Age-related changes in pharmacodynamics may also be relevant.
ALTERED PHARMACODYNAMICS IN THE
ELDERLY
Age-related
changes in pharmacodynamics may also be relevant. The most important concept in
regard to pharmacodynamics is sensitivity, that is the measure-ment of a
response to a given dose of drug. Sensitivity is independent of dose- and
age-related changes in the pharmacokinetics (Jackson, 1994). It may be
diffi-cult to quantify in elderly patients, who may show both increased and
decreased responsiveness to medi-cation. The mechanisms include changes to
organ systems such as age-related impairment of homeo-static mechanisms, as
well as changes at receptor and cellular level (Jackson, 1994).
Warfarin acts by inhibiting the synthesis of clotting
factors II, VII, IX and X by inhibiting regeneration of vitamin K oxide. Early studies
suggested that respon-siveness to warfarin increases with age (O’Malley et al., 1977), possibly because of
greater inhibition of vitamin
K-dependent clotting factors per plasma concentration of warfarin in this age
group (Shepherd et al., 1977). However,
two retrospective studies have failed
to show any association of increased age and bleeding complications (Gurwitz et al., 1988) or devi-ation from target
international normalised ratio (Britt et
al., 1992). Nonetheless, elderly patients were found to require, on average, a lower dose of warfarin than younger
patients to maintain the same degree of anticoagulation (Redwood et al., 1991). Although there is
uncertainty as to the precise mechanism of the increased sensitivity to
warfarin amongst elderly people, one possibility is an increased sensitivity to
enzyme inhibition rather than differences in substrate availability (Jackson,
1994). Warfarin is a racemate of R and S stereoisomers and is subject to
interindi-vidual variability in stereospecific metabolism, which may be
exaggerated in the elderly.
Elderly
people also show increased sensitivity to the effects of the benzodiazepines;
this may be due to altered tissue sensitivity or different rates of entry of
the drug into the central nervous system, as well as the alteration in
pharmacokinetics already mentioned. For example, the extent and duration of
action of nitrazepam on psychomotor function was more marked in elderly
subjects despite the plasma concen-trations being similar in young and old, suggest-ing
increased sensitivity of the ageing brain to this benzodiazepine (Castleden et al., 1977). Similarly, the plasma
concentration of diazepam required to induce a predetermined level of sedation
for dental and endo-scopic procedures fell progressively between the ages of 20
and 80 years (Cook, Flanagan and James, 1984). Although there is some evidence
of pharmacody-namic tolerance developing to the sedative effects of
benzodiazepines with long-term use (Swift et
al., 1984), dizziness, fainting, blackouts and falls are more common in
elderly people taking these drugs regularly (Hale, Stewart and Marks, 1985).
Furthermore, benzo-diazepines appear to adversely affect the safety of the
older driver, particularly when compounds with long half-lives or very high
doses are used (Ray, Thapa and Shorr, 1993).
In
many cases, the increased response to a drug in an elderly patient can be
explained by pharmacokinetic changes. For example, the administration of
nifedipine to elderly people is associated with a reduction in first-pass
metabolism and clearance compared with young volunteers. This results in higher
and more prolonged plasma concentrations and explains the increased hypotensive
effect in this age group (Robertson et al.,
1988). However, altered homeostatic mechanisms due to impaired baroreceptor
function in the elderly may also contribute (Gribbin et al., 1971). In younger patients, a fall in blood pressure leads
to a compen-satory tachycardia partly offsetting the fall in cardiac output,
but with increasing age this effect is reduced. This means that the heart-rate
response to standing is diminished and may cause orthostatic hypoten-sion,
which is defined as a reduction in systolic blood pressure of at least 20 mmHg
occurring in response to a change from a supine to an upright position (Mets,
1995). The prevalence of ortho-static hypotension has been reported to be
between 10% and 30% for elderly people and is particularly associated with the
use of antihypertensive medication (Mets, 1995).
On
the other hand, -adrenoceptors may show a reduction in both numbers (Schocken
and Roth, 1977) and responsiveness to agonists and antagonists with age (Dillon
et al., 1980; Ullah, Newman and
Saunders, 1981; Kendall et al., 1982;
Feldman et al., 1984; Pan et al., 1986; Scarpace, 1986). Despite
this, elderly patients with hypertension appear to respond well to
-adrenoceptor blockers, but they may be more troubled by postural hypotension
due to the impaired homeostatic mechanisms already mentioned. Similarly,
although there is a decline in function in the renin-angiotensin system with
age (Skott and Geise, 1984), the ACE inhibitors cause a greater reduction in
blood pressure in elderly people (Ajayi, Hocking and Reid, 1986), particularly
after the first dose (Cleland et al.,
1985). This may relate to higher baseline blood pressure in the elderly.
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