diuretics or β-blockers first for hypertension?

Practical Therapeutics

Drugs 23: 394-402 (1982) 0012-6667/82/0500-0394/$4.50/0 © ADIS Press Australasia Pty Ltd. All rights reserved.

Diuretics or ~-Blockers First for Hypertension?

Judith A. Whitworth and Priscilla Kincaid-Smith

Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria

Life assurance data indicate that there is an increased risk of cardiovascular mortality for even minor elevations of blood pressure (Metropolitan Life Insurance Co., 1961). It has been known for many years that the clinical course (Kincaid-Smith et al., 1958) of malignant or accelerated hypertension can be radically improved by treatment (Harington et al" 1959). Similarly, the benefits of treatment in moderate to severe hypertension (i.e. diastolic blood pressure greater than Il0mm Hg) have been widely recognised since publication of the results of the Veterans' Administration Study (1970). More recently, the Australian Therapeutic Trial in Mild Hypertension (1980) has demonstrated that in patients with mild hypertension without any evidence of end-organ damage, antihypertensive therapy is of benefit in reducing mortality from cardiovascular disease.

Thus the evidence, in Australia at least, suggests that patients with diastolic blood pressures over 95mm Hg will benefit from antihypertensive therapy. In view of the fall in blood pressure on placebo treatment in the Australian study, it has been suggested (Doyle, 1982) that the logical approach is to follow patients with mild hypertension until it is evident that their pressure is falling, in which case they simply require regular review, or remaining high or

increasing, in which case they should start therapy. In patients with moderate or severe hypertension,

drug treatment is instituted early. However, both in these patients and in the large group of mild hypertensive patients, careful attention should also be paid to non-drug treatment. Hypertension is treated because it is a risk factor for cardiovascular disease, and thus patients should be advised about other cardiovascular risk factors, particularly smoking and obesity.

Recent studies have shown that smoking is very common among patients with malignant hypertension (Isles et al., 1979), in whom smoking is strongly associated with renal failure and mortality. Thus, hypertensive smokers have an increased risk of vascular disease and of developing malignant hypertension with a particularly lethal cause.

There is a strong assocation between obesity and blood pressure, and weight loss is usually associated with a fall in blood pressure (Reisin et al" 1978). Thus, patients should be encouraged to attain and maintain their ideal weight.

The role of sodium restriction is still controversial. There is a greal deal of epidemiological data relating hypertension to sodium intake between different populations, and within populations there are at least some studies suggesting that hypertensive patients have a higher salt intake than normotensives. There is

Diuretics or ~-Blockers Rrst for Hypertension?

also evidence to suggest that salt restriction will lower blood pressure in subjects with essential hypertension (Morgan et al., I 979b). The Kempner rice-fruit diet was effective in the management of severe hypertension, and recently Morgan has shown that modest salt restriction can reduce diastolic blood pressure in mild hypertension by about 7 mm Hg. If one excludes patients with salt-wasting renal or adrenal disease, then the risks of reducing salt intake in mild hypertensives are negligible and on present evidence it seems reasonable to suggest a moderate reduction in sodium intake in hypertensive patients.

1. Mechanisms of Action

1.1 ~-Adrenoreceptor Blocking Drugs

The mechanism by which ~-adrenoreceptor blocking drugs reduce blood pressure is not clear. These drugs reduce cardiac output with acute administration, and although this effect may be important in the long term, a number of other possible mechanisms exist, including reduction in plasma renin activity, effects on the central nervous system, and peripheral effects on presynaptic ~-receptors. These drugs are all competitive inhibitors of ~-receptors and are analogues of isoprenaline.

The ~-adrenoreceptor blockers have a variety of different properties which are highlighted in the marketing literature. The differences, however, are not of great significance in clinical practice in the majority of patients. Cardioselectivity means that a ~adrenoreceptor blocking agent is more potent on the ~1-receptor (cardiac) than on tlie ~2-receptor (bronchial tree). This, however, is a relative property, and all of the so-called cardioselective ~-adrenorecep· tor blockers do have some activity at the ~2-receptor. Partial agonist activity means the drug can stimulate ~-receptors, but this does not prevent the effects of blockade of bronchial ~-receptors. Dosage and frequency of administration are determined by a number of factors, including first-pass metabolism and other pharmacokinetic properties.

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1.2 Diuretics

A wide range of diuretics are used in the treatment of hypertension, but thiazide diuretics are the most commonly prescribed.

The thiazides act in the diluting segment of the nephron and also possess carbonic anhydrase inhibiting activity. They differ principally in their duration of action. The loop diuretics, for example frusemide (furosemide) and ethacrynic acid, are more potent than the thiazides, and have a more rapid onset and shorter duration of action. They inhibit chloride reabSOrPtion in the ascending limb of the loop of Henle. The potassium-sparing diuretics, for example amiloride and triamterene, act in the distal nephron. Spironolactone is an aldosterone antagonist. These drugs are relatively weak diuretics.

An increase in salt and water excretion by the kidney is an important part of the antihypertensive mechanism of action of diuretics, but whether this is the sole factor is debatable (Parijs et al., 1973). It is not clear whether the hypotensive effect of thiazide diuretics is directly related to the reduction in extracellular fluid and plasma volume (Tarazi et al., 1970), or whether it reflects an alteration in vascular smooth muscle sodium content. Jones and Nanra (1979), in a randomised double-blind crossover trial in patients with severe renal failure, showed that chlorothiazide significantly reduced both standing and supine blood pressure (I 3/ 5mm Hg), and suggested that the antihypertensive effect was probably due to a change in peripheral vascular resistance and not to volume contraction.

2. Efficacy

2.1 Diuretics

Thiazide diuretics have been widely used since 1957. They lower blood pressure by about 10mm Hg systolic and 5mm Hg diastolic in hypertensive subjects. In occasional patients this fall may be as high as 20/ 10mm Hg, but in general only a minority of


patients will be adequately controlled using a thiazide diuretic alone. In a recent study from the UK (Balin et al., 1980) only 16 % of patients attending 3 hospital hypertension clinics were controlled on diuretics alone. Thiazides have the major advantage that in addition to producing a fall in blood pressure, they potentiate the effects of the other antihypertensive agents.

In elderly patients thiazides have been regarded as the drug of choice (Editorial, 1980). Elderly patients appear to tolerate thiazide diuretics better than many other hypotensive drugs and postural effects are relatively minor in this age group. Recently, it has been shown in a study from Melbourne that elderly patients on thiazides have a higher mortality than those in whom blood pressure was lowered by other means (Morgan et al., 1980). This clearly needs further evaluation and is of interest in view of Laragh's suggestion that high plasma renin activity is a risk factor for cardiovascular disease (Brunner et al., 1972), as diuretics are a potent stimulus for renin release.

In a double-blind study of the long term effects of diuretics on uncomplicated mild and moderate essential hypertension in 52 patients, Finnerty et al. (1977) found that frusemide 40mg twice daily or hydrochlorothiazide 50mg twice daily, significantly lowered mean supine blood pressure. The fall in blood pressure was less with frusemide than with hydrochlorothiazide. In this study the cumulative incidence of hypokalaemia was 8 % for the frusemide group compared with 62 % for the hydrochlorothiazide group. It should be noted, however, that the doses used in this study were large (frusemide 40mg twice daily, hydrochlorothiazide 50mg twice daily). At 18 months, hydrochlorothiazide had resulted in a mean fall in blood pressure of 291 I 7 mm Hg compared with 181 13mm Hg for frusemide.


~-Adrenoreceptor blocking drugs will produce a fall in blood pressure when used alone in about two-

396

thirds of patients, but this is markedly potentiated by the addition of a thiazide diuretic (Laver et al., 1974), an argument for commencing treatment with a thiazide diuretic rather than with a ~-blocking drug.

On the other hand, ~-adrenoreceptor blocking drugs are of proven value in the management of anginal chest pain and have also been shown to decrease mortality after acute myocardial infarction (Norwegian Multicenter Study Group, 1981). As patients with hypertension are at risk of developing ischaemic heart disease, a possible protective effect of ~-blockers in this group is a strong argument for their use.

~-Blockers have been reported to be ineffective in lowering blood pressure in certain races, for example West Indians and West Africans (Waal-Manning, 1981).

3. Dosage and Frequency of Administration

3.1 Diuretics

There is evidence to suggest that relatively low doses of diuretics may be advantageous in the management of hypertension. At conventionally used doses there may be an increase in side effects and metabolic disturbances without any increase in hypotensive potency. In a study in patients with essential hypertension, Carney et al. (1976) showed that 25 and 100mg of chlorthalidone per day reduced blood pressure to a similar extent, but the higher dose caused a greater reduction in extracellular fluid volume, a larger rise in plasma renin activity and serum uric acid, and a higher incidence of hypokalaemia. In a further study, this group (Morgan et al., 1979a) treated 24 hypertensive patients with chlorothiazide 500mg/day, frusemide 40mg/day and chlorthalidone 25mg/day in a random fashion. The antihypertensive effect of each diuretic was significant, and all 3 were similar in magnitude. The antihypertensive effect of chlorthalidone and chlorthiazide were both present after 24 hours and persisted for a longer time with chlorthalidone, being


present 72 hours after cessation of the drug. Side effects were more common with frusemide. The authors concluded that chlorthalidone could be given at 48- to 72-hour intervals and that other diuretics may be given once daily to exert their full antihypertensive effect.


Propranolol has been reported to be effective when used once daily in hypertensive subjects. In 26 patients with essential hypertension on chlorthalidone therapy, once or 3 times daily doses of propranolol were compared in a crossover study (van den Brink et al., 1980). Blood pressure was similar on the 2 different regimens. Similar results have also been reported from Stanford (Rudd et al., 1980). Other ~

adrenoreceptor blocking drugs have also been shown to be effective when used in a single dose (Bullen et al., 1980).

4. Metabolic Consequences: Risk Factors/or Cardiovascular Disease

4.1 Plasma Renin Activity

In 1972, Laragh's group published a study in which they found that patients with so-called low renin essential hypertension had fewer strokes or myocardial infarcts than those with normal or high plasma renin activities. This led them to suggest that high plasma renin activity is a risk factor (through the vasculotoxic effects of angiotensin II) for cardiovascular disease (Brunner et al., 1972). Other studies have failed to confirm this hypothesis (Doyle et al., 1973; Mroczek et al., 1973). One of the major criticisms of the original study was that the diastolic blood pressure was higher in the high plasma renin group than in the normal or low plasma renin patients. In none of the studies were data prospective, and various definitions were used for renin profIling. Many of these patients were treated, and thus the renin status

397

on treatment may have been quite different from that of treatment used in categorisation of renin subgroups. Nonetheless, these findings encouraged physicians, particularly in the USA, to use ~

adrenoreceptor blocking drugs for patients with normal or high plasma renin activities because of the drugs' action in lowering plasma renin activity, and to use diuretics which raise renin in patients with low renin essential hypertension. It has been claimed that patients with so-called low renin hypertension respond poorly to ~-blocking drugs (Buhler et al., 1972), but other workers have disputed that the hypotensive effects of these drugs are dependent on their reninlowering effect (Morgan, 1976).

Although the study of Morgan et al. (t 980) in elderly hypertensives suggests that thiazides may be

associated with increased cardiovascular mortality in this age group, this remains to be proven, as does any association between this effect and changes in plasma renin activity. Elderly hypertensive subjects have lower plasma renin activity as a group than do younger hypertensives, and might thus be expected to respond well to thiazide therapy. At present there is little convincing evidence that profiles of renin activity should be used to determine whether ~-blockers or thiazide diuretics should be used first in the treatment of hypertension.

4.2 Lipids

The effects of both thiazide diuretics and ~

adrenoreceptor blocking drugs on lipids and lipoproteins in hypertensive subjects have been examined. In a study from Norway (Leren et al., 1980) in 23 hypertensive men aged from 47 to 55 years, propranolol (in doses of up to 80mg twice daily) reduced serum high density lipoprotein cholesterol by 13 %, reduced the ratio of high to low density lipoprotein plus very low density lipoprotein cholesterol by IS %, increased total triglycerides by 24 % and increased serum uric acid by 10% . Decreased high density lipoprotein cholesterol concentrations are associated with an increased risk of


coronary heart disease. Waal-Manning (J 976) reported a 42 % increase in total triglycerides in patients after 12 months on the ~-adrenoreceptor

blocker metoprolol, and Tanaka et al. (1976) found a reduction in high density lipoprotein cholesterol in 10 elderly patients on propranolol for 8 weeks. In a study of 4 different ~-blockers, atenolol, pindolol, propranolol and metoprolol, Shaw et al. (1978) found a rise in total triglyceride concentrations with all 4 drugs. Whether or not these unfavourable effects of ~-adrenoreceptor blocking agents on blood lipids have any long term clinical importance is not clear. However, they appear to be worth considering in deciding on a choice of first-line therapy, particularly in patients with mild hypertension, who will be treated over long periods of time.

There are also data showing that thiazide diuretics lead to increases in serum lipids. In the Veteran's Administration study of mild hypertension, patients on chlorthalidone had an increase in total serum cholesterol, and in very low and low density lipoprotein (Goldman et al., 1980; Schnaper et al., 1977). In a randomised crossover control study, Grimm et al. (1981) have shown an increase in both cholesterol (6 % with hydrochlorothiazide, 8 % with chlorthalidone) and triglyceride (I 7 % with hydrochlorothiazide, IS % with chlorthalidone) concentrations. They further showed that a cholesterol-lowering diet could largely prevent this increase (Grimm et al., 1981). Low density lipoprotein cholesterol was significantly increased by chlorthalidone and very low density lipoprotein cholesterol was significantly increased by both diuretics. It should be noted, however, that the diuretic dosage used in this study was high, 100mg once daily, and the authors did suggest that the magnitude of the effect could be related to dosage, although this was not studied.

4.3 Uric Acid Concentrations

In the Norwegian study, propranolol increased uric acid concentrations by I 0 % after 8 weeks of antihypertensive treatment, and this change was

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highly significant. The effects of diuretic therapy on plasma uric acid

concentrations are well known. In a double-blind crossover trial comparing the uricosuric diuretic tienilic acid with hydrochlorothiazide in 38 patients with mild to moderate hypertension, we (Walker et ai., 1980) found a rise in serum uric acid concentrations from O.34mmol/L on placebo to 0.44mmol/L after 12 weeks on SOmg hydrochlorothiazide. With tienilic acid, on the other hand, serum uric acid feli. The tendency of thiazide diuretics to raise serum uric acid is of particular importance to the substantial group of patients with both hypertension and gout. In the long term hyperuricaemia may be deleterious as there is evidence suggesting that it is a risk factor for cardiovascular disease (Tweeddale and Fodor, 1979).

4.4 Blood Glucose Concentrations

In our study comparing hydrochlorothiazide and tienilic acid, we did not show any significant effect of diuretic therapy on blood glucose concentrations (Walker et ai., 1980). However, the tendency for thiazide diuretics to impair glucose tolerance is well documented (Kohner et ai., 197 I), and thiazide diuretics have also been associated with the development of hyperosmolar non-ketotic hyperglycaemic coma (Curtis and Horrigan, 1972).

With ~-adrenoreceptor blockers, on the other hand, hypoglycaemia may be a problem in patients with diabetes or with prolonged fasting.

4.S Serum Potassium Concentrations

Postassium depletion is a well recognised complication of diuretic therapy. In our study of 38 patients with mild to moderate hypertension, hydrochlorothiazide produced a highly significant fall in serum potassium concentrations from 4.0mmol/L on placebo to 3.6mmol/L after 12 weeks (Walker et al., 1980). The cardiovascular consequences of


potassium depletion include a decrease in atrioventricular conduction and an increase in ectopic activity, and this can be very important in patients at risk for arrhythmia, for example after acute myocardial infarction. In patients with hypertension who are otherwise well, routine potassium supplementation is not indicated.

~-Adrenoreceptor blockers may increase serum potassium by inhibiting intracellular potassium shifts, but this is rarely of clinical significance, except in patients with renal failure.

5. Side Effects

5.1 Thiazide Diuretics

Side effects of which patients complain are relatively uncommon with thiazide diuretics. Clinical gout, dry mouth and, less commonly, muscle weakness and cramps may occur (Bulpitt et al., 1979), and recently the MRC Working Party of Mild to Moderate Hypertension (1981) has shown an association between bendrofluazide treatment and impotence.


Side effects with the ~-blocking drugs can be troublesome. Bronchospasm can be life-threatening, and thus it is important to enquire about previous asthma or bronchitis. The so-called cardioselective ~-blocking drugs are not entirely safe in this regard, as they can also produce bronchospasm. ~-Blockers should not be used in patients with Raynaud's disease or intermittent claudication as they can worsen these conditions.

The ~-blocking drugs have been reported to cause depression, and they may be troublesome in patients with diabetes. ~-Blockers should not be used in patients with heart failure unless this is being controlled by diuretics and I or digitalis (unless heart failure is secondary to hypertension, in which case lowering the blood pressure is crucial). The ~-

399

blockers should not be used in phaeochromocytoma until the patient is fully a-blocked.

Tiredness and weakness is a frequent complaint and vivid dreams can be troublesome. Therapy with ~-blockers may interfere with exercise capacity and this may be troublesome, particularly in young athletic subjects. In the MRC report, impotence occurred more commonly in men on propranolol than in a placebo group.

There has recently been considerable interest in the effects of ~-blockers on renal function. Early studies using creatinine clearance suggested that renal function was not adversely affected by ~-adrenoreceptor blocking drugs. More recently, studies using inulin clearance have suggested that propranolol reduces glomerular filtration rate and renal blood flow as measured by aminohippuric acid clearance (Bauer and Brooks, 1979). The effects of both selective and nonselective ~-blockers on renal function are at present under investigation.

6. Cost

Considering the number of patients with mild hypertension who, according to the Australian Therapeutic Trial (1980), require treatment, the cost of therapy clearly must be a consideration. Generally speaking, diuretic therapy is less expensive than ~-blocker therapy.

7. Fixed Ratio Combinations of Diuretics and ~-Blockers

Whether therapy for hypertension is instituted. with diuretics or ~-adrenoreceptor blocking drugs, most patients will need additional therapy. Compliance is a major problem in hypertensive patients who take tablets not for relief of symptoms but for some projected future benefit in reduction of cardiovascular mortality. Thus, multiple drug regimens should be made as simple as possible for the patient. One approach which has found favour in Europe is


the combination of drugs in a fixed ratio preparation. Such preparations have been claimed to lead to better patient compliance than use of the component drugs separately.

Fixed ratio combinations demand that the dosage of each component used should contribute to the hypotensive effect and individual components should have similar pharmacokinetic parameters and a relatively narrow dosage range. With some ~-blockers, for example propranolol, a marked first-pass effect with variable absorption could lead to a relatively wide dosage range, and thus make a fixed ratio combination difficult.

Opinion tends to be divided about the value of such fixed dose ratio combinations. Advantages include simplicity and improvement in patient compliance, but the major disadvantage is inflexibility. A fixed ratio will only be suitable for a proportion of patients, and as diuretics may be effective at low dose, doubling the dose of a fixed ratio combination will provide a relatively high diuretic dosage with all its attendant metabolic problems.

8. Conclusions

Drug therapy has been shown to reduce cardiovascular mortality in patients with mild as well as severe hypertension. Diuretics lower blood pressure by reducing extracellular fluid and plasma volume, and thiazide diuretics may also reduce peripheral vascular resistance, possibly by altering vascular smooth muscle sodium content. ~-Adrenoreceptor

blockers reduce cardiac output and plasma renin activity, and have central as well as peripheral effects on presynaptic ~-receptors. Thiazide diuretics lower blood pressure in most patients, but only a small proportion are adequately controlled on diuretic therapy alone. Diuretics have the major advantage of potentiating other hypotensive drugs. ~-Blocking drugs alone reduce blood pressure in about two-thirds of patients, but are potentiated by diuretics. They are of particular value in patients with ischaemic heart disease. Both ~-blocking drugs and thiazide diuretics

400

have adverse effects on cardiovascular risk factors such as cholesterol, triglyceride and uric acid concentrations. Whether these metabolic effects have any long term consequences is not yet known. Potassium depletion with diuretics can be a problem in patients at risk for arrhythmia, for example after acute myocardial infarction. Diuretics have relatively few side effects, whereas ~-blockers have a number of potentially serious side effects (e.g. bronchospasm, vasospasm, heart failure).

It is our current practice to use diuretics first in the drug treatment of hypertension, and to use ~-blockers as second-line drugs. However in certain clinical circumstances, for example in patients with clinical gout or ischaemic heart disease, we prefer to commence treatment with ~-adrenoreceptor blocking drugs. Other physicians, with a great deal of experience in managing patients with hypertension, prefer to use ~-blockers first. Patients with mild hypertension may require treatment over many years. Clearly, the question of whether to use diuretics or ~-blocking drugs first for hypertension will only be answered defmitively by well-designed controlled clinical trials.

References

Australian Therapeutic Trial in Mild Hypertension: Report by the Management Committee. Lancet I: 1261-1267 (1980).

Balin, L.J.; Bulpitt, CJ.; Coles, E.C; Dollery, CT.; Gear, J.S.W.; Harper, G.; Johnson, B.F.; Munro-Faure, A.D. and Turner, S.C: Long-term anti-hypertensive drug treatment and blood pressure control in 3 hospital hypertension clinics. British Heart Journal 43: 74-79 (1980).

Bauer, lH. and Brooks, C.S.: The long-term effect of propranolol on renal function. American Journal of Medicine 66: 405-410 (1979).

Brunner, H.R.; Laragh, J.H.; Baer, L.; Newton, M.A.; Goodwin, F.T.; Krakoff, L.R.; Bard, R.H. and Buhler, F.R.: Essential hypertension: Renin and aldosterone, heart attack and stroke. New England Journal of Medicine 286: 441-449 (1972).

Buhler, F.R.; Laragh, J.G.; Baer, L.; Vaughan, E.D. and Brunner, H.R.: Propranolol inhibition of renin secretion. New England Journal of Medicine 287: 209-214 (1972).

Bullen, M.U.; Whitworth, J.A. and Kincaid-Smith, P.: Comparison of single dose and twice daily timolol therapy in mild


hypertension. Medical Journal of Australia 2: 514-515 (980).

Bulpitt, C.J.; Hoffbrand, 8.1. and Dollery, e.T.: Contribution of drug treatment to symptoms of hypertension in patients; in Gross and Strasser (Eds) Mild hypertension: Natural History and Management, pp.291-302 (Pitman Medical, London

1979). Carney, S.; Gillies, A.I. and Morgan, T.: Optimal dose of a

thiazide diuretic. Medical Journal of Australia 2: 692-693 (976).

Curtis, J. and Horrigan, F.: Chlorthalidone induced hyperosmolar hyperglycaemic non ketotic coma. Journal of the American Medical Association 220: 1592-1593(972).

Doyle, A.E.: When to begin treatment in hypertension; in Kincaid-Smith and Whitworth (Eds) Hypertension: Mechanisms and Management (ADIS Press, Sydney, in press 1982).

Doyle, A.E.; Jerums, G.; Johnston, e.1. and Louis, W.J.: Plasma renin levels in vascular complications in hypertension. British Medical Journal 2: 206-207 (973).

Editorial: Hypertension in the over-sixties. Lancet I: 1396 (980). Finnerty, F.A.; Maxwell, M.H.; Lunn, J. and Moser, M.:

Long-tenil effects of furosemide and hydrochlorothiazide patients with essential hypertension. Angiology 28: 125-133 (1977).

Goldman, A.; Stelle, B.; Schnaper, H.; Fitz, A.; Frohlich, E. and Perry, H.M.: Serum lipoprotein levels during chlorthalidone therapy. Journal of the American Medical Association 244: 1691-1695 (980).

Grimm, R.H.; Leon, A.S.; Hunninghake, D.B.; Lenz, K.; Hannan, P. and Blackburn, H.: Effects of thiazide diuretics on plasma lipids and lipoproteins in mildly hypertensive patients. Annals oflnternal Medicine 94: 7-11 (981).

Harington, M.; Kincaid-Smith, P. and McMichael, J.: Results of treatment in malignant hypertension: A 7 year experience in 94 cases. British Medical Journal 2: 969-980 (959).

Isles, C.; Brown, J.1.; Cuming, A.M.M.; Lever, A.F.; McAreavey, D.; Robertson, J.A.S.; Hawthorne, V.M.; Stewart, G.M.; Robertson, J.W.K. and Wapshaw, J.: Excess smoking in malignant phase hypertension. British Medical Journal I: 579-581 (J979).

Jones, B. and Nanra, R.S.: Double blind trial of anti-hypertensive effect of chlorothiazide in severe renal failure. Lancet 2: 1258-1260 () 979).

Kincaid-Smith, P.; McMichael, J. and Murphy, E.A.: The clinical course and pathology of hypertension with papilloedema (malignant hypertension). Quarterly Journal of Medicine, New Series XXVII: 117-153 (J958).

Kohner, E.M.; Dollery, e.T.; Lowry, e. and Schumer, B.: Effect of diuretic therapy on glucose tolerance in hypertensive patients. Lancet I: 986-990 (I971).

Laver, M.e.; Fang, P. and Kincaid-Smith, P.: Double-blind comparison of two beta-blocking drugs with previous therapy in

the treatment of hypertension. Medical Journal of Australia I:

401

174-176 (I974). Leren, P.; Foss, P.O.; Helgeland, A.; Hjermann, I.; Holme, I. and

Lund-Larsen, P.G.: Effect of propranolol and prazosin on blood lipids. Lancet 2: 4-6 () 980),

Medical Research Council Working Party Report on Mild to Moderate Hypertension: Adverse reactions to bendrol1uazide and propranolol for the treatment of mild hypertension. Lancet 2: 539-543 () 981).

Metropolitan Life Insurance Company: Blood pressure: Insurance experience. Metropolitan Life Insurance Co., New York (1961).

Morgan, T.: Beta-adrenoreceptor blocking drugs in the treatment of hypertension. Australia and New Zealand Journal of Medicine 6: 612 (1976).

Morgan, T.O.; Adam, W.R.; Hodgson, M. and Myers, 1.: Duration of effect of different diuretics. Medical Journal of Australia 2: 315-316 0979a).

Morgan, T.; Myers, J. and Carney, S.: The evidence that salt is an important aetiological agent, if not the cause of hypertension. Clinical Science 57: 45 7S-46 2S () 97 9b).

Morgan, T.O.; Adam, W.R.; Hodgson, M. and Gibberd, R.S.: Failure of therapy to improve prognosis in elderly males with hypertension. Medical Journal of Australia 2: 27-31 ()980).

Mroczek, W.J.; Finnerty, F.A. and Catt, K.F.: Lack of association between plasma renin and history of heart attack or stroke in patients with essential hypertension. Lancet 2: 464-468 () 973).

Norwegian Multicenter Study Group: Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. New England Journal of Medicine 304: 801-807 (I981).

Parijs, J.; Joossens, J.V.; van der Linden, L.; Verstreken, G. and Amery, A.K.P.e.: Moderate sodium restriction and diuretics in the treatment of hypertension. American Heart Journal 85: 22-34 (1973).

Reisen, E.; Abel, R.; Modan, M.; Silverberg, D.S.; Eliahou, H.E. and Modan, B.: Effect of weight loss without salt restriction on the reduction of blood pressure in overweight hypertensive patients. New England Journal of Medicine 198: 1-6 (1978).

Rudd, P.; Beilston, B.; Tul, V. et aI.: Once daily regimen for propranolol antihypertensive therapy. Current Therapeutic Research 27: 29-39 (1980).

Schnaper, H.; Fitz, A.; Frohlich, E.; Goldman, A.; Perry, H.M. and Steele, B.: Chlorthalidone and serum cholesterol. Lancet 2: 295 (1977).

Shaw, J.; England, J.D.F. and Hua, A.S.P.: Beta-blockers and plasma triglycerides. British Medical Journal I: 986 () 978).

Tanaka, A.N.; Sagaguchi, K.; Oshige, K.; Niimura, T. and Kinehisa, T.: Effect of chronic administration of propranolol on lipoprotein composition. Metabolism 25: 170-175 (1976).

Tarazi, R.C.; Dustan, H.P. and Frohlich, E.D.: Long-term thiazide

therapy in essential hypertension. Circulation 41: 709-717 ()970).

Diuretics or ~-Blockers First for Hypertension? 402

Tweeddale, N.G. and Fodor, G.1 .: Elevated serum uric acid: A

cardiovascular risk factor? Nephron 23 (Supp!. I): 3-6 (1979).

Waal-Manning, H.1.: ~-Blockers and labetalo!. Current Therapeutics 22 (6): 101-113 (1981).

van den Brink, G.; Boer, P.; van Asten, 1'.; Dorhout Mees, E.1.

and Geyskes, G .G. : One and three doses of propranolol a day

in hypertension . Clinical Journal of Pharmacology and Thera

peutics 27: 9-15 (1980).

Veterans' Administration Co-operative Study Group on Antihypertensive Agents. Journal of American Medical Association 213: 1143-1152 (1970).

WaaI-Manning, H.1 .: Metabolic effects of ~-adrenoreceptor

blockers. Drugs II (Supp!. I): 121-126 (1976).

Walker, R.G.; Young, C.K.; Hua, A.S.P.; Thomas, G.W.; Whit

worth, J .A. and Kincaid-Smith, p.s.: Tienilic acid in the treat

ment of mild to moderate hypertension. Qinical and Experi

mental Pharmacology and Physiology 7: 473-476 (1980).

Author's address: Dr Judith A. Whitworth . Department of Nephrology , Royal Melbourne Hospital , Parkville. 3050. Victoria (Australia).

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