Age-Related Changes in Pharmacokinetics and Pharmacodynamics

Pharmacokinetics represents an array of processes by which drugs are liberated, absorbed, distributed, metabolized, and eliminated from the organism. The major pharmacokinetic processes investigated in older adults are distribution and renal elimination despite extensive knowledge of global physiological age-related changes and impaired homeostatic capacity that would plausibly alter other pharmacokinetic parameters and processes. In addition, most pharmacokinetics studies on older adults have been done on single-dose administration, which does not resonate with elders' higher likelihood of chronic multiple morbidity and consequent need for chronic dosing and steady-state examinations.

Absorption involves three main processes—diffusion, penetration, and permeation—that take place through active or passive mechanisms. According to the place of administration, the sites of absorption include the oral/ocular/nasal/rectal mucosa, the gastrointestinal (GI) tract, the respiratory tract, and the skin and subcutaneous tissue. Absorption in the GI tract may be affected by age-related changes such as reduced GI motility and gastric evacuation, reduced regional blood supply, and higher likelihood of duodenal and small intestine diverticula. Even though the main form of transport through the GI tract, passive diffusion, is not affected by normal age changes, active transport through intestinal mucosa is reduced due to age-related declines such as atrophy of the intestinal mucosa that reduces the typical absorptive area, changes in the shape of the villus, lengthening of the crypts, prolonged replication time of the crypt stem cells, limited villus motility, and impaired water barrier. Many studies have reported significant age-related reductions in glucose, galactose, calcium, and iron absorption that can have clinical implications for elders. Absorption rates can also be affected by concurrent drug administration and drug interactions. Although not studied sufficiently and without major clinical implications, intramuscular and subcutaneous absorption may be affected by reduced peripheral blood flow, increased connective tissue in the muscles, and altered permeability of the capillary walls; whereas percutaneous absorption may be reduced due to decreased skin hydration and surface lipid content, increased keratinization, decreased peripheral blood supply, and impaired microcirculation.

Distribution represents the passage of the drug through the organism toward its specific place of action. Changes in the volume of distribution have been examined extensively in older adults and have been shown to affect significantly and differently hydrophilic or lipophilic drugs. Due to age-related decreases in the lean body mass and total body water, the volume of distribution for hydrophilic drugs diminishes; whereas the volume of distribution for lipophilic drugs increases due to increases in the fat tissue. These changes in the body composition may result in increased accumulation, delayed peak concentration and elimination, and increased half-life of lipophilic drugs (benzodiazepines). Drugs circulate bound to various extents to plasma proteins, but only the free fraction of the absorbed drug can operate at the place of action. Therefore, hypoproteinemia, especially hypoalbuminemia, may result in higher concentrations of free drug fractions and consequent overdose effects, especially for highly albumin-bound drugs. This aspect is additive to reductions in the volume of distribution, resulting in augmented rates of drug clearance. Another factor potentially affecting the volume of distribution for drugs is the reduced cardiac output that may occur with aging and that results in reduced splanchnic, renal, and peripheral blood supply.

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