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GERIATRIC THERAPY Marian G. Suarez, M.D. Diplomate, American Board of Internal Medicine and Geriatrics The Pharmacology of Aging The world population is aging. Data from US Bureau of Census showing some projected population growth number. World Demographics (US Bureau of Census, International Database, 1996)Merck Manual,Geriatrics,1999 1. Growth of 65+ increase dramatically 1996-2025 % of ≥60 years old expected to increase from 17% to 82% in Europe (about 200% in developing countries) 2. China and India Has the largest total population Will have the largest absolute numbers of elderly World Demographics (US Bureau of Census, International database, 1996) Merck Manual,Geriatrics,1999 3. 2020: Expected to have >1 billion persons ≥60 yrs old 4. 85 yrs old and over: “Oldest old” will increase to 18 million by 2050 5. Centenarians will increase from 57,000 persons (1996) to 447,000 (2040) Epidemiology of Medication Use in the Elderly 1. 2. 65 + comprise 13% US population consume 30% of all prescription drugs consume 40% of all non-prescription drugs 2004: Health care cost for >65 + ~50% of National Health Care Bill (substantial portion spent on medications) Epidemiology of Medication Use in the Elderly 3. On average-older adult uses 2-4 different prescription drugs at the same time 4. Community dwellers (65-84) – 61% >3 drugs/year 37% receive ≥ 5 19% receive >7 5. Elderly NH patient- receive 6-8 meds daily 33%- 9-14 drugs daily Epidemiology of Medication Use in the Elderly 6. Women more likely than men use prescription medication 7. Several studies show at least 90% of elderly use 1 + over the counter drugs (OTC) 8. Most common OTC drugs: Analgesics,Vitamins,Nutritio nal supplements,Laxatives, Antacids,Antihistamines Epidemiology of Medication Use in the Elderly 9. Polypharmacy associated with increase incidence of adverse drug reactions (ADRs) 10. ADR responsible for 10-17% of hospital admissions of elderly outpatients (other studies: ADR→35% of all hospital admission in the high risk elderly ≥ 5 drugs daily Major Responsibility of the Pharmacist Prevention Rapid identification And resolution of drug-related problems Categories of Drug-Related Problems 1. Untreated medical problem (patient with medication problem require prescription drug but does not receive the drug) 2. Improper drug selection (taking the wrong drug) 3. Underdosage (too little of correct drug) 4. Failure to receive drug Categories of Drug-Related Problems 5. Overdosage 6. Adverse Drug Reaction 7. Drug Interaction (drugdrug ;drug-food; drug-disease interaction) 8. Drug use with no indication WHO Definition of ADR (Adverse Drug Interaction) Noxious, unintended & undesired effect of a drug, which occurs at doses used in humans for prophylaxis, diagnosis or therapy Excludes: o therapeutic failures o intentional/ accidental overdoses o drug abuse o “adverse events” due to error in drug administration or noncompliance History of ADR 1960-1970’s – data suggested age as a risk factor for development of ADR 1980 – spontaneous ADR reports to FDA indicating rate of ADR in 65+ y/o, nearly double of younger individuals (problem of inappropriate Rx to older individuals was acknowledged & publicized by medical & advocacy groups for this elderly History of ADR 1980-1990 – gov’t regulatory & legislative occurred to improve policy making; and to decrease ADR in geriatric patients 1987 – Omnibus Budget Reconciliation Act (OBRA) established regulations for use of sedative-hypnotics & antipsychotics in Medicare-certified NH History of ADR (continued…) 1990 – OBRA required all states to conduct DUR (Daily Utilization Reviews) of Medicaid Rx drug claims 1995 – Report on “Prescription Drugs and the Elderly” concluded inappropriate use of Rx drugs = significant health problems in the elderly 2001 – FDA released a guidance for industry to submit revised labeling for drugs already in the market Prescribers, Dispensers and Monitors of medication must understand age-related changes affecting the dispositon of drugs. Age-Related Changes in Pharmacokinetics Pharmacokinetics study of the absorption, distribution, metabolism, and excretion of drug “what the body does to the drug” Pharmacodynamics “what the drug does to the body” Drug Administration (route: oral, intravenous, intravascular, inhalational, intranasal, topical) Absorption Bioavailability (ie. Fraction of drug availablevariable) Metabolism (liver, kidney, others) Distribution Depot drug: Lipid Water Circulating drug: Protein-bound Free Excretion Drug Effect Renal (glomerular filtration, tubular secretion) Benefit (efficacy) Adverse Effect (side effect or toxicity) Hepatic Other (skin, lung, gastrointestinal) Schematic Representation of Drug Pathway Pharmacokinetic Principles in the Elderly 1. Drug Absorption Age-related physiologic changes can include: Decreased acid production Decreased absorptive surface (mucosal atrophy) Decreased splanchnic perfusion Decreased GI motility Generally no significant age-related ABSORPTION for most drugs BIOAVAILABILITY BIOAVAILABILITY – refers to the fraction of an administered drug that reaches the circulation - variable IV med – 100% Oral drug usually later Pharmacokinetic Principles in the Elderly 2. Drug distribution Age-related physiologic changes include: Decreased total body water- water-soluble drugs (lithium, digoxin, aminoglycosides: lower maintenance dose to avoid ADR) Decreased lean body mass Decreased serum albumin (binds acid i,e.warfarin, phenytoin) Pharmacokinetic Principles in the Elderly Increased a1- acid glycoprotein (AAG)- binds basic drugs (lidocaine, propranolol) Protein-bound [inactive drug] Free drug [active drug] ie. Warfarin 99% protein-bound, has increased anticoagulant activity & toxicity in patients w/ decreased albumin levels • Increased total body fat Lipid-soluble drugs (eg benzodiazepines) increase volume of distribution in elderly; remain in fat depots for prolonged period exerting their effect long after drug has been withdrawn Pharmacokinetic Principles in the Elderly Drug Metabolism Age-related physiologic changes include: Decreased hepatic mass Decreased hepatic blood flow (40%) Age-related decrease in liver blood flow directly influence the rate of drug extraction from the blood Pharmacokinetic Principles in the Elderly Drugs are metabolized in the liver by Phase I or Phase II metabolism Phase I metabolism (e.g. oxidation, reduction, hydrolysis) declines in the elderly due to decreased hepatic blood flow ( to nearly half by 85y/o) – Diazepam/ Flurazepam w/ prolonged duration of activity Phase II metabolism- primarily conjugation (e.g. glucoronidation, sulfation) less affected by aging Pharmacokinetic Principles in the Elderly Cytochrome P450 (CYP) system- family of enzymes involved in oxidative metabolism Comprises 3 major groups: CYP1 CYP 2 CYP 3A – accounts for metabolism of ~ 50% of drugs CYP minimally altered by age alone Many drugs/ other substances alter effects of CYP enzymes Multiple drugs may induce or inhibit CYP450 enzymes Common Inhibitors & Inducers of CP 450 Enzymes Inhibitors Cimetidine Ciprofloxacin Diltiazem Erythromycin Fluconazole Grapefruit juice Haloperidol Theophylline Verapamil Inducers Carbamazepine Charbroiled meat Morphine Omeprazole Phenobarbital Phenytoin Prednisone Rifampicin Tobacco smoking Pharmacokinetic Principles in the Elderly Drug excretion Age-related physiologic changes include: Decreased renal blood flow ( creatinine clearance) Decreased GFR (~ 50% bet. ages 2090) – “unbound drugs” Decreased tubular secretion (protein bound drugs) Pharmacokinetic Principles in the Elderly Drugs potentially toxic in the elderly due to predominant renal elimination: Aminoglycosides, amantadine, lithium, digoxin, procainamide, cimetidine, NSAIDS Pharmacokinetic Principles in the Elderly Glomerular Filtration Rate (GFR) is approximated by calculating creatinine clearance. The formula, Cockroft & Gault Equation, is used to adjust drug dosage: Creatinine clearance= 140-age x wt (kg) 72 x serum creatinine In females, the result is multiplied by 0.85 Age-related Changes in Pharmacodynamics “what drug does to the body”- may be due to changes in: Drug receptors- blunted homeostatic mechanism predisposes to respiratory depression, sedation & constipation Drug-receptor interactionless active baroreceptor reflexes predispose elderly on antihypertensives to postural hypotension Altered adaptive homeostatic responses or organopathology- impaired thermoregulatory response to cooling predispose them on barbiturates or phenothiazines in hypothermia Primary Approaches to Determine Appropriateness of medication Prescribing in the Elderly Drug Lists- most familiar “BEERS CRITERIA” Published 1991- identified inappropriate meds use in NH residents (19 meds to be avoided, 11 criteria re: doses, frequencies, duration of med Rx that should not be exceeded in frail NH residents) Updated 1997- to apply to older people in all care settings (28 medications to be avoided, doses & frequencies of administration not to be exceeded & 35 meds to be avoided in elderly known to have any of several common conditions (drugdisease criteria) Drug Utilization Review (DUR) Evaluation of drug use in a given health environment against predetermined criteria to assess appropriateness of drug therapy Implicit Method Focus on appropriateness of a patients’ entire medication regimen rather than on a single drug or drug class & combines medical history and the clinician’s judgment & knowledge 6 Domains to Measure Inappropriate Prescribing 1. 2. 3. 4. 5. 6. Lack of indication Improper schedule Inadequate dosage Potential drug interaction Therapeutic duplication Allergy Suboptimal Prescribing 1. Overuse or Polypharmacy Prescribing w/o proper indication According to patient expectation for a prescription Polypharmacy can lead to ADRs Contributes to development of several “geriatric syndromes” ie. cognitive impairment, delirium, falls, urinary incontinence & increases health care costs 2. Inappropriate Use Rx of a med w/ more potential risk than benefit Rx that does not agree w/ accepted medicine standards Improper drug selection Appropriate drug but wrong dose (too low/too high) Suboptimal Prescribing 3. Underutilization Omission of a drug indicated for Rx or prevention of a disease condition Underprescribing [ie. Use of warfarin for atrial fibrillation; Rx of cancer pain] Appropriate Rx for the Elderly 1. Dosage determination “start slow & go slow” 2. Compliance Unintentional noncompliancedue to forgetfulness, confusion, decreased vision Intentional noncompliance- due to side effects; financial barriers 3. Role of Pharmacist Provide services in DUR Improve compliance Simplify drug regimens Increase patient education General Principles for Improved Geriatric Prescribing 1. Obtain thorough history of a drug use from all physicians & sources 2. Evaluate the need for drug therapy 3. Periodically review medication regimen/ avoid polypharmacy 4. Know pharmacology of drug(s) prescribed 5. Check renal function & adjust drug doses accordingly 6. Simplify drug regimen/ help ensure compliance 7. Develop awareness of the COST of medications 1997 Beers criteria Table 1. Potentially Inappropriate Medications for Use in the Elderly Propoxyphene Indomethacin Phenybutazone Pentazocine Trimethobenzamine Methocarbamol, cansoprodol, Oxybutynin, chloroxazone, metaxalone, cyclobenzapine Amitriptyline, chlordiazepoxide- amytriptyline, perphenazineamitriptyline Doxepin Flurazepam Meprobamate Lorazepam, 3mg; oxazepam, 60mg; alprazolam, 2mg; temazepam, 15mg; zolpidem, 5mg; traizolam, 0.25mg Disopyramide Methyldopa; methyldopa + HCTZ Reserpine Dicyclomine; hyoscyamine; propantheline Reserpine; reserpine + HCTZ Chlorpheniramine, diphenhydramine, Hydroxyzine, cyproheptadine, promethazine Ergot mesylate Iron supplements > 325mg All barbiturates except phenobarbital Meperidine Ticlopidine Comparisons of Initial Doses Recommended in FDA- approved Product labeling versusLower Effective Doses Reported in the Medical Literature Drug Recommended Initial Dose (mg) Effective Lower Dose (mg) 400 200 50-75 10-25 Amlodipine besylate 5 2.5 Atenolol 50 25 Atorvastatin Ca 10 2.5 & 5 Bisoprolol fumarate 5 2.5 Bupropion HCl 100 BID 50 BID Celecoxib 100 BID 50 BID Cerivastatin Na 0.4 0.2 or 0.3 Chlorthalidone 15 12.5 Cimetidine HCl 800 HS 400 HS 0.625 0.3 50 BID-QID 25 TID Doxepin HCl 75 10, 25 or 50 Ethacrynic acid 50 25 20 BID or 40 QD or BID 10 BID or 20 QD Acebutolol HCl Amitriptyline Estrogens, conjugated Diclofenac Na Famotidine Comparisons of Initial Doses Recommended in FDA- approved Product labeling versusLower Effective Doses Reported in the Medical Literature Drug Recommended Initial Dose (mg) Effective Lower Dose (mg) 5 2.5 60 BID 20 TID or 40 BID Fluoxetine HCl 20 2.5, 5 or 10 Flurazepam HCl 30 QHS 15 QHS Furosemide 80 40 Hydrochlorothiazide 25 12.5 400 TID-QID 200 TID Imipramine HCl 75 10-25 Lisinopril 10 5 Losartan potassium 50 25 Lovastatin 20 10 Metorpolol tartrate 50-100 50 Misoprostol 200ug 50 or 100ug QID 100 BID 50 QD or BID 150 BID or 300 HS 25 BID or 100 HS 50-75 10 or 25 Felodipine Fexofenadine HCl Ibuprofen Nefazodone HCl Nizatidine Nortriptyline HCl Comparisons of Initial Doses Recommended in FDA- approved Product labeling versusLower Effective Doses Reported in the Medical Literature Drug Recommended Initial Dose (mg) Effective Lower Dose (mg) 20 10 Ondansetron HCl 8 BID 1-4 TID Penbutolol sulfate 20 10 Pravastatin Na 10-20 5-10 Propranolol HCl 80 40 Ramipril 2.5 1.25 Ranitidine HCl 150 BID or 300 HS 100 BID Sertraline HCl 50 25 once daily Simvastatin 10-20 2.5, 5 or 10 Spironolactone 50-100 25 Torsemide 10 5 Trazodone HCl 150 25-100 100 BID 25-100 QD 75 37.5 or 50 (in divided doses) 120-180 90 10mg vs 5mg 7.5 HS Omeprazole Triamterene Venlafaxine HCl Verapamil HCl Zolpidem tartrate