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effects, mainly after reaching steady state. Commonly used fat‐soluble drugs include amiodarone, desipramine, diazepam, and haloperidol.

Medications are typically metabolized by the liver and excreted by the kidneys. Liver size may decline with age, and reductions of blood flow of 25–47% have been reported in people between the ages of 25 and 90.¹⁵ Drugs that undergo ‘first‐pass’ metabolism by the liver depend on hepatic blood flow. If hepatic blood flow is decreased, it may lead to increased systemic bioavailability of the drugs, putting patients at risk for side effects. Unfortunately, there are no systematic ways to determine if and how much hepatic blood flow is decreased in a typical older person. Liver metabolism is through Phase I or II reactions. Phase I reactions are mainly catalysed by the cytochrome P450 (CYP) system and are more affected by age than Phase II reactions. Of the over 1000 known CYP enzymes, 50 are functionally active in humans, and 5 are the most clinically relevant (See Table 10.2). Medications affected by the CYP system can be substrates (metabolized by CYP enzymes), inducers (increase the production of specific CYP enzymes), or inhibitors (impair specific CYP enzyme function). Co‐administration of a substrate and an inducer leads to increased metabolism and decreased effectiveness of the substrate medication. Co‐administration with an inhibitor leads to decreased metabolism, increased blood levels, and increased toxicity of substrate medications. Thus, even if a patient has been on a certain drug for some time without side effects, the addition of a new drug may alter the CYP metabolism of the old drug, resulting in a side effect. Table 10.2 can be used with individual patients to determine potential drug–drug interactions due to effects on the CYP system.

Table 10.2 Practical tool to identify drugs that interact with Cytochrome P‐450 enzymes, resulting in higher risk of side effects.

CYP enzymes	Substrates	Inhibitors	Substrate side effects	Inducer	Substrate therapeutic effects
1A2
2C9
2C19
2D6
3A4
Metabolized by liver but enzyme unknown
Not metabolized by liver

      Renal blood flow is reduced by about 1% per year after age 50,¹⁷ and average clearance declines by 50% from age 25 to 85.¹⁵ If a drug is more than 60% excreted by the kidneys, a reduction in renal function can affect its elimination, leading to a longer half‐life and/or higher blood levels of the drug. If a drug in this category must be used, the prescriber can increase the interval between doses, decrease the dose, or both, depending on the situation. Although the effects of age on renal function are somewhat more predictable than on liver function, the increased ratio of fat mass to fat‐free (lean muscle) mass, risk of malnutrition, and prevalence of multimorbidity limits the use of blood urea nitrogen (BUN) and creatinine as sole markers to determine renal function. Despite its limitations, the Cockcroft‐Gault formula is used to estimate creatinine clearance (CrCl) for appropriate drug dosing:

      See Chapter 91, “Geriatric Nephrology,” for more information on the use of equations to estimate renal function in ageing.

      The expression of genes may influence the metabolism of drugs, the availability of drugs at their site of action, and how drugs bind to their target receptors. Thus, an individual’s genetic makeup will affect the clinical efficacy and potential side effects of medications. Pharmacogenetics is an emerging field of study that employs genomic and epigenomic biomarkers to identify the differences in drug effects to guide clinical decision‐making when prescribing medications for individual patients.¹⁸ Existing guidelines and algorithms addressing inappropriate medications and deprescribing do not consider pharmacogenetics. Due to the complex nature of this field, much more research is needed to determine the most cost‐effective biomarkers for daily clinical use.¹⁹ Hopefully, in the next few decades, pharmacogenetic applications will become available in the clinical setting to help prescribers determine the probability of individual patients responding to certain drugs and the risk of side effects.

Tools for medication management

Clinicians making real‐time decisions on medication management have available to them a variety of tools that can be used to guide prescribing. These tools have been developed to help identify medications that should be avoided, drug–drug/drug–disease interactions, and optimal medication doses. They also provide opportunities for educating patients, families, and clinical trainees. While each tool has both benefits and drawbacks in daily use, it is important for prescribers to become familiar with these tools and proficient in the clinical application of at least one. Table 10.3 lists the various available tools, which are described further here.

      The most widely known tool is the Beers Criteria, introduced in 1991 by the American Geriatrics Society and updated most recently in 2019.²⁰ It was created by geriatrician Dr Mark Beers and an expert panel using the Delphi method with the ‘intention to improve medication selection; educate clinicians and patients; reduce adverse drug events; and serve as a tool for evaluating quality of care, cost, and patterns of drug use of older adults’. A list of potentially inappropriate medications (88 drugs) are divided into five categories, detailed in six tables^20,21:

      1 Drugs with potentially inappropriate use in older adults.

      2 Drug‐disease (or syndrome) interactions that might exacerbate the disease (or drugs with potentially inappropriate use in older adults with some specific health conditions).

      3 Drugs to be used ‘with caution’ in older adults.

      4 Drug–drug interactions that should be avoided.

      5 Medications to be avoided or adjusted given underlying renal function.

      6 A list of drugs with ‘strong anticholinergic properties’.

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