Clinical Pharmacology and Therapeutics

PHARMACODYNAMIC CHANGES 57
DISTRIBUTION
Ageing is associated with loss of lean body mass, and with an
increased ratio of fat to muscle and body water. This enlarges
the volume of distribution of fat-soluble drugs, such as
diazepam and lidocaine, whereas the distribution of polar
drugs such as digoxin is reduced compared to younger adults.
Changes in plasma proteins also occur with ageing, especially
if associated with chronic disease and malnutrition, with a fall
in albumin and a rise in gamma-globulin concentrations.
HEPATIC METABOLISM
There is a decrease in the hepatic clearance of some but not all
drugs with advancing age. A prolonged plasma half-life (Figure
11.2), can be the result either of reduced clearance or of increased
apparent volume of distribution. Ageing reduces metabolism of
some drugs (e.g. benzodiazepines) as evidenced by reduced
hepatic clearance. The reduced clearance of benzodiazepines
has important clinical consequences, as does the long half-life of
several active metabolites (Chapter 18). Slow accumulation may
lead to adverse effects whose onset may occur days or weeks
after initiating therapy. Consequently, confusion or memory
impairment may be falsely attributed to ageing rather than to
adverse drug effects.
Diazepam t 1/2 (h)
120
100
80
60
40
20
0 10 20 30 40 50 60 70 80 100
Age (years)
Figure 11.2: Relationship between diazepam half-life and age in
33 normal individuals. Non-smokers,
° ; smokers, •. (Redrawn
with permission from Klotz U et al. Journal of Clinical
Investigation 1975; 55: 347.)
Table 11.1: Examples of drugs requiring dose adjustment in the elderly
Aminoglycosides (e.g. gentamicin)
Atenolol
Cimetidine
Diazepam
Digoxin
Non-steroidal anti-inflammatory drugs
Oral hypoglycaemic agents
Warfarin
RENAL EXCRETION
The most important cause of drug accumulation in the elderly
is declining renal function. Many healthy elderly individuals
have a glomerular filtration rate (GFR) 50 mL/min. Although
glomerular filtration rate declines with age, this is not necessarily
reflected by serum creatinine, which can remain within the
range defined as ‘normal’ for a younger adult population
despite a marked decline in renal function. This is related to the
lower endogenous production of creatinine in the elderly secondary
to their reduced muscle mass. Under-recognition of
renal impairment in the elderly is lessened by the routine
reporting by many laboratories of an estimated GFR (eGFR)
based on age, sex and serum creatinine concentration and
reported in units normalized to 1.73 m 2 body surface area
(mL/min/1.73 m 2 ). When estimating doses of nephrotoxic
drugs, it is important to remember that the drug elimination
depends on the absolute GFR (in mL/min) rather than that normalized
to an ideal body surface area (in mL/min/1.73 m 2 ),
and to estimate this if necessary using a nomogram (see
Chapter 7) that incorporates height and weight, as well as age,
sex and creatinine.
Examples of drugs which may require reduced dosage in
the elderly secondary to reduced renal excretion and/or
hepatic clearance are listed in Table 11.1.
The principal age-related changes in pharmacokinetics are
summarized in Figure 11.1.Key points
Key points
Pharmacokinetic changes in the elderly include:
• Absorption of iron, calcium and thiamine is reduced.
• There is an increased volume of distribution of fatsoluble
drugs (e.g. diazepam).
• There is a decreased volume of distribution of polar
drugs (e.g. digoxin).
• There is reduced hepatic clearance of long half-life
benzodiazepines.
• Declining renal function is the most important cause of
drug accumulation.
PHARMACODYNAMIC CHANGES
Evidence that the elderly are intrinsically more sensitive to
drugs than the young is scarce. However, the sensitivity of the
elderly to benzodiazepines as measured by psychometric tests
is increased, and their effects last longer than in the young. It is
common clinical experience that benzodiazepines given to the
elderly at hypnotic doses used for the young can produce prolonged
daytime confusion even after single doses. The incidence
of confusion associated with cimetidine is increased in
the elderly. Other drugs may expose physiological defects that
are a normal concomitant of ageing. Postural hypotension can
occur in healthy elderly people, and the incidence of postural
hypotension from drugs such as phenothiazines, β-adrenoceptor