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Prescribing in the Elderly Karen Birmingham, PharmD, BCPS Specialty Clinical Pharmacy Services Group Health Objectives Review pharmacokinetic changes due to aging. Summarize effects of illness on drug action. Present assessment tools and discuss high risk drug classes. List some major drug-drug and drug-herbal interactions. Identify actions to help prevent adverse drug events in the elderly. “Quote”worthy Definitions Aging Elderly “Progressive accumulation of random changes” “Age nearing or surpassing the average life span” “Time-related loss of functional units” “Age 65 years and older” “Better than the alternative” “Always 15 years older than me” A Global “Gray Tsunami” By 2006: By 2030: Almost 500 million people worldwide ≥ 65 years old Total world population over 9 billion Elderly in developing countries ↑ by 140% World population ≥ 65 years old ~ 1 billion By 2050: 20% of all elderly patients will be ≥ 80 years old U.S. Elderly Constitute 13% of the population Consume 34% of all prescription medications Use 40% of all over-the-counter drugs Up to 50% of elderly take multiple medications Medicare population analysis in 1999 (n=1.2 million) 82% had at least one chronic condition 24% had at least four chronic conditions Prescription Drug Use by Elderly % www.cdc.gov Prescription $ Per Chronic Condition $ www.cdc.gov Drugs Most Used by Elderly Patients Clinical Pharmacology and Therapeutics 2007 ADE, ADR and ME Annals of Internal Medicine 2004 Adverse Drug Events Occur in 20% of elderly patients Account for 5-10% of hospitalizations Prevalence of 5-37% in hospitalized patients Nearly 20% ranked as severe Fatal outcomes in 6% of cases Repeat hospitalizations in 30% of ADEs Interventions required in ~30% of patients Affect ~ 350,000 long-term care patients annually Adverse Drug Events and Death “If medication-related problems were ranked as a disease by cause of death, it would be the 5th leading cause of death in the United States.” Archives of Internal Medicine 2003 Risk Factors For Adverse Drug Events Inappropriate prescribing Polypharmacy Misuse of OTC products Lack of appropriate drug monitoring Complicated dosing instructions Language or educational barriers Nonadherence How a Drug Does What It Does The Pharmacologic Basis of Therapeutics, 11th ed. Changes Due to Aging ↓ lean body mass ↓ total body water ↓ volume of distribution of water-soluble drugs ↑ body fat ↑ volume of distribution of lipophilic drugs ↑ half-life ↑ time to steady-state concentration ↑ gastric pH ↓ absorption surface ↓ GI mobility Altered drug absorption cognitive changes ↑ sensitivity to anticholinergics Altered HPA axis ↓ hepatic circulation ↓ hepatic mass ↓ first-pass metabolism ↓ activation of prodrug ↑ bioavailability ↓ glomerular filtration rate ↓ renal circulation ↓ renal clearance Adapted from Journal of the American College of Cardiology 2010 Cytochrome P450 Enzyme System • Fifty human CYP450 genes • Estimated 8-10 isoforms responsible for drug metabolism • Large range of activity in healthy humans (6-fold difference in rates) • Weight-adjusted CYP3A clearance more rapid in women • Currently no predictive data for effects of age on CYP2C • Faster clearance of CYP2D6 in men; decrease doses of drugs ~10-20% for women, decrease ~20% more in elderly women • Renal impairment may affect CYP P450 due to decreased gene expression The Pharmacological Basis of Therapeutics 1996 Drug Metabolism and Aging Adapted from Bressler and Bahl, Mayo Clinic Proceedings 2003 P-Glycoprotein and Drug Disposition Efflux transporter Found in hepatocytes, intestinal mucosal cells, and blood-brain barrier Conflicting results from small studies: Animal studies suggest differences between male and female, not yet observed in humans One study showed no significant difference in leukocyte P-glycoprotein in comparisons of young healthy adults vs. elderly healthy and frail adults Another study suggested decreased blood-brain barrier P-glycoprotein activity, possibly exposing brain to higher levels of drugs Age Effects on Hemostasis Coagulation Proteins ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ Factor V Factor VII Factor VIII Factor IX Factor XIII Fibrinogen kininogen prekallikrein Fibrinolytic Proteins ↑ D-dimer ↑ PAI-1 ↓ plasmin Anticoagulant Proteins Antithrombin III Protein C Protein S TFPI M ↓ ↔ ↔ ↓ Adapted from Journal of the American College of Cardiology 2010 F ↓ ↑ ↑ ↑ Pharmacodynamics in the Elderly Drug Name Drug Action diltiazem antihypertensive PR interval prolongation furosemide diuretic scopolamine cognitive function morphine analgesia diazepam sedation verapamil antihypertensive warfarin anticoagulant Drug Effect Adapted from British Journal of Pharmacology 2004 Effect of Illness on Drug Actions absorption gastrointestinal pH gastrointestinal motility gastric contents serum albumin distribution changes in binding sites increased endogenous inhibitors renal impairment metabolism hepatic impairment drug interactions excretion receptor interaction renal impairment gastrointestinal motility changes in number changes in sensitivity altered target site = Drug Response 1) Altered: -metabolism -cell environment -concentrations 2) Tolerance 3) Resistance 4) Interactions Congestive Heart Failure Effects Parameter bioavailability distribution metabolism Alteration bowel edema reduces drug absorption of oral drugs first pass metabolism altered by hepatic congestion peripheral edema decreases absorption of topical/subcutaneous/intramuscular agents unpredictable due to changes in total body water and tissue perfusion reduced liver perfusion alters drug metabolism impaired renal function may inhibit drug elimination excretion pharmacodynamic increased risk of radiocontrast nephropathy increased sensitivity to antiarrhythmic medication Adapted from Clinics in Chest Medicine 2003 High Risk Drugs Assessment Tools Year Country 1991 1997 2000 2007 2008 USA Canada Canada France Ireland 2008 2009 2010 Japan Norway Italy Tool Beers (updated in 1997 and 2003) Canadian Criteria IPET - Improving Prescribing in Elderly Tool French Consensus Panel List STOPP – Screening Tool of Older Persons’ Prescriptions START – Screening Tool to Alert to Right Treatment Japanese Beers Criteria NORGEP – Norwegian General practice Unnamed Adapted from Annals of Pharmacotherapy 2010 Medication Appropriateness Index Criterion Drug-drug interactions? Standard Weight Modified Weight 2 2 2 3 2 1 3 1 1 1 1 2 1 0 Practical directions? 2 1 0 0 Cost effective compared with other drugs of equal efficacy? 1 0 Drug-disease interactions? Is the drug indicated? Is the drug effective? Unnecessary drug duplication? Appropriate therapy duration? Correct dosage? Correct directions? Adapted from Annals of Pharmacotherapy 2010 Anticholinergic Risk Scale 3 points 2 points 1 point amitriptyline amantadine carbidopa-levodopa atropine baclofen entacapone carisoprodol cetirizine haloperidol chlorpheniramine cimetidine methocarbamol chlorpromazine clozapine metoclopramide cyproheptadine cyclobenzaprine mirtazapine dicyclomine desipramine paroxetine diphenhydramine loperamide pramipexole hydroxyzine loratadine quetiapine imipramine nortriptyline ranitidine promethazine olanzapine risperidone meclizine prochlorperazine selegiline promethazine tolterodine trazodone Adapted from Archives of Internal Medicine 2008 Drug Burden Index (DBI) Total drug burden = BAC +BS DBI: E = __D__ + D ↑ DBI = ↓ physical performance and cognition Equations from Archives of Internal Medicine 2007 The Big Issues Cognition, sedation, falls GI toxicity Cardiopulmonary effects Bleeding/clotting Renal impairment Liver toxicity High Risk For Falls Anticholinergics scopolamine atropine belladonna pentobarbital hyoscyamine phenobarbital secobarbital propantheline dicyclomine Muscle Relaxants carisoprodol methocarbamol cyclobenzaprine chlorzoxazone meprobamate metaxalone Tricyclic Antidepressants amoxapine amitriptyline Antihistamines diphenhydramine, hydroxyzine, cyproheptadine Antiemetics promethazine, trimethobenzamide Benzodiazepines diazepam, flurazepam, triazolam, chlordiazepoxide Narcotics meperidine, propoxyphene doxepin imipramine protriptyline clomipramine Recommendations for Screening Perform fall risk screening on all elderly patients, including: History of falls or problems with gait/balance Complete medication review, including prescriptions, over-the-counter drugs, herbal products, nutritional supplements, etc. Chronic condition risk factors, e.g. osteoporosis, cardiovascular disease, visual impairment, etc. Assessment of vitamin D deficiency Relative GI Toxicity of NSAIDs Nabumetone Etodolac Salsalate Sulindac Diclofenac Ibuprofen Ketoprofen Aspirin Naproxen Flurbiprofen Piroxicam Fenoprofen Indomethacin Meclofenamate Least Most Adapted from Carman, EBRx Newsletter 2009 Other Adverse Effects of NSAIDs Renal GI salt/H20 retention abdominal pain edema anorexia hyperkalemia gastric erosions ↓ antihypertensive effects hemorrhage ↓ diuretic effects anemia ↓ urate excretion perforation diarrhea Coagulation inhibit platelet activation hemorrhage bruising ADEs After Start of Pain Prescriptions Adapted from Solomon, Archives of Internal Medicine 2010 Acetaminophen Present in multiple OTC products and prescription pain medications Maximum daily dose often exceeded in community and in hospitals Increasing reports of severe hepatotoxicity Higher risk in patients who abuse alcohol and/or exceed dose recommendations By 2014, all acetaminophen prescription products must have no more than 325 mg acetaminophen per dosage unit New dose limit set by FDA in January 2011 Risk of Respiratory Depression + morphine hydromorphone meperidine hydrocodone fentanyl GI Drugs promethazine cimetidine promethazine aprepitant macrolides azole antifungals protease inhibitors antimicrobials psychotropics benzodiazepines tricyclic antidepressants MAOIs benzodiazepines tricyclic antidepressants MAOIs analgesics skeletal muscle relaxants skeletal muscle relaxants antihistamines diphenhydramine hydroxyzine diphenhydramine hydroxyzine High Risk Drugs in Illness Condition Medications Effect Seizures clozapine, bupropion, chlorpromazine lowered seizure threshold Clotting Disorders aspirin, NSAIDS, ticlopidine, dipyridamole, clopidogrel, prolonged clotting time, inhibited platelet aggregation Parkinsonism metoclopramide, antipsychotics antidopaminergic and cholinergic effects Arrhythmias tricyclic antidepressants proarrhythmic effects and QT interval changes Obesity olanzapine weight gain COPD sedatives/hypnotics respiratory depression Benign prostatic hypertrophy anticholinergics, narcotics, muscle relaxants urinary hesitancy High Risk For Cardiovascular Disease sodium polystyrene sulfate piperacillin, ticarcillin ranitidine fluid retention heart failure exacerbation Stimulants amphetamines diethylpropion methylphenidate phentermine ↑ blood pressure CV Drugs short-acting nifedipine short-acting dipyridamole disopyramide rapid ↓ in blood pressure ↑ risk of syncope, stroke ↑ risk of heart failure Oral Estrogens conjugated estrogen esterified estrogenmethyltestosterone estropipate ↑ risk of stroke High Sodium Drugs Drug Interactions Drug interactions and polypharmacy Hospitalizations within one week of interactions Two drugs = DDI occurrence in ~ 13% of patients Six drugs = DDI occurrence in ~ 80% of patients Glyburide + cotrimoxazole= 35/909 patients Digoxin + clarithromycin = 27/1051 patients ACE inhibitors + diuretics = 43/523 patients Concomitant alcohol use by 20% of elderly Many patients report use of nutritional or herbal supplements. Watch Out For These Interactions Watch Out For These Interactions Drug Interactions With Herbals gingko ginseng garlic ginger antithrombotic X X X X ACEI/ARB X Ca++ blockers X X -blockers X X statins X X amiodarone X digoxin warfarin X St. John’s wort X X X X X X X X X X X X X X X X echinacea X X X X X X ADEs: Drug Shortages and Recalls Pre-diluted methotrexate was unavailable; a vial of dry powder was reconstituted incorrectly and the patient received less than the prescribed dose Wrong dose of morphine administered after 4 mg/mL prefilled syringes were replaced with 5 mg/mL vials Cancellations of surgeries and procedures Chemotherapy treatments delayed in a patient with a high potential for remission while attempting to find a source of the needed drug Unintended intraoperative awareness occurred when a patient was given too little propofol based on weight in an attempt to conserve supplies Shortage of IV sulfamethoxazole/ trimethoprim) led to refractory cases of pneumocystis pneumonia from alternative treatment with clindamycin and primaquine Prevention of ADEs Frequent medication review and reconciliation Evaluation of indications, benefits, side effects Review of preprinted orders or prescription pads Ensure medication literacy Pharmacologic “debridement” Utilization of online drug evaluation tools Routine pharmacist consultation “We've put more effort into helping folks reach old age than into helping them enjoy it.” ~Frank A. Clark