Combined Diuretic and Sympatholytic Therapy in Elderly Patients with Predominant Systolic Hypertension

psychosis and tardive dyskinesia. Am J Psychiatry, 1980; 137:629-30 25 Tyrer PJ, Lader MH. Response to propranolol and diazepam in somatic and psychic anxiety. Br Med J 1974; 2:14-6 26 Waal HJ. Propranolol-induced depression. Br Med J 1967; 2:50 27 Pett M, Bethell MS, Coates A, et ale Propranolol in schizophre­ nia: 1. Comparison of propranolol, chlorpromazine and placebo. Br J Psychiatry 1981; 139:105-11 28 ltil TM. Drug treatment of therapy-resistant schizophrenic patients. In: Arieti S, ed. The world biennial of psychiatry and psychotherapy. New York: Basic Books, Inc, 1973:246-64 29 Granville-Grossman KL, Turner E The effect of propranolol on anxiety. Lancet 1966; 1:788-90 30 Bonn JA, Turner ~ Hicks D. Beta-adrenergic receptor blockade

with practolol in treatment of anxiety. Lancet 1972; 1:814-15

31 Becker AI. Oxprenolol and propranolol in anxiety states: a

double-blind comparative study. S Afr Med J 1975; 50:627-29

32 Pitts FN Jr, Allen R. Beta-adrenergic blocking agents in the treatme~t ofanxiety. In: Fann WE, Karacan I, Pokorny AD, et al, eds. Phenomenology and treatment of anxiety. New York: Spectrum Publications, 1979:337-49 33 Burrows CD, Davies B, Fail L, et ale A placebo controlled trial of diazepam and oxprenolol for anxiety. Psychopharmacology 1976; 50:177-79 34 Staesen J, Fagard R, Grauwels R, Lijnen ~ Amery A. Double­ blind crossover study with the new antihypertensive agent CP-804-S. In: Proceedings, 9th scientific meeting of the Interna­ tional Society of Hypertension. Mexico City: International Society of Hypertension, 1982

Combined Diuretic and Sympatholytic Therapy in Elderly Patients with Predominant Systolic Hypertenslon* Michael A Webe~ M.D.; Jan I. M. Drayer, M.D.; and David R. Gray, Phann. D.

It has been speculated that the convenience and palatability of low-dose combination antihypertension treatment might enhance therapeutic effectiveness and compliance, espe­ cially in eiderly patients. To test this possibility, patients over 60 years of age with predominant systolic hypertension were treated with a combination of a diuretic, chlorthali­ done, and the centrally acting inhibitor of sympathetic activity, clonidine. The results of active treatment in these patients (n = 13) were compared with those of a placebo (n = 11). Active therapy with low doses ofchlorthalidone and clonidine (usually once daily) controlled blood pressure (systolic pressure <140 mm Hg) in 12 of the 13 patients without inducing orthostatic hypotension. Administration of placebo did not result in signi6cant changes in biood pressure. The diuretic-clonidine combination induced only small decreases in serum potassium levels and small in­ creases in uric acid; no signi6cant changes in creatinine clearance were observed. Both active and placebo therapy were tolerated without signmcant side effects. This study *From the Section of Clinical Pharmacology and Hypertension, Veterans Administration Medical Center, Long Beach, CalifOrnia, and the University of California, Irvine. Reprint requests: Dr. Weber, VA Medical Center Wl30, 5901 East Seventh, Long Beach 90822 418

reveals that combined therapy with low doses of chlorthali­ done and clonidine is effective, convenient, and palatable in controUing blood pressure in elderly patients with predomi­ nant systolic hypertension and supports the idea that treat­ ment with sympathoinhibitory and volume-depleting agents is appropriate for this form of hypertension. is now recognized that hypertension in the aged is a I t critical risk factor for forms of cardiovascular disease.

all More specifically, it has been shown that increased systolic blood pressure, even when diastolic blood pressure remains normal, is associated with a highly significant increase in the likelihood of major morbid events or death. 1 Although large­ scale prospective studies designed to evaluate the efficacy of treatment in preventing the complications of predominant systolic hypertension are still incomplete, it is appropriate to search for effective and palatable treatment strategi~s for this condition. As with younger people, the etiology of hypertension in the aged is generally not cleat: Although it has been the­ orized that the aging process may be associated with a loss of elasticity and compliance in the arterial circulation that can lead to an increase in total peripheral resistance, it has not been shown that these structural vascular changes are closely linked to the occurrence or severity of hypertension in this group of patients. Because of the progressive decline in glomerular filtration rate that occurs with increasing age, it is possible that older individuals may have some difficulty in adequately handling sodium loads. It has been observed that older individuals with hypertension are more likely than their younger counterparts to have a suppressed plasma renin level, which is a possible indicator of sodium and volume retention. 2 A further potential mechanism for the hypertension in the aged may be related to changes in peripheral vascular J,i-adrenergic receptors. It has been shown that the number of these receptors declines with advancing age, 3 and that progressively ~ater amounts of (.i-adrenergic stimuli are required to achieve standardized responses. 4 Since the vascular p-receptor, which mediates vasodilation, normally has an attenuating effect on blood pressure changes brought about by sympathetic activity, it could be speculated that the disappearance of p-receptors could contribute to the development of hypertension. In­ deed, it has been found that the blood pressure response to a standardized sympathetic stimulus tends to increase in older age groups. s To maximize treatment compliance and palatability in the elderly patients participating in this study, we used Com­ bipres (Boehringer Ingelheim Ltd), a combination antihyper­ tensive preparation containing the sympathoinhibitory agent clonidine and the diuretic chlorthalidone. Although this form of treatment did not allow us to test the individual mechanisms discussed earlier; we found that this low-dose therapeutic combination was particularly effective in patients with predominant systolic hypertension. METHODS

The study was performed in 24 men, all aged greater than 60 years (range, 62 to 83 years). In each case a diagnosis of essential hypertension had been made on the basis ofexcluding other forms"of hypertension by conventional clinical, biochemical, and radiologic means. To be eligible for entry into the study, each patient had a Central AIpha-Adret KX:8PIOt'8

Table l-CliraictJl Valua in Elderly ftJtientI tDith Predominantly Sy.tolic Hypertenlion &fore arad After 1J Weeb of

Treatment with Placebo (n U) or tDith a Combination ofClalorthalitlone Gnd Clonidine (n 13)

=

=

Active 1ieatment

Placebo Measurement Supine systolic blood pressure, mm Hg Supine diastolic blood pressure, mm Hg Supine heart rate, bpm Upright systolic blood pressure, mm Hg Upright diastolic blood pressure, mm Hg Upript heart rate, bpm Body weight, kg

Before

During

Before

During

167±3

161±S

170±S*

141±3*

95±2

92±2

9O±3t

84±3t

69±3

69±4

74±3

73±3

162±2

IS7±S

172±4*

135±4*

94±3 80±3 71.7±4.2

93±2 7S±4 71.6±4.4

93±3t 79±3 BO.l±3.2

85±3t 78±2 79.7±3.2

*pmbined with chlortha1idone, 15 mg (Combipres, Boehringe~ Irwelheim Lt
follow~

in the placebo group except for the medication. For each group, blood and urinary chemistries were measured at the end of the initial placebo phase and at the end of the treatment protocol. Plasma renin acQvity and urinary aldosterone excretion were mea­ sured by radioimmunoassay methods. tU Routine biochemistry values were measured by standard methods. The significance m treatment-induced changes was assessed by the paired Student's t test within groups, and by the unpaired t test between groups. Values ~ given as mean ± SEM. RESUIXS

Of the 13 patients randomized to the active treatment group, ten achieved a satisfactory blood pressure response (decrease in supine systolic blood pressure to 140 mm Hg or less, or a fall of at least 20 mm Hg) with the single hour-of­ sleep dose ofCombipres; two patients required a twice-daily dose ofComb.pres in order to respond, but the final patient failed to respo~d despite receiving the higbes~ dose. None of the 11 patients in the placebo group exhibited a response. The

Table I-Blood and Urinary Chemiat'll Valua ~efore and After 1J W__ ofTretJtment tfElderly H ~ ftJtientI willa Placebo (n = U) or tDith a Combination rf C ~ and Clonidirae (f;I = 1~) Placebo Measurement Serum sodium

concentration, mEq/L Serum potassium

concentration, mEqlL Serum uric acid

concentration, mgldl Crea&inecl~ce,mVmin

Active 1ieatment

Before

During

Before

141±0.2

141:tO.6

141±0.7

140±O.S

4.3±0.1

4.4±0.1

4.1±0.1*

3.8±0.1*

S.6±0.4 86±15

5.7±0.3 9O±17

6.7±0.S* 81±8

8.6±0.S*

BO±10

1.9±0.S

1.3±0.3

2.4±0.6

3.9± 1.0

3.1±0.6

S.9±1.6

4.6± LIt

9.2±2.7t

150± 19

133±28

17S±24

160±21

During

Plasma renin activity, nglmllhr A1do~terone

excretion rate, ...gI~ hr Urinary sodium excretion, mEq/24 hr

*p
417

detailed clinical data are summarized in 11lble 1. In the active group, both systolic and diastolic blood pressure fell signifi­ cantly in both the supine and uprigllt postures. The changes observed in upright pressures were not significantly greater than those observed in supine pressures. There was no significant change in heart rate in either posture. Body weight remained constant throughout the study. There were no signi6cant changes in any of these parameters in the placebo group. There were no significant side effects in either group, and no patient was withdrawn from the study for this reason. Chemistry values during the study are summarized in 18ble 2. The patients receiving active treatment experienced Significant decreases in serum potassium concentration and increases in serum uric acid concentration. Both the aldosterone excretion rate and plasma renin activity rose during treatment, but only the change in aldosterone was signi6cant. Renal function, as measured by creatinine clear­ ance, remained constant throughout the study as did urinary sodium excretion. There were no signi6cant changes in any of these values during the study in the placebo group.

DISCUSSION

In contrast to the patients receiving placebo, in whom no signi6cant changes in blood pressure occwred, patients receiving active treatment with clonidine and chlorthalidone exhibited marked antihypertensive responses. Because this study was performed in the elderly (minimum age 60 years), the chieforientation was toward systolic hypertension. Thus, the criteria for entry to the study was a systolic blood pressure of 160 mm Hg or greater and a diastolic blood pressure of 100 mm Hg or less. The treatment used worked particularly well in this form of predominant systolic hypel'­ tension. 1\velve of the 13 patients achieved the criterion of response: a fall in systolic blood pressure to 140 mm Hg or less, or a fall of at least 20 mm Hg. Although there was a Significant reduction in diastolic blood pressure as well, this was of only relatively small amplitude. None of the patients experienced orthostatic hypotension. Because the patients were given only combination therapy throughout the study, it is not really possible to discuss the specificity of either of the active antihypertensive compo­ nents, clonidine and chlorthalidone, in this type ofhyperten­ sion. However, there are reasons for believing that both volume factors and excessive sensitivity to sympathetic activity may be important in the hypertension of the aged. Thus, it is of interest that low doses ofa volume-depleting and a sympathetic-inhibitory agent were so effective. Indeed, an acceptable blood pressure response was attained in ten of the

418

13 patients using only the minimal daily dosage: clonidine 0.1 mg and chlorthalidone 15 mg. It is possible that the effective­ ness and long duration of this low-dose therapy was enhanced by the decreased rates of drug metabolism and excretion known to occur in the aged. 8 The responsiveness ofpatients to such relatively low doses brings about two additional bene6ts. (1) There appears to be an avoidance of undesirable side effects. In this study no patient was compelled to discontinue treatment because of. symptomatic side effects, and in fact we found that patients tolerated this therapy with no serious complaints. Moreover, apart from a small decrease in plasma potassium concentra­ tion and a slight increase in plasma uric acid concentration, both reflecting the expected effects of the diuretic, there were no biochemical changes. Plasma renin activity and urinary aldosterone excretion both rose, but to a lesser extent than has been reported previously when more conventional doses of diuretics were used. 8 Of particular importance, there was no significant change in renal function as measured by endogenous creatinine clearance. (2) A majority of pa­ tients could be treated effectively with once-daily adminis­ tration. We anticipate that the convenience of the single daily dose taken at the hour-of-sleep, together with the general avoidance of undesired side effects, would result in good long-term compliance with treatment. REFERENCES

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33:482-87 6 Sealey JE, Laragh JR. Radioimmunoassay of plasma renin activ­ ity. Semin Nuel Med 1975; 5:189-202 7 Sealey JE, Buhler FR, Laragh JH, Manning EH, Brunner HR. Aldosterone excretion: physiological variations in man measured by radioimmunoassay or double-isotope dilution. Cire Res 1972; 31:367-78 8 O·MalIey Ie, Judge 1: Crooks J. Geriatric clinical pharmacology and therapeutics. In: Avery G, ed. Drug treatment: principles and practice eX clinical pharmacology and therapeutics. Sydney: ADIS Press, 1980:158-81 9 Weber MA, Drayer JIM, Rev A, Laragh JH. Disparate patterns eX aldosterone response during diuretic treatment eX hypertension. Ann Intern Med 1977; 87:558-63