Curr Hypertens Rep (2015) 17:30 DOI 10.1007/s11906-015-0542-4

ANTIHYPERTENSIVE AGENTS: MECHANISMS OF DRUG ACTION (ME ERNST, SECTION EDITOR)

Personalizing the Diuretic Treatment of Hypertension: the Need for More Clinical and Research Attention Samuel J. Mann & Michael E. Ernst

# Springer Science+Business Media New York 2015

Abstract Neither randomized controlled trials nor efforts to identify genetic markers have been helpful with regard to the goal of individualizing diuretic therapy in the treatment of hypertension, a goal that receives little clinical or research attention. This review will examine, and bring attention to, the considerable yet overlooked information relevant to individualizing diuretic therapy. It will bring attention to clinical, biochemical, and pharmacological clues that can be helpful in identifying who is likely to respond to a diuretic, who needs a stronger diuretic regimen, which diuretic to prescribe, and how to minimize adverse effects. New directions for clinical research aimed at individualizing use in hypertension will be explored. Research and clinical attention to the goal of individualizing diuretic treatment in hypertension need to be renewed, to help us achieve greater hypertension control with fewer adverse effects and lower costs.

Keywords Diuretics . Hypertension . Torsemide . Hydrochlorothiazide . Spironolactone . Chlorthalidone

This article is part of the Topical Collection on Antihypertensive Agents: Mechanisms of Drug Action S. J. Mann (*) Division of Nephrology and Hypertension, NY Presbyterian Hospital-Weill Cornell Medical College, 424 East 70th St, New York, NY 10021, USA e-mail: [email protected]

Introduction Diuretics are a crucial drug class in the management of hypertension. Their efficacy in lowering blood pressure and in preventing cardiovascular events has been repeatedly documented. And in many patients, hypertension cannot be controlled without a diuretic and without the diuretic regimen that is right for them. Recent diuretic research in hypertension has been dominated by large randomized, controlled trials (RCTs) that assess cardiovascular outcome and inform treatment guidelines. Guidelines based on those trials are informative, but do not offer strategies for individualizing diuretic treatment, a topic that receives minimal clinical and research attention. Recent efforts to personalize treatment have focused on the search for genetic predictors of responsiveness to diuretics. However, reported associations between candidate genes and the response to thiazide diuretics are rarely replicated [1]. And the usefulness of genome-wide association studies is limited by the large number of genes identified, and the small impact of each. Thus, personalization of diuretic therapy in hypertension requires us to look in directions other than the large RCTs and genetics. This review focuses on the clinical, biochemical, and pharmacokinetic clues, often widely overlooked, that can help in selecting the diuretic regimen that is right for the individual patient. It will point out aspects of diuretic use where adequate research is lacking and is needed.

The Three Diuretic Categories (Table 1)

M. E. Ernst Department of Pharmacy Practice and Science, College of Pharmacy, The University of Iowa, 200 Hawkins Dr, Iowa City, IA 52242, USA e-mail: [email protected]

Thiazide and Thiazide-Like Diuretics

M. E. Ernst Department of Family Medicine, Carver College of Medicine, The University of Iowa, 200 Hawkins Dr, Iowa City, IA 52242, USA

The thiazide and thiazide-like diuretics bind to the sodium/ chloride transporter along the distal convoluted tubule. The

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Table 1 The three types of diuretics used to treat hypertension [45, 75] Thiazides and thiazide-like diuretics Hydrochlorothiazide Chlorthalidone Indapamide Metolazone Loop diuretics Furosemide Torsemide Bumetanide Ethacrynic acida Potassium-sparing agents Mineralocorticoid receptor antagonists Spironolactone

a

Hypertension is not an approved indication

Eplerenone Epithelial sodium channel blockers Amiloride Triamterenea

most widely prescribed thiazide and thiazide-like diuretics are listed in Table 1. Hydrochlorothiazide (HCTZ) is by far the most prescribed, although the benefit in terms of cardiovascular outcome of chlorthalidone and indapamide is better documented. Metolazone may have a greater natriuretic effect than other thiazides in patients with chronic kidney disease (CKD), possibly due to effects in the proximal tubule [2, 3]. It is usually prescribed in combination with a loop diuretic, providing a powerful diuretic effect in patients with advanced CKD [4]. There has been extensive debate concerning the selection of HCTZ versus CTD as the first-step diuretic in treating hypertension. The widely used 25 mg dose of HCTZ is clearly less effective than 25 mg of CTD in lowering blood pressure [5, 6•]. However, the 50 mg dose is roughly equivalent to 25 mg of CTD with regard to antihypertensive effect and cardiovascular outcome [7, 8••]. Importantly, many patients do respond to lower doses (e.g., 12.5–25 mg of HCTZ or 12.5 daily or every other day of CTD), which confer a lower risk of adverse metabolic effects [9]. Outcome studies have demonstrated the benefit, in terms of cardiovascular events, of treatment with CTD, HCTZ, and indapamide [10••, 11–14]. A recent meta-analysis concluded that CTD reduced cardiovascular events by 21 % more than HCTZ did, although at least part of that difference may be related to relative dose [10••]. Regardless, it is likely that the blood pressure achieved, rather than the choice of diuretic, is the key factor in cardiovascular outcome [13].

Usual dose range, mg/day

Half-life, h

12.5–50 12.5–25 1.25–2.5 2.5–5

6–15 40–60 15–24 8–14

20–80 twice daily 2.5–10 0.5–2 twice daily 25–100

1.2 3.3 2 1–4

25–50

1.4 (+ active metabolites with longer half-life) 4–6

50–100 5–10 50–100

6–9

Loop Diuretics Loop diuretics inhibit the reabsorption of sodium and chloride in the thick ascending limb of the loop of Henle. They cause a more potent but briefer diuresis than the thiazide diuretics. The diuresis is then followed by retention of sodium which may mitigate the antihypertensive effect. In clinical practice, the use of loop diuretics for hypertension, rightly or wrongly, has been largely limited to patients with chronic kidney disease (CKD). The possible role of loop diuretics in treating hypertension is discussed below. Potassium-Sparing Diuretics The potassium-sparing diuretics are frequently combined with a thiazide or loop diuretic, enhancing the antihypertensive effect while reducing the risk of diuretic-induced hypokalemia. Because of the risk of hyperkalemia, potassiumsparing agents should not be prescribed to patients with advanced renal disease; they can be prescribed, albeit cautiously, to patients with mild-to-moderate renal dysfunction. Combining a potassium-sparing agent with an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blockers (ARB) increases the risk of hyperkalemia, mainly in patients with CKD. There are two categories of potassium-sparing diuretics (Table 1), mineralocorticoid receptor antagonists (MRAs) and epithelial sodium channel blockers.

Curr Hypertens Rep (2015) 17:30

The Mineralocorticoid Receptor Antagonists (MRAs) The MRAs spironolactone and eplerenone block the effects of aldosterone on luminal sodium permeability in the distal tubule, connecting tubule and cortical collecting duct, resulting in increased sodium excretion and reduced potassium excretion. They are effective add-on drugs for treatment of resistant hypertension [15, 16]. The more expensive eplerenone, which binds more specifically to mineralocorticoid receptors, is prescribed largely for patients who experience side effects such as erectile dysfunction or gynecomastia with spironolactone. Although not adequately assessed, a dose of 50–100 mg of eplerenone may be the equivalent to 25 mg of spironolactone [17]. Epithelial Sodium Channel (ENaC) Blockers Amiloride and triamterene block sodium/potassium exchange in the epithelial sodium channels of the distal nephron, thus inhibiting potassium excretion. Amiloride, approved for treating hypertension, is a well-tolerated alternative in patients who cannot tolerate spironolactone. It is more effective than spironolactone in the 5–8 % of black patients who have volume-related hypertension due to a polymorphism in an ENaC subunit [18–20]. Triamterene is not commonly prescribed by itself and is not approved for treating hypertension. At the 37.5 mg dose commonly combined with 25 mg of HCTZ, it does not reliably prevent hypokalemia [21].

Strategies for Strengthening the Diuretic Regimen Volume excess is a frequent component of resistant hypertension, even if it is not clinically apparent [22, 23]. The failure to strengthen the diuretic regimen beyond the usual 25 mg of HCTZ is perhaps the most frequent error made in managing resistant albeit easily remediable hypertension [22, 23]. Who Should Be Given a Higher Diuretic Dose and Who Should Not Strengthening the diuretic regimen is most likely to lower blood pressure in patients with volume-mediated hypertension. We lack reliable genetic markers, but available clinical and biochemical clues can help in identifying those most likely to benefit from strengthening the diuretic regimen. A key question is whether a high sodium intake blunts the antihypertensive effect of a diuretic and thus requires a stronger diuretic regimen. Decades-old studies say no, but examined much higher diuretic doses than those prescribed today [24, 25]. In contrast, increased sodium intake has been reported to increase blood pressure in patients taking just 25 mg of HCTZ

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[26]. Further studies employing current diuretic dosage are needed. Sodium intake is usually assessed by diet history, which is generally unreliable, or by a 24-h urine collection, which, although the Bgold standard,^ is burdensome, often incompletely collected, unsuitable for serial monitoring, and subject to considerable day-to-day variation. The accuracy of the more convenient spot urine sodium/creatinine ratio is being evaluated [27]. The persistence of edema during diuretic therapy suggests persisting volume excess, although other causes, such as venous insufficiency or a calcium channel blocker (CCB) or alpha-receptor blocker use, must be considered. Importantly, the absence of edema does not preclude the presence of volume-mediated hypertension. Plasma renin activity (PRA) is also an indicator of responsiveness to a diuretic [28–31]. Contraction of blood volume by diuretics stimulates renin secretion. Therefore, a low PRA (

Personalizing the diuretic treatment of hypertension: the need for more clinical and research attention.

Neither randomized controlled trials nor efforts to identify genetic markers have been helpful with regard to the goal of individualizing diuretic the...
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