Older adults, also known as seniors or elders, are individuals who are 65 years and older. The advancements in healthcare globally have helped increase longevity, resulting in a growing aging population worldwide. It is estimated that the percentage of individuals aged 65 and older will increase from 10% in 2022 to 16% in 2050. ^{1 – 3} Additionally, the report predicts that by 2050, the ratio of the elderly population to children under the age of five will be 2:1. ³ This increase in the elderly population is primarily attributed to lower mortality and higher survival rates. Figure 1 and Figure 2 illustrate the top 50 countries with the highest percentage of older population, ² as well as the distribution of the world’s oldest populations by country or territory in 2022 and 2050 ³ respectively.

One of the main health concerns among older adults is the presence of multimorbidity. Multimorbidity is defined as the presence of two or more non-communicable diseases, for example, hypertension, ⁴ diabetes, ^{5 , 6} depression, and so on. ⁷ A recent study reported a global prevalence of multimorbidity of 37.2%. ⁸ The same study pointed out that 51% of adults aged 60 years and above have multimorbidity. This finding is similar to an Indian study, which reported an increasing prevalence of multimorbidity from 48.31% in those aged 45 years and above to 73.86% in those aged above 75 years. ⁹ Similarly, a study from Malaysia reported that 40.6% of the country’s older adults have multimorbidity. ¹⁰ Multimorbidity is common among older adults due to declining physiological function and the presence of shared risk factors such as smoking, a sedentary lifestyle, and an unhealthy diet which lead to the onset and progression of chronic diseases.

Pharmacotherapy treatment is the mainstay for many non-communicable diseases. The increasing prevalence of multimorbidity leads to older adults being prescribed a higher number of medications, resulting in polypharmacy and hyperpolypharmacy. Polypharmacy is when a patient uses five or more medications, while hyperpolypharmacy is when they use ten or more medications. ^{11 – 13} The reported prevalence of polypharmacy in the literature varies widely, ranging from 2.6% to 86.6%. ^{14 , 15} Despite the benefits of managing multimorbidity, increased medication consumption can have unwanted effects on older adults. This article aims to guide healthcare providers (HCPs) in optimizing pharmacotherapy for older adults taking into consideration the unique physiological changes and challenges that come with aging.

Polypharmacy significantly increases the risk of medication-related problems among older adults. These problems include drug interactions, inappropriate prescribing, prescribing cascade, medication non-adherence, and more. ^{16 , 17} Drug interactions are more common among older adults with polypharmacy and can manifest in various ways, such as drug-drug interactions, drug-disease interactions, or drug-food interactions.

Drug-drug interactions typically decrease the effectiveness of medication by either inhibiting drug metabolism or increasing clearance. For instance, an elderly patient with hypertension who takes non-steroidal anti-inflammatories (NSAIDs) for knee pain may experience a drug interaction with an ACE inhibitor, leading to elevated serum potassium levels and reduced kidney function.

In the case of drug-disease interactions, chronic NSAID use in a heart failure patient can exacerbate their condition. Additionally, drug-food interactions can impact the outcome of pharmacotherapy by altering the drug’s pharmacokinetics. One common example is warfarin, a vitamin K antagonist, taken with green leafy vegetables high in vitamin K content, which can affect the anticoagulation stability of warfarin.

Inappropriate prescribing is common among older adults ranging from 45.3% to 51%. ¹⁸ One of the leading causes of polypharmacy besides comorbidities is overprescribing. Overprescribing refers to prescribing medications more than necessary for patients. Overprescribing tends to increase with age and higher prevalence was reported among older people near the end of life in some studies up to 76%. ¹⁹ A study conducted in the United States, reported that antidepressants, thyroid hormones, proton pump inhibitors, H ₂ receptor blockers, and analgesics were commonly overprescribed medications among older adults. ²⁰ In addition to overprescribing, underprescribing can also be an issue. Underprescribing or underprescription is defined as the failure to prescribe a drug that is indicated for the management of a condition or illness, despite the absence of a valid basis for doing so. ²¹ Underprescribing can also occur to avoid polypharmacy among older adults. A study reported that the prevalence of underprescribing ranges from 22% to 70% among the older population. ²² Numerous factors, such as multimorbidity, polypharmacy, dementia, frailty, risk of adverse pharmacological events, lack of specific clinical trials for older patients, and economic concerns, are linked to under-prescription. ^{23 , 24} Underprescribing leads to negative outcomes such as an increased risk of cardiovascular events, deteriorating disability, hospitalisation, and mortality. ^{25 , 26}

Medication adherence refers to the extent to which a person follows a doctor’s instructions for taking medications. ²⁷ This includes taking the right medication, at the right dose, at the right frequency, and at the right time. Medication adherence can be challenging for older adults with multimorbidity and polypharmacy thus, leading to non-adherence. There are several risk factors identified for non-adherence among older adults with multimorbidity and polypharmacy. Cognitive decline is observed among the aging population which leads to unintentional omission of medications. ^{28 , 29} Moreover, the complexity of pharmacotherapy prescribed for such patients does not help with adherence levels either. ^{30 , 31} Other reported factors include sex, medication cost, lack of social support, health literacy, and self-administration of drugs. ^{32 – 34}

Adverse drug reactions (ADRs) are common and widely reported among older adults with polypharmacy and multimorbidity. ^{35 , 36} This is due to age-related changes in pharmacokinetics and pharmacodynamics, such as decreased hepatic and renal function, longer elimination half-lives, and higher sensitivity to medications. Older adults are more susceptible to ADRs compared to younger adults. ADRs often lead to increased hospital admissions with stays of up to 6 days and a mortality rate of 0.34%. ³⁷ Medications commonly associated with ADRs include analgesics, antithrombotics, proton pump inhibitors, antihypertensives, antidepressants, antipsychotics, and bisphosphonates. ^{38 – 40} Drug-drug interactions have also been identified as a significant factor in ADRs development. Specific drugs that are known to cause ADRs due to interactions include warfarin, aspirin, heparin, and other antithrombotic agents. ^{41 , 42} These drugs can interact with proton pump inhibitors, antidepressants, and antiplatelets leading to gastrointestinal or cerebral haemorrhagic events.

Multimorbidity and polypharmacy increase the likelihood of prescribing cascade events in older adults. A prescribing cascade is when an adverse drug event (ADE) is mistaken for a new medical condition, leading to the unnecessary addition of another medication. ⁴³ For example, a diuretic may be prescribed to reduce edema caused by calcium channel blockers used for hypertension. Another common prescribing cascade involves prescribing an antiparkinsonian agent to address extrapyramidal symptoms caused by antipsychotic agents. These cascades not only worsen the effects of an unrecognized ADR but also contribute to the development of chronic polypharmacy. ¹¹

When prescribing pharmacological agents to older adults, it is crucial to consider pharmacokinetic changes such as absorption, distribution, metabolism, and elimination. The pharmacokinetics of medications can be affected by age-related pharmacologic changes as well as sex-related changes and multimorbidity, which are more common in the elderly. Additionally, pharmacokinetic changes in older adults can be affected by geriatric syndromes as well. ⁴⁴

Ageing affects all organ systems including the gastrointestinal system which is responsible for the absorption of medicated oral preparations. The gastrointestinal system plays a crucial role in motility, enzyme and hormone secretion, and the digestion of food. One common complaint among older adults is xerostomia or dry mouth. Xerostomia can be caused by systemic diseases like Sjogren’s syndrome, pharmacological agents such as atropine, and radiation therapy that damages the salivary glands. Salivary gland hypofunction may impair drug absorption through the oral mucosa, such as sublingual glyceryl trinitrate, reducing clinical efficacy. ⁴⁵

The walls of the small and large intestines reduce in size among older adults leading to a reduced surface area, and impaired absorption. ⁴⁶ Additionally, an aging-related decrease in hydrochloric acid production can lead to impaired absorption of certain drugs such as aspirin, and early release of drugs from enteric-coated oral formulations. ⁴⁷ The passage of medications from the stomach into the small intestine can be prolonged by age-related delay in gastrointestinal motility or the consumption of anticholinergic medications. ⁴⁸ Delayed motility can impair absorption, onset of action, peak drug concentration, and clinical effects of medications like paracetamol, which is absorbed in the upper small intestine.

As a person ages, body fat increases while total body water, blood, and plasma volume decline. These changes result in an increased volume of distribution and half-life of lipophilic drugs like diazepam. Therefore, when the same medication dose is prescribed to older adults and young people, it can lead to higher levels of free drugs and greater effectiveness in older adults, potentially causing toxicity. Additionally, it can decrease the distribution of hydrophilic drugs like digoxin and lithium. In addition to changes in plasma volume, older adults also experience decreases in plasma proteins such as albumin and lean tissue as they age. Drugs with high protein binding, like warfarin and phenytoin, may become unbound when albumin levels are reduced, especially during illness, leading to an increased risk of toxicity. ⁴⁹ On the other hand, α-1-acid glycoprotein increases with age, resulting in decreased free concentrations of basic drugs such as amoxicillin, potentially leading to inadequate dosing.

The impact of first-pass metabolism by the liver decreases with age. The decline in hepatic metabolism is characterized by a decrease in liver mass, blood flow, and hepatic enzymes such as cytochrome P-450, flavine monooxygenases, and UDP glucuronosyl transferases. ⁴⁹ A study in Japan stated that hepatic unbound clearance fell by 32% at age 80 and 40% at age 90 compared to age 40, implying a 0.80% annual decline with age. ⁵⁰ Hence, older adults may have higher circulating drug concentrations for a given oral dose. Drugs such as nitrate, propranolol, phenobarbital, and nifedipine are some examples of medications with an increased risk of toxic effects due to a decline in physiological function. The hepatic metabolism of drugs can also be impacted by smoking, reduced hepatic blood flow in heart failure patients, and the use of medications that activate or inhibit the cytochrome P-450 metabolic enzymes.

The aging process not only affects the absorption, distribution, and metabolism of drugs but also alters the renal elimination of drugs. The size of the kidney decreases by 20-30% between the age of 30 to 80 years. ⁴⁹ Besides structural changes, the glomerular filtration rate (GFR), renal plasma flow, and tubular function also decrease with age. ⁵¹ More often, the serum creatinine level is maintained within the normal range despite reduced GFR due to less muscle mass. ⁵² Therefore, drug doses should be tailored according to the measured renal clearance of the patient using equations such as CKD Epidemiology Collaboration, Berlin Initiative Study, and Full Age Spectrum which are more accurate than Cockcroft–Gault. ⁵³ Drugs that rely heavily on renal elimination such as sildenafil, clozapine, amoxicillin, and others require a reduction in dose and/or frequency to avoid toxic plasma concentrations of drugs. ⁵⁴

Pharmacodynamics as opposed to pharmacokinetics examines the drug’s action on the body. It can be affected by receptor binding and sensitivity, post-receptor effects, chemical interactions, and physiological changes due to disease, genetic mutations, aging, or other drugs. ⁵⁵ Therefore, older adults may have a different physiological response to the same drug dosing compared to younger patients. Increasing age can increase sensitivity to most drugs such as digoxin, warfarin, opioids, antipsychotics, and diuretics. However, β-adrenoceptor responsiveness decreases with age due to decreased activation of adenylyl cyclase and reduced production of cAMP. ⁵⁶ This means that β-blocker doses may need to be increased to achieve an adequate response.

In addition, older adults also have increased sensitivity to anticholinergic drugs. The side effects of these drugs include dry mouth, constipation, delirium, blurred vision, and urinary retention. Commonly consumed medications with anticholinergic effects include antipsychotics, tricyclic antidepressants, and sedative antihistamines. Taking multiple medications with anticholinergic effects can result in an anticholinergic burden, which, when combined with aging, may lead to cognitive decline and a loss of functional capacity. ⁵⁷ Furthermore, older adults with a moderate to high anticholinergic burden are at an increased risk of falls. ⁵⁸ Therefore, it is highly encouraged to regularly review medications and consider deprescribing drugs with anticholinergic effects.

Despite the challenges associated with pharmacotherapy management in older adults, there are practical ways to resolve these issues. The following steps can be taken to overcome pharmacotherapy challenges in older adults:

A medication review is a routine practice conducted in healthcare settings by doctors, pharmacists, and nurses. ⁵⁹ This process can be valuable in identifying medications with anticholinergic burden, potentially inappropriate medications (PIMs), and prescribing cascade events that are commonly observed in older adults. When performed correctly and regularly, medication reviews can help detect many drug-related issues early on, such as side effects, adverse effects, interactions, or missed doses. ⁶⁰ The primary goal of a medication review is to ensure that medications are functioning as intended and addressing the patient’s health concerns. Additionally, it can simplify medication regimens and promote adherence in older adults with polypharmacy. The medication review process can take place in various settings, including nursing homes, hospitals, primary care facilities, community pharmacies, and during home visits.

From a patient’s perspective, a medication review provides an opportunity for older adults and their caregivers to discuss any concerns or questions they have about their medications with a HCP. This open communication can lead to better medication management and improved overall health.

In recent years, the National Health Service in England has introduced a comprehensive medication review called Structured Medication Review (SMR). SMRs are evidence-based and thorough reviews of a patient’s medication, taking into account all aspects of their health. The SMRs are intended for patients with hyperpolypharmacy, severe frailty, and potentially addictive pain management medications, which are commonly found in older adults. ⁶¹ These SMRs can be implemented by healthcare facilities in different countries to improve the optimization of prescribed medications.

By addressing medication errors, improving adherence, and ensuring optimal medication use, medication reviews can significantly improve health outcomes for older adults. This can lead to fewer hospitalisations, improved quality of life, and a reduction in healthcare costs. In addition to this, medication reviews can also help prevent falls and related injuries. ⁶² Figure 3 describes the optimization of pharmacotherapy in older adults.

Deprescribing has recently gained popularity due to an aging society with an increasing number of individuals living with various chronic diseases. Deprescribing is defined as the process of tapering, withdrawing, discontinuing, or stopping medications to reduce potentially problematic polypharmacy, ADE, and inappropriate or ineffective medicine use. ⁶³ Deprescribing is a practical approach to reducing ADRs, improving adherence, reducing pill burden, lowering fall risk, and enhancing quality of life. ^{64 , 65}

A multicenter controlled trial conducted in Australia found that a deprescribing strategy significantly decreased the number of medications prescribed to older adults with polypharmacy, with no adverse events reported. ⁶⁶ The most frequently deprescribed medication classes were supplements, gastric acid suppressants, statins, oral hypoglycemics, and diuretics. Deprescribing medications like diuretics can potentially prevent the prescribing cascade. Furthermore, deprescribing reduces exposure to high-risk anticholinergics, thus decreasing the anticholinergic burden in older adults and avoiding unwanted side effects such as dry mouth, constipation, urinary retention, cognitive impairment, and dementia. ⁶⁷ Similarly, a randomized controlled trial in Ireland reported that deprescribing significantly reduced polypharmacy and medication costs in frail older adults. ⁶⁸

Deprescribing can be accomplished in five simple steps ^{69 , 70} ;

Step 1: Obtain a comprehensive medication history and assess adherence.

Step 2: Identify any PIMs.

Step 3: Decide if the dosage can be lowered or if the medication can be discontinued.

Step 4: Develop a plan for tapering and withdrawing the medication.

Step 5: Monitor the outcomes, including improvements in clinical parameters, and ADRs.

There are numerous tools available to assist clinicians in deprescribing medication. A popular tool is the STOPP/START (Screening Tool of Older Persons’ Prescriptions/Screening Tool to Alert to Right Treatment) criteria. It is a physiological systems-based explicit set of criteria that aims to define clinically important prescribing problems related to PIMs and potential prescribing omissions. ⁷¹ Other useful tools that can be used in clinical settings include the Medication Appropriateness Index, Good Palliative-Geriatric Practice, Current medicines, Elevated risk, Assess, Sort, Eliminate algorithm, and Beers Criteria. ⁷² Identifying prescribing cascades in clinical practice can be challenging for clinicians. Therefore, the ThinkCascades tool was recently developed through a modified Delphi process with an international multidisciplinary expert panel to identify clinically important prescribing cascades affecting older adults, which helps prevent and manage polypharmacy. ⁷³

Due to the complex interplay of age-related physiological changes, multimorbidity, and declined cognitive function, individualized treatment approaches are crucial for older adults. A one-size-fits-all approach is not sufficient, as health heterogeneity increases to varying degrees with age. ^{74 , 75} Therefore, prescribers need to consider older adults’ comorbidities, and physiological functions such as renal function, cognitive function, functional status, and life expectancy before prescribing any medications.

When it comes to prescribing medications for older adults, a key principle that HCPs need to remember is ‘start low, go slow’. Initiating medications with low doses and titrating up the dosage until a desirable treatment outcome has been achieved including the absence of adverse effects, is important. Tools like STOPP/START and Beers Criteria can be used when prescribing medications for older adults. Prescribing combination medications such as felodipine and enalapril in a single formulation, can reduce polypharmacy and improve adherence among older adults.

Individualized treatment recognises the unique life experiences and challenges older adults face, such as loss, retirement, or changes in living situations. This fosters a more empathetic and relatable therapeutic environment. For instance, frail older adults may have difficulties in managing complex insulin therapy, so simplifying or de-escalating the treatment would benefit them greatly. ⁷⁶ Treatment plans can be adjusted as needed to accommodate changes in health or preferences, ensuring the approach remains safe and effective over time. Overall, individualized treatment empowers older adults to take charge of their well-being and achieve a higher quality of life.

The development of geriatric-specific guidelines is crucial for improving the care of older adults. The need for population-specific guidelines arises from the unique challenges faced by older adults. These challenges include physiological changes, polypharmacy, and cognitive decline. General clinical guidelines available in most healthcare facilities might not address these complexities, potentially leading to poorer health outcomes. One of the major challenges in developing guidelines is determining best practices or recommendations based on available evidence. This is because the majority of clinical trials may not include older adults in the study, so the outcomes may not be generalised for this population. Clinical trials need to consider the inclusion of older adults as the population is expected to grow in the future. Pharmacy-related geriatric guidelines should be developed in hospitals, primary care clinics, nursing homes, and community pharmacies to provide optimal prescribing. Some of the pharmacy-related geriatric guidelines include the Pharmacist’s Comprehensive Geriatric Assessment in France, the Medication Therapy Adherence Clinic for Geriatrics and the Geriatric Pharmacy Pocket Book in Malaysia. ⁷⁷ These guidelines not only help clinical pharmacists but also other HCPs in making treatment decision.

Patient education plays a critical role in optimizing pharmacotherapy for older adults. Understanding their medications helps older adults take them correctly, at the right times, and for the intended duration. This reduces the risk of missed doses or misuse, leading to better treatment outcomes. Educated patients are more likely to identify potential problems like drug interactions or side effects and medications that potentially increase the risk of falls. ⁷⁸ They can then communicate these concerns to their HCPs, preventing complications. Knowledge about medications empowers older adults to manage their conditions more effectively. They can recognise signs of improvement or worsening health, allowing for timely adjustments to their treatment plan. Understanding their medications fosters a sense of control and autonomy in older adults. This can lead to greater satisfaction with their healthcare and a more active role in their treatment decisions.

There are some practical ways to provide patient education in daily practice. Firstly, tailored communications are key. Older adults typically experience sensory loss, memory decline, and slower processing of information. Therefore, it is important to use clear, concise language and address individual needs and learning styles. Speak slowly, clearly, and loudly enough for them to understand the information being conveyed. Visual aids or written information can also be helpful as a reference for older adults. ⁷⁹ Emphasize potential side effects of prescribed medications, proper medication administration, and when to seek medical attention. It is crucial to create a comfortable environment where older adults can ask questions and express concerns without fear of judgment. Patient education should also be extended to family members or caregivers who assist with medication management. In addition to verbal communication, patient education handouts, either physical or electronic, can be provided to patients and their caregivers for Ref. 40. This will undoubtedly improve the care provided to older adults.

A multidisciplinary approach is beneficial for optimizing pharmacotherapy. The team can include geriatricians, physicians, pharmacists, nurses, dieticians, physiotherapists, and other specialists. By combining expertise from various disciplines, the team can gain a holistic understanding of the patient’s health, including medical conditions, cognitive function, and social circumstances. This allows for a more individualized medication plan. Collaboration among team members helps identify and prevent potential medication errors, minimizing the risk of ADRs. A study conducted in the United States reported that a multidisciplinary team consisting of clinical pharmacists has led to significantly more deprescribing of PIMs. ⁸¹ Through education and support from various HCPs, patients are more likely to understand and adhere to their medication regimens. Open communication within the team ensures everyone involved is on the same page about the patient’s treatment plan and avoids overlapping medical records and prescriptions. The collaborative effort exhibited by the multidisciplinary team can optimize medication use to improve the older adult’s health, quality of life, and functional ability.

Prescribing medications for older adults involves a unique set of ethical considerations, especially regarding patient autonomy and shared decision-making. Older adults cherish their independence and their ability to take charge of their healthcare. HCPs must respect this autonomy by offering clear information about medications, possible side effects, and treatment objectives in a way that is easy to comprehend, taking into account any cognitive limitations. Patients should feel empowered to ask questions and voice any concerns they may have. Ultimately, the decision to accept or decline medication lies with the patient, even if it contradicts the doctor’s advice.

However, patient autonomy can be compromised by a few factors. Older adults with cognitive impairment have difficulties comprehending complex medication information and making informed decisions. In addition to cognitive impairment, polypharmacy dampers autonomy by creating adherence issues. When autonomy is challenged, shared decision-making becomes crucial. This involves including the patient in discussions but may also involve incorporating input from trusted family members or caregivers. Family members can provide valuable insights into the patient’s medical history, daily functioning, and preferences. The patient’s level of understanding and decision-making ability should always be prioritised. If the patient lacks capacity, a healthcare proxy or legal guardian may need to be involved. Clear communication with both the patient and family is essential to ensure everyone understands the treatment plan and its potential benefits and risks. Overall, the goal is to find a balance between respecting patient autonomy and ensuring their well-being. This can involve a flexible approach that adapts to the individual needs and circumstances of each older adult.

The older adult population is heterogeneous, with differences in physiology due to aging altering pharmacokinetics and pharmacodynamics, functional disabilities, cognitive impairment, and multimorbidity to varying degrees. This leads to an increased incidence of polypharmacy and ADRs. Therefore, optimizing pharmacotherapy for the growing older adult population will greatly benefit their health.