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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 drugs) will have a longer half‐life, increasing risk for side 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.