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risk for drug interactions causing serious harm was demonstrated in 13% of older patients in 2010.³ From another study in Sweden, the use of five or more medications increased from 18% to 42% in 1992 and 2002, respectively.⁴ This same trend was observed in yet another study in Italy, in which an increase from 43% to 53% was detected in 2000 and 2010.⁵

The definition of polypharmacy is broad and sometimes puzzling. It has been defined in about 24 ways,⁶ many times inconsistently. This has led to confusion about what truly is inappropriate prescribing, resulting in challenges to identifying and measuring it. Without a standard cut‐off point for the number of prescriptions or non‐prescription drugs used, the most precise definition pertains to the use of multiple medications and more than what is deemed medically necessary.⁷ The Omnibus Budget Reconciliation Act of 1987, responsible for setting standards for care in United States nursing homes, describes unnecessary medications as those prescribed without indication or evidence of ongoing therapeutic benefit, used in excessive dose or duration, and in the presence of adverse consequences.^8,9

      There is good evidence that the concomitant use of five or more medications is related to adverse reactions, most notably related to frailty, disability, mortality, and falls.¹⁰ A study conducted by the Department of Veterans Affairs (VA) healthcare system found that problems related to drug interactions or inappropriate dosing were up to 12 times higher in patients taking eight or more medications.¹¹ Adverse drug events are common in geriatric patients, with evidence that 1 in 20 older adults seeks medical care due to this problem.¹² Taking this into account, polypharmacy itself should really be considered a geriatric syndrome, since, not uncommonly, it may have consequences far more concerning than the maladies for which the medications were initially intended.¹³

      Appropriate medication management in older adults can be challenging, and multiple factors need to be considered for potential benefits to outweigh possible risks. Prescribing problems such as drug interactions, unsuitable medications, wrong doses, and costly options are very common. At least one prescribing problem can be found in 50% of patients with a mean age of 75 and prescribed a median of five medications, with drug–drug interactions being problematic in 30% of those patients.¹¹ In patients on 5 to 9 medications, a 50% probability of drug‐drug interaction was detected, and this rate surged to 100% for those on at least 20 medications.¹⁴

      The application of ‘evidence‐based’ guidelines to the geriatric population must be done with extreme thoughtfulness, because it is imperative for patients (and, by extent, families or care proxies) to fully understand the indications and potential risks of their pharmacotherapies. Cohesiveness in informed and shared decision‐making is paramount, and a detailed review of medications with watchful prescribing practices should be taken as one of the top priorities in the healthcare of older adults.

      In this chapter, we aim to provide a greater understanding of pharmacotherapy in the ageing patient and a set of prescribing tools that will help improve medication management for older adults. Special attention will be paid to the newer concept of deprescribing with a focus on improving clinical outcomes in a standardized and individualized patient‐centred manner.

Ageing physiology affects medication efficacy and tolerance

As people age, expected physiologic changes occur that affect the efficacy and tolerability of medications (see Table 10.1). It is best to understand this in the context of expected pharmacodynamics (how the medication acts in the body, i.e. the body’s responsiveness or sensitivity at a given concentration) and pharmacokinetics (how the medication moves through the body) with ageing. Older adults may be more sensitive to certain medication classes (such as psychotropics) or less sensitive to certain classes (such as beta‐adrenergics). Changes to physiologic reserve, coupled with the increased risks of frailty and multimorbidity, cause variable responses to medications that cannot always be predicted at the time of medication prescription. Therefore, it is important to adequately educate patients about this and consider any new symptom as a potential medication reaction, even if atypical.

Table 10.1 Age‐related changes pertinent to geropharmacology.

Pharmacological parameter	Age‐related changes	Clinical effect
Tissue sensitivity	Alterations in:Receptor number and affinityNuclear responsesSecond messenger function	Patients are more sensitive or less sensitive to a given medication.
Absorption	Decrease in:Splanchnic blood flowAbsorptive surfaceGastrointestinal motility Increased gastric pH	Minimal changes associated with ageing in the absence of underlying gastrointestinal disease
Distribution	Decrease in:Serum albuminTotal body waterLean body mass Increase in:Fat mass	Higher concentration of drugs:Protein‐boundWater‐soluble Longer elimination half‐life:Lipid‐soluble
Metabolism	Reduced liver blood flow Decreased Phase I drug metabolism	Decreased biotransformation and first‐pass metabolism
Excretion	Decreased renal perfusion, glomerular filtration rate, and tubular secretion Reduced creatinine clearance	Decreased renal elimination leading to longer half‐life and/or higher serum concentration

      Medications move through the body in four steps: absorption, distribution, metabolism, and excretion. Although there are age‐related decreases in gastric motility and blood flow and an increase in gastric pH, drug absorption is not significantly affected unless there are other underlying gastrointestinal diseases (e.g. diabetic gastroparesis). There are no adequate studies in the elderly concerning the absorption of delayed‐release, transdermal, or transbronchial formulations to make general recommendations concerning these types of drugs. One should always consider if a medication is best absorbed with food (e.g. megestrol acetate) or without food (e.g. levodopa/carbidopa, levothyroxine).

      Two important concepts concerning drug distribution in the elderly are (i) protein binding and (ii) volume of distribution. Serum albumin is the major drug‐binding protein, and it declines in sick patients due to cytokine excess and malnutrition.¹⁵ In other words, albumin is a negative acute‐phase reactant. Highly protein‐bound drugs thus have a greater than expected free drug level in the body when serum albumin levels decrease. Prescribers must consider protein status when assessing serum drug levels against reported therapeutic ranges for medication efficacy or toxicity. It is also essential to recall that the therapeutic range routinely reported in such assays may not be an accurate guide to either efficacy or toxicity in the geriatric patient as such ranges have typically been defined in non‐elderly subjects.¹⁶

      Volume of distribution (Vd) is the virtual space a particular drug occupies in a given patient. Two common changes that occur with age and that affect Vd are

       Decrease in total body water and lean body mass ➔ Decreased Vd

       Increase in total body fat ➔ Increased Vd

      If Vd is decreased, then drugs that distribute into this compartment (e.g. water‐soluble drugs) will distribute less effectively, resulting in a higher plasma concentration and putting patients at increased risk for side effects, mainly with initial doses. Commonly used water‐soluble drug include digoxin, aminoglycoside antibiotics, atenolol, sotalol, theophylline, hydrochlorothiazide, lithium, and several sedative‐hypnotics and alcohol. If Vd is increased, then drugs that distribute here (e.g. fat‐soluble

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