Altered Pharmacodynamics in the Elderly

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Chapter: Pharmacovigilance: Drugs and the Elderly

Age-related changes in pharmacodynamics may also be relevant.


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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