Slide 1 Antiseizure Drugs in Elderly Patients Angela Birnbaum, Ph.D. Professor Epilepsy Research and Education Program Center for Clinical and Cognitive Neuropharmacology College of Pharmacy University of Minnesota Slide 2 Objectives 1) Discuss epilepsy in elderly patients 2) Discuss how pharmacokinetics change in the elderly 3) Learn about antiseizure drugs 4) Medication management Slide 3 Why should we care about the elderly?
Incidence per 100,000 1950 1960 1970 1980 1990 2000 2010 2020 2030 2040 2050 Percentage Slide 4 Growth of the Elderly in the U.S. population 25 20 % 65-84 % 85 + 15 10 5 0 Year From: Taeuber, Bureau of the Census Slide 5 Age-Specific Incidence of Epilepsy by Gender in Rochester, Minnesota 1935-1984 200 150 100 Males Females Total 50 0 0 5 10 15 20 30 40 50 60 70 80 Annegers JF, et al. Epilepsia. 1995;36:327-33. Hauser WA, et al. Epilepsia. 1993;34:453-68. Age (years) [5] Slide 6 Etiology of Epilepsy, Age 65+ 12% 5% 2% 2% 51% Cryptogenic 51% Stroke 38% Degenerative 12% Tumor 5% 38% Trauma 2% Infection 2% Hauser WA, et al. Epilepsia. 1993;34:453-68.
Health Status Slide 7 Incidence of Epilepsy/Seizure Cases in US Nursing Homes For incidence in US nursing homes - All residents of any US Medicare/Medicaid certified NH - From 2003-2007 - Excluded those with epilepsy on admission - Excluded those with less than 3 years of MDS Among 3,613,926 residents followed forward - 1,640 new-onset epi/sz cases/100,000 patient-years - 12 times higher than in the community dwelling elderly - Approximately 20 times the rate in young adults Leppik, Eberly, Harms, Birnbaum, Journal of the American Medical Directors Association, vol 12(3), 2011 Slide 8 Health Status of Elderly Patients Not all elderly patients are alike Age Young healthy Young Medical problems Young frail Middle healthy Middle Medical Problems Middle frail Old healthy Old Medical problems Old frail Slide 9 Characteristics of Elderly Groups Elderly not homogenous Community dwelling elderly similar to young Frail population Nursing home High number of co-medications High number of ASD (~10%) High number of co-morbidities Very limited drug concentration data available
Slide 10 Considerations in Geriatric Epilepsy Management Aging Process Underlying Pathology Management Seizure Frequency Comorbidities Medication Side Effects Pharmacokinetics Slide 11 Pharmacotherapy in the Elderly Slide 12 Goals of Epilepsy Care Eliminate seizures with no side effects; alternatively Reduce the number Decrease the severity Minimize side effects Optimize quality of life Excitation Glutamate Aspartate Normal CNS Function Inhibition GABA
Slide 13 Chronology of ASD Development 1st generation ASDs 2 nd generation ASDs Year Drug Year Drug 1912 Phenobarbital 1993 Felbamate 1938 Phenytoin 1994 Gabapentin 1947 Mephenytoin (no longer available) 1994 Lamotrigine 1954 Primidone 1996 Topiramate 1960 Ethosuximide 1997 Tiagabine 1968 Diazepam 1999 Oxcarbazepine 1974 Carbamazepine 1999 Levetiracetam 1975 Clonazepam 2000 Zonisamide 2005 Pregabalin 1978 Valproate 2009 Rufinamide 2009 Vigabatrin 2011 Clobazam 3 rd generation ASDs Year Drug 2009 Lacosamide 2011 Ezogabine 2012 Perampanel 2013 Eslicarbazepine Slide 14 Indications for ASDs Epilepsy Headache Psychiatric disorders Neuropathic pain Behavior Weight loss Movement disorders Spasticity Slide 15 Medication Selection Seizure type Co-medications Medical conditions Age of the patient Insurance coverage Allergies Adherence challenges
Slide 16 New onset seizures Seizure Type Partial Onset Generalized Absence First Line Therapy Carbamazepine Gabapentin Lamotrigine Oxcarbazepine Phenobarbital Phenytoin Topiramate Valproic Acid Lamotrigine Topiramate Valproic Acid Lamotrigine Ethosuximide Valproic Acid Slide 17 What is an Adverse Drug Reaction? Definition: An unexpected or dangerous reaction to a drug or an unwanted effect caused by the administration of a drug Adverse Event and Side Effect You may not experience an adverse event Usually happens within the first month No absolutely safe drug exists Most are minor - diarrhea, headache, etc. Some are serious Slide 18 What is a Medication Interaction? Definition: A measurable modification of the action of one drug by another substance (medication, herbal product, dietary supplement, etc) May cause adverse drug reactions Minor (temporary symptoms) or Serious (life threatening reactions) May occur when starting or stopping a medication Preventable Adverse Drug Reactions: A focus on drug interactions. http://www.fda.gov/cder/drug/drugreactions/default.htm
Slide 19 Herbs: Natural Safe Herbal products are not well regulated Lack of data that they work for what is claimed Lack of data about safety Other active ingredients not identified Amount of active ingredients in each bottle not guaranteed May interact with prescription medications Just because it s natural doesn t mean it s safe - warfarin and St. John s wort Slide 20 Types of Drug Interactions Drug-drug: Valproic acid and lamotrigine Drug-food: Carbamazepine and grapefruit juice Drug-dietary supplement: Calcium and phenytoin Drug-herbal: warfarin and St. John s Wort Drug-disease: medications that lower the seizure threshold and epilepsy Slide 21 Pharmacokinetics in the Elderly
Slide 22 bsorption istribution etabolism limination Absorption Body Metabolism Enzymes Elimination Distribution Tissue Distribution Plasma Protein Binding Slide 23 As we age. Absorption Blood flow to stomach and intestines Acidity Stomach emptying Intestinal motility Distribution Muscle Fat Metabolism Blood flow to liver Size of liver/# hepatocytes Excretion Blood flow to kidneys Size of kidneys Ability to filter As a result drug interactions can change over time There are few studies characterizing ASD pharmacokinetics in the elderly Slide 24 Pharmacokinetic Characteristics Desired PK Antiseisure Characteristics Drugs Multiple formulations Yes Yes & No Birnbaum 2012 Protein binding (>85%) Low Low & High Metabolized by liver No Yes & No Induces/inhibits liver metabolism No Yes & No Renally cleared Yes Yes & No Type of Pharmacokinetics Linear Linear & Nonlinear
Slide 25 Pharmacokinetics: Does it matter? 76 year old woman Referred in 1992 - new onset Seizures Dementia Cerebellar degeneration Arrived in wheelchair Scheduled for nursing home placement Total drug concentration measurements phenytoin total - 19 mg/l (normal 10-20 mg/l) valproate total - 86 mg/l (normal 50-100 mg/l) Slide 26 Pharmacokinetics: Does it matter? Stopped drug Unbound concentrations phenytoin - >2 mg/l (normal 1-2 mg/l) valproate - 22 mg/l (normal 6-15 mg/l) Left hospital walking on own Loved to dance with husband What happened pharmacokinetically? Protein binding - >80% Inhibition of metabolism Slide 27 Co-Medication Use in Elderly Nursing Home Residents on ASDs Drug Category Antidepressants Antipsychotics 19% 12.7% Benzodiazepines 22% Thyroid Supplements Antacids Antiseizure Drugs 14% 8% 12% Maintenance Medication Use by Elderly Nursing Home Residents Calcium Channel Blockers Warfarin Cimetidine 7% 5.9% 2.5% + ASD ASD 6 meds 5 meds 0 5 10 15 20 25 % of Antiseizure Drug Recipients 30 Lackner, Cloyd, Thomas, Leppik, Epilepsia 39:1083-87, 1998
Slide 28 Epilepsy and stroke Number one cause of epilepsy in people older than 50 Side effects of medicine can make the effects of the stroke a little worse Make sure you know about any other medications and if it is safe to mix with any epilepsy medications efmn.org Slide 29 How to Optimize ASD Therapy Titrate dose or serum concentration to response Increase dose until seizure control is attained; or until unacceptable side effects occur Consider adding 2nd ASD if first is not effective Individual ranges May be different than suggested therapeutic range Slide 30 Only the right dose differentiates between a poison and a remedy Paracelsus, 1493-1541
Percent of Residents Slide 31 Antiseizure drugs--best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies When therapeutic response is reached When steady state dosing is reached 5 half lives When new drug added or other drug removed if there is potential for drug interaction Hepatic Absorption Renal elimination Toxicity Therapeutic Drug Monitoring Breakthrough seizure Slide 32 Interpreting ASD concentrations Suggested therapeutic ranges based on younger adults Concentrations will fluctuate due to: - absorption, elimination, time, and laboratory assays For younger adults - older ASDs (PHT, CBZ, VPA) CV 20-25% Elderly - <30%? - nursing home elderly may be more variable Slide 33 Total PHT Concentrations in Nursing Home Residents Beverly Enterprises Nursing Homes - First Collected Blood Draw 35 30 45% 46% 9% 25 20 15 N = 387, 65 years Women = 67% Mean Cp = 11.7 ± 6.4 ug/ml Mean dose = 4.9 ± 1.8 mg/kg 10 5 0 0-<5 5-<10 10-<15 15-<20 20-<25 25-<30 30+ Total PHT Concentration (ug/ml) Birnbaum, Hardie, Conway, Bowers, Lackner, Graves, Leppik, AJGP vol 1(2): 90-95, (Dec 2003)
Total PHT Concentrations (ug/ml) Percent of Residents Slide 34 Valproic Acid Dose in Nursing Home Residents Beverly Enterprises Nursing Homes - First Collected Blood Draw 30.00 25.00 20.00 15.00 10.00 5.00 0.00 Psychiatric Seizure <25 25-49.9 50-74.9 75-99.9 >100 Total VPA Concentration (ug/ml) N = 146 Women = 64% Dose (mg/kg) 65-74 = 19.4 ± 11.4 75-84 = 16.3 ± 12.1 85+ = 11.3 ± 7.6 p =0.003 Cp (ug/ml) 65-74 = 56.4 ± 25.8 75-84 = 47.7 ± 22.6 85+ = 38.7 ± 23.1 p = 0.003 Birnbaum, Hardie, Conway, Bowers, Lackner, Graves, Leppik, Epilepsy Research 62(2-3); 157-162; 2004 Slide 35 Expected Concentration Pattern with Chronic Dosing Too high: Side effects! Too low: Seizures! Time of Dose Time of Dose Time of Dose Slide 36 Individual Total Phenytoin Serum Concentrations in Elderly Nursing Home Residents 35 Aged 65-74 Aged 75-84 Aged 85+ 30 (n=18) (n=21) (n=17) 25 20 15 10 5 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 Individual Elderly Residents Categorized by Age Group at Enrollment Birnbaum, Hardie, Leppik, Conway, Bowers, Lackner, Graves, Neurology, 60:555-559 (2003)
Slide 37 Interpreting Drug Concentrations Variability in total ASD concentrations in some Why? Absorption? Metabolism? Protein binding? Kidney? Do NOT change ASD doses based on ONE level No need to measure total ASD levels? Editorial: Lesser, Neurology 60:534-535; Journal Watch: vol23(7):56 Assess pharmacokinetic possibilities May need to measure unbound ASDs? May need to record adverse events when drawing blood samples? Are there possibly interacting medications? Is a medication being added or removed? Slide 38 Organizing Medications to Minimize Issues Slide 39 Systems for Increasing Medication Adherence Pill boxes Decrease forgotten doses Helps prevent taking extra doses Calendar or check list Timers Medication placement By the kitchen sink By the night stand Pre-packaged by the pharmacy Involving household members
Slide 40 Is it safe to take with other medicine including over-the-counter medicine, vitamins, or herbals? Many medications are involved in a lot of drug interactions If you use the same pharmacy (or chain pharmacy) this can be checked quickly Drug interaction software Does not always include herbal products May take the pharmacist some time to research Slide 41 Avoiding Interactions - Prevention Maintain a list of ALL the drugs and supplements My medicine list Keep it updated Keep lists in wallet or purse Share lists with physicians and pharmacists Include all medications: prescription and over the counter Supplements Herbal supplements See if there are questions before beginning a new product Most drug interactions can either be prevented or managed Slide 42
Slide 43 Overall Pharmacy Tips Use the same pharmacy Drug history in one place Check for drug interactions Get to know the staff Better customer service A few to get by Help with vacation supplies Pharmacists are available when other healthcare providers are not (evenings, weekends) Recommend less expensive alternatives Slide 44 Where to find drug information Your Pharmacist Web sites Product sites www.rxlist.com www.fda.gov Slide 45 Want more assistance? Medication Therapy Management (MTM) Pharmacist reviews medications Makes recommendations Works with your providers Medicare part D benefit Contact your insurance to see if you have the benefit and to find a pharmacist providing services
Slide 46 Conclusions The incidence of epilepsy in the elderly is high Pharmacokinetic issues are probable in the elderly - Physiological changes as we age - Presence of high number of co-medications - Presence of co-morbidities Populations of elderly may have different PK issues - concentrations variable in some nursing home elderly - elderly may be more sensitive to drug = lower doses Optimize dosing administration Identify possible drug issues - interactions