Drug Reactions, Resistance, and Polypharmacy
Drug reaction: An unwanted or harmful reaction, experienced following the administration of a drug or combination of drugs under normal conditions of use, which is suspected to be related to the drug.
Drug resistance: The reduction in effectiveness of a medication.
Polypharmacy: The concurrent use of multiple medications by a patient.
The older population has long represented the largest consumer group of medications. While this might suggest at first glance a pro-active approach by healthcare professionals toward the pharmacological management of disease, it is important to emphasize that the aging process, with or without the presence of common conditions such as chronic kidney disease, liver disease, and heart failure, is associated with significant alterations in the pharmacokinetics and the pharmacodynamics of numerous drugs (Mangoni 2005; Mangoni and Jackson 2004; Mangoni and Jarmuzewska 2019; Reeve et al. 2015). Furthermore, older adults, particularly those with significant frailty and comorbidity burden, are typically neglected from premarketing clinical trials. Therefore, there are increasing concerns regarding the routine, one-size-fits-all application of the evidence-based recommendations in clinical guidelines, formulated according to the results of such trials, to the routine care of a complex patient population that is characterized by significant interindividual variability in organ function and homeostatic capacity (Mangoni 2018; Mangoni and Pilotto 2016).
The combination of high, often off-label, medication use, pharmacokinetic and pharmacodynamic alterations in this group, inevitably reduces the capacity of healthcare professionals and patients to predict the effects of drugs, increasing at the same time the risk of drug–drug and drug–disease interactions (Mangoni 2018). The latter typically manifest as adverse drug reactions (ADRs), a common cause of hospitalization, disability, and even death, in old age. This chapter provides an overview of the recent temporal trends in drug prescribing, the potential negative impact of polypharmacy and inappropriate medication use on ADRs, and the challenges with applying the evidence from clinical trials conducted in younger, healthier participants to the routine pharmacological management of older adults. Opportunities for further research in these areas are also discussed.
Key Research Findings
Prescribing and Polypharmacy
There is good evidence, from epidemiological studies and governmental databases, that older adults are prescribed an ever-increasing number of drugs. For example, in a recent study investigating the temporal trends in medication use in two cohorts of older adults participating in the Cognitive Function and Aging Study in England, the proportion of participants taking ≥5 medications, a commonly accepted definition of polypharmacy, quadrupled from 12.2%, during the period 1991–1994, to 49.6%, during the period 2008–2011 (Gao et al. 2017). Specific drug classes, particularly statins, angiotensin-converting enzyme inhibitors, antiplatelet drugs, anticholinergic drugs, and proton pump inhibitors, were the main contributors to the increased use of medications over time in this and in other studies (Gao et al. 2017; Hollingworth et al. 2010; Sumukadas et al. 2014). A temporal increase in medication use and in the prevalence of polypharmacy in older adults has also been observed in other countries (Kantor et al. 2015) (See “Polypharmacy and Frailty”).
While the appropriate use, and the regular monitoring, of multiple drugs for the management of coexisting disease states in one individual is considered good clinical practice, several studies have also reported strong associations between the presence of polypharmacy and inappropriate prescribing, prescribing omissions, and risk of ADRs in old age (Galvin et al. 2014; Kuijpers et al. 2008; Lavan and Gallagher 2016). Furthermore, there is good evidence that polypharmacy predicts several adverse clinical outcomes in older adults, e.g., hospitalization, falls, and death, independently of other important clinical and demographic confounders (Gnjidic et al. 2012; Lu et al. 2015; Wang et al. 2015). The recent evidence of an independent association between polypharmacy and frailty also suggests that multiple drugs taken by a patient might adversely affect physical and/or cognitive function, thus reducing independence and increasing the risk of disability over time (Gutierrez-Valencia et al. 2018) (See “Polypharmacy and Frailty”).
Adverse Drug Reactions
ADRs, particularly in the context of polypharmacy, impose a significant public health and financial burden worldwide. Two landmark studies have investigated the association between ADRs and hospital admission in the older population. The first study, conducted in the UK in 18,820 patients admitted to hospital, reported a prevalence of ADRs of 6.5%. ADRs were directly responsible for hospital admission in 80% of cases, primarily manifested in the form of gastrointestinal bleeding, and involved aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), diuretics, and warfarin as the main responsible agents. The most commonly observed drug–drug interactions involved aspirin and warfarin, aspirin and other NSAIDs, diuretics and other diuretics, and diuretics and angiotensin-converting enzyme inhibitors. A total of 2.5% of patients died as a direct result of an ADR. The projected annual cost of ADR-related admissions was GBP 466 M (EUR 706 M, USD 847 M) (Pirmohamed et al. 2004). The second study, conducted in USA in a sample of 12,666 subjects with a condition that the treating physician explicitly attributed to ADRs, reported that 37.5% required hospitalization and that 48.1% involved patients ≥80 years. The population rate of hospitalizations for ADRs in subjects ≥85 years was approximately 3.5 times higher than that in subjects 65–69 years. The four most commonly implicated drugs were warfarin, insulins, antiplatelet drugs, and oral antidiabetic drugs. The main clinical presentations were hemorrhage, hypoglycemia, and electrolyte or fluid disturbances (Budnitz et al. 2011). These studies support the concept that ADRs are a common cause of hospitalization and that a relatively limited type and number of drugs account for the majority of the ADR-related clinical burden in the older population.
Several age-associated physiological and pathophysiological changes in organ and system function, affecting drug pharmacokinetics, can significantly contribute to the augmented risk of ADRs. The most clinically significant alterations involve the clearance of medications, particularly those undergoing Phase I metabolism or renal clearance, and drug absorption. Non-oral drug administration and administration via enteral tubes also requires special attention in older adults. However, the additional contribution of renal disease, liver disease, heart failure, and frailty, in different combinations, is increasingly recognized as an important factor accounting for the pharmacokinetic, as well as pharmacodynamic, variability in old age (Mangoni and Jackson 2004; Mangoni and Jarmuzewska 2019; Reeve et al. 2015). Pending further research in this complex area, it is recommended that older adults are treated with a tailored approach according to clinical response and risk of ADRs, and the regular monitoring of the function of key organs, particularly the kidney, other comorbidities, and concomitant medications. For example, the dose of digoxin, a drug that primarily undergoes renal clearance, in an older adult with chronic atrial fibrillation and heart failure should be regularly reviewed in the context of potential changes in glomerular filtration rate and treatment with nephrotoxic drugs such as NSAIDs.
Despite the strong epidemiological evidence supporting the significant negative impact of ADRs, it is important to emphasize that predicting and detecting ADRs can be particularly challenging in the older patient population for a number of reasons (Mangoni 2012). First, different drugs taken by a patient may cause similar toxicity. For example, a patient with heart failure taking antidepressants, diuretics, ACE inhibitors, and proton pump inhibitors might experience life-threatening hyponatremia with reduced level of consciousness, requiring hospitalization and treatment in intensive care. As each of these agents is known to cause hyponatremia, their concomitant administration might delay, and even prevent in some cases, the identification of a clear cause–effect relationship between specific drugs and the electrolyte imbalance. Second, the occurrence of new clinical symptoms and/or signs might erroneously be interpreted by the treating physician as a new disease state that requires additional drugs, rather than a new ADR caused by a drug that is currently prescribed. For example, the onset of bradykinesia in a patient treated with an antipsychotic drug for 8 months might lead to the diagnosis of Parkinson’s disease, rather than the recognition of drug-induced Parkinsonism, with the consequent inappropriate initiation of treatment with levodopa. This characterizes the well-described phenomenon of “prescribing cascade,” which inevitably perpetuates and aggravates polypharmacy (Rochon and Gurwitz 2017). Third, some ADRs are characterized by a different, nonspecific, clinical presentation in older adults. For example, thyroid dysfunction in the form of hypothyroidism during treatment with the antiarrhythmic drug amiodarone might present with different manifestations, e.g., lack of concentration and dry skin, in older patients when compared to younger cohorts, e.g., cold intolerance, weight gain and constipation (Bensenor et al. 2012). Fourth, as previously discussed, the lack of robust premarketing data on drug efficacy and safety in older, “real-life,” clinical trial participants might significantly delay the recognition, characterization, and magnitude of specific ADRs in this group during the postmarketing phase (Hilmer et al. 2012; Prosser et al. 2018). Fifth, there is increasing evidence that specific medications and medication classes, particularly drugs with anticholinergic and/or sedative effects, adversely affect physical function and cognition both in the short term and in the long term (Kouladjian et al. 2014; Ruxton et al. 2015). However, the onset and the progression of physical and/or cognitive decline is often a slow process that can be mistakenly attributed to advancing age per se.
Several tools have been recently developed to identify drugs that might be inappropriate, or even dangerous, in older patients during medication reviews conducted in hospital, outpatient clinics, or other community settings. The use of such tools has been shown to significantly reduce the number of inappropriate medications and the risk of ADRs (Clyne et al. 2016; Dalton et al. 2018; O’Connor et al. 2016; Thompson et al. 2018; Walsh et al. 2016).
Assessing the Efficacy and Safety of Pharmacological Treatment
By and large, drug prescribing in clinical practice is guided by several important factors such as a correct diagnosis, assessment of disease severity, selection of treatment choices and goals, presence of comorbidities, patient preferences, and access to healthcare services. In this context, drugs are typically developed and approved for marketing based on their effects on objective markers of disease response, such as blood pressure, serum cholesterol concentrations, or viral load. The clinical trials that investigate such effects form the evidence-based knowledge for the development and the update of clinical guidelines and professional recommendations worldwide. However, the clinical and demographic characteristics of the subjects recruited in such trials are often significantly different from that of patients managed in routine clinical practice. This is a particularly important issue in the older patient population, which is typically characterized by a significant interindividual variability in organ function, comorbidities, functional status, concomitant medications, and life expectancy. As a result, the routine application of recommendations from clinical guidelines that are based on the results of studies conducted in younger patient cohorts and/or “healthy” older adults might be problematic when managing a complex and diverse patient population. Furthermore, the use of disease-centered end-points, based on objective markers of response in conventional clinical trials, might need substantial revisiting in older patients, particularly those with significant frailty and poor quality of life (Mangoni and Pilotto 2016) (See “Frailty in Clinical Care”). For example, differences in treatment targets between older adults and younger patient cohorts have recently been outlined in professional guidelines for the management of important conditions such as hypertension and diabetes (Leung et al. 2018; Makin and Stott 2018).
A related issue is whether the achievement of a specific treatment goal, based on an objective parameter, is more meaningful than maintaining an acceptable quality of life, particularly in patients approaching the end of life. In this context, a comprehensive assessment of patient-centered physical, cognitive, and functional domains might provide useful information when selecting specific treatment plans and/or reviewing the need for specific drugs. This approach is gaining popularity in the management of cancer and cardiovascular disease and is likely to better identify those patients that are more likely to benefit from aggressive versus conservative treatment strategies (Afilalo et al. 2014; Ethun et al. 2017). At the same time, selected markers of functional status and quality of life might also serve as patient-centered end-points, in combination with conventional disease-centered end-points, in future studies of pharmacological interventions in the older population. Examples of this approach have recently been reported in older patients with dementia, depression, and acute illness (D’Onofrio et al. 2015; Pilotto et al. 2012; Volpato et al. 2018).
Future Directions of Research
More research is warranted to determine whether the adverse outcomes associated with polypharmacy, and the reported associations between polypharmacy and frailty, are mediated by specific drugs or classes of drugs. This has important practical implications for the future development and implementation of deprescribing strategies, particularly whether such interventions should cover each drug taken by a patient or focus on specific agents. Additional studies are also required to confirm the generalizability of available prescribing tools identifying appropriate versus inappropriate drugs in different health care settings, and their short- and long-term benefits on clinical outcomes. Finally, intervention trials that include older adults with different degrees of comorbidity and frailty are warranted to ascertain whether patient-centered end-points might facilitate the development of new therapeutic principles that improve quality of life, and reduce inappropriate medication use, in old age.
The progressive increase in medication use requires urgent and effective interventions to identify inappropriate prescribing and reduce the frequency and the impact of ADRs in the older population worldwide. A number of strategies, such as a greater participation of “real-life” older adults in clinical trials, a better recognition of ADRs as part of regular medication reviews and/or during care transitions, and the validation and widespread use of robust tools that identify inappropriate prescribing, are likely to reduce the burden of polypharmacy and improve outcomes in older adults. However, additional research is also warranted to appropriately revisit commonly accepted treatment goals in younger patient cohorts and identify new, more meaningful, patient-centered end-points that might be particularly important in patients with significant degrees of frailty and/or those approaching the end of life.
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