may be effective blood pressure lowering agents, there may be compelling reasons for the selection of one agent over another for a specific patient’s treatment. Similarly, the wisdom to avoid a medication due to safety or effectiveness considerations in the presence of patient-specific factors is often predicated on Pharmacokinetics Age-related physiologic changes associated with aging, including gradual declines in organ function and altered body composition, impact the four major pharmacokinetics processes. Absorption Most orally administered drugs are absorbed in the small intestine after undergoing dissolution in the stomach. Age- related changes in gastric pH, which rises with increasing age, and/or the concomitant use of medications that raise gastric pH (e.g., proton pump inhibitors, histamine-2 receptor antagonists) can alter the dissolution and eventual absorption of orally administered medications. Weakly acidic drugs may undergo more extensive absorption, while weakly basic drugs may be associated with reduced systemic absorption. Additionally, certain acid labile medications formulated with sustained- release properties to delay dissolution and absorption until the formulation reaches the small intestine may dissolve in the stomach more readily in the presence of higher gastric pH, leading to degradation and reduced bioavailability of the medication. Additionally, physiologic changes (dysmotility), concomitant pathologies (diabetic gastroparesis), and other medications (anticholinergics) may contribute to reduced gastric motility, which further impacts the dynamic of altered absorption in addition to the effects of elevated gastric pH. Lastly, the absorption and extraction of some medications are impacted by transporters (e.g., p-glycoprotein), whose function may also change with advancing age, albeit in a less predictable fashion (Maher et al., 2020). Altered absorption of drugs by other routes of administration is also possible. Topical or transdermal drugs may be more extensively absorbed due to changes in skin integrity. Reduced blood flow to muscle and overall muscle mass could alter the rate and extent of intramuscular medications in a variety of ways. Distribution Once a medication enters the systemic circulation following absorption, its physiochemical properties will influence whether it remains in the circulatory system (e.g., blood volume) or is distributed to other body compartments such as adipose tissue, muscle, bone, or the central nervous system. Characterizing a medication’s volume of distribution (Vd) is a method to quantify the extent to which a medication passes beyond the circulatory compartment (Buxton, 2023). Given an average adult blood volume of 0.25 L/kg, drugs with a reference Vd greatly exceeding that value can be assumed to extend beyond the circulatory compartment into other tissues. Gentamicin is a good example of a drug whose Vd is like circulatory volume; thus, its penetration into other tissues or compartments such as adipose, lung, or brain is limited. On the other extreme, amiodarone is estimated to have a volume of distribution of 20–30 L/kg. While this value is not physiologically realistic, it indicates that the drug distributes vastly outside the circulatory compartment, including into lung tissue, which forms the basis for some of the pulmonary toxicity associated with the drug. In addition to the Vd properties attributed to an individual drug, age-related changes may also affect distribution. Older adults generally have reduced muscle mass, reduced total body water, and increased body fat. Collectively, these factors alter the normal distribution characteristics of hydrophilic drugs, generally reducing the Vd, which may lead to higher serum concentrations of the drug. Conversely, drugs whose physiochemical nature confers lipophilic properties would be expected to distribute more widely beyond the circulatory compartment, for example, into adipose tissue, which may lead to lower serum concentrations in the short term but accumulation and toxicity in the longer term. Age-related reductions in albumin concentrations for
understanding the medication’s mechanism of action. Once a treatment decision is made to use a certain class of medications, additional factors for selecting a specific drug within that class may include pharmacokinetic differences (see below), dosage form options, and affordability, among others. highly protein bound drugs may be associated with an increased fraction of unbound (pharmacologically actionable) drugs in the circulation. This is disproportionately higher than the drug concentration reflected in a serum sample. The impact of protein binding is limited to a small number of medications (e.g., phenytoin); however, there are significant toxicity risks associated with their use in older adults. Metabolism Xenobiotics are substances that may be ingested and foreign to the body. Most drugs, which are synthetically produced, are considered xenobiotic substances. The eventual elimination of a xenobiotic from the body largely depends on that substance’s metabolism (conversion) into a smaller molecule with water- soluble properties that will facilitate renal excretion. While not an exclusive pathway, most drug metabolism is associated with liver-mediated functions. Phase I reactions are most closely associated with oxidation by drug-metabolizing enzymes in the cytochrome P (CYP) 450 system but also include reduction and hydrolysis reactions. Phase II reactions largely involve the processes of glucuronidation, sulfation, and/or conjugation. There exist a variety of CYP enzymes, each of which influences numerous medications. Also, a number of medications are mediated by multiple CYP450 enzymes. It is likely that age- related physiologic changes in organ function, including reduced hepatic blood flow, liver mass, and hepatic oxygen supply, can lead to reduced functionality of the drug metabolism process. Such reduced functionality may contribute to drug accumulation and increased frequency and/or severity of adverse effects. There is limited evidence that age-related changes in some CYP enzymes occur, but additional research is needed to validate this data (Jin and Zhong, 2023). An individual’s genetic traits can also influence the underlying capacity of CYP450 enzymes. This topic, pharmacogenomics, will be discussed separately. Elimination While some drugs may be removed from the body by deposition into the biliary tract, most drugs undergo elimination through renal excretion. The functional unit of the kidney, the nephron, is thought to reach maximal function around age 30, with a slow, continual decline in function of approximately 1% per year beyond age 40 (Tam, 2016). As such, most older adults are assumed to have reached such a decline in kidney function as to be considered renally impaired regardless of serum creatinine, urinary output, or other markers of renal function. For the large number of medications eliminated from the body by renal excretion, the decline in kidney function attributable to aging, combined with underlying diseases such as diabetes and hypertension, has been associated with delayed drug elimination manifested as prolonged duration of effect and/or elevated serum levels. Both of these factors increase the prospects for additional, more prevalent, or more severe adverse effects compared to younger adults with normal renal function. Self-Assessment Quiz Question #2 Which of the following has the greatest age-related impact on a drug reaching the site of action?
a. Distribution. b. Absorption. c. Excretion. d. Metabolism.
Clinicians should recall that serum creatinine (SCr) reflects circulating amounts of muscle breakdown products and that increases in SCr often correlate with reduced renal elimination
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Book Code: RPTTX2024
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