Polypharmacy

Function

Conventionally, polypharmacy is considered something to be avoided, and there is evidence that inappropriate prescribing is 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 6 or more comorbid conditions on 4 to 6 medicines are no more likely to have unexpected hospital admissions than those with 1 to 3 medications. Hence, clinicians must 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 for reasons other than clinical indications, resulting in adverse patient outcomes and not achieving the therapeutic objective. One study concluded that it could no longer be assumed that polypharmacy was always harmful and that the clinical reasoning by 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 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 older than 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 severe consequences of inappropriate medication use in older adults. The drug classes commonly associated with avoidable 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 when 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 administering a drug combination that differs from the response expected from the known effects of each of these 2 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 adverse effects (ADE) of other drugs by misinterpreting the ADE as a new medical condition; clinical 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 that 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. However, 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 decrease with aging; the liver extracts less drug.
• 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; hydrophilic (water-soluble) drugs have a lower volume of distribution. Examples include ethanol and lithium.

• Another specific change with aging is increased fat stores. As a result, lipophilic (fat-soluble) drugs have an increased volume of distribution. Examples include diazepam, trazodone, and flurazepam.

• Albumin, the primary plasma protein drugs bind to, 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 additional unbound drugs are typically eliminated. However, there is a decrease in elimination with aging, resulting in the accumulation of unbound drugs in the body. Examples include 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 I or phase II 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 with a less severe pharmacological effect than the parent compound. However, some drugs are modified to more active compounds through Phase I reactions (eg, diazepam).

• Phase II pathways include glucuronidation, conjugation, and acetylation. Drugs metabolized through phase II pathways can mainly be excreted by urine or bile. An example is lorazepam, which is oxidized by phase I reactions and then metabolized by glucuronidation. The phase I reactions, catalyzed by cytochrome P450, are more likely to be impaired in older people than phase II reactions. Medications metabolized through phase II 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 a drug's elimination are 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.
• Creatinine production is reduced due to decreased lean muscle mass with aging. The reduced glomerular filtration rate counters decreased creatinine production, and serum creatinine stays normal. Consequently, serum creatinine does not accurately reflect creatinine clearance in older people. 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 medicine studied and the effect measured.[15] Controlled studies of drug effects require plasma or site-of-action drug concentrations to 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 reduced cyclic AMP synthesis.[16]

Deprescribing

Deprescribing is the term for 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 (2023) 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][19]

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 severe 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 adverse outcomes like falls and reduce health care costs. While prescribing multiple medications cannot be avoided in a specific patient scenario, healthcare professionals should balance 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.[20]

The 2023 AHA/ACC Guideline for Chronic Coronary Disease emphasizes several key points: optimal prescribing, reducing medication burden and polypharmacy, deprescribing, and mitigating adverse drug reactions.[21]

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 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 medicines.
• Exercise careful medication reconciliation during care transitions, 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.[22]
• Consider patients' goals of care and life expectancy when assessing medication appropriateness.
• The polypharmacy does not consider the medications that were reduced in dose but not discontinued.[23]
• 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.[24]
• A study investigated using artificial intelligence (AI) to reduce polypharmacy. The 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 to polypharmacy and its solution.[25] 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.[26]

Enhancing Healthcare Team Outcomes

Every healthcare worker, including the pharmacist and nurse practitioner, must regularly determine what medications each patient takes, and monitoring the patient's medications is an interprofessional team effort. Duplicate medications require removal from the patient's regimen after consulting 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 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 the prescriber or pharmacist to verify their suspicions and take corrective measures. 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 interprofessional healthcare team members (clinicians, nurses, pharmacists) must 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 to delete duplicate and extraneous agents from the patient's regimen and medication therapy. 

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.[27]

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 cooperation and decision-making, and a patient-centered approach to evaluate each older adult's unique needs.[28] 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).[29]

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. As indicators of patients' health, multi-drug combinations could be used to recognize patients at risk of an ER visit shortly.[30] Similarly, the ARMOR tool (Assess, Review, Minimize, Optimize, and Reassess) can monitor and reduce the burden of polypharmacy.[31]