A “Risk” Approach to Adverse Drug Reactions

Adverse drug reactions (ADR) occur more frequently in older than in younger persons, perhaps most frequently in the fastest-growing segment of the United States population, the oldest-old. Even recent reassessments show that at least 10% of elderly admitted to hospitals are admitted because of adverse drug reactions and that number may, indeed, be somewhat higher.1–3 More importantly, the latest FDA adverse drug reaction report, published in 1986, shows that people over 60, who constitute 17% of the population, were associated with about one third of all hospitalization reports and one half of all death reports. Apparently, adverse drug reactions have a more severe effect on older than younger patients. These facts assume increasing importance with the growth of the home-care sector. Already, for every patient in a nursing home, there are about four patients of equal age and equally serious medical status being cared for in their homes.4 Physicians rarely participate in home care,5 yet the Royal College of Physicians has stated that one of the three major reasons for adverse drug reactions in the elderly is the poor supervision of chronic care drugs.6 Gosney and Tallis7 reported in 1984 that approximately 24% of hospitalized elderly patients were affected by adverse drug reactions and interactions. Their study indicates that almost 66% of these reactions were avoidable and another 18% were probably avoidable, had the prescriber used the knowledge base currently available. Thus, it is important to recapitulate the known reasons for adverse drug reactions. Multiple Pathology At least 80% of the elderly suffer from at least one chronic disease and of those, as many as 40% may suffer from two or more chronic diseases.8 Disease states such as anemia, cardiac failure, degenerative vascular disease, diabetes, hypertension, arthritis, and others may alter a patient's response to drug therapy. For example, uncontrolled cardiac failure alters the absorption profile of furosemide, and nephrotic syndrome, cirrhosis of the liver, and idiopathic edema can all blunt the diuretic response to furosemide. One other possible outcome of multiple pathology is the increased susceptibility of aged individuals to decompensation under stress due to a progressive loss of physiologic reserve. The cardiovascular system and the central nervous system are especially vulnerable to this effect. Multiple Drug Use Another outcome of multiple pathology often is multiple drug use. There is an estimated 30% chance of adverse interactions among persons who consume two or more drugs. That percentage, of course, increases with an increasing number of concurrently administered drugs.9,10 Mismanagement of Drugs Although no definite data are available, it is generally recognized that more than 50% of older patients, similar to younger patients, mismanage the administration of their drugs, either completely defaulting or over- and under-using their medications. Some simply are not capable of following directions of a complex therapeutic regimen.11 Regrettably, drug-induced delirium and confusional states may often be responsible for drug mismanagement,12 as may be vision and hearing impairment frequently encountered in older patients. Altered Drug Handling Capacity The physiologic scatter in response to drugs is much wider in older than younger patients, and drug action is much less predictable13,14 These changes can, in part, be explained on the basis of the pharmacodynamic and pharmacokinetic hypotheses of altered drug action in the elderly.15 The Pharmacodynamic Hypothesis In general, altered drug action with age can be attributed to changes in the brain, central nervous system, cardiovascular system, receptors, and endocrine system.16–20 Perhaps age-related drug action is related to altered drug receptor interaction. Elderly are more sensitive to the effects of some drugs such as barbiturates21 and benzodiazepines.22–24 Age-related changes have been documented for the benzodiazepine brain receptors.25 However, older patients also become less sensitive to some drugs such as beta blockers and beta agonists.26 The Pharmacokinetic Hypothesis With advancing age, there may be pronounced changes in the rate with which a drug moves through the body. Major alterations have been documented in the disposition of drugs, ie, distribution, metabolism, and excretion. With advancing age, the ratio between lean body weight (volume of distribution for water-soluble drugs) and lipid tissue (volume of distribution for lipid-soluble drugs) changes, even if there is no change in weight. Lean body weight decreases. Thus, it might be expected that a given dose of a drug achieves higher serum levels.27,28 The liver, while losing weight with advancing age, probably does not undergo loss of function. The main deficiency that occurs is the liver's reduced capacity to oxidize or hydroxylate certain highly protein-bound, lipid soluble drugs.29 Of clinical importance is the fact that a 40% to 50% reduction in hepatic blood flow occurs, decreasing the removal of certain drugs during the “first pass” through the liver, thus prolonging their half-lives.30 Psychotropic drugs, often prescribed for the elderly, are among the drugs most importantly affected. It has been suggested that a reduction in excretory function is the major factor causing adverse drug effects in the elderly. A 55% reduction in renal blood flow by age 80 in 66% of all elderly is associated with a 33% reduction in glomerular filtration rate.31 In turn, the reduction in kidney function is accompanied by a reduction in standard creatinine clearance.32 Thus, drugs excreted in parallel with creatinine clearance, such as digoxin, should be used at a reduced dose to avoid cumulation and toxicity. Mere knowledge of the listed factors has not served to reduce adverse drug reactions substantially in the elderly, perhaps because of the lack of application of this knowledge. An additional approach might be feasible if “risk factors” that predispose subcategories of elderly to specific adverse reactions can be identified. Lamy10 developed the conceptual framework of primary, secondary, and tertiary aging factors which collectively heighten the risk of adverse drug reactions to the elderly patient. Primary aging factors are defined as the normal physiologic changes which occur with the aging process. Secondary aging factors are the pathophysiological changes in the older population which, in concert with primary aging factors, could alter the patient's response to a particular medication. In addition, socioeconomic and behavioral factors, termed tertiary aging factors, can increase the risk to the patient. Tertiary factors include smoking, diet, physical activity (or lack of it), non-adherence to a prescribed and agreed-upon regimen, anxiety, and fear. Additional factors are loss of spouse, loss of income, and loss of family. Finally, medications, by their actions and side effects, can alter a patient's response to other medications and illnesses. An elderly patient could be placed at greater risk for a serious adverse event based on the interplay of these risk factors. If these factors can be defined for a particular circumstance, a high risk patient could be monitored and drug selection could be based on the degree of risk attributed to these factors. To illustrate this model, possible risk factors for delirium have been separated into the four main risk categories (Table 1). By identifying those factors which predispose patients to adverse drug reactions, medication selection could help to minimize adverse drug reactions and eliminate unnecessary health care costs and maintain quality of life. These patients could be monitored more closely, given alternative drug therapy, or identified more readily as suffering from an adverse drug effect as opposed to the onset of an additional pathology. This format is not limited to the example given, but could be applied to orthostatic hypotension, hypothermia, renal dysfunction, and peptic ulcer disease, among others.