CHAMP: Bedside Teaching Drugs and the Aging Hospitalized Patient Paula M. Podrazik, MD Adverse Drug Reactions and the Aging Hospitalized Patient Teaching Trigger: An elderly patient is admitted with delirium secondary to a suspected adverse drug reaction to a medication or medications in combination. Clinical Question: Why is the aging patient at risk for adverse drug reactions (ADRs)? How can ADRs be minimized in the aging hospitalized patient? Teaching Points: 1. Backgound information: a. Adverse drug reactions (ADRs) represent any undesirable drug effect at standard drug treatment doses. These reactions include amplified drug effects, side-effects, drug-drug interactions, drug-disease interactions, drug-nutrient interactions. ADRs do not include adverse drug withdrawal events or therapeutic failures. b. Adverse drug events (ADE) include ADRs and errors of drug administration. Errors in drug administration represent an error that can occur at any step in the process from writing a medication order—to the drug being dispensed to the patient. 2. Older patients are at greater risk of ADRs because they are on greater #s of medications, have more co-morbid conditions and take certain medications that put them at higher risk of ADRs (high risk/low benefit medications). 3. Summary of risk factors for ADRs in the elderly are: a. increased #s of medications b. increased #s of medical problems c. high risk medications (high risk/low benefit drugs, e.g., Demerol, benadryl) d. aspects of aging pharmacology, history of prior ADRs, and fragmented medical care probably play a role but the evidence from the literature is mixed. 4. Although ADRs may seem to be inevitable in hospitalized patients, there is evidence that some of this error is preventable. 5. Strategies for reducing ADRs by drug review: a. reduce #s of unnecessary medications b. avoid high risk-low benefit drugs—find a lower risk alternative c. certain aspects of aging pharmacology, e.g., the aging kidney, the aging liver, aspects of aging pharmacodynamics such as the blunting of the baroreceptor reflex in the aging patient. d. review for hazardous drug interactions (drug-drug, drug-disease, drug- nutrient) 6. Drug review should be ongoing from the point of admission until discharge, especially in the older patient on greater than 5 medications. 7. Discarding, adding or changing medications in the older hospitalized patient must be done in concert with the patient’s primary care physician. Polypharmacy in the Aging Hospitalized Patient Teaching Trigger : During presentation of an admitting H&P, > than 5 medications noted. Reviewing the MAR at bedside, > than 5 medications noted. At the point of discharge, > than 5 medications are identified on the discharge instruction sheet. Clinical Question: What is the importance of reducing polypharmacy in the aging hospitalized patient? Teaching Points: 1. Polypharmacy is defined as the administration of more drugs than clinically indicated. 2. The risk of a drug interaction greatly increases to approximately 50-60% when greater than 5 medications are taken. For patients taking 10 medications, there is approximately a 90% risk of drug interactions. 3. Approximately 50% of the elderly in the community setting take one or more unnecessary meds. So ….the point of entry into the hospital is an important opportunity for medication review and discussion with the primary care physician re: eliminating unnecessary medications. 4. At hospital discharge, the elderly are taking the greatest number of medications, making medication review and communication with the primary care physician likewise crucial in reducing the number of unnecessary medications. 5. The lower the # of medications the less risk for an ADR—so review for medications that have no indication or have lost an indication. 6. Corollary: If you see a new symptom complaint and the patient is on an increased # of medications—think ADR in the differential diagnosis and review the medication list. Drugs and Aging Pharmacokinetics Teaching Trigger: An elderly patient is admitted with digoxin toxicity. Clinical Question: What are the pharmacokinetic changes that occur with aging? Which of these changes contibute to digoxin toxicity? Teaching Points: Overview: 1. Pharmacokinetics deals with the drug properties from the point of drug absorption to its distribution, transformation (usually in the liver), and drug elimination (most commonly via the liver and kidney). 2. Pharmacodynamics measures the intensity of a drug response at its receptor site. 3. Most of drug research looks at the pharmacokinetic properties of drugs because these properties are easier to quantify than pharmacodynamic properties of drugs. 4. In general, older patients are excluded from drug trials, esp., the older old (>75) and the oldest old (>85 years of age). a. In general, the exclusion of the old from drug trials is seen in investigational trials and also in most Phase III trials due to small sample sizes. b. Drug trials have exclusion criteria that often encompass the co-morbid conditions or medications that are common in an aging person. c. Much of the drug prescribing information for the oldest old group is extrapolated from the younger elderly population. d. Little is known from formal research about the combining of drugs in “vivo”, commonly seen in the aging population. e. The deficiencies in knowledge regarding drug disposition and efficacy in the geriatric population, particularly with regard to cardiovascular drugs, need to be bridged to enable the development of clinical guidelines for use and use in combination in the aging population. 5. Pharmacokinetic changes with aging: a. Drug absorption: no clinically significant change with normal aging. However, may see slower absorption with increased time to effect due to decrease in gastric pH, motility and absorptive surface. Slower absorption may be seen due to increased gastric emptying time in the older patient. b. Drug Distribution: i. Volume of distribution (Vd)—represents an estimate of the fluid volume required to distribute a drug evenly throughout the body. ii.Vd of a drug is determined by its plasma protein binding, tissue binding characteristics and polarity. iii.Changes in protein binding can affect the Vd of a drug. Warfarin (99%) protein bound is one such example. A common drug interaction with warfarin is displacement from its protein binding sites. Amiodarone, rifampin, phentoin, keto/iatraconazole antifungals, and sulfonamides are drugs known to cause displacement of warfarin. With aging: i. With increase in body fat from ages 20 to approximately 60-70 years, the Vd for lipophilic (nonpolar) drugs can increase with aging, e.g., TCAs, antipsychotic agents. After age 70, both body fat and lean body mass decrease and so does Vd. ii.The decrease in serum albumin seen with aging is usually secondary to disease. Acute phase reactant decreases in albumin are also partially counterbalanced by -1 acid glycoprotein; so total protein binding is not usually effected in the elderly. Aging and digoxin: i. Digoxin has a narrow toxic-therapeutic window, avidly muscle bound and renally excreted. Digoxin toxicity can be anticipated in the aging patient due to a loss of muscle mass resulting in more unbound digoxin, loss of renal function with decreased clearance of the drug and the effects of other commonly drugs taken in combination such as diuretics to decrease renal drug clearance. c. Hepatic drug biotransformation and clearance See Drugs and the Aging Liver d. Renal drug clearance See Drugs and the Aging Kidney Drugs and the Aging Liver Teaching Trigger: Reviewing the MAR a potent Cytochrome P450 inhibitor or inducer is identified. Clinical Question: What happens to the aging liver? Why is the aging patient at particular risk for drug interactions with regard to liver biotransformed drugs? Teaching Points: 1. Background: a. Liver metabolism occurs in the Cytochrome P450 system—a multigene family of approximately 100 variations of enzymes responsible for metabolizing drugs, food, chemicals, toxins, hormones. Most metabolism occurs in CYP 1,2,3. Phase I reactions are oxidative. Phase II reactions are acetylation and conjugation reactions. b. With aging: i. Decrease in liver blood flow by 35% or greater—so there is a decrease in high clearance liver metabolized drugs including amitriptyline, labetolol, lidocaine, propranolol, verapamil. ii. CYP450 Phase I oxidative processes decrease. 2. CYP450 and pharmaceuticals: a. CYP3A metabolizes > 60% of prescribed drugs including: calcium channel blockers, certain beta-blockers, most “statins”, warfarin, amiodarone. b. CYP3A Inhibitors include: amiodarone, cimetadine, cyclosporin, erythromycin, azole antifungals, grapefruit juice. c. CYP2D6 metabolizes: metoprolol, propranolol, tramadol, codeine, oxycodone, TCAs, SSRIs. d. CYP2D6 Inhibitors include: cimetadine, SSRIs, quinidine e. CYP 450 Inducers include: rifampin, primidone, tegretol, phenytoin f. With aging: The aging patient takes many prescribed drugs, often in great # and/or in combination. For example, if a CYP3A inhibitor such as amiodarone is prescribed, anticipate increased drug levels of digoxin, warfarin. Drugs and the Aging Kidney Teaching Trigger: At admission or during review of the MAR at bedside, a 90 year old with CHF is noted to have a normal Cr of 1.1 and on multiple drugs cleared by the kidney. Clinical Question: What happens to the kidney with aging? What is the most accurate way to estimate renal function at bedside in the aging adult? Teaching Points: 1. Renal function declines with aging starting at age 30-40— at a rate of about 1% per year. 2. NHANES III REFERENCE POPULATION MEAN GFR Age /Average GFR (mL/min/1.73m2) 20-29/116 30-39/107 40-49/99 50-59/93 60-69/85 >69/75 3. Serum creatinine measures in the aging patient are inaccurate. Creatinine is a product of muscle breakdown, but with aging there is decrease in muscle mass and its breakdown and muscle mass between the genders is different, hence the serum creatinine does not accurately reflect GFR. . 4. Cr Clearance measured by 24-hour collections generally provides a poor estimate of true GFR due to a variety of factors in collection, analysis, pharmacology and physiology. 5. At bedside, one can estimate Cr Clearance as a measure of GFR using the Cockcroft-Gault equation: Cr Clearance= ( (140-age)*wt(kg)/72 *serum Cr ) (x 0.85 in women) 6. The recommended best estimation of GFR by the National Kidney Disease Education Program (NKDEP) of the NIH, the Kidney Disease Outcome Quality Initiative (K/DOQI) of the National Kidney Foundation, and the American Society for Nephrology is the use of a prediction equation based on serum creatinine to estimate GFR. This method of estimating GFR in adults is a modified version of the Modification of Diet in Renal disease (MDRD) equation, based on Cr, age, sex, race, but not weight. Results are normalized to average adult body surface area of 1.73 m2 and uniformly reported in mL/min/1.73m2: GFR estimate= 186x(Cr)-1.154x (Age)-0.203x (0.742, if female) x (1.21, if African American) Drugs and Aging Pharmacodynamics Teaching Trigger #1: An 80 year old admitted for chest pain has a near syncopal episode in-hospital after being started on cardiac meds including: nitrates and a beta- blocker. Clinical Question: What are the changes in drug pharmacology and aging physiology that effect doing and contribute to the near syncope in this patient. Note: See the discussion below of the blunting of the baroreceptor reflex with aging and decrease in beta-blockade with aging. With beta-blockers still start low and go slow, but dose to effect because: 1. Increase in conduction system disease with age. 2. Beta-blocker side effects 3. Beta-blockers and other disease entities, e.g., asthma, COPD 4. Beta-blockers are often used with other HR slowing meds. Teaching Trigger #2: An 83 year old is admitted to the hospital with delirium. PMH includes dementia, lumbar spinal stenosis, and depression. The medication list includes: Elavil, Paxil, Aricept, Ativan--prn agitation. The daughter recently had added Tylenol PM for sleep to her mother’s medications. Note: See discussion below of drugs with anticholinergic properties. Note the cummulative effects of the anticholinergic properties in Paxil, Elavil, tylenol PM (acetaminophen + benadryl) Clinical Question: What are some pharmacodynamic age-related changes that could be contributing to the potentially delirium causing medication combination in this case? Teaching Points: Overview: 1. Pharmacodynamics attempts to quantify the intensity of drug effect at its receptor site with a given drug dose or concentration. 2. In pharmacodynamic study, the drug-receptor model is most commonly used. 3. In clinical practice, the relationship of drug dose or concentration versus response approximates a sigmoidal shape. A threshold concentration is required to see initial effect, with an essentially linear relationship through 20%-80% of the dosing range and a plateau that represents a drug dose or concentration at which maximal drug effect is seen. Most of therapeutic drug dosing is done in the linear portion of the curve and maximal drug effect is avoided because of potential drug toxicity. With Aging: 1. Decline in beta-adrenergic responsiveness due to both decrease in receptor numbers and altered G-protein coupling to the beta-adrenergic receptor occurs with aging. Clinically, a decline in maximal heart rate to exercise and stress is seen. Pharmacologic response to beta-agonists and antagonists declines with aging. 2. Although the cardiovascular system shows a decrease in response to parasympathetic blockade, more pronounced central nervous system side effects occur with use of anticholinergic drugs, including urinary retention and delirium. Age-related changes in other parts of the autonomic nervous system are less clearly defined. 3. Reflex responses to drug effects are also affected by aging. The baroreceptor reflex, important in modulating changes in blood pressure, is blunted with aging. .
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