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Polypharmacy with Multi-Mechanism Drugs: A Hidden Risk for Drug Interactions and Adverse Effects

Written By

Alfredo Briones-Aranda

Submitted: 02 September 2025 Reviewed: 07 October 2025 Published: 19 November 2025

DOI: 10.5772/intechopen.1013524

Polypharmacy and Inappropriate Medication Use IntechOpen
Polypharmacy and Inappropriate Medication Use Edited by Farid Badria

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Polypharmacy and Inappropriate Medication Use

Farid Badria

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Abstract

Drugs may overlap in their pharmacokinetic and pharmacodynamic processes, including absorption, distribution, biotransformation, excretion, and mechanism of action. Such overlaps increase the likelihood of interactions as the number of prescribed drugs increases. As a result, polypharmacy carries a significant risk of adverse effects, particularly in older adults. This chapter focuses on drugs such as biguanides, statins, and selective serotonin reuptake inhibitors that act through multiple mechanisms (polypharmacology) and may interact directly or indirectly with the serotonergic system, present in the gastrointestinal tract, platelets, and the central nervous system. A clearer understanding of interactions between drugs that share similar targets (hidden polypharmacy) can improve knowledge of the pathophysiology underlying adverse drug reactions, and this insight may also be applied to prevent such interactions.

Keywords

  • polypharmacy
  • Polypharmacology
  • drug-drug interactions
  • older adults
  • oral hypoglycemics
  • statins
  • selective serotonin reuptake inhibitors
  • serotonergic system

1. Introduction

Advances in technology worldwide have driven exponential growth in medical research, resulting in the significant improvements in human health. This progress has contributed to demographic and epidemiological shifts associated with longer life expectancy. Consequently, population aging—now affecting most countries—has become a critical issue and a major challenge for health systems worldwide [1].

Why do aging and the rise of multiple health problems occur together? Aging is well known to bring about a range of physiological changes and is closely associated with a higher prevalence of chronic degenerative diseases (CDDs), including type 2 diabetes mellitus (T2DM), as well as cardiovascular, renal, and rheumatologic conditions, among others [2, 3].

In this complex context, multi- and interdisciplinary medical care is essential, with daily clinical collaboration providing common ground for specialists such as internists, cardiologists, and geriatricians, as well as other health professionals including nurses, gerontologists, nutritionists, psychologists, and physiotherapists. When faced with frailty and CDDs, these professionals may prescribe multiple pharmacological treatments alongside self-care measures, such as promoting physical activity and adopting hygienic-dietary strategies, all aimed at helping patients cope and maintain homeostasis.

Polypharmacy is generally defined as the use of five or more medications [4], which may be potentially inappropriate [4, 5] or unnecessary [6]. Its prevalence is particularly high among older adults: It is estimated that more than 50% take five or more drugs, and over 10% take 10 or more [7], greatly increasing risks to their health and overall well-being [8]. According to a WHO report published in 2019, polypharmacy is a major and growing public health problem across healthcare settings worldwide [9].

As noted above, drugs may overlap in their pharmacokinetic processes—absorption, distribution, biotransformation, and excretion—and may also share similarities in their mechanisms of action. Such overlaps can lead to drug-drug interactions (DDIs), with the number of prescribed medications being a major contributing factor [10, 11].

The clinical outcomes of DDIs can range from diminished to enhanced effects of one or more drugs, with the latter often manifesting as adverse drug reactions (ADRs) [12].

However, the emergence of multi-mechanism drugs—agents that act on multiple targets simultaneously (pleiotropic)—has introduced new challenges. These drugs were initially designed to improve efficacy but also add hidden risks of interaction. Some can initiate biochemical changes that directly or indirectly trigger cascades of additional effects, impacting multiple systems. In line with this, most drugs used in the treatment of oncological [13] or psychiatric [14] disorders are characterized by multiple mechanisms of action (polypharmacology). For example, clozapine, used as an antipsychotic, can interact with several neurotransmission systems, including dopaminergic, serotonergic, muscarinic, and histaminergic pathways [15]. Similarly, tyrosine kinase inhibitors can block various enzymes that cancer cells rely on to grow and divide rapidly [16]. Nevertheless, other drugs with this same characteristic—such as oral hypoglycemics (78%) and statins (62%)—are of particular importance due to their frequent prescription as part of polypharmacy in studies involving geriatric populations [17].

In consideration of the above, the primary purpose of this chapter is to explore the risks of DDIs and ADRs associated with hidden polypharmacy involving drugs with polypharmacology, such as oral hypoglycemics, statins, and selective serotonin reuptake inhibitors (SSRIs). This analysis draws on experimental and clinical research with the aim of proposing strategies for the responsible prescription of these medications in adults over 65 years of age with CDDs.

Because polypharmacy in the geriatric population can negatively affect health—ranging from an increased risk of DDIs to the onset of adverse effects such as cognitive decline [18], cataracts [19], and malnutrition [20]—it also contributes to poor treatment adherence [6] and increased hospitalizations caused by ADRs [21]. These consequences are closely linked to greater frailty and higher healthcare costs [6].

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2. Physiological changes associated with aging that may influence pharmacokinetic processes

2.1 General considerations

The world is undergoing a major demographic shift. By 2050, the number of people over 60 years of age is expected to rise from 600 million to nearly 2 billion, with the fastest and largest growth occurring in developing countries, where the elderly population is projected to quadruple over the next 50 years [22]. Aging has been defined in many ways, but a comprehensive perspective describes it as a process involving morphological, functional, and psychological changes that alter the structure and function of different systems, increasing an individual’s vulnerability to environmental stress and disease [23]. However, the pace of these changes varies across organs and systems, as well as among individuals. Aging is also characterized by alterations in the phases of pharmacokinetic processes, which may affect the bioavailability and therapeutic effectiveness of prescribed drugs [24].

On the other hand, it is necessary to revisit two closely related terms that could cause confusion: polypharmacology and polypharmacy (Figure 1). The former refers to molecules that can interact with multiple molecular targets [25], while the latter, defined earlier, has two dimensions. Traditional polypharmacy refers to the prescription and administration of several potentially inappropriate drugs that may interact primarily at the pharmacokinetic level, such as through shared metabolism (Figure 1). In contrast, hidden polypharmacy may refer to the use of a drug with polypharmacology, which can lead to complex problematic interactions at both the pharmacokinetic and pharmacodynamic levels [25, 26], since multiple actions of a single drug may provoke the adverse effects comparable to those observed with traditional polypharmacy (Figure 1). However, the term hidden polypharmacy may also apply when herbal medicines or dietary supplements are combined with the standard treatments, a practice frequently observed among geriatric patients and often not reported to their treating physicians [27].

Figure 1.

Differences and similarities between traditional and hidden polypharmacy. Created with https://BioRender.com.

Therefore, before addressing the potential interactions of drugs with polypharmacology, it is necessary to establish a theoretical framework concerning the physiological changes that occur during aging and strongly influence pharmacokinetic processes.

Figure 1 shows that traditional polypharmacy, which consists of the administration of five or more drugs, may involve interactions at the pharmacokinetic level and trigger adverse drug reactions (ADRs). By contrast, in hidden polypharmacy, a single drug with multiple mechanisms of action (polypharmacology) can interact at the pharmacodynamic level and produce equivalent ADRs.

2.2 Oral absorption

Evidence on age-related changes in gastric secretion is inconsistent. Some studies report that gastric acid secretion does not significantly decline in healthy older adults [28, 29], while others suggest it may even increase [30]. In addition, cases of achlorhydria and hypochlorhydria have been documented in this population [31, 32]. Such changes can directly affect drug solubility and gastric emptying. It is well established that higher gastric acidity reduces the dissociation of acidic drugs, and their lower polarity in this state favors absorption. By contrast, weakly basic drugs (e.g., ketoconazole, ampicillin, and iron supplements) dissociate more readily in an acidic pH, which limits their absorption. In hypochlorhydria, the reduced acidity may impair the dissociation and absorption of weakly basic drugs such as ketoconazole [33].

Most studies on age-related gastric emptying report that it is delayed and reduced in older adults. This slowing is generally associated with decreased appetite and impaired absorption of both nutrients and drugs [34].

2.3 Distribution

Total body water remains stable compared with that of young adults until about age 60, after which it gradually declines [35]. This reduction is thought to result mainly from a loss of intracellular water, as extracellular water remains stable. These changes directly affect highly water-soluble drugs such as acetaminophen: A smaller apparent volume of distribution (Vd) leads to faster rises in plasma concentrations after administration, underscoring the need for initial dose adjustments [36].

In contrast, adipose tissue tends to increase from about age 30 onward, which can expand the Vd of lipophilic drugs such as benzodiazepines [37, 38]. This results in lower plasma concentrations and greater drug accumulation in fat tissue, contributing to redistribution and prolongation of half-life.

Drug binding to plasma proteins is also influenced by age. In healthy older adults, plasma albumin levels may decline by up to 30% compared with younger adults, causing drugs that bind strongly to this protein to exhibit the increased pharmacological activity [39, 40]. These effects are even more pronounced in pathological conditions such as chronic malnutrition and renal failure, where plasma protein levels may be significantly reduced [41].

One of the most widely studied effects of aging is the decline in cardiac output, which leads to reduced circulating volume, increased vascular resistance, and microcirculatory changes. These alterations limit the body’s ability to distribute drugs efficiently and may affect the Vd [42]. Notably, the hepatic and renal vascular networks are among the most impacted by reduced blood flow in older adults [43].

2.4 Metabolism

In older adults, physiological changes such as reduced liver mass, decreased hepatic blood flow, and diminished metabolic capacity alter drug metabolism. These factors play a key role in the decline of first-pass metabolism often seen in geriatric patients [42, 43]. As a result, the bioavailability of certain drugs, such as propranolol, may rise significantly, requiring lower initial doses [44, 45]. Conversely, reduced first-pass metabolism can hinder the activation of several prodrugs, including angiotensin-converting enzyme inhibitors like enalapril, potentially leading to lower systemic levels of the active compound [46].

Overall, the decline in hepatic metabolism in older adults varies by drug and by individual. Age-related changes mainly affect phase I metabolism (oxidation, reduction, and hydrolysis), whereas phase II metabolism (glucuronidation, acetylation, and sulfation) is generally less impacted [47, 48].

In addition, the hepatic and intestinal enzyme CYP3A4 is the most abundant, and approximately 50% of marketed drugs are metabolized through this pathway [49]. This enzyme is particularly relevant for drugs that act as substrates, inducers, or inhibitors. Of special concern is the combination of CYP3A4-inhibiting drugs with pleiotropic drugs that behave as substrates [50]—for example, a macrolide administered together with a statin, a scenario discussed later in this chapter.

Another important consideration involves psychiatric [51] and oncological [52] patient populations, who are often treated with polypharmacy regimens. In these cases, combinations such as the chemotherapeutic agent cyclosporine together with a CYP3A4 inhibitor like the antifungal itraconazole can trigger toxic effects [53].

Finally, another key factor is the presence of polymorphisms associated with the CYP2D6 gene, which reduces hepatic biotransformation and affects the metabolism of various drugs, including antidepressants, antipsychotics, opioid analgesics, beta-blockers, and antiarrhythmics. Such alterations may promote drug accumulation and consequently increase the risk of ADRs [54].

2.5 Elimination

In older adults, physiological changes that can affect renal drug elimination include reduced renal blood flow, decreased glomerular filtration, and diminished tubular secretory capacity [55, 56]. Renal function is commonly assessed using the pharmacokinetic parameter clearance, which depends on creatinine elimination. Creatinine clearance declines by about one-third between ages 20 and 90, although the rate of decline varies among individuals [57, 58].

Reduced glomerular filtration and tubular function are the main factors limiting the clearance of many drugs, including water-soluble antibiotics, diuretics, digoxin, beta-blockers, lithium, and nonsteroidal anti-inflammatory drugs (NSAIDs) [55, 59, 60]. In addition, the combined administration of angiotensin-converting enzyme inhibitors (ACEIs), NSAIDs, and diuretics can reduce both renal blood flow and glomerular filtration, thereby enhancing nephrotoxicity [61]. These effects are further aggravated by common comorbidities in older adults, such as T2DM and hypertension [58, 62].

The clinical significance of reduced renal excretion in older adults lies in its potential to cause adverse drug reactions (ADRs) or drug toxicity. For medications with a narrow therapeutic index, such as aminoglycoside antibiotics [63], digoxin, and lithium [64], even slight accumulation can result in serious ADRs [56, 65]. Thus, impaired renal function in older adults must be carefully considered to avoid overdosing.

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3. Examples of drugs with multiple mechanisms of action that may increase the risk of interactions and ADRs in the geriatric population

3.1 Oral hypoglycemics

3.1.1 Pharmacokinetics of biguanides

Among this group, metformin is the most widely used drug for the treatment of T2DM. It is absorbed in the small intestine with an approximate bioavailability of 50–60% [66]. Metformin shows minimal binding to plasma proteins, is not metabolized in the liver, and is not excreted in bile. Instead, it is eliminated almost entirely by the kidneys, primarily through active tubular secretion [67]. Currently, there is no strong clinical evidence of pharmacokinetic DDIs involving metformin.

3.1.2 Importance of the multiple effects of metformin and their possible implications for adverse drug reactions

Metformin is considered a drug with polypharmacological properties, as it can act on multiple regions of the body, including the gastrointestinal system, liver, pancreas, and skeletal muscle [68]. In older adults, significant delays in gastric emptying may occur, potentially affecting the intestinal absorption of metformin. The main transporters involved in its absorption and intestinal transport include: a) organic cation transporter 1 (OCT-1), b) plasma membrane monoamine transporter (PMAT), and c) serotonin transporter (SERT), among others [69, 70]. Because much of this evidence comes from animal studies, further research in humans is needed (Figure 1).

OCT-1 can be inhibited by proton pump inhibitors (PPIs) such as pantoprazole [71], which may reduce metformin absorption and, in turn, lower its hypoglycemic effect [72]. Moreover, combining these drugs can lead to gastrointestinal side effects, including diarrhea and abdominal discomfort [73].

In the intestine, metformin can also reduce glucose absorption [74] and impair the absorption of vitamin B12 and bile acids [75, 76]. Gastrointestinal intolerance is a well-recognized syndrome associated with metformin. Diarrhea is among the most common clinical manifestations [75, 77], although other studies have identified nausea and vomiting as the additional major adverse effects [78, 79].

One proposed mechanism for gastrointestinal intolerance involves the GLP-1 receptor [79]. Another theory suggests that metformin may alter intestinal 5-HT levels, triggering diarrhea, nausea, and vomiting similar to metformin intolerance [80]. Metformin also has structural similarities to selective 5-HT3 receptor agonists [81], which acts on receptors that regulate nausea and vomiting [80]. However, some studies have found no consistent evidence linking metformin-induced nausea to interactions with this receptor [80, 81].

Interestingly, metformin may also interact with other serotonergic receptor subtypes, such as 5-HT1A and 5-HT1B. In previous studies, the antagonists WAY-100635 and GR-127935—specific blockers of the 5-HT1A and 5-HT1B receptors, respectively—were found to inhibit the antinociceptive effects of metformin [82]. In addition, stimulation of the 5-HT2C receptor can enhance 5-HT release from the duodenum [83].

Gluconeogenesis is the metabolic process of producing glucose from non-carbohydrate precursors such as lactate, glycerol, and certain amino acids. It plays a key role in maintaining normal blood glucose levels, particularly during fasting or when glycogen stores are depleted. Metformin inhibits gluconeogenesis, thereby lowering blood glucose. It also acts on the mitochondrial respiratory chain by inhibiting Complex I [84]. Consequently, by limiting the liver’s ability to convert lactate into glucose, metformin may increase the blood lactate levels.

Although metformin is considered safe for most patients with T2DM, in certain situations it may increase the risk of lactic acidosis, particularly when combined with drugs that impair its renal clearance, disrupt acid–base balance, or alter lactate metabolism [85].

Medications such as NSAIDs, angiotensin-converting enzyme inhibitors, and angiotensin II receptor antagonists can acutely reduce glomerular filtration, leading to metformin accumulation and an increased risk of lactic acidosis, particularly in the setting of dehydration or hypovolemia [85, 86, 87]. Additional risk factors include excessive alcohol consumption, high doses of metformin combined with prolonged fasting, intense physical exercise, renal impairment, severe infections, and carbon dioxide poisoning, all of which can further raise the likelihood of lactic acidosis [88, 89].

T2DM is characterized by impairments in both insulin secretion and insulin sensitivity [90]. Insulin release from pancreatic β-cells plays a central role in the disease’s etiology, but the complex regulation and mechanisms by which metformin influences β-cell insulin secretion are not yet fully understood [91]. Evidence suggests that metformin can downregulate the nitric oxide (NO) system in β-cells, which normally acts as a negative regulator of insulin secretion. In experimental models, metformin suppresses NO overproduction induced by high glucose concentrations or sulfonylureas, potentially restoring the insulin secretory response [92, 93].

The 5-HT1B and 5-HT2C receptors also play distinct roles in regulating insulin secretion from pancreatic β-cells [94, 95]. However, studies have shown that activation of the 5-HT1B receptor in humans and the 5-HT2C receptor in mice reduces insulin release (Figure 1) [95, 96].

These findings are both intriguing and complex, as the 5-HT1A [97] and 5-HT1B [98] receptors—potential targets of metformin—are not only expressed in β-cells but also located on the platelet plasma membrane, where the 5-HT1B receptor in particular has been associated with platelet aggregation (Figure 2) [98, 99].

Figure 2.

Possible sites of action of metformin. The diagram illustrates metformin’s interactions at the intestinal, pancreatic, vascular, and central nervous system (CNS) levels. In each of these regions, this biguanide may specifically interact with serotonergic and GABAergic receptors, as well as with the serotonin transporter. Created with BioRender.com.

The GABAergic system has likewise been linked to insulin secretion [100]. Evidence suggests that GABA may promote β-cell proliferation [101], and benzodiazepine receptor agonists have been shown to enhance pancreatic β-cell function (Figure 2) [102]. Another noteworthy finding is metformin’s potential affinity for the GABAA receptor, reported in preclinical studies, where this biguanide demonstrated the anxiolytic effects through interaction with the GABAA receptor [103].

Additional evidence of the complex interplay between the serotonergic system (SS), the GABAergic system, behavioral disorders, and the metabolic disturbances characteristic of T2DM is the presence of 5-HT1B, 5-HT2C, and GABAA receptors in various regions of the CNS (Figure 1), including the raphe nuclei, hippocampus, and prefrontal cortex—areas involved in memory regulation [104], depression [105], and anxiety [106]. Notably, there is a bidirectional relationship between the metabolic dysfunction associated with T2DM and the prevalence of depression [107].

Metformin’s multiple mechanisms of action add a significant layer of complexity to its clinical use, beyond the potential DDIs associated with biguanides. For example, in older adults undergoing polypharmacy, PPIs may be prescribed for acid-peptic disease or SSRIs for depression. Riskier prescriptions, such as benzodiazepines for sleep disorders in diabetic patients treated with metformin, may also be introduced. Another frequent scenario is the use of NSAIDs, such as acetylsalicylic acid, for vascular disease prevention.

Given these situations, physicians should be especially vigilant for ADRs that may appear difficult to explain but could, in fact, be linked to metformin’s ability to interact with the serotonergic and GABAergic systems in multiple regions of the body.

3.2 Statins

3.2.1 Pharmacology of statins

Statins are a group of drugs that include lovastatin, pravastatin, simvastatin, fluvastatin, cerivastatin, rosuvastatin, and atorvastatin. Their mechanism of action is based on inhibition of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR) [108].

Atorvastatin is rapidly absorbed after oral administration, with peak plasma concentrations reached in about 4 hours. Its absolute bioavailability is 12%, and both the rate and extent of absorption are influenced by the time of administration and food intake [109]. Atorvastatin binds to plasma albumin by approximately 98% and has a half-life of roughly 14 to 20 hours [86]. After hepatic metabolism, it is excreted primarily in the bile [110].

Statins are indicated for reducing elevated total cholesterol, low-density lipoprotein cholesterol (LDL-C), very-low-density lipoprotein (VLDL) synthesis, and circulating triglycerides in patients with primary hypercholesterolemia [111]. By improving dyslipidemia, statins reduce the risk of cardiovascular events and mortality [112].

Atorvastatin is mainly metabolized by CYP3A4, which makes it vulnerable to DDIs with enzyme inhibitors such as clarithromycin and erythromycin [113]. In such cases, plasma concentrations of atorvastatin may rise substantially, increasing the risk of adverse effects including myopathy and rhabdomyolysis [114].

Atorvastatin is also a substrate of hepatic transporters, including OATP1B3. Co-administration with cyclosporine, an OATP1B1 inhibitor, can significantly increase its bioavailability [115]. In contrast, CYP3A4 inducers such as rifampicin may reduce plasma concentrations of atorvastatin [116]. Furthermore, combining atorvastatin with fibrates or niacin increases the risk of myopathy and rhabdomyolysis through additive effects on muscle pathways [117, 118].

In addition, statins have been associated with clinically evident cases of acute liver injury, presenting with hepatocellular or cholestatic patterns [119]. Concomitant use with other drugs that carry a risk of hepatotoxicity—such as NSAIDs [120], selective serotonin reuptake inhibitors (SSRIs) [121], amoxicillin-clavulanic acid [122], and anticonvulsants [120]—may potentiate liver damage.

3.2.2 Importance of the multiple effects of atorvastatin and potential adverse drug reactions

It is also important to consider the concomitant effects that may result from atorvastatin-induced cholesterol reduction. Cholesterol is the primary substrate for the synthesis of several steroid hormones [123, 124].

With regard to hormones, some studies have suggested that statins may slightly reduce the synthesis of certain steroids, although results have been inconsistent. Clinical and epidemiological evidence has generally shown no significant effects on the production of cortisol, total or free testosterone, estradiol, LH, or FSH [125, 126, 127]. However, in women with polycystic ovary syndrome, statins have been shown to reduce androgen levels and improve hyperandrogenism, although their use for this purpose is not recommended outside of cardiovascular indications [125].

Conflicting evidence has also been reported regarding a possible bidirectional interaction between statins and gonadal hormones. For instance, statin use has been associated with an increased risk of T2DM in postmenopausal women [127, 128], and in this same group, one study found that intensive statin therapy over 1 year did not slow the progression of coronary calcification [129]. Conversely, other studies have suggested that statins do not significantly affect gonadal function or fertility in either men or women, nor do they appear to alter the menstrual cycle or progesterone synthesis in premenopausal women [130, 131]. It is important to note, however, that women have been underrepresented in statin trials, and data on efficacy and safety in this population remain limited.

In light of the above, hormonal status is an important factor that may influence the development of statin-related adverse effects. Further and more in-depth research is needed to account for this variable and to clarify the presence or absence of such potential effects.

Regarding the SS, statins may influence 5-HT neurotransmission through both cholesterol-dependent and cholesterol-independent mechanisms. Experimental studies have shown that chronic cholesterol depletion induced by statins can alter the function and dynamics of 5-HT1A receptors, reducing their coupling to G proteins and their ability to bind ligands. These alterations may help explain the symptoms of anxiety and depression observed in some patients undergoing statin therapy (Figure 3B) [132, 133].

Figure 3.

Influence of statin-induced membrane cholesterol reduction on serotonergic receptors.

Statins have also been shown to enhance 5-HT reuptake through SERT in a fluoxetine-dependent manner, via cholesterol-independent lipid signaling pathways, specifically through the regulation of isoprenylation intermediates such as farnesyl pyrophosphate [134]. These effects on the SS have been demonstrated in cell and animal models; however, their clinical significance remains uncertain, as some studies have suggested a possible association between statin use and the development of depression [133].

Statins have been used for nearly four decades, with their effectiveness in treating cardiovascular disease well supported by extensive evidence. Nevertheless, many studies have also linked them to potential adverse effects on mental health.

Preclinical studies have associated statins with cognitive impairment. In male rats, daily oral administration of pravastatin or atorvastatin (10 mg/kg) for 18 days impaired learning during the final days of treatment, an effect that was fully reversed after discontinuation [135]. Likewise, in a novel object recognition task, pravastatin significantly impaired memory.

Furthermore, oral administration of simvastatin at doses of 10 or 30 mg/kg/day in rats for 4 weeks led to impaired spatial memory, as measured by the Barnes maze test [136]. Similarly, in a study with male guinea pigs, the effects of simvastatin (2 mg/kg) and atorvastatin (1 mg/kg, oral) were evaluated over 6 weeks. Spatial memory was tested using the Morris water maze, and animals treated with statins spent significantly more time outside the platform area compared with controls [137].

The memory impairment observed may be explained by several interconnected mechanisms. One key factor is the structural role of cholesterol in neuronal membranes, where it is essential for synapse formation, neurotransmitter release, and the proper function of membrane receptors such as Glu, DA, and 5-HT receptors [138].

Lipophilic statins, such as atorvastatin, can cross the blood-brain barrier and lower brain cholesterol levels. This may impair synaptic plasticity and neuronal transmission, contributing to deficits in spatial and recognition memory [139]. Such effects are linked to reduce membrane fluidity and decreased availability of anchoring sites for receptors such as 5-HT1A and 5-HT7, which depend on intact lipid microdomains for effective signaling [140, 141].

Several studies have also shown that, in certain contexts, atorvastatin can exert proinflammatory effects, increasing cytokines such as IL-1β, TNF-α, and IL-6—particularly in experimental models with prior immune challenges or under hormonal conditions such as estrogen deprivation [142]. The activation of inflammatory pathways may further exacerbate cognitive decline by suppressing neurotrophic factors such as BDNF and impairing neurogenesis in the hippocampus, a region critical for memory consolidation [142].

Panel A illustrates the membrane cholesterol configuration that provides anchoring and stability to the 5-HT1A and 5-HT7 serotonergic receptors, as well as the potential interaction of certain statins with the 5-HT transporter. Panel B depicts the possible impact of statin-induced membrane cholesterol reduction on serotonergic receptors. Created with https://BioRender.com

It is therefore plausible to suggest that the combination of estrogen deficiency and subchronic atorvastatin treatment in animals involves complex mechanisms that may act synergistically to worsen memory impairment. Both factors also affect the SS, as cholesterol depletion [141] and estrogen deficiency [143] have been shown to alter the density and function of serotonergic receptors, including 5-HT1A and 5-HT7R. Such changes directly impact processes such as working memory, consolidation, and spatial learning, which are associated with these receptors (Figure 3) [143].

In this context, the convergence of lipid dysfunction, estrogen deficiency, neuroinflammation, and serotonergic disruption may represent key interrelated factors underlying statin-induced cognitive deficits in animal models. Collectively, these findings underscore the complexity of statins’ effects on cognitive function.

Finally, although randomized clinical trials and systematic reviews have not demonstrated significant differences in cognitive performance, memory, executive function, or in the incidence of dementia or Alzheimer’s disease between statin users and controls [144, 145], it remains important to monitor pharmacovigilance data and pursue further research on these potential cognitive effects. This is especially relevant in women, to better confirm or rule out ADRs and provide greater therapeutic certainty for this widely used drug class in the geriatric population.

3.3 Selective serotonin reuptake inhibitors

3.3.1 Pharmacology of selective serotonin reuptake inhibitors

SSRIs differ by specific compound but share general characteristics important for clinical practice. They have largely replaced tricyclic antidepressants as the first-line treatment for major depressive disorder [146]. In addition, they are indicated for anorexia nervosa, bulimia nervosa, and several anxiety-related disorders [147], including obsessive-compulsive disorder, panic disorder, social phobia, and post-traumatic stress disorder [148].

Furthermore, fluoxetine [149] and other agents such as duloxetine and venlafaxine—classified as serotonin-norepinephrine reuptake inhibitors (SNRIs)—are also widely used as first-line treatments for neuropathic pain [150].

SSRIs (fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram) are well absorbed orally but have moderate bioavailability due to first-pass hepatic metabolism. They are widely distributed in tissues and bind extensively to plasma proteins [147]. Elimination occurs primarily through hepatic cytochrome P450 isoenzymes, resulting in substantial interindividual variability in plasma concentrations and an increased risk of DDIs.

In the CNS, SSRIs alter serotonin (5-hydroxytryptamine, 5-HT) release and reuptake, influencing synaptic plasticity and functional connectivity in brain regions associated with depression, including the anterior cingulate cortex, amygdala, and hippocampus [151, 152, 153]. Modulation of 5-HT2C receptor activity can either enhance or counteract SSRI effects on 5-HT release and the antidepressant response, as demonstrated in preclinical studies [154, 155, 156].

Fluoxetine and paroxetine are potent CYP2D6 inhibitors, which can elevate plasma concentrations of drugs metabolized through this pathway, including antipsychotics (haloperidol and clozapine), tricyclic antidepressants, and certain beta-blockers.

Consistent with this, a growing number of previous studies have reported that combining SSRIs with newer antipsychotics (e.g., clozapine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone, quetiapine) in geriatric patients has been associated with cases of arrhythmias, QTc interval prolongation on electrocardiograms, orthostatic hypotension, and confusion [157]. These alterations have, in turn, been linked to an increased risk of falls that may lead to fractures [158].

Fluvoxamine mainly inhibits CYP1A2 and CYP2C19, potentially increasing levels of drugs such as theophylline, warfarin, and several anticonvulsants (Figure 4).

Figure 4.

Multiple effects of SSRIs. The diagram outlines both the pharmacokinetic and pharmacodynamic effects of SSRIs that may explain adverse drug reactions related to interactions at the metabolic, renal, vascular, and central nervous system levels. In the latter two regions, these drugs may alter SS physiology, potentially leading to adverse outcomes such as elevated blood pressure and hemorrhage. Created with https://BioRender.com.

In addition, SSRIs can interact with other neurotransmitter systems. Fluoxetine and paroxetine, for instance, inhibit nicotinic receptors, which may contribute to the neurological side effects and alter cholinergic activity [159].

SSRIs may also increase the risk of upper gastrointestinal bleeding by inhibiting platelet SERT [146, 160]. This risk can be further elevated when they are used in combination with drugs that affect hemostasis, such as NSAIDs or anticoagulants [161, 162].

3.3.2 Importance of the multiple indirect effects of SSRIs and their possible implications for adverse drug reactions

As with the two drug groups discussed above, SSRIs may also have overlapping effects because of their ability to modulate extracellular 5-HT levels. Since the SS is involved in multiple organs and systems, changes in 5-HT concentrations can trigger a wide range of effects and may interact with the mechanisms of action of other drugs.

Although some adverse effects of SSRIs are rare, they are clinically significant due to the sharp rise in their use over recent decades, especially among older adults and patients with T2DM and depression [163]. In addition, serious adverse effects are increasingly being reported, including hyponatremia, bleeding, increased risk of suicidal ideation, and cardiovascular complications with certain SSRIs.

SSRI-induced hyponatremia is defined as a plasma sodium concentration below 136 mEq/L. Symptoms typically appear at levels under 130 mEq/L, with values below 125 mEq/L considered severe. At 125–130 mEq/L, gastrointestinal symptoms are most common, while lower levels are associated with neuropsychiatric manifestations.

Risk factors for hyponatremia include age over 65 years, female sex, concomitant diuretic use, low body weight, and baseline plasma sodium levels near the lower limit of normal before initiating SSRI therapy (Figure 3) [164].

SSRI therapy has also been linked to increased reports of hypertension, both as a new-onset condition and as worsening of preexisting hypertension [165]. However, the magnitude of this risk appears to vary among different agents, and no clear dose-response relationship has been established [166].

In terms of cardiovascular safety, certain SSRIs—particularly citalopram and escitalopram—can prolong the QTc interval, a concern especially relevant for patients with heart failure or those at risk of arrhythmias [167, 168].

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4. Possible strategies to prevent drug interactions involving multiple mechanisms of action in the geriatric population

The risk of developing DDIs—and consequently ADRs—is well known to increase in proportion to the number of drugs prescribed. The more medications a patient takes, the greater the likelihood of overlapping pharmacokinetic and pharmacodynamic processes.

Beyond these overlaps, special attention should be given to drugs with multiple mechanisms of action, whether direct or indirect, such as biguanides, statins, and SSRIs, which have been discussed above as illustrative examples.

For this reason, physicians must exercise particular caution when prescribing these drugs as part of therapy for older adults.

Since drugs with multiple mechanisms of action add an extra layer of risk to DDIs, they further increase the likelihood of interactions with other medications and, consequently, the exponential probability of developing ADRs.

Thus, even when fewer than five drugs are prescribed, the presence of a single drug with multiple mechanisms of action should be taken seriously. In such cases, strategies should be implemented to prevent or promptly detect the potential adverse effects.

Building on the discussion above, an algorithm has been developed to provide a clear and practical framework for managing the prescription of drugs with polypharmacology in the geriatric population (Figure 5).

Figure 5.

Algorithm for the management of drugs with multiple mechanisms of action.

When assessing the risk of clinically relevant DDIs in older adults, additional factors should be considered, including multiple prescribers, infrequent or inadequate monitoring, impaired drug elimination pathways, and pharmacogenetic variability. Effective communication between healthcare providers and patients is therefore essential, with treating physicians and nurses playing a central role in ensuring that patients are fully informed.

Recent research has shown that polypharmacy resulting from inappropriate drug selection or the use of medications without a valid indication is associated with an increased incidence of DDIs. This, in turn, raises the risk of ADRs and hospitalizations, contributing to a greater economic burden for both patients and healthcare systems [8, 169].

The prevention of polypharmacy and DDIs that may cause ADRs in geriatric patients requires a systematic, multidisciplinary approach grounded in current evidence. Strategies recommended in the medical literature include:

  1. The Beers criteria, together with the clinical tools STOPP/START, can help physicians identify potentially inappropriate medications and possible risks of DDIs when prescribing for geriatric patients [170, 171]. The STOPP/START criteria are particularly valuable, as they take into account physiological systems and emphasize periodic reviews of all prescribed drugs, including over-the-counter medications and supplements. These tools prioritize the assessment and the development of an individualized care plan, involving both the patient and the multidisciplinary healthcare team, in line with comprehensive medication management.

  2. Implement deprescribing processes, that is, the planned and supervised withdrawal of non-essential or high-risk medications, especially in patients with multimorbidity and limited life expectancy. This process should be individualized and aligned with the patient’s therapeutic goals and preferences, involving pharmacists and other members of the healthcare team [172, 173]. Therefore, it is advisable to consult algorithms, particularly for drugs that may cause tolerance and dependence, such as antipsychotics and opioid analgesics, since strategies for gradual withdrawal can vary depending on the type of medication [174].

  3. Perform medication reconciliation at every care transition (admission, discharge, outpatient visit), identifying duplications, DDIs, and prescribing errors. This practice is especially important in settings such as emergency departments and primary care [171].

  4. Incorporate comprehensive geriatric assessment to identify vulnerabilities and age-related changes in pharmacokinetics and pharmacodynamics, and adjust pharmacotherapy according to the patient’s renal, hepatic, and cognitive function, as well as overall functional status [175].

  5. Use Clinical Decision Support Systems (CDSS), evidence-based software programs that integrate patient-specific information at the point of care [176], to assist healthcare professionals in achieving diagnostic precision and optimizing the effectiveness of pharmacological treatments [170, 171]. Alongside these tools, advances in the application of artificial intelligence (AI) strategies, such as mining large volumes of complex data, allow for the prediction of DDIs and promote more efficient, accurate, and comprehensive pharmacovigilance. These developments ultimately enhance patient safety and support the rational use of medications [177, 178].

  6. Promote collaboration among physicians, pharmacists, nurses, and other professionals—particularly in nursing homes and home care—to optimize pharmacotherapy and reduce risks [56, 173]. This includes training prescribers and educating patients about regulatory measures, such as black box warnings, which are prominently displayed on drug labels and highlight specific risks, including monitoring requirements or restrictions on use. Examples include common black box warnings for certain antidepressants (suicidal thoughts), opioids (addiction, overdose), and some antibiotics (tendon rupture) [179]. All of these measures are part of risk minimization programs [180], which should be considered in every prescription and at each transition of care.

  7. In addition, it is essential to consider other strategies based on the principles of rational prescribing [181]. Particularly in chronic treatments involving drugs with a high potential for interaction, it is advisable to start with a low dose, proceed gradually, and discontinue therapy whenever possible. Maintaining close communication with the patient is also critical to foster health literacy strategies, which can help minimize risks in prescribing [182].

These strategies, supported by the medical literature, have been shown to reduce the incidence of adverse reactions, hospitalizations, and complications associated with polypharmacy in older adults.

ADRs can have direct economic implications due to the increased rates of hospitalization, morbidity, mortality, and associated costs [183]. They may also negatively affect family finances through potential loss of work, caregiver burden, and changes in family dynamics. In addition, ADRs place added financial stress on healthcare systems [184], especially in developing countries.

Therefore, the effective implementation of preventive strategies requires institutional commitment and the integration of review and prescribing processes into daily clinical practice [185, 186].

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5. Future perspectives

Let us imagine a near-future scenario in which every older adult has a microchip containing their complete medical history, including key genetic profile data such as hepatic cytochrome subtype. At the start of a consultation, this microchip could automatically connect to software powered by AI, which would analyze the patient’s clinical data and compare the evidence with the most recent advances in clinical research.

In this way, when the physician issues a prescription, the program could estimate and alert for the presence of hidden polypharmacy, the probability of DDIs and ADRs, and encourage rational polypharmacy, where deprescribing through algorithms is continually promoted.

Moreover, this system could also have the capacity to send and install an application on the patient’s mobile phone, providing the treatment plan and a reminder system for prescription schedules. In parallel, the program could generate and schedule videos to educate the patient about their pharmacological treatment, necessary precautions when taking medications, guidelines for early detection and reporting of ADRs, and counseling to avoid foods or dietary supplements that could interact with the prescribed therapies.

All of the above is already possible today, but only in separate components: Electronic medical records exist, as do AI-based programs that can guide physicians in identifying inappropriate drugs or those at risk of drug interactions, as discussed earlier.

However, despite these advances, it remains difficult to integrate all these elements into a single program, since differences still exist in the formats used for medical records across institutions and specialties. This represents a major obstacle to continuity of care for the geriatric population, particularly when a patient is repeatedly hospitalized in different institutions or requires consultations with multiple specialties.

Having up-to-date clinical information available electronically—including pharmacological treatments—would foster greater effectiveness in therapy, medical care, and pharmacovigilance.

It is essential to give special consideration to drugs with multiple mechanisms of action because of the higher risk they pose for DDIs.

Therefore, promoting further research into metformin’s ability to regulate the serotonergic and GABAergic systems in pancreatic β-cells, as well as in platelets, the immune system, and the CNS, represents a key challenge that would help clarify the possible mechanisms of interaction among drugs that share similar targets, enabling the prevention or explanation of ADRs. In addition, leveraging this knowledge to innovate and explore the potential of biguanides in the treatment of other diseases is essential.

Statins and SSRIs, due to their multiple mechanisms of action, may indirectly affect SS function—statins by altering extracellular 5-HT levels, and SSRIs by lowering cholesterol levels. Both mechanisms could impact the functionality of the serotonergic system. Further research on these drugs would therefore improve the understanding of SS-related DDIs.

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6. Conclusions

Biguanides, statins, and SSRIs, through their polypharmacological actions, may interact directly or indirectly with the SS, which is present in various systems including the gastrointestinal tract, pancreas, platelets, and CNS.

Prescribing a drug with multiple mechanisms of action as part of polypharmacy in the geriatric population may significantly increase the risk of DDIs associated with adverse drug reactions (ADRs).

It is important to note that in hidden polypharmacy the risks of adverse effects are often underestimated, highlighting the need to strengthen individualized pharmacovigilance strategies based on effective communication between healthcare professionals and patients, fostering training for the former and education for the latter.

Therefore, before prescribing any drug with polypharmacological properties, its use should be carefully evaluated and, whenever possible, reconsidered. If prescribing is necessary, both family members and healthcare professionals must remain vigilant for the appearance of ADRs in order to ensure timely intervention and prevent serious outcomes.

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Submitted: 02 September 2025 Reviewed: 07 October 2025 Published: 19 November 2025

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