drug therapy use of diuretics in patients with hypertension...diuretic† relative carbonic...

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 361;22 nejm.org november 26, 2009 2153

review article

Drug Therapy

Use of Diuretics in Patients with Hypertension

Michael E. Ernst, Pharm.D., and Marvin Moser, M.D.

From the Department of Pharmacy Prac-tice and Science, College of Pharmacy, and Department of Family Medicine, Carver College of Medicine, University of Iowa, Iowa City (M.E.E.); and the Section of Cardiovascular Medicine, Yale Univer-sity School of Medicine, New Haven, CT (M.M.). Address reprint requests to Dr. Ernst at the Department of Family Medi-cine, University of Iowa Hospitals and Clinics, 200 Hawkins Dr., 01291-A PFP, Iowa City, IA 52242, or at [email protected].

N Engl J Med 2009;361:2153-64.Copyright © 2009 Massachusetts Medical Society.

Thiazide diuretics became available in the late 1950s and were the first effective oral antihypertensive agents with an acceptable side-effect profile.1,2 A half-century later, thiazides remain important medications for the treatment of hypertension. These agents reduce blood pressure when administered as monotherapy, enhance the efficacy of other antihypertensive agents, and reduce hypertension-related morbidity and mortality. This review focuses on thiazides, the diuretics most often indicated for long-term therapy for hypertension; loop diuret-ics and potassium-sparing agents are briefly considered.

Clinic a l Ph a r m acol o gy of Thi a zides

Chemistry and Mechanism of Action

Diuretic therapy for hypertension originated in 1937 with the discovery that sulfon-amides caused acidemia and mild diuresis by inhibiting carbonic anhydrase in the proximal tubule.3,4 Chlorothiazide, a benzothiadiazine derivative, was isolated dur-ing a search for more potent inhibitors of carbonic anhydrase5; chlorothiazide was found to be a more effective diuretic and also to unexpectedly increase the excretion of chloride, rather than bicarbonate.6 This effect on excretion eventually led to iden-tification of the upstream portion of the distal convoluted tubule as the major site of action of the thiazides, where they interfere with sodium reabsorption by inhib-iting the electroneutral sodium–chloride symporter (Fig. 1).7 Activity against car-bonic anhydrase, although maintained by some thiazides, is considered irrelevant to their mechanism of action, since sodium that is rejected proximally is reabsorbed downstream in the renal tubule in the thick ascending limb. Despite structural varia-tion among the different congeners, the term thiazide diuretic includes all diuretics believed to have a primary action in the distal tubule.

Pharmacokinetics

The pharmacokinetic activities of thiazides are not uniform. All are absorbed oral-ly and have volumes of distribution equal to or greater than body weight (Table 1).8-10 Thiazides are extensively bound to plasma proteins, which helps limit their filtration by the glomeruli, in effect trapping the diuretic in the vascular space and allowing for its delivery to secretory sites of the renal proximal tubular cells. Or-ganic anion transporters may also assist by concentrating thiazides in the tubular lumen.11

The onset of action occurs after approximately 2 to 3 hours for most thiazides, with little natriuretic effect beyond 6 hours.12 Their metabolism, bioavailability, and plasma half-lives are variable. The latter two pharmacokinetic features are the most clinically relevant, as they determine the dose and frequency of administra-


n engl j med 361;22 nejm.org november 26, 20092154

tion. Chlorothiazide is relatively insoluble in lip-ids, and large doses are required to achieve levels sufficient to reach the site of action. Hydrochlo-rothiazide has relatively greater bioavailability; approximately 60 to 70% is absorbed, and food

intake enhances absorption.8,9 Some thiazides un-dergo extensive metabolism, whereas others are excreted nearly intact in urine. A 50% reduction in hydrochlorothiazide absorption is observed in patients with heart failure. Relatively little else is known about the influence of disease on the phar-macokinetics of thiazides.8

Most thiazides have a half-life of approximately 8 to 12 hours, just permitting effective once-daily dosing.9 Among thiazides, chlorthalidone is uniquely long-acting, with an elimination half-life of 50 to 60 hours, owing to its large volume of distribution.13 Nearly 99% of chlorthalidone is bound to erythrocyte carbonic anhydrase, and the drug has a stronger inhibitory effect than other thiazides against several catalytically active mammalian isoforms.14,15 The substantial parti-tioning of chlorthalidone into erythrocytes creates a tissue reservoir that allows the constant seep-ing of chlorthalidone back into plasma, through which it exerts its therapeutic effect.14 This depot effect of chlorthalidone may be advantageous in patients who occasionally miss doses, and the agent appears to retain measurable efficacy when given less frequently than once daily.16,17

Pharmacodynamics

Hemodynamic EffectsThe hemodynamic effects of thiazides can be sep-arated into short-term and long-term phases (Ta-ble 2).18 Initial decreases in blood pressure are attributed to the reductions in extracellular fluid and plasma volumes, leading to depressed cardiac preload and output.19 Dextran administration dur-ing this short-term phase will restore plasma vol-ume and blood pressure to pretreatment levels. Counterregulatory activation of the sympathetic nervous system and the renin–angiotensin–aldo-sterone system induces a transient rise in periph-eral vascular resistance, although this is not usually sufficient to negate the blood-pressure reduction.20 Combining a thiazide with an angio-tensin-converting–enzyme (ACE) inhibitor or an angiotensin II–receptor blocker (ARB) can oppose this transient rise in resistance and increase the antihypertensive response.

The long-term antihypertensive response to thiazides cannot be reliably predicted by the de-gree of initial reduction in plasma volume, which eventually returns to near-normal levels. Volume expansion due to the use of dextran at this stage no longer restores the blood pressure to pretreat-

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Filtered blood out(efferent arteriole)

Unfilteredblood in(afferent arteriole)

Aldosterone

Urine

Na+

Na+Cl−

Na+

2Cl−

K+

Na+/K+

NaHCO3

Proximal convoluted tubule

(65–70%)

Distal convoluted tubule (5%)

Loop of Henle (25%)

Collecting duct

(1–2%)

Glomerulus

Thick ascending limb

Thick descending limb Cortex

Medulla

Cortex

Kidney

Medulla

Renal artery

Renal vein

Loop diuretics

K+-sparing diuretics and mineralocorticoid-receptor

antagonists

Thiazides

Carbonic anhydrase inhibitors

NaCl

Na

2Cl

K

Figure 1. Sites of Diuretic Action in the Nephron.

The percentage of sodium reabsorbed in a given region is indicated in pa-rentheses. “K+-sparing agents” collectively refers to the epithelial sodium-channel inhibitors (e.g., amiloride and triamterene) and mineralocorticoid-receptor antagonists (e.g., spironolactone and eplerenone). Sodium is reabsorbed in the distal tubule and collecting ducts through an aldoster-one-sensitive sodium channel and by activation of an ATP-dependent so-dium–potassium pump. Through both mechanisms, potassium is secreted into the lumen to preserve electroneutrality. Sodium-channel inhibitors preserve potassium by interfering with the sodium–potassium pump, whereas mineralocorticoid-receptor antagonists spare potassium through their inhibitory effect on aldosterone. NaHCO3 denotes sodium bicarbonate.

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ment levels.21-23 A more likely explanation for the persistent antihypertensive effects of most thia-zides is an overall reduction in systemic resistance, although the exact mechanisms are unclear.24 Evi-dence suggests that chlorthalidone may not lower systemic resistance, even after 8 to 12 months of therapy, indicating that other mechanisms may be responsible.17 It is not yet clear whether thi-azides have direct vasodilatory properties or in-duce a reverse autoregulation phenomenon; they have also been proposed to cause structural mem-brane changes or altered ion gradients.24 A sim-pler possibility is that a low level of prolonged diuresis produced by long-term thiazide admin-istration may maintain a nominal state of volume contraction, thereby promoting a downward shift in vascular resistance.12

Thiazides have substantial residual effects after discontinuation. Rapid volume expansion, weight gain, and decreased renin levels occur after stop-ping thiazides, but blood pressure rises slowly and does not immediately reach pretreatment lev-els.18,25 With adherence to lifestyle modifications (e.g., weight loss, reduction in sodium and alco-hol intake), nearly 70% of patients may not require antihypertensive medications for up to 1 year after long-term thiazide-based therapy is withdrawn.26

Tolerance to DiureticsThe use of diuretics elicits both short- and long-term adaptations intended to protect intravascu-lar volume. Short-term tolerance may result from a period of post-dose antinatriuresis triggered by the initial reduction in extracellular fluid volume, corresponding to a decline in the drug level in plasma and tubular fluid to below the diuretic threshold.27 Activation of the renin–angiotensin–aldosterone system and the sympathetic nervous system, as well as suppression of the secretion of atrial natriuretic peptide and renal prostaglandin, also contribute to short-term tolerance.27 Post-dose sodium retention is significantly influenced by di-etary sodium intake. Sodium restriction promotes an overall negative sodium balance and enhances the therapeutic response to thiazides, whereas per-sistently high dietary sodium offsets this effect.28

Long-term diuretic adaptation, or the braking effect, refers to a gradual return of the sodium–chloride balance to an electroneutral level. Persis-tent volume removal appears to trigger long-term activation of the renin–angiotensin–aldosterone system, increasing circulating angiotensin II levels, which in turn promotes increased proximal so-dium reabsorption and limits the overall delivery of sodium to the distal site. Other volume-inde-

Table 1. Pharmacokinetic Characteristics of the Thiazide Diuretics Approved for Use in the United States.*

Diuretic†

Relative Carbonic Anhydrase Inhibition‡ Oral Bioavailability

Volume of Distribution Protein Binding Route of Elimination

Elimination Half-Life

percent liters per kilogram percent hr

Thiazide-type

Chlorothiazide ++ 15–30 1 70 100% Renal 1.5–2.5

Hydrochlorothiazide + 60–70 2.5 40 95% Renal 9–10

Methychlothiazide — — — — Hepatically metabolized —

Polythiazide + — — — 25% Renal 26

Bendroflumethiazide 0 90 1.0–1.5 94 30% Renal 9

Thiazide-like

Chlorthalidone +++ 65 3–13 99 65% Renal 50–60

Metolazone + 65 113 (total)§ 95 80% Renal 8–14

Indapamide ++ 93 25 (total)§ 75 Hepatically metabolized 14

* All the diuretics listed are available in generic form in the United States as monotherapy, except polythiazide (not currently available) and bendroflumethiazide (available only in combination with nadolol). Dashes indicate an absence of data.

† The terms thiazide-type and thiazide-like are used to group thiazides on the basis of the presence of a benzothiadiazine molecular structure. Thiazide-like diuretics lack the benzothiadiazine structure but have a mechanism of action similar to that of thiazide-type diuretics, which have the benzothiadiazine structure.

‡ Plus signs indicate inhibition, with greater numbers of plus signs reflecting increased inhibition (lower inhibition constants); the zero indi-cates an inhibition constant of 0.

§ The volumes of distribution of metolozone and indapamide are given for the total volume, in liters; data on liters per kilogram were not available.



pendent mechanisms may be involved, including the up-regulation of sodium transporters down-stream from the primary site of diuretic action and structural hypertrophy of distal nephron segments.29-31

Tolerance to diuretics can be overcome by ad-ministering higher doses or combinations of di-uretics. For example, synergistic diuresis occurs when a thiazide is added to loop-diuretic mono-therapy in patients with edema.32 Occult volume expansion can be present in patients with resis-tant hypertension, despite existing diuretic ther-apy; increasing the dose of diuretics may improve the blood pressure.33 High doses and combina-tions of diuretics must be used carefully to avoid renal injury and marked electrolyte disturbances.

Diur e tic Ther a py for H y pertensi v e Patien t s

Many physicians consider thiazides the diuretics of choice for long-term therapy. On average, after adjustment for reductions seen with the use of pla-cebo, thiazides induce a reduction in the systolic and diastolic blood pressures of 10 to 15 mm Hg and 5 to 10 mm Hg, respectively. Hypertension responding preferentially to thiazides is considered to be low-renin or salt-sensitive hypertension. The elderly, blacks, and patients with characteristics associated with high cardiac output (e.g., obesity) tend to have this type of hypertension. Thiazides also correct the hypertension and electrolyte ab-normalities associated with pseudohypoaldos-teronism type 2 (Gordon’s syndrome), a rare mendelian form of hypertension in which the so-dium–chloride symporter is excessively active. Thi-azides potentiate other antihypertensive agents

when they are used in combination, often produc-ing an additive decrease in blood pressure. The ad-dition of a thiazide minimizes racial differences usually observed in response to monotherapy with inhibitors of the renin–angiotensin–aldosterone system, and the use of such an inhibitor can lessen the degree of the hypokalemia and the metabolic perturbations that may be evoked by thiazides.

The dosing of thiazides has evolved in parallel to our progressive understanding of their mech-anism of action and dose–response relationships. Earlier use of high doses was based on the belief that efficacy was directly linked to the amount of renal sodium excretion and reduction in plasma volume; the larger the dose, the greater the as-sumed reduction in blood pressure. However, thi-azides are now used in substantially smaller doses, and the term low-dose thiazide has become syn-onymous with hydrochlorothiazide at a dose of 12.5 to 25 mg per day (or the equivalent dose of another thiazide). Approximately 50% of patients will respond initially to these low doses. In the Systolic Hypertension in the Elderly Program (SHEP),34 chlorthalidone given at a dose of 12.5 mg per day controlled blood pressure, for several years, in more than 50% of patients. Increasing the dose of hydrochlorothiazide from 12.5 to 25 mg per day may result in a response in an additional 20% (approximately) of patients; at 50 mg per day, 80 to 90% of patients should have measurable de-creases in blood pressure.35 Increased electrolyte losses at the higher doses of diuretics may pre-clude their routine use.

For many hypertensive patients, several agents will be needed to achieve desired blood-pressure targets. Combination regimens that include a thi-azide can achieve therapeutic synergy while min-

Table 2. Hemodynamic and Physiological Effects after Initiation and Cessation of Diuretic Therapy.

VariableShort-Term Phase

(first 2–4 wk) Long-Term Phase (mo) Post-Therapy Period

Cardiac output Decrease Increase (return to pretreatment level)

No change

Plasma volume Decrease Increase (near-return to pretreat-ment level)

Increase (possibly exceeding pre-treatment level)

Plasma renin activity Increase Increase Decrease (return to pretreatment level)

Peripheral resistance Transient increase Gradual decrease Increase (gradual return to pre-treatment level)

Blood pressure Decrease Decrease Gradual increase

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imizing adverse effects.36 The lack of appropriate diuretic use is often identified as the primary drug-related cause of resistance to treatment.37

Diuretics in Renal Impairment

Thiazides are typically considered ineffective when the glomerular filtration rate decreases below 30 to 40 ml per minute per 1.73 m2 of body-surface area, although direct evidence is lacking. Small studies have shown that thiazides can elicit an an-tihypertensive response in patients with chronic kidney disease38,39; however, their use in patients with severe renal impairment remains impracti-cal, for two reasons: first, the reduced glomeru-lar filtration rate limits the overall filtered sodi-um load reaching the distal tubule; and second, reabsorption in the distal tubule is only modestly effective as compared with that in the large-capac-ity, thick ascending limb.12 These features under-score the rationale for substituting so-called high-ceiling diuretics that act more proximally, in the loop of Henle, in hypertensive patients with renal impairment.

Metolazone, a quinazoline derivative, is an ex-ception among thiazides because it retains its ef-ficacy in patients who have renal insufficiency or other diuretic-resistance states.40 Its effect is lim-ited by slow, erratic absorption; the more predict-able bioavailability of other thiazides makes them better suited as long-term therapy of hypertension. Metolazone should be reserved for use in combi-nation with loop diuretics in patients with volume overload whose fluid and electrolyte balance are being closely monitored. It is administered daily for a short period (3 to 5 days), with administra-tion reduced to thrice weekly after this period or after euvolemia is achieved.27

Loop Diuretics

Diuretics that act in the loop of Henle can lower blood pressure but are less effective in the long term than thiazides.41 Most loop diuretics have a short duration of action (approximately 6 hours), resulting in an initial diuresis that is followed closely by a period of antinatriuresis lasting up to 18 hours per day when the drug is administered once daily. A net neutral sodium balance, or even a positive balance, can occur with the use of loop diuretics. These agents are most appropriate for the treatment of hypertension that is complicated by a reduced glomerular filtration rate (



Diur e tics in Tr i a l s w i th C a r diova scul a r End Poin t s

The efficacy of thiazides in reducing the risk of major cardiovascular events was first established in 1967, in the landmark Veterans Affairs Coop-erative Study.45 In the ensuing years, thiazide reg-imens have proved highly effective in the preven-tion of stroke, coronary heart disease, and heart failure (see the Supplementary Appendix, available with the full text of this article at NEJM.org).

Combined meta-analyses and systematic re-views report that, as compared with placebo, thi-azide-based therapy reduces relative rates of heart failure (by 41 to 49%), stroke (by 29 to 38%), coro-nary heart disease (by 14 to 21%), and death from any cause (by 10 to 11%).46-48 These and other analyses also show that the benefit from thia-zides is broadly similar to that from other antihy-pertensive drugs, with results consistent across age and sex strata.46-51 The largest randomized, blinded study performed to date, the Antihyper-tensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),52 compared initial treatment consisting of chlorthalidone, at a dose of 12.5 mg per day, with treatment consisting of amlodipine, lisinopril, or doxazosin. The 42,418 high-risk study participants were 55 years of age or older, and 35% were black. The doxazosin treat-ment was stopped prematurely owing to a signifi-cantly greater incidence of heart failure events than with chlorthalidone. At the end of the study, no significant differences were found between the chlorthalidone group and any other treatment group in the rate of the composite primary end point of fatal coronary heart disease or nonfatal myocardial infarction; however, chlorthalidone was superior with respect to several predefined secondary end points, including heart failure (vs. amlodipine and lisinopril) and stroke (vs. lisino-pril). The explanation for these findings may be related to the improved blood-pressure control maintained throughout the study in the patients receiving chlorthalidone as compared with those receiving another treatment. Analyses of data stratified on the basis of race and metabolic status consistently indicate that chlorthalidone, used as initial therapy, was not surpassed by any of the three comparison drugs with regard to antihyper-tensive efficacy or event-rate reduction.53-57

Although chlorthalidone and hydrochlorothi-azide have been commonly used in the United

States, other thiazides, such as bendroflumethia-zide and indapamide, have also been studied. Re-cently, the use of a sustained-release indapamide-based regimen as initial therapy led to relative reductions of 39%, 64%, and 21% in the rates of fatal stroke, heart failure, and death, respectively, in patients older than 80 years of age.58

Ther a peu tic Con trov er sies

The concept of a class effect among thiazides has been promulgated in the absence of comparative studies. In the United States, this debate largely centers on whether to use hydrochlorothiazide or chlorthalidone.59 Chlorthalidone is frequently sug-gested for use, since the rate of cardiovascular events has been reduced in every study in which it was used, including at the low doses in the SHEP study and ALLHAT, whereas the effects of other thiazide regimens have been less consis-tent.60 Trials in which hydrochlorothiazide was associated with favorable reductions in the rate of cardiovascular events have typically used higher doses (between 25 and 50 mg per day) than cur-rently advocated. These dose-based differences are underappreciated, and the perception that thia-zides are interchangeable is reinforced by the abun-dance of fixed-dose combinations containing low-dose hydrochlorothiazide. Two trials of low-dose hydrochlorothiazide in combination with other medications showed less effectiveness as com-pared with the nonthiazide regimen.61,62

Hydrochlorothiazide and chlorthalidone are of-ten incorrectly described as equipotent.10 How-ever, early trials comparing the two drugs often involved the administration of hydrochlorothia-zide twice daily to achieve reductions in blood pressure similar to those effected by chlorthali-done.63,64 When evaluated on the basis of the dose required to achieve equivalent reductions in the systolic blood pressure, 24-hour ambulatory blood-pressure monitoring confirmed that chlor-thalidone is approximately twice as potent as hydrochlorothiazide.65 These findings may be at-tributable to the ability, with chlorthalidone thera-py, to maintain efficacy throughout the night and reduce the gradual rise in blood pressure that may occur during the interval between daily doses.

Whether hydrochlorothiazide and chlorthali-done are interchangeable in reducing the risk of cardiovascular events is questionable. An analy-sis in the Multiple Risk Factor Intervention Trial

drug ther apy


(MRFIT) suggested a lower mortality rate in the group randomly assigned to undergo a “special intervention” in clinics predominantly using chlorthalidone than in those predominantly us-ing hydrochlorothiazide, but the assignment to a specific diuretic was not randomized, and the study design precluded an ability to reliably sepa-rate diuretic effects from those of the other con-current interventions.66 Conversely, a meta-analy-sis that did not include the MRFIT findings has suggested no significant differences between the two agents.67

Optimal Role of Diuretics — Initial or Add-On Therapy?

Despite a long, well-established record of efficacy, the role of thiazides in hypertension therapy con-tinues to provoke debate.68 Based on the benefits observed in studies in which thiazides were used as initial therapy in a stepped-care approach, with agents added sequentially, guidelines for hyper-tension therapy in the United States have advocated thiazides as initial treatment since 1977, when the first Joint National Committee report was is-sued.69 In contrast, British guidelines recommend diuretics more selectively, such as for use in the elderly and blacks.70 European guidelines endorse several antihypertensive agents, including diuret-ics, as initial therapy.71 An update from the Joint National Committee is anticipated in the near future.

Slightly more than one third of the patients in the United States who are eligible for thiazide ther-apy actually receive it.72 The reasons for this low rate of use may include the absence of corporate promotion of diuretics and the heavy marketing of newer medications.73 Pleiotropic effects in addition to the blood-pressure–lowering effect have been hypothesized for ACE inhibitors and ARBs but not for thiazides.74 In addition, there is discussion about the importance of adverse electrolyte and metabolic changes in association with thiazides and whether these changes abrogate the overall blood-pressure–lowering benefits of the drugs.75,76

Cumulative evidence from trials suggests that the magnitude of blood-pressure lowering is the most important determinant in reducing the car-diovascular risks associated with hypertension.49 As diuretics are eventually required in many hy-pertensive patients to achieve blood-pressure goals, debate about their role as initial or add-on thera-py may be predominantly academic.

S a fe t y a nd A dv er se Effec t s of Thi a zides

Much of the criticism against thiazides is directed toward their adverse-effect profile, but low doses are usually well tolerated and have been shown to improve quality-of-life measures.77 Most compli-cations of thiazide therapy are related to the dose and duration of use (Fig. 2).

Thiazides can reduce the excretion of calcium and uric acid and thereby increase their plasma levels, and the drugs increase potassium and magnesium excretion, potentially leading to hy-pokalemia and hypomagnesemia. On average, measured plasma potassium levels decrease by about 0.3 to 0.4 mmol per liter with typical dos-ing of thiazide monotherapy,78 but coadministra-tion of an ACE inhibitor or an ARB can reduce the incidence of clinically relevant hypokalemia. In ALLHAT, the average potassium level among pa-tients receiving chlorthalidone decreased from 4.3 mmol per liter to 4.1 mmol per liter over a 4-year period.52 The plasma potassium level should be measured at baseline, before the initiation of thiazide monotherapy; a potassium-sparing agent may be considered if the baseline level is less than 3.8 mmol per liter.

Maintaining potassium homeostasis is essen-tial, since epidemiologic evidence implicates hy-pokalemia in the pathogenesis of thiazide-induced dysglycemia.79 The importance of potassium bal-ance is also emphasized by findings from the SHEP study, in which the rate of coronary events among patients with potassium levels below 3.5 mmol per liter was reduced to a lesser degree than among patients with higher potassium levels.80 Hypokalemia can be managed with the use of a potassium-sparing agent or supplemental potas-sium chloride. Potassium-sparing agents are pre-ferred because they correct the underlying cause. Dietary salt restriction can also minimize thia-zide-induced potassium losses.28

New-onset diabetes has been reported in pa-tients receiving thiazides; however, newly diag-nosed diabetes occurs over time in many hyper-tensive patients, regardless of which class of antihypertensive agent is used. Data suggest that receipt of thiazides, as compared with other anti-hypertensive agents, over several years may lead to an excess of 3 to 4% of new cases of diabetes.79

In ALLHAT, the rates of fatal and nonfatal myo-cardial infarction were similar among patients re-



ceiving chlorthalidone, despite the fact that newly diagnosed diabetes was more frequent in the chlorthalidone group (seen in 11.6% of patients) than in the amlodipine group (9.8%) or the lisinopril group (8.1%).54 To date, no analyses of ALLHAT data have indicated that the develop-ment of diabetes obviates the benefit of the thiazide.53-57 Similar findings have been report-ed in a large meta-analysis and in long-term follow-up data of the SHEP cohort.81-83 Despite these reassurances, newly diagnosed diabetes in patients receiving thiazides remains a potential concern, since the period of monitoring for long-

term diabetes-related adverse effects on cardiovas-cular outcomes may have been too short.

Few clinically relevant drug interactions oc-cur with the use of thiazides; most notably, non-steroidal antiinflammatory drugs diminish the therapeutic effect of thiazides by causing sodium retention. Thiazides can increase serum lipid lev-els, primarily total cholesterol and low-density li-poprotein cholesterol levels, by approximately 5 to 7% in the first year of therapy.84 A summary of common clinical problems encountered with thi-azides, and potential solutions, are detailed in Table 3.

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Diuresis Hypomagnesemia

Increased distal Ca++ reabsorption

Decreased uric acid clearance Hyperuricemia

Impaired renal H2O excretion Hyponatremia

Decreased renal blood flow Prerenal azotemia

Increased activation of RAAS Kaliuresis Hypokalemia

Impaired insulin resistance Dysglycemia

Diuretic

Increased proximal Na+ reabsorption Increased arterial resistance

Possible limitation of blood-pressure lowering

Decreased plasma volume Increased proximal Ca++ reabsorption

Decreased cardiac output OrthostasisDecreased Ca++ clearance

Ada

ptat

ions

to d

iure

tics

Increased activation of RAAS Kaliuresis Hypokalemia

Impaired insulin resistance Dysglycemia

?

Figure 2. Potential Complications of Diuretics and Their Associated Mechanisms.

RAAS denotes the renin–angiotensin–aldosterone system.

drug ther apy


Conclusions

Diuretics are a heterogeneous class of antihyper-tensive medications that have long demonstrated effectiveness in reducing blood pressure and the risk of cardiovascular events. With proper atten-tion to appropriate selection, dosing, and moni-toring, diuretic-based regimens can greatly improve the ability to achieve blood-pressure goals. Few

pharmacologic discoveries have advanced the treat-ment of any disease in such a profound and en-during manner.

Dr. Ernst reports receiving advisory fees and consulting fees from Takeda Pharmaceuticals; and Dr. Moser, advisory fees from Takeda Pharmaceuticals and GlaxoSmithKline and lecture fees from Kaiser and the Consortium for Southeastern Hyper-tension Control. No other potential conflict of interest relevant to this article was reported.

Table 3. Common Clinical Problems Encountered with Thiazides, and Possible Solutions.*

Clinical Problem Possible Solution

Attack of acute gouty arthritis Obtain uric acid level, and discontinue thiazide if level is elevated. Recheck level after resolution of the attack, and assess the need for prophylaxis. Use another antihypertensive agent if uricosuric prophylaxis is not tolerated or indicated.

Hypokalemia (serum potassium ≤3.5 mmol/liter) Correct hypomagnesemia if present. Add potassium-sparing agent or supple-mental potassium chloride. Advise salt restriction. If blood pressure is not controlled, consider adding a RAAS inhibitor.†

Increase in serum creatinine from baseline level Assess hydration status and discontinue any concurrent and unnecessary nephrotoxic drugs (e.g., NSAIDs). Recognize that a slight elevation in cre-atinine may be the result of improved blood-pressure control in patients with microvascular disease, in whom renal function is dependent on blood pressure for adequate perfusion.

No apparent response to hydrochlorothiazide at a dose of 25 mg/day

Assess lifestyle and advise salt restriction if needed. Consider increase in di-uretic dose, switch to longer-acting thiazide such as chlorthalidone, or addition of RAAS inhibitor.†

Report of dizziness on standing Check for orthostasis. Reduce diuretic dose if necessary. Assess hydration status, and insure diuretic is administered in the morning. Instruct the patient to stand up slowly.

Discovery of asymptomatic hyponatremia Assess concurrent medications (e.g., SSRIs) and determine risks and benefits of continuing thiazide. Evaluate patient for excessive water intake.

Thiazide therapy recommended for patient with docu-mented history of allergy to a sulfa antibiotic

Sulfa antibiotic allergy is not a contraindication to receiving a thiazide. The risk for cross-sensitivity appears to be more dependent on an underlying propensity for atopy than on any specific cross-reactivity among the classes. If true allergy to thiazide is documented, ethacrynic acid (a non–sulfa-containing thiazide) can be used.

Report of muscle cramps Check serum potassium level and normalize if low. Consider another diuretic if electrolyte levels are normal.

Impaired fasting glucose level or diabetes at baseline Institute appropriate management of cardiovascular risk factors. Thiazide use is not precluded.

Development of diabetes during thiazide therapy Institute appropriate management of diabetes and related cardiovascular risk factors. The average excess increase in glucose attributed to thiazide use is approximately 3–5 mg/dl (0.2–0.3 mmol/liter). Thiazides will probably be necessary for achieving blood-pressure targets. The addition of a RAAS inhibitor† should be considered, especially if blood pressure is not con-trolled.

Nocturia or incontinence Avoid thiazide dosing in the afternoon or evening. Limit evening fluid intake. Consider discontinuing thiazide if symptoms are intolerable.

Baseline GFR



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