Attenuation of hypotensive effect of propranolol and thiazide diuretics by indomethacin.

The effects of 100 mg indomethacin daily for three weeks on blood pressure and urinary excretion of prostaglandin F2 alpha were studied in a double-blind, placebo-controlled comparison of two groups of patients with essential hypertension, eight receiving propranolol and seven thiazide diuretics. Compared with placebo, adding indomethacin to the patients'' established antihypertensive treatment increased blood pressure by 14/5 Hg supine and 16/9 mm Hg erect in the patients receiving propranolol, and by 13/9 mm Hg supine and 16/9 mm Hg erect in the patients receiving thiazide diuretics (all p less than or equal to 0.05). The excretion of the major urinary metabolite of prostaglandin F2 alpha was reduced by 67% in the propranolol-treated patients and by 57% in those receiving a thiazide diuretic. Body weight increased by 0 . 8 kg (propranolol) and 1 . 1 kg (thiazide diuretic) when indomethacin was given, but there were no significant changes in creatinine clearance, urinary sodium excretion, or packed cell volume in either treatment group. These results suggest that products formed by the arachidonic acid cyclo-oxygenase contribute to the regulation of blood pressure during treatment with both propranolol and thiazide diuretics. Inhibition of the cyclo-oxygenase with indomethacin partially antagonises the hypotensive effect of these drugs.     

Approach to drug therapy for hypertension.

Prevention of complications of hypertension requires the lowering of blood pressure. The therapeutic goal is to achieve and maintain a diastolic pressure of less than 90 mm Hg with minimal adverse effects. The treatment of patients with established diastolic blood pressures between 90 and 104 mm Hg (determined from three separate readings) should be individualized; general measures such as weight loss and salt restriction should be tried first as an alternative to drug therapy. Patients with diastolic pressure in excess of 104 mm Hg should be treated with antihypertensive drugs; the first step should be the use of a thiazide diuretic in addition to general measures. Patients with diastolic pressures of 90 to 115 mm Hg may require the addition of a beta-adrenergic-receptor antagonist, methyldopa or clonidine if the therapeutic goal is not achieved; rarely they require the further addition of hydralazine or prazosin. Patients with diastolic pressures of 116 to 129 mm Hg usually require initially both a thiazide diuretic and a beta-blocker, methyldopa or clonidine; if the therapeutic goal is not achieved, hydralazine or prazosin is added, and if a further hypotensive effect is required guanethidine can be added. Patients with severe hypertension (diastolic pressures greater than 130 mm Hg) may require urgent treatment with combinations of drugs of all three levels. Emphasis should be placed on individualized therapy and patient compliance in the assessment of therapeutic failures. These "step-care" guidlines represent a framework for antihypertensive therapy devised from information available in 1977. It is not a rigid scheme and should be adjusted to the individual patient to ensure as normal a life as possible.     

Comparison of thiazides and amiloride in treatment of moderate hypertension.

The biochemical disturbance produced by thiazide diuretics and by amiloride during treatment of moderate hypertension were compared. Two parallel studies were initiated. In one 40 patients with newly diagnosed hypertension were treated with metoprolol and a diuretic, either hydrochlorothiazide or amiloride. In a second study 38 patients receiving longstanding treatment with hypotensives and thiazides either continued the treatment or replaced the thiazide with amiloride. Initial biochemical assessments were compared with those after two years in the study. In previously untreated patients, thiazide produced a significant fall in plasma potassium and hyperuricaemia that did not occur with amiloride (p less than 0.001). Those patients receiving long term treatment for their hypertension who continued to take thiazides had persistent hypokalaemia and hyperuricaemia. Substitution with amiloride corrected the hypokalaemia and serum uric acid returned toward normal ranges, but this change was not statistically significant. Patients receiving long term treatment also had impaired glucose tolerance, this remained unchanged in those receiving thiazide but was corrected in those receiving amiloride. Compared with amiloride thiazides produced undesirable but reversible biochemical changes. As control of hypertension was equally effective with both preparations, we suggest that a combination of amiloride with a beta blocker in treatment of moderate hypertension in preferred.     

Randomised study of six beta-blockers and a thiazide diuretic in essential hypertension

Atenolol was compared with five other beta-blockers and a thiazide diuretic in a randomised cross-over trial of once-daily treatment of essential hypertension. Atenolol was significantly better at reducing resting and exercise blood pressures at 24 hours than any of the other drugs and had a low incidence of side effects. Both timolol and acebutolol had a significant hypotensive effect at 24 hours and a low incidence of side effects, suggesting that further increases in dosage might be effective and well tolerated. Labetalol proved ineffective when given once daily, and the high incidence of side effects, equalled only by pindolol, would probably prohibit further increases in dosage. Bendrofluazide was equal or superior to all the beta-blockers except atenolol at reducing resting blood pressure, and its cheapness still makes it an agent of first choice in mild or moderate essential hypertension.     

Effect of thiazide on rates of bone mineral loss: a longitudinal study.

OBJECTIVE--To determine the effect of thiazide diuretic drugs on rates of bone mineral loss. DESIGN--Longitudinal, observational study with a mean follow up of five years. SETTING--Hawaii Osteoporosis Center, Honolulu. SUBJECTS--1017 Japanese-American men born between 1900 and 1920, of whom 378 were treated for hypertension (study group) and 639 did not have hypertension (control group). INTERVENTION--Thiazide diuretics were taken by 325 men for a mean of 11.9 years; 53 men took antihypertensive drugs other than thiazides. MAIN OUTCOME MEASURE--Rate of bone loss estimated from serial photon absorptiometric scanning at three skeletal sites (calcaneus, distal radius, and proximal radius). RESULTS--Rates of bone loss at all three sites were significantly reduced among thiazide users when compared with controls. The reductions in loss rate ranged from 28.8% (p = 0.02) (distal radius) to 49.2% (p = 0.0005) (calcaneus) relative to the controls. At all three sites the men taking other antihypertensive drugs had faster loss rates (22.6-43.1%) than those of the controls but the difference was significant only for the distal radius. CONCLUSION--Thiazide diuretics slow the rate of bone loss in elderly men.     

Comparison of thiazide‐like diuretics versus thiazide‐type diuretics: a meta‐analysis

Thiazide diuretics are widely used for the management of hypertension. In recent years, it has been actively debated that there is interchangeability of thiazide‐type diuretics hydrochlorothiazide and thiazide‐like diuretics including indapamide and chlorthalidone for the treatment of hypertension. With the purpose of seeking out the best thiazide diuretic for clinicians, we summarized the existing evidence on the two types of drugs and conducted a meta‐analysis on their efficacy in lowering blood pressure and effects on blood electrolyte, glucose and total cholesterol. Twelve trials were identified: five based on the comparison of indapamide versus hydrochlorothiazide and seven based on the chlorthalidone versus hydrochlorothiazide. In the meta‐analysis of blood pressure reduction, thiazide‐like diuretics seemed to further reduce systolic BP ([95% CI]; ?5.59 [?5.69, ?5.49]; P < 0.001) and diastolic BP ([95% CI]; ?1.98 [?3.29, ?0.66]; P = 0.003). Meanwhile, in the analysis of side effects, the incidence of hypokalemia ([95% CI]; 1.58 [0.80, 3.12]; P = 0.19), hyponatremia ([95% CI]; ?0.14 [?0.57, 0.30], P = 0.54), change of blood glucose ([95% CI];0.13 [?0.16, 0.41], P = 0.39) and total cholesterol ([95% CI]; 0.13 [?0.16, 0.41], P = 0.39) showed that there is no statistical significant differences between the two groups of drugs. In conclusion, using thiazide‐like diuretics is superior to thiazide‐type diuretics in reducing blood pressure without increasing the incidence of hypokalemia, hyponatraemia and any change of blood glucose and serum total cholesterol.     

Minoxidil for severe hypertension after failure of other hypotensive drugs.

Forty-four patients with severe hypertension who were resistant to treatment with more conventional hypotensive drugs or could not tolerate the side effects were treated with minoxidil, a potent peripheral vasodilator. A beta-blocking drug and a diuretic were used routinely to control, respectively, the tachycardia and fluid retention caused by minoxidil. During treatment the outpatient supine blood pressure fell from a mean of 221/134 mm Hg to 162/98 mm Hg. Eleven patients required additional or alternative hypotensive agents before blood pressure was adequately controlled. Side effects were minor, although the invariable hirsuties caused by minoxidil was unacceptable to three women. The possibility of cardiotoxic effects, raised by early studies in dogs, has not been excluded, and therefore this drug should be used only in patients with severe hypertension. In such patients minoxidil appears to be most effective.     

Newer Drugs in the Treatment of Hypertension

The treatment of essential hypertension still consists of the judicious combination of two or more agents. The chemical nature, pharmacology, side effects and relative merits of two groups of drugs are reviewed: (1) agents interfering with the synthesis, storage and release of endogenous catecholamines and (2) oral diuretic agents. Rauwolfia compounds, bretylium tosylate, guanethidine, alpha-methyldopa and pargyline hydrochloride comprise the first group; thiazide derivatives, phthalimidine compounds and spironolactones constitute the second. Guanethidine is the most potent and most extensively used agent in the second group. While not yet fully assessed, alpha-methyldopa and pargyline hydrochloride are useful in selected cases. The intrinsic hypotensive properties of oral diuretics, their low incidence of side effects and their ability to potentiate the more potent agents make them useful adjuncts in the long-term treatment of hypertension. Attention is drawn to the potential diabetogenic and hyperuricemic effects of the thiazides and phthalimidine compounds.     

New drugs in hypertension.

Clonidine, propranolol, bethanidine and debrisoquine effectively decrease blood pressure by suppressing renin secretion or interfering with function of the sympathetic nervous system. In man these compounds exert an antihypertensive effect within several hours or days and their duration of action is sufficient to permit administration twice or thrice daily. Clonidine and propranolol are especially useful if sexual dysfunction or postural hypotension is undesirable. Although bethanidine and debrisoquine may produce these adverse effects, they are beneficial in severe hypertension and produce fewer side effects than guanethidine. Clonidine frequently causes sedation, and rebound hypertension may occur with sudden cessation of therapy. Injudicious use of propranolol may provoke heart failure or asthma in susceptible individuals. The combination of a thiazide diuretic with propranolol and one of hydralazine, bethanidine and debrisoquine may be used to treat severe or complicated hypertension.     

Lack of effect of beta-blocker on flat dose response to thiazide in hypertension: efficacy of low dose thiazide combined with beta-blocker.

Increasing the dose of a thiazide diuretic used alone in patients with essential hypertension has little further effect on blood pressure but increases the deleterious metabolic consequences of the diuretic. The effect of a beta-blocker on this flat dose response is not known. In two randomised crossover studies the effect of 12.5 mg, 25 mg, and 50 mg hydrochlorothiazide combined with 400 mg acebutolol was assessed. The mean fall in supine blood pressure was about 15% and was the same whatever dose of thiazide was used with the beta-blocker. As the dose of hydrochlorothiazide was increased, however, there was evidence of increasing metabolic consequences of the diuretic. The study did not define the minimum dose of diuretic, and doses of hydrochlorothiazide lower than 12.5 mg might be as effective. These results suggest that many patients who are being treated with a combination of a beta-blocker and a diuretic are receiving unnecessarily large amounts of the diuretic without benefit to their blood pressure and with adverse metabolic consequences.     

Comparison of natriuretic,uricosuric, and antihypertensive properties of tienilic acid,bendrofluazide, and spironolactone.

The antihypertensive properties of the new diuretic tienilic acid were investigated. Thirteen previously untreated hypertensive patients took part in a double-blind crossover study in which 30 days'' treatment with tienilic acid 250 mg, bendrofluazide 5 mg, and spironolactone 100 mg were compared. Bendrofluazide caused the greatest natriuresis on the first treatment day and the most rapid fall in blood pressure. The ultimate antihypertensive effect of all three drugs was similar. Tienilic acid caused a noticeable reduction in serum urate concentrations and a rise in urate clearance, in contrast to the other two agents, which caused slight urate retention. Tienilic acid and bendrofluazide caused falls and spironolactone a rise in plasma potassium concentrations. No untoward effects were seen from any of the drugs. It is concluded that tienilic acid is a moderately potent diuretic that lowers plasma urate concentrations. It may be the drug of first choice for hypertensive patients who already have gout or are likely to develop it when taking thiazide diuretics.     

Factors Affecting Blood Pressure Variability: Lessons Learned from Two Systematic Reviews of Randomized Controlled Trials

Systematic reviews can often reveal much more than the original objective of the work. The objectives of this retrospective analysis were to answer three basic questions about blood pressure variability: 1) Does blood pressure entry criterion have an effect on baseline blood pressure variability? 2) Do thiazide diuretics have a significant effect on blood pressure variability? and 3) Does systolic blood pressure vary to the same degree as diastolic blood pressure? This analysis of blood pressure variability is based on resting standardized research setting BP readings from two systematic reviews evaluating blood pressure lowering efficacy of thiazide diuretics from double blind randomized controlled trials in 33,611 patients with primary hypertension. The standard deviation reported in trials was the focus of the research and the unit of analysis. When a threshold systolic or diastolic blood pressure value is used to determine entry into a trial, baseline variability is significantly decreased, systolic from 14.0 to 9.3 mmHg and diastolic from 8.4 to 5.3 mmHg. Thiazides do not change BP variability as the standard deviation and coefficient of variation of systolic blood pressure and diastolic blood pressure did not differ between thiazide and placebo groups at end of treatment. The coefficient of variation of systolic blood pressure was significantly greater than the coefficient of variation of diastolic blood pressure. Entry criterion decreases the baseline blood pressure variability. Treatment with a thiazide diuretic does not affect blood pressure variability. Systolic blood pressure varies to a greater degree than diastolic blood pressure.     

Debate: does it matter how you lower blood pressure?

The evidence base for drug treatment of hypertension is strong. Early trials using thiazide diuretics suggested a shortfall in prevention of coronary heart disease. The superiority of newer drugs has been widely advocated but trial evidence does not support an advantage of beta-blockers, angiotensin converting enzyme inhibitors, calcium channel blockers or alpha-blockers for this outcome. Even meta-analyses have failed to clarify matters. If this issue is to be settled, bigger and better trials of longer duration in high-risk patients are needed. Meanwhile, the importance of rigorous blood pressure control using multiple drugs has been established. This should be the focus of our attention rather than agonising over differences in cause-specific outcomes that may not be generalisable to all patient populations.     

Contemporary practice patterns in the management of newly diagnosed hypertension

OBJECTIVE: To determine what proportion of patients with hypertension are managed in accordance with guidelines established by the Canadian Hypertension Society. DESIGN: Retrospective medical record review. SETTING: Outpatients seen in primary care offices and internal medicine referral clinics in Edmonton. PATIENTS: All 969 adults who presented with a new diagnosis of essential hypertension from Sept. 1, 1993, to Dec. 31, 1995. OUTCOME MEASURES: Initial laboratory tests performed, advice concerning nonpharmacologic treatment given, antihypertensive drugs prescribed and any contraindications to thiazide diuretics or beta-adrenergic blocking agents documented. RESULTS: The mean age of the 969 patients in the sample was 52.5 years; 129 (13%) of the patients were older than 70 years of age; and 500 (52%) were women. Most of the patients (704, 73%) had mild or moderate diastolic hypertension. In the 617 patients who underwent laboratory tests related to hypertension, the creatinine level was determined in 466 (76%), the cholesterol level in 372 (60%), a urinalysis was conducted in 378 (61%), the serum potassium level was checked in 343 (56%), the sodium level in 323 (52%) and an electrocardiogram was performed in 303 (49%). Liver function tests, which are not recommended in the guidelines, were performed in 338 patients (55%). Although there were differences in prescribing among physicians in the 711 patients given first-line therapy, most (238, 34%) were prescribed angiotensin-converting-enzyme (ACE) inhibitors. Lifestyle modification, without drug therapy, was suggested for 180 (25%) of the patients. Although the guidelines recommend their use for first-line drug therapy, only 82 patients (12%) were given beta-adrenergic blocking agents and only 75 (11%) were given thiazide diuretics. Of the patients who were prescribed an antihypertensive other than a thiazide or beta-adrenergic blocking agent as first-line drug therapy, only 161 (43%) had a documented contraindication to thiazides or beta-adrenergic blocking agents. CONCLUSIONS: There is variation in the contemporary care of patients with hypertension. Further studies are required to determine the reasons underlying physicians'' noncompliance with the evidence-based guidelines established by the Canadian Hypertension Society.     

The Prevalence and Prognosis of Resistant Hypertension in Patients with Heart Failure

Background

Resistant hypertension is associated with adverse clinical outcome in hypertensive patients. However, the prognostic significance of resistant hypertension in patients with heart failure remains uncertain.

Methods and Results

The 1 year survival and heart failure re-hospitalization rate of 1288 consecutive patients admitted to a university hospital for either newly diagnosed heart failure or an exacerbation of prior chronic heart failure was analyzed. Resistant hypertension was defined as uncontrolled blood pressure (>140/90 mmHg) despite being compliant with an antihypertensive regimen that includes 3 or more drugs (including a diuretic). A total of 176 (13.7%) heart failure patients had resistant hypertension. There was no difference in all cause mortality, cardiovascular mortality, and heart failure related re-hospitalization between patients with versus without resistant hypertension. Diabetes [hazard ratio = 1.62, 95% confidence interval = 1.13–2.34; P = 0.010] and serum sodium >139 mmol/L (hazard ratio = 1.54, 95% confidence interval = 1.06–2.23; P = 0.024) were independently associated with resistant hypertension. Patients with resistant hypertension had a relatively higher survival rate (86.9% vs. 83.8%), although the difference was not significant (log-rank x² = 1.00, P = 0.317). In patients with reduced ejection fraction, heart failure related re-hospitalization was significantly lower in patients with resistant hypertension (45.8% vs. 59.1%, P = 0.050).

Conclusions

Resistant hypertension appears to be not associated with adverse clinical outcome in patients with heart failure, in fact may be a protective factor for reduced heart failure related re-hospitalization in patients with reduced ejection fraction.     

Role of the renal kallikrein-kinin system in the development of salt-sensitive hypertension

The role of the renal kallikrein-kinin system in the development of salt-sensitive hypertension was studied using mutant kininogen-deficient Brown-Norway Katholiek (BN-Ka) rats, which generate no kinin in their urine, and other hypertensive rat models. It was found that ingestion of a low sodium diet or infusion of NaCl in doses slightly above 0.15 M caused hypertension and sodium accumulation in erythrocytes and the cerebrospinal fluid of kininogen-deficient BN-Ka rats. Development of hypertension in the deoxycorticosterone-acetate-salt model was completely prevented by administration of a newly discovered inhibitor, ebelactone B, of carboxypeptidase Y-like exopeptidase (an urinary kininase). The urinary kallikrein excretion of spontaneously hypertensive rats was lower than that of Wistar Kyoto rats at 4 weeks of age and did not increase by administration of furosemide, a diuretic agent, although approximately 50% of the diuretic action of this agent was dependent upon the renal kallikrein-kinin system in normal rats. In conclusion, the renal kallikrein-kinin system works as a safety valve for excess sodium intake.     

Mild hypertension: a clinical trial conducted in hospital general practice.

To compare findings in a hospital trial of hypotensive drugs with those in a general practice trial several patients with mild hypertension were studied at the same time in hospital and in general practice. They received bendrofluazide and potassium chloride or bendrofluazide, potassium chloride, and reserpine according to a double-blind crossover protocol, and blood biochemical values were studied over eight weeks and six months. When reserpine was withdrawn from nine women they followed a modified protocol comparing bendrofluazide and potassium chloride with potassium chloride alone. The blood pressure values measured by the general practitioners were similar to those measured in hospital. Both the diuretic alone and the diuretic with reserpine produced significant falls in blood pressures. Although plasma renin activity increased on diuretic treatment, continued treatment did not produce a further increase, and levels gradually declined towards normal.     

Effects of a beta-adrenolytic and a diuretic vis-à-vis hyper-reninemia induced by isoprenaline in anesthetized dogs. Value of beta blocking-diuretic interaction]

Intravenous injection of isoproterenol increases plasma renin activity (PRA) in anesthetized dogs. S. 464, a new beta adrenergic blocking agent, injected five minutes before isoproterenol, inhibits plasma renin hyperactivity. On the other hand, teclothiazide, a thiazide diuretic, induces no significant modification of the isoproterenol-induced increase of PRA. The combination of both compounds (five parts of S. 464, one part of diuretic), assumes the same inhibitory effects as S. 464 alone. These results and other experimental data (antihypertensive and diuretic activities) are discussed and explain the interest of such an association as a rational therapy of arterial hypertensive disorders.     

The effect of fat intake and antihypertensive drug therapy on serum lipid profile: a cross-sectional survey of serum lipids in male and female hypertensives

The present study aimed to investigate the effect of betablocker with diuretics therapy on serum cholesterol and high density lipoprotein (HDL-C) lipids in cross-sectional data (age, sex, weight, and body mass index (BMI), smoking/alcoholic consumption) and supplemented vegetarian low-fat diet with daily low fat energy intake, salt intake, duration of drug therapy, and serum protein as effective measures of lowering blood pressure among hypertensives in both males and females. Hypertensive patients on betablocker and/or thiazide therapy were compared in cross-section study with their age, blood pressure, fat intake, serum lipid profile, BMI, and serum albumin in males and females. Dietary fat intake and serum lipid profile were income related. Betablocker and diuretics therapy in combination with dietary fat intervention was beneficial for prolonged dyslipidemia control. Serum cholesterol level was main contributing factor dependent on BMI, duration of drug, and socio-economic factors. Fat intake contributed in hypertension and serum cholesterol levels. A cross-sectional data analysis showed beneficial effects of “low fat-salt-smoking-alcohol consumption and combined polyunsaturated fatty acid with antihypertensive therapy approach” to keep normal dyslipidemia and hypertension. Low fat intake, low salt, smoking, alcohol consumption, and combination of dietary oil supplements with lipid betablockers and diuretic modulators were associated with low hypertension and controlled dyslipidemia in Asian sedentary population.     

Ventricular extrasystoles during thiazide treatment: substudy of MRC mild hypertension trial.

One short term and one long term study of the relation between ventricular extrasystoles and thiazide treatment were carried out during the Medical Research Council''s mild hypertension trial. In the short term study 110 patients were randomly assigned to one of three treatment groups, bendrofluazide with or without potassium supplements, or placebo. They were studied before starting treatment and nine to 10 weeks later while still taking their randomly assigned drugs. No significant increase in the number of ventricular extrasystoles was associated with short term thiazide treatment, although serum potassium concentrations changed as expected. In the long term study 214 patients who had completed an average of two years'' treatment with randomly assigned bendrofluazide or a placebo were studied while continuing to take their trial tablets; the 214 included 20 people who had been randomised at entry to the bendrofluazide group and who had a subsequent history of hypokalaemia. These 20 patients were studied before and after being further randomised to two groups, one continuing treatment without change and one continuing with bendrofluazide and also taking potassium supplements. Counts of ventricular extrasystoles were significantly higher (p = 0.025) in those receiving long term thiazide treatment than in their controls; however, there was no significant association between the number of ventricular extrasystoles and serum potassium concentrations in this group, although the correlation between number of extrasystoles and serum urate concentrations was significant (p = 0.035). Pooled data for both studies showed a highly significant correlation between number of ventricular extrasystoles, and serum potassium concentrations (r = -0.185; p = 0.003), but the correlation with serum urate concentrations was of similar strength (r = 0.178; p = 0.004). These biochemical changes may be acting merely as markers of thiazide intake, and the explanation of the association between thiazide treatment and ventricular extrasystolic activity therefore remains uncertain.