Understanding pharmacokinetics in older adults is crucial due to demographic trends showing a growing population of older individuals (Clifford et al, 2016; Reis da Silva, 2023a; 2023b). Older adults experience various pharmacokinetic and pharmacodynamic changes that affect how medications are absorbed, metabolised, and eliminated, leading to differences in drug response compared to younger adults (Pallesen et al, 2022). These alterations increase the risk of adverse drug reactions, especially in the context of managing conditions like sepsis that require precise drug therapy (Clifford et al, 2016).
The physiological and pathological changes associated with ageing, such as decreased physiological reserve and alterations in pharmacokinetic and pharmacodynamic factors, make older adults particularly vulnerable to medicine-related adverse effects (Yamada, 2023).
Polypharmacy, a common occurrence among older adults, further complicates the situation by increasing the risk of adverse drug events (Pallesen et al, 2022). The use of multiple medications to manage the multimorbidity often seen in older adults raises concerns about drug interactions and the potential for adverse outcomes (Dias et al, 2019). Additionally, older adults may exhibit altered pharmacokinetic and pharmacodynamic profiles, including reduced renal and hepatic clearance, increased volume of distribution of lipid-soluble drugs, and increased sensitivity to certain drug classes (Tayer-Shifman et al, 2021). These changes necessitate careful consideration when prescribing medications to older adults to ensure efficacy and safety.
Moreover, older adults are often excluded from clinical trials, leading to limited data on drug safety and efficacy in this population (Bettonte, 2024). This exclusion hampers the understanding of how age-related changes impact pharmacokinetics and pharmacodynamics, highlighting the need for more research in this area (Bettonte, 2024). Individualising pharmacotherapy based on these age-related changes, drug interactions, and geriatric dosage considerations can lead to better treatment outcomes and tolerability in older adults (Amundson et al, 2022).
In the context of specific conditions like major depressive disorder, understanding pharmacokinetic and pharmacodynamic drug interactions is essential for mitigating the risk of adverse effects related to augmentation therapy, especially in older adults (Amundson et al, 2022). Similarly, in diseases like systemic lupus erythematosus, where neuropsychiatric manifestations can occur in older adults, considering age-related pharmacokinetic and pharmacodynamic changes is crucial for effective diagnosis and management (Tayer-Shifman et al, 2021). Frailty assessment can aid in tailoring therapeutic decisions for conditions like coronary artery disease in older adults, taking into account age-related pharmacokinetic and pharmacodynamic changes, polypharmacy, and potential drug interactions (Cacciatore, 2023).
Pharmacokinetic changes with ageing
This section will delve into the specific changes that occur in the pharmacokinetic processes – absorption, distribution, metabolism, and excretion – as people age. Each subsection will discuss the physiological basis for these changes and their implications for drug therapy.
Absorption
Changes in gastrointestinal function and their impact on drug absorption
The absorption of drugs in older adults is influenced by changes in gastrointestinal function, which can impact the bioavailability of medications (Yamada, 2023). Age-related alterations in the pH values of different parts of the gastrointestinal tract can directly affect important determinants of drug absorption, such as stability, dissolution, and ionization (Jovanovic, 2022). Additionally, altered gastrointestinal transit time and absorption due to enzymatic changes, phase I metabolism in the liver, and changes in the excretory rate due to renal impairment are factors that impact drug absorption in older adults (Wright, 2023). These changes can lead to variations in drug absorption, potentially affecting the efficacy and safety of medications in the elderly population (Mian et al, 2018).
Furthermore, age-related changes in pharmacokinetics and pharmacodynamics may increase the risk of adverse effects such as falls in older adults (Reis da Silva, 2023a; 2024a), emphasising the importance of understanding these alterations in drug response (Virnes et al, 2022). Understanding how aging affects drug absorption is crucial for optimising medication regimens in older adults. By considering the impact of age-related changes in gastrointestinal function and other pharmacokinetic factors, healthcare providers can tailor drug therapy to the specific needs of elderly patients, ensuring both efficacy and safety in pharmacological interventions.
Factors affecting drug bioavailability in older adults
Among the possible references provided, the most relevant reference for factors affecting drug bioavailability in older adults is the study by Finkelstein et al (2016a). This highlights the potential use of precision medicine for older adults with polypharmacy, emphasising the impact of altered metabolism and the presence of geriatric syndromes on the likelihood of experiencing adverse drug events and hospitalisation (Finkelstein et al, 2016a). Polypharmacy can significantly affect drug bioavailability due to interactions between multiple medications and their effects on metabolism and absorption (Finkelstein et al, 2016a). Understanding how genetic factors and pharmacogenomics influence drug responses in older adults with polypharmacy is crucial for optimising medication regimens and minimising the risk of adverse events (Finkelstein et al, 2016a).
Polypharmacy, often driven by the management of multiple medical conditions in older adults, can lead to an increased risk of adverse drug events and drug interactions, affecting drug bioavailability and overall treatment outcomes (Mukete and Ferdinand, 2015). The use of multiple medications can impact dietary intake, metabolism, and drug absorption, potentially altering the bioavailability of essential nutrients and medications in older adults (Aðalbjörnsson and Ramel, 2021). Moreover, polypharmacy is associated with a higher risk of adverse events such as falls (Reis da Silva, 2023a; 2024a), heart failure, and exacerbation of existing medical conditions, underscoring the importance of considering the impact of multiple medications on drug bioavailability in this population (Mukete and Ferdinand, 2015).
In addition to polypharmacy, factors such as solubility, drug distribution, protein binding, and absorption can also influence drug bioavailability in older adults (Bhalani et al, 2022). The physicochemical properties of drugs, their interactions with food, and the gastric residence time can affect the absorption and bioavailability of medications in the elderly (Bhalani et al, 2022). Furthermore, age-related changes in gastrointestinal function, renal function (Reis da Silva, 2024b), and liver metabolism can affect drug absorption and distribution, further complicating the pharmacokinetics of medications in older adults (Bhalani et al, 2022).
Overall, factors affecting drug bioavailability in older adults are multifaceted and encompass aspects such as polypharmacy, genetic variability, metabolic changes, and drug interactions. Understanding these factors is essential for optimising medication regimens, minimising adverse drug events, and improving treatment outcomes in older people
Distribution
Alterations in body composition
Changes in body composition, such as increased fat and decreased muscle mass, are significant factors affecting the distribution of drugs in older adults. Ageing is associated with a shift in body composition characterised by an increase in fat mass and a decrease in muscle mass (Roshan et al, 2021). This redistribution of fat from peripheral and subcutaneous sources to a central location contributes to an increase in the waist–hip ratio in older adults, accompanied by a loss of muscle mass and strength (Roshan et al, 2021; Reis da Silva, 2023a). Alterations in body composition, particularly the loss of muscle mass, can have implications for drug distribution in the body, as muscle mass plays a crucial role in drug metabolism and distribution (Chung, 2014).
Pharmacokinetic changes and clinical implications
Recommendations for prescribing practice
The loss of muscle mass and strength, commonly known as sarcopenia, is a prevalent concern among older adults and can affect drug distribution due to changes in lean body mass (Steinmeyer et al, 2019). Ageing leads to a progressive reduction in total body water and lean body mass, resulting in a relative increase in body fat (Schrock et al, 2017). These changes in body composition can influence the volume of distribution of drugs, potentially affecting their pharmacokinetics and efficacy in older adults (Mikkola et al, 2019). Furthermore, the decline in muscle mass and the increase in fat mass with ageing can contribute to changes in metabolic processes, affecting the distribution and elimination of medications in older people (Dolbow et al, 2016).
Research has indicated that resistance training programs can help counteract the age-related loss of muscle mass and improve body composition in older adults (Zhu et al, 2022; Reis da Silva, 2023a; 2024a). By enhancing muscle mass and strength through resistance exercises, older adults can potentially improve drug distribution and metabolism, leading to better treatment outcomes and overall health. Additionally, interventions aimed at addressing changes in body composition, such as reducing fat mass and preserving lean body mass, may play a crucial role in optimising drug distribution and response in older adults.
Effects on volume of distribution and plasma protein binding
A study by Korzekwa and Nagar (2016) provides valuable insights into predicting the volume of distribution based on drug plasma protein binding and tissue partitioning. The model presented in this study emphasises the importance of understanding drug plasma protein binding and tissue distribution in predicting the volume of distribution for drugs. Plasma protein binding plays a crucial role in determining the distribution of drugs in the body, as it influences the fraction of the drug available for distribution to tissues and organs (Korzekwa and Nagar, 2016). By considering the plasma protein binding characteristics of a drug, researchers and clinicians can better predict its volume of distribution and optimize dosing regimens for improved therapeutic outcomes.
Additionally, the research by Valkó et al (2018) discusses the application of biomimetic high-performance liquid chromatography (HPLC) to estimate lipophilicity, protein binding, and phospholipid binding of potential peptide therapeutics. The study provides insights into the relationship between lipophilicity, protein binding, and volume of distribution, highlighting the importance of understanding these parameters in drug distribution and pharmacokinetics.
By assessing total plasma protein binding and volume of distribution, researchers can gain valuable information on how drugs interact with plasma proteins and tissues, influencing their distribution and pharmacological effects (Valkó et al, 2018).
Metabolism
Age-related changes in liver function and enzyme activity
The study by Rest et al (2016) provides valuable insights into the metabolic effects of a lifestyle intervention in older adults, highlighting the potential benefits of a 25% reduction in energy balance over 13 weeks on metabolic health. This research demonstrates metabolic health improvements in older adults, as monitored by traditional and novel metabolic markers (Rest et al, 2016). Understanding the metabolic changes induced by lifestyle interventions in older adults is crucial for promoting healthy ageing and preventing age-related metabolic disorders.
Moreover, research by Park et al (2023) explores the relationship between perceived stress, obesity, and hypertension in Korean adults and older adults, shedding light on the complex interplay between psychological stress and metabolic disorders. This study underscores the importance of addressing stress management in the prevention and management of metabolic diseases, particularly in older populations (Park et al, 2023). By elucidating the connections between stress, obesity, and hypertension, researchers can develop targeted interventions to improve metabolic health in older adults.
Additionally, the study by Kim et al (2021) investigates the correlation between cardiopulmonary metabolic energy cost and lower-limb muscle activity during inclined treadmill gait in older adults. This research reveals that older adults expend 7–20% more metabolic energy than younger adults while walking on flat surfaces or uphill for a given distance (Kim et al, 2021). Understanding the metabolic demands of physical activities in older adults is essential for designing exercise programmes that promote cardiovascular health and metabolic fitness in aging populations.
Implications for drug metabolism
A study by Xu et al (2019) offers valuable insights into age-associated changes in cytochrome P450 (CYP) enzymes and related phase-2 proteins in the livers of rats. Cytochrome P450 enzymes are essential for phase I drug metabolism, playing crucial roles in the biotransformation of various compounds, including drugs, dietary chemicals, and endogenous molecules (Xu et al, 2019). Understanding the alterations in CYP enzymes and phase-2 proteins in the context of ageing is vital for comprehending age-related changes in drug metabolism and potential implications for medication efficacy and safety in older adults.
Furthermore, research by Konstandi and Johnson (2023) delved into age-related modifications in CYP-dependent drug metabolism, emphasising the impact of stress on hepatic drug metabolism. Ageing is accompanied by a progressive reduction in liver volume and blood flow, factors that significantly influence hepatic drug metabolism and the activity of cytochrome P-450 enzymes (Konstandi and Johnson, 2023). Stress, in conjunction with ageing, can further exacerbate alterations in drug metabolism, highlighting the intricate interplay between physiological changes, stress responses, and drug metabolism in older individuals.
Excretion
Decline in renal function with age
The decline in renal function with age is a significant concern in older adults, as evidenced by various studies exploring the impact of aging on kidney health. The study by Mekuria et al (2016) focuses on renal function impairment in HIV-positive individuals, highlighting the association between age and declining kidney function. This research underscores the importance of understanding age-related changes in renal function, particularly in vulnerable populations such as HIV-positive individuals (Mekuria et al, 2016). Age-related decline in renal function is a common phenomenon that can have implications for the management of various health conditions, including HIV.
Furthermore, Luo et al (2020) investigate the association between serum lipoprotein(a) levels and reduced renal function, emphasising the role of lipoprotein(a) as a potential risk factor for kidney dysfunction. This study highlights the importance of monitoring lipid profiles and renal function in older adults to identify individuals at risk for declining kidney function (Luo et al, 2020). Age-related changes in lipid metabolism and renal function underscore the need for comprehensive assessments to mitigate the impact of age-related renal decline.
Future directions in geriatric pharmacokinetics
Moreover, the research by Sommerer et al (2015) examines psychosocial and physical outcomes following kidney donation, shedding light on the impact of renal function changes associated with kidney donation. This study provides insights into the alterations in renal function post-donation, emphasising the need to consider age-related changes in kidney health when evaluating the outcomes of kidney donation (Sommerer et al, 2015). Understanding the implications of kidney donation on renal function can inform clinical decision-making and postoperative care in older donors.
Impact on drug clearance and the importance of renal dose adjustment
Riccobene et al (2014) offered valuable insights into the pharmacokinetic studies of ceftaroline fosamil in select populations, including healthy older subjects and those with renal impairment or end-stage renal disease requiring haemodialysis. Ceftaroline pharmacokinetic parameters varied with different degrees of renal impairment, leading to recommended dosage adjustments for patients with moderate to severe impairment (Riccobene et al, 2014). This highlights the importance of considering renal function in drug clearance and the necessity of renal dose adjustment to ensure appropriate dosing regimens in individuals with renal impairment.
Furthermore, research by Thamlikitkul et al (2017) focused on dosing and pharmacokinetics of polymyxin B in patients with renal insufficiency. Despite the poor correlation between creatinine and polymyxin B clearance, current prescribing information recommends adjusting polymyxin B dosing based on renal function (Thamlikitkul et al, 2017). This underscores the importance of individualised dosing regimens and renal dose adjustment to optimise drug clearance and minimise the risk of adverse effects in patients with renal insufficiency.
Clinical implications for prescribing
To address the clinical implications for prescribing practices, particularly focusing on dosage adjustments, drug–drug interactions, and the role of therapeutic drug monitoring, it is crucial to consider the potential references provided. The study by Halloran et al (2018) on polypharmacy and drug–drug interactions in older and younger people living with HIV sheds light on common interactions in polypharmacy and strategies to mitigate risks. Understanding the prevalence and impact of drug–drug interactions in individuals with HIV can inform prescribing practices and interventions to minimise adverse effects and optimise treatment outcomes (Halloran et al, 2018).
Moreover, research by Zaraa (2015) on the prevalence of antipsychotic polypharmacy underscores concerns related to polypharmacy, including the risk of adverse effects, drug–drug interactions, increased non-adherence, and higher healthcare costs. Addressing the challenges associated with antipsychotic polypharmacy requires careful monitoring, individualised dosing strategies, and a comprehensive understanding of potential drug interactions to ensure safe and effective medication use in patients (Zaraa, 2015).
Additionally, a study by Wood et al (2022) on medication optimisation using pharmacogenomic testing in a complex mental health population highlighted the role of therapeutic drug monitoring in optimising pharmacotherapy. By incorporating pharmacogenomic testing and individualised dosing strategies, healthcare providers can tailor treatment regimens to patient-specific genetic profiles, enhancing medication efficacy and minimising the risk of adverse drug reactions (Wood et al, 2022).
Special considerations in pharmacotherapy for older adults
In addressing the special considerations in pharmacotherapy for older adults, focusing on polypharmacy, pharmacogenetics, and adherence and compliance, the following references can be used:
Conclusion
Understanding pharmacokinetics in older adults is crucial for optimising prescribing practices, minimising adverse drug reactions, and improving treatment outcomes. Age-related changes in drug absorption, metabolism, and elimination processes require tailored approaches to medication management. Further research and clinical trials are needed to fill existing knowledge gaps and enhance pharmaceutical care for this demographic. Alternative body composition, including increased fat and decreased muscle mass, significantly impact drug distribution in older adults.
Strategies focused on preserving muscle mass, reducing fat mass, and enhancing overall body composition can potentially improve drug distribution and metabolism, resulting in better treatment outcomes. Understanding plasma protein binding's impact on distribution volume is essential for predicting drug distribution and optimising dosing regimens. Metabolic health outcomes in ageing individuals can be influenced by lifestyle interventions, stress management, and physical activity. Addressing metabolic factors through targeted interventions and understanding daily activities can support healthy aging and improve overall metabolic wellbeing.
Age-related changes in liver function and enzyme activity have significant implications for drug metabolism in older adults. Monitoring renal function is crucial for early detection and management of kidney dysfunction. Understanding the impact of renal function on drug clearance and implementing individualised dosing regimens is crucial for safe and effective pharmacotherapy in populations with renal insufficiency.
In conclusion, leveraging pharmacogenetic information, understanding genetic factors influencing drug response, and implementing personalised medicine approaches are essential for optimising pharmacotherapy in older adults with polypharmacy.