Systemic Hypertension- Pedro Aranda, MD, and Eduardo Lopez de Nova&, MD

puretics are still among the most frequently used antlhypertensive drugs in the treatment of hyper- tenston. Their pharmacologic and hemodynamic @roperties are based on the water and salt metabo- lism’in the path&hysidogy of high blood pressure. Initially, there is a reduction ofpbsma and extra- ce@u ftuid v@ume; cardiac output also decreases. After this early-phase, cardiac ou’*pu’ returns to nocmat with an accompanying decrease in periph- eral resistance so as to correct the underlying he- modynamic fault of the hypertensiye state. Diuret- ics have a high therapeutic efficacy either as mono- therapy or fn combination with 4 blockers, angio- tensin-converting enzyme inhibitors or cakium an- tagonists.

The main problem with the use of diuretics is re- lated to their metabolic side-effects, which are dose-related. Currently, there is a tendency to administer low-dose djureties, which result in fewer clinical and metabolic side effects, but with a con- tinued antihypwtensive efficacy. Therefore, low doses of diuretics can be recoriimeuded as initial therapy in the stepped-care approach of hyperten- SIOII.

(Am J Cardiol lSIfP;fi5:72H-76H)

From the Hypertension Unit, Regional Hospital, Malaga, Spain. Address for reprints: Pedro Aranda, MD, Hypertension Unit, Re-

gional Hospital, Malaga, Spain.

S ince their introduction in clinical practice in 1957’ to the present day, diuretics have been the most frequently used antihypertensive agent.2 Both

the first therapeutic recommendations from the World Health Organization committee of experts3 and the latest recommendations of the Joint National Committee on Detection, Evaluation, and Treatment of Hypertension in 19884 have consistently proposed diuretics as the hyper- tensive drugs of choice.

Recently, it has been argued that changes are needed in the conventional antihypertensive therapeutic ap preach of using diuretics and @ blockers, mainly due to the possible negative biochemical effects and clinical in- tolerance of these agents5

Faced with this prospect,‘the reasons for considering diuretics as the antihypertensives of choice (Table I) and their related negative clinical-biochemical effects should be examined.

EPIDEMIOLOGIC AND PHY$lOPATHOLOGlC ROLE PLAYED BY S~DIURj IF’THE DEVELOPMENT AND PERFISFNCE OF HIGH BLOOD PRESSWE

From an epidemiologic standpoint, there appears to be a direct relationship between the consumption of sodi- um and the prevalence of high blood pressure.6 This rela- tionship between sodium chloride and blood pressure has recently been demonstrated by the Intersalt Cooperative Research Group.’ These results indicate that the urinary excretion of sodium is significantly related to blood pres- sure regardless of body mass ratio and alcohol intake.

However, despite the difficulties encountered in con- ducting studies on the role of sodium restriction in the reduction of blood pressure, several investigators7-9 con- cluded that sodium dietary restriction leads to a short- and long-term decrease in blood pressure in hypertensive patients. There appears to be great heterogeneity in the response of blood pressure to the intake and to the deple- tion of sodium. Two clearly different population sub- groups exist, a sodium-sensitive one that responds to changes in the intake of sodium and a sodium-resistant one that does not.6,10

These clinical epidemiologic considerations on the role of sodium intake in the development and persistence of high blood pressure are based on physiopathologic aspects. They focus on the role played by sodium as a result of a deficient renal excretion, a disturbance in the transmembrane ion transport, or an increase in peripher- al vascular resistance. * l,l 2 Thus, in a salt-sensitive popu- lation, an increase in the intake of sodium chloride would lead to an increase in peripheral vascular resistance and

72H THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

TABLE I Advantages for the Use of Diuretics as Initial Antihypertensive Therapy

Epidemiologic and physiopathologic role of sodium in the pathogenesis of high blood pressure

Hemodynamic and pharmacologic effects Therapeutic efficacy Good compliance Relatively inexpensive

blood pressure. The increase in both sodium and intracel- lular calcium leads to vascular reactivity and to an in- crease in symbathetic activity which, apart from increas- ing the peripheral vascular reactivity, would lead to a blockade in the renal excretion of sodium (Fig. 1).

ANTIHY~ERTENSIVE PHARMACOLOGIC AND HEMODYN~MIC EFFECTS OF DIURETICS: THERAPEUTIC EFFICACY

Hemodynamically, diuretics decrease blood pressure initially by reducing the volume of extracellular fluid and cardiac output with a compensatory increase in peripher- al vascular resistance. However, in the medium to long term, cardiac output tends to normalize. This depends on the diuretic dosage and the sustained decrease m periph- eral vascular resistance,13,14 which is the major physio- pathologic factor in the maintenance of the hypertensive state. Although the mechanisms that maintain a low pe- ripheral vascular resistance are not completely defined, the vasodilating action of diuretics (Fig. 2) appears to be directly mediated by a reduction in vascular reactivity, a secondary effect of the decrease in the intracellular level of sodium and calcium in the smooth muscle cells of the

t ’ ingesLthetic actwty Intracellular Na+ . .

1 t Intracellular Ca++ I

+ Vas~+~~~e

P.VR

t H.B.P.

+ : Sodium ;;++ : Calcium P.V.R. : Peripheral vascular resistance H.6.P : High blood pressure

FIGURE 1. Mechanisms of i ncreasingbloodpressureinthe ealt-m pqndatb . H.B.P. = high blood presswe; P.V.R. = peripheral vascular resistance.

Vasodilator effect

Dir L! \ Mediated

J

Na’ w Interference I

Ca” Exchange t Synthesis PGE,

Prostacyclin

1 Senkitlvity to : - angiotensin II - norepinephrine - actinomyosin - Ca”

7 / Peripheral vascular resistance

Nat : Sodium Ca” : Calcium PGE, : Prostaglandin E,

flGURE 2. Pharmawbgk ajltihypertensive effects ol diwet- ice. PGE2 = pro&a&&n E2.

vascular wa11,14-I6 or indirectly by reducing the vasocon- stricting response of arterioles to the action of endogenous vasoconstricting stimuli (catecholamines, angiotensin, actomyosin) or promoting the synthesis of vasodilating substances, such as prostacyclin or kallikreins.r3-I7 Alter- natively, the same adjustment that normalizes cardiac output, by self-regulation of tissues, may be responsible for the sustained reduction in peripheral vascular resis- tance.r6

Therefore, epidemiologic and physiopathologic impli- cations of sodium in the pathogenesis of high blood pres- sure and the pharmacologic effects of diuretics enable us to consider these drugs as one of the antihypertensive groups of choice.

With regard to their antihypertensive response, diu- retics have an efficacy similar to that of the angiotensin- converting enzyme inhibitors, calcium antagonists and 0 blockers in the treatment of mild to moderate hyperten- sion and may be used as monotherapy or in combination with the other hypertensive agents.r7-19 Moreover, diu- retics may help to counteract in many patients the hyper- tensive effects of a high salt intake or the concurrent use of sodium-retaining drugs, such as nonsteroidal anti-in- flammatory drugs, l 3 and to prevent the water and salt retention that may be produced by some vasodilators such as hydralazine or minoxidi1.13*16*17

With the exception of hypertensive situations compli- cated by edematous states or kidney failure, or those that require a rapid volume depletion, for which loop diuretics might be chosen, thiazide diuretics are preferable for the treatment of uncomplicated hypertension. ’ 3,1 ’

Opposed to loop diuretics, thiazide diuretics have been shown to produce a flat dose-response curve, and their antihypertensive efficacy does not improve significantly

THE AMERICAN JOURNAL OF CARDIOLOGY MAY 2, 1990 73H

A SYMPOSIUM: INDAPAMIDE AND ANTIHYPERTENSIVE STRATEGY

TABLE II Factors Influencing the Effects of Diuretics on the

Renal Management of Potassium and Magnesium

Type of diuretic Dose Duration of treatment Degree of salt restriction Normal balance of potassium and magnesium Associated diseases: left ventricular hypertrophy, ischemic heart

disease

when the dose is increased.13J7,20~21 High doses of diuret- ics trigger a series of reflex-type mechanisms, such as sympathetic hyperactivity and activation of the renin- aldosterone-angiotensin system, in response to the exces- sive loss of water and salt.‘3J7~22~24 Nevertheless, this is not a general response, because in some patients a direct correlation has been described between volume loss and reduction of blood pressure after the use of thiazides.25

Therefore, the current trend in the use of diuretics for treating uncomplicated hypertension is to give thiazides at low doses because of their high therapeutic efficacy.

Spironolactone and potassium-sparing diuretics (tri- amterene or amiloride) have a very mild antihypertensive actionI so they tend to be used only in combination with a thiazide or loop diuretic to prevent subsequent potassi- um loss. Nevertheless, the use of low doses of thiazides is associated in most patients with a mild potassium loss which may be counteracted, without the need for addi- tional distal-acting diuretics, by a diet with moderate salt restriction and a potassium-rich intake.‘3,‘7,26

Apart from the excellent results obtained with the use of diuretics as monotherapy for the treatment of mild to moderate essential hypertension, especially in blacks and the elderly, they provide an excellent adjuvant to other

antihypertensive agents. 4,‘9 Lower doses of diuretics are required when they are used in combination with @ blockers,‘8*27 angiotensin-converting enzyme inhibi- tors’8,28 and calcium antagonists29 because of the in- creased therapeutic efficacy. This may also improve the clinical tolerance of diuretics.28J0

DISADVANTAGES OF DIURETICS The problems derived from the use of diuretics in the

treatment of hypertension are related to their clinical tolerance and to the negative metabolic effects on urice- mia, serum potassium levels and lipid or carbohydrate meta~lism.‘3,‘5,‘7,31,3*

Most clinical and biochemical side effects are dose dependent and can be minimized by reducing the dose of these drugs.‘3~17,20,30,32 The most frequently observed ad- verse effects (> 1%) include gastrointestinal disturbances (vomiting, nausea, diarrhea), weakness, dizziness, skin rash, sexual dysfunction and impotence, and muscle cramps.31*33*34 Excessive doses of diuretics or their use in patients prone to volume depletion, such as the elderly or patients with disturbed sympathetic reflexes, may cause orthostatic hypotension. 14,31 Apart from the dose, other factors that lower clinical tolerance are old age35 or the presence of associated pathologic conditions, such as gout, dysfunction of the prostate and diabetes mellitus.

Most metabolic side effects induced by diuretics are the result of varying degrees of volume contraction after water and salt depletion. 36 These can be minimized to a great extent by the use of low doses.‘3J7~20~30~36

The most important negative metabolic effects attrib- utable to antihypertensive treatment with diuretics is their arrhythmia-induced potential as a result of hypoka- lemia and hypomagnesemia.32,37,38 Physiopathologically,

6M 12 M 6M 12M

A Cholesterol mg O/O

13 8

3

-2

-7

22

17 12

7

2

-3

n lndapamide 2.5 mg n 30 =

lid $l;;halldone n = 34

q Chlorthalldone 25 mg n=16

A HDL-c mg % 0 HCTZ 50 mg n = 28

4 2 0 HCTZ

25 mg n= 19

0 -2 -4

STANDARD DOSES LOW DOSES

FIGURE 3. Lipid pmfile moditi- catlonwlthstandardandlow dosesofmlerentdiudlcs. HClZ = hydmcbmthiazide; HDL-c = high-density lipopmtein MM=-.

74H THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

hypokalemia is the result of the urinary loss of sodium and potassium and of the activation of the angiotensin- renin system induced by volume contraction.36 The ar- rhythmogenic effect of hypokalemia, increased by the loss of magnesium,3”39 seems to be related both to an increased sympathetic activity3 ’ and to an increase in the irritability of myocardial tissue due to changes in the intracellular/extracellular potassium ratio.26

The concern over diuretic-induced hypokalemia has recently been questioned.40,41 A controversy exists about the role of diuretic-induced hypokalemia in the develop- ment of arrhythmias; some studies suggest an increased risk,37Jsg42 while others have failed to confirm it.43-45

Although the initial results of the Multiple Risk Fac- tor Intervention Tria146 showed a greater mortality in the subgroup of patients with high blood pressure and elec- trocardiographic abnormalities treated with diuretics, neither the final report of the Medical Research Coun- ci147 nor The Hypertension Detection and Follow-Up Program48 observed any adverse effects of diuretic thera- py on the cardiovascular mortality of patients. Moreover, the arrhythmogenic action of diuretics is likely to be directly related to their protracted use, particularly in prone persons, such as those with ischemic disease,22’41 basal electrocardiographic disturbances46 or left ventricle hypertrophy.31,37,40

In contrast, the potassium losses caused by diuretics may be minimized by using low doses,13,17,26,39,40 reducing sodium intake and increasing potassium in- take,13J7,26,31 or adding potassium-sparing distal diuret- ics (Table II).

Diuretics may lead to glucose intolerance or trigger the onset of diabetes, especially in obese persons or those with a family history of diabetes.17,47 Physiopathologi- tally, this appears to be related to the suppression of the pancreatic release of insulin induced by hypokalemia,49 and there is evidence that these effects can be prevented by maintaining suitable levels of potassium.26 Clinically, hyperglycemia usually appears with long-term use and disappears when treatment is discontinued.17 Although there is no evidence that these disorders of carbohydrate metabolism can increase the vascular risk of hypertensive patients, the blood sugar levels of hypertensive patients treated with diuretics should be regularly checked.

Although the prevalence of hyperuricemia in non- treated hypertensive patients is high, it is even greater after the use of diuretics, as a result of an excessive volume contraction.17,36 Treatment is not required, ex- cept in susceptible patients, or in those with plasma levels of uric acid in excess of 65 pmol/liter in women or 77 pmol/liter in men.i7

Finally, increases in triglycerides, total cholesterol and low-density lipoprotein and very low density lipopro- tein cholesterol fractions have been described with the use of diuretics, mainly thiazides,17,50J1 furosemide, xipa- mide, bumetanide, metolazone or pyretanide.50J 1 These changes in the lipid profile are quantitatively variable, dose-dependent,13qr7,50-52 and physiopathologically relat- ed to a greater sympathetic activity, release of catechol- amines, and to a reactive hyperinsulinism, to compen- sate for the increase in glucose after the increase in

growth hormone.50y52 Indapamide, a diuretic classified as an indoline, with a mechanism and place of activity ap- parently similar to the thiazides,50 does not seem to cause any negative changes in the lipid prolile,50,53,54 even in hypertensive patients with hypercholesterolemia55 (Fig. 3). The effects of diuretics on lipids tend to decline on a long-term basis31,34,40 or when they are discontinued5’ The clinical effect on the vascular morbidity and mortali- ty of hypertensive patients with all these lipid changes, generally within a normal range,40 needs to be deter- mined.

In conclusion, because of the epidemiologic and phys- iopathologic implications of sodium in the development and persistence of hypertension, and the vasodilating he- modynamic effects, high therapeutic efficacy, minimal clinical and biochemical side effects, relatively low cost and, in general, good compliance, low doses of diuretics should continue to be considered as antihypertensive agents of choice.36,40

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activity. Am J Med 1981:70:762-768. 39. Ryan MP. Diuretics and potassium magnesium depletion. Am J Med 1987:82:suppl 3A:38-47. 40. Moser M. In defense of traditional antihypertensive therapy. Hypertension 1988:12:324-326. 41. Struthers AD. Diuretics and arrhythmias in hypertension: is there cause for concern: ACE Report 50. In: Nicholls MG, ed. Great Britain; Cower Academic Journal, 1988. 42. HolliIield JW, Staton PE. Thiazide diuretics, hypokalemia and cardiac ar- rhythmias. Acto Med Stand 1981:suppl647:67-73. 43. Papademitriou V, Burris JF, Notargiacomo A, Fletcher RD. Freis ED. Thiazide therapy is not a MUX of arrhythmia in patients with systemic hyperten- sion. Arch Intern Med 1988;148:1272-1276. 44. Leif PD, Beligon I, Mates J. Diuretic induced hypokalemia does not cause ventricular ectopy in uncomplicated essential hypertension (abstr). Kidney Inr 1984;25:203. 45. Madias JE, Madias NE, Gavras HP. Non-arrhythmogenicity of diuretic- induced hypokalemia. Arch Intern Med 1984;144:2171~2176. 46. Multiple Risk Factor Intervention Trial: Risk factor changes and mortality results. JAMA 1982:248:1465-1476. 47. Medical Research Council Trial of Treatment of Mild Hypertension: Princi- ple results. Medical Research Council Working Party. Br Med J 1985;291:97- 104. 48. The Hypertension Detection and Follow-Up Program Cooperative Research Group: The effect of antihypertensive drug treatment on mortality in the presence of resting electrocardiographic abnormalities at baseline. The HDFP experience. Circulation 1984;70:996-1003. 49. Effect of thiazides on carbohydrate metabolism in patients with hypertension. N Engl J Med 1961:265:1028-1033. 50. Lardinois CK, Neuman SL. The effects of antihypertensive agents on serum lipids and lipoproteins. Arch Intern Med /988;/48:1280-/28888. 51. Ames RP, Hill P. Elevation on serum lipid levels during diuretic therapy of hypertension. Am J Med 1976.61:748-757. 52. Ames RP. Serum lipid and lipoprotein disturbances during antihypertensive therapy. Hasp Formulary 1981;16:1476-1486. 53. Beiling S, Vukovich RA, Neiss ES, Zisblatt M, Webb EM, Losi M. Long- term experience with indapamide. Am Heart J 1983;106:258-262. 54. Gerber A, Weidmann P, Branchetti MG. Serum lipoproteins during treat- ment with the antihypertensive agent indapamide. Hypertension 1985;7:suppI 2:164-169. 55. Scalabrino A, Galeone F, Giuntoli F. Clinical investigation on long-term effects of indapamide in patients with essential hypertension. Curr Ther Res 1984;35:17-22.

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