Thiazide Diuretic Therapy Research Articles

Évolution de la densité minérale osseuse chez des hommes ostéoporotiques et hypercalciuriques traités par diurétiques thiazidiques

A few studies suggest that thiazide diuretic agents may have modest beneficial effects on bone. Few data are available on the effects of these medications in patients with osteoporosis and hypercalciuria. Objective. – To evaluate the effects of thiazide diuretic therapy on bone mass and urinary calcium excretion in hypercalciuretic osteoporotic male patients. Patients and methods. – Osteoporosis was defined as a greater than 2.5 standard-deviation decrease in bone mineral density (BMD) at the lumbar spine or hip (T score) We used an open-label prospective design to compare 14 patients with hypercalciuretic osteoporosis treated with a thiazide diuretic for 18 months and 13 patients with primary osteoporosis treated with calcium and vitamin D supplementation. Mean age was 53.5 ± 9.6 years in the thiazide group and 48.7 ± 8.4 years in the calcium–vitamin D supplementation group. The following serum parameters were assayed at baseline: 25 OH-D3, 1,25 OH-D3, parathyroid hormone (PTH), and bone turnover markers. Urinary calcium excretion and BMD by dual-energy X-ray absorptiometry at the spine and hip were determined at baseline and after 18 months of treatment. Results. – Annual BMD increases were similar in the two groups during the 18-month treatment period: lumbar spine, 0.6% ± 2.5% ( P = 0.47) in the thiazide group and 0.004% ± 3% ( P = 0.78) in the supplementation group; femoral neck, 0.47% ± 2.6% ( P = 0.89) and 1.1% ± 3.2% ( P = 0.22); total hip, 0.65% ± 2.5% ( P = 0.37) and 0.12% ± 2.1% ( P = 0.51). Urinary calcium excretion fell by 45.9% in the thiazide group from baseline to study completion ( P = 0.0015). Conclusion. – We found no evidence that thiazide therapy increased bone mass in patients with hypercalciuria and osteoporosis as compared to calcium–vitamin D supplementation in patients with osteoporosis but no hypercalciuria. In contrast, our results establish the efficacy of thiazide diuretics in reducing urinary calcium excretion, an effect that may decrease the risk of urinary lithiasis. Studies in larger patient cohorts treated for longer periods are needed to confirm or refute our findings.

Bone mineral density changes in hypercalciuretic osteoporotic men treated with thiazide diuretics

A few studies suggest that thiazide diuretic agents may have modest beneficial effects on bone. Few data are available on the effects of these medications in patients with osteoporosis and hypercalciuria. Objective. – To evaluate the effects of thiazide diuretic therapy on bone mass and urinary calcium excretion in hypercalciuretic osteoporotic male patients. Patients and methods. – Osteoporosis was defined as a greater than 2.5 standard deviation (S.D.) decrease in bone mineral density (BMD) at the lumbar spine or hip ( T-score). We used an open-label prospective design to compare 14 patients with hypercalciuretic osteoporosis treated with a thiazide diuretic for 18 months and 13 patients with primary osteoporosis treated with calcium and vitamin D supplementation. Mean age was 53.5 ± 9.6 years in the thiazide group and 48.7 ± 8.4 years in the calcium–vitamin D supplementation group. The following serum parameters were assayed at baseline: 25OH-D3, 1,25OH-D3, parathyroid hormone (PTH), and bone turnover markers. Urinary calcium excretion and BMD by dual-energy X-ray absorptiometry at the spine and hip were determined at baseline and after 18 months of treatment. Results. – Annual BMD increases were similar in the two groups during the 18-month treatment period: lumbar spine, 0.6 ± 2.5% ( P = 0.47) in the thiazide group and 0.004 ± 3% ( P = 0.78) in the supplementation group; femoral neck, 0.47 ± 2.6% ( P = 0.89) and 1.1 ± 3.2% ( P = 0.22); total hip, 0.65 ± 2.5% ( P = 0.37) and 0.12 ± 2.1% ( P = 0.51). Urinary calcium excretion fell by 45.9% in the thiazide group from baseline to study completion ( P = 0.0015). Conclusion. – We found no evidence that thiazide therapy increased bone mass in patients with hypercalciuria and osteoporosis as compared to calcium–vitamin D supplementation in patients with osteoporosis but no hypercalciuria. In contrast, our results establish the efficacy of thiazide diuretics in reducing urinary calcium excretion, an effect that may decrease the risk of urinary lithiasis. Studies in larger patient cohorts treated for longer periods are needed to confirm or refute our findings.

Combining renin-angiotensin-aldosterone system blockade with diuretic therapy for treatment of hypertension.

The rationale for using angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARBs) in combination with thiazide diuretic therapy has centred formerly around antihypertensive synergy and counter-balancing adverse metabolic effects, particularly on potassium homeostasis. However, two recent landmark clinical trials that included high-risk hypertensive patients have now provided an evidence base for this form of combination therapy by demonstrating the efficacy of perindopril/indapamide and losartan/ hydrochlorothiazide in reducing vascular morbidity and mortality, a proportion of the benefit being unaccounted for by blood pressure reduction alone. Several unresolved issues remain concerning class effects versus specific drug effects, optimal dosing, potential differences in efficacy between ACE-I and ARBs, whether elderly mild hypertensives benefit from this form of combination therapy, and the possibility that the optimal regimen may be a triple combination of ACE-I, ARB and thiazide diuretic. These issues will be resolved by ongoing and future major endpoint trials in hypertension.

Antihypertensive Pharmacogenetics: Effects of Angiotensin-Converting-Enzyme (ACE) Genotype-By-Gender Interaction on Blood Pressure (BP) Responses to a Thiazide Diuretic in Essential Hypertension (EHT)

41 Previous studies suggest that genetic factors influence the BP response to changes in Na + balance by altering activity of the renin-angiotensin system. The insertion/deletion (I/D) polymorphism of the ACE gene is known to be associated with variation in plasma ACE activity and may influence BP in a gender-specific manner. To assess effects of the ACE genotype and gender on BP responses to diuretic therapy, we measured the I/D polymorphism in community-based samples of 197 Blacks (133 women, 64 men) and 187 Whites (77 women, 110 men) with EHT (mean age= 48±7 years), who underwent monotherapy with hydrochlorothiazide (HCTZ) for 4 weeks. Consistent with other studies, the D-allele was associated with significant codominant increases in plasma ACE activity in all race-gender groups. Univariate predictors of greater declines in both systolic BP (SBP) and diastolic BP (DBP) were higher pretreatment BP ( P <0.001), Black race ( P ≤0.005), female gender ( P <0.001), older age ( P ≤0.064), and lower waist/hip ratio ( P ≤0.087). In linear models that considered the effects of all predictors, there was significant interaction between the effects of ACE genotype and gender on the responses of both SBP ( P ≤0.004) and DBP ( P <0.001) to HCTZ. Among women of both races, mean declines in SBP ( P ≤0.012) and DBP ( P ≤0.025) were greater in II than in DD homozygotes. In contrast, among men of both races mean declines in SBP ( P ≤0.164) and DBP ( P ≤0.007) were greater in DD than in II homozygotes. In both genders, BP declines were intermediate in heterozygotes. Thus, although the effects of ACE genotype on plasma ACE activity are independent of gender, the effects of ACE genotype on BP responses to thiazide diuretic therapy appear to be gender-specific.

Antihypertensive Pharmacogenetics: Effects of Angiotensin-Converting-Enzyme (ACE) Genotype-By-Gender Interaction on Blood Pressure (BP) Responses to a Thiazide Diuretic in Essential Hypertension (EHT)

41 Previous studies suggest that genetic factors influence the BP response to changes in Na + balance by altering activity of the renin-angiotensin system. The insertion/deletion (I/D) polymorphism of the ACE gene is known to be associated with variation in plasma ACE activity and may influence BP in a gender-specific manner. To assess effects of the ACE genotype and gender on BP responses to diuretic therapy, we measured the I/D polymorphism in community-based samples of 197 Blacks (133 women, 64 men) and 187 Whites (77 women, 110 men) with EHT (mean age= 48±7 years), who underwent monotherapy with hydrochlorothiazide (HCTZ) for 4 weeks. Consistent with other studies, the D-allele was associated with significant codominant increases in plasma ACE activity in all race-gender groups. Univariate predictors of greater declines in both systolic BP (SBP) and diastolic BP (DBP) were higher pretreatment BP ( P P ≤0.005), female gender ( P P ≤0.064), and lower waist/hip ratio ( P ≤0.087). In linear models that considered the effects of all predictors, there was significant interaction between the effects of ACE genotype and gender on the responses of both SBP ( P ≤0.004) and DBP ( P P ≤0.012) and DBP ( P ≤0.025) were greater in II than in DD homozygotes. In contrast, among men of both races mean declines in SBP ( P ≤0.164) and DBP ( P ≤0.007) were greater in DD than in II homozygotes. In both genders, BP declines were intermediate in heterozygotes. Thus, although the effects of ACE genotype on plasma ACE activity are independent of gender, the effects of ACE genotype on BP responses to thiazide diuretic therapy appear to be gender-specific.

Age- and gender-related use of low-dose drug therapy: the need to manufacture low-dose therapy and evaluate the minimum effective dose.

Low-dose drug therapy is promoted as a way to maximize benefit and minimize adverse drug effects when prescribing for older adults. This population-based study evaluates the age and sex-related use of two common therapies: thiazide diuretics, where evidence supports the use of low-dose therapy, and beta-blockers, where trials have not evaluated the minimum effective dose. Using linked administrative databases we identified all of the 120,613 persons dispensed a thiazide diuretic therapy and 12,908 myocardial infarction survivors dispensed beta-blocker therapy in Canada's largest province. We used logistic regression models to study the association of age and sex with dispensing of low-dose thiazide diuretic and beta-blocker therapy at doses lower than evaluated in trials. Of 120,613 older people dispensed a thiazide diuretic, 32,372 (26.8%) were dispensed a low dose. Patients 85 years of age or older, relative to the youngest group, were 30% more likely to be dispensed low-dose therapy (OR=1.31; 95% CI, 1.27 to 1.36; P < .001). Women were 8% more likely than men to be dispensed a low-dose thiazide diuretic (OR=1.08; 95% CI, 1.05 to 1.11; P < .001). Of 10,991 myocardial infarction survivors dispensed atenolol, metoprolol, propranolol, or timolol, 9458 (86.1%) were dispensed a lower-than-evaluated dose. Patients 85 years of age or older, relative to those in the youngest group, were more than twice as likely to be dispensed a lower-than-evaluated beta-blocker therapy dose (OR=2.28; 95% CI, 1.74 to 3.04; P < .001). No difference was noted in the use of beta-blocker therapy dose by sex (OR=1.0; 95% CI, .89 to 1.15; P = .95). Low-dose thiazide diuretic therapy prescribed widely to older people, particularly those of advanced age and women. The vast majority of myocardial infarction survivors were dispensed beta-blocker therapy at lower-than-evaluated doses. These findings highlight the need to manufacture low-dose thiazide diuretic therapy and to evaluate the minimum effective dose of beta-blocker therapy.

Thiazide diuretics and the initiation of anti-gout therapy

While physiologic and epidemiologic evidence link diuretic therapy with hyperuricemia, no previous study has quantified the risk for initiation of treatment specific for hyperuricemia or gout among elderly patients taking thiazide diuretics. We performed a retrospective cohort study of 9249 enrollees aged 65 or older in the New Jersey Medicaid program who were newly started on an antihypertensive medication from November 1981 through February 1989 and who had no prior use of anti-gout therapy (allopurinol, colchicine, or a uricosuric) during the preceding one-year period. We used Cox proportional hazards analysis to determine the risk for the initiation of anti-gout therapy in patients using various antihypertensive treatment regimens relative to no antihypertensive exposure. Patient follow-up extended for up to two years. Antihypertensive exposure was characterized over the entire period of follow-up according to the following categories: thiazide diuretic therapy alone; non-thiazide antihypertensive therapy; thiazide diuretic therapy in combination with any non-thiazide antihypertensive agent(s); and no antihypertensive use. Antihypertensive exposure was entered into the model as a time-varying covariate. Estimates of risk were adjusted for age, sex, race, nursing home residence, number of prescriptions filled, intensity of physician use, hospitalization history, and year of antihypertensive treatment initiation. The adjusted relative risk for the initiation of anti-gout therapy was 1.00 (95% CI, 0.65 – 1.53) for non-thiazide antihypertensive therapy alone, 1.99 (95% CI, 1.21 – 3.26) for thiazide diuretic therapy, and 2.29 (95% CI, 1.55 – 3.37) for thiazide diuretic therapy in combination with any non-thiazide agent(s). Risk for anti-gout therapy was significantly increased for thiazide doses of ≥25 mg/day (in hydrochlorothiazide equivalents); no significant increase in risk was seen for lower doses. We conclude that use of thiazide diuretics in doses of 25 mg/day or higher is associated with a significantly increased risk for initiation of anti-gout therapy. Such treatment may reflect the occurrence of clinical sequelae of diuretic-induced hyperuricemia or the inappropriate treatment of asymptomatic hyperuricemia.

Risk factors for non-insulin-dependent diabetes mellitus requiring treatment in the elderly.

To examine the relationship of possible modifiable risk factors, including obesity, physical activity level, alcohol consumption, blood pressure, and thiazide diuretic use with the development of non-insulin-dependent diabetes mellitus (NIDDM) requiring treatment among a large cohort of community-dwelling elderly. The East Boston Senior Health Project, one of four components of the National Institute on Aging-sponsored Established Populations for the Epidemiologic Study of the Elderly (EPESE). Residents of East Boston who were 65 years of age or older. We performed a prospective cohort study with follow-up over two consecutive 3-year time periods beginning in 1982-1983. The main outcome measure was the occurrence of NIDDM, defined as new treatment with a hypoglycemic agent. A total of 2737 study participants contributed 4682 3-year intervals for analysis. NIDDM requiring hypoglycemic therapy occurred in 185 participants over the duration of the study. High body mass index (> 26 kg/m2) (adjusted odds ratio 2.4, 95% confidence interval 1.3-4.4) and low physical activity level (adjusted odds ratio 1.5, 95% confidence interval 1.0-2.1) were significant predictors of NIDDM in a multiple logistic regression model adjusting for age, sex, blood pressure, and self-report of "high blood sugar" moderate alcohol consumption (0.5-<1 ounce per day) had an inverse relation to NIDDM of borderline significance (adjusted odds ratio 0.4, 95% confidence interval 0.2-1.0). Those receiving one or more non-thiazide antihypertensive agents had a higher risk of developing NIDDM in a model including age, sex, body mass index, various antihypertensive regimens, physical activity level, alcohol consumption, blood pressure, and self-report of "high blood sugar." Thiazide diuretic therapy alone or in combination with another antihypertensive was not associated with NIDDM. Our findings suggest a positive relationship of obesity and low physical activity level with the development of NIDDM requiring treatment in elderly persons. The inverse association of borderline significance between moderate alcohol use and NIDDM deserves further study. Thiazide diuretic therapy conferred no excess risk for developing NIDDM in this older population although selection factors in the choice of antihypertensive therapy may partially explain the absence of a thiazide effect.

Diuretic therapy for hypertension and the risk of primary cardiac arrest.

The results of trials of the primary prevention of coronary heart disease have suggested that treating hypertension with high doses of thiazide diuretic drugs might increase the risk of sudden death from cardiac causes. In contrast, treatment with low doses of thiazide reduces the risk of coronary heart disease. To examine the association between thiazide treatment for hypertension and the occurrence of primary cardiac arrest, we conducted a population-based case-control study among enrollees of a health maintenance organization. The case patients were 114 persons with hypertension who had a primary cardiac arrest from 1977 through 1990. The control patients were a stratified random sample of 535 persons with hypertension. The patients' treatment was assessed with the use of a computerized pharmacy data base. Records of their ambulatory care were reviewed to determine other clinical characteristics. The risk of primary cardiac arrest among patients receiving combined thiazide and potassium-sparing diuretic therapy was lower than that among patients treated with a thiazide without potassium-sparing therapy (odds ratio, 0.3; 95 percent confidence interval, 0.1 to 0.7). As compared with low-dose thiazide therapy (25 mg daily), moderate-dose therapy (50 mg daily) was associated with a moderate increase in risk (odds ratio, 1.7; 95 percent confidence interval, 0.7 to 4.5), and high-dose therapy (100 mg daily) was associated with a larger increase in risk (odds ratio, 3.6; 95 percent confidence interval, 1.2 to 10.8) (P value for trend, 0.02). The addition of a potassium-sparing drug to low-dose thiazide therapy was associated with a reduced risk of cardiac arrest (odds ratio, 0.4; 95 percent confidence interval, 0.1 to 1.5). Both the dose of thiazide drugs and the addition of potassium-sparing drugs influence the risk of primary cardiac arrest. These results may explain the differences in the effect of antihypertensive therapy on mortality from coronary heart disease in previous clinical trials.

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.

Potassium supplements and potassium-sparing diuretics. A review and guide to appropriate use.

Epidemiological and clinical studies suggest that low dietary potassium intake may have an important role in determining the development of diseases such as hypertension, and perhaps even stomach cancer, and that increased potassium intake may have beneficial effects in several other conditions. Dietary adjustment or active potassium supplementation has been suggested as a natural, less costly and safe method of increasing potassium levels, although active supplementation with tablets or solutions is not recommended in healthy people with normal serum potassium levels. However, increasing dietary potassium intake in the elderly and in patients with renal impairment must be considered with caution. Diuretics have a long established role in the management of hypertension and heart failure. There is no convincing evidence to suggest that the small reduction in plasma potassium levels associated with low dose thiazide and loop diuretic therapy needs to be routinely prevented by the use of potassium-sparing drugs. In non-digitalised patients little association has been found between mild diuretic-induced hypokalaemia and arrhythmias. Thus, the routine prophylactic use of potassium-sparing diuretics in combination with non-potassium-retaining diuretics for the treatment of hypertension and oedematous states is not justified. Based on current evidence, treating all patients whose serum potassium level decreases below 3 mmol/L is recommended, although for certain patients at particular risk of hypokalaemia, levels may need to be maintained above 3.5 mmol/L. In overt hypokalaemia, several therapeutic options are available to the clinician. These include increased consumption of potassium-rich foods, the use of salt substitutes, medicinal potassium supplementation or distal tubular (potassium-sparing) diuretics.

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.

Antihypertensive Drug Therapy and the Initiation of Treatment for Diabetes Mellitus

To quantify the risk for the occurrence of hyperglycemia requiring initiation of therapy among patients taking various antihypertensive regimens. Case-control study. New Jersey Medicaid program. The study included New Jersey Medicaid enrollees 35 years of age or older. The 11,855 case patients were newly started on a hypoglycemic agent (oral agent or insulin) between 1981 and 1990. The 11,855 controls were selected randomly from among other Medicaid enrollees. The frequency of initiation of hypoglycemic therapy was increased for users of virtually all antihypertensive agents relative to nonusers after adjustment for age, gender, race, nursing home residency, number of days hospitalized, total number of prescriptions, and selected medication exposures. The estimated relative risk for initiation of hypoglycemic therapy was 1.40 for patients receiving thiazide diuretics (95% CI, 1.26 to 1.58) and ranged from 1.56 to 1.77 for patients receiving other antihypertensive medications, depending on the medication category. A higher risk was associated with multiple-agent regimens, whether they excluded a thiazide diuretic (odds ratio, 1.76; CI, 1.49 to 2.07) or included one (odds ratio, 1.93; CI, 1.75 to 2.13). When the analysis was restricted to users of antihypertensive agents (n = 8005), the risk associated with other single-agent antihypertensive regimens was not significantly different from that associated with thiazide diuretics. However, patients receiving multiple-agent regimens continued to be at increased risk for hyperglycemia requiring hypoglycemic therapy relative to those who used thiazide diuretic therapy alone. The association between antihypertensive therapy and the initiation of treatment for diabetes mellitus is more closely related to the intensity of therapy than to the individual agent used. Our data do not support the hypothesis that thiazide diuretics are more strongly associated with the initiation of hypoglycemic therapy than are other antihypertensive agents.

Not everyone needs supplementation during thiazide diuretic therapy

Not everyone needs supplementation during thiazide diuretic therapy

CAPTOPRIL AND HYDROCHLOROTHIAZIDE—A SAFE ANTIHYPERTENSIVE FOR USE IN GENERAL PRACTICE?

The combination of captopril and hydrochlorthiazide was assessed in 15 hypertensive patients in a general practice setting. The first aim was to determine whether the fall in blood pressure, noted after the first dose of an ACE inhibitor given alone, became unacceptable when the drug was given with a diuretic. The second aim was to assess the impact of the ACE inhibitor on the biochemical abnormalities associated with thiazide diuretic therapy. The drug combination markedly reduced blood pressure but not below 110 systolic after the first dose. In the long-term the treatment significantly lowered blood pressure but did not produce any significant or clinically relevant changes in serum chemistry.

Relation of cardiovascular disease to potassium and magnesium deficiencies

Potassium and magnesium deficiencies, particularly those induced by conventional loop and thiazide diuretic therapy, have been linked in clinical studies to an increased frequency in serious arrhythmias and mortality in acute myocardial infarction. Magnesium repletion has been shown not only to increase magnesium levels, but also to increase muscle potassium and to decrease the frequency of ventricular ectopic beats. Potassium replenishment alone may have a detrimental effect in magnesium-depleted patients. The potassium-sparing diuretic spironolactone (Aldactone ®) has been shown to spare both potassium and magnesium, and may therefore be a more appropriate diuretic therapy in patients at cardiovascular risk.

Primary Prevention With Metoprolol in Patients With Hypertension

To the Editor.— The results of the Metoprolol Atherosclerosis Prevention in Hypertensives (MAPHY) Study, 1 showing lower mortality with metoprolol use compared with thiazide diuretic therapy, is concordant with many of our beliefs that thiazides are potentially harmful while β-blockers may be cardioprotective. The MAPHY Study, by Wikstrand et al, used neither a placebo group nor actuarial data. As such, three possibilities exist. β-Blockers may be mortality neutral while diuretics have increased mortality, β-blockers may be cardioprotective while diuretics are mortality neutral, or β-blockers are cardioprotective and diuretics have increased mortality. In a previous study by Morgan et al, 2 moderately hypertensive men were treated with either placebo, low-salt diet, high-dose thiazide, or β-blocker. When compared with actuarial data there were twice as many deaths than predicted in the diuretic-treated group and expected numbers of deaths in all other groups. In the study by Wikstrand et al it is clear

Diuretic-Associated Hypomagnesemia in the Elderly

Serum magnesium concentration was measured in 320 consecutive elderly patients (mean age, 81 years) receiving diuretic therapy at the time of hospital admission. When compared with serum concentrations of 250 elderly patients who were not taking diuretics at the time of hospital admission, only the group taking thiazide diuretics had a significantly reduced mean serum level. The 24-hour urine sampling from representative subgroups demonstrated impaired magnesium-conserving ability in hypomagnesemic subjects receiving loop and thiazide diuretic therapy. Patients taking therapy that included a potassium-sparing diuretic had no significant evidence of reduced magnesium-conserving ability. Dietary assessments of the study population revealed suboptimal magnesium intake in the diet.

Systemic systolic hypertension in the elderly: Correlation of hemodynamics, plasma volume, renin, aldosterone, urinary metanephrines and response to thiazide therapy

Twenty-four men, mean age 63 +/- 1.7 years, with systemic systolic hypertension were studied before and after 1 month of therapy with oral hydrochlorothiazide, 50 mg/day. The control mean plasma volume was 2,664 +/- 96 ml, cardiac index 3.9 +/- 0.2 liters/min/m2, stroke volume index 52 +/- 2 ml/beat/m2, systemic vascular resistance 1,351 +/- 80 dynes s cm-5, plasma aldosterone 8.6 +/- 1.0 ng/dl and 24-hour urinary excretion of metanephrines 0.371 +/- 0.044 mg. On renin-sodium profiling in 23 patients, 12 were classified into a normal group and 11 into a low-renin group; none had high renin values. Based on multiple regression analysis, the 24-hour urinary excretion of total metanephrines appeared to be the single most important factor explaining 28% of the variability in systolic blood pressure (BP). After therapy with oral hydrochlorothiazide, the elevated systolic BP decreased (p less than 0.0001) and diastolic BP decreased (p less than 0.005), with concomitant reduction in systemic vascular resistance (p less than 0.03). Patients in both the normal- and low-renin groups had normal plasma volume and responded similarly to thiazide diuretic therapy, without symptomatic side effects.

Selected mechanisms of diuretic-induced electrolyte changes

Thiazide diuretic therapy has been associated with several biochemical electrolyte imbalances including potassium loss. The onset, duration and magnitude of potassium excretion can influence decisions concerning drug therapy, particularly in hypertensive patients at risk if they develop diuretic-induced hypokalemia. The potassium depletion seen during the course of antihypertensive therapy with thiazides is brought about by 2 primary mechanisms: the increased delivery of sodium to the distal tubules for sodium-potassium exchange, and the development of secondary hyperaldosteronism, which causes resorption of sodium with a loss of potassium into the urine. The diuresis caused by thiazides is maximal between 8 and 12 hours. However, resultant volume contraction stimulates elevated serum aldosterone levels, which can be present for 24 hours or longer. Therefore, potassium loss may exceed the period of diuresis. Diuretics are effective antihypertensive therapy in many patients with mild hypertension. Potassium-sparing agents can offset potassium imbalance that often occurs with diuretics, and thus, these agents have become an important addition to the physician's treatment armamentarium for appropriate patients.