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Pharmacological Considerations in Treating Geriatric Patients April 25, 2007 Kathryn McMahon Learning Objectives After reading this text the participant should be able to: 1. Explain how aging-related decline in organ function impacts pharmacokinetics with specific emphasis on the kidneys, liver, blood volume and skeletal muscle. 2. Describe aging-related concerns for the use of digoxin, warfarin, NSAIDS, sedative/hyponotics, and drugs with anticholinergics effects. 3. Explain how poly-pharmacology impacts on adverse effects in geriatric populations. 4. Describe how the pathologies commonly seen in the geriatric population are expected to alter pharmacological properties and lead to predictable complications. 5. Discuss measures that a physician can take to avoid over-medication of the elderly. I. Introduction A. Definitions 1. Geriatric – 65 y or older. 2. Homeostenosis - the progressive constriction of homeostatic reserve of organs II. “Rules of Thumb” for drug therapy in geriatric and elderly 1. Take a careful drug history. The disease to be treated could be drug-induced. Drugs being taken could lead to predictable adverse effects of the drug(s) to be prescribed. 2. Prescribe only for specific and rational indications. 3. “Start low and go slow.” Define the response goal of all drug therapy. Initiate the therapy with small doses and titrate toward that desired response goal. Wait at least 3 half lives (adjusted for age) before increasing the dose. If “normal” adult dosage does not result in expected response, check blood levels. If expected response does not occur at the appropriate blood level of drug, switch to a different drug. 4. Always be alert for and suspicious for drug reactions and interactions. Check what drugs (prescription, OTC, herbals, recreational) the person is taking. 5. Simplify the drug regime as much as possible. Try to use drugs that can be taken at the same time of day. Reduce the number of drugs taken whenever possible, i.e. “Stop more drugs than you start.” III. Predictions of the Affect of Aging on Pharmacology Differences affecting GI absorption - GI function including gastric acidity, gastric emptying, and GI motility are expected to be decreased. Overall though, GI absorption of most drugs is minimally altered in the absence of pathology of the GI tract. Differences affecting drug distribution Increased fat mass and decreased muscle mass, leading to an increased fat to lean ratio and decreased lean body mass, are predicted in the elderly. These changes predict decreased volumes of distribution of hydrophilic drugs and increased volumes of distribution of lipophilic drugs. Because of homeostenotic decreases of liver function, albumin production is predicted to be decrease in the elderly and, on average, albumin levels are decreased by about 12.5% of the elderly. This predicts that drugs which have a high affinity to albumin, such as warfarin, would have increased free drug concentrations in the blood. Differences affecting drug metabolism - Blood flow to organs is predicted to be decreased. Blood flow to liver is decreased by 40 to 45%. Liver mass is also expected to be decreased. These two predictions suggest that drugs metabolized by the liver would be expected to be less rapidly metabolized in elderly. Within the liver cell itself, metabolism of drugs can also be changed. Unfortunately some drug metabolism is decreased while some is increased in elderly. As a first approximation, one should predict that a drug is metabolized less, and this will potentially lead to higher blood levels and/or more long-lasting effects. Differences affecting drug elimination - Blood flow to the kidneys is predicted to be decreased in the elderly and glomerular filtration rate is also predicted to be decreased. As a general rule the glomerular filtration rate is decreased by 1%/year after age 50. Also remember that blood creatine levels are not accurate estimates of renal function in the elderly because of the loss of muscle mass due to aging-related atrophy. Instead, creatine clearance (CC) should be used for an approximation of renal function. Table I Creatine Clearance Estimates in Adults Age CC (ml/min/m2) 20 y 140 50 y 127 80 y 97 The net result of the cumulative aging-related changes to the kidney is predicted to be decreased elimination of drugs by the kidney. Pharmacodynamic differences - Aging-related changes in target organ response to drugs can be seen but they can be increased or decreased responsiveness that are specific to the drug. This leads to a situation where it is difficult to predict how an elderly individual will respond to a drug. This pharmacodynamic unpredictability in conjunction with the potential alterations in pharmacokinetic properties of a drug leads to the recommendation that drug therapy be started at low dose and titrated on the basis of tolerability and response in the elderly (“start low and go slow”). IV. Responses to co-morbidity & poly-pharmacy (including OTCs) of note in geriatric population Affecting absorption - The most significant of these are due to drugs having anticholinergic effects altering absorption of other drugs. Affecting drug distribution – Many pathologies (i.e. heart failure, dehydration, edema, ascites, renal disease/failure, malnutrition, hepatic cirrhosis & some cancers) and poly-pharmacies affect drug distribution. Affecting metabolism - The liver’s ability to recover from injury decreases with age and so recent history of liver disease should trigger a cautionary note for therapies involving drugs metabolized to inactive products by the liver. Congestive heart failure can decrease both the blood flow to liver and metabolic rates within liver leading to predictions of decreased drug metabolism. Poly-pharmacy, as in any age group, often causes changes in drug metabolism. There are few aging-specific examples of drug-drug interactions that affect metabolism. Titrating drugs in elderly to identify the minimal effective dose is generally wise to avoid adverse effects due to unpredictable changes in drug metabolism. V. Specific drugs that warrant special note in elderly Drug Affected Digoxin Drugs of Concern for Drug-Drug Interactions Interaction Interacting Drugs Increased digoxin Quinidine, indomethacin, verapamil concentration or effect nifedipine, dilitiazem, esmolol, (symptoms: arrhythmias, flecainide, hydroxychloroquine, GI disturbances, & CNS) ibuprofen, quinine, tolbutamide, amiodarone, erythromycin, tetracycline & spironolactone Decreased digoxin Antacids, pysllium, kaolin-pectin, concentration or effect aminosalicyclic acid, colestipol, (symptoms: progression of sulfasalazine, antineoplastics, or reappearance of heart cholestyramine & metoclopramide failure or atrial fibrillation) Warfarin Increased probability of NSAIDs gastric erosion & bleeding Drugs that slow warfarin Sulph antibiotics (e.g. sulfamethoxazole, metabolism - Reduction of Bactrim®) intestinal flora responsible Macrolides (e.g. erythromycin) for vitamin K production Quinolines (e.g. ciprofloxacin, Cipro®) by antibiotics is probable Phenytoin as well as decreased metabolism and clearance of warfarin. (symptoms: excess anticoagulation) Drug-Disease Interactions Disease Benign prostatic hyperplasia Drugs Adverse Effect Decongestants Acute urinary retention with adrenergic agonist or mimetic activity Cardiac conduction Verapamil, atenolol Heart block Chronic Obstructive Pulmonary Disease (COPD) β adrenergic blockers Bronchoconstriction & Respiratory depression Dementia Benzodiazepines, Opiates Delirium Diabetes Corticosteriods Hyperglycemia Hypertension NSAIDS Increased blood pressure Hyponatremia Diuretics Decreased serum Na Postural hypotension Diuretics, vasodilators & Ca channel blockers Syncope, falls, hip fractures Commonly Used Drugs with High Potential for Severe Adverse Drug Reactions Considered “High Severity” by HCFA for Nursing Home Residents who are > 65 y Class or Drug Amitriptyline (Elavil®) Risk Anticholinergic effects (blurred vision, constipation, urinary hesitancy, confusion) Digoxin (Lanoxin®) Cardiac arrthymias due to digoxin intoxication Anticholinergics Dicyclomine (Bentyl®) Adverse anticholinergic effects (blurred vision, constipation, urinary hesitancy, confusion) Sedative/hypnotics Excessive sedation including respiratory depression and ataxia and other motor impairment leading to falls and accidents. NSAIDs Gastric bleeding Metoclopramide (Reglan®) Depression, dystonic reactions, Parkinsonism and tardive dyskinesia