PHARMACODYNAMICS AND DRUG ACTION Aging and susceptibility to drug-induced orthostatic hypotension Objective: To test the hypothesis that the short-term effect of transbuccal nitroglycerin (glyceryl trinitrate, 0.0625 to 1.5 mg) on orthostatic cardiovascular responses would predict the effect of a diuretic (5
mg bendroflumethiazide daily for 1 week), particularly in elderly subjects who may be at higher risk for orthostatic hypotension. Methods: This was a randomized crossover study. Participants were 17 elderly (age range, 63 to 84 years) and 15 younger (age range, 19 to 35 years) healthy ambulant volunteers. Interventions and measures of outcome included blood pressure (BP; in millimeters of mercury) and heart rate (HR; in beats per minute) changes with standing, which were measured before administration of medication and after each drug treatment. Results: Subjects in the elderly and younger groups had different BP and HR changes (mean percentage change) at 1 minute after standing in all three study phases (unmedicated, elderly: BP, 4%/ + 1%; HR, + 12%; young: BP, + 2%/ +12%; HR, + 27%; p = 0.06 for BP, p < 0.01 for HR; bendroflumethiazide, elderly: BP, 9%/ 3%; HR, + 17%; young: BP, + 1%!+ 11%; HR, +33%; p < 0.05 for all; nitroglycerin (0.25 mg), elderly: BP, 15%/ 12%; HR, +21%; young: BP, 6%/ + 7%; HR, + 38%; p 1.5 in
1.5
-
-o a)
-6
1.0 -
00 00
0.5
-
**
000
0000000
YOUNG
ELDERLY
Objective Response
(-.)
Subjective Response
Fig. 4. Maximum tolerated doses of nitroglycerin (glyceryl trinitrate [GTN]) in each subject in the two age groups. Closed circles represent subjects who, during the first 3 minutes after standing, had a drop in systolic blood pressure of at least 20 mm Hg more than in the unmedicated state. Open circles represent subjects who were unable to continue because of symptoms (dizziness or headache). Subjects who tolerated the maximum dose of 1.5 mg are included in the figure as >1.5 mg. Median values are shown by horizontal lines. **Difference between groups (p < 0.01).
Table I. Effects of bendroflumethiazide (5 mg daily for
7
days) on body weight, hematocrit, and
biochemical parameters Elderly subjects Weight (kg) Hematocrit (%) Potassium concentration (mmol/L) Plasma chloride concentration (mmol/L) Plasma bicarbonate concentration (mmol/L) Creatinine (jimol/L)
0.7 +2.2 0.5 6.0
± ± ± ± +4 ± +4 ±
0.2** 2.0 0.1** 0.9** 0.5** 2*
Younger subjects
1.5 +1.2 0.7 5.7
± ± ± ± +3 ± +5 ±
0.4** 0.3* 0.1** 1.1**
0.5** 3**
Data are mean values ± SEM. *p < 0.05; **p < 0.01, significant changes within groups (before versus after treatment). There were no significant differences between groups.
lute. It is possible that the elderly subjects were able to compensate for the venodilatory effects of nitroglycerin, which predominate at low doses,24 but were unable to compensate at higher doses, which also cause arteriolar dilation. Despite the clinical observation of the frequency of nitrate-induced orthostatic hypotension in elderly subjects, there have been few formal studies of the phenomenon. In fact, it has been reported that a postural change from supine to standing after a dose of nitroglycerin had no additional effects on blood pressure in institutionalized elderly
subjects. 17 This negative observation was probably related to the timing of the postural stress (at 30 minutes after dose administration) when the vasodilating effect was likely to have terminated in most subjects.2526 There was a strong positive correlation between the effects of the two drugs used in the study (Fig. 5), despite their different basic mechanisms of action. It would be expected that the impact of both drugs on orthostatic blood pressure control would be predominantly attributable to a reduction in the effective circulating blood volume in the standing position, through
284
CLIN PHARMACOL THER SEPTEMBER 1992
Tonkin and Wing
elderly o young N =31
'
20 GT N
0 10
...,
---
---
..--
r
p
=0.65
mg bendroflumethiazide daily for 1 week), particularly in elderly subjects who may be at higher risk for orthostatic hypotension. Methods: This was a randomized crossover study. Participants were 17 elderly (age range, 63 to 84 years) and 15 younger (age range, 19 to 35 years) healthy ambulant volunteers. Interventions and measures of outcome included blood pressure (BP; in millimeters of mercury) and heart rate (HR; in beats per minute) changes with standing, which were measured before administration of medication and after each drug treatment. Results: Subjects in the elderly and younger groups had different BP and HR changes (mean percentage change) at 1 minute after standing in all three study phases (unmedicated, elderly: BP, 4%/ + 1%; HR, + 12%; young: BP, + 2%/ +12%; HR, + 27%; p = 0.06 for BP, p < 0.01 for HR; bendroflumethiazide, elderly: BP, 9%/ 3%; HR, + 17%; young: BP, + 1%!+ 11%; HR, +33%; p < 0.05 for all; nitroglycerin (0.25 mg), elderly: BP, 15%/ 12%; HR, +21%; young: BP, 6%/ + 7%; HR, + 38%; p 1.5 in
1.5
-
-o a)
-6
1.0 -
00 00
0.5
-
**
000
0000000
YOUNG
ELDERLY
Objective Response
(-.)
Subjective Response
Fig. 4. Maximum tolerated doses of nitroglycerin (glyceryl trinitrate [GTN]) in each subject in the two age groups. Closed circles represent subjects who, during the first 3 minutes after standing, had a drop in systolic blood pressure of at least 20 mm Hg more than in the unmedicated state. Open circles represent subjects who were unable to continue because of symptoms (dizziness or headache). Subjects who tolerated the maximum dose of 1.5 mg are included in the figure as >1.5 mg. Median values are shown by horizontal lines. **Difference between groups (p < 0.01).
Table I. Effects of bendroflumethiazide (5 mg daily for
7
days) on body weight, hematocrit, and
biochemical parameters Elderly subjects Weight (kg) Hematocrit (%) Potassium concentration (mmol/L) Plasma chloride concentration (mmol/L) Plasma bicarbonate concentration (mmol/L) Creatinine (jimol/L)
0.7 +2.2 0.5 6.0
± ± ± ± +4 ± +4 ±
0.2** 2.0 0.1** 0.9** 0.5** 2*
Younger subjects
1.5 +1.2 0.7 5.7
± ± ± ± +3 ± +5 ±
0.4** 0.3* 0.1** 1.1**
0.5** 3**
Data are mean values ± SEM. *p < 0.05; **p < 0.01, significant changes within groups (before versus after treatment). There were no significant differences between groups.
lute. It is possible that the elderly subjects were able to compensate for the venodilatory effects of nitroglycerin, which predominate at low doses,24 but were unable to compensate at higher doses, which also cause arteriolar dilation. Despite the clinical observation of the frequency of nitrate-induced orthostatic hypotension in elderly subjects, there have been few formal studies of the phenomenon. In fact, it has been reported that a postural change from supine to standing after a dose of nitroglycerin had no additional effects on blood pressure in institutionalized elderly
subjects. 17 This negative observation was probably related to the timing of the postural stress (at 30 minutes after dose administration) when the vasodilating effect was likely to have terminated in most subjects.2526 There was a strong positive correlation between the effects of the two drugs used in the study (Fig. 5), despite their different basic mechanisms of action. It would be expected that the impact of both drugs on orthostatic blood pressure control would be predominantly attributable to a reduction in the effective circulating blood volume in the standing position, through
284
CLIN PHARMACOL THER SEPTEMBER 1992
Tonkin and Wing
elderly o young N =31
'
20 GT N
0 10
...,
---
---
..--
r
p
=0.65
