical clinical definition of epilepsy, Epilepsia 2014; 55:475-482. This definition was also adopted as a position of the International League Against Epilepsy (ILAE).

3. 3 Epilepsy: overview ‘Umbrella term’ for a group of heterogeneous disorders characterized by excessive excitability of neurons in the CNS All seizures are caused by abnormal electrical disturbances in the brain. Different kinds of seizures –May present with a range of symptoms from as subtle as a blank stare… to as marked as unconsciousness or convulsions In U.S.  2.3 million people have epilepsy Incidence is highest during the 1 st year of life and in the elderly Between 60-70% of patients can be seizure-free with drug therapy. Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

4. 4 Seizures: what is the focus? Definition.... The seizure focus is the site in the brain from which the seizure originated. Seizures arise from many possible conditions, such as: Congenital defects Hypoxia at birth Head trauma Cancer And more

5. 5 The symptoms of any particular seizure depend on the location in the brain of the seizure focus Where are the hyperexcitable neurons located? −More limited part of the brain  partial or local seizure −Larger portion of the brain  generalized seizure Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc. Seizures: what is the focus?

6. 6 Seizures: Types Partial (focal) seizures – Simple partial – Complex partial – Secondarily generalized Generalized seizures –Tonic-clonic (grand mal) – Absence (petit mal) – Atonic – Myoclonic – Status epilepticus (SE) – Febrile Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

7. 7 Antiepileptic Drugs (aka AEDs, or “antiseizure medications”) Effects: –Suppress discharge of neurons within a seizure focus –Suppress propagation of seizure activity from the focus to other areas of the brain Mechanisms of action involving: –Sodium –Calcium –Glutamate –GABA –(potassium?) Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

8. 8 Therapeutic Goals Treatment goal:  seizures to an extent that allows patient to live a normal life * Balance seizure control vs. acceptability of undesired side effects Non-drug treatment options: –Neurosurgery (best success rate) –Vagal nerve stimulation –Ketogenic diet Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

9. 9 Therapeutic Goals, cont’d Diagnosis and drug selection –Most AEDs selective for specific seizure disorders –Must accurately diagnose seizure & then then treat with AED that treats that type of seizure * May have to try several AEDs before an effective regimen can be established Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

10. 10 Therapeutic Goals, cont’d Drug evaluation –Trial period –Need to determine effectiveness –Frequent dosage adjustment may be needed Patient teaching Monitoring plasma drug levels –Traditional AEDs vs. newer AEDs –Helpful in major convulsive disorders –Less helpful for absence seizures Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

11. 11 Therapeutic Considerations Promoting patient adherence *Seizure control dependent on patient compliance Withdrawing antiepileptic drugs –Spontaneous remission –Withdraw slowly over a period of 6 weeks to several months Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

12. 12 Classifications of Antiepileptic Drugs Two major categories: Both equally effective – neither group superior Traditional antiepileptic drugs (AEDs) –phenytoin –carbamazepine –valproic acid –and others Newer AEDs –oxcarbazepine –Lamotrigine –Levetiracetam –and others Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

13. 13 Phenytoin [Dilantin] Especially effective against partial and tonic-clonic seizures Mechanism of action: selective inhibition of sodium channels Varied oral absorption Half-life: 8 to 60 hours Dosage is highly individualized Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

14. 14 Figure 24-1A Relationship between dose and plasma level for phenytoin compared with most other drugs. Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

15. 15 Figure 24-1B Relationship between dose and plasma level for phenytoin compared with most other drugs. Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

16. 16 Phenytoin (cont’d) Adverse effects –Nystagmus –Sedation –Ataxia –Diplopia –Cognitive impairment –Gingival hyperplasia –Skin rash ** Teratogenic in animals & humans Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

17. 17Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc. Gingival hyperplasia Phenytoin (cont’d)

18. 18 Phenytoin (cont’d) Drug interactions –Decreases the effects of oral contraceptives, warfarin, and glucocorticoids –Increases levels of diazepam, isoniazid, cimetidine, alcohol, valproic acid Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

19. 19 Carbamazepine [Tegretol] Uses: –Epilepsy –Bipolar disorder –Trigeminal and glossopharyngeal neuralgias Mechanism of action Adverse effects –Neurologic effects: nystagmus, ataxia –Hematologic effects: leukopenia, anemia, thrombocytopenia –Dermatologic effects: rash, photosensitivity reactions Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

20. 20 Valproic Acid [Depakene, Depakote, Depacon] Uses –Seizure disorders –Bipolar disorder –Migraine MOA Adverse effects –GI effects –Hepatotoxicity: liver failure –Pancreatitis Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

21. 21 Phenobarbital One of our oldest AEDs Effective, inexpensive, can be admin once daily MOA – potentiates GABA Uses –Epilepsy (partial and generalized tonic-clonic seizures) –Promotes sleep and sedation Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

22. 22 Newer AEDs First line treatment Are equally effective Are better tolerated Less drug interactions –Oxcarbazepine (Trileptal) –Gabapentin (Neurontin) –Levetiracetam (Keppra) –Pregabalin (Lyrica) Initially approved as adjunctive therapy but now some agents approved for monotherapy Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

23. 23 Lamotrigine (Lamictal) Phenyltriazine class of drugs MOA: Unknown; suspect effects on sodium channels Dose: 25 mg – 200 mg PK: Rapidly absorbed orally Peak plasma level 1.4 - 4.8 hours Overdose: No antidote, supportive care Drug Interactions: OC’s and other AED’s Adverse Effects: mood changes, anxiety, dizziness, drowsiness, blurred vision Life threatening: Steven’s Johnson syndrome esp in children and at high doses Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

24. 24 Alzheimer’s Disease

25. 25 Alzheimer’s Disease Pathophysiology Degeneration of neurons –Role of hippocampus → Important role in memory –Role of cerebral cortex → Speech, perception, reasoning, higher functioning Reduced cholinergic transmission –In advanced disease, levels of ACh are 90% below normal Beta-amyloid and neuritic plaques –Form outside of neurons esp. hippocampus and cortex causing neuronal injury

26. 26 Alzheimer’s Disease Pathophysiology Neurofibrillary Tangles and Tau –Tangles inside the neurons form along with plaques outside the neuron Apolipoprotein E4 (apoE4) –Genetically inherited, 1 or 2 copies ↑ risk Endoplasmic reticulum-associated binding protein Homocysteine –Elevated levels ↑ risk

27. 27 Figure 22-1A Healthy Neuron

28. 28 Figure 22-1B Histologic changes in Alzheimer's disease.

29. 29 Alzheimer’s Disease Symptoms Memory loss Confusion Disoriented Impaired judgment Personality changes Difficulty with self-care Behavior problems –wandering, pacing, agitation, screaming Inability to recognize family members Inability to communicate

30. 30 Alzheimer’s Disease: First Approved Drugs Cholinesterase Inhibitors −Prevent breakdown of ACh by AChE with resulting enhanced transmission Do not cure AD and do not stop progression but they may slow progression For use in pts with mild to moderate symptoms May improve quality of life (QOL) & cognitive function for some patients but no evidence of marked improvement or delay of disease progression

31. 31 Alzheimer’s Disease: Cholinesterase Inhibitors Donepezil (Aricept) –Daily dosing: Oral –Metabolized P450 pathway Rivastigmine (Exelon) –BID dosing-oral also patch –Metabolized by cholinesterase Galantamine (Razadyne) –Daily ER or BID –Metabolized P450 pathway

32. 32 Alzheimer’s Disease: NMDA Antagonist NMDA receptor antagonists (N-methyl-D-aspartate) MOA: Modulates glutamate at NMDA receptors promoting calcium influx, thereby increasing signaling NMDA receptors believed to play a critical role in learning and memory Memantine (Namenda) –Indicated for moderate to severe AD –Half life 60-80 hours –Dizziness, Headache, Confusion –Dose 5 - 21 mg depending on formulation

33. 33 Figure 22-2 Memantine mechanism of action.

34. 34 Questions? Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.