Advanced, Clinical Subspecialties
In simple terms, pharmacokinetics describes “what the body does to a drug,” whereas pharmacodynamics describes “what the drug does to the body.” Drugs are distributed to blood and organs, where they are metabolized, degraded, or secreted, thus decreasing the drug concentration over time (pharmacokinetics). The effect of this drug, both intended and unintended, can be described by pharmacodynamics. Elderly patients may be more sensitive to any particular drug due to changes in drug-specific absorption, compartment-specific distribution, metabolism, and/or excretion, leading to higher end-organ concentrations of the drug (pharmacokinetics) versus changes in the drug’s intended effect at the receptor (pharmacodynamics), or from both.
Any patient’s drug-specific pharmacokinetics depend on both patient-related and drug-related factors. When addressing the patient-related factors, one may interrogate each of the individual contributors to pharmacokinetics: absorption, distribution, metabolism, and excretion:
● Absorption: theoretically, absorption of drugs increases due to decreased small bowel surface area, slowed gastric emptying, and increased gastric pH. Clinically, these changes are inconsequential for most drugs, with one notable exception being calcium carbonate. Calcium carbonate absorbs poorly in comparatively alkalotic environments, leading to constipation.
● Distribution: as mentioned earlier, increased adiposity and decreased total body water leads to increased lipophilic volume of distribution and decreased hydrophilic volume of distribution. Lipophilic drug duration subsequently increases with a subsequent decrease in plasma concentration per unit dose, while hydrophilic drug duration decreases with a subsequent increase in plasma concentration per unit dose. Decreases in hepatic synthetic function leads to hypoalbuminemia and decreased protein binding, increasing the free drug availability of many common anesthetics (barbiturates, benzodiazepines, synthetic opioids) as well as perioperative medications (notably phenytoin and warfarin). Increased alpha 1-acid glycoprotein decreases the free drug availability of local anesthetics, though this does not contribute to local anesthetic resistance; elderly patients are in fact more sensitive to local anesthetics due to changes at the level of the neuron.
● Metabolism: many common perioperative medications are metabolized hepatically via the cytochrome P450 system. Elderly patients have relatively decreased hepatic size and blood flow (in addition to other common comorbidities of the elderly, such as heart failure and smoking), contributing to decreased phase I drug metabolism, which relies on the cytochrome P450 system to oxidize, reduce, and hydrolyze drugs. (Phase II acetylation and conjugation are relatively unaffected by aging.)
● Elimination: as one ages, glomeruli become less functional and decrease in number, leading to a variable decrease in glomerular filtration rate. Creatinine may not increase with age due to decreased muscle mass and physical activity, and elderly patients should be presumed to have decreased glomerular filtration despite normal-appearing creatinine. The clinical impact of age-related changes in glomerular filtration depend on the extent that renal elimination contributes to total systemic elimination as well as the drug’s therapeutic index. Elderly patients are more susceptible to changes in drug serum concentration when acutely ill, and maintenance of daily drugs may need to be adjusted when patients become acutely or profoundly dehydrated.
Decidedly less certain are the pharmacodynamic implications of aging. Drug sensitivity certainly changes with age, in part due to target site receptor density, signal transduction, and the multitude of homeostatic processes that preserve normal end-organ function. Generally, drug sensitivity increases with few notable exceptions (e.g. alpha agonists and beta antagonists). For example, even after taking into account the pharmacokinetic effects, lipophilic benzodiazepines have an increased effect in the elderly, which may be explained by age-related changes in GABA-A receptors.