**Abstract**

Population ageing is one of the most significant social transformations of the twenty-first century. The increase in average life expectancy was a successful challenge achieved in the modern world. However, nowadays a new challenge arises for all society: achieving a better quality of life for increasing people's life. The comorbidities associated with ageing make elderly prone to polypharmacy. On the other hand, physiological and cognitive changes interfere with drugs' pharmacodynamics and pharmacokinetics contributing to drug-related problems which have been reported to account for a large percentage of emergency treatment and hospitalizations of older people, increasing the costs with health in the most aged regions. In order to reduce the use of potentially inappropriate medicines in this population, strategies and tools have been developed in recent years to assess the appropriateness medication use in the elderly.

**Keywords:** polypharmacy, elderly, pharmacodynamics, pharmacokinetics, potentially inappropriate medication

#### **1. Introduction**

Ageing is an inevitable process characterized by declining functions and increased susceptibility to certain diseases. Biologically, ageing results from a variety of molecular and cellular damage over time, leading to a gradual decrease in physical and mental capacity, increasing the risk of illness and death [1]. The fragility acquired by the elderly population with ageing is related to the gradual decrease of the physiological reserve and the failure of the homeostatic mechanisms. Thus, a cumulative decline is promoted in several physiological systems, and there is an exhaustion of the body's reserves, starting to have a greater vulnerability to changes in health status [2]. The mechanisms associated with ageing are determined by environmental factors but also by genetic factors, which regulate the expression of genes that can be especially important for this process [3].

With ageing, many chronic diseases arise, requiring the use of a higher number of drugs. Polypharmacy, defined as the use of five or more drugs, is a significant public health problem, particularly in the older adults, since it is responsible for the increase of adverse drug reactions (ADR) and, frequently, for the rise of the morbidity and mortality in this population [4]. There are many other important

issues related to the problem of polypharmacy, such as the interaction between drugs, organization and adherence to treatment [4].

Through the normal ageing process, changes occur with impact on the pharmacodynamics and pharmacokinetics of drugs. These changes may be related to the function of particular organs, homeostatic mechanisms and also to the ability to respond to specific receptors, causing greater vulnerability and susceptibility to ADR in older patients [5] frequently associated with the use of potentially inappropriate medication (PIM) in this population [6]. The inappropriate prescription in older patients occurs when the risk of adverse effects exceeds the clinical benefit, especially when there are more effective alternatives available [7]. The use of PIM is a public health challenge because it has high prevalence rates in different health contexts [8].

Although older adults are the primary consumers of medicines, the truth is that clinical trials are usually carried out on younger people, and the physiological changes that occur with ageing are not considered. With the rise of older people in the world, the needs associated with the resources of health systems will continue to increase, and several challenges will arise.

Over the past few years, to reduce the use of PIM in the older population, strategies and tools of explicit and implicit criteria have been developed to evaluate the appropriateness of medication use in the older patients. These criteria are useful tools for clinical practice, as a support for clinical decision.

## **2. Physiological and pharmacological changes in the elderly**

The normal ageing process implies the occurrence of several physiological, biological, physical and psychological changes, which can affect the elderly patient' quality of life and modify the ability to reach the best health outcomes [9]. The changes caused by ageing are associated with complex pathophysiology, variability in organ function and the presence of comorbidities, specific to this population [2]. When young, the human body has a sizeable physiological reserve to sustain the function of most organs. However, in early adulthood, the first physiological changes that can affect drug effects begin to occur, and the decline of cellular activity becomes a gradual and continuous process. In older adults, this reserve is increasingly diminished with decreasing in homeostatic mechanisms activity [10].

All of these factors contribute to the frailty of older adults making them more prone to drug-related problems. Most older people can experience significant changes in drug pharmacokinetics and pharmacodynamics due to age-related physiological changes and become more susceptible and vulnerable to adverse effects [7].

#### **2.1 Age-related changes in pharmacokinetics**

The bioavailability of a drug depends on many factors and all stages of pharmacokinetics (absorption, distribution, metabolism and excretion) and can be modified with ageing [9, 11]. A summary of the main pharmacokinetics changes can be consulted in **Table 1**.

There are several available routes of administration. However, the most common is the oral route. Although ageing is associated with decreased gastric emptying and peristalsis, in the absence of pathology, the absorption of most drugs does not decrease with age [9]. However, the presence of pathologies that affect the gastrointestinal organs can affect absorption. Furthermore, food intake can also affect drugs' absorption. The fraction of the drug dose administered that reaches the bloodstream, after oral administration, can be influenced by several other factors,


*ACEI, angiotensin conversion enzyme inhibitors; ARBs, angiotensin II receptor blockers; NSAIDs, nonsteroidal anti-inflammatory drugs.*

#### **Table 1.**

*Impact physiological changes and pharmacokinetics in older adults [9, 11–13].*

such as gastric pH, gastrointestinal motility, intestinal permeability and mucosal integrity, function and expression of drug carriers and gastrointestinal blood flow [11].

Drugs absorption after intramuscular or subcutaneous administration can be modified in older patients because there is a reduction in blood perfusion of the tissues [12].

After absorption, the drug enters the bloodstream and is distributed through the body. The distribution will influence the amount of active substance available to prosecute an effect at a specific target. Factors such as the extent of binding to tissues and plasmatic proteins, changes in body composition and protein synthesis can affect the distribution of drugs [11]. The volume of distribution can be affected by the proportions of lean body mass and fat body mass. With ageing, there is a reduction in the amount of body water and an increase in fat, so there are changes in the distribution of drugs that depend on lipid solubility. Also, the half-life of a drug increases with the volume of distribution. Thus, a decrease in the volume of distribution for hydrophilic drugs results in higher plasma concentrations and a lower half-life in older patients. Some examples are drugs such as digoxin and theophylline. As the volume of distribution increases, the half-life of liposoluble drugs increases, affecting, for example, long-acting benzodiazepines that can accumulate in the body [12].

Metabolism consists of converting an active substance in simpler and more polar substances, called metabolites. These metabolites are inactive or have modified activity. In the case of prodrugs, metabolism is necessary to convert the prodrug in an active drug. Therefore, hepatic metabolism is essential for the elimination of drugs from the body. Hepatic metabolism depends on hepatic blood flow, the transport of the drug from the blood to the hepatocytes and the ability to metabolize the drug [11]. It can be difficult to predict changes in liver metabolism for each patient. In addition to age, the nutritional status of the elderly also affects the rate of metabolism of the drug [12]. Moreover, the increase of inflammatory conditions in older adults can compromise the enzymes associated with the metabolism of many

drugs. Frailty is associated with higher inflammatory markers and a reduction in the activity of esterases (enzymes class that catalyse hydrolysis reactions) [5].

With ageing, the composition of gut microbiome also changes. Intestinal bacteria play a role in the metabolism of drugs as they, being mostly anaerobic, participate in chemical reactions of reduction and hydrolysis of molecules. The changes caused by this phenomenon occur mainly in frailty older adults and longterm nursing homes residents. They have a decreased enzyme induction capacity, which can lead to an increase in genetic silencing with age. Also, external factors such as exposure to environmental contaminants are responsible for altering gene expression. These changes reflect the differential biological ageing [5].

Most drugs are eliminated through the kidneys, and in older adults, the ability to concentrate urine is reduced, consequently, there is a need for a higher amount of urine to excrete the same amount of toxic waste compared to young adults. The decline in renal function is mainly due to the decrease in the glomerular filtration rate (GFR) and the reduction in renal blood flow. With ageing, the decline in glomerular filtration is quite evident. The decreased in renal function increases the risk of ADR, and therefore, special attention should be given when prescribing, to older patients, drugs excreted by kidneys. For drugs that have a narrow therapeutic index and are excreted through the kidneys, such as digoxin, metformin and lithium, it is especially important to adjust and monitor the treatment [12].

This decrease in GFR can be explained by an increase in urea excretion and a reduction in creatinine production in older adults. The renal plasma flow is reduced by 50%, and the kidney's ability to increase baseline GFR by at least 20% (the renal reserve) also decreases significantly with ageing [13].

Sodium reabsorption is reduced in the older adults, and drugs that promote the excretion of salt and water, such as thiazides and loop diuretics, can induce hyponatraemia, hypovolaemia and renal failure. Also, renal excretion of potassium is significantly reduced with ageing, so drugs such as angiotensin-converting-enzyme inhibitor (ACEI), angiotensin II receptor blockers (ARBs), aliskiren, digoxin, potassium-sparing agents, beta-blockers and nonsteroidal anti-inflammatory drugs (NSAIDs) can induce hyperkalaemia [13].

#### **2.2 Age-related changes in pharmacodynamics**

Age-related pharmacodynamic changes may also occur. However, these are more difficult to study than pharmacokinetic changes because there is low evidence of the mechanism underlying these changes.

Many response measures are subjective and can be influenced by several factors. These changes represent how drugs react in the body after absorption. The central nervous system (CNS) and the cardiovascular system, as well as the homeostatic mechanisms, are the most affected with the ageing process. Since most medicines used by the older adults have strong anticholinergic properties, the principal ADR that occur in this population are confusion, drowsiness and an increased risk of falls and fractures [14]. Due to all the physiological changes, an older adult's ability to recover from an illness is often diminished, and symptoms may remain partially for a long time.

Age-related pharmacodynamic changes are associated with receptors (number, activity and expression) and with the ability to signal transduction and changes in homeostatic mechanisms [15].

Thus, in the older adults, there is an impaired circulatory response, an increased risk of falls and fractures, changes in thermoregulation mechanisms, laryngeal reflexes compromised with increased risk of aspiration or pneumonia, dehydration and bleeding due to changes in vascular stability and impaired cognitive ability. Therefore, drugs with sedative effects can considerably increase the risk of ADR in older patients [16].

#### *Elderly and Polypharmacy: Physiological and Cognitive Changes DOI: http://dx.doi.org/10.5772/intechopen.92122*

Considering the drugs that act in the CNS, there is an increased sensitivity to the action of benzodiazepines, which can cause a high degree of sedation and impaired psychomotor performance in older adults, making them more favourable to the occurrence of falls and fractures. With increasing age, the ability to respond to antipsychotic drugs also increases, so there is an increased risk of anticholinergic and extrapyramidal effects, orthostatic hypotension and adverse cerebrovascular effects. The increase in the response capacity to antidepressants also increases the risk of anticholinergic effects in the elderly, being responsible for causing gastrointestinal bleeding and hyponatraemia. These population also have an increased sensitivity to intravenous and inhaled anaesthetic and opioid medications, with an increased risk of respiratory depression and reduced tolerability to these drugs. Furthermore, with ageing, there is an increased sensitivity to the adverse effects caused by lithium, increasing the risk of neurotoxic effects in these population [10, 17].

Concerning drugs that act on the cardiovascular system, the main pharmacodynamic changes associated with age are related to the reduction of the baroreceptor response to low blood pressure and the increase in the sinoatrial suppressive effect, interfering with the administration of calcium channel blocker drugs, causing an effect that can lead to the occurrence of orthostatic hypotension, falls and a decrease in heart rate. With ageing, there is a change in the signal transduction of the beta receptor and negative regulation of the beta-adrenergic receptors, so that there may be a reduction in the effectiveness of beta-blocking agents at doses considered normal. The reduction in GFR causes a decrease in the capacity of diuretic and natriuretic responses. NSAIDs reduce the effects of diuretics, and there is a compromise in adaptive and homeostatic mechanisms, thus reducing the effectiveness of diuretics in doses considered normal, and a high risk of hypokalaemia, hypomagnesaemia and hyponatraemia may occur. NSAIDs can also reduce the effects of ACEI. Since older patients are more sensitive to warfarin, there is an increased risk of bleeding when taking anticoagulant drugs [10, 17].

The presence of comorbidities is also responsible for pharmacodynamic changes during the ageing process. For example, the presence of psychiatric disorders such as schizophrenia, depression and dementia can alter the function of several neurotransmitters [16].
