With age, health-related comorbidities increase. Aging contributes to significant functional changes in organ systems and results in decreased homeostatic capacity. Aging also affects body composition, increased volume of distribution for fat-soluble drugs, reduced clearance of multiple medications. The ongoing changes in the body’s physiology with aging are associated with an increased risk of adverse reactions to commonly used medications. The definition of polypharmacy is the simultaneous use of 5 or more drugs.

Mild cognitive impairment (MCI) is defined as cognitive decline more than expected for an individual’s age and level of education but interfering notably with daily life activities. On the other hand, dementia is more severe and widespread with a significant effect on daily function. Multiple long-term follow-up studies have shown that most mild cognitive impairment progress to dementia or Alzheimer’s dementia. People with MCI are 3 to 4 times more likely to develop dementia when compared to those with normal cognition.

Polypharmacy can be appropriate and inappropriate. Inappropriate polypharmacy primarily refers to over-the-counter medications, supplements lacking evidence-based indications, and interacting with other medicines, thus doing more risks than benefits. Clinical consequences of polypharmacy in older adults are adverse drug reactions, depression, disability, falls, frailty, increased healthcare use, postoperative complications, mortality, and caregiver burden.

Multiple drug-drug and drug-disease interactions are associated with polypharmacy in the elderly. Over a long time, the continued use of polypharmacy can also create new comorbidities, requiring more medications. This vicious cycle makes the elderly weaker, resulting in decreased strength, falls, increased dependence on others, increased morbidity, and mortality. An Italian multicenter cohort study conducted by Trevisan C et al. studied adults with MCI for one year. About 50% of study participants took >3 drugs per day; at the end of one year, the odds of dementia were sixfold higher in this group compared with similar adults taking < 3 drugs/day.

Etiology

The risk factors for polypharmacy-related mild cognitive impairment are age over 65, multiple comorbidities including hypertension, diabetes, obesity, cerebrovascular accidents, low socio-economic status, and lower education. Any increase in the number of medications prescribed to individuals raises the risk of unexpected drug interactions and their side effects, leading to impaired cognitive or physical capability. Over time, the cumulative exposure of multiple drugs with changes in body homeostasis with age makes the elderly vulnerable to pronounced mental and physical decline.

The elderly with multiple comorbidities are at increased risk for adverse drug reactions and drug interactions because of age-related physiological changes in the body. Many patients see numerous specialists and may fill medications at various pharmacies. The complex and rapid changes in older adult’s care in multiple settings by multiple providers contribute to polypharmacy and their undesirable outcomes.

Potentially inappropriate medications like benzodiazepines, anticholinergics, antipsychotics, antidepressants, and opioids can affect cognition and frailty in the geriatric population.  Effective and constant communication between healthcare providers and patients and their families can help identify potentially inappropriate medications, essential in reducing polypharmacy and its complications.

Epidemiology

The US population older than 65 who take five or more prescription medications increased from 24% to 39% between 1999 and 2012. Studies estimate that nursing home patients take eight different medications on average, and medication errors occur in two-thirds of such patients. Geriatric polypharmacy is associated with increased health care utilization, costs, medication nonadherence, and functional decline.

 In the US alone, there would be 72.1 million individuals aged more than 65 by 2030, which is more than double the number of older people in 2000. Older adults comprise about 15% of the total US population, but they account for 30 to 35% of prescription and nonprescription medication use. According to the published data, by 2030, the population age 65 and older will represent 20% of the US population and about 50% of healthcare costs. The current prevalence of polypharmacy is between 8 to 78% in Age group more than 65. Older adults in the US are the largest consumers of medications, making polypharmacy a significant public health problem.

Pathophysiology

With age, the number of health-related comorbidities also increases. As the number of comorbidities increases, so does the number of medications. This complex relation leads to polypharmacy, a geriatric syndrome. With age elderly become frail, characterized by diminished strength and endurance, falls, increased functional dependence.

The risk factors mentioned above, along with the use of multiple medications, make cognitive impairment more severe and pronounced when compared to healthy adults who are not taking any medicines.

History and Physical

A detailed history focusing on the baseline function, specifically physical and cognitive ability, should be obtained from multiple sources. Getting the list of all medications and their frequency, duration, dose titrations, if any, over-the-counter medications, including herbal supplements, should be obtained in detail. A detailed evaluation of symptoms, including fatigue, difficulty with ambulation, recent weight loss, should be obtained as a part of the geriatric evaluation. Evaluating nutrition status, including self-care, feeding, good sleep, ability to take medications, maintain weight, is crucial and requires frequent evaluation. Further history should be obtained from family members if available.

The United States preventative task force does not necessarily recommend for or against the cognitive screening impairment in older adults age 65 and above, but clinicians should be vigilant to identify early signs and symptoms of cognitive impairment. Dementia screening indicators can help geriatricians and primary care providers screen for cognitive impairment in office setup. 

The health care provider should have a clear understanding of all medications and their indications. Any change in cognition and a decrease in baseline function should raise concern for new or adjusted medication.

Treatment / Management

Once other causes of cognitive decline are ruled out, polypharmacy triggering a mild cognitive decline in the elderly should be the working diagnosis. After a thorough discussion with the patient and family, the patient’s other providers’ focus on adjusting medications should be an integral part of managing geriatric cognitive decline related to polypharmacy.

A clear understanding of polypharmacy and its relation to cognitive decline is essential in managing this complex geriatric syndrome. There is no specific treatment for polypharmacy-related cognitive decline. The starting point is to obtain a detailed history, medical records from the hospital, pharmacy, and controlled substance refill reporting. The brown bag assessment is the gold standard for medication reconciliation where patient brings everything they are taking in a brown bag to the appointment including hospital visits.

Deprescribing – Total number of medications taken by patients is the single most important predictor of inappropriate medication use. Deprescribing has been demonstrated as a helpful tool in the optimization of medication management. The goal is to target one drug at a time. First, look for medications that have no valid reason for being used, assess risk versus benefit, and prioritize removing medicines with the lowest help with high risk. Avoid prescribing cascade (when medications are used to treat the side effects of other medications) and new to market medications. If the patient takes over-the-counter herbal or supplement products, assess their efficacy and safety. Always run patients’ prescription and over-the-counter medicines, herbal products, and accessories through a point of care interaction checker in an app or online.

Studies have demonstrated that deprescribing is feasible in the clinical setting, especially when it incorporates patient preferences, shared decision making, and an interdisciplinary team. Medication-specific algorithms can facilitate deprescribing in the clinical environment.

Creating a systematic method to address polypharmacy in older patients by properly performing medical reconciliation during every visit, minimizing the use of potentially inappropriate medications, and ensuring appropriate monitoring can help improve long-term outcomes and avoid medication-related adverse events and cognitive decline. Polypharmacy contributes to significant medical and economic burdens on patients and their families, and providers should use patient-focused approaches. Discussing alternative nonpharmacologic methods to treat simple symptoms should be a priority. The goal in managing polypharmacy is to improve and optimize patients’ overall function and quality of life.

Differential Diagnosis

The relation between polypharmacy and mild cognitive impairment is a challenging diagnosis. It requires thorough evaluation to rule out other organic causes, including depression, hypothyroidism, B12 deficiency, chronic alcoholism, Parkinson’s disease. Once the diagnoses mentioned earlier are excluded, polypharmacy should be considered a cause of mild cognitive impairment.

Prognosis

The prognosis of mild cognitive impairment in the context of polypharmacy, in general, is favorable. Identifying the appropriate drug and risk factors and managing the underlying organic cause with alternative medications when feasible should be strongly considered. Isolated polypharmacy as a sole cause of mild cognitive impairment without other risk factors should recover well once the offending agent is identified and removed. The natural aging process, presence of diabetes, hypertension, and cerebrovascular disease might contribute to cognitive decline over time.

Complications

Polypharmacy, old age, underlying frailty pose multi-level challenges in the management of complications. Complications of polypharmacy include adverse drug reactions(ADRs), falls resulting in head injury, mild cognitive impairment with and without behavioral changes, and dementia.

Polypharmacy can lead to ADRs from multiple drug interactions, herbal supplements, and over-the-counter medications. The most predominant risk factor for ADRs is the number of drugs taken, i.e., more the medicines, the risk of ADRs increases exponentially. Other adverse events from polypharmacy include decreased medication compliance resulting in worsening of underlying medical problems, poor quality of life, increased office visits, unnecessary drug costs, excessive healthcare expenses, hospital admissions, and even death.

Consultations

Geriatricians and pharmacists should always be consulted by primary care physicians when in doubt about older adults’ medications and drug interactions.