An article published in MSD Manual defined pharmacokinetics as ‘what the body does to the drug’ – involving absorption; distribution across body compartments; metabolism; and excretion.

The authors stated that with aging, there are changes in all these areas, while some changes are more clinically relevant. The metabolism and excretion of many drugs decrease with age—requiring that doses of some drugs be decreased. Yet, toxicity may develop slowly because concentrations of chronically used drugs increase for 5 to 6 half-lives, until a steady state is achieved. For instance, certain benzodiazepines – diazepam, flurazepam, chlordiazepoxide or their active metabolites, have half-lives of up to 96 hours in older patients. Signs of toxicity may not appear until days or weeks after therapy is started.

This article elaborated that despite an age-related decrease in small-bowel surface area, slowed gastric emptying, and an increase in gastric pH, changes in drug absorption tend to be clinically inconsequential for most drugs. One clinically relevant exception is calcium carbonate, which requires an acidic environment for optimal absorption – increases in gastric pH can decrease calcium absorption and increase the risk of constipation. Hence, older adults should use a calcium salt (e.g., calcium citrate) that dissolves more easily in a less acidic environment. Another example of altered absorption with increased gastric pH is early release of enteric-coated dosage forms—increasing the risk of GI adverse effects.

With age, body fat generally increases and total body water decreases. Increased fat increases the volume of distribution for highly lipophilic drugs like diazepam and chlordiazepoxide, and may increase their elimination half-lives. In addition, serum albumin decreases and alpha 1-acid glycoprotein increases with age, but the clinical effect of these changes on serum drug binding varies with different drugs. In patients with an acute disorder or malnutrition, rapid reductions in serum albumin may enhance drug effects because serum concentrations of unbound drug may increase. Phenytoin and warfarin are examples of drugs with a higher risk of toxic effects when the serum albumin level decreases.

Overall hepatic metabolism of many drugs through the cytochrome P-450 enzyme system decreases with age. For drugs with decreased hepatic metabolism, the clearance typically decreases by 30-40%. However, rate of drug metabolism varies greatly from person to person, and dose adjustments should be individualized. Furthermore, hepatic clearance of drugs metabolized by phase I reactions is more likely to be prolonged in older adults. Usually, age does not greatly affect the clearance of drugs that are metabolized by conjugation and glucuronidation – phase II reactions.

First-pass metabolism—hepatic metabolism that occurs before a drug reaches the systemic circulation—is also affected by aging, decreasing by about 1%/year after the age of 40. Thus, for a given oral dose, older adults may have higher circulating drug concentrations. Important examples of drugs with a high risk of toxic effects include nitrates, propranolol, phenobarbital and nifedipine. Other factors that may influence hepatic metabolism of drugs are – smoking, decreased hepatic blood flow in patients with heart failure and taking drugs that induce or inhibit cytochrome P-450 metabolic enzymes.

Source: MSD Manual. Dec 2018