Pharmacokinetics is the study of drug movement throughout the body and it is described by four basic parameters: drug absorption, distribution, metabolism, and excretion. All parameters are affected by aging to a varying extent.
Changes in body composition with aging have profound influence on the distribution of drugs and their resultant steady-state plasma concentrations. With increases in total body fat and concomitant decreases in total body water, the elderly experience alterations in their volumes of distribution (Vd) to many pharmacological agents. This has far reaching implications in the peak plasma concentrations of drugs, the time course of their action, and the degree to which they exert their therapeutic and adverse effects (Sadean and Glass 2003).
Highly water soluble drugs (i.e., acetylsalicylic acid), as well as their hydrophilic metabolites, would be expected to achieve higher overall plasma concentrations in the setting of decreased total body water. Similarly, lipophilic drugs (i.e., diazepam) would be expected to achieve a lower overall plasma concentration, as they are taken up more avidly and stored by the increased adipose tissue. This results in an increased Vd and a prolonged elimination half-life forlipid-soluble agents (Sadean and Glass 2003).
Changes in cardiovascular physiology also have a profound impact on the distribution of drugs. As expected, decreases in cardiac output that accompany the normal aging process result in reduced tissue perfusion. This results in increased circulatory times, a delay of drug transfer from their sites of administration to their sites of action, and a delay to peak drug effects. Furthermore, decreased perfusion to excretory organs, such as the liver and kidneys, results in an overall increase in the duration of action of many commonly administered drugs.
In addition to reduced perfusion, reductions in hepatic and renal mass are expected to result in a reduced clearance of many drugs. As described above, reductions in hepatocyte mass, along with reduced hepatic perfusion, are expected to slow metabolic processes in the liver. This is particularly important for those drugs that are highly extracted by the liver or for drugs that undergo extensive first-pass metabolism. These agents depend on hepatic blood flow for their overall elimination (i.e., morphine sulfate), and in the setting of reduced hepatic perfusion, their clearance can be reduced by as much as 30-40% (McLean and Couteur 2004). As a result, one should reduce maintenance dosing for those particular agents in the elderly.
Age-related changes in serum albumin concentration can also affect the Vd of many commonly administered medications in the elderly. There is an apparent 10% increase in the unbound fraction of many pharmacologic agents in the elderly, mirroring the decrease in serum albumin (McLean and Couteur 2004). The effects of decreased protein binding are more pronounced for drugs that are highly extracted by the liver, extensively protein bound, and administered intravenously. This includes agents such as fentanyl, haloperidol, lidocaine, and midazolam. As a result, dosage readjustments are often necessary to avoid excessive toxicity associated with the increased bioavailability of those particular agents (McLean and Couteur 2004, Sadean and Glass 2003).
Similarly, reduced renal mass, renal blood flow, and glomerular filtration is expected to slow drug excretion from the body, particularly for those agents that rely heavily on renal elimination pathways [i.e., nonsteroidal anti-inflammatory drugs (NSAIDs)] (McLean and Couteur 2004). These two processes operate in tandem and have profound influences on drug elimination in this population. As a result, initial dosing and maintenance dosing should be adjusted, as many circumstances call for dose reductions of 10-25% in the elderly.
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