treatment of systemic hypertension

Treatment of Systemic Hypertension

GRAHAM A. MacGREGOR, MD

Most patients with high blood pressure (BP) can be managed by using one of 4 classes of compounds: a diuretic, p blocker, converting enzyme inhibitor or calcium antagonist. It is becoming clear, however, that different patients respond to different drugs and that side effects also vary from 1 patient to another. In many patients in whom 1 drug is not sufficient to lower BP, the combination of a low dose of 2 drugs, particularly a diuretic combined with a /3 blocker or a converting enzyme inhibitor, is an effective way of decreasing BP further. An understanding of the mechanisms whereby drugs lower BP and why they are additive with some drugs and not with others is clearly important in the more rational use of drugs.

The finding that much lower doses of drugs can be used is also important; the combination of a low dose of 2 drugs may not only be more effective in lowering BP but also have less side effects than a higher dose of a single drug. In patients with more resistant hypertension that is not controlled by 1 or 2 drugs combined, the next logical step is to add a third drug. Before doing this, however, it is important to check that the patient is complying with treatment and to consider secondary causes. Ideal- ly, such patients should be referred to someone with a special interest in high BP as they are more likely to have an underlying cause for their hypertension.

(Am J Cardiol 1987;80:9E-12E)

Ii igh blood pressure (BP) is now recognized as one of the most important predisposing factors to the development of cardiovascular disease, i.e., strokes, heart attacks, renal disease and peripheral vascular disease.l Indeed, along with cigarette smoking, high BP is one of the most preventable causes of premature death. Community studies have revealed that from 5%

to 30% of the population may have high BP and of those with high BP, approximately 95% to 98% have so-called “essential” hypertension, i.e., high BP for reasons that are not understood. It is important to real- ize that the risk of cardiovascular disease is not con- fined solely to those persons who have high BP but applies throughout the entire range of BP; even those people in the upper range of “normal” BP have a greater risk than those in the lower range.l

Salt: Much circumstantial and some direct evidence suggests that salt intake may play an important role in either causing, precipitating or aggravating the development of essential hypertension.2 Recent work has suggested possible mechanisms whereby a high salt intake may cause an increase in BP through an

From the Blood Pressure Unit, Department of Medicine, Char- ing Cross and Westminster Medical School, London, England.

Address for reprints: G. A. MacGregor, MD, Blood Pressure Unit, Department of Medicine, Charing Cross and Westminster Medical School, London W6 SRF, England.

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inherited defect in the kidney’s ability to excrete sodium; this causes a greater increase in the mechanisms designed to excrete this extra sodium, which, at the same time, may be in part responsible for the increase in peripheral resistance and thereby the high BP. Clearly, a better understanding of these mechanisms and particularly the identification of people at risk could lead to the prevention of essential hypertension, and many countries are now recommending that ev- eryone should gradually reduce salt intake.

Benefits of treatment: There is now very clear evidence from studies all over the world that lowering high BP reduces the risks of high BP, particularly strokes, heart failure and renal disease and in several studies, ischemic heart disease. Indeed, the only ques- tions that are left from these studies is what level of BP should be treated and what methods should be used to lower high BP. As more of these studies are reported, the level of BP where treatment is justified becomes lower. Studies from Australia,3 the Hypertension De- tection and Follow-Up Program study4 from the U.S. and the Medical Research Council trial5 from the United Kingdom all suggest that patients with a consistent systolic BP above 160 mm Hg or a consistent dia- stolic BP above 95 mm Hg will benefit from BP-lowering therapy. Many of these studies did not include a large number of patients over the age of 60, because there was some controversy about whether it was worthwhile to treat older patients. However, a recent

IOE A SYMPOSIUM: HYPERTENSION-THE PREVENTABLE CARDIOVASCULAR RISK FACTOR

study from Europe has clearly demonstrated that the elderly also benefit from BP-lowering therapy.6

Nonpharmacologic therapy: All patients with high BP, whatever the severity, should be instructed on nonpharmacologic ways to lower BP. By far the most impressive evidence for an effect of nonpharmacologic therapy on lowering BP is that of salt restriction.2 Early studies used very severe salt restriction (around 10 mmol [0.5 g] of sodium chloride a day), which is not very practical for most patients. More recent evidence suggests that more moderate reduction of sodium intake to-around 81) mmols (5 g) of sodium chloride a. day does cause a decrease in BP in many patients with essential hypertension. Although this alone is not al- ways sufficient to control BP, several studies have now confirmed that salt restriction increases the effective- ness of many of the antihypertensive drugs, particular: ly p blockers and converting enzyme inhibitors. If moderate salt restriction does not control BP, then the addition of a fi blocker or a converting enzyme inhibitor becomes very effective,

Several other dietary alterations have also been suggested to lower BP. Increasing potassium intake may lower BP but this effect is not so apparent when patients restrict salt intake.7 The amount of potassium needed also is too great to do by dietary means alone. Other studies have suggested that reducing fat intake or increasing magnesium or calcium intake may also lower blood pressure but evidence for these is contro- versia12 There is much more evidence for the role of obesity and weight reduction and studies now suggest that weight reduction, particularly if combined with salt restriction, may cause a decrease in BP.* Excessive alcohol intake is also now recognized as a potential cause, if not an aggravating factor, of high BP in some patients. There is also some suggestion that regular exercise may have a BP-lowering effect, but contrary to popular opinion, there is only 1 controlled study that has shown an effect of B,P decrease with a reduction in stress.g Most other studies have shown negative results.

In general, therefore, it makes sense to instruct all patients with high BP to cut back their salt intake by about half, by not adding salt to food or cooking and avoiding foods that contain very high amounts of salts. It also would appear sensible to increase potassium intake at least by increasing fresh fruit and vegetable consumption and to decrease saturated fat intake. Weight loss in the obese and regular exercise in the unfit may also be of benefit. Nevertheless, it must be realized that in most patients with more moderate to severe ,hypertension, BP cannot be lowered by these maneuvers; it is necessary to use BP-lowering drugs.

Pharmacqlogic iherapy Thiazide diuretics: The thiazide diuretics were first

introduced in the late 1950s and until recently have formed the backbone of BP-lowering therapy. Several studies have suggested that increasing a diuretic dos- age has little further effect on lowering BP in most patients but does increase the deleterious metabolic

consequences of the diuretics, for instance, hypokalemia.lO This flat BP dose response to increasing amounts of diuretics has been shown by using inhibitors of the renin system to be due to an increased release of renin and angiotensin II due to the greater sodium loss from the higher doses of diuretics.ll These higher levels of angiotensin II block the BP-lowering effect of the greater loss of sodium with the higher dose of diuretic. In spite of this knowledge, it is still common practice in many parts of the world to use large doses of diuretics with little advantage to the patient; in some patients, severe hypokalemia, sodium and water de- pletion and the development of gout have occurred. Further, large doses of diuretics are also associated with marked side effects. For instance, in the Medical Research Council study 15% of the male patients with- drew from diuretic therapy (10 mg of bendrofluazide), and the most outstanding side effect wasdevelopment of impotence. l2 Large doses of thiazide diuretics should therefore be avoided. ‘Increasingly,’ diuretics are not being used on their own even at lower doses but are being used in combination with a /3 blocker or a converting enzyme inhibitor.

Bet& blockers:.The introduction of /I blockers in the mid-1960s and their widespread acceptance .in. the 1970s for the treatment of high BP was a major ad- vance over centrally acting drugs such as methyldopa and clonidine. However, as with the diuretics many of the early studies of /3 blockers were performed using very large doses with no evidence of a dose response but much evidence of increased side effects. In spite of the widespread use of /3 blockers in high BP, there is still controversy about the mechanism whereby they lower BP. At least 1 of the mechanisms whereby BP is lowered is through inhibition of renin release and a reduction in circulating levels of angiotensin IV3 Sev- eral studies have demonstrated an additive effect between ,8 blockers and diuretics and this additive effect is likely to be due to the inhibition by the /3 blocker of the compensatory increase in renin release caused by the diuretic. @blockers, however, appear to only inhib- it sympathetically mediated renin release and increasing amounts of diuretics combined with p blockers may still cause a progressive compensatory increase in renin release and, thereby, angiotensin II concentra- tions with no further BP decrease. An important question in the treatment of patients with a ,f!? blocker and a diuretic is: what is the minimum dose of diuretic that is necessary and is there a flat dose response to the combination?

To examine this question, 2 randomized crossover studies were carried out with hydrochlorothiazide and the p blocker acebutolol, 400 mg once daily, in patients with essential hypertension.14

In the first study, acebutolol4OO mg once daily and hydrochlorothiazide 25 ‘rng once daily for 1 month were compared with acebutolol4OO mg once daily and hydrochlorothiazide 50 mg once daily for 1 month in a randomized crossover study in patients with essential hypertension who were receiving no other treatment. As Figure 1 shows, the increased dose of hydrochloro-

September 18, 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 60 11E

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FIGURE 1. Blood pressure before and after treatment with acebutolol 400 mg once daily and hydrochlorothiazide either 50 or 25 mg once daily for 1 month in 12 patients. Adapted from Br Med J.14

thiazide caused no further decrease in BP, but plasma potassium levels with the higher dose of thiazide were lower, although the difference was not significant. There was also a higher uric acid level and a significant increase in plasma renin activity.

In the second study 3 different dose combinations were given for 4 weeks each in a random order. The 3 combinations were acebutolol4OO mg with hydrochlorothiazide 12.5 mg, acebutolol400 mg with hydrochlorothiazide 25 mg and acebutolol 200 mg with hydrochlorothiazide 12.5 mg. As Figure 2 shows, comparing the part of the study where acebutolol400 mg and 12.5 or 25 mg of hydrochlorothiazide were used, there was little difference in BP. With the low dose of acebutolol (200 mg) and hydrochlorothiazide (12.5 mg], the BP decrease was less but nevertheless the BP decrease with this combination was maintained over 24 hours [Fig. 3). Our study demonstrates that a once-daily combination of a low dose of /3 blocker combined with the thiazide diuretic is effective in lowering BP in mild to moderate hypertension but the BP decrease was more or less identical whatever dose of diuretic was used with the ,6 blocker. This flat dose response to a thiazide diuretic in the presence of a ,6 blocker indicates that low doses of thiazide diuretics should be used in combination with a ,8 blocker. This flat dose response to the diuretic even in the presence of a /3 blocker is important because of the increasing adverse metabolic consequences of unnecessarily high doses of thiazide diuretics.

Angiotensin converting enzyme inhibitors: The angiotensin converting enzyme inhibitors are an alter- native to ,8 blockers when p blockers are not effective or cannot be tolerated.15 They work by blocking the enzyme that converts angiotensin I to angiotensin II leading to a marked decrease in circulating angiotensin II levels. Several studies have demonstrated an additive effect of converting enzyme inhibitors with

FIGURE 2. Blood pressure before and after treatment with acebutolol 400 mg once daily and hydrochlorothiazide either 25 mg or 12.5 mg once daily for one month in 12 patients. Adapted from Br Med 5.14

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FIGURE 3. Blood pressure before and after treatment with acebutolol 200 mg once daily and hydrochlorothiazlde 12.5 mg once daily for one month measured four and 24 hours after last dose. Adapted from Br Med J.14

diuretics. More recent studies using the 2 converting enzyme inhibitors now on the market, captopril and enalapril, have shown that low doses should be used to avoid adverse reactions, particularly in patients with renal failure.

Calcium antagonists: Verapamil and nifedipine have been used for many years in the treatment of angina but it is only recently that their BP-lowering effect has been recognized. They are of particular interest because it appears that their effect is related to the severity of the high BP. Some evidence, particularly from forearm blood flow studies, suggests that they are lowering BP, in part, through a mechanism whereby BP is raised. Several studies have now demon-

12E A SYMPOSIUM: HYPERTENSION-THE PREVENTABLE CARDIOVASCULAR RISK FACTOR

strated that nifedipine has an additive effect on BP when combined with a converting enzyme inhibitor and a ,6 blocker but there is controversy about the role of diuretics when added to nifedipine. They are particularly effective in patients with more resistant hypertension.16

References 1. Kannel WB. Role of blood nressure in cardiovascular morbiditv and mortality. Prog Cardiovasc Dis 1674;17:5-25. 2. MacGregor GA. Sodium is more important than calcium in essential hypertension. HFpertension 1985;7:628-637. 3. Australian National Blood Pressure Studv Management Committee. The Australian therapeutic trial in mild hypertension. ihncet 1980;1:1261-1267. 4. Hypertension Detection and Follow-Up Program Cooperative Group. Five year findings of the hypertension detection and follow-up program. I. Reduc- tion in mortahtv of persons with high blood pressure including mild hyperten- , ,. sion. TAMA 1979;242:2562-2571, - 5. Medical Research Council Working Party. MRC trial of treatment of hypertension: principal results. Br Med J 1985;291:97-104. 6. Amery A, Birkenhlger W, Brixko P, Bulpitt C, Clement D, DeSchaepdryver A. Faaard R. Forte I. Henrv IF. Leonetti G. O’Mallev K. Strasser T, Deruvttere M, l%llery c, For&e F, H&dy R, joossens jV, Lund-Johansen P, P&e j, Tuomilehto J, Williams B. Mortality and morbidity results from the European Working Party on high blood pressure in the elderly trial. Lancet 1985;1:1349- 1354.

7. Smith Sj, Markandu ND, Sagnella GA, MacGregor GA. Moderate potassium chloride supplementation in essential hypertension: is it additive to moderate sodium restriction? Br Med 1 1985;290:110-113. 8. Fagerbeg B, Andersson OK, Isaksson B, Bjorntorp P. Blood pressure control during weight reduction in obese hypertensive men: separate effects of sodium and energy restriction. Br Med J 1984;288:11-14. 9. Pate1 C, Marmot MC, Terry DJ. Controlled trial of biofeedback-aided behavioural methods in reducing mild hypertension, Br Med ] 1981;282:2005- 2008. 10. Berglund G, Andersson 0. Low doses of hydrochlorothiazide in hypertension: antihypertensive and metabolic effects. Eur J Clin Pharmacol 1976; 30:177-182. 11. Leonetti G, Terzoli L. Sala C, Bianchini C, Sernesi L. Zanchetti A. Rela- tionshin between the hvootensive and renin-stimulatine actions of diuretic therapy in hypertensivk’patients. Clin Sci Mel Med 19~8;55:307~309S. 12. Medical Research Council Working Party on Mild to Moderate Hyperten- sion Adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension. Lancet 1981;2:539-543. 13. Buhler FR, Laragh JH, Baer L, et al. Propranolol inhibition of renin secretion. A specific approach to diagnosis and treatment of renin-dependent hypertensive disease. N Engl r Med 1972;287:1204-1209. 14. MacGregor GA. Banks RA. Markandu ND. Bavliss I. Roulston I. Lack of

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effect of beta-blocker on flat dose response to thiazide in’hypertension: effica: cy of low dose thiazide combined with beta-blocker. Br Med J 1983;286:1535- 1538. 15. Edwards CRW, Padfield PL. Angiotensin converting enzyme inhibitors- past, present and bright future. Lancet 1985;1:30-34. 16. Calcium Antagonists in the Treatment of Hypertension. Proceedings of a Symposium, Scheveningen, The Netherlands, September 17-18, 1982. Hy- pertension 1983;5:suppl.

treatment of systemic hypertension

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