Potential risk factors for adverse drug reactions in elderly patients : contribution to safer drug prescribing

Abstract

Because of demographic aging the proportion of elderly persons in the population is increasing, especially in industrialized countries. Increasing age is associated with a higher prevalence of comorbidities possibly necessitating pharmacotherapy. Elderly persons are not only treated with more drugs than younger ones, but they are also more vulnerable to adverse drug reactions (ADRs). The aim of the thesis was to elucidate potential risk factors that increase the risk for ADRs in the elderly with the purpose to improve safety of medical treatment. First, the literature was reviewed in order to get an overview on the potential risk factors already known. It has been shown that not only physiological changes that affect pharmacokinetic and/or pharmacodynamic effects of drugs, but also specific drugs and drug classes may increase the risk for ADRs. Two studies were then performed to evaluate specific aspects of drug prescribing, which may enhance the risk for ADRs. In the first study age-specific differences in the prevalence of clinically relevant potential drug-drug interactions (pDDIs) in ambulatory dyslipidemic patients treated with a statin were evaluated. Practitioners from different parts of Switzerland collected data for a total of 2’742 patients treated with a statin which attended their practice. Medical treatment was screened for clinically relevant pDDIs, defined as a DDI that could have had a potential serious outcome, using an interactive electronic drug interaction program. The prevalence of clinically relevant pDDIs was significantly higher in patients aged ³75 years than in patients aged £54 years (18.4% versus 7.9%; p < 0.001). This was ascribed to a higher number of diseases (3.5 versus 2.8; p < 0.001) and pharmacologically active substances prescribed (5.8 versus 3.8; p < 0.001). Beside polypharmacy, also heart failure and arrhythmia have been identified as risk factors for pDDIs in elderly patients. The more frequent prescription of cardiovascular drugs with a high potential for drug interactions (e.g. amiodarone and digoxin) was mainly responsible for the observed increase in statin and non statin pDDIs. The aim of the second study was to retrospectively evaluate and compare the prevalence of potentially inappropriate medication (PIM) use and prescription of drugs with strong anticholinergic properties in 800 elderly patients hospitalized on general medical or geriatric wards throughout hospital stay. PIMs as defined by the Beers criteria and anticholinergic drugs have been associated with a higher risk for ADRs in patients aged ³65 years. At hospital discharge, geriatric patients had a lower prevalence of use of PIMs that should generally be avoided than at admission (15.9% versus 22.1%; p < 0.05), whereas no difference was observed in medical patients. Overall, the three most prevalent inappropriate drugs/drug classes were amiodarone, long-acting benzodiazepines and anticholinergic antispasmodics. On the other hand, geriatric patients were discharged with a higher prevalence of use of PIMs that should be avoided in the presence of specific underlying diseases compared to medical patients (23.7% versus 11.7%; p < 0.001). The main reason was the higher prescription rate of benzodiazepines to patients with a history of falls and syncope. There was neither a difference in the prevalence of patients with anticholinergic drugs at admission nor at discharge between medical and geriatric patients. Compared with internists, geriatricians appeared to be more aware of PIMs that should generally be avoided. However, the results of this study should be interpreted with caution, because some of the drugs identified as potentially inappropriate may in fact be beneficial when the patient’s individual clinical condition is taken into consideration. Finally, a patient with lithium intoxication as a result of a drug-drug interaction (DDI) with rofecoxib is presented. This 68-year-old woman had several risk factors that finally resulted in the clinical manifestation of the DDI, illustrating well the problems of pharmacotherapy in the elderly. The already impaired renal function (calculated creatinine clearance 40 mL/min) deteriorated after the addition of rofecoxib, a selective cyclooxygenase 2 (COX-2) inhibitor. As a consequence, renal clearance of lithium was impaired, leading to an accumulation of the drug and symptoms of lithium intoxication such as vomiting, hypokinesia and tremor. Selective COX-2 inhibitors seem therefore not to be safer than conventional nonsteroidal anti-inflammatory drugs concerning their effect on renal function, especially in patients with renal insufficiency. Depending on the underlying disease, medical treatment with drugs associated with a high potential for DDIs and/or ADRs may not always be avoided. Knowledge of the potential risk can help to take appropriate measures to lower the probability for an adverse outcome, e.g. close monitoring of the patient, dose adjustment or selection of an alternative drug.