Geriatric Drug Therapy

Pharmacokinetics

The time course of drug exposure is determined by pharmacokinetic parameters including absorption, distribution, metabolism, and elimination. The drug effect is primarily determined by this exposure, which can be quantified by serum drug concentrations over time. It is assumed that increased exposure is more likely to result in toxic medication effects. Thus, an understanding of pharmacokinetic changes in older adults is useful for determining risks of adverse drug reactions and can help guide medication selection and dosing.

The effect of physiologic changes on drug absorption is an important consideration for orally ingested medications. Changes in gastric pH, gastric emptying, splanchnic blood flow, bowel motility, and absorptive capacity all impact drug availability. For example, the increase in gastric pH seen in older adults can decrease the dissolution of medications that are weak bases, reducing absorption and resulting in lower serum drug levels. Conversely, decreased bowel motility can increase transit time, allowing more opportunity for absorption to occur, leading to increased serum drug levels. Clearly, age-related changes in the gastrointestinal system can have a varied effect on drug absorption, leading to unpredictable effects on serum drug concentrations. As an example, decreased absorptive capacity coupled with decreased bowel motility can increase transit time, leading to a net neutral effect on drug exposure. Gastrointestinal and other comorbidities can have a greater effect on absorption than age alone. Given these considerations, it would be prudent in the ED to use the intravenous route for acute conditions, when rapid drug absorption is needed to achieve a therapeutic concentration.

Age-related changes in body composition have an effect on the distribution of drugs. There is an increase in total body fat and a decrease in relative skeletal muscle mass in older adults compared to young adults. This change in body composition accelerates between 60 to 75 years and then may start to decline. Lipophilic medications have a greater volume of distribution with increasing adiposity, whereas the opposite is true for hydrophilic medications. Opioid analgesics such as fentanyl and most sedatives (e.g., benzodiazepines, propofol) are very lipophilic, so there is distribution and accumulation of the drug within adipose tissue, and its metabolites are renally eliminated. With prolonged use, this can lead to an increased duration of effect due to redistribution of drug from tissue to serum and central nervous system. Conversely, hydrophilic medications such as digoxin would require lower loading doses in older adults to achieve similar serum concentrations due to a smaller volume of distribution. This has the potential for drug toxicity if not dosed appropriately for age.

Most drugs require biotransformation into polar metabolites before final elimination. This primarily occurs in the liver via phase 1 metabolism by cytochrome P450 enzymes (oxidation) or phase 2 (conjugation, acetylation, sulfation) reactions. With advanced age, hepatic mass and blood flow may decrease by up to 40%, which reduces the delivery of medications to the liver and their subsequent metabolism. This decrease in first-pass metabolism improves drug bioavailability resulting in increased serum levels and potentially increasing the risk of drug toxicity for certain agents. Drugs with a high hepatic extraction ratio are more dependent on hepatic blood flow for drug metabolism, and the slowing of hepatic metabolism seen with age has mainly been related to changes in phase 1 pathways. For example, morphine is a high–extraction ratio drug and would lead to greater drug exposure as hepatic blood flow is reduced. Commonly used benzodiazepines in the ED also vary in their metabolic pathways. Midazolam undergoes phase 1 metabolism, and hepatic impairment would lead to drug accumulation, especially with repeated or prolonged use. Conversely, lorazepam undergoes phase 2 conjugation and is preferred in patients with hepatic impairment because this metabolic pathway is less dependent on hepatic blood flow. The effect of aging on phase 1 metabolism via CYP3A4 is controversial. This enzyme represents the metabolic pathway for most medications, and studies have shown no significant differences between younger and older populations.

Renal blood blow, renal mass, and the number of nephrons decrease with age, leading to a decrease in renal function. In a longitudinal study, renal function decreased by approximately 10% for each decade between 30 and 80 years of age. This decrease was independent of comorbid conditions and was attributed to aging alone. Although this decline is likely to occur in most patients, up to one-third may have no decline, and some may have an increase in renal function. Kidney function is expressed as the glomerular filtration rate (GFR) and is routinely estimated by the Cockcroft-Gault equation. However, this equation may not accurately estimate the GFR, so the modification of diet and renal disease (MDRD) equation has been suggested as a more accurate estimation. Common equations used to calculate creatinine clearance and estimate GFR are in Box 180.1 . Discordance in drug doses selected may occur 10% to 40% of the time when comparing the two equations, and there has been considerable debate regarding the most appropriate equation to use in practice. ^,

Typically, drug dosing in manufacturers’ labeling per the US Food and Drug Administration is based on creatinine clearance determined by the Cockcroft-Gault equation and, as such, most pharmacists continue to use this equation for drug dosing. The Cockcroft-Gault equation is also easier to calculate compared to the MDRD. While many electronic health records and laboratories use MDRD to calculate and report GFR, there is no universal industry standard approach, and it is important to know which equation is used to calculate the GFR reported in the medical record. Although cumbersome, one approach is to calculate estimated GFR based on both equations and evaluate if there is a discrepancy in dosing recommendations. This approach is useful if the initial estimate is close to a cut-off value that would alter the dosing regimen. If a discrepancy exists, the decision to use a more or less conservative dosing strategy will depend on the clinical scenario. In general, a low-dose approach should be used for medications with a narrow therapeutic index, particularly when the risk of toxicity is high and serum concentration monitoring is not available. In general, medication dosing should be higher in the ED when the implications for therapeutic failure warrant such an approach, assuming the medication has a broad safety margin. An example would be erring on the side of more aggressive dosing when using antibiotics in a patient with sepsis or febrile neutropenia. Thus, clinical circumstances may override drug dosing recommendations, especially when there is discordance between equations, and professional judgment is always required. These equations use the serum creatinine level to estimate creatinine clearance, which is affected by muscle mass. Therefore, although serum creatinine values may be normal, they may not accurately estimate renal function in some older adults, especially those with less musculature. For all older patients, some providers routinely round serum creatinine values less than 1 mg/dL up to 1 mg/dL to account for reduced muscle mass; however, this practice should be avoided because it has been shown to underestimate clearance.

Given the limited number of repeat doses typically administered in the ED, even in patients with hepatic or renal impairment, drug accumulation is unlikely to be clinically meaningful. If, however, several doses of a medication are administered in the ED, especially when patients are boarded, drug toxicity or prolonged effects may become clinically relevant. In general, a “start low and go slow” approach is prudent in older patients. When this strategy is used, it is critical to reevaluate the patient after the anticipated onset of the administered medication to determine if additional doses are necessary because failure to do so could lead to undertreatment. The risks versus benefits of drug therapies generally increase with age, suggesting that a more conservative approach is warranted, particularly when using drugs with a narrow therapeutic index. Pharmacokinetic changes in older adults are listed in Table 180.1 .

Pharmacodynamics

Even at similar plasma concentrations, drugs may have altered effects in older adults, perhaps because of changes in the number and sensitivity of receptors, signal transduction, and reduction in homeostatic processes that help maintain equilibrium. Thus, physiologic mechanisms that help restore function are attenuated, leading to an exaggerated or relatively unopposed pharmacologic effect. Pharmacodynamic changes in older adults that are most relevant to consider in the ED include those that pertain to the cardiovascular, central nervous, and coagulation systems. For example, there is a decreased response to both β-adrenergic receptor agonists and antagonists. Conversely, there is no age-related change in α ₁ -adrenergic receptor sensitivity. Calcium channel blockers cause a greater drop in blood pressure and heart rate in older adults compared to younger adults, so the risk for postural hypotension is higher in older adults. The diminished inotropic response to catecholamines contributes to this risk. In the ED, non-dihydropyridine calcium channel antagonists such as diltiazem or verapamil are commonly used for patients with supraventricular tachycardias. Lower doses are appropriate in older adults, especially when the patient has tenuous blood pressure.

There is increased sensitivity to benzodiazepines in older adults, and lower doses are needed to obtain similar sedative-hypnotic effects. This is because of changes in the structure, composition, and function of the γ-aminobutyric acid (GABA) receptor complex. Similarly, in one investigation, older patients required less propofol for the induction and maintenance of sedation during procedures in the ED. The dose required for induction was 0.5 mg/kg less than in the cohort of young adults. In older adults, it is more suitable to start propofol with a 0.5-mg/kg rather than the 1-mg/kg bolus that is typically recommended. Some studies have shown that older patients have increased sensitivity to opioids. Pharmacodynamic effects in these studies were measured in terms of electroencephalographic readings, which do not reliably indicate the presence of pain. However, the risk of adverse effects and interactions due to the use of concurrent medications is likely increased in older adults, suggesting that a cautious approach is appropriate when dosing opioids.

There is an age-related decrease in dopamine content in the central nervous system, which predisposes patients who are given neuroleptics and other dopamine antagonists to extrapyramidal symptoms. Similarly, there is a decrease in acetylcholine synthesis in older adults, which increases the risk for anticholinergic neurotoxicity with commonly used antihistamines, antispasmodics, and antiparkinsonian agents.

Bleeding is a potentially life-threatening consequence of anticoagulants. Historically, warfarin has been the most commonly used oral anticoagulant, although, more recently, newer oral agents such as direct thrombin and factor Xa inhibitors have become available. At similar warfarin plasma concentrations, there is greater vitamin K inhibition in older adults. Thus, it is recommended that warfarin should be initiated at a daily dose of 5 mg or less for older adults, when indicated. In the ED, this may occur for patients discharged after a venous thromboembolism in conjunction with low-molecular-weight heparin as bridge therapy. There is emerging evidence supporting the early use of direct-acting oral anticoagulants for certain patients presenting with a venous thromboembolism (VTE). While data regarding the use of direct-acting oral anticoagulants in older patients being discharged from the ED with VTE are sparse, when used, careful attention must be paid when selecting an agent and formulating a dosing regimen. Certain agents, such as dabigatran, should be avoided in advanced age (greater than 80 years of age), while others, such as apixaban, require an adjustment when renal dysfunction is present in patients above a certain age threshold ( Table 180.2 ). ^, Dosing regimens and recommendations for adjustment also differ based on indication. In addition, therapeutic drug monitoring is not routinely available for these agents, making it difficult to assess the degree of anticoagulation, further enhancing the need for nuance and attention to detail to ensure they are being used appropriately. The other primary anticoagulant used in the ED is intravenous heparin for acute coronary syndrome or venous thromboembolism. Patient age does not correlate with heparin dose requirements, so heparin dose adjustments are not required.