In people who are aged >65 years, pharmacokinetics are influenced more by the loss of kidney

function than by the aging process of any other organ. A GFR of 30 to 60 ml/min, suggestive of stage
3 kidney disease, is observed in 15 to 30% of elderly people. Drug dosing must be adjusted to both
changing pharmacokinetics and pharmacodynamics; the pharmacodynamics might be influenced by
the aging of other organs, too. Using our NEPharm database, we extracted abstracts with
pharmacokinetic parameters since 1999 from a weekly PubMed search. The recorded data were
analyzed and compared with published recommendations on drug dosage and use in the elderly.
Purely age-related changes in pharmacokinetic parameters were recorded from publications on 127
drugs. The analysis of our NEPharm records revealed an average (mean +/- SD) age-related
prolongation of half-life of 1.39-fold (corresponding to +39 +/- 61%). Contrasting to common
opinion, mean changes in clearance (-1 +/- 54%) and volume of distribution (+24 +/- 56%) were even
less. The modest changes in pharmacokinetics do not suggest general dosage modifications in the
elderly for most drugs. Changes in pharmacodynamics justify the common medication rule in the
elderly-"start low + go slow"-especially for drugs that act on the central nervous system; however,
in the case of anti-infective and anticancer therapy, the rule should be "hit hard = start high + go
fast" to produce the target effect also in the elderly.

Absorption: Despite an age-related decrease in small-bowel surface area and an increase in gastric
pH, changes in drug absorption tend to be trivial and clinically inconsequential.

Distribution: Total body water decreases by 10 to 15% between ages 20 and 80 years. In contrast,
the percentage of body weight that is body fat increases from 18 to 36% in men and from 33 to 45%
in women. The relative decrease in total body water and thus in sodium space leads to higher blood
(and often tissue) concentrations of some water-soluble drugs. Increased body fat increases the
volume of distribution for lipophilic drugs and may result in increased elimination half-lives.

Hepatic metabolism: With age, hepatic mass and hepatic blood flow decrease. Decreased
hepatic blood flow significantly affects hepatic elimination of drugs in rare situations--eg,
when a drug with high clearance, such as lidocaine, is given IV.

Although expression of drug-metabolizing enzymes in the cytochrome P-450 system does not
appear to decrease with age, overall hepatic metabolism of many drugs by these enzymes is
reduced. For drugs with reduced hepatic metabolism (see Table 6-2), clearance typically
decreases 30 to 40%. Theoretically, maintenance drug doses should be reduced by the same
percentage; however, the rate of hepatic metabolism of drugs can vary greatly from person to
person, and individual titration is required.

Renal elimination: With age, renal mass and renal blood flow (mainly in the renal cortex)
decrease significantly. After age 30, creatinine clearance decreases an average of 8
mL/min/1.73 m2/decade in about two thirds of persons but remains the same in the rest.
However, serum creatinine levels may remain within normal limits because the elderly have
less lean body mass and produce less creatinine. Decreases in tubular function parallel those
in glomerular function.

These physiologic changes decrease renal elimination of drugs (see Table 6-2).
Pharmacodynamics

In the elderly, the effects of similar drug concentrations at the site of action may be larger or
smaller than those in younger persons (see Table 6-3). The difference may be due to changes
in drug-receptor interaction, in postreceptor events, or in adaptive homeostatic responses;
among frail patients, the difference is often due to organ pathology.

Increased sensitivity due to aging must be considered when drugs that can have serious
adverse effects are used. These drugs include morphine, pentazocine, warfarin, angiotensin-
converting enzyme inhibitors, diazepam (especially given parenterally), and levodopa. Some
drugs whose effects are reduced with normal aging (eg, tolbutamide, glyburide, -blockers)
should also be used with caution in elderly patients because serious dose-related toxicity can
occur and signs of toxicity may be delayed.