The term polypharmacy is often used but not well defined. There are varied definitions in medical literature, but in general, polypharmacy has been defined as a single patient taking more than 5 drugs every day, with excessive polypharmacy defined as the prescription of 10 or more daily medications [3,48]. Polypharmacy may be used to describe excessive or unnecessary medications, inappropriate prescribing, or excessive use, overuse, or duplication of medications. There has been a call to redefine polypharmacy beyond an arbitrary number of medications [14,48]. In some cases of multimorbidity and chronic conditions (e.g., hypertension), the use of multiple medications may be the best practice according to clinical guidelines; this may be referred to as "appropriate polypharmacy" [15]. However, even when the prescription of multiple medications is warranted, it raises the risks of drug interactions, compliance issues, and adverse effects. Generally, the term polypharmacy has a negative connotation and is associated with the co-prescribing of potentially inappropriate medications.

In older adults, certain drugs are considered inappropriate when the adverse pharmacodynamics, pharmacokinetics, and/or risk of drug interactions outweigh the potential benefits. In 1991, Mark H. Beers, MD, and his colleagues established a list of medications considered potentially inappropriate for patients 65 years of age or older. Known as the AGS Beers criteria (Table 1), the resource was designed to educate prescribers, improve prescribing practices, and enhance quality assurance. Prescribers should review the medication regimen and determine the medical necessity of each drug the patient takes. The Beers criteria list continues to be updated (most recently in 2019) and used to guide and evaluate prescribing practices in geriatric patients. Notable new inclusions to the 2019 update of the list are glimepiride, methscopolamine, and pyrilamine [4].

The Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP) criteria focus on the avoidance of potentially inappropriate prescribing in elderly patients experiencing acute illness [5]. This tool places a special focus on potential drug-drug interactions, duplicate drug class prescriptions, and techniques to minimize adverse drug reactions. Criteria are organized according to physiologic system, which may make the tool easier to use. STOPP is designed to be used in conjunction with the Screening Tool to Alert doctors to the Right Treatment (START) criteria, which provides guidance on the medications that are recommended for older patients with specific conditions/diseases (e.g., arthritis, depression) [18]. STOPP/START criteria were first published in 2008 and were updated in 2014, with a 31% increase in the number of criteria [49]. Several new categories were included in the 2014 update, including STOPP categories of antiplatelet/anticoagulant drugs; drugs affecting, or affected by, renal function; and drugs that increase anticholinergic burden. New START categories include urogenital system drugs, analgesics, and vaccines [49].

Pharmacokinetic processes altered in aging include absorption, first-pass metabolism, bioavailability, distribution, protein binding, and renal/hepatic clearance. Age-related physiologic factors that may affect the absorption of drugs include delayed emptying time of the stomach, altered pH of the stomach contents, and slowed gastrointestinal tract motility. Changes in these processes begin with alterations in the functioning of individual cells.

In older patients, cells become less efficient at performing necessary functions. This may be the result of atrophy, hypertrophy, hyperplasia, dysplasia, and neoplasia. Atrophy is the shrinkage of cells and is most commonly noted in the brain, heart, skeletal muscle, and reproductive organs. It may result in dementia or contracture. In some cases, cells enlarge due to an increase of proteins in cell structures; this is referred to as hypertrophy. It has been hypothesized that this change may be a compensatory mechanism in response to atrophied cells. Hypertrophic changes in older patients may result in cardiomegaly or benign prostatic hypertrophy. Similarly, older patients are at increased risk for hyperplasia, or the increased reproduction of cells. This overgrowth of cells may lead to the development of benign growths (e.g., focal nodular hyperplasia, sebaceous hyperplasia) or it may be a precursor to cancer. Dysplasia is also more common in older adults. This is characterized by mature cells becoming disorganized and abnormal in size and/or shape. This is often a first stage in the development of neoplasia, or the new growth of benign or cancerous tumors.

The functioning of the liver plays a significant role in the metabolism of drugs. The liver is the major site of drug transformation and elimination, and drugs administered by the oral route must pass through the liver prior to reaching systemic circulation. The enzyme cytochrome P-450 (CYP-450) is the most important factor in the first phase of drug metabolism, and this enzyme is primarily expressed in the liver. However, the liver's capacity to metabolize medications (and toxins) with CYP-450 is reduced by at least 30% in older patients [19]. In addition, the liver undergoes structural and microscopic changes with aging (e.g., reduced blood flow), and liver damage is repaired more slowly. As such, the metabolism of substances by the liver decreases, causing reduced inactivation of medications. This places older adults at increased risk for side effects due to reduced clearance of medications, which can be potentiated by the presence of hepatic disease. In many cases, elderly patients require reduced doses to adjust for these changes.

Age- and illness-related declines in kidney function necessitate dosage adjustments and possibly avoidance of certain medications. Renal elimination is a common form of drug excretion, and the rate by which medications are cleared lengthens with age. This can extend the action of drugs that undergo renal elimination, including morphine, heparin, lisinopril, and furosemide. Even with kidney changes, decreased muscle mass and limited physical activity can maintain serum creatinine levels within normal limits [19]. This can be misinterpreted as a sign of normal kidney function despite deficits. As such, caution is required when prescribing to elderly patients even when kidney function appears normal.

Older adults often have multiple conditions, the treatment of which may call for several medications. This potentially necessary polypharmacy can quickly escalate to be a burden on patients and/or their caregivers. The use of multiple medications has been associated with decreased adherence due to cost, complexity of regimens, and burnout. If possible, steps should be taken to limit the number of medications to those most effective for the patient. If a single medication may be of benefit for more than one of a patient's conditions, it should be preferred over multiple agents. Selecting the appropriate medication(s) for geriatric patients is made even more complicated by the lack of clinical guidelines and completed research focusing on this population.

CMS regulations state that nursing facility residents should only receive medications when the potential benefits outweigh the risks or burden of treatment [12,50]. There must be a clear clinical indication and diagnosis for any medication, and prescribed medications should be given for the proper duration at the correct dose. State surveyors review patients' medication regimens to assess for unnecessary medications. If a patient is found to have been prescribed an unnecessary drug, the facility may receive a citation (referred to as F-Tag 757 or F757) for violating the CMS requirement to avoid unnecessary medications. In 2014, CMS issued a memo indicating that surveyors have been trained to increase investigations for unnecessary drugs, particularly antipsychotic medications in the management of dementia [20]. In 2017, F-tag 758 (F758) was issued as a unique survey item to ensure the patient's drug regimen is free from unnecessary psychotropic medications [52]. These regulations are intended to help promote or maintain the patient's highest functional, emotional, and physical level of wellness. To comply with F757 and F758, each patient's drug regimen should be monitored on a regular basis, with goals of treatment identified. Only drugs that are medically necessary should be administered in the correct dosages and for only the clinically indicated duration. After a medication has been ordered, the patient should be monitored for therapeutic response, adverse reactions, interactions, and necessity of ongoing treatment. Any significant decline in functional or physical status should be immediately correlated with any new drugs or changes in drug dosages. Significant declines in status should be recognized and evaluated, with adjustment of the medication regimen if warranted.

CMS regulations state that nursing facility residents should only receive medications when the potential benefits outweigh the risks or burden of treatment [12,50]. There must be a clear clinical indication and diagnosis for any medication, and prescribed medications should be given for the proper duration at the correct dose. State surveyors review patients' medication regimens to assess for unnecessary medications. If a patient is found to have been prescribed an unnecessary drug, the facility may receive a citation (referred to as F-Tag 757 or F757) for violating the CMS requirement to avoid unnecessary medications. In 2014, CMS issued a memo indicating that surveyors have been trained to increase investigations for unnecessary drugs, particularly antipsychotic medications in the management of dementia [20]. In 2017, F-tag 758 (F758) was issued as a unique survey item to ensure the patient's drug regimen is free from unnecessary psychotropic medications [52]. These regulations are intended to help promote or maintain the patient's highest functional, emotional, and physical level of wellness. To comply with F757 and F758, each patient's drug regimen should be monitored on a regular basis, with goals of treatment identified. Only drugs that are medically necessary should be administered in the correct dosages and for only the clinically indicated duration. After a medication has been ordered, the patient should be monitored for therapeutic response, adverse reactions, interactions, and necessity of ongoing treatment. Any significant decline in functional or physical status should be immediately correlated with any new drugs or changes in drug dosages. Significant declines in status should be recognized and evaluated, with adjustment of the medication regimen if warranted.

Adverse drug reactions (ADRs) represent a significant economic burden to the healthcare system, causing nearly 450,000 emergency department visits annually for older adults; adults older than 65 years of age are nearly seven times more likely to be hospitalized after an emergency visit than those younger than 65 years of age [9]. Most hospitalizations among older adults are due to poor monitoring of anticoagulants, diabetes medications, anticonvulsants, and opioids [9].

There are five major categories of ADRs: side effects, hypersensitivity, idiosyncratic response, toxic reactions, and adverse drug interactions. Side effects are secondary effects of a drug and may be dose related. Hypersensitivity to a drug is immunologically mediated. In severe cases, anaphylaxis may occur. An idiosyncratic response is an unusual or unexpected reaction. Toxic reactions are often related to the dose or duration of drug therapy. Less often, build-up of metabolites may precipitate a toxic reaction, as with digoxin or phenytoin toxicity.

The FDA has issued a black box warning for warfarin regarding the risk of major or fatal bleeding. This risk is increased in patients older than 65 years of age with high-intensity coagulation (i.e., INR >4), variable INR, and/or other comorbidities [45]. Frequent INR monitoring is recommended along with careful dosage adjustment. Warfarin is contraindicated in patients with active bleeding, gastrointestinal bleeding, hemorrhagic stroke, blood dyscrasias, recent surgery, a high risk for non-compliance, and moderate-to-severe hepatic impairment. Caution is recommended in patients older than 65 years of age and in patients with a history of falls due to the risk of subdural hematoma and severe or fatal bleeding.

Age-related changes in drug absorption, distribution, metabolism, and clearance should be considered in all older patients with diabetes. For frail patients, the risks of intensive glycemic control often outweigh the benefits. Elderly patients may have a variable dietary intake related to physical or mental illness. If a patient skips a meal because he or she feels ill but takes or is given the usual dosage of insulin (especially fast-acting insulin), hypoglycemia will occur. Even when adequate calories are consumed, the older adult's intestinal absorption of those calories is slowed. As a patient ages, the adrenergic response to low blood glucose diminishes or disappears. Additionally, the preliminary symptoms of hypoglycemia, including lack of motor skills and confusion, may be misdiagnosed or unrecognized [43]. This can result in hypoglycemia unawareness in elderly patients with diabetes, which can allow the condition to become more severe. Unawareness of hypoglycemia is associated with a six-fold and nine-fold increased risk of severe hypoglycemia in patients with type 1 and type 2 diabetes, respectively [44].

Intense diabetes treatment and tight glycemic control can have serious consequences in elderly patients [21,22]. In the geriatric population, hypoglycemia is associated with an increased risk of myocardial infarction, functional decline, falls, and cognitive impairment. The AGS recommends a target glycated hemoglobin (HbA1c) of 7.5% to 8% in older patients with moderate comorbidities and life expectancy less than 10 years; the American Diabetes Association recommends a more relaxed goal of 8% to 8.5% for older patients with complex medical issues [23,51]. When diabetes is aggressively managed using guidelines more appropriate for younger adults, older patients are at risk for hypoglycemia and other complications. When deciding whether to offer or continue treatment of diabetes for patients older than 70 years of age, the benefit/risk ratio should factor in comorbidities, cognitive status, ability to self-manage, life expectancy, and vulnerability to hypoglycemia [24].

A sleep hygiene regimen is a universally applicable prevention and treatment strategy that can improve sleep quality for those with and without a specific sleep disorder. Sound sleep hygiene practices should be discussed with patients and/or caregivers, and willingness to undertake these and other nonpharmacologic options should be assessed and encouraged [16]. Exercise history should also be obtained, and when levels are inadequate, exercise as treatment should be discussed. Increased physical activity has been shown to be as effective as benzodiazepines in improving sleep patterns in several studies [17]. Other nonpharmacologic treatment options include relaxation therapy and sleep restriction [17]. These are often first-line treatments due to the low cost, lack of side effects, and no risk of dependency. The use of over-the-counter sleep aids (especially those containing antihistamines) should be discouraged, as should the use of alcohol, due to marginal efficacy and reduction in sleep quality and because they may cause residual drowsiness and have the potential for dependency [17].

Typical (e.g., haloperidol, thorazine) and atypical antipsychotics (e.g., olanzapine, risperidone) are considered dangerous when used in patients with dementia, and the FDA has issued a black box warning that elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk for death (mainly due to cardiovascular or infectious causes) compared with placebo [45]. In terms of liability, the burden of proof lays with providers and caregivers to provide the documentation that the medication is medically necessary.

A prescribing cascade occurs when a patient has an ADR and additional drugs are prescribed to control the symptoms of this reaction (Figure 1). Adverse drug reactions should be vigilantly ruled out prior to diagnosing a new medical condition.

Medication reconciliation is the process of creating and updating a current medication list as compared with any previous lists. This should be conducted: