The term polypharmacy was used over one and a half centuries ago to refer to issues related to multiple-drug consumption and excessive use of drugs. Since then, it has evolved with different meanings and different situations including but not limited to "unnecessary drug use" and "medication use without indication." Based on the review of current data, the use of 5 or more medications is an acceptable definition of polypharmacy. This cut off point of 5 medications has been shown to be associated with the risk of adverse outcome such as falls, frailty, disability, and mortality in older adults [1]. The World Health Organization suggest that while the definition is numerical, emphasis should be on evidence-based practice and that the goal must be to reduce inappropriate polypharmacy.

Polypharmacy in the Elderly

Even though persons aged 65 years and older comprise about 14% of the total population, they account for over one-third of total outpatient spending on prescription medications in the United States. Based on a recent population bulletin, the number of people over age 65 is projected to at least double from 46 million today to more than 98 million by 2060. Polypharmacy is a particular concern in older people[2] due to the following reasons.

Multi-Morbidity

Aging places individuals at risk of multi-morbidity (coexistence of 2 or more chronic health conditions) due to associated physiological and pathological changes and increases the chances of being prescribed multiple medications.[3]

Adverse Drug Effects

An adverse drug effect (ADE) refers to an injury resulting from the use of a drug. An adverse drug reaction (ADR) is an ADE that refers to harm caused by a drug at usual dosages. ADEs are estimated to be indicated in 5% to 28% of acute geriatric medical admissions. Preventable ADEs are among one of the serious consequences of inappropriate medication use in older adults. The drug classes commonly associated with preventable ADEs are cardiovascular drugs, anticoagulants, hypoglycemics, diuretics, and NSAIDs. Adverse drug effects are higher in older adults due to metabolic changes and decreased drug clearance that come with age. This risk compounds by increasing numbers of drugs used. The Beer’s criteria and STOPP (Screening Tool Of Older Persons' Potentially inappropriate medications) criteria are frequently used tools to detect potentially inappropriate medications in the elderly and hence to guide proper medication prescribing in the elderly.[4][5]

Drug Interactions

The use of multiple medications increases the potential for drug-drug interactions and for prescription of potentially inappropriate medications. A drug-drug interaction refers to the pharmacologic or clinical response to the administration of a drug combination that differs from the response expected from the known effects of each of these two agents when given alone. Cardiovascular drugs are most commonly involved in drug-drug interactions. The most common adverse events related to drug-drug interactions are neuropsychological (delirium), acute renal failure, and hypotension.

Medication Non-Adherence

Polypharmacy can lead to problems with medication adherence in older adults, especially if associated with visual or cognitive decline, associated with aging and resulting in bad outcomes like treatment failure or hospitalizations.[3]

Prescribing Cascades

Polypharmacy increases the possibility of prescribing cascades when additional drugs are prescribed to treat the adverse effects (ADE) of other drugs by misinterpreting the ADE as a new medical condition, clinical veridic examples are reported in the literature [6] [7] [8]. Polypharmacy can be overlooked because the symptoms it causes as a result of drug interactions or side effects of drugs, for example, tiredness, sleepiness, decreased at alertness, constipation, diarrhoea, incontinence, loss of appetite, confusion, falls, depression, or lack of interest in usual activities, may be confused with symptoms of normal ageing or sometimes lead to the prescription of more drugs to treat the new symptoms.

The risk for Hip Fracture

Polypharmacy has been shown as an independent risk factor for hip fractures in older adults in some case-control studies; although the number of drugs may have been an indicator of a higher likelihood of exposure to specific types of drugs like central nervous system (CNS)-active drugs associated with falls. [9]

Use of Over-the-Counter and Complementary Medications

The use of over-the-counter (OTC) medications has increased over the past decade with studies showing that these agents are highly prevalent in the elderly population. The challenging part is only less than half of the patients discuss the use of herbal supplements or other products or complementary medicine with their medical providers. [10] Analgesics, laxatives, vitamins, and minerals are among some of the most commonly used classes of OTCs. The FDA is not authorized to evaluate or regulate the use of dietary supplements, and proper knowledge of exact ingredients or consequences of their use is not available. There are safety issues regarding their use including risks for herb-drug interactions.

Transitions of Care

Transitions in care, between hospital and home or institutional setting like a nursing home, are a common source of medication errors and puts patients at risk for polypharmacy. This is because many times, patients start new medications or stop previous medications, which can cause a lot of medication errors and negative outcomes.[11]

Changes in Pharmacokinetics Associated with Aging

Pharmacokinetics refers to drug absorption, distribution, metabolism, and elimination.[12]

Absorption

• Aging does not affect the extent of drug absorption significantly but the rate of absorption may be slower. Because of this, the peak serum concentration of a drug may be lower, and the time to reach it delayed in older patients. But the overall amount absorbed (bioavailability) does not differ in patients based on age. There are exceptions to this scenario and includes those drugs with an extensive first-pass effect that may have higher serum concentrations or increased bioavailability as liver size and hepatic blood flow decreases with aging and hence less drug is extracted by the liver.
• Other factors impacting drug absorption include the way medications are taken, what it is taken with, comorbidities, or inhibition or induction of enzymes in the gastrointestinal (GI) tract.

Distribution

Distribution refers to where in the body a drug penetrates and how it is spread through the body [13]. It is expressed as the volume of distribution (Vd), with units of volume (litres) or volume per weight(L/kg).

• Older adults have less body water and lean body mass hence, hydrophilic (water-soluble) drugs have a lower volume of distribution. Examples are ethanol or lithium.

• Another typical change with aging is increased fat stores; therefore. lipophilic (fat-soluble) drugs have an increased volume of distribution. Examples are diazepam, trazodone, and flurazepam.

• Albumin, the primary plasma protein to which drugs bind, is usually lower in older adults. Because of that, there is a higher proportion of unbound (free) and pharmacologically-active drug, which is not a problem in younger patients as normally, additional unbound drugs are eliminated. However, with aging, there is a decrease in elimination resulting in the accumulation of the unbound drug in the body. Examples are ceftriaxone, phenytoin, valproate, warfarin, diazepam, and lorazepam.

Metabolism

Metabolic conversion of drugs can occur in the liver, intestinal wall, lungs, skin, kidneys, and other organs. With aging, there is a decrease in hepatic blood flow and liver size, drug clearance of some drugs by the liver may be decreased by up to 30% in older adults. Drug metabolism occurs through either phase 1 pathways/reactions or phase 2 pathways.

• Phase I pathways include hydroxylation, oxidation, dealkylation, and reduction by cytochrome P450 (CYP) enzymes. Most drugs metabolized through this pathway can be converted to metabolites of a minor pharmacological effect than the parent compound; however, some drugs are modified to more active compounds through Phase I reactions (v.g. diazepam)

• Phase II pathways include glucuronidation, conjugation, and acetylation. Drugs metabolized through phase 2 pathways can be excreted by urine or bile, mainly. An example is lorazepam, after oxidation by phase I reactions, it is metabolized by glucuronidation.

The phase I reactions, catalyzed by cytochrome P450, are more likely to be impaired in the elderly than phase II reactions thus, medications metabolized through phase 2 pathways are preferred for older adults. [14]

Elimination

Elimination refers to a drug’s final routes of exit from the body. The terms used to express elimination are a drug's half-life and clearance. For most drugs, elimination is through kidneys as either the parent compound or as a metabolite or metabolites.

• With aging, renal size and renal blood flow decreased, and hence glomerular filtration declines.
• Also, due to a decrease in lean muscle mass with aging, the production of creatinine is reduced. The reduction of glomerular filtration rate counters the decreased creatinine production, and serum creatinine stays in the normal range. Serum creatinine is not an accurate reflection of creatinine clearance in the elderly. When prescribing a new medication or changing doses, the Cockcroft- Gault equation can be used to estimate a patient’s creatinine clearance.

Age-Associated Changes in Pharmacodynamics

The molecular, biochemical, and physiologic effects of a drug are studied by pharmacodynamics [15]; pharmacodynamics can change with aging, but the changes are specific to the drug studied and to the effect measured, generalizations cannot be made. Controlled studies of drug effects require plasma or site of action drug concentrations to can establish age differences in drug responses, as for example, elderly patients present a reduced beta-adrenergic receptor response to some ligands, salbutamol, a beta2-agonist and the beta-antagonist, propranolol, show reduced responses due to reduced post-receptor events, specifically, a reduction on cyclic AMP synthesis. [16]

The care of older adults can be challenging because they may require multiple medications to manage their complex medical problems. Optimizing their medication regimen is one of the critical elements in comprehensive geriatric care. Preventable adverse drug events are one of the serious consequences of polypharmacy, and this possibility should always be considered when evaluating an older patient with a new symptom until proven otherwise. This strategy can prevent prescribing cascades and even risk of hospitalizations. Also, being cognizant of specific issues related to polypharmacy like increased risk for hip fractures, falls and decrease in cognitive functions can help avoid a lot of negative outcomes like falls and decrease health care costs. While prescribing multiple medications cannot be avoided in a specific patient scenario, healthcare professionals should aim for a balance between over-prescribing and under-prescribing and consider medication appropriateness based on life-expectancy and goals of care.

Strategies to Prevent Polypharmacy

• Maintain an accurate medication list and medical history and update whenever possible
• Encourage patients to bring all medications including prescription, OTC drugs, supplements, and herbal preparations
• Review any changes with patient and caregiver and if possible, provide all the changes in writing
• Use the fewest possible number of medications and the simplest possible dosing regimen
• Try to link each prescribed medication with its diagnosis
• Discontinue all unnecessary medications
• Screen for drug-drug and drug-disease interactions
• Use a team approach if possible involving the caregiver or family and pharmacist (community pharmacist)
• Avoid starting potentially harmful medications; use Beer’s criteria
• Try to start a new medication at the lowest dose and then titrate slowly
• Avoid starting medications to combat the potential side effects of other medications
• Careful medication reconciliation during transitions of care including proper communication handoffs to accepting providers. Ensuring a close post discharge follow up for updating medical history and medications can help in preventing medication errors, treatment failures, and rehospitalizations[17].
• Consider goals of care and life-expectancy of patients when assessing medication appropriateness