Influence of Ageing on the Pharmacodynamics and Pharmacokinetics of Chronically Administered Medicines in Geriatric Patients: A Review

Abstract

As people age, the efficiency of various regulatory processes that ensure proper communication between cells and organs tends to decline. This deterioration can lead to difficulties in maintaining homeostasis during physiological stress. This includes but is not limited to cognitive impairments, functional difficulties, and issues related to caregivers which contribute significantly to medication errors and non-adherence. These factors can lead to higher morbidity, extended hospital stays, reduced quality of life, and even mortality. The decrease in homeostatic capacity varies among individuals, contributing to the greater variability observed in geriatric populations. Significant pharmacokinetic and pharmacodynamic alterations accompany ageing. Pharmacokinetic changes include decreased renal and hepatic clearance and an increased volume of distribution for lipid-soluble drugs, which prolong their elimination half-life. Pharmacodynamic changes typically involve increased sensitivity to various drug classes, such as anticoagulants, antidiabetic and psychotropic medications. This review examines the primary age-related physiological changes in geriatrics and their impact on the pharmacokinetics and pharmacodynamics of medications.

Key Points

As people age, their body’s response to medications (pharmacodynamics) can shift, making some drugs more potent or less effective. These changes mean that older adults may experience stronger side effects or reduced therapeutic benefits, which require careful adjustment of treatments to balance effectiveness and safety.

Ageing impacts the ways in which medications are absorbed, distributed, metabolised and excreted from the body. These changes in pharmacokinetics can require dose modifications and more frequent monitoring to ensure drugs are processed at an appropriate rate and achieve the intended effects without causing harm.

Older adults often use multiple medications, therefore, careful management of potential pharmacodynamic and pharmacokinetic interactions is critical. These interactions can lead to unexpected adverse effects, highlighting the need for vigilant assessment and monitoring to maintain safe and effective treatment outcomes.

Introduction

Geriatric patients, defined as those aged > 65 years, are among the highest consumers of medications [1]. The complexity of pharmacotherapy in geriatrics is increased due to age-related physiological changes, multiple coexisting diseases, and the concurrent use of several medications, prescribers, and pharmacies. Ageing is a multifaceted concept encompassing the cumulative local effects occurring at the molecular, cellular, and tissue levels [3]. It results from these underlying changes rather than being the cause of them. Although a comprehensive definition of ageing is elusive, certain traits are commonly recognised. The most significant aspect is the gradual reduction in functional units over time. These units are the smallest structures able to carry out the specific physiological roles of their respective organs, such as nephrons in the kidneys, alveoli in the lungs, or neurons in the brain [3, 4]. Another characteristic is the disruption of regulatory processes that ensure functional integration between cells and organs. This disruption reduces the ability to maintain homeostasis under physiological stress, decreasing viability and increasing vulnerability [4, 5]. Ageing involves both functional decline and anatomical and physiological changes that can cause system decompensation if they surpass a certain threshold [2]. This review aims to explore the key age-related physiological changes that influence various organ systems and their impact on pharmacodynamics (PD) and pharmacokinetics (PK). Specifically, it examines how ageing alters the body’s response to drugs (PD) and affects drug absorption, distribution, metabolism, and elimination (PK), emphasising the interplay between these changes and their implications for drug efficacy, safety, and therapeutic management in older adults.

Defining PD changes has been more challenging than PK changes, primarily because many drugs have an amplified effect in geriatric individuals due to decreased drug clearance, leading to higher serum concentrations [4]. It is widely recognised that geriatric patients are more prone to certain drug toxicities and adverse drug effects (ADEs) because of these elevated serum levels. For instance, geriatric patients experience heightened cardiac toxicity from anthracyclines and increased neurotoxicity [2]. Benzodiazepines also illustrate this point, as geriatrics tend to show more sedation and reduced performance compared to younger individuals at the same plasma concentration [5]. Factors such as loss of neuronal substance [6], reduced synaptic activity [7], impaired brain glucose metabolism [8], and rapid drug penetration into the central nervous system (CNS) contribute to the increased sensitivity and stronger response of geriatrics to drugs that affect the peripheral nervous system (PNS) and CNS [9]. On the other hand, PK involves the movement of drugs and their metabolites through the body, covering absorption, distribution, metabolism and excretion (ADME) [4].

Method

A systematic search was conducted in accordance with PRISMA guidelines, focusing on the topic. The databases used for this search were PubMed, ScienceDirect, and Scielo, covering articles published between 2014 and 2024. The search targeted studies that explored ways in which ageing affects the PD and PK of medications administered long-term in geriatric patients. Keywords such as ‘ageing’, ‘pharmacodynamics’, ‘pharmacokinetics’, ‘chronic medication’, and ‘geriatric patients’ were employed. After the initial search, articles were screened based on their titles and abstracts to select relevant studies. Only articles in English were considered.

Pharmacodynamics Considerations in Geriatrics

Pharmacodynamics describes the effects of drugs on the body [4]. The pharmacological impact of a drug is influenced by the quantity and affinity of target receptors at the site of action, as well as signal transduction and homeostasis regulation [10]. Understanding PD changes in geriatrics is particularly challenging. Research has indicated some alterations in PD for drugs affecting the CNS and cardiovascular system. For instance, geriatrics show diminished sensitivity in their cardiac β-1 and β-2 adrenergic receptors (refer to Table 1), leading to a weakened response to β-agonists such as dobutamine (a β-1 agonist) and salbutamol (a β-2 agonist) [11, 12]. The exact mechanisms behind these changes remain largely unknown. Hypothesised mechanisms include variations in neurotransmitter and receptor concentrations, hormonal shifts, increased blood-brain barrier permeability, reduced P-gp activity, and compromised glucose metabolism [4, 13]. Additionally, alterations in homeostatic mechanisms, like weakened reflex tachycardia and disrupted regulation of temperature and electrolyte balance [10] can increase the likelihood of adverse drug reactions (ADRs) (refer to Table 1).

Table 1.

Provides an overview of the pharmacodynamic considerations specific to geriatric patients

Pharmacodynamic factor	Impact on geriatrics
Altered receptor sensitivity	Decreased sensitivity may necessitate higher doses for therapeutic effect
Drug metabolism	Slowed metabolism leads to prolonged drug action and increased risk of drug accumulation
Physiological changes	Age-related changes in organ function affect drug distribution and elimination pathways
Increased susceptibility to ADEs	Greater vulnerability to ADEs, necessitating careful dose adjustment
Pharmacodynamic interactions	Potential interactions with co-existing conditions and polypharmacy require consideration

It highlights how ageing influences drug responses and efficacy, emphasising key factors such as changes in receptor sensitivity, altered drug metabolism, and increased susceptibility to ADEs. Understanding these pharmacodynamic nuances is crucial for optimising medication therapy and ensuring safe and effective treatment outcomes in geriatrics [4, 10, 14]

ADEs adverse drug effects

Pharmacokinetic Considerations in Geriatrics

Drug Absorption

Pharmacokinetic studies on ways in which ageing affects drug absorption have yielded mixed results. Changes in absorption due to ageing are minimal. Interactions between drugs, diseases, and foods are the primary factors that can alter absorption [4, 16]. Age-related changes in drug absorption are not typically clinically significant, as absorption generally does not decrease markedly [16, 17]. However, drugs like levodopa show a notable increase in absorption rates in geriatric patients, likely due to reduced dopa-decarboxylase in the gastric mucosa [18]. In contrast, the absorption of drugs like iron and vitamin B, which rely on active transport mechanisms, is reduced [4]. For medications like penicillins, diazepam, and metronidazole that are absorbed via passive diffusion in the gut, age-related changes do not appear to be significant [11]. Hypochlorhydria, a condition more prevalent in older adults, can decrease the absorption of weakly basic drugs like ketoconazole [11, 23]. Generally, dosage adjustments are not necessarily solely due to ageing. Gastrointestinal tract (GIT) absorption becomes more important in patients with atrophic gastritis. Although gastric secretion does not significantly decline in healthy geriatrics, some drugs that need an acidic environment for ionisation, such as iron supplements, are affected by changes in gastric acid production [4, 19].

It is worth noting that geriatric patients are strongly associated with decreased and delayed gastric motility. Delayed gastric emptying affects drugs that are unstable in acidic environments, as it postpones their arrival at the preferred absorption site [4, 15]. A notable exception is calcium carbonate, which requires an acidic environment for optimal absorption [15]. Delayed gastric motility can benefit this drug by prolonging its presence in the stomach, enhancing absorption [4, 17]. Increased gastric pH, often observed in geriatric patients with atrophic gastritis, suggests that geriatrics should use calcium salts like calcium citrate, which dissolve more easily in less acidic conditions [20]. Enteric-coated medications, such as aspirin, may release early in the stomach due to altered absorption linked to increased gastric pH in geriatric patients, raising the risk of gastrointestinal (GI) ADEs [4, 20]. Also, geriatric patients are associated with reduced splanchnic blood flow and decreased intestinal mucosal surface area [4, 21, 22]. Ageing affects pancreatic secretion, leading to a significant decline in major enzymes like trypsin [23]. Discrepancies in these findings may stem from different methods used to assess drug absorption.

The rate of absorption at which subcutaneous or intramuscular medications are absorbed from their administration site into the bloodstream can be slowed by reduced tissue blood flow and accelerated by decreased muscle mass (which predominantly affects depot drug formulations) [4]. Additionally, declines in chest wall flexibility, ventilation–perfusion balance, and alveolar surface area can hinder the absorption of inhaled medications [26]. Therefore, while the ageing process generally impacts drug absorption, it does not usually have significant clinical relevance.

Drug Distribution

The distribution of medications throughout the body of geriatrics differs significantly from younger patients, which can lead to potential overdose risks. Geriatric patients typically experience a 20–40% increase in body fat, alongside a 10–15% decrease in lean body mass and total body water [4]. This altered composition affects the distribution volume of hydrophilic and lipophilic drugs, causing higher concentrations of hydrophilic drugs and prolonging the elimination half-life of lipophilic drugs. Lipophilic drugs like chlordiazepoxide, morphine, and amiodarone tend to have a larger distribution volume in geriatric patients, creating a larger reservoir within the body [4]. Because drug clearance is proportional to distribution volume, lipophilic drugs exhibit longer clearance times, resulting in extended durations of action and increased risk of residual effects, as observed with drugs like acitretin and first-generation H1-antihistamines (diphenhydramine) used for chronic hives [4, 25].

Conversely, hydrophilic drugs such as digoxin, lithium, ethanol, and theophylline have a reduced distribution volume, leading to higher plasma concentrations and necessitating smaller doses to achieve therapeutic levels [4, 26, 27]. Increased plasma concentrations can also affect the onset and duration of action of drugs like digoxin and lithium. Drug distribution changes in geriatric patients also decrease intracellular body fluid [4]. In contrast, lipid-soluble nonpolar drugs have increased volumes of distribution with age, leading to prolonged half-lives. This has been observed in drugs like diazepam, thiopentone, lignocaine, and chlormethiazole [4, 26–28]. For water-soluble drugs, the reduced volume of distribution is often balanced by decreased renal clearance, with little net effect on the elimination half-life [4, 26, 27].

Acidic drugs such as diazepam, phenytoin, warfarin, and acetylsalicylic acid primarily bind to albumin. In contrast, basic drugs like lidocaine and propranolol bind to α1-acid glycoprotein [4, 28–30]. While concentrations of these proteins generally remain stable with age, albumin levels can decrease due to conditions like malnutrition or acute illness; whereas α1-acid glycoprotein levels may increase during acute kidney injury [30, 31]. The unbound (free) concentration of a drug is crucial for its pharmacological effect and poses a higher risk of toxicity, particularly with drugs like valproic acid [4]. Changes in plasma protein binding theoretically could impact drug interactions or effects, particularly for highly protein-bound drugs such as phenytoin and warfarin, and may exhibit enhanced effects and increased ADRs with low albumin levels [4, 32].

As renal function declines with age and geriatric patients often have multiple comorbidities, concurrent drug therapies can lead to competition for protein binding sites in the bloodstream [33–35]. This competition may displace some drugs, resulting in a higher free fraction and altering drug PK. Ageing often results in reduced renal function, particularly glomerular filtration rate (GFR), affecting the clearance of many drugs, such as water-soluble antibiotics [35], diuretics [36], digoxin [37] water-soluble β-adrenoceptor blockers [4], lithium [38, 39] and non-steroidal anti-inflammatory drugs (NSAIDs) [40]. The clinical significance of reduced renal excretion depends on the drug’s toxicity. For drugs with a narrow therapeutic index, such as aminoglycoside antibiotics, digoxin, and lithium, even slight accumulation can lead to serious ADEs [34, 35].

Drug Metabolism and Clearance

Drug metabolism predominantly occurs in the liver, which alters with age (refer to Table 1). First-pass metabolism refers to the process by which a drug or other substance is metabolised before it enters the systemic circulation [4]. This primarily takes place in the liver, where enzymes such as cytochrome P450 3A4 (CYP3A4) play a crucial role, as seen with drugs like propranolol and lidocaine. First-pass metabolism can also occur in the gut, involving substances like benzylpenicillin, calcium antagonists, and insulin, where CYP3A4 is also active [4]. As people age, the effect of first-pass metabolism diminishes, likely due to a decrease in liver size and blood flow, as well as reduced activity of CYP and other biotransformation enzymes like flavin monooxygenases and UDP glucuronosyl transferases [4]. Consequently, the bioavailability of drugs that undergo significant first-pass metabolism and typically have low bioavailability, such as opioids and metoclopramide, can substantially increase [4]. Therefore, these drugs, particularly those with a narrow therapeutic index, should be started at a low dose. Alternatively, different administration routes such as intravenous, intramuscular, transdermal, and sublingual should be considered [4]. The first-pass activation of several prodrugs, including the angiotensin-converting enzyme (ACE) inhibitors enalapril and perindopril, may also decrease with reduced first-pass metabolism, potentially leading to lower systemic levels of the active drug. Conversely, increased bioavailability of drugs like propranolol and labetalol, which undergo extensive HFP metabolism. Reduced hepatic blood flow and decreased liver mass are the key factors contributing to diminished first-pass metabolism in geriatrics [4, 42–49]. This alteration can significantly increase the bioavailability of drugs like propranolol, necessitating lower initial doses (refer to Table 2).

Table 2.

Overview of pharmacodynamic changes that occur with ageing, highlighting their impact on drug action and the corresponding adjustments needed in dosing to ensure efficacy and safety in geriatric patients [4]

Pharmacological agent	Pharmacological effect	Age related changes		Recommendations for dosing
		Increased	Decreased
Beta agonists	Bronchodilation		✓	Increase gradually based on effect
Beta-blocking agents	Antihypertensive effect		✓	Increase gradually based on effect
Benzodiazepines	Sedation	✓		Decrease and monitor patients Only select glucoronidated benzodiazepines (e.g., lorazepam)
Antipsychotics	Sedation	✓		Decrease dose
Vitamin K antagonists	Anticoagulant	✓		Decrease based on INR
Furosemide	Diuretic		✓	Increase and monitor
Morphine	Analgesic	✓		Lower the dose or switch to an alternative
Verapamil	Antihypertensive effect	✓		Decrease dose, may need to add a laxative

INR international normalised ratio

Liver metabolism involves Phase I and Phase II processes that enhance drug hydrophilicity and facilitate excretion [4]. Age-related declines in the CYP450system may increase the bioavailability of drugs with high first-pass clearance (refer to Table 2), prompting dosage adjustments for medications like simvastatin and verapamil [4]. Numerous studies have demonstrated substantial decreases in the clearance of drugs processed by Phase 1 liver pathways, primarily because of age-related reductions in liver size and blood flow (refer to Table 3), although enzyme activity generally remains unchanged [4, 49, 50]. Conflicting findings exist regarding enzyme induction by factors like smoking in geriatrics. However, enzyme inhibition appears to be consistent across age groups. Less research has focused on the effects of ageing on conjugative metabolism, with most studies indicating no significant age-related changes. Recent observations suggest that reduced renal function can impact not only renally excreted drugs but also those extensively metabolised by the liver. This is due to decreased liver CYP450 activity, which is secondary to reduced gene expression in renal failure [48–50]. Thus, age-related declines in renal function could potentially influence hepatic drug metabolism, warranting further investigation. Phase II pathways like glucuronidation appear less affected by age, as seen with drugs such as lorazepam (refer to Table 2). Phase II metabolic pathways are preferred over the Phase I metabolic pathways because of their ability to evade fluctuations in bioavailability [4, 50].

Table 3.

Outlines the key pharmacokinetic parameters affected by the ageing process, including absorption, distribution, metabolism, and excretion, and provides insights into possible adjustments in medication dosing to accommodate these changes

	Increased	Decreased/diminished	Potential effect on the drugs	Recommendations for dosing	Examples of drugs that might be affected
Absorption [4, 33]					Propranolol, enalapril, aspirin, metoprolol
Gastric pH	✓		Reduced bioavailability of medications	Effect is not considered clinically significant
Gastrointestinal blood flow		✓		Effect may not be clinically significant
Gastric acid production		✓	Drug dissolution impaired Reduced drug bioavailability	Effect is not considered clinically significant	Erythromycin
Gastric motility		✓	Reduced drug bioavailability	Effect may not be clinically significant; consideration of a higher dose or alternative route of administration may be warranted.	Vitamin B12
First-pass metabolism	✓	✓	Increased (high clearance drugs) plasma concentration Decreased (for prodrugs) plasma concentration	Initiate therapy with a low dose (slow dosing is based on effect) Consider transdermal administration Effect not clinically significant	Morphine Nitroglycerin Valaciclovir
Distribution [4, 26, 27, 33]					Amiodarone, diazepam, digoxin, lithium, warfarin
Plasma albumin/affinity		✓	Drug toxicity	Dose based on effect (INR) Start low Free drug concentration increased.	Acenocoumarol
α1-acid glycoprotein	✓		Standard dose may be inadequate	Reduce loading dose Free concentration of basic drug decreased	Theophylline
Proportion of body fat	✓		Prolonged lipid-soluble drug half-life Distribution of lipid soluble drugs increased	Prolonged effect after discontinuation	Macrolides
Lean body mass		✓	Increased plasma concentration Water soluble drug distribution decreased	Lower standard dose of drugs with narrow therapeutic index Increased plasma concentration. Standard dose might be insufficient	Digoxin
Metabolism [4, 33, 54]					Propranolol, enalapril, amlodipine, theophylline, phenytoin
Hepatic blood flow		✓	Drugs with a high extraction ratio are associated with the largest reductions in hepatic clearance	Initiate therapy with a low dose Dose based on effect and side effects	Morphine
CYP450		✓	Decreased first pass effect of prodrug Competition for CYP450 hepatic enzymes	Effect not clinically significant Drug dosing is based on clinical effect Drug activity variable	Enalapril Macrolides
Elimination [4, 33, 34]					Furosemide, glipizide, morphine, digoxin, spironolactone
Renal function		✓
Glomerular filtration rate		✓	Risk of toxicity increased due to accumulation of drug in plasma	Monitor serum plasma concentrations	Gentamycin
Renal plasma flow		✓	Decreased drug removal	Initiate therapy with a low dose	Digoxin

CYP450 cytochrome P450, INR international normalised ratio

The liver’s ability to clear drugs and other substances is affected by factors such as hepatic blood flow, intrinsic clearance (which includes organ size, enzyme mass, and activity), and protein binding (refer to Table 3). For drugs that are highly extracted by the liver, clearance is primarily determined by hepatic blood flow (flow-limited metabolism) [4]. Conversely, for drugs with low extraction rates, clearance is mainly influenced by intrinsic clearance (capacity-limited) blood flow, which has minimal impact on clearance [4]. Drugs can be categorised into three groups based on their extraction ratio (E): high (E > 0.7, like metformin and nifedipine), intermediate (E between 0.3 and 0.7, like acetylsalicylic acid and triazolam), and low (E < 0.3, like digoxin and atenolol). Therefore, the age-related reduction in liver blood flow primarily affects the clearance of high extraction ratio drugs [4].

Transdermal drug absorption remains consistent between younger and geriatric patients, despite age-related thinning of the epidermis [4]. Nevertheless, smaller doses of transdermal drugs may be required in geriatrics due to age-related changes in drug metabolism [4]. For topical products, the reduction in hydration and lipid content of geriatric skin could theoretically reduce the absorption of hydrophilic drugs [51]. For geriatric patients, who often use multiple medications, transdermal delivery can be advantageous to bypass GI absorption and hepatic first-pass (HFP) metabolism, reducing ADEs and improving adherence [4]. Ageing is linked to a decline in HFP metabolism, probably due to reduced liver mass and blood flow (refer to Table 3).

Table 2 highlights some key age-related changes in PD. Since the impact of age on drug sensitivities varies depending on the drug and the specific response being assessed, making broad generalisations can be challenging. Research on drug sensitivity must include measurements of drug concentrations in plasma, as age-related PK differences can either amplify or diminish variations in drug response.

Drug Elimination

Elimination refers to the final process by which a drug exits the body. For most drugs, elimination occurs primarily through the kidneys. Kidney function typically starts to decline around mid-life and continues to decline with age [4]. This decline is linked to changes such as reduced kidney size and filtering capacity [52]. Common geriatric conditions like diabetes mellitus and hypertension can further worsen this decline [4]. Decreased GFR associated with ageing affects the clearance of hydrophilic drugs due to changes in total body weight and reduced distribution volume [4]. Adjustments in drug dosages are necessary based on measured renal function to ensure effective therapy.

As people age, their lean muscle mass decreases, which counters the expected increase in serum creatinine levels. Therefore, serum creatinine concentration becomes a less reliable indicator of renal function in the geriatrics [4, 53]. To prevent toxicity from drug accumulation in geriatric patients with decreased renal function, dosage reduction is advised for drugs with a narrow therapeutic index such as digoxin and theophylline (refer to Table 3). Drugs with active metabolites, such as spironolactone, should be used cautiously due to the potential for metabolite accumulation and intensified pharmacological effects in patients with reduced renal function (refer to Table 3). Adjustments in daily doses or dosing frequency are necessary for drugs that heavily rely on renal elimination [4, 48]. Maintenance doses may need adjustment during periods of illness, dehydration, or recovery from dehydration, as renal function can fluctuate [4, 48].

Pharmacokinetic and Pharmacodynamic Implications in Clinical Setting

Ageing Process

Ageing is a natural biological process marked by a steady and progressive decline in physiological and metabolic functions across various levels, including molecular, organellar, cellular, tissue, and organ systems. This decline is influenced by genetic, environmental, and lifestyle factors, leading to a deterioration of overall bodily functions and increased susceptibility to mortality [55, 56]. Metabolically, ageing is associated with significant changes in body composition, insulin resistance, and a reduction in the effectiveness of several key signalling pathways, such as those involving growth hormone, insulin/insulin-like growth factor 1 (IGF-1), and sex steroid regulation [57, 58]. Additionally, ageing impacts various biochemical processes, including inflammation [59], protein homeostasis [60], oxidative stress response [61], excretion [62] and energy metabolism. These age-related diseases impose a significant economic and psychological burden on patients, their families, and society at large.

Research indicates that ageing is the primary risk factor for numerous diseases, including cardiovascular conditions, diabetes, neurodegenerative disorders, and other common serious illnesses [61, 63]. Numerous strategies for mitigating age-related diseases have been widely researched, including calorie restriction through diet and exercise, as well as pharmaceutical treatments targeting specific cells and molecules [64]. While these treatments have shown promising results in various models, medication for the elderly remains a complex issue requiring careful consideration. This is due to the limited clinical data available, which makes it difficult to confirm the positive effects of these drugs. Additionally, the potential negative effects of these medications must also be thoroughly evaluated.

Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS), are increasingly prevalent as populations age, with age being the primary risk factor [65]. As ageing progresses, cellular repair mechanisms deteriorate, leading to oxidative stress, mitochondrial dysfunction, and the accumulation of neurotoxic proteins that contribute to neuron loss [66]. For instance, in Alzheimer’s disease, abnormal amyloid-beta proteins form plaques, while in Parkinson’s disease, alpha-synuclein aggregates impair motor neurons. These degenerative processes lead to progressive loss of brain function, manifesting as cognitive decline in Alzheimer’s and motor dysfunction in Parkinson’s [65]. Age-related changes in the immune system, particularly microglial cell activation and chronic inflammation, exacerbate neurodegeneration. Although ageing is the most significant risk factor, genetic predispositions, such as the APOE-e4 gene in Alzheimer’s, and lifestyle factors also play a role [65, 67]. Research into strategies such as calorie restriction, exercise, and pharmaceutical treatments targeting specific cells and molecules has shown promise in mitigating age-related diseases, yet challenges remain due to limited clinical data and the need for careful evaluation of medication effects, particularly in the elderly. As neurodegenerative diseases continue to grow in prevalence, their impact on quality of life and healthcare systems necessitates ongoing research and comprehensive strategies for prevention and management.

Geriatric Pharmacotherapy

Certain drug categories present special risks for geriatrics. Although some are appropriate for younger adults, they can be too hazardous for geriatrics. Geriatric patients are highly sensitive to the effects of anticholinergic drugs, as they can significantly impact the CNS leading to cognitive impairment. Common ADEs of anticholinergic drugs in geriatrics include constipation, urinary retention (particularly in men with benign prostatic hyperplasia), blurred vision, orthostatic hypotension, among others. Even at low doses, these medications can impair the body’s ability to regulate temperature, potentially increasing the risk of heatstroke by inhibiting sweating. As a general principle, geriatrics should avoid medications with anticholinergic effects whenever possible [4, 68, 69]. This approach helps mitigate the risks of CNS-related symptoms and other ADEs associated with these drugs, promoting safer medication management in geriatric populations. Therefore, it is important to study the relationship between ageing and the body’s response to drugs and by further examination compare the effects of various drug classes in both older and younger individuals.

Central Nervous System Drugs

Psychotropic Pharmacological Agents

Psychotropic medications are frequently used to treat mental health conditions such as depression and anxiety, especially when non-pharmacological approaches have not been effective [69]. They are also used to manage challenging behaviours, including the behavioural and psychological symptoms of dementia (BPSD) [69, 70].

The use of psychotropic medications tends to increase with age [71]. In care homes across Western Europe, studies have shown that up to 63% of residents are prescribed at least one psychotropic drug [72, 74]. This high rate of use is also observed among geriatrics in community settings [75]. Geriatric patients are more sensitive to the effects and side effects of drugs that affect the CNS [76]. Psychotropic use in this population has been linked to an elevated risk of severe adverse effects, including falls [77–79], stroke [80, 81], and mortality [77, 82].

It is well established that geriatrics are particularly susceptible to the adverse effects of psychotropic medications. These adverse effects include delirium, extrapyramidal symptoms, arrhythmias, and postural hypotension, to mention a few [83, 84]. Geriatrics are more likely than younger people to be hospitalised due to adverse drug reactions related to psychotropic medications [85]. The risk of such reactions increases significantly with the number of medications used and with advancing age. Therefore, it is crucial for healthcare providers who care for geriatrics, in any setting, to be well-informed about these medications and to effectively identify and manage any side effects or adverse reactions.

Benzodiazepines

Benzodiazepines, being lipid-soluble, tend to have a prolonged half-life in geriatric individuals due to their accumulation in fat tissues. This extended duration of action, combined with the increased sensitivity of geriatrics to sedative-hypnotics, can lead to delirium [86]. According to Beers' criteria, it is advisable to avoid long-acting benzodiazepines in the elderly, with a preference for short- and intermediate-acting options [86, 87].

Advancing age is linked to heightened sensitivity to the CNS effects of benzodiazepines [89]. For instance, diazepam can induce sedation at lower doses and plasma concentrations in geriatrics. Similarly, sensitivity to loprazolam increases with age [6]. The precise mechanisms behind this heightened sensitivity to benzodiazepines in the elderly remain unclear.

The adverse effects of benzodiazepines, such as dizziness, ataxia, drowsiness, and impaired psychomotor function, tend to become more pronounced with age [90]. This increased susceptibility to sedation and psychomotor impairment in the elderly may be due to reduced drug clearance and higher plasma concentrations, as benzodiazepines are lipid-soluble [6, 86, 90]. Benzodiazepines with long durations of action, like diazepam, are especially prone to accumulation, leading to a higher likelihood of sedative effects and psychomotor impairment [91]. Research has shown that geriatric individuals taking benzodiazepines with a long elimination half-life face an increased risk of falls [92, 93], a higher likelihood of hip fractures [94], and a greater chance of being involved in motor vehicle accidents due to sedation [90].

There are no randomised controlled trials (RCTs) specifically assessing buspirone for anxiety treatment in geriatric patients. However, data from adult studies suggest that it could be a valuable adjunct for managing anxiety disorders [95, 96]. Buspirone has shown effectiveness in treating generalised anxiety disorder (GAD) with fewer side effects compared to benzodiazepines. Several cases report its usefulness in addressing agitation and anxiety in dementia patients [96]. Unlike benzodiazepines, buspirone does not cause respiratory depression, cognitive impairment, or increase the risk of falls. However, it may have higher discontinuation rates, possibly due to its delayed onset of action [96].

Maust et al. observed that benzodiazepine usage increased with age among members of a large health maintenance organisation in the USA [97]. Additionally, Lukačišinová et al. reported a higher usage of benzodiazepines in European countries mainly Spain, Croatia and Serbia [98], with diazepam, alprazolam, lorazepam and bromazepam being frequently prescribed. Research indicates a troubling trend in the increasing use of benzodiazepines among geriatric patients, particularly during hospitalisation [99, 100]. Studies show that a significant number of geriatric patients are prescribed benzodiazepines while hospitalised, raising concerns about the potential for chronic use following discharge. This is especially problematic given that new prescriptions at discharge can lead to long-term dependence [101].

Notably, the prevalence of benzodiazepine use remains consistent across age groups, even among those aged > 65, who are generally more vulnerable to the sedative effects of these medications. For instance, data reveal that even in the highest age bracket, 11.9% of individuals continue to use benzodiazepines. This persistence in prescribing practices highlights the need for heightened awareness and careful monitoring of benzodiazepine use in geriatrics, especially considering the associated risks of cognitive impairment and falls [101].

It is well-established that long-term benzodiazepine use carries significant risks, and abrupt discontinuation can lead to withdrawal symptoms [102]. While cognitive impairments are clearly associated with the acute administration of benzodiazepines, research varies on the extent of cognitive deficits in long-term users. Some studies indicate that chronic use leads to persistent cognitive difficulties, while others suggest that cognitive impairments in healthy long-term users are only modest [101–103]. Additionally, there is some evidence linking chronic benzodiazepine use to an increased risk of developing dementia later on [104, 105]. Recent studies highlight a concerning trend in the prescribing of benzodiazepines among adults. Between 2003 and 2015, primary care office visits where benzodiazepines were prescribed nearly doubled, rising from 3.8 to 7.4% [100]. This increase suggests a growing reliance on these medications for managing anxiety and sleep disorders, despite their known risks, particularly in geriatric populations. Moreover, a significant proportion of hospitalised patients—29.5%—received at least one benzodiazepine during their stay [100]. This high frequency raises alarms about the potential for dependence and the continuation of benzodiazepine use post-discharge, which can contribute to adverse effects, including cognitive decline and increased fall risk. These findings underscore the importance of reassessing prescribing practices and considering safer alternatives, especially for vulnerable populations [106].

Antidepressants

Depression stands out as a leading cause of disability globally and significantly contributes to the overall burden of disease [107]. In geriatric populations, it is one of the most prevalent psychiatric disorders, posing serious risks for both disability and mortality [108]. Alarmingly, nearly 50% of depression cases in geriatric patients remain undiagnosed [116]. Estimates of depression prevalence in this age group vary widely, with the World Health Organization (WHO) suggesting rates between 10 and 20% [109]. Among individuals with mental health issues, approximately 40% are diagnosed with a depressive disorder, which correlates with a 40% increased risk of premature death compared to their peers [109].

It is well established in the literature that geriatrics metabolise medications more slowly than younger individuals, making them more susceptible to adverse side effects or acute toxic reactions. Additionally, geriatrics are more likely to have multiple medical conditions that require additional medications, further complicating antidepressant treatment [110]. Clinical data specific to treating depression in elderly patients are limited, often leading to treatment recommendations based on studies conducted in younger populations or small studies involving elderly patients. Moreover, the medically ill and the “oldest old” (those aged > 85 years) are typically excluded from clinical trials, resulting in a scarcity of data on these groups [111–113].

The manifestation of depression in geriatrics is often complicated by cognitive issues, as symptoms such as memory difficulties, distress, and anxiety can overshadow the underlying depression [108, 114]. This misdiagnosis can hinder appropriate treatment, exacerbating physical disabilities and interfering with rehabilitation efforts [108, 115, 116]. The ramifications of untreated depression extend beyond individual health, leading to economic burdens due to increased healthcare costs and lost productivity [108–117]. Given these complexities, addressing mental health in the elderly is crucial, especially to prevent escalating suicide rates in an increasingly ageing society [108]. Prioritising the detection and treatment of depression can have profound effects on both individual well-being and public health outcomes.

Tricyclic Antidepressants

For many years, tricyclic antidepressants (TCAs) were the primary treatment option for depression [118]. While effective, their adverse effects make them less suitable, particularly for geriatric patients. Tricyclic antidepressants can cause a range of side effects due to muscarinic receptor blockade, including dry mouth, sweating, tachycardia, urinary retention, blurred vision, postural hypotension, and confusion [118, 119]. Of particular concern is postural hypotension, which can lead to serious outcomes such as sudden drops in blood pressure, increasing the risk of hip fractures (especially femoral neck fractures) [120, 121]. Tricyclic antidepressants, as introduced in the 1950s as a treatment for depression, still remain a viable option for certain patients [131]. Particularly those whose depression has not responded to newer, less toxic antidepressants like selective serotonin reuptake inhibitors (SSRIs) [123]. Despite the preference for SSRIs in contemporary practice, TCAs continue to hold therapeutic value.

Research has highlighted a concerning relationship between depression and bone health, indicating that depression is linked to lower bone density and an increased risk of fractures [122]. The connection between SSRI use and fracture risk has been extensively studied, leading to considerable attention on how these medications affect bone health [133]. In particular, the association between TCA use and osteoporotic fractures has been documented in numerous studies [122, 125]. While many reports indicate a significant relationship between TCA use and an increased risk of fractures, some studies have failed to find a significant correlation [126–128]. This inconsistency in findings suggests that the impact of TCAs on bone health may require further investigation, particularly considering the complexities of patient populations and comorbid conditions.

The TCAs can induce cardiovascular complications such as arrhythmias, heart blocks, myocardial infarction (MI), stroke, and reduced atrioventricular conduction [119, 129]. Amitriptyline is known for causing sedation and has strong anticholinergic effects [130, 131]. Imipramine has antiarrhythmic properties [132], while nortriptyline can make it difficult to fall asleep [133, 134]. Among TCAs, nortriptyline and desipramine tend to be better tolerated by older adults [119]. Nevertheless, second-generation antidepressants are generally favoured for geriatric patients and those with heart disease, as they have fewer side effects and are less toxic in overdose situations [135]. It is important to recognise that all antidepressants can potentially cause delirium in geriatric patients. Thus, TCAs are prone to induce delirium, due to their anticholinergic properties [136, 137].

Atypical Antidepressants

Atypical antidepressants are newer compounds that offer the benefits of TCAs but with significantly fewer side effects. These pharmacological agents are believed to have various mechanisms of action even though they are from the same class [138]. Bupropion, an aminoketone with three pharmacologically active metabolites, is an effective and well-tolerated antidepressant for geriatric patients. Although its exact mechanism of action is not fully understood, bupropion likely exerts its effects through noradrenergic pathways [138]. The main side effects of bupropion include insomnia, agitation, and headache. The most severe side effects of bupropion include a reduced seizure threshold and an increased risk of worsening suicidal thoughts [138, 139].

Mirtazapine has not been extensively studied in the context of treating late-life anxiety disorders, but one investigation focused on its use in geriatric patients with post-traumatic stress disorder (PTSD) [96]. Crocco et al. reported on a study which found mirtazapine to be effective for managing PTSD symptoms in this demographic. Its favourable side effect profile and minimal potential for drug-drug interactions make mirtazapine a recommended option for geriatric patients [96]. Mirtazapine can be particularly beneficial for geriatric adults experiencing anxiety alongside sleep disturbances or appetite loss. Its sedative properties can help improve sleep, while its appetite-stimulating effects can address weight-loss issues [96]. Thus, mirtazapine presents a safe and effective treatment option for geriatric patients dealing with both anxiety and related symptoms, positioning it as a valuable tool in managing their overall well-being. A 2018 systematic review and network meta-analysis comparing the efficacy and acceptability of numerous antidepressants found mirtazapine to be among the most effective in head-to-head trials. The evidence suggests that mirtazapine is beneficial across all levels of depressive severity and can address a wide range of depression-related symptoms [140]. Additionally, a recent RCT assessed mirtazapine for the treatment of methamphetamine-use disorder. The study found that mirtazapine reduced methamphetamine use and high-risk HIV behaviours, with these benefits persisting beyond the treatment period [141].

Selective Serotonin Reuptake Inhibitors (SSRIs)

Ageing and mental illness pose significant challenges for both patients and healthcare providers. Late-life depression often develops alongside medical comorbidities, cognitive decline, socioeconomic challenges, and bereavement. Due to the prevalence of depression, antidepressant use is widespread among individuals aged ≥60 years, with around 19% reporting use [142]. However, many in this age group receive antidepressant treatment at suboptimal doses or for insufficient durations. For example, a German study found that 26% of older adults on SSRIs and 41% on serotonin and norepinephrine reuptake inhibitors (SNRIs) were given subtherapeutic doses [143]. Similarly, in the USA, 35% of geriatric patients diagnosed with depression were prescribed antidepressants at low-intensity regimens, with 8% receiving inadequate doses, 19% insufficient treatment durations, and 15% inadequate follow-up care [111]. These suboptimal treatments are concerning, especially as SSRIs and SNRIs are generally considered easy to administer. Additionally, inappropriate medications, such as benzodiazepines and anticholinergics, are commonly prescribed to geriatrics on antidepressants, with around 56% of this population affected [144]. As a result, deprescribing has become vital for optimising medication use. Extensive guidelines recommend avoiding anticholinergics and benzodiazepines in geriatric patients due to the increased risks of falls and cognitive decline, highlighting the need for practical solutions to overcome barriers to deprescribing and to identify safer alternatives [87, 145].

Fluoxetine is commonly prescribed for geriatric patients [146]. However, despite extensive research supporting its efficacy and safety, there are limited published data on the pharmacokinetics of this drug in the elderly. Despite its widespread use, 30–40% of patients treated with fluoxetine do not achieve an adequate therapeutic response, and 50% of individuals diagnosed with major depressive disorder fail to respond to initial SSRI therapy [146–148]. The factors contributing to this unexpected response to fluoxetine have not been extensively studied in the Mexican population. However, previous research has aimed to identify various factors that may influence the therapeutic response to other SSRIs and predict a successful treatment outcome [149, 150]. These elevated fluoxetine levels may lead to toxic effects in geriatric patients, including excessive CNS stimulation, sleep disturbances, and increased agitation [151]. Among SSRIs, paroxetine has a high affinity for muscarinic receptors, similar to nortriptyline. High-quality evidence shows that paroxetine has strong anticholinergic properties and carries a significant risk of causing sedation and orthostatic hypotension, making it unsuitable for use in geriatric patients [87]. Instead, several safer alternatives are recommended for this population, including citalopram, escitalopram, sertraline, venlafaxine, mirtazapine, and bupropion.

Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors (MAOIs) belong to a distinct class of antidepressants used to treat various forms of depression and certain nervous system disorders, including panic disorder, social phobia, and depression with atypical features. Although MAOIs were the first antidepressants developed, they are not the preferred treatment due to their dietary restrictions, side effects, and safety risks. They are typically reserved as a treatment option when other medications have proven ineffective [152]. While MAOIs are often considered risky and challenging to manage, medications like phenelzine are relatively safe and effective for use in older adults [112]. However, it is essential to be mindful that MAOIs can lead to complications such as hypotension, hypertension, and food-drug interactions. Moclobemide, on the other hand, is well tolerated by elderly patients. Although a restrictive diet is unnecessary, patients should still be informed about potential interactions with painkillers and other antidepressants [112].

Mood Stabilisers and Antiepileptics

Mood-stabilising drugs are commonly prescribed to prevent the recurrence of depression and to manage and treat bipolar disorder. This group of medications includes lithium as well as anticonvulsants such as carbamazepine and valproic acid [153, 154]. Recent longitudinal studies of long-term care residents with dementia in Canada reveal a noteworthy trend: while there has been a 6% decline in antipsychotic prescribing, there has been a significant increase in the use of both sedative and non-sedative antidepressants, as well as a small increase (2%) in the use of mood stabilisers [155, 156]. Notably, these analyses did not specifically address mood stabilisers, and the patterns observed align with findings from cross-sectional studies in Europe and Australia, where antidepressants are the most commonly prescribed, followed by sedative-anxiolytics and antipsychotics [83, 157].

Lithium, commonly used to treat bipolar disorder and mania, requires careful plasma concentration monitoring, particularly in geriatrics [39, 158]. Since lithium is metabolised and excreted by the kidneys, and kidney function tends to decline with age, dosages should be reduced for elderly patients [38, 159]. Additionally, geriatrics with coexisting physical conditions who take multiple medications that can disrupt water and electrolyte balance may experience dangerous fluctuations in lithium levels [38]. Lithium can also affect renal sodium excretion [160, 161], alter thyroid function [38], and cause heart conduction disturbances [162], necessitating close monitoring. The concurrent use of thiazide diuretics should be avoided or accompanied by a reduction in lithium dosage, as these diuretics can decrease lithium excretion [163]. There is limited evidence supporting the use of mood stabilisers for treating anxiety disorders, particularly in geriatric patients. Most research on mood stabilisers in geriatrics focuses on bipolar disorder rather than anxiety, and the studies are often constrained by small sample sizes. Even lithium, one of the most widely recognised mood stabilisers, shows minimal and mixed results that are not specifically linked to anxiety treatment [96]. In Ontario, Canada, a notable shift in prescribing patterns was observed, with divalproex being favoured over lithium for patients aged ≥ 65 years, despite a lack of strong justification for this change [39]. Shulman et al. conducted a Delphi survey focused on lithium maintenance therapy in older-age patients with bipolar disorder (OABD). The survey endorsed lithium as the preferred first-line treatment for maintenance therapy in OABD. A consensus was also reached on the essential blood tests, appropriate lithium serum levels, and the identification of toxicity signs during treatment [164].

Anticonvulsant medications, often used as mood stabilisers, have been studied for their potential in treating anxiety-related conditions. Research supports the use of carbamazepine and lamotrigine for PTSD, although findings on valproate in PTSD have been inconsistent [96]. Valproate has shown some effectiveness in treating panic disorder and social anxiety, while lamotrigine has been beneficial in PTSD, panic disorder with agoraphobia, and unipolar depression with comorbid anxiety [96]. However, despite these findings in adults, anticonvulsants pose significant risks for geriatrics due to side effects such as cognitive slowing, tremor, liver issues, rash, and sedation, which can be particularly disabling [96]. Therefore, these medications are generally not recommended as first-line treatments for anxiety disorders in geriatric patients due to their side-effect profiles.

The incidence and prevalence of epilepsy are highest among the elderly, nearly twice that of children, and it continues to increase with age. For individuals aged > 80 years, the frequency is about three times higher than in children. With global populations ageing, the number of epilepsy cases in the elderly is expected to rise [165]. Selecting appropriate antiepileptic drugs (AEDs) for elderly patients is crucial, given the PK and PD changes they experience, as well as their increased susceptibility to drug-drug interactions due to polypharmacy for comorbid conditions. Both the International League Against Epilepsy (ILAE) and the American Epilepsy Society/American Academy of Neurology (AES/AAN) recommend lamotrigine and gabapentin as effective monotherapies for newly diagnosed and untreated focal seizures based on strong evidence [165, 166]. However, no specific guidelines exist for geriatric patients with other seizure types. This population is more sensitive to AED adverse effects, and compliance often suffers more due to these side effects than due to the efficacy of the drugs. Thus, when treating epilepsy in geriatric patients, clinicians should consider the PK, comorbidities, and concurrent medical treatments [165, 167].

In treating epilepsy, geriatric patients generally require lower doses of AEDs compared to younger adults. However, higher doses of valproic acid (VPA) may be necessary for patients taking medications that induce hepatic microsomal enzymes. Controlled-release preparations, administered once daily, can improve compliance and potentially lead to seizure freedom in some elderly patients [177]. Geriatrics are more vulnerable to the adverse effects of AEDs than younger individuals, with dose-dependent and idiosyncratic reactions occurring more frequently [169]. Common side effects of VPA include nausea, vomiting, abdominal pain, and heartburn. To minimise these side effects, a slow tapering of the dosage is recommended, especially in elderly patients. A severe side effect of VPA, due to its idiosyncratic toxicity, is hepatotoxicity [169].

Pharmacokinetics studies have indicated significant differences in VPA distribution between elderly and younger populations [177]. The efficacy of VPA has been established through studies primarily involving younger adults, and although elderly patients were included, they represented a minority. Valproic acid has demonstrated comparable effectiveness to other AEDs like carbamazepine and phenytoin for various seizure types, including partial-onset and generalised tonic-clonic seizures. Notably, VPA does not exacerbate myoclonic jerks, which is an advantage over some other AEDs [168]. Newer AEDs tend to be more suitable for elderly patients due to their lower risk of side effects and fewer drug interactions. Traditional AEDs like carbamazepine, phenytoin, and phenobarbital are enzyme inducers, which can reduce the efficacy of medications such as anticoagulants, antidepressants, and cardiovascular drugs. In contrast, valproate is an enzyme inhibitor and may increase the concentration of other drugs. Newer AEDs like lamotrigine and levetiracetam, with minimal drug interactions, may be more appropriate for geriatrics on multiple medications [165].

Since hepatic metabolism decreases with age, careful dose adjustments and slow titration are important to minimise the effects of AEDs that rely on liver metabolism, such as carbamazepine. Similarly, for drugs that are excreted through the kidneys, like levetiracetam or pregabalin, dose reductions may be necessary in cases of reduced creatinine clearance (CrCl) [165]. High-protein-binding AEDs, such as phenytoin, require dose adjustments in patients with low albumin levels to prevent toxicity [170]. Additionally, oxcarbazepine can cause hyponatraemia, especially in geriatric patients, so sodium levels should be monitored [165, 171]. Combining valproate with topiramate may lead to encephalopathy, so this combination should be used with caution [172]. Extended-release AEDs or those with a long half-life, allowing once-daily dosing, may enhance patient compliance [165]. Clinical trials have shown that while lamotrigine and carbamazepine have similar efficacy, lamotrigine is better tolerated. A retrospective study comparing numerous AEDs in patients aged > 55 years found that lamotrigine had the highest 12-months retention rate (79%), significantly higher than carbamazepine, gabapentin, oxcarbazepine, phenytoin, and topiramate. Levetiracetam followed with a retention rate of 73%, also significantly higher than carbamazepine and oxcarbazepine [165, 173, 174].

Psychostimulants

Since their introduction in the 1930s, psychostimulants such as amphetamine and methylphenidate have been utilised in the treatment of depression. Methylphenidate, a CNS stimulant, is approved by the US Food and Drug Administration (FDA) for managing attention-deficit/hyperactivity disorder and narcolepsy [175, 176]. Depression, apathy, and fatigue are common among medically ill geriatric adults and patients with advanced diseases and have been linked to increased morbidity and mortality. Methylphenidate has been used to address these symptoms due to its fast-acting effects [175]. However, some studies have reported elevated liver enzymes and blood pressure changes in geriatric patients undergoing long-term treatment with this medication [175, 177]. In 2015, Lavretsky et al conducted the first randomised, placebo-controlled trial to assess the efficacy and tolerability of a combined treatment strategy using methylphenidate and citalopram in geriatric depression. This study compared the combination therapy to citalopram or methylphenidate monotherapy, as well as to a placebo group [178]. The results demonstrated a significant improvement in both depression severity and cognitive performance in the three treatment groups receiving active medication compared to the placebo group. These findings suggest that combining methylphenidate with citalopram could be a more effective approach to treating depression in geriatric patients than monotherapy with either agent alone.

Amphetamines and anorectic agents carry a high risk of causing dependence, hypertension, angina, and MI, particularly in elderly patients [179, 180]. Since these drugs can exhibit significant cardiovascular effects, this is particularly concerning in older populations, as ageing is often associated with conditions like hypertension and atherosclerosis [181]. The use of amphetamines can potentially heighten cardiovascular risks, leading to serious outcomes such as MI, stroke, and sudden death in individuals with pre-existing cardiovascular conditions [182]. Given these risks, it is crucial to conduct thorough cardiovascular assessments before and during treatment with these medications in geriatrics, ensuring that their use is carefully monitored. A retrospective study by Michielsen et al. suggested that stimulants can be a safe treatment option for geriatric patients with ADHD, provided that cardiovascular parameters are carefully monitored and appropriately managed during treatment [183]. This highlights the importance of regular cardiovascular assessments and vigilant management of any cardiovascular risks, ensuring that the benefits of stimulant use outweigh the potential risks in this vulnerable population.

Antipsychotic Drugs

Antipsychotic drugs are commonly used to manage psychiatric disorders in geriatric patients. For agitated dementia with delusions, the first-line treatment is typically an antipsychotic drug, with the potential addition of a mood stabiliser if necessary [184]. Regulatory agencies issued warnings in the mid-2000s regarding the use of atypical antipsychotics in people with dementia due to an increased risk of death and stroke in this population [184]. Similarly, cohort studies have demonstrated an association between the use of typical antipsychotics and a heightened risk of mortality in geriatric individuals [184, 185]. However, it has been suggested that this observed relationship might be influenced by “confounding by indication,” as many cohort studies included people with terminal illnesses or delirium without adjusting for the severity of their condition. This could also help explain why the risk of mortality appears to be highest during the first month of antipsychotic use [186].

The use of antipsychotic medications, particularly clozapine and olanzapine, has been linked to an increased risk of treatment-induced diabetes mellitus and dyslipidaemia, especially in patients receiving risperidone. Recent studies have also highlighted a modest, time-limited increase in the risk of acute MI associated with antipsychotic use among community-dwelling older adults initiating cholinesterase inhibitors [187]. In 2005, the FDA issued a warning regarding the elevated risk of all-cause mortality in elderly patients with dementia using antipsychotics, which was later extended to conventional antipsychotics in 2008. Despite ongoing debates and mixed conclusions in the scientific literature, regulatory agencies continue to recommend caution, noting that the use of atypical antipsychotics for behavioural and psychotic disorders in dementia is off-label [187]. Additionally, both conventional and atypical antipsychotics have been associated with an increased risk of sudden death and pneumonia, likely due to their anticholinergic effects leading to complications such as swallowing difficulties. Other serious risks, such as deep venous thrombosis, have also been reported [187].

While atypical antipsychotics like quetiapine are sometimes prescribed off-label for anxiety disorders, their safety in elderly patients is still under scrutiny [96]. Quetiapine has shown efficacy in generalised anxiety disorder and may be beneficial when used as an adjunct to SSRIs for obsessive-compulsive disorder and post-traumatic stress disorder. However, safety data for long-term use, particularly in geriatrics, are limited, and there are concerns regarding metabolic side effects, including impacts on endocrine function [96]. In direct comparison of treatments, no significant difference was found between olanzapine and risperidone when combined with an SSRI, while quetiapine demonstrated better efficacy than ziprasidone as an adjunct. However, the use, tolerability and safety profile of antipsychotics in elderly patients with anxiety remain under-researched. Their use raises concerns, as many atypical antipsychotics are linked to metabolic changes, and treatments that do not impact endocrine function are preferable. The increased risk of death in cognitively impaired geriatric patients associated with antipsychotic use should also discourage their use. Over time, antipsychotics may contribute to osteopenia and bone loss, posing significant risks for geriatric individuals. As a result, antipsychotics should not be considered standard treatment for anxiety in elderly patients [96].

Cardiovascular Drugs

Antihypertensives

Hypertension is a significant risk factor for cardiovascular disease, stroke, and renal disease, and its prevalence notably increases with age, affecting approximately 65% of geriatric patients [188]. The pathophysiology of hypertension in the elderly is complex and multifactorial. According to guidelines for treating hypertension in geriatric patients, this condition is characterised by increased total peripheral vascular resistance, decreased arterial compliance, a tendency towards reduced cardiac output and circulating blood volume, increased blood pressure variability due to age-related baroreceptor function decline, and decreased blood flow with dysregulated auto-regulation in critical organs such as the brain, heart and kidneys. These age-related changes should be considered when managing blood pressure in the elderly to avoid adverse effects, such as postural hypotension, which can increase the risk of falls and major fractures. It is important to note that in elderly patients, the risk of cardiovascular disease is directly related to systolic and pulse pressures, and inversely related to diastolic pressure. While there are guidelines for managing systolic pressure, clear recommendations for a tolerable threshold for diastolic blood pressure in older adults are lacking [189–195].

Several challenges can hinder the attainment of target blood pressure in geriatric patients. Lowering blood pressure may lead to cognitive impairments, confusion, sleepiness, dizziness, and syncope associated with postural hypotension, all of which can significantly affect quality of life. Additionally, many trials demonstrating benefits of hypertension treatment in geriatric patients were conducted with relatively healthy participants. Therefore, caution is needed when applying these findings to frail elderly individuals [196, 197]. All antihypertensive drugs can predispose older patients to symptomatic orthostatic hypotension, postprandial hypotension, falls, and syncope. The adverse effects vary depending on the specific antihypertensive drugs used, their dosages, the presence of co-morbidities, and potential drug-drug interactions [198, 199].

Delirium linked to β-blocker use may manifest through symptoms like confusion, disorientation, agitation, aggression, as well as visual and auditory hallucinations [200]. Calcium channel blockers also have notable adverse effects; for example, verapamil is primarily linked to bradyarrhythmia and constipation, while nifedipine is associated with hypotension, peripheral oedema, skin rash, and tachycardia [201]. Fahie et al. reported that verapamil's inhibition of slow calcium channels in pancreatic beta cells can suppress insulin release, potentially resulting in hyperglycaemia. When a patient presents with bradycardia, hypotension, metabolic acidosis and hyperglycaemia, it may signal verapamil toxicity. The most severe risks associated with verapamil overdose are bradycardia and hypotension, which can be fatal if not properly treated [36].

Diuretics

Age-related changes in renal tubular function can influence how drugs affect the kidneys, particularly with organic acid diuretics like furosemide and bumetanide [202, 203]. For example, the renal tubular clearance of bumetanide is lower in geriatrics compared to younger individuals, attributed to decreased renal tubular secretion in the elderly [202]. As a result, higher plasma levels of diuretics in elderly patients may lead to toxic effects. Diuretic therapy in geriatric patients requires careful management due to their increased susceptibility to fluid and electrolyte imbalances, such as hypokalaemia, hyponatremia, hypomagnesemia and volume depletion [203–205]. Additionally, diuretics can trigger delirium through dehydration and electrolyte disturbances [206].

Several studies have examined the impact of ageing on the PK of intravenously administered furosemide. They found that while the volume of distribution remains similar between older and younger individuals, renal clearance is reduced and the half-life is prolonged in the elderly. This diminished effect of furosemide in older adults is primarily attributed to decreased tubular secretion, potentially due to reduced renal plasma flow [4, 207].

Okoye et al. reported on numerous studies that explored potential hormonal changes and their association with clinical parameters such as heart failure symptoms, blood pressure, and heart rate. The findings contribute to a broader understanding of diuretic withdrawal in heart failure management [208]. In a related study by Rohde et al., it was demonstrated that 65% of patients tolerated diuretic withdrawal with no decline in exercise capacity or deterioration [209]. Romano et al. reported that no patients required resumption of diuretic therapy or experienced cardiovascular death or rehospitalisation for acute decompensated heart failure following loop diuretic withdrawal [210].

In terms of renal function, Okoye et al observed significant improvements in urea and creatinine levels among diuretic withdrawal patients after 3 months [209]. However, Romano et al. found a worsening of renal function in patients continuing on loop diuretics [210], while another study showed no difference in creatinine and blood urea nitrogen between groups with or without loop diuretics [208]. These mixed findings underscore the importance of careful patient selection when considering loop diuretic discontinuation in heart failure [209].

Digitalis

Digoxin is effectively absorbed in the gastrointestinal tract, but with geriatrics, the time to peak plasma concentrations is extended from an average of 38 h in younger individuals to 69 h in older adults. Consequently, the time required to achieve steady-state plasma concentrations increases from 7 days to 12 days in the elderly. Reduced lean body mass, a common consequence of ageing, also decreases the distribution volume of digoxin [109]; thus, necessitating a reduction in loading doses by approximately 20%. Several factors contribute to an increased risk of digoxin toxicity in geriatrics, including renal impairment, temporary dehydration and the use of NSAIDs, which are prevalent in this age group [212]. In elderly patients, the reduced renal clearance can cause even standard doses of digoxin to accumulate, leading to toxicity and delirium. Since digoxin is primarily cleared through the kidneys and its clearance is directly related to CrCl, the systemic clearance of digoxin decreases by 50% in older adults with normal clearance. As clearance is a key factor in determining the maintenance dose, the daily dosage of digoxin should be adjusted downward based on renal function and body weight [211].

A study by Qamer et al. aligned with previous research that highlights the benefits of digoxin in reducing the risk of hospital readmission in patients with heart failure, without significantly impacting overall mortality [212]. Notably, this study extends prior observations by demonstrating that these benefits occur even in patients who are concurrently receiving treatment with ACE inhibitors, ARBs, and beta-blockers [212]. Qamer et al. reported on earlier randomised controlled trials, which have shown digoxin to reduce hospital admission rates in ambulatory heart failure patients who were on ACE inhibitors [213]. Real-world studies have further confirmed that digoxin is associated with a lower risk of heart failure readmission in patients treated with a combination of ACE inhibitors, ARBs, and beta-blockers. This underscores the potential utility of digoxin as part of a comprehensive heart failure management strategy, particularly for reducing readmissions [213, 214].

Statins

In geriatric patients, statins are generally well tolerated, with most adverse effects being mild and short-lived. Tolerance to statins like rosuvastatin, atorvastatin, simvastatin, and pravastatin appears consistent across these treatments in the broader population [215]. Research indicates that the safety profiles of atorvastatin and simvastatin are comparable in patients younger and older than 65 years who have stable coronary disease. However, monitoring levels of creatine kinase and liver enzymes (aspartate aminotransferase [AST] and alanine transaminase [ALT]) is essential when using statins, as these medications can lead to rhabdomyolysis and myopathy in both elderly and younger individuals [19–217]. A study by Khan et al. highlighted that musculoskeletal symptoms can be experienced by patients taking statins [218], Russo et al reported on the abnormalities in creatine kinase and liver enzymes precipitating drug-induced liver injury being frequently a reported side effect reported by clinicians [219].

McIver et al. reported that patients initiating atorvastatin should undergo baseline liver function tests and a lipid panel, followed by a repeat lipid panel 6 weeks after starting therapy [216]. Liver function tests should be repeated as needed based on clinical indications. Once the patient is stable, lipid levels can be monitored every 6 to 12 months. While statin therapy is generally safe, it can lead to small increases in creatine kinase levels, especially with higher doses. For instance, rosuvastatin 20 mg daily caused an 8 U/L increase, while atorvastatin 40 mg daily led to a 20 U/L increase. Despite this, myopathy remains a rare side effect and is more likely to occur at higher doses [220]. Additionally, periodic monitoring of serum blood glucose levels is advisable for patients with diabetes or those at risk of developing the condition [216]. Elderly individuals, due to their shorter life expectancy and higher burden of comorbidities, may derive fewer benefits from statin therapy compared to younger populations. This makes it critical to balance the advantages and disadvantages of statin use, especially when high doses are prescribed. Although statins have been shown to reduce cardiovascular risk, the benefit-risk ratio must be carefully evaluated in geriatric patients, who often have more complex health profiles.

Statins have been consistently shown to reduce cardiovascular events in both younger and older populations. For patients aged over 65 years, statin therapy reduces the risk of major cardiovascular events by 19%, which is comparable to the 22% reduction seen in younger individuals [231]. However, the benefits of statin treatment typically become evident after at least one year of continuous use. In a study where patients were treated with pravastatin 40 mg daily, there was a 15% reduction in the risk of developing cardiovascular diseases such as MI, stroke, and cardiovascular death compared to placebo, and LDL cholesterol levels were reduced by 34% [221, 222]. The Study Assessing Goals in the Elderly (SAGE) trial, which compared atorvastatin 80 mg with pravastatin 40 mg, showed that patients on atorvastatin had lower all-cause mortality, although the reduction in major cardiovascular events was not statistically significant [221]. Similarly, the Heart Protection Study (HPS), which followed patients on simvastatin or placebo for five years, reported a significant reduction in coronary death (18%) and coronary events (25%) across all age groups, including those over 65 years [221]. Other trials, such as one that tracked numerous patients after MI, found that while statins reduced mortality by 11% in those aged 65–79 years, there was no significant mortality benefit in patients aged > 80 years [221]. Regarding the development of diabetes, studies have shown only a small increase in the incidence of newly diagnosed diabetes in geriatric patients on intensive statin therapy compared to those on moderate doses. However, patients on higher doses had a significantly reduced risk of recurrent acute coronary syndrome, making the benefits of continued statin therapy outweigh the risks, even when diabetes develops. Consequently, stopping statins when diabetes occurs is generally not recommended, as the cardiovascular risk increases significantly after cessation, and it is unclear whether diabetes is reversible upon discontinuation of statins [257].

Antiplatelet

As the incidence of strokes and transient ischaemic attacks increases with age, their prognosis worsens, making atherothrombotic cerebrovascular disease a significant health concern, especially in ageing Western populations. Consequently, finding effective treatments for both the primary and secondary prevention of these conditions is crucial. Antiplatelet drugs are commonly prescribed to geriatric patients for the primary prevention of MI and the treatment of cerebral transient ischemic attacks and ischemic strokes. However, some studies have indicated that bleeding complications associated with antiplatelet agents may be more severe in geriatric patients [223, 224].

Aspirin, clopidogrel and ticlopidine have been used to prevent stroke. Like aspirin, both ticlopidine and clopidogrel help prevent thrombosis and associated cardiovascular and cerebrovascular events [225, 226]. Aspirin is the most widely prescribed antiplatelet drug for stroke prevention and can significantly lower the rate of recurrent strokes, although the annual recurrence rate remains above 3.58% [226, 227]. One study comparing ticlopidine with aspirin for recurrent stroke prevention in non-White patients found ticlopidine to be more effective than aspirin [235]. However, a separate study involving African American patients found no significant difference in recurrent stroke rates between the two drugs [226]. In contrast, the clopidogrel versus aspirin in patients at risk of ischaemic events trial (CAPRIE) showed that clopidogrel was more effective than aspirin in preventing ischemic stroke, heart attack, and vascular disease-related deaths [235]. Current guidelines advise against using aspirin for primary prevention in adults aged > 70 years, as the risk of major bleeding likely outweighs its potential benefits in reducing cardiovascular events, and the anticipated cancer risk reduction is less likely to be observed [228]. Given the available data, it may be more appropriate to prioritise other primary prevention strategies for cardiovascular disease and tailor aspirin use, especially in geriatrics, based on their individual cardiovascular disease and bleeding risks. In the elderly, various factors influence bleeding risk, such as a history of gastrointestinal bleeding, liver or kidney disease, fall risk, frailty, and the use of anticoagulants or NSAIDs. Additionally, meta-analysis findings suggest that only low-dose aspirin should be considered if deemed necessary [229, 230]. The use of enteric-coated aspirin and concurrent proton pump inhibitors may also be considered to minimise the risk of gastrointestinal bleeding. Verdoia et al reported that older acute coronary syndrome patients treated with dual antiplatelet therapy had increased ADP-mediated platelet aggregation, indicating reduced effectiveness of ADP-antagonists, particularly in patients aged > 70 years, regardless of whether they were treated with clopidogrel or ticagrelor [231]. However, some studies have shown conflicting findings. Certain meta-analyses suggest that age may be inversely related to low platelet reactivity in patients receiving a ticagrelor maintenance dose. This highlights the heterogeneity in elderly populations, where some individuals exhibit a pro-thrombotic phenotype while others are at higher haemorrhagic risk. The variability emphasises the need for more refined tools to assess risks and customise antiplatelet strategies in this age group [232].

Anticoagulants

Despite evidence supporting the efficacy of these medications, there are significant concerns about their use in geriatric patients. Advanced age is linked to platelet dysfunction, reduced synthesis of coagulation factors, and increased fragility of blood vessels [233]. Additionally, the presence of concurrent physical and medical issues heightens the risk of both mechanical and non-mechanical falls, ultimately increasing the likelihood of major bleeding. Administering anticoagulant therapy to prevent stroke in the elderly is particularly challenging due to their heterogeneity, which includes higher rates of comorbidities, polypharmacy, frailty, and cognitive decline, along with functional and psychosocial concerns. This population also faces increased risks of both thromboembolism and bleeding. Additionally, age has been recognised as a significant barrier to clinicians prescribing anticoagulants.

To overcome age-related barriers and ensure the safe administration and dosing of direct oral anticoagulants (DOACs), it is essential to conduct a comprehensive geriatric assessment. This evaluation should consider factors such as life expectancy, cognitive function, functional status, and comorbidities to determine the net clinical benefit tailored to the individual patient. However, current European clinical practice guidelines advise that stroke risk should be evaluated using the CHA2DS2-VASc score. Nevertheless, there is significant variability in the published data regarding the mortality of atrial fibrillation (AF) patients in relation to their CHA2DS2-VASc score, particularly when considering factors such as patient history, drug treatments, and overall clinical condition [234–236]. The guidelines also suggest that DOACs are preferable for geriatric patients, as they reduce the risk of stroke without increasing the likelihood of major bleeding. Consequently, DOACs provide a greater net clinical benefit, encompassing both thromboembolic and bleeding risks, compared to vitamin K antagonists [237].

Despite the recommendations, geriatric patients are at an increased risk for both thromboembolic events and anticoagulant-related bleeding compared to younger individuals. The current data on DOAC use in geriatrics primarily come from prespecified subgroup analyses within larger clinical trials [238]. Dabigatran compared to other anticoagulants, has been associated with a higher incidence of bleeding in geriatrics although differences in trial design might account for this [238]. Despite this, the overall efficacy and safety outcomes were consistent with the main trials, showing no significant link between age and treatment response. For instance, with edoxaban, DOACs demonstrated a reduction in major bleeding and intracranial haemorrhage in patients aged ≥ 75 years compared to younger patients [239]. A recent Phase 3 trial in geriatric patients aged ≥ 80 years, considered unsuitable for standard oral anticoagulants, found that a low daily dose of edoxaban (15 mg) was more effective than placebo in preventing stroke or systemic embolism, although it caused more (not statistically significant) gastrointestinal bleeding [240].

Multiple meta-analyses support the clinical benefits of DOACs over vitamin K antagonists in geriatrics [237]. In a meta-analysis examining patients treated for acute venous thromboembolism and stroke prevention in AF, DOACs showed similar efficacy to vitamin K antagonists in patients aged ≥ 75 years, with comparable results between the elderly subgroup and the broader study population. However, the bleeding risks varied: apixaban and edoxaban reduced major bleeding compared to vitamin K antagonists in both geriatrics and overall populations, while rivaroxaban had similar bleeding risks to vitamin K antagonists. Dabigatran, at both 150-mg and 110-mg doses, was linked to a higher risk of gastrointestinal bleeding than vitamin K antagonists in geriatrics [241]. A systematic review and meta-regression analysis involving AF patients aged > 65 years on antithrombotic therapy for stroke prevention compared warfarin to DOACs across numerous studies. The DOACs were superior to warfarin in reducing stroke or thromboembolic risk and mortality. Also, DOACs showed a lower major bleeding risk, although real-world studies showed less significant differences in major bleeding risk in randomised clinical trials and in real-world settings. Major bleeding was comparable to warfarin with dabigatran and rivaroxaban, but lower with apixaban and edoxaban [242]. Real-world data from the START2-Register Study, focussed on geriatric patients, aged ≥ 85 years who started anticoagulation (either with vitamin K antagonists or DOACs) after a venous thromboembolism event. On follow-up, patients on DOACs had higher rates of both bleeding and thrombotic events compared to those on warfarin. However, venous thromboembolism recurrence was low and similar between both groups, and the mortality rate was significantly lower in the DOAC group [243]. Frailty, cognitive impairment, and the risk of falls should generally not be reasons to withhold anticoagulant treatment, except in cases of severe frailty or when life expectancy is very limited. This view was shared by most study participants. However, evidence suggests that frail patients are less likely to receive anticoagulant treatment at the time of hospitalisation compared to non-frail patients [244, 245].

Concerns have emerged about the effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) in real-world clinical settings, particularly in patients with multiple comorbidities and concurrent medication use. This is especially true for vulnerable geriatric patients with atrial fibrillation, who were largely underrepresented in clinical trials. As a result, NOACs are often underused or under dosed in these patients due to fears of excessive fall-related intracranial bleeding, cognitive impairment leading to poor adherence, multiple drug-drug interactions, low body weight, or impaired renal function [246–250]. In addition to a significantly lower risk of intracranial bleeding and a comparable risk of major bleeding for both standard and reduced doses of NOACs, studies have shown that the risk of gastrointestinal bleeding may be similar or even higher with NOACs, particularly at standard doses. However, meta-analyses assessing bleeding risk in older patients revealed significant heterogeneity—this variability could be due to differences in the safety profiles of individual NOACs [250, 254–260].

In geriatric patients, particularly those at risk of falls, the decision to initiate anticoagulation therapy for AF requires a careful balance between the risk of bleeding, particularly intracranial haemorrhage, and the benefit of preventing thromboembolism. While falls are common among the very elderly and often cited as a reason to avoid anticoagulation, research suggests that the benefits of anticoagulant therapy can still outweigh the risks. For example, observational data indicate that anticoagulation is beneficial in older AF patients at risk of falls, especially when their annual stroke risk exceeds 5% [251, 252]. In fact, a modelling study found that an elderly AF patient would need to fall approximately 295 times per year for the risk of subdural hematoma to negate the stroke prevention benefits of anticoagulation [252].

In trauma cases involving ground-level falls, studies show that the incidence of intracranial bleeding or mortality is not higher in patients on vitamin K antagonists compared to those on antiplatelet therapy [253]. Additionally, predicting which patients are at high risk of falls and subsequent bleeding is challenging. In one study, individuals identified as high-risk had only a slightly increased risk of bleeding compared to those classified as low-risk, indicating that anticoagulation may not cause substantial harm in AF patients prone to falls [252]. For patients with chronic kidney disease, anticoagulation therapy also presents challenges. A meta-analysis of numerous cohort studies demonstrated that warfarin, compared to no anticoagulation, lowers the risk of stroke, thromboembolism, and mortality in AF patients with severe chronic kidney disease, without a significant increase in major bleeding [254]. However, in end-stage chronic kidney disease patients requiring dialysis, warfarin increases the risk of major bleeding without significantly reducing stroke risk or mortality [254]. The DOACs, which vary in their degree of renal clearance, are another option. Patients with CrCl below 30 mL/min were excluded from most DOAC trials in stroke prevention for AF, and the use of DOACs in those with CrCl < 15 mL/min is generally contraindicated. Nevertheless, caution is advised when using DOACs in patients with CrCl between 15 and 30 mL/min, as most treatment guidelines recommend careful dose adjustment based on renal function [252, 254].

Antidiabetic

Diabetes is a significant health issue among the elderly, affecting at least 20–25% of individuals aged > 65 years, with this number expected to rise substantially in the coming decades [255].

Treating geriatric patients with diabetes requires attention not only to glucose control but also to blood pressure, aspirin therapy, and lipid management, balancing the risks and benefits of each treatment. While preventing complications such as neuropathy, vision loss, heart attacks, and strokes is crucial, the impact of treatment on an individual’s quality of life should be carefully considered [256]. Clinical trials show that it takes only 2–3 years of blood pressure and lipid-lowering treatment to reduce the risk of cardiovascular events, like heart attacks and strokes, but it may take up to 8 years of glycaemic control to reduce the risk of microvascular complications [256, 257]. For many older adults, particularly those aged > 85 years, the time needed to realise the benefits of these medications may exceed their life expectancy, highlighting the need for more studies on the use of such treatments in the elderly and frail populations. While the advantages of strict glycaemic control in geriatrics remain unclear, the risks of aggressive diabetes management are well-documented. Hypoglycaemia is a major concern, particularly because it can impair cognitive function and increase the risk of falls and fractures in geriatric patients, leading to significant health issues or even death. Although organisations like the American Diabetes Association (ADA) have established blood glucose monitoring goals, it is widely accepted that frail geriatric patients who are prone to frequent hypoglycaemia may benefit from more relaxed targets for A1C, fasting plasma glucose, and postprandial glucose to avoid the dangers of low blood sugar. Hypoglycaemia not only contributes to physical harm but also causes psychosocial distress, as patients often live in fear of experiencing hypoglycaemic episodes [257].

Age-related physiological changes, combined with the likelihood of polypharmacy, place geriatric patients at a greater risk of hypoglycaemia and other medication-related side effects. These individuals may also face challenges with medication adherence, increased drug costs, and a higher risk of drug interactions [4]. Therefore, reviewing the medication regimen with geriatrics (or their caregivers) is essential to identify potential side effects and improve adherence, thus minimising adverse events. Evidence guiding diabetes treatment in geriatric patients is limited and often extrapolated from studies in younger populations. While hypoglycaemia is the primary risk associated with treatment, it can usually be managed through diligent monitoring and clear communication between healthcare providers and patients [258]. Polypharmacy increases the risk of medication-related issues, including interactions, adverse reactions, and non-adherence. Consequently, treatment decisions should prioritise patient safety, adherence, and quality of life, with individualised goals for each patient being of utmost importance.

In geriatric patients with diabetes, therapy often aims to control both basal glucose levels and postprandial spikes. A common approach involves using basal (long-acting, once-daily) and bolus (short-acting, prandial) insulin to address these needs. However, since many elderly individuals with type 2 diabetes still have some insulin production, oral therapies are typically considered first [259]. Diabetes treatments can be categorised based on their pharmacological action, focusing on addressing basal glucose needs, prandial control, or insulin resistance. Oral antihyperglycaemic drugs, such as sulfonylureas and metformin, along with newer injected hormonal treatments, can lower A1C levels by 1–2%. For those with A1C levels above 9%, combination therapies or early insulin initiation may be needed for optimal control [259].

Geriatrics with type 2 diabetes are more likely to experience coexisting conditions like hypertension, coronary heart disease, stroke, and disability compared to their non-diabetic counterparts. They also face a higher risk of hospitalisation and geriatric syndromes, including cognitive decline, falls, and polypharmacy, which increase the likelihood of drug-related side effects and interactions. This makes careful monitoring and selection of pharmacological treatments, including diabetes medications, essential in geriatric patients [256]. The management of diabetes in geriatrics can lead to severe complications, even with relatively low doses of medication.

Metformin is the first-line treatment for geriatrics due to its safety and effectiveness. However, it should be paused during hospitalisations, before procedures, or when acute illnesses affect kidney, liver, or heart function, as there is an increased risk of lactic acidosis. For instance, sulfonylureas, particularly long-acting types like chlorpropamide and glibenclamide, have been associated with potentially life-threatening hypoglycaemia, especially in frail geriatric patients with compromised renal function [255, 260]. Rosiglitazone has been linked to an increased risk of congestive heart failure, acute MI, and mortality when compared to other oral hypoglycaemic agents. On the other hand, pioglitazone does not carry these risks but both drugs have been associated with increased bone loss in elderly women, although not in men. Additionally, rosiglitazone has been shown to raise the risk of bone fractures in the elderly [40, 261]. The American Geriatrics Society's Beers Criteria 2019 advises avoiding these drugs in older adults. Thiazolidinediones, too, can worsen heart failure and cause peripheral oedema [87, 259].

Dipeptidyl peptidase 4 (DPP-4) inhibitors are of interest for managing diabetes in hospitalised patients due to their minimal side effects and neutral impact on major cardiovascular outcomes [259]. In hospital settings, DPP-4 inhibitors have been linked to similar glycaemic control and lower hypoglycaemia rates compared to insulin [259]. However, saxagliptin has been associated with a higher risk of heart failure hospitalisations in geriatric patients, although evidence is mixed [259]. Some studies report an increased risk, while a recent meta-analysis suggests that DPP-4 inhibitors do not significantly raise the risk of heart failure. Therefore, when considering DPP-4 inhibitors in geriatrics with type 2 diabetes, it is important to account for existing comorbidities, particularly heart failure [259].

Cardiovascular outcome trials have shown that sodium–glucose cotransporter 2 inhibitors (SGLT2i) and GLP-1 receptor agonists provide cardiovascular protection in diabetic patients with established atherosclerotic cardiovascular disease (ASCVD) and those at higher ASCVD risk, including patients aged > 65 years [259]. However, the use of SGLT2 inhibitors in hospitalised patients with hyperglycaemia is less favourable due to the increased risk of urinary and genital infections, potential volume depletion, and diabetic ketoacidosis. Similarly, GLP-1 receptor agonists may not be ideal for frail geriatric patients suffering from malnutrition, sarcopenia, or cachexia, as these drugs can cause gastrointestinal side effects [259].

Inappropriate prescribing of anti-diabetes medications is common in elderly hospitalised patients, yet there is no explicit tool designed to identify such prescribing practices specifically in older adults with diabetes. Recent studies indicate that while insulin remains the preferred method for managing glycemia in hospitalised patients, DPP-4 inhibitors may be suitable for certain individuals, such as those with well-controlled diabetes nearing discharge [259].

There is ongoing debate surrounding the cardiovascular safety of sulfonylureas, particularly regarding their potential link to increased mortality from cardiovascular disease. Retrospective studies have suggested a higher incidence of cardiovascular events in patients on sulfonylureas compared to metformin, but other studies, including the UK Prospective Diabetes Study (UKPDS), found no such increase in cardiovascular mortality. A meta-analysis of trials comparing newer sulfonylureas with other anti-diabetic drugs similarly reported no significant difference in cardiovascular outcomes. The concern over cardiovascular toxicity may be related to older sulfonylureas affecting ATP-dependent potassium channels in cardiac cells, while newer sulfonylureas are more selective for pancreatic receptors [259]. The GLP-1 receptor agonists, such as exenatide and liraglutide, have been shown in randomised trials to effectively reduce blood glucose levels and lower A1c by around 1%. These agents also promote dose-dependent weight loss, which may be advantageous for overweight or obese patients. However, in frail or undernourished elderly individuals, this weight loss could be harmful and should be considered when initiating treatment with these drugs [259].

Anti-inflammatory

Non-steroidal anti-inflammatory drugs (NSAIDs) carry an elevated risk of hyperkalaemia, renal failure, and gastrointestinal bleeding, which can be particularly severe in the elderly and those with chronic kidney disease or diabetes [262–264]. Cyclo-oxygenase (COX)-2 inhibitors offer comparable pain relief and functional improvement as traditional NSAIDs for geriatric patients with osteoarthritis and rheumatoid arthritis. However, they may still cause serious adverse effects, including gastroduodenal disorders, and are not suitable for patients with cardiovascular or renal conditions [265]. Like standard NSAIDs, COX-2 inhibitors can lead to renal failure, hypertension, and exacerbation of cardiac failure, with these effects being dose dependent. Moreover, COX-2 inhibitors have a thrombotic risk, particularly at high doses or with prolonged use, which further restricts their use in elderly populations [266].

Wongrakpanich et al. reported on a study which conducted a prospective community-based study with numerous participants aged ≥ 66 years to investigate the impact of NSAID use on the progression of chronic kidney disease in geriatric individuals. They found that prolonged exposure to NSAIDs was linked to a higher risk of rapid chronic kidney disease progression [267]. Similarly, Kate et al. developed a model to predict acute kidney injury in hospitalised geriatrics, identifying that combinations of medications, including NSAIDs and diuretics, were predictive of acute kidney injury in this population. The American Geriatric Society (AGS) advises against the use of NSAIDs in patients with stage IV and V chronic kidney disease, specifically those with a CrCl of less than 30 mL/min [268].

Salicylates, frequently used over-the-counter, are common culprits in morbidity and mortality among the elderly. Chronic salicylate intoxication can occur even at therapeutic doses due to interactions with other medications and diminished liver and kidney function, which impair the metabolism and excretion of salicylates [269]. Geriatrics often self-medicate for various aches and pains with salicylate-containing products, increasing the risk of toxicity. Inadvertent overdosage can also be problematic, with salicylate toxicity frequently going undiagnosed, leading to significant morbidity and even death [269]. Wongrakpanich et al analysed a case-control study involving geriatric patients who were hospitalised for the first time with congestive heart failure. They compared NSAID users (excluding low-dose aspirin) with non-users and found that NSAID use was linked to a higher risk of initial hospital admission due to congestive heart failure. Therefore, both COX-2 inhibitors and non-selective NSAIDs may be associated with increased cardiovascular risks, and the risk/benefit profile of each medication should be carefully considered before prescribing to individual patients [267].

Wongrakpanich et al. further looked into a study which involved numerous community-dwelling individuals aged > 60 years and found that 26% used NSAIDs. Their findings indicated that NSAID use was a predictor of hypertension, with an odds ratio of 1.4 [267]. Another study conducted a 7-year prospective study on geriatric individuals aged > 65 years to examine the effects of NSAIDs on cognitive function. Their results showed no significant association between NSAID use and the incidence of dementia or cognitive decline [267]. Similarly, another study found no link between NSAID use and the development of cognitive impairment or dementia [267]. Additionally, COX-2 inhibitors, such as celecoxib, did not demonstrate any benefit in slowing the progression of cognitive diseases in patients with pre-existing dementia. A supporting study conducted a multicentre randomised controlled trial over one year and found no association between celecoxib use (200 mg twice daily) and the progression of Alzheimer's disease [267].

A randomised controlled trial evaluated the effects of celecoxib and naproxen on depressive symptoms in geriatric individuals aged > 70 years and found no difference between the treatment groups and placebo regarding late-life depression [267]. Similarly, in 2015, Jankowsky et al. performed a randomised controlled trial with 189 elderly subjects aged 60–75 to assess the impact of ibuprofen on bone mineral density after 36 weeks of exercise, finding no significant difference between ibuprofen and placebo groups [270]. A double-blind RCT conducted using piroxicam versus placebo in geriatric patients aged > 70 years who were hospitalised due to infection-induced inflammation (characterised by elevated C-reactive protein and/or fibrinogen levels). They found that piroxicam improved muscle performance compared to placebo, indicating that NSAIDs may reduce inflammation in such cases [267]. Regarding the risk of falls, NSAIDs appear to be a major contributing factor. Walker et al reported a 10-fold increased likelihood of falling with NSAID use (including low-dose aspirin) [267]. A meta-analysis that linked NSAID use to an increased risk of falls, with an unadjusted odds ratio of 1.21 [267]. Polypharmacy is also a key risk factor for falls in the elderly [271]. Interestingly, a 2016 study by Zia et al. showed that the use of ≥ 2 fall risk-increasing drugs (FRIDs), rather than polypharmacy alone, was a significant predictor of falls [272]. The NSAIDs are classified as important FRIDs, suggesting that falls related to polypharmacy in earlier studies may be driven by the use of multiple FRIDs.

Antiulcer

Proton pump inhibitors (PPIs) are generally deemed safe and effective for geriatric patients. However, prolonged use beyond one year has been linked to an increased risk of hip fractures, a risk that appears to be dose dependent, possibly due to impaired calcium absorption. Although PPIs do not require dosage adjustment in patients with renal impairment, those with hepatic impairment should have their doses reduced [273, 274]. Cimetidine, a histamine-2 antagonist, is known for its significant drug interactions and potential adverse effects, including bradycardia, arrhythmias, confusion, depression, thrombocytopenia, neutropenia, and gynecomastia. Due to these risks, cimetidine is not recommended as a first-line agent for geriatric patients [275]. The AGS Beers Criteria do not recommend the use of famotidine in geriatrics with CrCl less than 50 mL/min and/or experiencing delirium [9].

A nested case-control study from New Zealand revealed that current PPI users had a significantly higher risk of developing acute interstitial nephritis [276]. Similarly, several retrospective analyses have linked the onset of acute interstitial nephritis to the use of PPIs, such as lansoprazole and omeprazole. Additionally, numerous cases of PPI-related acute interstitial nephritis have been reported [277]. Regarding acute kidney injury, multiple nested case-control studies have found that PPI users are at greater risk [273, 277]. A population-based study also showed that initiating PPI therapy in individuals aged ≥ 66 years increased the incidence of acute kidney injury [278]. Likewise, cohort studies have consistently demonstrated an elevated risk of acute kidney injury in PPI users [279, 280]. A meta-analysis of cohort and case-control studies further confirmed that PPI users exhibit a higher prevalence of acute kidney injury [281].

In terms of bone health, a meta-analysis of numerous case-control and cohort studies found a slight increase in the incidence of hip, spine, and other fractures in PPI users [277]. Another meta-analysis, showed a similar increased risk of fractures (hip, spine, and any-site) with PPI use. Some studies within this analysis specifically linked PPI use to a higher risk of hip fractures [282]. Additionally, a case-control study focusing on men aged ≥ 45 years demonstrated a heightened risk of hip fracture with longer PPI use duration [277]. The study also found that patients with greater medication adherence and those who recently began PPI therapy in the last 7 days had an increased risk of hip fractures [277]. Longer exposure to PPIs is likely to have a more consistent detrimental effect on bone health, though the reasons for increased risk with recent PPI use remain unclear. Some studies have explored the interaction between PPI therapy and the risk of bone fractures when combined with other medications. Lee et al., using a Korean health insurance database, found an increased risk of hip fractures in PPI users compared with nonusers. Another case-control study examined the interaction between PPIs and histamine-1-receptor antagonists (H1RAs) on fracture risk [274]. The authors hypothesised that H1RAs might mitigate the impact of PPIs on bone health and discovered that while PPI users had an increased risk of all fractures and hip fractures, the combined use of PPIs and H1RAs was associated with a decreased overall fracture risk. However, the interaction was not significant for hip fractures. Further studies are needed to clarify whether histamine release due to PPI use contributes to the risk of bone fractures [276]. Khalili et al. conducted a prospective cohort study and discovered that women who regularly used PPI therapy for at least two years had an increased risk of hip fracture, after accounting for factors like body mass index, physical activity, and calcium intake. Additionally, the risk of hip fracture was more pronounced among current and former smokers using PPIs [274]. In a separate study, Ding et al. performed a retrospective cohort study to examine the relationship between PPI adherence and fracture risk in elderly patients using administrative pharmacy claims, survey, and Medicare data. They measured PPI adherence through the proportion of days covered, where higher proportion of days covered values indicated better adherence [283]. Another study explored whether acid-lowering therapy, such as PPIs, was associated with an increased risk of falls, hypothesising that this could be a mechanism for increased fracture risk. They collected data from the UK Health Improvement Network in patients aged 40–89 years [274]. In contrast, a study by Lewis et al in Australia found a significant association between long-term PPI use (over 1 year) and falls in older women at high risk for falls [284]. This post hoc analysis, followed by a replication study, demonstrated that PPI therapy for at least 1 year was linked to increased risk of fracture-related hospitalisations and an elevated risk of self-reported falls after adjusting for fall risk factors and vitamin D therapy [284].

The reduced intestinal calcium absorption secondary to PPI use has been proposed as a potential mechanism behind the increased fracture risk, although most studies did not include older adults or dialysis patients. A retrospective cohort study conducted using the New England Veterans Healthcare database, identifying patients with incident Clostridium difficile infection (CDI) treated with metronidazole or vancomycin [274]. The use of PPIs during CDI treatment significantly increased the risk of recurrent CDI within 90 days [274]. Similarly, McDonald et al conducted a retrospective cohort study in Canada, following patients with healthcare-associated CDI to assess for recurrence within 15–90 days [285]. Continuous PPI use was defined as PPI use for at least 75% of the hospital days or a discharge prescription valid beyond 90 days from the initial CDI diagnosis. Some studies indicate that the use of oral anticoagulants is linked to an increased risk of gastrointestinal bleeding, leading many clinicians to prescribe PPIs as a preventive measure. While other studies argue that the most frequent inappropriate reason for PPI therapy is GI bleeding prophylaxis during anticoagulant or antiplatelet therapy, noting that the indication for PPIs in these cases remains unclear. Additionally, chronic pain is common among patients with end-stage renal disease (ESRD) and non-dialysis chronic kidney disease, and NSAIDs are frequently prescribed. However, results showed that NSAIDs were prescribed with PPIs less often in the chronic kidney disease group, likely due to concerns about the risks of NSAID use in renal impairment. It is also possible that other physicians were prescribing NSAIDs or that chronic kidney disease patients were using over-the-counter NSAIDs [286].

Antibiotics

As kidney function declines with age, the clearance of drugs primarily eliminated through this organ is generally reduced in geriatric patients. Antibiotics, many of which are excreted by the kidneys, need to be administered with caution in geriatrics. For example, antibiotics such as vancomycin, meropenem, and ofloxacin amongst others may require dose adjustments to avoid potential toxicity [287].

Nitrofurantoin also poses risks of renal impairment in geriatric patients [288]. Although nitrofurantoin is effective against many strains of Escherichia coli and Enterococci, its activity is limited against other bacteria such as Enterobacter, Klebsiella among other species [289]. Common adverse effects of nitrofurantoin include pulmonary reactions (such as pneumonitis, vasculitis, and pleuritis) and allergic reactions (including cutaneous rashes, fever, and anaphylaxis) [290]. The American Geriatrics Society's 2015 Beers Criteria Update Expert Panel revised its recommendation regarding the use of nitrofurantoin in patients with renal impairment, lowering the threshold from a CrCl of less than 60 to < 30 mL/min [291]. This adjustment is based on two retrospective studies that demonstrated the safety and efficacy of nitrofurantoin in this population. This change, along with growing resistance to sulfamethoxazole/trimethoprim and fluoroquinolones, highlights the advantages of nitrofurantoin and may explain its increased use among geriatric patients [291, 292]. Overall, antibiotics used for urinary tract infections, such as trimethoprim/sulfamethoxazole, fluoroquinolones, nitrofurantoin, amoxicillin, cephalosporins, and aminoglycosides, are generally cleared renally. Therefore, dose adjustments are recommended for patients with reduced renal function [293, 294].

The increased fat content in older adults enhances the solubility of lipophilic drugs in tissues, extending the half-life of lipid-soluble medications such as rifampin, fluoroquinolones, macrolides, oxazolidinones, tetracyclines, amphotericin B, and many imidazole antifungals [33]. Conversely, reduced total body water and lean mass decrease the solubility of water-soluble drugs in tissues, leading to higher plasma concentrations of hydrophilic drugs, including aminoglycosides, beta-lactams, and glycopeptides [33]. In elderly patients with severe infections, full loading doses of aminoglycosides and glycopeptides are recommended. Additionally, elevated plasma alpha-1-acid glycoprotein levels in geriatrics can reduce the free concentration of basic antimicrobials, such as macrolides [33].

Chronic diseases common in elderly patients, such as oedema from chronic heart failure and ascites from cirrhosis or chronic liver disease, can affect drug distribution. These conditions can cause fluid accumulation near infection sites, leading to the dilution of standard antimicrobial doses, which may result in treatment failure even when plasma drug levels appear therapeutic [33]. Furthermore, reduced plasma albumin levels, often due to proteinuria, malnutrition, or chronic illness, can decrease the fraction of protein-bound drugs, thereby increasing the concentration of free drug in the plasma [33]. This phenomenon affects acidic antimicrobials like penicillins, ceftriaxone, sulphonamides and clindamycin [33]. Co-administration of DOACs with CYP 450 enzyme or P-gp transporter inducers can accelerate the metabolism of DOACs, leading to subtherapeutic levels and increased risk of stroke, heart attack, or thromboembolism. Rifampin, a potent inducer of both CYP 450 enzymes and P-gp transporters, can lower DOAC concentrations, heightening clotting risks [33, 295, 296]. On the other hand, antimicrobials such as clarithromycin, erythromycin, fluconazole, itraconazole, and ketoconazole inhibit CYP450 enzymes, while macrolides and certain antifungals inhibit P-gp transporters. When these inhibitors are used with DOACs, they reduce the metabolism of the anticoagulants, raising their plasma levels and increasing the risk of bleeding [296].

Geriatric patients with reduced renal function, whether from ageing or chronic kidney disease, face heightened risks when using nephrotoxic antimicrobials like aminoglycosides, vancomycin, beta-lactams, rifampin, and some fluoroquinolones. The risk is compounded by polypharmacy, where nephrotoxic medications such as NSAIDs, furosemide, and thiazide diuretics are frequently used. Continued use of these drugs alongside nephrotoxic antimicrobials can lead to acute kidney injury or renal failure, potentially requiring temporary or permanent renal replacement therapy.

For each of these medication classes, careful consideration of the potential benefits versus risks and close monitoring for adverse drug effects are essential in geriatric patients due to age-related physiological changes and increased susceptibility to medication-related problems (refer to Table 4).

Table 4.

Overview of common pharmacological drugs and their potential adverse effects in geriatric patients, highlighting the increased risks and considerations for geriatrics

Pharmacological agent	Effects on geriatrics
Analgesics
Non-steroidal anti-inflammatory drugs	• Increases the risk of GI bleeding
	• May elevate blood pressure
	• Increased risk of renal and/or hepatotoxicity
Selective COX-2 inhibitors	• Increases the risk of GI bleeding
Antihypertensives
Calcium channel blockers	• Risk of orthostatic hypotension and peripheral oedema
	• Increase mortality risk
Potassium-sparing diuretics	• Risk of hyperkalaemia
Anxiolytic
Benzodiazepines	• Increased risk of cognitive impairment, delirium, falls, fractures
Anti-Parkinsons
Levodopa	• Increased risk of confusion and orthostatic hypotension
Antihistamines
Diphenhydramine	• Exacerbates cognitive symptoms (cholinergic effects)
Antiulcer
Lansoprazole	• Risk of hip fracture
Antibiotics
Aminoglycosides	• Elevated risk of nephrotoxicity (age related or chronic kidney disease)
Antidepressants
Tricyclic antidepressants	• Anticholinergic effects exacerbate existing cognitive impairment and cardiac issues
Selective serotonin reuptake inhibitors	• QT prolongation
Serotonin-norepinephrine reuptake inhibitors	• Elevation of blood pressure
	• Diarrhoea
Anti-hyperglycaemic
SGLT2 inhibitors	• Increase the risk of urinary tract infections and genital fungal infections
	• May lead to hypovolaemia and orthostatic hypotension
Biguanide	• Poses a risk of lactic acidosis
Sulfonylureas	• Increase the risk of hypoglycaemia
Anticoagulants
Warfarin	• Increased risk of drug toxicity
Digitalis glycosides
Digoxin	• Increased risk of drug toxicity

COX-2 cyclo-oxygenase, GI gastrointestinal, SGLT2 sodium-glucose cotransporter 2

Authors’ Perspective

Geriatric individuals face multiple practical issues in taking their medications correctly, such as difficulties in reading instructions, handling packaging, preparing doses, and remembering to take the medication. Consequently, patients and their prescribers might alter drug administration methods, like opening capsules to ease swallowing or crushing tablets for use in feeding tubes, which can affect the drug’s safety and efficacy due to risks of degradation, dosing inaccuracies, or altered bioavailability. Therefore, it is crucial for healthcare providers to regularly discuss practical medication issues with geriatric patients to ensure proper medication use.

Initiating drug therapy in geriatric patients should begin with the lowest effective dose, especially in cases involving multiple medications. Careful consideration should be given to potential drug interactions, drug-disease interactions, and drugs metabolised via CYP450 enzymes. Choosing drugs with lower interaction risks based on the patient’s medication profile is crucial, and monitoring for adverse effects of potential interactions is essential. Tailoring treatment regimens to the individual’s functional, psychological, social, and economic status can help minimise challenges in treating geriatric patients. Patient and caregiver understanding of prescriptions is important for promoting adherence, as are routine follow-up visits to assess treatment effectiveness and identify adverse effects. Ageing often brings about symptoms such as confusion, decreased appetite, and memory issues, which can sometimes be confused with drug-related effects. Educating patients and caregivers about over-the-counter medications, dietary supplements, and potential drug-food interactions is critical.

Due to age-related impairments in organ and body functions, it is vital to consider the special needs of geriatrics during drug development, authorisation and prescribing. Balancing pharmaceutical formulations, delivery methods, PK, toxicity, and clinical indications is essential for successful drug therapy in geriatric patients. This approach ensures drug safety, minimises adverse drug effects, and enhances patient adherence. While achieving optimal pharmacotherapy for geriatrics can be challenging due to physiological changes, healthcare providers play a crucial role in maximising patient benefit through careful management and monitoring.

Conclusion

The ageing process induces significant structural and functional changes across all organ systems, resulting in a reduced capacity to maintain homeostasis, particularly under physiological stress. Although some organ systems may retain baseline functionality at rest, the decline in functional reserve enhances vulnerability to stressors. Key PK changes include alterations in body composition, such as increased adiposity and reduced total body water, which expand the volume of distribution for lipid-soluble drugs and reduce the clearance of both lipid- and water-soluble drugs. These changes collectively prolong the plasma elimination half-life of many therapeutic agents. Concurrently, ageing-associated PD shifts, such as heightened receptor sensitivity and diminished compensatory homeostatic responses, further increase drug sensitivity. The interplay between reduced clearance, altered distribution, and impaired PD regulation underscores the importance of tailoring drug regimens to the physiological and pharmacological profiles of older adults. Advancing our understanding of age-related changes in PK and PD is critical for optimising drug therapy and improving prescribing practices in this population.

Declarations

Funding

Open access funding provided by University of KwaZulu-Natal.

Conflict of Interest

The authors declare no conflicts of interest.

Authors' Contributions

NN contributed to the design, data collection, analysis of the results and to the writing of the manuscript. The author(s) approved final version to be reviewed and possibly published.

Data Availability Statement

Not applicable.

Ethics Approval

Not applicable.

Code Availability

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.