Current Drug Metabolism, 2011, 12, 647-651 647 1389-2002/11 $58.00+.00 © 2011 Bentham Science Publishers The Risk of Adverse Drug Reactions in Older Patients: Beyond Drug Metabolism Graziano Onder, Fabrizia Lattanzio*, Miriam Battaglia, Francesco Cerullo, Roberta Sportiello, Roberto Bernabei and Francesco Landi Centro Medicina dell’Invecchiamento, Università Cattolica del Sacro Cuore, Rome, Italy, *Scientific Direction, Italian National Re- search Center on Aging (INRCA), Ancona, Italy Abstract: Changes in pharmacokinetics and pharmacodynamics, associated with increasing age, are often considered the only culprits of increasing Adverse Drug Reactions (ADR) rate observed in older adults, but other factors may be responsible for a reduction in drug effi- cacy and increase the risk of iatrogenic illness in this population. The aging process is characterized by a high level of complexity, which makes the care of older adults and the use of medications a challenging task. In particular, comorbidity, geriatric syndromes, cognitive and functional deficits, limited life expectancy are typical conditions observed in older adults which may reduce the efficacy of pre- scribed drugs and increase the risk of iatrogenic illness. As a consequence, a comprehensive assessment and management of the health care problems, with the goal of recognizing and preventing potential drug-related problems and improve quality of prescribing is neces- sary to reduce the risk of ADR. Several studies have assessed the effect of a comprehensive geriatric assessment and management on drug prescribing and drug related illness, showing a substantial improvement in quality of prescription and a reduction in rate of ADR. In addition, clinical guidelines providing recommendations regarding the use of drugs in chronic disease rarely assess the level of complex- ity observed in older adults and therefore they should be applied with caution in this population. Keywords: Adverse drug reactions, older adults, geriatric evaluation and management, comorbidity, disability, cognitive impairment. INTRODUCTION Adverse Drug Reactions (ADR) are a major burden on health care. In Western countries, ADR cause 3-5% of all hospital admis- sions , and are responsible for about 5-10% of inhospital costs [1- 4]. Older patients are particularly vulnerable to ADR because age is associated with changes in pharmacokinetics and pharmacodynam- ics that may alter drug metabolism leading to a higher rate of ADR [5,6]: 1. reduction in gastric acidity influences drugs absorption; 2. fall in gastric emptying and splanchnic blood causes a reduction in first pass metabolism; 3. changes in body composition (increase in body fat and reduction in body water and lean body mass)affect drug distribution to body tissues; 4. reduction in serum albumin causes a raise in free fraction of drugs which are bound to albumin; 5. impairment in liver and kidney function substantially reduces drug clearance; 6. the concomitant use of multiple drugs impairs the drug clearance process. Factors affecting drug metabolism are often considered the only culprits of increasing ADR rate associated with increasing age, but other conditions may cause a reduction in drug efficacy and increase the risk of iatrogenic illness. OLDER ADULTS, COMPLEXITY AND IATROGENIC ILL- NESS The aging process is characterized by a high level of complex- ity, which makes the care of older adults and in particular the use of medications a challenging task [7]. Typically, older adults show the co-occurrence of multiple chronic diseases (comorbidity) and con- ditions – like urinary incontinence, delirium or falls – that cannot be ascribed to a specific organ system pathology and have multiple causes (the so called geriatric syndromes) [8,9]. This high degree of complexity is further complicated by the presence of cognitive and functional impairment, which is common in this population. Phar- macological treatment of this complex patient represents a chal- lenge for prescribing physician and it may cause several iatrogenic hazards. *Address correspondence to this author at the Centro Medicina dell’ Invec- chiamento Università Cattolica del Sacro Cuore 00168, Rome, Italy; Tel: +39 06 30154341; Fax: +39 06 3051911; E-mail: graziano_onder@rm.unicatt.it Comorbidity - the presence of comorbidity, defined as the con- comitant presence of multiple coexisting diseases in the same indi- vidual, is a major issue in geriatrics and will increase its importance in the next future. The prevalence of comorbidity increases with age, mostly due to the higher frequency of individual chronic condi- tions in advanced age [10-15]. The high level of comorbidity ob- served in older adults has clearly a relevance to the occurrence of iatrogenic illness and several studies have suggested that number of coexisting diseases is associated with an increased risk of ADR [1,16,17]. Indeed, this findings may be related to several factors. First explanation includes the occurrence of drug-disease interac- tion [18]. This phenomenon happens when drugs that are helpful in one disease have the potential to exacerbate an underlying disease or medical disorder. For example, some beta-blockers taken for heart disease or high blood pressure can worsen asthma and mask hypoglycemia in diabetic patients or metoclopramide for gastric dysmotility may increase dopamine receptor blockade and worsen motor symptoms in a patient with Parkinson’s disease. Second explanation includes the occurrence of specific condi- tions that may alter drug metabolism. Typical examples of this phe- nomenon are kindey and liver diseases which lead to a reduced drug clearance and therefore to a higher risk of ADR [19-21]. Another common condition that may impair drug metabolism and lead to iatrogenic illness is heart failure (HF) [22]. Indeed, pathophysi- ological changes in pharmacokinetics are common in patients with HF, including diminished renal and hepatic blood flow, reduced splanchnic blood flow and liver metabolic capacity and hepatic ve- nous congestion [23]. In addition, HF is associated with a reduction in the volume of distribution and it plays an important role in the down-regulation of hepatic CYP involved in drug metabolism through several mechanisms which include hepatocellular damage, hypoxia and elevated levels of pro-inflammatory cytokines [24]. Finally, specific health conditions may lead to an increased rate of ADR by a non-metabolic mechanism. For example, several stud- ies have suggested the presence of an association between depres- sion and iatrogenic illness [25]. Indeed, depressed patients can am- plify somatic symptoms, causing an higher report rate of ADR and psychological symptoms of emotional distress can lead to an in- creased attention directed towards one’s body, with a consequent decrease in the threshold of any noxious somatic sensation [26-28].