Drugs in the management of hypertension. Part I

Appraisal and reappraisal of cardiac therapy Edited by Arthur C. DeGraff and Julian Frieden Drugs in the management of hypertension. Part I Lot B. Page, M.D. Henry M. u M.D. James J. Sidd, M.D. Newton, and Boston, Mass. The importance of detecting and treating asymptomatic hypertension has belatedly dawned on the medical profession and the public almost simultaneously. It is still repugnant to both physicians and patients, t h a t persons who feel well, and are living active and productive lives should be given expensive and complex medication programs which frequently cause disagreeable side effects, in order to reduce the risk of catastrophes which seem remote and theoretical. Nevertheless, the compelling evidence that elevated blood pressure, even of mild degree, is associated with enhanced risk of cardiovascular disease, l and t h a t the risk is substantially reduced by lowering blood pressure 1-3 cannot be ignored. Furthermore, high blood pressure is the most potent single risk factor in which intervention is both feasible and effective. For the vast majority of hypertensive patients, good blood pressure control can be achieved with combinations of the antihypertensive medications currently available. Nevertheless, the imperfections of the antihypertensive drugs are evident, All are capable of causing side effects within the ordinary dose range, and most require multiple dose schedules. A high degree of patient compliance is required to follow these programs, and in some patients satisfactory control is difficult or impossible to achieve even with multiple drug therapy. New, potent drugs, still undergoing clinical tests give promise for better and more trouble-free control. Even so, the goal of uniformly effective, simple, and symptom-free drug therapy of hypertension still seems far away. From the Departments of Medicine, Newton-Wellesley Hospital and Tufts University School of Medicine, Newton and Boston, Mass. Received for publication Jan. 19, 1976. Reprint requests to: Lot B. Page, M.D., 2000 Washington St., Newton Lower Falls, Mass. 02162. 810 An even more distant goal is to prevent the development of an age-related rise in blood pressure which is the precursor of primary hypertension. Evidence suggesting that a preventive approach is possible has previously been reviewed2 Physiological studies on large numbers of hypertensive patients in recent years indicate that a heterogeneous variety of abnormalities is involved in sustaining elevated blood pressure. Under controlled conditions, patients appear to vary in the extent to which abnormalities in peripheral resistance, cardiac output, plasma volume, the renin-angiotensin-aldosterone system and the sympathetic nervous system contribute to elevated blood pressure2 Antihypertensive medications vary in their mode of action, and can be chosen specifically to oppose these abnormalities. This has raised hopes t h a t appropriate drugs can be specifically fitted to individual patients?- 6 On the other hand, physiologic profiles may vary over time in individual patients, 7 and side effects of drugs, as well as degree of hypotensive responses still cannot be accurately predicted for all patients. Eventually, predictive fitting of treatment p r o g r a m s may become possible. At present, drug programs must be individualized based on patients' responses. Individual programs nevertheless should be based on knowledge of the pharmacology of the antihypertensive drugs. Tranquilizers and sedatives have no established role in the treatment of hypertension, and their use should be discouraged. Diuretics A wide variety of diuretic drugs exhibit sustained antihypertensive action. The mechanisms by which they lower blood pressure are not thoroughly understood. The orally administered diuretics have their major actions at one of June, 1976, Vol. 91, No. 6, pp, 810-815 Drugs in m a n a g e m e n t of hypertension Table I. Classification of diuretics Major site of action Group I Loop of Henle Group II Cortical diluting segment Generic name Ethacrynic acid Furosemide Chlorothiazide Hydrochlorothiazide Hydroflumethiazide Bendroflumethiazide Benzthiazide Trichlormethiazide Methyclothiazide Polythiazide Cyclothiazide Chlorthalidone Quinethazone Metolazone Group III Distal tubule and collecting duct Spironolactone Triamterene Amiloride Trade name (s) Effec~ve oral dose range mg./day Commercially available dose (mg.) Edecrin Lasix Diuril Hydrodiu~il,Esidrix, Oretic Saluron Bunaron, Naturetin Exna Metahydrin Naqua Enduron Renese Anhydron Hygroron Hydromox Zaroxolyn 50-?* 40-?* 500-1000 50-100 25, 50 20, 40 250, 500 25, 50 25-50 2-5 25-50 4-8 50 2, 5, 5 50 2, 4 5-10 4-8 1-6 50-100 50-200 1-5 2, 5, 5 1, 2, 4 2 50. 100 50 2. 5, 5 Aldactone Dyrenium 100-400~ 100-200 25 100 Not available in U.S A. *No upper dose limit established,see text. tUsual dose = 100 mg./day. Largerdoses used in primaryhyperaldosteronismand "low renin" hypertension,see text. the three sites along the renal t u b u l e (see T a b l e I); these are (1) the ascending limb of H e n l e ' s loop, (2) the cortical diluting segment, a n d (3) the distal t u b u l e a n d collecting duct. Diuretic p o t e n c y is g r e a t e s t for the "loop diuretics" (group I) i n t e r m e d i a t e for benzothiadiazines, a n d o t h e r c o m p o u n d s which act on the cortical diluting s e g m e n t (group II), and w e a k e s t for t h e agents which a c t on the distal t u b u l e a n d collecting d u c t (group I I I ) . Group I. T h e "loop diuretics." f u r o s e m i d e and e t h a c r y n i c a c i d inhibit salt a n d w a t e r reabsorption b y t h e ascending limb of H e n l e ' s loop. R e a b sorption of sodium a n d chloride in this s e g m e n t of the t u b u l e is a c c o m p a n i e d b y limited, passive r e a b s o r p t i o n of water. T h i s process is an essential f e a t u r e of the u r i n a r y c o n c e n t r a t i o n a n d diluting mechanisms. T h e loop diuretics therefore interfere with b o t h the c o n c e n t r a t i n g a n d diluting ability of t h e kidney. Until recently, chloride r e a b s o r p t i o n was t h o u g h t to be a passive consequence of active sodium r e a b s o r p t i o n t h r o u g h o u t the renal tubule. However, recent studies indicate t h a t in t h e t h i c k ascending limb of H e n l e ' s loop, chloride is t h e actively r e a b s o r b e d ion. 8 Burg 9 ~~ h a s shown t h a t the m a j o r action of b o t h furo- American Heart Journal semide a n d e t h a c r y n i c acid is inhibition of active chloride t r a n s p o r t in this segment. Group ]]. T h e diuretic agents in this group exert their m a j o r diuretic action on the cortical diluting s e g m e n t of the renal tubule, distal to the loop of Henle. I n c l u d e d are chlorothiazide, and its congeners, a n d the non-thiazide c o m p o u n d s chlorthalidone, q u i n e t h a z o n e , and metolazone. M a x i m a l dilution of the urine is p r e v e n t e d by these agents, b u t c o n c e n t r a t i n g ability is unaffected. T h e agents in groups I and I I all increase excretion of sodium, chloride, a n d potassium. Group III. T h e distal diuretics spironolactone, t r i a m t e r e n e , and amiloride inhibit sodium reabsorption a t aldosterone sensitive sites in the distal t u b u l e a n d collecting duct. Sodium r e a b s o r p t i o n in this s e g m e n t of t h e t u b u l e is linked to secretion of p o t a s s i u m and h y d r o g e n ion. S p i r o n o l a c t o n e c o m p e t i t i v e l y inhibits t h e action of aldosterone, whereas the actions of t r i a m t e r e n e a n d amiloride are u n r e l a t e d to the presence of aldosterone. A n t i h y p e r t e n s i v e e f f e c t s o f d i u r e t i c s . Initially, the diuretics produce negative sodium a n d w a t e r balance, resulting in a fall in body weight, extracellular fluid and p l a s m a volumes, a n d cardiac output. R e n a l blood flow and g l o m e r u l a r filtra- 81 1 Page, Yager, and Sidd tion rate also fall slightly 11 and plasma renin activity increases. These effects occur in normotensive as well as in hypertensive subjects. In hypertensive patients these changes are accompanied by a fall in blood pressure, whereas no significant blood pressure reduction occurs in normotensive subjects. Dietary salt restriction has similar antihypertensive actions. Over a three to four week period of diuretic treatment, cardiac out put slowly returns to normal and plasma and extracellular fluid volume increase. It is likely t hat enhanced proximal tubular reabsorption in response to the initial volume depletion plays an important role in this readjustment. Stimulation of the renin-angiotensin-aldosterone system may also play a role. Studies of total exchangeable sodium balance, ECF and water balance in patients on long-term thiazide therapy have shown a return to pretreatment values. 12-14 Recent studies TM 16 have demonstrated a persistent small reduction of extracellular fluid and plasma volumes. Small reductions of glomerular filtration rate (GFR) also persist. A major factor in sustaining the antihypertensive effect of diuretics appears to be the slow development of diminished peripheral resistance. Several mechanisms to account for this change have been postulated. These include salt and water depletion of the arteriolar wall, an effect on autonomic control of vascular tone, and an effect on vascular smooth muscle reactivity. These theories remain to be substantiated. Thiazides have been shown to reduce vascular reactivity to norepinephrine and angiotensin. Conflicting data have been published on the effect of these diuretics on electrolyte content of arterial tissues. Although diuretics may reduce blood pressure through several mechanisms, strong evidence presently exists only for the role of persistent reduction of total body sodium content and plasma volume. Uses. Oral diuretics should be the cornerstone of most antihypertensive regimens. Mild to moderate hypertension is often controllable w i t h a diuretic alone. In more severe hypertension, these agents have been shown to enhance the effects of the other antihypertensive drugs, most of which can cause salt and water retention. Diuretics are generally well t o l e r a t e d , The polyuria which they induce lasts only days to a few weeks in non-edematous patients. In contrast 812 to many antihypertensive agents, diuretics produce no significant postural hypotension, and they are not associated with the development of tachyphylaxis. When used alone, diuretics lowered blood pressure significantly in 40 to 66 per cent of patients in different series. 17, 1~ Conway and Lauwers" reported an average reduction of 26/17 mm. Hg. Patients with diastolic pressures below 110 mm. Hg were f r e q u e n t l y rendered normotensive. Severe hypertension is not likely to be controlled with diuretics alone. However, several reports indicate t hat the same dose of diuretic results in a greater fall in blood pressure in severe, than in mild hypertension29, ~0 Choice of diuretic agent and dosage. To achieve smooth reduction of blood pressure, all of the oral diuretics must be administered at least once daily. Maximum effectiveness is achieved only after three to four weeks of therapy. T he thiazides were introduced in 1957 and have been the most widely used diuretics in the treatment of hypertension, Among the available pharmacologic preparations in group II, chlorothiazide 0.5 to 1.0 Gm. daily, hydrochlorothiazide 50 to 100 mg. daily, and chlorthalidone 100 to 200 mg. daily have been shown to have Comparable potency. T he other members of group II appear to have equivalent antihypertensive activity. Metolazone, 2.5 mg. daily has antihypertensive 9 effects comparable to hydrochlorothiazide, but experience with the drug is limited. Although thiazides can measurably reduce GFR when given parenterally, 11 this effect is negligible following oral administration. Loop diuretics. Most comparative studies indicate t h a t the antihypertensive potency of group I and group II diuretics are equivalent. ~'~ One recent crossover trial found hydrochlorothiazide more effective than furosemide in hypertension. ~ The greater diuretic potency of loop diuretic increases the risk of severe volume contraction, hypokalemia, and metabolic alkalosis w h e n compared to the less potent group II drugs. In edematous, azotemic, or refractory hypertensive patients, no ceiling dose has been established for loop diuretics. Their use should probably be reserved for the following clinical situations: 1. Hypertensive patients with congestive heart failure whose extracellular fluid volume cannot be adequately controlled with less potent diuretics. Intravenous use of furosemide or ethacrynic June, 1976, Vol. 91, No. 6 Drugs in management of hypertension acid promotes rapid excretion of sodium and is particularly useful in the t r e a t m ent of acute pulmonary edema associated with hypertension. 2. In hypertensive emergencies intravenous loop diuretics are useful adjuncts to therapy with intravenous vasodilators to counteract the strong sodium retaining effect of these agents. 3. When large doses of such drugs as alpha methyl dopa, hydralazine, or minoxidil are used, the resultant renal tubular sodium reabsorption may vitiate the antihypertensive action of these drugs when even maximal doses of less potent diuretics are used concomitantly. Substitutions of loop diuretics for the group II and III diuretics in such patients may result in weight loss and improved blood pressure control. ~7 4. In hypertensive patients with renal insufficiency, the high potency of the loop diuretics may be required to achieve adequate volume contraction. In such patients, an initial rise in blood urea nitrogen and creatinine is often followed by stabilization in renal function. ~3 Distal diuretics. Some investigators have found spironolactone in doses of 100 rag. daily to be as effective as thiazides or chlorthalidone in the t r e a t m e n t of unselected primary hypertension.~9. 39 Others have reported less marked reduction of blood pressure with spironolactone. 31' 3 2 Conflicting data have also been published concerning whether spironolactone and thiazides have additive antihypertensive properties. 33 34 The antipressor effect of triamterene has been reported to be weaker t ha n hydrochlorothiazide and chlorthalidone. 3~' 36 Occasionally, in patients treated with a group I or group II diuretic, secondary sodium retention and rise in blood pressure toward pre-treatment levels may occur. This may result from a brisk rise in aldosterone secretion induced by volume contraction. In this situation, the addition of spironolactone or triamterene may cause a modest diuresis and improved blood pressure control. 37 Distal diuretics also counteract the kaliuretic effects of the other oral diuretics. However, the commercially available combinations of a thiazide and spironolactone or triamterene do not reliably maintain the serum potassium within the normal range, and serum potassium should be determined frequently when any diuretic regimen is initiated. Recently, the use of spironolactone in the diagnosis and management of hypertension asso- American Heart Journal ciated with primary hyperaldosteronism and low plasma renin activity has been advocated. 7 ~8-4o Spark and Melby 38 reported t h a t high doses of spironolactone produced marked weight loss and normalization of blood pressure in patients with primary hyperaldosteronism but not in those with secondary hyperaldosteronism, while correcting the electrolyte abnormalities in both groups. T hey concluded that spironolactone acts in patients with primary hyperaldosteronism by a direct inhibitory effect on aldosterone activity. Bravo and colleagues 41 hold an opposing view, t h a t spironolactone works non-specifically to produce plasma and extracellular fluid volume depletion in these patients. T hey have demonstrated blood pressure responsiveness to volume depletion and salt restriction in patients with primary hyperaldosteronism as well as an additive effect of thiazide and spironolactone on blood pressure in this group21 Spironolactone has been found highly effective in lowering blood pressure in patients with primary hypertension and low plasma renin levels ("low renin hypertension") but relatively ineffective in patients with normal renin levels. ~- 40 Several other crossover studies have shown the low plasma renin activity group to respond as well to hydrochlorothiazide or chlorthalidone as to spironolactone22~ 43 In these studies the blood pressure response to either drug was better in the low plasma renin activity group. A smaller percentage of patients with normal plasma renin activity also responded to both agents. Adverse effects. All of the agents in groups I and II may induce hypokalemia and metabolic alkalosis. In some patients a high dietary potassium intake is adequate to maintain normal potassium balance. However, m any will require supplemental potassium chloride in doses of 40 to 80 mEq. per day or addition of a "potassiumsparing" group III diuretic to the regimen. The more potent diuretics may produce volume depletion and hyponatremia. Hyperuricemia is a common side effect of any of the agents in groups I and II. The use of thiazides raises the already high incidence of hyperuricemia among primary hypertensive patients from 25 to 35 per cent to 65 to 70 per cent24 Unless associated with a pre-existing history of gout or the development of gouty attacks after initiating therapy, asymptomatic hyperuricemia probably need not be treated. 8 13 Page, Yager, and Sidd C a r b o h y d r a t e i n t o l e r a n c e develops in some p a t i e n t s . T h i s is g e n e r a l l y n o t a c l i n i c a l p r o b l e m except in diabetic p a t i e n t s who m a y require a d j u s t m e n t of h y p o g l y c e m i c t h e r a p y . T h e r e is a low i n c i d e n c e w i t h t h e s e a g e n t s of serious allergic r e a c t i o n s s u c h as t h r o m b o e y t o p e nia, l e u k o p e n i a , or v a s c u l i t i s . R a r e l y , t h i a z i d e s have caused cholestatic j a u n d i c e a n d toxic pancreatitis. E t h a c r y n i c acid a n d f u r o s e m i d e c a n p r o d u c e r e v e r s i b l e h e a r i n g loss w h e n u s e d i n h i g h doses. S e v e r a l cases of p e r m a n e n t h e a r i n g deficit h a v e b e e n r e p o r t e d a f t e r e t h a c r y n i c acid a d m i n i s t r a tion. S u g g e s t i v e e v i d e n c e also l i n k s f u r o s e m i d e t o i r r e v e r s i b l e d e a f n e s s . 45 Spironolactone and triamterene may induce serious h y p e r k a l e m i a w h e n n o t g i v e n c o n c u r r e n t l y w i t h a n o t h e r d i u r e t i c or w h e n g i v e n t o p a t i e n t s t a k i n g h i g h d i e t a r y p o t a s s i u m i n t a k e or potassium supplements including salt substitutes. T h e risk of h y p e r k a l e m i a is p a r t i c u l a r l y g r e a t w h e n t h e s e a g e n t s are u s e d i n t h e p r e s e n c e of r e n a l i n s u f f i c i e n c y , a n d severe r e n a l f a i l u r e c o n t r a i n d i c a t e s t h e i r use. Triamterene may produce gastrointestinal upset. T h i s is g e n e r a l l y o v e r c o m e b y t a k i n g doses a t m e a l t i m e s . A r a r e c o m p l i c a t i o n of t r i a m t e r e n e is a n a n e m i a of folic acid deficiency. 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