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.     

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.     

Hypokalaemia and diuretics: an analysis of publications.

Published data have been used to define the characteristics of the fall in serum potassium concentration after taking diuretics and the efficacy of the various treatments given to prevent or correct it. The average fall is less after the usual doses of frusemide (about 0.3 mmol/l) than after the usual doses of thiazides (about 0.6 mmol/l) and is little influenced by the dose or duration of treatment. The fall with a given drug is the same in heart failure and hypertension, but the initial serum potassium concentration is higher in heart failure, so that the final value is lower in hypertension. In standard doses potassium supplements are less effective than potassium-retaining diuretics in correcting the hypokalaemia. The relation between the average serum potassium value and the frequency of low values (hypokalaemia) is such that very low values after taking diuretics are unusual in patients with hypertension or heart failure. Hypokalaemia would almost disappear as an important complication of diuretic treatment if it was defined as a value less than 3.0 mmol/l rather than as a value less than 3.5 mmol/l.     

Can general practitioners use training in relaxation and management of stress to reduce mild hypertension?

To see whether general practitioners could effectively carry out training in relaxation and management of stress to reduce mild hypertension a study was carried out with a subsample of phase 2 of the Medical Research Council''s treatment of mild hypertension trial.¹ In the main mild hypertension trial patients had been receiving either an active drug or placebo for six years. In phase 2 a subsample of these patients were randomly allocated either to continue or to stop receiving the active drug or placebo. In a further subsample patients were again randomised to receive or not to receive relaxation therapy. This factorial design presented an additional opportunity to assess whether patients controlled with active drugs might have their blood pressure maintained by this behavioural therapy once drug treatment was stopped and to assess whether blood pressure might be further reduced by this therapy in patients who had been under regular medical supervision for as long as six years and who had already received non-pharmacological advice. The therapy was conducted by general practitioners in group sessions once a week for eight weeks. The training in relaxation was accompanied by galvanic skin resistance biofeedback. At one year follow up blood pressure in the relaxation subgroups was either maintained (in the group who had stopped receiving drugs) or reduced further (in the group who had continued receiving drugs and in both placebo groups), while in the control group it had increased in all the subgroups, but particularly in those who had stopped receiving drugs. Differences in changes in blood pressure between the relaxation and control groups were significant. There were five new cardiovascular events, including evidence of myocardial ischaemia in blindly coded electrocardiograms in the control group, compared with one in the treatment group.General practitioners, if motivated, can successfully apply this technique of training those with mild hypertension in relaxation and management of stress.     

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.     

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.     

Contribution of atenolol,bendrofluazide, and hydrallazine to management of severe hypertension.

The efficacy of various combinations of atenolol, bendrofluazide, and hydraliazine given twice daily was assessed in a double-blind trial on 39 patients with moderate to severe essential hypertension. Concurrent treatment with all three drugs proved most effective and produced a mean reduction in blood pressure of 43/31 mm Hg. In the dosage used, hydrallazine affected only the diastolic blood pressure, and when added to either bendrofluazide or bendrofluazide plus atenolol it produced a further mean reduction in pressure of 6 mm Hg. Once-daily treatment with atenolol and bendrofluazide was as effective in reducing blood pressure as the same combination given twice daily, and the hypotensive effect was still present at least 24 hours after the last dose of tablets. A combined tablet of atenolol and bendrofluazide taken once daily would be a simple regimen to follow and would provide almost as much hypotensive effect as a twice-daily regimen incorporating a modest dose of hydrallazine. The hypotensive effect of atenolol was equal to that of bendrofluazide on systolic pressure but significantly better than that of bendrofluazide on diastolic pressure. Atenolol reduced plasma renin and urate concentrations but increased plasma potassium levels. The biochemical effects of atenolol, therefore, may be an advantage over those of bendrofluazide when deciding on first-line treatment for essential hypertension.     

Diuretic treatment of resistant hypertension.

In patients with hypertension resistant to three or four drugs including a thiazide diuretic substitution of frusemide for the thiazide, or the addition of spironolactone, produced significant reductions in blood pressure and body weight. The response did not depend on the presence of overt fluid retention, renal impairment, or the use of antihypertensive drugs of high potency. Women had larger responses than men. Expansion of the plasma or extracellular fluid volume is an important cause of resistance to treatment even when a thiazide diuretic is used. An increase in diuretic treatment should be tried before using the postganglionic adrenergic blockers or minoxidil in resistant hypertension.     

Course of blood pressure in mild hypertensives after withdrawal of long term antihypertensive treatment. Medical Research Council Working Party on Mild Hypertension.

A series of 1418 men and 1,347 women with mild hypertension (diastolic phase V 90-109 mm Hg) aged 35-64 who had either had long term antihypertensive treatment with bendrofluazide or propranolol or taken placebo tablets for a similar period were randomly allocated to groups in which their tablets were either stopped or continued. The course of blood pressure and of biochemical variables was followed up for two years. Mean blood pressures rose rapidly after the withdrawal of active treatment, and between nine months and one year after stopping treatment the antihypertensive effect had almost disappeared. The effect persisting longer than this, and possibly due to resetting of the baroreceptors or of other blood pressure control mechanisms, was very small, and as the rise in mean pressure was due to an upward movement in general distribution there was no evidence of a subgroup in whom these mechanisms had been permanently reset to a clinically important extent. After withdrawal of propranolol the rise in pressure was more rapid in younger than in older people. After stopping bendrofluazide pressure rose more rapidly in men who had had higher pressures before and during treatment; this effect was not seen in women. Disturbances in biochemical variables associated with drug treatment had largely resolved by the end of two years after withdrawal. Stopping placebo tablets made no consistent difference to blood pressure.     

Familial ADH-responsive diabetes insipidus: response to thiazides and chlorpropamide

Twenty cases of familial ADH-responsive diabetes insipidus were identified within five generations, and eight patients were studied by one of two established dehydration protocols. In each case there was partial to total failure of response to the initial administration of ADH which was slowly corrected by continued administration. This initial failure can lead to misinterpretation of the dehydration test unless the medullary solute washout effect is taken into account in chronically polyuric patients.Treatment consisted of thiazides and/or chlorpropamide. All cases responded well.The response to chlorpropamide suggests that the failure of ADH production is not complete in these patients, and that the major defect is a failure of ADH release in response to normal stimuli. Chlorpropamide may act by either facilitating ADH release or by synergistically interacting with available ADH at the tubular level.     

Circadian variations of blood pressure in patients with different degrees of hypertension. Changes induced by hypotensive treatment

Arterial pressure was continuously recorded for 24--48 h in 3 normotensive subjects and in 60 hypertensive patients. The greatest variations occurred in those with labile, mild or moderate hypertension compared to those with severe hypertension or normal blood pressure. Atenolol (100-200 mg) administered once or twice daily produced a significant reduction of arterial pressure and a smaller response to the cold pressor test, hand grip and step test in patients with established hypertension, but little change in those with labile hypertension. The evening dose was not followed by a decrease in pressure greater than that observed without treatment, but determined a smaller rise on awaking.     

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.     

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.     

Community care compared with hospital outpatient care for hypertensive patients.

Three hundred and seventy-six patients with treated diastolic blood pressures of less than 105 mm Hg and no history of accelerated hypertension or renal failure were selected from among those attending the Hammersmith Hospital hypertension clinic. Their average lying treated blood pressure was 146 mm Hg systolic and 90 mm Hg diastolic and average age 56 years; 18% were black, 6% Asian, and 76% white. The patients were mostly having multiple treatment, 90% receiving a diuretic, 35% methyldopa, 33% propranolol, 18% atenolol, 9% hydrallazine, and 7% bethanidine. They were randomly allocated to either two years of further hospital outpatient care or referred back to their general practitioners. During the two years 19 (10%) of the 187 patients followed up in hospital defaulted and three had their treatment discontinued. Twelve (6%) of the 189 followed up by their general practitioners defaulted from follow-up and nine had their treatment discontinued. At the end of the trial the average lying blood pressure was 148 mm Hg systolic and 88 mm Hg diastolic in the hospital group and 149 mm Hg systolic and 90 mm Hg diastolic in the general practice group. The change in blood pressure was calculated for each individual and showed an average fall of 1.6 mm Hg in standing diastolic pressure in the hospital group and a rise of 1.4 mm Hg in the general practice group (p less than 0.05). The 90% confidence limits for a difference in standing diastolic pressure between the groups were 1 and 5 mm Hg with the pressure lower in the hospital group. General practice care was not quite as effective in controlling blood pressure as continued specialist supervision over two years in this selected group of treated outpatients with mild or moderate hypertension, but these results show that the discharge back to general practitioners of patients who are well controlled after hospital treatment is a sensible policy.     

Effect of Prolonged Thiazide Treatment on Renal Lithium Clearance

Renal lithium clearances were determined after the administration of a small test dose of lithium carbonate in 22 patients when they were on long-term treatment with thiazides and when they were not on such treatment. Thiazide administration led to a 24% reduction in the lithium clearance. Diuretic drugs should be used with caution in patients given lithium treatment, and lithium should be used with caution in patients receiving diuretic treatment.     

Advanced carcinoma of the prostate: treatment with a gonadotrophin releasing hormone agonist.

Ten patients with advanced progressive adenocarcinoma of the prostate were treated with a long acting analogue of gonadotrophin releasing hormone. Eight of these patients responded to treatment in terms of pain relief and clinical regression of tumour. Serum gonadotrophin and testosterone concentrations were significantly suppressed by the end of the second week of treatment, testosterone concentrations being comparable with those achieved by castration. The two patients who failed to respond had both relapsed previously when receiving conventional treatment, and neither showed any endocrine response to the analogue. Superagonists of gonadotrophin releasing hormone may be the treatment of choice in adenocarcinoma of the prostate, but further trials are required to establish long term safety and efficacy.     

Reduced concentrations of potassium,magnesium, and sodium-potassium pumps in human skeletal muscle during treatment with diuretics

Animal studies have shown that potassium depletion induced by diuretics or potassium deficient fodder leads to a selective decrease in the concentrations of potassium and in the concentration of sodium-potassium pumps in skeletal muscle. In 25 patients who had received diuretics for 2-14 years the mean concentrations of potassium, magnesium, and sodium-potassium pumps were measured in skeletal muscle biopsy specimens and were significantly lower than in those from a group of age matched controls. The reductions in all three variables were significant in those patients receiving diuretics for arterial hypertension as well as in those being treated for congestive heart failure. In 14 patients the mean muscle potassium concentration was below the control range, but only one of those was hypokalaemic (3·4 mmol/l), and 13 were receiving potassium supplements. In 15 patients the mean muscle magnesium concentration was below normal, and the mean muscle potassium and magnesium concentrations showed a linear correlation. In 12 patients in whom the mean muscle potassium concentration was below 80 μmol/g wet weight there was a linear correlation between the cellular potassium:sodium ratio and the concentration of ³H-ouabain binding sites indicating that potassium deficiency also leads to a down regulation of sodium-potassium pumps in human skeletal muscle.In spite of potassium supplements long term treatment with diuretics may lead to potassium and magnesium deficiencies, which are not detectable using the standard methods of serum analysis. The changes in concentrations of electrolytes and sodium-potassium pumps associated with treatment with diuretics may impair muscle function and potassium homoeostasis and interfere with the distribution of digitalis glycosides.     

Controlled trial of long term oral potassium supplements in patients with mild hypertension.

A 15 week randomised double blind placebo controlled trial of oral potassium supplements (48 mmol daily) was conducted in 37 patients who had mildly increased blood pressure and a normal dietary intake of sodium. After a two month run in and a one week baseline period the patients were randomly assigned to receive either potassium supplements (n = 18) or placebo (n = 19). By the third week of treatment blood pressure in the actively treated group had decreased significantly compared with that in the placebo group, though the decrease reached its maximum after 15 weeks. Urinary potassium excretion increased significantly in the group who received potassium supplements, but no significant changes were found in plasma sodium and potassium concentrations or in urinary sodium excretion. In a subgroup of 13 patients who underwent a further nine weeks of treatment with oral potassium supplements at half of the previous dose (24 mmol daily) their blood pressure, at the end of this second study period, was still significantly lower compared with their baseline value but not with that of the placebo group. These results show that moderate oral potassium supplements are associated with a long term reduction in blood pressure in patients who have mild hypertension.     

Hypokalemia during the treatment of arterial hypertension with diuretics.

In a study of 50 patients with uncomplicated arterial hypertension the administration of hydrochlorothiazide, 50 to 100 mg daily or every other day, with or without reserpine, 0.25 mg daily, resulted in a fall in the mean blood pressure from 182/113 to 144/92 mm Hg. The mean duration of therapy was 19 months. The mean serum potassium concentration was 4.3 mmol/l before the onset of therapy. It fell during the first 6 weeks of treatment, but seldom below 3.5 mmol/l, then rose gradually and spontaneously to 4.1 mmol/l after 19 months of therapy. All the patients remained asymptomatic. These findings bring into question the routine use of potassium supplements or a potassium-sparing diuretic, such as spironolactone or triamterene, during the treatment of hypertension with diuretics such as the thiazides. The use of potassium supplements or a potassium-sparing agent may induce hyperkalemia in spite of the simultaneous administration of a diuretic that acts more proximally. Since hyperkalemia is potentially lethal, the serum potassium concentration should be carefully monitored in any patient receiving potassium supplements or a potassium-sparing agent.     

Sustained effects of biofeedback-assisted relaxation therapy in essential hypertension.

The usefulness of biofeedback-assisted relaxation as an adjunct or substitute for pharmacotherapy in essential hypertension can be enhanced if the effects are shown to persist after formal treatment has ended. Patients with essential hypertension successfully treated with biofeedback-assisted relaxation were recalled for follow-up yearly after the termination of treatment. Twenty-six of 40 patients met the BP criterion for success. At one-, two-, and three-year follow-up, 31%, 38%, and 27% of the successful completers continued to meet the criterion for success. The pretreatment-posttreatment decreases in BP were accompanied by decreases in forehead muscle tension and urinary cortisol. Forehead muscle tension, urinary cortisol, and anxiety levels were significantly lower than pretreatment one year after the end of treatment. Self-report data were used to assess continued relaxation practice. No relationship was found between practice and any other dependent measure. It appears that some patients trained in biofeedback-assisted relaxation can maintain lowered blood pressure, muscle tension, anxiety, and cortisol levels over the long term; however, the role of relaxation practice in maintaining these lowered levels remains unclear.