Long-term Thiazide Therapy Research Articles

Baroreflex function during 45-degree passive head-up tilt before and after long-term thiazide therapy in the elderly with systolic systemic hypertension

The ratio of the 30th to the 15th cardiac cycle duration on an electrocardiogram (30:15 ratio) immediately after active standing from the supine position has been used as one of the markers of baroreflex function. A ratio of ≤1.0 has been suggested to indicate baroreflex dysfunction. Blood pressure (BP) changes were measured and the 30:15 ratio was calculated after standing and during 45-degree passive head-up tilt from the supine position in 10 nondiabetic men (mean age ± SE 70.1 ± 1.05 years, and BP <150/90 mm Hg). After tilt the decrease in systolic BP (from 132 ± 4.8 to 117 ± 6.3 mm Hg; p < 0.001) appeared to be larger than that after standing (from 132 ± 4.6 to 123 ± 5.8 mm Hg; p < 0.01), whereas the 30:15 ratios were 0.965 ± 0.006 and 0.970 ± 0.014, respectively, which suggested baroreflex dysfunction. Although the mean of the 2 ratios did not differ, the variance appeared to be less during tilting than after standing. Thus, the 45-degree passive head-up tilt appeared to be a better and more uniform inducer of orthostatic stress than active standing. Therefore, 45-degree head-up tilt was used in a group of 10 nondiabetic male patients (aged 70 ± 1.46 years) with isolated systolic hypertension (systolic BP >160 mm Hg, diastolic BP of <90 mm Hg) to assess their baroreflex function. Upon tilting, their systolic BP decreased from 190 ± 5.5 to 179 ± 5.8 mm Hg (p < 0.05) and their 30:15 ratio was 0.985 ± 0.011. The ratio had no correlation with systolic BP in either group. Patients were then treated with oral hydrochlorothiazide 50 mg/ day. After 1 month of therapy, systolic BP decreased from 190 ± 5.5 to 173 ± 9.3 mm Hg, and this decrease was maintained at 1 year (167 ± 7.7 mm Hg); the 30:15 ratios were 0.977 ± 0.01 and 0.995 ± 0.01, respectively, comparable to the pretreatment value. Thus, the depressed baroreflex function (30:15 ratio ≤1) in nondiabetic elderly patients seemed to be a phenomenon of advance dage rather than related to systolic hypertension, and long-term thiazide diuretic therapy did not affect this autonomic mechanism in these patients.

Hemodynamic response to orthostatic stress in the elderly with systolic systemic hypertension before and after long-term thiazide therapy

The hemodynamic effects of orthostatic stress in elderly subjects with systolic hypertension were studied before and after long-term hydrochlorothiazide therapy (50 mg daily). Sixteen nondiabetic men aged 70 ± 1 (SE) years participated in the study initially, and 12 completed 1 year of therapy. Patients underwent 45 ° head-up incline on a tilt table before, after 1 month and after 1 year of therapy. Hemodynamic variables were measured in the following situations: (1) the supine position, (2) immediately after completion of passive 45 ° head-up position at 0 minute, (3) at 15 minutes in the tilted state while patients performed intermittent foot movements to minimize gravitational pooling and simulate the standing position outside the laboratory, and (4) after returning to the supine position. Systolic and diastolic blood pressure (BP) decreased significantly after 1 month of therapy, and this reduction was maintained up to 1 year in all aforementioned body positions, with the exception of diastolic BP at 0 minute of tilt, which was significant at 1 year only. Before therapy was begun, there was a significant reduction in systolic BP immediately after completion of fitting; however, this was statistically insignificant both at 1 month and 1 year of therapy. Thus, the data may help dispel the concern of exacerbating the hypotensive response to orthostatic stress in patients with systolic hypertension after long-term thiazide diuretic therapy.

Thiazide treatment of hypertension: Effects of thiazide diuretics on serum potassium, magnesium, and ventricular ectopy

Thiazide diuretics are considered to be the cornerstone of contemporary antihypertensive therapy and are generally recommended as the initial treatment for patients with mild to moderate, uncomplicated hypertension. Hypokalemia and hypomagnesemia are two metabolic alterations that are associated with long-term thiazide therapy. Thirty-five patients (20 with low renin status and 15 with normal renin status) with mild to moderate essential hypertension were treated with hydrochlorothiazide in a dose-titration experiment after a four-week lead-in period. The initial daily dose was 12.5 mg; this was increased at four-week intervals to 25 mg, 37.5 mg, and 50 mg daily. The endpoint dose of this titration was that dose at which-the patient's blood pressure normalized, or the dose of 50 mg, if that dose was reached. Patients were maintained on their end-point dose of hydrochlorothiazide for 24 weeks of continuous thiazide monotherapy beyond the dose titration. The serum potassium and serum magnesium levels during the control period were 4.4 ± 0.2 mmol/liter and 2.30 ± 0.08 mg/dl, respectively. During dose titration, each incremental increase of hydrochlorothiazide produced a decrease in blood pressure and a stepwise decrease in serum potassium and magnesium levels. A previously reported study involving 38 patients with mild to moderate hypertension (22 with low renin status and 16 with normal renin status) used similar methods to study higher-dose thiazide therapy. An initial dose of 50 mg daily of hydrochlorothiazide was administered; this was increased at four-week intervals to 100 mg, 150 mg, and 200 mg. The serum potassium and serum magnesium levels during the control period were 4.5 ± 0.2 mmol/liter and 2.1 ± 0.18 mg/dl, respectively. In the hypertensive patients with normal renin status, doses of hydrochlorothiazide greater than 50 mg did not result in further blood pressure lowering effects; however, the undesirable effects of hypokalemia and hypomagnesemia continued to be manifested and increased at higher doses of hydrochlorothiazide. Thirty-eight patients who had previously experienced hypokalemia, palpitations, or cardiac arrhythmia were placed on hydrochlorothiazide therapy for one to three months and were monitored for arrhythmias after treadmill exercise. The occurrence of premature ventricular contractions correlated significantly with the decrease in serum potassium (r = 0.73, p <0.001) and serum magnesium (r = 0.68, p <0.001) levels during hydrochlorothiazide therapy and with the product of the change of the two cations (r = 0.81, p <0.001).

Potassium and magnesium abnormalities: Diuretics and arrhythmias in hypertension

Thiazide diuretics are widely accepted as the cornerstone of antihypertensive treatment programs. Hypokalemia is a commonly encountered metabolic consequence of long-term thiazide therapy but the effect of thiazide on serum magnesium is less well known. Thirty-eight patients (22 low renin, 16 normal renin) with moderate diastolic hypertension were treated with hydrochlorothiazide administered twice a day. The initial daily dose was 50 mg; this was increased at four week intervals to 50 mg, 100 mg, 150 mg, and 200 mg. Dose escalation was discontinued when either normalization blood pressure was attained or the 200 mg dose level was reached. Patients were then maintained with their hydrochlorothiazide dose for 24 weeks of continuous thiazide monotherapy. The serum potassium during the control period was 4.5 +/- 0.2 mmol/liter. During dose escalation and long-term maintenance therapy, the serum potassium and magnesium levels fell in a step wise, dose-dependent fashion. In another 38-patient study, the effects of hydrochlorothiazide therapy (100 mg daily) on the occurrence of premature ventricular contractions were observed during rest as well as during static and dynamic exercise. During rest 0.6 +/- 0.08 premature ventricular contractions per minute (mean +/- SEM) were observed, and during dynamic exercise 0.8 +/- 0.15 premature ventricular contractions per minute. During hydrochlorothiazide therapy (50 or 100 mg per day) premature ventricular contractions per minute were 1.4 and 5.7, respectively. The occurrence of premature ventricular contractions correlated significantly with the decrease observed in serum potassium (r = 0.71, p less than 0.001) and in serum magnesium (r = 0.68, p less than 0.001). Thiazide therapy appears to cause both potassium and magnesium depletion, and decreases in both correlate well with the appearance of ventricular ectopic depolarizations.

Selective effects of thiazide therapy on serum 1α,25-dihydroxyvitamin D and intestinal calcium absorption in renal and absorptive hypercalciurias

The effect of long-term thiazide therapy (hydro-chlorothiazide, 50 mg twice/day) on intestinal calcium (Ca) absorption and serum 1α,25-dihydroxy-vitamin D [1α,25-(OH) 2D] concentration was examined in 10 patients with renal hypercalciuria (RH), many of whom had hyperabsorption of Ca, and in 11 cases of absorptive hypercalciuria (AH), all of whom had intestinal hyperabsorption of Ca. In patients with RH, the intestinal Ca absorption decreased significantly during thiazide therapy (mean treatment period of 15 mo) from 0.68 ± 0.09 SD to 0.56 ± 0.10 ( p < 0.01), commmensurate with the “correction” of the renal leak of Ca and secondary hyperparathyroidism. Furthermone, serum 1α,25-(OH) 2D decreased significantly from 5.2 ± 2.2 SD ng/dl to 3.7 ± 0.8 ng/dl ( p < 0.025) during thiazide therapy. In patiens with AH, the intestinal hyperabsorption of calcium persisted during thiazide treatment 0.69 ± 0.07 versus 0.69 ± 0.06), despite restoration of normal urinary Ca. Serum 1α,25-(OH) 2D was virtually unchanged during treatment (4.5 ± 1.4 ng/dl versus 4.7 ± 0.9 ng/dl). The results support the hypothesis that the intestinal hyperabsorption of Ca in RH is a result of increased serum concentration of 1α,25-(OH) 2D secondary to the hyperparathyroid state, while that in AH may not be totally dependent on increased concentrations of 1α,25-(OH) 2D.

Selective effects of thiazide on intestinal absorption of calcium in absorptive and renal hypercalciurias

The effect of long-term thiazide therapy on the intestinal Ca absorption was measured in 10 well-defined cases of absorptive hypercalciuria with intestinal hyperabsorption of Ca and 8 with renal hypercalciuria (“renal leal” of CA), many of whom had hyperabsorption of Ca. In most cases of absorptive hypercalciuria, the intestinal hyperabsorption of Ca persisted during treatment, despite restoration of normal urinary Ca. In contrast, the intestinal Ca absorption decreased significantly during thiazide therapy in 7 of 8 patients with renal hypercalciuria commensurate with the “correction” of the renal leak of Ca and secondary hyperparathyroidism. The results support the hypothesis that the intestinal hyperabsorption of Ca in absorptive hypercalciuria may be primary, whereas that in renal hypercalciuria may be associated with the hyperparathyroid state.

Effect of long-term thiazide therapy on intestinal calcium absorption in patients with recurrent renal calculi

Recurrent calcium-containing renal calculi are a common and poorly understood problem. Thiazide diuretics decrease urinary calcium excretion but their effect on other parameters of calcium metabolism is not established. The purpose of this study was to determine the effect of chronic administration of thiazide diuretics on intestinal calcium absorption, skeletal calcium turnover, and urinary calcium excretion, and to use this information to attempt to clarify the pathogenesis of idiopathic hypercalciuria. Forty-one patients with recurrent calcium-containing renal calculi were studied; 73% had hypercalciuria, 44% had increased intestinal absorption, and 7% had increased bone turnover. Thiazide diuretics given to 22 patients for 3–16 mo resulted in a consistent reduction in urinary calcium excretion, while calcium absorption was unchanged (< 6%) in 12 patients and significantly decreased (by 20%) in ten patients. Decreased intestinal absorption appeared to be a secondary effect of thiazides, presumably due to reduced urinary calcium losses. Bone turnover was significantly decreased by thiazides in each case in which it had been elevated and was unchanged in patients with initially normal values. These results indicate that increased bone turnover is probably not the primary defect in idiopathic hypercalciuria. The effects of long-term thiazide diuretic therapy on intestinal calcium absorption suggest that there may be two different subpopulations of patients with hypercalciuria, one with primary intestinal hyperabsorption which persists despite correction of urinary losses, and one with primary renal loss of calcium.

Long-term thiazide therapy in essential hypertension. Evidence for persistent alteration in plasma volume and renin activity.

Plasma volume (RIHSA) and peripheral plasma renin activity (Pickens' method) were measured in eight essential hypertensive patients treated with thiazide diuretics alone for periods ranging from 6 to 24 months. Treatment was then stopped and measurements repeated at weekly intervals for a month. During the first week of discontinuance, body weight and plasma volume rose in all ( P &lt; 0.001 for both), while peripheral plasma renin activity fell from 3.66 to 1.04 ng/ml ( P &lt; 0.005), and serum sodium concentration was practically unchanged. Over the next 3 weeks, both plasma volume and body weight gradually fell from the high first week "rebound" values to plateau at levels higher than those obtained during treatment (2741 vs. 2567 ml, P &lt; 0.001 and 76.1 vs. 74.7 kg, P &lt; 0.001, respectively). At the same time, peripheral plasma renin activity remained stable and markedly lower than during treatment ( P &lt; 0.001), while blood pressure gradually rose. Extracellular water (ECW) was measured serially (radiobromine) in five patients; in all, body weight variations were completely accounted for by changes in ECW, and ratio of plasma to interstitial fluid volume remained stable. These data indicate that blood pressure reduction by longterm thiazide therapy was associated with persistent plasma volume contraction and occurred despite increased peripheral renin activity. There was no evidence for chronic intracellular dehydration, and variations in peripheral renin activity were related to changes in plasma volume and not to serum sodium concentration.

Effects of treatment in hypertension results of a controlled study

Morbidity, mortality, and target organ function have been followed in a double-blind study of a predominantly Negro clinic population with mild to moderately severe hypertension over a 2-year period. Patients were placed randomly on either hypotensive drug therapy (reserpine, thiazide, guanethedine) or matched placebos. There were 6 treatment failures among 45 patients in the treatment group and 19 failures among 42 patients in the placebo group. All but one of the failures in the placebo group improved or cleared upon early institution of appropriate hypertensive and supportive therapy. Abnormalities in carbohydrate metabolism and serum uric acid levels were found in patients receiving long-term thiazide therapy. Hypertensive disease in the Negro population of Baltimore is a serious, life-threatening condition. Our study provides evidence of the need for continuous close supervision, and the provision of organized teams devoted to the care, of such a population.