Continuing Education Activity

Polypharmacy refers to using five or more medications based on a review of current data. 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. The cutoff point of 5 drugs is associated with the risk of adverse outcomes such as falls, frailty, disability, and mortality in older adults; hence optimization of medication regimen is one of the critical elements in comprehensive geriatric care. This activity reviews the key elements of polypharmacy therapy in the clinical setting. It discusses how members of an interprofessional team can more effectively manage the care of patients taking multiple medications.

Objectives:

• Identify the definition of polypharmacy.
• Describe the reasons for recognizing and managing polypharmacy in the elderly.
• Describe the strategies that can help minimize polypharmacy.
• Outline how an interprofessional approach helps prevent polypharmacy.

Introduction

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 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 drugs is associated with the risk of adverse outcomes such as falls, frailty, disability, and mortality in older adults.[1] 

The World Health Organization suggests that while the definition is numerical, emphasis should be on evidence-based practice and the goal of reducing inappropriate polypharmacy. The United States has one of the world's highest medication usage rates per capita. Management of polypharmacy is a challenge for all health care providers. Hence, this article will review strategies to reduce polypharmacy and skills to improve medication use management.[2]

Function

Conventionally, polypharmacy is considered something to be avoided, and there is evidence that potentially inappropriate prescribing is likely to be associated with polypharmacy. However, more recent research has identified that appropriately managing patients with targeted medications can prevent unplanned hospital admissions. For example, patients with six or more comorbid conditions on four to six medicines are no more likely to have unexpected hospital admissions than those with one to three medications. Hence clinicians need to differentiate between appropriate polypharmacy when all medicines are prescribed to achieve the specific therapeutic objective and medication therapy has been optimized to prevent adverse drug reactions.

In contrast, inappropriate (conventional) polypharmacy is when one or more medications are prescribed than clinically indicated, resulting in adverse patient outcomes and not achieving the therapeutic objective. A study concluded that it could no longer be assumed that polypharmacy was always harmful and that the clinical reasoning in which medicines have been prescribed needed to be considered. However, confirming that patients only receive the appropriate and targeted drug therapy for disease management should be the goal.[3]

Issues of Concern

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 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 for the following reasons.[4]

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.[5]

Adverse Drug Effects

An adverse drug effect (ADE) is an injury from drug use. An adverse drug reaction (ADR) is an ADE that refers to harm caused by a drug at usual dosages. ADEs are estimated to be 5% to 28% of acute geriatric medical admissions. Preventable ADEs are among 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 the number of drugs used.

Drug Interactions

Multiple medications increase the potential for drug-drug interactions and the 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 drug interactions-related adverse events are neuropsychological (delirium), acute renal failure, and hypotension.[6]

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.[5]

Prescribing Cascades

Polypharmacy increases the possibility of prescribing cascades when additional drugs are prescribed to treat other drugs' adverse effects (ADE) by misinterpreting the ADE as a new medical condition; clinical veridic examples are reported in the literature.[2][7][8] Polypharmacy can be overlooked because of the symptoms it causes as a result of drug interactions or side effects of drugs, for example, tiredness, sleepiness, decreased alertness, constipation, diarrhea, incontinence, loss of appetite, confusion, falls, depression, or lack of interest in usual activities, may be confused with symptoms of normal aging or sometimes lead to the prescription of more drugs to treat the new symptoms.

The risk of Hip Fracture

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

Use of Over-the-Counter and Complementary Medications

Over the past decade, over-the-counter (OTC) medications have increased, 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 the most commonly used OTC classes of OTCs. The FDA is not authorized to evaluate or regulate the use of dietary supplements, and proper knowledge of the 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 put patients at risk for polypharmacy, which can cause a lot of medication errors and adverse outcomes.[11]

Changes in Pharmacokinetics Associated with Aging

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

Absorption: Aging does not significantly affect the extent of drug absorption, but the absorption rate may be slower. Because of this, the peak serum concentration of a drug may be lower, and the time to reach it is delayed in older patients. But the overall amount absorbed (bioavailability) does not differ in patients based on age.

• Exceptions include 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; hence, less drug is extracted by the liver.
• Other factors impacting drug absorption include how 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 (liters) 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 and lithium.

• Another specific change with aging is increased fat stores; therefore. As a result, 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 drugs, 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, and 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 (e.g., diazepam)

• Phase II pathways include glucuronidation, conjugation, and acetylation. Drugs metabolized through phase 2 pathways can mainly be excreted by urine or bile. An example is the drug lorazepam which, after oxidation by phase I reactions, 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 exit routes from the body. The terms used to express elimination are a drug's half-life and clearance. For most drugs, elimination is through the kidneys as either the parent compound or as a metabolite or metabolites.

• With aging, renal size and blood flow decrease, and glomerular filtration declines.
• Also, due to a decrease in lean muscle mass with aging, the production of creatinine is reduced. The reduced glomerular filtration rate counters decreased creatinine production, and serum creatinine stays normal. Consequently, serum creatinine does not accurately reflect creatinine clearance in the elderly. However, the Cockcroft- Gault equation can estimate a patient's creatinine clearance when prescribing a new medication or changing doses.

Age-Associated Changes in Pharmacodynamics

The molecular, biochemical, and physiologic effects of a drug are studied by pharmacodynamics; pharmacodynamics can change with aging, but the changes are specific to the drug studied and the effect measured; generalizations cannot be made.[15] Controlled studies of drug effects require plasma or site of action drug concentrations to can establish age differences in drug responses; 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]

Deprescribing

Deprescribing describes the discontinuation of medicines; the concern is that most deprescribing in clinical settings is reactive, for example, in response to an adverse drug reaction or therapeutic failure. The focus should be on clinicians being proactive in deprescribing when the clinician and patient decide to discontinue the medication after evaluating the risk-benefit analysis.[17]

Beers Criteria

The American Geriatrics Society (AGS) updated Beers Criteria (2019) are especially helpful for Potentially Inappropriate Medication (PIM) usage in older adults and are widely used by clinicians, educators, researchers, and healthcare administrators in the United States.[18]

Clinical Significance

The care of older adults can be challenging because they may require multiple medications to manage their complex medical problems. Therefore, 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 the risk of hospitalizations. Also, being aware of specific issues related to polypharmacy, like increased risk for hip fractures, falls, and decreased 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 care goals.

Polypharmacy is common in patients taking opioids for the long term, and administering interacting medications may increase the risk of opioid overdose. A study was conducted to determine nonopioid medications that may increase opioid overdose. The major investigation quantified the odds ratio (OR) between opioid overdose and nonopioid medication dispensed in the 90 days directly before the opioid overdose date after adjustment for prescription opioid dosage and benzodiazepine prescribing. Polypharmacy with opioids and benzodiazepines may increase confusion, risk of falls, and hip fracture.[19]

Other Issues

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, supplements, and herbal preparations.
• Review any changes with the 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 Beers 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.
• Exercise 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 prevent medication errors, treatment failures, and rehospitalizations.[20]
• Consider goals of care and life expectancy of patients when assessing medication appropriateness.
• The polypharmacy does not consider the medications that were reduced in dose but not discontinued.[21]
• The integration of STOPP (Screening Tool of Older Person's Prescriptions) & START (Screening Tool to Alert to Right Treatment) for medication review in multi-morbid older people in clinical settings.[22]
• A study investigated using artificial intelligence(AI) to reduce polypharmacy. Results of the study were promising, and it endorsed the use of a multi-disciplinary research team consisting of specialists in AI, medicine, biostatistics, pharmacy, public health, law, and ethics, which can analyze polypharmacy from additional points of view and will contribute to an in-depth understanding of the clinical, social, and ethical issues related polypharmacy and its solution.[23] However, HIPPA(the Health Insurance Portability and Accountability Act) compliance, data privacy, and ethical challenges need to be addressed before the application of AI in healthcare and polypharmacy.[24]

Enhancing Healthcare Team Outcomes

Every healthcare worker, including the pharmacist and nurse practitioner, must regularly determine what medications each patient takes; monitoring the patient's medications is an interprofessional team effort. Duplicate medications require removal from the patient's regimen after consulting with the clinician who initially prescribed them. The date of prescribing and duration must be stated during each clinic visit. If nursing staff suspects duplicate therapy, they should consult with a pharmacist and bring it to the prescriber's attention. The key reason for checking medications is to prevent polypharmacy which can lead to significant adverse patient outcomes. If any healthcare team member suspects duplicate or inappropriate therapy, they must immediately consult with the prescriber or pharmacist to verify their suspicions so corrective measures can be taken. This dynamic emphasizes the need for open communication and meticulous record keeping.

Each year, thousands of elderly patients suffer injuries or even mortality because of adverse effects from multiple medications. The pharmacist must have a list of all patient medications and continually update the physician and nurse practitioner for duplicates and unnecessary medications. All members of the interprofessional healthcare team (clinicians, nurses, pharmacists) need to educate the patient on why they are taking a given drug and help them or their caregiver understand the regimen as much as possible. This information must be made available to the interprofessional healthcare team so duplicate and extraneous agents can be deleted from the patient's regimen and medication therapy. [Level 5]

OPERAM (optimizing therapy to prevent avoidable hospital admission in multimorbid older adults), a cluster randomized controlled trial, was conducted to study the effect of optimizing drug therapy on drug-related hospital admissions in older adults with polypharmacy and multimorbidity. The trial concluded that inappropriate prescribing is common in older adults with comorbidities and polypharmacy admitted to the hospital, which can be reduced through an intervention to optimize pharmacotherapy. However, further measures are needed to recognize pharmacotherapy optimization interventions that decrease inappropriate prescribing and enhance patient outcomes.[25] [Level 1]

Nursing, Allied Health, and Interprofessional Team Interventions

A study assessed the role of nurse practitioners in polypharmacy. The implication of the study results to clinical practice includes improving communication and collaboration between healthcare providers, identification and management of polypharmacy, using technology to reinforce collaboration and decision-making, and a patient-centered approach to evaluate each older adult's unique needs.[26] Given the hazards and burdens of polypharmacy and potentially inappropriate medications, nurses should use patient-centered approaches and nonpharmacologic strategies to treat common symptoms and optimize patient outcomes and QOL(Quality of life).[27]

Nursing, Allied Health, and Interprofessional Team Monitoring

Healthcare providers can now monitor the common multi-drug combinations for association with adverse health outcomes analysis. A study identified the combination of acetaminophen, oxycodone, and prochlorperazine as overrepresented in the 30-days before emergency room visits. It is necessary to note that this association doesn't mean causation. Still, as indicators of patients' health, multi-drug combinations could be used to recognize patients at risk of an ER visit shortly.[28] Similarly, the ARMOR tool(Assess, Review, Minimize, Optimize, and Reassess) can monitor and reduce the burden of polypharmacy.[29]