Thiazides General Statement (Monograph)

Drug class: Thiazide Diuretics
- Diuretics, Thiazide
- Thiazide Diuretics
VA class: CV701

Introduction

Thiazides are diuretics and antihypertensive agents.

Uses for Thiazides General Statement

Edema

Thiazide diuretics are used in the management of edema resulting from a number of causes; however, careful etiologic diagnosis should precede the use of any diuretic. There are no substantial differences in the clinical effects or toxicity of comparable dosages of the thiazides or thiazide-like diuretics except that metolazone may be more effective than other thiazide-like diuretics in the management of edema in patients with impaired renal function. Determination of the specific agent to be used is, therefore, usually determined by factors such as cost and patient convenience.

Heart Failure

Clinical Role

Thiazides are used in the management of edema associated with heart failure. Most experts state that all patients with symptomatic heart failure who have evidence for, or a history of, fluid retention generally should receive diuretic therapy in conjunction with moderate sodium restriction, an agent to inhibit the renin-angiotensin-aldosterone (RAA) system (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, angiotensin receptor-neprilysin inhibitor [ARNI]), a β-adrenergic blocking agent (β-blocker), and in selected patients, an aldosterone antagonist. Some experts state that because of limited and inconsistent data, it is difficult to make precise recommendations regarding daily sodium intake and whether it should vary with respect to the type of heart failure (e.g., reduced versus preserved ejection fraction), disease severity (e.g., New York Heart Association [NYHA] class), heart failure-related comorbidities (e.g., renal dysfunction), or other patient characteristics (e.g., age, race). The American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) state that limiting sodium intake to 1.5 g daily in patients with ACCF/AHA stage A or B heart failure may be reasonable. While data currently are lacking to support recommendation of a specific level of sodium intake in patients with ACCF/AHA stage C or D heart failure, ACCF and AHA state that limiting sodium intake to some degree (e.g., less than 3 g daily) in such patients may be considered for symptom improvement.

Diuretics play a key role in the management of heart failure because they produce symptomatic benefits more rapidly than any other drugs, relieving pulmonary and peripheral edema within hours or days compared with weeks or months for cardiac glycosides, ACE inhibitors, or β-blockers. However, since there are no long-term studies of diuretic therapy in patients with heart failure, the effects of diuretics on morbidity and mortality in such patients are not known. Although there are patients with heart failure who do not exhibit fluid retention in the absence of diuretic therapy and even may develop severe volume depletion with low doses of diuretics, such patients are rare and the unique pathophysiologic mechanisms regulating their fluid and electrolyte balance have not been elucidated.

Most experts state that loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide, torsemide) are the diuretics of choice for most patients with heart failure, especially in those with renal impairment or substantial fluid retention, since loop diuretics increase sodium excretion to 20–25% of the filtered load of sodium, enhance free water clearance, and maintain their efficacy unless renal function is severely impaired (e.g., creatinine clearance less than 5 mL/minute). In contrast, thiazide diuretics increase fractional sodium excretion to only 5–10% of the filtered load, tend to decrease free water clearance, and lose their efficacy in patients with moderate renal impairment (e.g., creatinine clearance less than 30 mL/minute). However, thiazides may be preferred in some patients with concomitant hypertension because of their sustained antihypertensive effects. In patients who develop azotemia or hypotension before therapeutic goals are achieved, consideration to decreasing the rate of diuresis may be made, but diuretic therapy should continue until fluid retention is eliminated, provided that decreases in blood pressure remain asymptomatic; excessive concern about hypotension and azotemia may result in suboptimal diuretic therapy leading to refractory edema.

Efficacy

Diuretics increase urinary sodium excretion and decrease physical signs of fluid retention in patients with heart failure. Results of short-term studies in patients with heart failure indicate that diuretic therapy is associated with a reduction in jugular venous pressures, pulmonary congestion, ascites, peripheral edema, and body weight within a few days of initiating such therapy. In addition, diuretics may improve cardiac function, symptoms, and exercise tolerance in these patients. However, since there are no long-term studies of diuretic therapy in patients with heart failure, the effects of diuretics on morbidity and mortality are not known. Nevertheless, most long-term studies of therapeutic interventions for heart failure have been in patients receiving diuretic therapy. Diuretics should not be used as monotherapy in patients with heart failure even if symptoms of fluid overload (e.g., peripheral edema, pulmonary congestion) are well controlled, because diuretics alone do not prevent progression of heart failure.

Dosing Considerations

Depending on the dosage employed, diuretics may alter the efficacy and safety of concomitantly used drugs in heart failure, and therefore diuretic dosage should be selected carefully. Excessive diuretic dosages may lead to volume depletion, which can increase the risk of hypotension in patients receiving ACE inhibitors or vasodilators and renal insufficiency in patients receiving ACE inhibitors or angiotensin II receptor antagonists. Inadequate diuretic dosages may lead to fluid retention, which can decrease the response to ACE inhibitors and increase the risk of β-blocker therapy. Patients with mild heart failure may respond favorably to low doses of diuretics, since absorption of diuretics from the GI tract is rapid and the drugs are distributed rapidly to the renal tubules in such patients; however, as heart failure advances, absorption of the drugs may be delayed because of bowel edema or intestinal hypoperfusion, and distribution may be impaired because of decreases in renal perfusion and function. Therefore, dosage of diuretics usually needs to be increased with progression of heart failure; eventually, patients may become resistant to even high dosages of diuretics. If resistance to diuretics occurs, IV administration of a diuretic or concomitant use of 2 or more diuretics (e.g., a loop diuretic and metolazone, a loop diuretic and a thiazide diuretic) may be necessary, or alternatively, short-term administration of a drug that increases blood flow (e.g., a positive inotropic agent such as dopamine) may be necessary. ACCF and AHA state that IV loop diuretics should be administered promptly to all hospitalized heart failure patients with substantial fluid overload to reduce morbidity. In addition, ACCF and AHA state that low-dose dopamine infusions may be considered in combination with loop diuretics to augment diuresis and preserve renal function and renal blood flow in patients with acute decompensated heart failure, although data are conflicting and additional study and experience are needed.

Maintenance Therapy

Once fluid retention has resolved in patients with heart failure, diuretic therapy should be maintained to prevent recurrence of fluid retention. Ideally, diuretic therapy should be adjusted according to changes in body weight (as an indicator of fluid retention) rather than maintained at a fixed dosage. Diuretics also should be continued in patients with comorbid conditions (e.g., hypertension) where ongoing therapy with the drugs is indicated.

Other Edematous Conditions

In edema secondary to nephrotic syndrome, thiazides may be useful if the patient fails to respond to corticosteroid therapy. Edema secondary to nephrotic syndrome is more likely to become refractory to therapy than edema associated with heart failure, and more potent diuretics may be required. Other forms of edema caused by renal disease and edema caused by corticosteroids and estrogens also may be relatively resistant to treatment with the thiazides. Thiazides and thiazide-like diuretics (with the exception of metolazone) are ineffective in patients with serum creatinine or BUN concentrations greater than about twice normal. Some clinicians state that thiazides are ineffective in patients with a glomerular filtration rate (GFR) of less than 15–25 mL/minute, whereas others suggest that use of a more potent diuretic should be considered whenever the GFR is less than 50 mL/minute.

Edema associated with pregnancy generally responds well to thiazides except when caused by renal disease. Hypertension during pregnancy also responds well, but preeclampsia and eclampsia may require more potent diuretics. The routine use of thiazides is contraindicated in pregnant women with mild edema who are otherwise healthy.

Hypertension in Adults

Thiazide diuretics are used alone or in combination with other classes of antihypertensive agents in the management of all stages of hypertension.

Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics); data from clinical outcome trials indicate that lowering blood pressure with any of these drug classes can reduce the complications of hypertension and provide similar cardiovascular protection. However, recommendations for initial drug selection and use in specific patient populations may vary across these expert guidelines. This variability is due, in part, to differences in the guideline development process and the types of studies (e.g., randomized controlled studies only versus a range of studies with different study designs) included in the evidence reviews. Ultimately, choice of antihypertensive therapy should be individualized, considering the clinical characteristics of the patient (e.g., age, ethnicity/race, comorbid conditions, cardiovascular risk factors) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, costs).

Thiazide diuretics historically have been considered the drugs of choice for most patients with uncomplicated hypertension because of their established benefits, cost, and favorable adverse effects profile. However, current evidence indicates no overall differences in clinical outcomes between thiazide diuretics and other classes of antihypertensive drugs, including calcium-channel blockers, ACE inhibitors, and angiotensin II receptor antagonists. While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes. Because many patients eventually will need drugs from 2 or more antihypertensive classes, experts generally state that the emphasis should be placed on achieving appropriate blood pressure control rather than on identifying a preferred drug to achieve that control.

Disease Overview

Worldwide, hypertension is the most common modifiable risk factor for cardiovascular events and mortality. The lifetime risk of developing hypertension in the US exceeds 80%, with higher rates observed among African Americans and Hispanics compared with whites or Asians. The systolic blood pressure (SBP) and diastolic blood pressure (DBP) values defined as hypertension (see Blood Pressure Classification under Uses: Hypertension in Adults) in a 2017 multidisciplinary guideline of the American College of Cardiology (ACC), AHA, and a number of other professional organizations (subsequently referred to as the 2017 ACC/AHA hypertension guideline in this monograph) are lower than those defined in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines, which results in an increase of approximately 14% in the prevalence of hypertension in the US. However, this change in definition results in only a 2% increase in the percentage of patients requiring antihypertensive drug therapy because nonpharmacologic treatment is recommended for most adults now classified by the 2017 ACC/AHA hypertension guideline as hypertensive who would not meet the JNC 7 definition of hypertension. Among US adults receiving antihypertensive drugs, approximately 53% have inadequately controlled blood pressure according to current ACC/AHA treatment goals.

Cardiovascular and Renal Sequelae

The principal goal of preventing and treating hypertension is to reduce the risk of cardiovascular and renal morbidity and mortality, including target organ damage. The relationship between blood pressure and cardiovascular disease is continuous, consistent, and independent of other risk factors. It is important that very high blood pressure be managed promptly to reduce the risk of target organ damage. The higher the blood pressure, the more likely the development of myocardial infarction (MI), heart failure, stroke, and renal disease. For adults 40–70 years of age, each 20-mm Hg increment in SBP or 10-mm Hg increment in DBP doubles the risk of developing cardiovascular disease across the entire blood pressure range of 115/75 to 185/115 mm Hg. For those older than 50 years of age, SBP is a much more important risk factor for developing cardiovascular disease than is DBP. The rapidity with which treatment is required depends on the patient’s clinical presentation (presence of new or worsening target organ damage) and the presence or absence of cardiovascular complications; the 2017 ACC/AHA hypertension guideline states that treatment of very high blood pressure should be initiated within 1 week.

Blood Pressure Classification

Accurate blood pressure measurement is essential for the proper diagnosis and management of hypertension. Error in measuring blood pressure is a major cause of inadequate blood pressure control and may lead to overtreatment. Because a patient’s blood pressure may vary in an unpredictable fashion, a single blood pressure measurement is not sufficient for clinical decision-making. An average of 2 or 3 blood pressure measurements obtained on 2–3 separate occasions using proper technique should be used to minimize random error and provide a more accurate blood pressure reading. Out-of-office blood pressure measurements may be useful for confirming and managing hypertension. The 2017 ACC/AHA hypertension guideline document (available on the ACC and AHA websites) should be consulted for key steps on properly measuring blood pressure.

According to the 2017 ACC/AHA hypertension guideline, blood pressure in adults is classified into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension. (See Table 1.) The 2017 ACC/AHA hypertension guideline lowers the blood pressure threshold used to define hypertension in the US; previous hypertension guidelines (JNC 7) considered adults with SBP of 120–139 mm Hg or DBP of 80–89 mm Hg to have prehypertension, those with SBP of 140–159 mm Hg or DBP of 90–99 mm Hg to have stage 1 hypertension, and those with SBP of 160 mm Hg or higher or DBP of 100 mm Hg or higher to have stage 2 hypertension. The blood pressure definitions in the 2017 ACC/AHA hypertension guideline are based upon data from studies evaluating the association between SBP/DBP and cardiovascular risk and the benefits of blood pressure reduction. Individuals with SBP and DBP in 2 different categories should be designated as being in the higher blood pressure category.

Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher blood pressure category (i.e., elevated BP).

The blood pressure thresholds used to define hypertension, when to initiate drug therapy, and the ideal target blood pressure values remain controversial. The 2017 ACC/AHA hypertension guideline recommends a blood pressure goal of less than 130/80 mm Hg in all adults who have confirmed hypertension and known cardiovascular disease or a 10-year atherosclerotic cardiovascular disease (ASCVD) event risk of 10% or higher; the ACC/AHA guideline also states that this blood pressure goal is reasonable to attempt to achieve in adults with confirmed hypertension who do not have increased cardiovascular risk. The lower blood pressure values used to define hypertension and the lower target blood pressure goals outlined in the 2017 ACC/AHA hypertension guideline are based on clinical studies demonstrating a substantial reduction in the composite end point of major cardiovascular disease events and the combination of fatal and nonfatal stroke when a lower SBP/DBP value (i.e., 130/80 mm Hg) was used to define hypertension. These lower target blood pressure goals also are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP. A linear relationship has been demonstrated between cardiovascular risk and blood pressure even at low blood pressures (e.g., 120–124 mm Hg SBP). The 2017 ACC/AHA hypertension guideline recommends estimating a patient’s ASCVD risk using the ACC/AHA Pooled Cohort equations (available online at [Web]), which are based on a variety of factors including age, race, gender, cholesterol levels, statin use, blood pressure, treatment for hypertension, history of diabetes mellitus, smoking status, and aspirin use. While the 2017 ACC/AHA hypertension guideline has lowered the threshold for diagnosing hypertension in adults, the threshold for initiating drug therapy has only been lowered for those patients who are at high risk of cardiovascular disease. Clinicians who support the 2017 ACC/AHA hypertension guideline believe that these recommendations have the potential to increase hypertension awareness, encourage lifestyle modification, and focus antihypertensive drug initiation and intensification in those adults at high risk for cardiovascular disease.

The lower blood pressure goals advocated in the 2017 ACC/AHA hypertension guideline have been questioned by some clinicians who have concerns regarding the guideline’s use of extrapolated observational data, the lack of generalizability of some of the randomized trials (e.g., SPRINT) used to support the guideline, the difficulty of establishing accurate representative blood pressure values in typical clinical practice settings, and the accuracy of the cardiovascular risk calculator used in the guideline. Some clinicians state the lower blood pressure threshold used to define hypertension in the 2017 ACC/AHA hypertension guideline is not fully supported by clinical data, and these clinicians have expressed concerns about the possible harms (e.g., adverse effects of antihypertensive therapy) associated with classifying more patients as being hypertensive. Some clinicians also state that using this guideline, a large number of young, low-risk patients would need to be treated in order to observe a clinical benefit, while other clinicians state that the estimated gains in life expectancy attributable to long-term use of blood pressure-lowering drugs are correspondingly greater in this patient population.

Treatment Benefits

In clinical trials, antihypertensive therapy has been found to reduce the risk of developing stroke by about 34–40%, MI by about 20–25%, and heart failure by more than 50%. In a randomized, controlled study (SPRINT) that included hypertensive patients without diabetes mellitus who had a high risk of cardiovascular disease, intensive SBP lowering of approximately 15 mm Hg was associated with a 25% reduction in cardiovascular disease events and a 27% reduction in all-cause mortality. However, the exclusion of patients with diabetes mellitus, prior stroke, and those younger than 50 years of age may decrease the generalizability of these findings. Some experts estimate that if the SBP goals of the 2017 ACC/AHA hypertension guideline are achieved, major cardiovascular disease events may be reduced by an additional 340,000 and total deaths by an additional 156,000 compared with implementation of the JNC 8 expert panel guideline goals but these benefits may be accompanied by an increase in the frequency of adverse events. While there was no overall difference in the occurrence of serious adverse events in patients receiving intensive therapy for blood pressure control (SBP target of less than 120 mm Hg) compared with those receiving less intense control (SBP target of less than 140 mm Hg) in the SPRINT study, hypotension, syncope, electrolyte abnormalities, and acute kidney injury or acute renal failure occurred in substantially more patients receiving intensive therapy.

Clinical Benefits of Thiazides in Hypertension

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which compared the long-term cardiovascular morbidity and mortality benefit of chlorthalidone (a thiazide-like diuretic), amlodipine (a long-acting dihydropyridine calcium-channel blocker), and lisinopril (an ACE inhibitor), supports the clinical benefits of thiazides in the management of hypertension.

ALLHAT provides strong evidence that usual dosages of chlorthalidone, amlodipine, and lisinopril are comparably effective in providing important cardiovascular benefit in a broad population of patients with stage 1 or 2 hypertension at risk for coronary heart disease, but apparent differences in certain secondary outcomes were observed. After a mean follow-up of 4.9 years, an intent-to-treat analysis revealed no difference in the primary outcome of combined fatal coronary heart disease or nonfatal myocardial infarction among the treatments. Compared with chlorthalidone, the relative risks for the primary outcome were 0.98 for amlodipine and 0.99 for lisinopril. In addition, all-cause mortality, a secondary outcome, did not differ among the treatments.

Chlorthalidone was superior to amlodipine (by 25%) in preventing heart failure overall and also for hospitalized or fatal cases, although the drugs were comparably effective in preventing overall cardiovascular disease. Subgroup analysis (age [younger than 65 years vs 65 years or older], race [black vs nonblack], gender, underlying diabetes mellitus status) revealed no subgroup differences in outcomes between amlodipine and chlorthalidone therapy. Unlike some previously reported evidence with short-acting calcium-channel blockers, ALLHAT revealed no evidence of excess coronary heart disease associated with long-acting calcium-channel blocker therapy.

Chlorthalidone also was superior to lisinopril in preventing aggregate cardiovascular events, principally stroke, heart failure, angina, and the need for coronary revascularization. Much of the superiority in reducing these events may be attributable to the greater antihypertensive effect of chlorthalidone (i.e., an overall difference of 2–4 mm Hg in SBP) compared with that of lisinopril. In addition, chlorthalidone was better tolerated than lisinopril.

In ALLHAT, an α-blocker (doxazosin) treatment arm was terminated prematurely after an interim analysis indicated that use of doxazosin in high-risk (at least 2 risk factors for coronary heart disease) hypertensive patients 55 years of age and older was associated with a higher risk of stroke and incidence of combined cardiovascular disease events.

Post hoc analysis of ALLHAT directly comparing cardiovascular and other outcomes in patients receiving amlodipine versus those receiving lisinopril revealed no difference in the primary outcome of combined fatal coronary heart disease or nonfatal MI between patients receiving the ACE inhibitor and those receiving the calcium-channel blocker. However, patients receiving lisinopril were at higher risk for stroke, combined cardiovascular disease, GI bleeding, and angioedema, while those receiving amlodipine were at higher risk of developing heart failure. ALLHAT investigators suggested that the observed differences in cardiovascular outcome may be attributable, at least in part, to the greater antihypertensive effect of amlodipine compared with that of lisinopril, especially in women and black patients.

Subgroup analysis for race-related effects revealed no difference in the primary outcome of combined fatal coronary heart disease or nonfatal MI among the treatments in both black and nonblack patients. However, substantial race-related effects were observed in the incidence of secondary outcomes (e.g., stroke, combined cardiovascular disease events, heart failure). Compared with chlorthalidone, the relative risk for lisinopril was 1.4 or 1 (in black or nonblack patients, respectively) for stroke and 1.19 or 1.06 (in black or nonblack patients, respectively) for combined cardiovascular disease events. When amlodipine was compared with chlorthalidone, the only race-related difference observed was in the incidence of heart failure; the relative risk was 1.46 or 1.32 (in black or nonblack patients, respectively). The relative risk for heart failure in black patients versus nonblack patients receiving lisinopril was not considered to be statistically significant, and the overall relative risk for both groups was 1.19. In addition, after 4 years, in each treatment group, blood pressure reductions were greater in nonblack than in black patients; about 68 or 60% of nonblack or black patients, respectively, achieved a SBP/DBP of less than 140/90 mm Hg. In nonblack patients receiving chlorthalidone, amlodipine, or lisinopril 69, 69, or 67% achieved the mentioned blood pressure, respectively, while in black patients receiving chlorthalidone, amlodipine, or lisinopril 63, 60, or 54% achieved such blood pressure, respectively.

Based on cost and other considerations (e.g., differences in secondary outcomes, differences in patient tolerance), ALLHAT provides compelling evidence that thiazides, in particular the long-acting drug chlorthalidone, should be considered as one of the initial drugs of choice in most patients with hypertension. ALLHAT did not include a first-line β-blocker treatment arm.

General Considerations for Initial and Maintenance Antihypertensive Therapy

Nonpharmacologic Therapy

Nonpharmacologic measures (i.e., lifestyle/behavioral modifications) that are effective in lowering blood pressure include weight reduction (for those who are overweight or obese), dietary changes to include foods such as fruits, vegetables, whole grains, and low-fat dairy products that are rich in potassium, calcium, magnesium, and fiber (i.e., adoption of the Dietary Approaches to Stop Hypertension [DASH] eating plan), sodium reduction, increased physical activity, and moderation of alcohol intake. Such lifestyle/behavioral modifications, including smoking cessation, enhance antihypertensive drug efficacy and decrease cardiovascular risk and remain an indispensable part of the management of hypertension. Lifestyle/behavioral modifications without antihypertensive drug therapy are recommended for individuals classified by the 2017 ACC/AHA hypertension guideline as having elevated blood pressure (SBP 120–129 mm Hg and DBP less than 80 mm Hg) and in those with stage 1 hypertension (SBP 130–139 mm Hg or DBP 80–89 mm Hg) who do not have preexisting cardiovascular disease or an estimated 10-year ASCVD risk of 10% or greater.

Initiation of Drug Therapy

Drug therapy in the management of hypertension must be individualized and adjusted based on the degree of blood pressure elevation while also considering cardiovascular risk factors. Drug therapy generally is reserved for patients who respond inadequately to nondrug therapies or in whom the degree of blood pressure elevation or coexisting risk factors, especially increased cardiovascular risk, require more prompt or aggressive therapy; however, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial. Recommendations generally are based on specific blood pressure levels shown in clinical studies to produce clinical benefits and can therefore vary depending on the studies selected for review.

The 2017 ACC/AHA hypertension guideline and many experts currently state that the treatment of hypertension should be based not only on blood pressure values but also on patients’ cardiovascular risk factors. For secondary prevention of recurrent cardiovascular disease events in adults with clinical cardiovascular disease or for primary prevention in adults with an estimated 10-year ASCVD risk of 10% or higher, the 2017 ACC/AHA hypertension guideline recommends initiation of antihypertensive drug therapy in conjunction with lifestyle/behavioral modifications at an average SBP of 130 mm Hg or an average DBP of 80 mm Hg or higher. For primary prevention of cardiovascular disease events in adults with a low (less than 10%) estimated 10-year risk of ASCVD, the 2017 ACC/AHA hypertension guideline recommends initiation of antihypertensive drug therapy in conjunction with lifestyle/behavioral modifications at an SBP of 140 mm Hg or higher or a DBP of 90 mm Hg or higher. After initiation of antihypertensive drug therapy, regardless of the ASCVD risk, the 2017 ACC/AHA hypertension guideline generally recommends a blood pressure goal of less than 130/80 mm Hg in all adults. In addition, an SBP goal of less than 130 mm Hg also is recommended for noninstitutionalized ambulatory patients 65 years of age or older. While these blood pressure goals are lower than those recommended for most patients in previous guidelines, they are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.

Most data indicate that patients with a higher cardiovascular risk will benefit the most from tighter blood pressure control; however, some experts state this treatment goal also may be beneficial in those at lower cardiovascular risk. Other clinicians believe that the benefits of such blood pressure lowering do not outweigh the risks in those patients considered to be at lower risk of cardiovascular disease and that reclassifying individuals formerly considered to have prehypertension as having hypertension may potentially lead to use of drug therapy in such patients without consideration of cardiovascular risk. Previous hypertension guidelines, such as those from the JNC 8 expert panel, generally recommended initiation of antihypertensive treatment in patients with an SBP of at least 140 mm Hg or DBP of at least 90 mm Hg, targeted a blood pressure goal of less than 140/90 mm Hg regardless of cardiovascular risk, and used higher SBP thresholds and targets in geriatric patients. Some clinicians continue to support the target blood pressures recommended by the JNC 8 expert panel because of concerns that such recommendations in the 2017 ACC/AHA hypertension guideline are based on extrapolation of data from the high-risk population in the SPRINT study to a lower-risk population. Also, because more than 90% of patients in SPRINT were already receiving antihypertensive drugs at baseline, data are lacking on the effects of initiating drug therapy at a lower blood pressure threshold (130/80 mm Hg) in patients at high risk of cardiovascular disease. The potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs should be considered when deciding a patient’s blood pressure treatment goal.

The 2017 ACC/AHA hypertension guideline recommends an ASCVD risk assessment for all adults with hypertension; however, experts state that it can be assumed that patients with hypertension and diabetes mellitus or chronic kidney disease (CKD) are at high risk for cardiovascular disease and that antihypertensive drug therapy should be initiated in these patients at a blood pressure of 130/80 mm Hg or higher. The 2017 ACC/AHA hypertension guideline also recommends a blood pressure goal of less than 130/80 mm Hg in patients with hypertension and diabetes mellitus or CKD. These recommendations are based on a systematic review of high-quality evidence from randomized controlled trials, meta-analyses, and post hoc analyses that have demonstrated substantial reductions in the risk of important clinical outcomes (e.g., cardiovascular events) regardless of comorbid conditions or age when SBP is lowered to less than 130 mm Hg. However, some clinicians have questioned the generalizability of findings from some of the trials (e.g., SPRINT) used to support the 2017 ACC/AHA hypertension guideline. For example, SPRINT included adults (mean age: 68 years) without diabetes mellitus who were at high risk of cardiovascular disease. While benefits of intensive blood pressure control were observed in this patient population, some clinicians have questioned whether these findings apply to younger patients who have a low risk of cardiovascular disease. In patients with CKD in the SPRINT trial, intensive blood pressure management (achieving a mean SBP of approximately 122 mm Hg compared with 136 mm Hg with standard treatment) provided a similar beneficial reduction in the composite cardiovascular disease primary outcome and all-cause mortality as in the full patient cohort. Because most patients with CKD die from cardiovascular complications, the findings of this study further support a lower blood pressure target of less than 130/80 mm Hg.

Data are lacking to determine the ideal blood pressure goal in patients with hypertension and diabetes mellitus; also, studies evaluating the benefits of intensive blood pressure control in patients with diabetes mellitus have provided conflicting results. Clinical studies reviewed for the 2017 ACC/AHA hypertension guideline have shown similar quantitative benefits from blood pressure lowering in hypertensive patients with or without diabetes mellitus. In a randomized, controlled study (ACCORD-BP) that compared a higher (SBP less than 140 mm Hg) versus lower (SBP less than 120 mm Hg) blood pressure goal in patients with diabetes mellitus, there was no difference in the incidence of cardiovascular outcomes (e.g., composite outcome of cardiovascular death, nonfatal MI, and nonfatal stroke). However, some experts state that this study was underpowered to detect a difference between the 2 treatment groups and that the factorial design of the study complicated interpretation of the results. Although SPRINT did not include patients with diabetes mellitus, patients in this study with prediabetes demonstrated a similar cardiovascular benefit from intensive treatment of blood pressure as normoglycemic patients. A meta-analysis of data from ACCORD and SPRINT suggests that the findings of both studies are consistent and that patients with diabetes mellitus benefit from more intensive blood pressure control. These data support the 2017 ACC/AHA hypertension guideline recommendation of a blood pressure treatment goal of less than 130/80 mm Hg in patients with hypertension and diabetes mellitus. Alternatively, the American Diabetes Association (ADA) recommends a blood pressure goal of less than 140/90 mm Hg in patients with diabetes mellitus. The ADA states that a lower blood pressure goal (e.g., less than 130/80 mm Hg) may be appropriate for patients with a high risk of cardiovascular disease and diabetes mellitus if it can be achieved without undue treatment burden.

Further study is needed to more clearly define optimum blood pressure goals in patients with hypertension, particularly in high-risk groups (e.g., patients with diabetes mellitus, cardiovascular disease, or cerebrovascular disease; black patients); when determining appropriate blood pressure goals, individual risks and benefits should be considered in addition to the evidence from clinical studies.

Choice of Initial Drug Therapy

In current hypertension management guidelines, thiazide diuretics are recommended as one of several preferred drugs for the initial treatment of hypertension. Results of clinical trials (e.g., ALLHAT) indicate that thiazide diuretics appear to prevent cardiovascular complications associated with hypertension as effectively as ACE inhibitors or calcium-channel blockers and better than β-blockers. (See Clinical Benefits of Thiazides in Hypertension under Hypertension in Adults: Treatment Benefits, in Uses.) These findings, in addition to cost and other considerations, have prompted some experts in the past to recommend thiazides as the initial drugs of choice in most patients with hypertension. ACC/AHA and most experts currently recommend selection of the initial antihypertensive agent from among several preferred drug classes that have been shown to reduce clinical events. The 2017 ACC/AHA hypertension guideline states that a thiazide or thiazide-like diuretic (preferably chlorthalidone), ACE inhibitor, angiotensin II receptor antagonist, or calcium-channel blocker are all acceptable choices for initial antihypertensive drug therapy in the general population of nonblack patients, including those with diabetes mellitus; drugs from any of these classes generally produce similar benefits in terms of overall mortality and cardiovascular, cerebrovascular, and renal outcomes. In black patients, including those with diabetes mellitus, the initial drug choice should include a thiazide diuretic or calcium-channel blocker. Because many patients eventually will need more than one antihypertensive drug to achieve blood pressure control, any of the recommended drug classes may be considered for add-on therapy.

In patients with hypertension and compelling indications (e.g., CKD with albuminuria [urine albumin 300 mg/day or greater, or urine albumin:creatinine ratio of 300 mg/g or equivalent in the first morning void]), angiotensin II receptor antagonists are usually considered an alternative for ACE inhibitor-intolerant patients. (See Chronic Kidney Disease under Hypertension in Adults: Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors, in Uses.) However, data indicate no difference in efficacy between ACE inhibitors and angiotensin II receptor antagonists with regard to blood pressure lowering and clinical outcomes (i.e., all-cause mortality, cardiovascular mortality, MI, heart failure, stroke, and end-stage renal disease). Adverse events (e.g., cough, angioedema) leading to drug discontinuance occur more frequently with ACE inhibitor therapy than with angiotensin II receptor antagonist therapy. Because of similar efficacy and a lower frequency of adverse effects, some experts believe that angiotensin II receptor antagonists should be used instead of an ACE inhibitor for the treatment of hypertension or hypertension with certain compelling indications.

Most guidelines no longer recommend β-blockers as first-line therapy for hypertension because of the lack of established superiority over other recommended drug classes and evidence from at least one study demonstrating that they may be less effective than angiotensin II receptor antagonists in preventing cardiovascular death, MI, or stroke. However, therapy with a β-blocker may still be considered in some patients with a compelling indication such as ischemic heart disease, history of MI, or heart failure.

Experts state that in patients with stage 1 hypertension (especially the elderly, those with a history of hypotension, or those who have experienced adverse drug effects), it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target blood pressure. Although some patients can begin treatment with a single antihypertensive agent, starting with 2 drugs in different pharmacologic classes (either as separate agents or in a fixed-dose combination) is recommended in patients with stage 2 hypertension and an average blood pressure more than 20/10 mm Hg above their target blood pressure. Such combined therapy may increase the likelihood of achieving goal blood pressure in a more timely fashion, but also may increase the risk of adverse effects (e.g., orthostatic hypotension) in some patients (e.g., elderly). Drug regimens with complementary activity, where a second antihypertensive agent is used to block compensatory responses to the first agent or affect a different pressor mechanism, can result in additive blood pressure lowering and are preferred. Drug combinations that have similar mechanisms of action or clinical effects (e.g., the combination of an ACE inhibitor and an angiotensin II receptor antagonist) generally should be avoided. Many patients who begin therapy with a single antihypertensive agent will subsequently require at least 2 drugs from different pharmacologic classes to achieve their blood pressure goal. Experts state that other patient-specific factors, such as age, concurrent medications, drug adherence, drug interactions, the overall treatment regimen, cost, and comorbidities, also should be considered when deciding on an antihypertensive drug regimen. For any stage of hypertension, antihypertensive drug dosages should be adjusted and/or other agents substituted or added until goal blood pressure is achieved. (See Follow-up and Maintenance Drug Therapy under Hypertension in Adults: General Considerations for Initial and Maintenance Antihypertensive Therapy, in Uses.)

Follow-up and Maintenance Drug Therapy

Several strategies are used for the titration and combination of antihypertensive drugs; these strategies, which are generally based on those used in randomized controlled studies, include maximizing the dosage of the first drug before adding a second drug, adding a second drug before achieving maximum dosage of the initial drug, or initiating therapy with 2 drugs simultaneously (either as separate preparations or as a fixed-dose combination). Combined use of an ACE inhibitor and angiotensin II receptor antagonist should be avoided because of the potential risk of adverse renal effects. After initiating a new or adjusted antihypertensive drug regimen, patients should have their blood pressure reevaluated monthly until adequate blood pressure control is achieved. Effective blood pressure control can be achieved in most hypertensive patients, but many will ultimately require therapy with 2 or more antihypertensive drugs. In addition to measuring blood pressure, clinicians should evaluate patients for orthostatic hypotension, adverse drug effects, adherence to drug therapy and lifestyle modifications, and the need for drug dosage adjustments. Laboratory testing such as electrolytes and renal function status and other assessments of target organ damage also should be performed.

Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors

Drug therapy in patients with hypertension and underlying cardiovascular or other risk factors should be carefully individualized based on the underlying disease(s), concomitant drugs, tolerance to drug-induced adverse effects, and blood pressure goal.

The following table lists compelling indications for which certain antihypertensive drug classes are recommended. The drug selections recommended for these compelling indications are based on favorable outcome data from clinical trials and existing expert guidelines; the specific drug classes that are included in the table are meant to be considered, but not necessarily all administered at the same time in an individual patient. For additional information on the management of hypertension in patients with compelling indications, individual expert clinical guidelines should be consulted.

Compelling indications for antihypertensive drugs are based on benefits from outcome studies or existing clinical guidelines; the compelling indication is managed in parallel with hypertension.

e.g., eplerenone, spironolactone

The 2017 ACC/AHA hypertension guideline states that in adults with diabetes mellitus and hypertension who do not have albuminuria, all first-line classes of antihypertensive agents (i.e., thiazide diuretics, ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers) are useful and effective; ACE inhibitors (or angiotensin II receptor antagonists if intolerant of ACE inhibitors) are preferred in patients with albuminuria.

The 2017 ACC/AHA hypertension guideline states that adults with hypertension and stage 1 or 2 CKD without albuminuria can be treated with any of the first-line classes of antihypertensive agents (i.e., thiazide diuretics, ACE inhibitors, angiotensin II antagonists, and calcium-channel blockers); use of ACE inhibitor or angiotensin II receptor antagonist may be reasonable in those with hypertension and stage 1 or 2 CKD with albuminuria or stage 3 CKD.

Ischemic Heart Disease

Adequate control of blood pressure in patients with ischemic heart disease substantially reduces cardiovascular morbidity and mortality (e.g., stroke, coronary events, death). The 2017 ACC/AHA hypertension guideline recommends initiating antihypertensive drug therapy in patients with stable ischemic heart disease who have a blood pressure of 130/80 mm Hg or higher; alternatively, other experts recommend initiating antihypertensive drug therapy in patients with coronary artery disease who have a blood pressure of 140/90 mm Hg or higher, including in those with stable ischemic heart disease. The selection of an appropriate antihypertensive agent should be based on individual patient characteristics, but may include ACE inhibitors and/or β-blockers, with the addition of other drugs such as thiazide diuretics or calcium-channel blockers as necessary to achieve blood pressure goals. Many experts recommend the use of ACE inhibitors in hypertensive patients with stable ischemic heart disease because of the cardioprotective benefits of these drugs; angiotensin II receptor antagonists are recommended as an alternative if ACE inhibitors are not tolerated or are contraindicated. Because of the demonstrated mortality benefit of β-blockers following MI, these drugs should be administered in all patients who have survived an MI. Aldosterone receptor antagonists are also recommended to reduce morbidity and mortality following an acute MI in patients with reduced left ventricular ejection fraction (LVEF) (40% or less) who develop symptoms of heart failure or have a history of diabetes mellitus.

Heart Failure

Thiazide diuretics may be considered in hypertensive patients with heart failure and mild fluid retention. ACCF, AHA, and the Heart Failure Society of America (HFSA) also recommend the addition of an aldosterone antagonist (i.e., spironolactone or eplerenone) in selected patients with chronic heart failure and reduced LVEF who are already receiving an agent to inhibit the renin-angiotensin system (e.g., ACE inhibitor, angiotensin II receptor antagonist) and a β-blocker. The 2017 ACC/AHA hypertension guideline states that diuretics should be used to control hypertension in patients with heart failure with preserved ejection fraction who have symptoms of volume overload.

Diabetes Mellitus

The presence of diabetes mellitus increases the risk of coronary events by twofold in men and fourfold in women, and observational studies suggest that the risk of cardiovascular disease is approximately twice as high in hypertensive patients with diabetes mellitus as in nondiabetic hypertensive patients. Epidemiologic data indicate that SBP and DBP exceeding 115 and 75 mm Hg, respectively, are associated with increased cardiovascular event rates and mortality in patients with diabetes mellitus. Data are lacking to determine the ideal blood pressure goal in patients with hypertension and diabetes mellitus. Some randomized clinical studies have shown benefit from lowering SBP to less than 140 mm Hg and DBP to less than 80 mm Hg in patients with diabetes mellitus and hypertension, while other data indicate that lower blood pressure targets (e.g., less than 130/80 mm Hg) provide additional benefits. (See General Considerations for Initial and Maintenance Antihypertensive Therapy under Uses: Hypertension in Adults.) Results of several studies indicate that adequate control of blood pressure in patients with type 2 diabetes mellitus reduces the development or progression of complications of diabetes (e.g., diabetes-related death, stroke, heart failure, microvascular disease).

The ADA recommends lifestyle/behavioral modification in adults with diabetes mellitus who have elevated blood pressure (i.e., higher than 120/80 mm Hg); if blood pressure is higher than 140/90 mm Hg, the ADA recommends prompt initiation of drug therapy in addition to these nondrug interventions. However, other experts recommend initiating drug therapy at a blood pressure of 130/80 mm Hg or higher in addition to nondrug interventions in such patients.

Experts state that initial treatment of hypertension in adults with diabetes mellitus and hypertension should include any of the usual first-line agents (thiazide diuretics, ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers). In adults with diabetes mellitus, hypertension, and albuminuria, treatment with an ACE inhibitor or angiotensin II receptor antagonist may be considered to reduce the progression of kidney disease. In the absence of albuminuria, the risk of progressive kidney disease is low, and ACE inhibitors and angiotensin II receptor antagonists have not demonstrated superior cardioprotection when compared with other first-line agents. Most patients with diabetes mellitus will require 2 or more antihypertensive agents to achieve blood pressure control.

Chronic Kidney Disease

Hypertensive patients with CKD (GFR less than 60 mL/minute per 1.73 m² or kidney damage for 3 or more months) usually will require more than one antihypertensive agent to reach target blood pressure. Use of ACE inhibitors or angiotensin II receptor antagonists may be reasonable in patients with diabetic or nondiabetic CKD (stage 1 or 2 with albuminuria or stage 3 or higher); these drugs have been shown to slow the progression of kidney disease. Evidence of a renoprotective benefit is strongest in those with higher levels of albuminuria. Increases in serum creatinine (up to 30%) may be observed as a result of a decrease in intraglomerular pressure and concurrent reduction in GFR. The 2017 ACC/AHA hypertension guideline states that in patients with less severe kidney disease (i.e., stage 1 or 2 CKD without albuminuria), any of the first-line antihypertensive agents (e.g., thiazide diuretics, ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers) can be used for the initial treatment of hypertension. Diuretics also may be useful in the management of CKD, and may potentiate the effects of ACE inhibitors, angiotensin II receptor antagonists, and other antihypertensive agents when used in combination. Thiazides are not effective in patients with advanced renal impairment (e.g., GFR less than 30 mL/minute per 1.73 m², serum creatinine 1.5 mg/dL or greater); loop diuretics should be used instead in such patients.

Cerebrovascular Disease

Some experts recommend a blood pressure goal of less than 140/90 mm Hg in patients with ischemic stroke or transient ischemic attack (TIA), while others state that a blood pressure goal of less than 130/80 mm Hg may be reasonable. The 2017 ACC/AHA hypertension guideline states that adults not previously treated for hypertension who experience a stroke or TIA and who have an established blood pressure of 140/90 mm Hg or higher should receive antihypertensive therapy a few days after the event to reduce the risk of recurrent stroke or other vascular events. In patients with a recent lacunar stroke, experts suggest that an SBP goal of 130 mm Hg may be reasonable based on results of a randomized open-label study (the Secondary Prevention of Small Subcortical Strokes [SPS3] trial). Although experts state that the optimal choice of drug for the management of hypertension in patients with a previous TIA or ischemic stroke is uncertain, available data indicate that a thiazide diuretic, ACE inhibitor, angiotensin II receptor antagonist, or the combination of a thiazide diuretic and an ACE inhibitor may be effective. Administration of an ACE inhibitor in combination with a thiazide diuretic has been shown to lower rates of recurrent stroke.

Other Special Considerations for Antihypertensive Drug Therapy

Race

Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control. In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blockers than to monotherapy with ACE inhibitors, angiotensin II receptor antagonists, or β-blockers. In a prespecified subgroup analysis of the ALLHAT study, a thiazide-like diuretic was more effective than an ACE inhibitor in improving cerebrovascular and cardiovascular outcomes in black patients; when compared with a calcium-channel blocker, the ACE inhibitor was less effective in reducing blood pressure and was associated with a 51% higher rate of stroke. However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar blood pressure lowering in black patients as in other racial groups. In addition, some experts state that when use of ACE inhibitors, angiotensin II receptor antagonists, or β-blockers is indicated in hypertensive patients with underlying cardiovascular or other risk factors, these indications should be applied equally to black hypertensive patients. (See Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors under Uses: Hypertension in Adults.)

Advanced Age

Antihypertensive drugs recommended for initial therapy in geriatric patients, including those with isolated systolic hypertension, generally are the same as those recommended for younger patients. US guidelines have provided inconsistent recommendations regarding the optimal target SBP in geriatric patients. While some experts have recommended a higher blood pressure threshold for initiating treatment (e.g., 150/90 mm Hg) and a higher target blood pressure (less than 150/90 mm Hg) for older patients, the 2017 ACC /AHA hypertension guideline generally recommends the same blood pressure treatment lowering goal in patients regardless of age. The recommendation of higher blood pressure goals in geriatric patients was based on studies providing moderate to strong evidence that lowering blood pressure to less than 150/90 mm Hg in individuals 60 years of age or older was associated with clinical benefits (i.e., reduction in incidence of stroke, heart failure, and coronary heart disease) and some evidence, albeit less compelling, that an SBP goal of less than 140 mm Hg provided no additional benefit over a higher SBP goal (e.g., 140–160 mm Hg) in this age group. The 2017 ACC/AHA hypertension guideline recommendation that patients 65 years of age and older generally should have the same target SBP goal of younger adults (less than 130 mm Hg) is supported by data from several large, randomized, controlled studies demonstrating that more intensive blood pressure control results in lower rates of cardiovascular disease in patients older than 65, 75, and 80 years of age and does not exacerbate orthostatic hypotension or increase the risk of injurious falls. However, elderly patients should be carefully monitored for orthostatic hypotension while they are receiving antihypertensive drugs, especially when 2 agents are initiated simultaneously. Some experts state that it can be assumed that most adults 65 years of age or older with hypertension have a 10-year ASCVD risk of at least 10%, which places these individuals in the higher-risk category that requires initiation of antihypertensive drugs at an SBP of 130 mm Hg or higher. In geriatric patients with hypertension, multiple comorbidities, and a limited life expectancy, clinical judgment and patient preference should be used to determine the intensity of blood pressure lowering and the choice of antihypertensive drugs.

In several controlled studies, thiazide diuretics alone or in combination with other antihypertensive agents have been shown to reduce morbidity and mortality effectively in patients 50 years of age or older, including those with isolated systolic hypertension. Antihypertensive therapy initiated with a calcium-channel blocker also has been shown to reduce cardiovascular morbidity in older patients with isolated systolic hypertension. Although some experts state that diuretics or calcium-channel blockers may be preferred in geriatric patients, ACE inhibitors and angiotensin II receptor antagonists also have shown beneficial effects and may be considered in this population. Results of a prospective, randomized, open-label study in about 6000 hypertensive patients 65–84 years of age (the Second Australian National Blood Pressure trial) have demonstrated that initiation of therapy with ACE inhibitors may result in slightly better outcomes (concerning cardiovascular events), particularly in men, than those associated with diuretics.

Thiazides may be preferred in patients with osteoporosis. Limited data suggest that thiazide therapy may have a secondary beneficial effect in geriatric patients of reducing the risk of osteoporosis secondary to the drugs’ effect on calcium homeostasis and bone mineralization.

Elevated Uric Acid and Gout

Hyperuricemia is common in patients with untreated hypertension and thiazides can increase serum uric acid concentrations. Thiazides generally should be avoided or used with caution in patients with a history of gout unless the patient is on uric acid-lowering therapy. (See Cautions: Electrolyte, Fluid, and Renal Effects.)

Hypertension in Pediatric Patients

Disease Overview

Clinical studies have shown that elevated blood pressure during childhood increases the risk of adult hypertension and metabolic syndrome. Additionally, children with hypertension are likely to experience accelerated vascular aging. Because the long-term health risks in hypertensive children and adolescents may be substantial, it is important that clinical measures be taken to reduce such risks and optimize health outcomes.

Primary hypertension is now the predominant form of hypertension seen in children and adolescents in the US. The general characteristics of a child with primary hypertension include older age (6 years of age or older), family history of hypertension, and excess body weight (overweight or obese). An extensive evaluation for secondary causes of hypertension is not needed in such patients or in those without physical examination findings suggestive of a secondary cause.

Secondary hypertension is more common in children than in adults. The most common secondary causes of hypertension in children are renal and renovascular diseases. Hypertension secondary to a renal cause should be strongly considered in hypertensive children, particularly in those younger than 6 years of age.

Obesity and other Risk Factors

Pediatric patients with primary hypertension frequently are overweight; the rate of hypertension increases with increasing body mass index (BMI) percentile. In addition, obesity in children with hypertension may be accompanied by other cardiometabolic risk factors (e.g., dyslipidemia, disordered glucose metabolism) that may affect blood pressure. Poor diet, inactivity, and obesity contribute to pediatric hypertension and lipid disorders. Children with other chronic conditions such as sleep-disordered breathing, CKD, and those born preterm also are more likely to have hypertension.

Blood Pressure Classification

The current definition of hypertension in children and adolescents is based on the normative distribution of blood pressure (auscultatory measurements) in healthy, normal-weight children. According to a 2017 clinical practice guideline of the American Academy of Pediatrics (AAP), normal blood pressure in patients 1 to less than 13 years of age is defined as an SBP and DBP that are less than in the 90th percentile for gender, age, and height, and hypertension is defined as an average SBP and/or DBP that is at least in the 95th percentile on at least 3 separate occasions. An ambulatory blood pressure monitor should be used to confirm a diagnosis of hypertension; however, for technical reasons, ambulatory monitoring may need to be limited to those who can tolerate the procedure and those for whom reference data are available. In patients 1 to less than 13 years of age, elevated blood pressure is defined as blood pressure levels that range from the 90th percentile or 120/80 mm Hg (whichever is lower) to less than the 95th percentile, stage 1 hypertension is defined as blood pressure levels that range from the 95th percentile to less than 12 mm Hg above 95th percentile (or 130/80–139/89 mm Hg, whichever is lower), and stage 2 hypertension is defined as blood pressure levels of at least 12 mm Hg above the 95th percentile (or at least 140/90 mm Hg, whichever is lower). For patients 13 years of age or older, hypertension is defined using the same blood pressure values as those recommended by ACC and AHA for adults (see Table 1). Using data from the 2001–2016 National Health and Nutrition Examination Survey (NHANES), the US Centers for Disease Control and Prevention (CDC) has estimated that approximately 800,000 individuals 12–19 years of age would be newly classified as having hypertension according to the 2017 ACC/AHA hypertension guidelines.

Considerations for Initial and Maintenance Antihypertensive Therapy

The overall goals for the treatment of pediatric hypertension include achieving a blood pressure that reduces both the risk of childhood target organ damage and the risk of hypertension and cardiovascular disease in adulthood. Lifestyle/behavioral modifications that include weight reduction (for those who are overweight or obese), dietary changes, and increased physical activity are strongly encouraged in pediatric patients to limit or prevent future or excess increases in blood pressure. Data from clinical studies suggest that the relationship between diet, physical activity, and blood pressure in childhood is similar to that observed in adults.

When a pediatric patient has been diagnosed with hypertension (blood pressure being in the 95th percentile or greater), management decisions should be determined by the degree or severity of hypertension. The treatment goal for most children and adolescents treated with antihypertensive drugs and lifestyle/behavior modifications is a reduction in blood pressure to less than in the 90th percentile or less than 130/80 mm Hg. While previous guidelines have recommended a goal blood pressure less than in the 95th percentile, some evidence suggests that markers of target organ damage can be detected among children with blood pressure greater than in the 90th percentile (or greater than 120/80 mm Hg). Because hypertension is a known risk factor for the progression of CKD, a target 24-hour mean arterial pressure (MAP) less than the 50th percentile by ambulatory blood pressure monitoring is recommended in children and adolescents with hypertension and CKD to reduce the rate of decline in kidney function.

Choice of Initial Drug Therapy

Drug therapy in the management of hypertension must be individualized and adjusted based on the degree of blood pressure elevation and other patient- and drug-related factors. Drug therapy generally is reserved for pediatric patients who inadequately respond to nondrug therapies or in whom the degree of blood pressure elevation or coexisting risk factors require more prompt or aggressive therapy. Some experts recommend antihypertensive drug therapy in all pediatric patients with symptomatic hypertension, those with secondary hypertension without a clearly modifiable factor (e.g., obesity), those with persistent hypertension who fail to respond to lifestyle/behavioral modifications (especially those with an abnormal echocardiogram), and those with diabetes mellitus or CKD.

For initial drug therapy, many experts recommend use of a single antihypertensive drug (e.g., an ACE inhibitor, an angiotensin II receptor antagonist, a long-acting calcium-channel blocker, a thiazide diuretic) given at the low end of the dosing range. Because black patients may not have a robust response to an ACE inhibitor, a higher initial dosage of an ACE inhibitor may be considered in such patients; alternatively, therapy may be initiated with a thiazide diuretic or long-acting calcium-channel blocker. Clinical studies comparing the effectiveness of different antihypertensive agents in children are lacking; however, a few studies have demonstrated no clinically important differences in the degree of blood pressure lowering among drugs. It is recommended that hypertensive pediatric patients with underlying or concurrent medical conditions receive specific classes of hypotensive agents (e.g., use of ACE inhibitors or angiotensin II receptor antagonists in children with diabetes, proteinuria, or CKD). For further information on drug therapy in patients with underlying or concurrent medical conditions, see Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors under Uses: Hypertension in Adults.

For additional information on the management of hypertension in children, the AAP Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents may be consulted at [Web].

Follow-up and Maintenance Drug Therapy

In pediatric patients who fail to respond adequately to initial therapy with a single drug (i.e., a thiazide diuretic, an ACE inhibitor, an angiotensin II receptor antagonist, a long-acting calcium-channel blocker), dosage of the initial drug therapy may be increased every 2–4 weeks until the desired blood pressure goal is achieved or the maximum recommended dosage is attained or tolerated; an antihypertensive agent from another class (preferably an agent having complementary mechanism of action with the initial drug) may then be added.

Although the dosage of antihypertensive drugs may be increased every 2–4 weeks based on home blood pressure measurements, the patient should be evaluated every 4–6 weeks by a clinician until blood pressure has normalized. After the patient’s blood pressure is at goal, the patient may be evaluated less frequently (i.e., every 3–4 months). Pediatric hypertensive patients also should be periodically monitored for target organ damage and adverse effects while emphasizing nonpharmacologic measures and the importance of drug therapy adherence.

Diabetes Insipidus

Thiazides have been widely used in the treatment of diabetes insipidus^{† [off-label]}. The drugs are effective in both the neurohypophyseal and nephrogenic forms of the disease, decreasing urine volume by up to 50%. Thiazides are particularly useful in nephrogenic diabetes insipidus, since this form of the disease is unresponsive to vasopressin or lypressin and chlorpropamide. Thiazides are also useful in patients who are allergic or refractory to vasopressin or lypressin and have been used in combination with one of these hormones and a low-salt diet in patients who excrete an exceptionally large volume of urine.

Other Uses

Thiazide diuretics have been used with success in the prophylaxis of renal calculus formation associated with hypercalciuria^{† [off-label]} and in the treatment of the electrolyte disturbances associated with renal tubular acidosis^{† [off-label]}.

Thiazides General Statement Dosage and Administration

Administration

Thiazides are administered orally. Chlorothiazide sodium is administered IV; however, the IV route should be reserved for emergency situations or when patients are unable to take the drug orally.

Dosage

Dosage of the thiazides should be adjusted according to the patient’s requirements and response. The response of the patient depends on factors such as the nature and degree of the disease, state of hydration, cardiac output, physical activity, diet, and concurrent administration of other drugs. Therapy should be adjusted to attain the maximum therapeutic effect at minimum dosage. Dosage among the individual thiazides varies greatly; however, the maximum diuretic response is approximately equal with all agents.

Maintenance therapy with thiazides may be intermittent, such as administration of the drug on alternate days or once daily 3–5 days a week to minimize electrolyte imbalances. In hypertensive patients, however, a decrease in hypotensive effect often occurs during intermittent therapy, except when agents with a very long duration of action (e.g., chlorthalidone, a thiazide-like diuretic) are used. If the response is reduced when intermittent therapy is instituted, the drug should be given more frequently and alternate measures should be used to minimize electrolyte disturbances.

Edema

In the management of severe edema, a large thiazide dosage may be administered until fluid retention is resolved, then a lower maintenance dosage may be instituted. Large initial dosages generally are not necessary in other conditions.

For the management of fluid retention (e.g., edema) associated with heart failure, experts state that diuretics should be administered at a dosage sufficient to achieve optimal volume status and relieve congestion without inducing an excessively rapid reduction in intravascular volume, which could result in hypotension, renal dysfunction, or both.

Hypertension

Chlorthalidone dosages of 12.5–25 mg once daily or hydrochlorothiazide dosages of 25–50 mg once daily have been shown to provide optimal benefit in patients with hypertension; the effectiveness of lower dosages is unknown or has been shown to be less effective in clinical studies. The usual dosages of other thiazide or thiazide-like diuretics for the treatment of hypertension include indapamide 1.25–2.5 mg once daily and metolazone 2.5–5 mg once daily.

The patient’s renal function and electrolytes should be assessed 2–4 weeks after initiation of diuretic therapy. Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled. If an adequate blood pressure response is not achieved with thiazide monotherapy, the dosage may be increased or another antihypertensive agent with demonstrated benefit (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, calcium-channel blocking agent) and preferably with a complementary mechanism of action may be added; if target blood pressure is still not achieved, a third drug may be added. (See Uses: Hypertension in Adults.) In patients who develop unacceptable adverse effects with a thiazide, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.

Blood Pressure Monitoring and Treatment Goals

Blood pressure monitoring using an out-of-office (home [self-monitored]) or ambulatory method (using a device that measures blood pressure over a 24-hour period) as an adjunct to in-office monitoring generally is recommended to provide a more reliable assessment of blood pressure; studies suggest that out-of-office blood pressure may be a better predictor of hypertension-induced organ damage and cardiovascular risk than office blood pressure. Periodic determination of blood pressure in both the morning and evening (before taking the morning or evening dose) is useful in monitoring daytime control and ensuring that the surge in blood pressure that occurs with arising has been modulated adequately. Occasionally, particularly in geriatric patients and those with orthostatic symptoms, monitoring should include blood pressure determinations in both the seated position and, to recognize possible postural hypotension, after standing quietly for 2–5 minutes.

Once antihypertensive drug therapy has been initiated, dosage generally is adjusted at approximately monthly intervals if blood pressure control is inadequate at a given dosage; additional drugs may need to be added to an antihypertensive drug regimen to achieve adequate blood pressure control. Once blood pressure has been stabilized, follow-up visits generally can be scheduled at 3- to 6-month intervals, depending on patient status.

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure. However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial. While other hypertension guidelines have based target blood pressure goals on age and comorbidities, the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk into decision making regarding treatment and generally recommends the same target blood pressure (i.e., less than 130/80 mm Hg) for all adults. Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient’s blood pressure treatment goal. (See General Considerations for Initial and Maintenance Antihypertensive Therapy under Uses: Hypertension in Adults.)

In children with hypertension with or without diabetes mellitus, blood pressure should be reduced to less than the corresponding age-adjusted 90th percentile value and to less than 130/80 mm Hg in adolescents at least 13 years of age. In children and adolescents with hypertension and CKD, the 24-hour mean arterial pressure (MAP) as determined by ambulatory blood pressure monitoring should be decreased to a value less than the 50th percentile.

Long-term Regimen Adjustments

A reduction in the dosage or number of antihypertensive drugs in the regimen may be possible in some patients after hypertension has been controlled effectively for an extended period. Such step-down therapy is more often successful in patients who are making lifestyle modifications. The reduction should be gradual and accompanied by frequent monitoring, since blood pressure often rises again to hypertensive levels.

Combination Therapy

When combination therapy is required in the management of hypertension, dosage of each agent can be adjusted first by administering each drug separately. If it is determined that the optimum maintenance dosage of both drugs corresponds to the ratio in a commercial combination preparation, a fixed combination may be used. Alternatively, therapy can be initiated with a fixed combination of 2 antihypertensive agents. Use of fixed-combination preparations may result in increased patient compliance. However, fixed-combination preparations containing 3 different antihypertensive agents may contain a thiazide diuretic dosage that is lower than recommended for the treatment of hypertension.

Whenever dosage adjustment is necessary, the drugs then can be administered separately again or increased with certain fixed combinations according to the manufacturer’s recommendations. Initiating therapy and adjusting dosage with separate administration of each drug are particularly important with combination preparations containing antihypertensive agents that have wide ranges in their effective dosages and may require frequent dosage alterations (e.g., methyldopa, guanethidine).

For information on commercially available preparations containing hydrochlorothiazide in fixed combination with a potassium-sparing diuretic, see the individual monographs in 40:28.10.

Dosage in Renal Impairment

For information on dosage of thiazide and thiazide-like diuretics in patient with renal impairment, see the individual monographs in 40:28.10.

Cautions for Thiazides General Statement

Adverse effects associated with some thiazides (e.g., hydrochlorothiazide) may be dose-related.

Electrolyte, Fluid, and Renal Effects

One of the most common adverse effects of the thiazides is potassium depletion which occurs in most patients. Potassium depletion may cause cardiac arrhythmias and is particularly important in patients receiving cardiac glycosides because hypokalemia potentiates the cardiac toxicity (e.g., increased ventricular irritability) of these agents. Potassium concentrations may be especially low in patients with primary or secondary aldosteronism, in patients with a low potassium intake, in those receiving other potassium-depleting drugs, and in patients with other losses of potassium, as in vomiting and diarrhea. Intermittent rather than continuous administration of the thiazides and/or ingestion of potassium-rich foods may reduce or prevent potassium depletion; however, prophylactic administration of a potassium supplement such as potassium chloride solution or a potassium-sparing diuretic may be necessary in patients whose serum potassium concentration is less than about 3 mEq/L. Enteric-coated potassium-containing tablets should not be used because of the possibility of GI ulceration.

Rarely, sudden death from cardiac arrest has been associated with thiazide monotherapy, and this effect may be dose related. Since the risk of sudden cardiac death with thiazide therapy appears to be reduced by the addition of a potassium-sparing diuretic, it has been suggested that changes in serum concentrations of potassium or magnesium may contribute to the risk of sudden cardiac death; however, possible reductions in thiazide dosage that may have accompanied the addition of a potassium-sparing diuretic also may have contributed to the risk reduction with combined therapy.

Hypochloremic alkalosis may occur with hypokalemia, especially in patients with other losses of potassium and chloride such as those with vomiting, diarrhea, GI drainage, excessive sweating, paracentesis, or potassium-losing renal diseases. Patients with hepatic cirrhosis who are receiving thiazides are also very susceptible to hypokalemic hypochloremic alkalosis with the thiazides. Blood ammonia concentrations may be further increased in patients with previously elevated concentrations. The diuretic may induce hepatic encephalopathy secondary to electrolyte imbalances.

Dilutional hyponatremia may occasionally occur or be aggravated during thiazide therapy and can be life-threatening. Such hyponatremia usually develops insidiously during chronic therapy and is asymptomatic and of modest degree, and in such cases, serum sodium concentrations return rapidly to within the normal range following withdrawal of the diuretic, water restriction, and potassium and/or magnesium supplementation. However, severe hyponatremia (serum sodium concentration less than 120 mEq/L) can occur rarely. Dilutional hyponatremia most commonly occurs in hot weather in patients with chronic heart failure or hepatic disease, is usually present before diuretic therapy, and is manifested by signs of edema associated with hyponatremia. Geriatric patients, especially females who are underweight, have poor oral intake of fluid and electrolytes, and/or excessive intake of low-sodium nutritional supplements, may be at increased risk of dilutional hyponatremia induced by the drugs. Dilutional hyponatremia usually is treated by restriction of fluid intake to about 500 mL per day and withdrawal of the diuretic. Sodium chloride should not be administered unless the hyponatremia is life threatening. If sodium chloride is administered to correct severe, symptomatic hyponatremia, care should be taken to avoid early overcorrection to normonatremia or hypernatremia since resultant rapid osmolar changes may be associated with the development of central pontine myelinolysis. Therefore, although prognosis appears to depend on rapid correction of severe hyponatremia during the first 1 or 2 days, such correction initially should only be to a state of mild hyponatremia; it is recommended that serum sodium concentration be corrected by no more than 20 mEq/L during the first 24 hours. Avoidance of hypernatremia during subsequent days also is important. Patients with severe, symptomatic hyponatremia generally should be managed in an intensive care facility with frequent monitoring of fluid and electrolyte balance.

Hypercalcemia may also occur infrequently in patients receiving thiazides, especially in patients receiving vitamin D or having mild hyperparathyroidism. Hypomagnesemia may also occur.

Hyperuricemia occurs in many patients receiving a thiazide or related diuretic. Hyperuricemia is usually asymptomatic and rarely leads to clinical gout except in patients with a history of gout, familial predisposition to gout, or chronic renal failure. If therapy is required, hyperuricemia and gout may be treated with a uricosuric agent.

Impairment of renal function, interstitial nephritis (which may be allergic), and reversible renal failure have been reported mainly in patients with preexisting renal disease (proliferative glomerulonephritis or nephrotic syndrome) who were receiving thiazides; however, a direct causative relationship has not been demonstrated.

Metabolic and Endocrine Effects

Pathologic changes in the parathyroid gland with hypercalcemia and hypophosphatemia have occurred occasionally during prolonged thiazide therapy. (See Cautions: Precautions and Contraindications.) Common complications of hyperparathyroidism such as nephrolithiasis, bone resorption, and peptic ulceration have not been reported.

Thiazides and related diuretics can produce hyperglycemia and glycosuria in diabetics. Insulin or oral antidiabetic agent requirements of diabetics may be altered by the thiazides and, in addition, diabetes mellitus has been precipitated in prediabetic patients receiving thiazides. However, results of a large, prospective, cohort study found that the increased risk of developing type 2 diabetes mellitus in patients receiving antihypertensive drug therapy (e.g., thiazide diuretics) appears to be related to the presence of hypertension. In this study, development of type 2 diabetes mellitus was shown to be almost 2.5 times more likely in hypertensive patients than in normotensive patients. In addition, once the study investigators accounted for the presence of hypertension, the risk of developing diabetes mellitus among hypertensive patients receiving thiazide diuretics was shown to be no greater than that among those receiving no drug therapy. Abnormal glucose tolerance usually does not develop in patients receiving thiazides who previously exhibited normal glucose tolerance. Hyperglycemia and impairment of glucose tolerance are almost always reversible by discontinuance of the drugs, and correction of hypokalemia may improve glucose tolerance.

Thiazides and related diuretics can slightly increase serum total cholesterol concentrations; increases in the low-density lipoprotein cholesterol and/or very low-density lipoprotein cholesterol subfractions appear to be principally responsible for these increases. The effect of these diuretics on high-density lipoprotein cholesterol concentrations has not been fully elucidated but appears to be variable. Increases in serum triglyceride concentrations also can occur in thiazide-treated patients. Whether changes in serum lipid and lipoprotein concentrations are dose-related and whether such changes persist during long-term diuretic therapy has not been established. In addition, the clinical importance of these effects is not known and further evaluation is needed. The diuretic-induced increase in serum cholesterol concentration can generally be counteracted by concomitant use of a diet low in saturated fat and cholesterol.

Uncommon Adverse Effects

Adverse effects of thiazides other than electrolyte and metabolic disturbances are rare.

Dermatologic and Sensitivity Reactions

Dermatologic reactions are uncommon with thiazides but purpura, photosensitivity, rash, alopecia, urticaria, erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, and polyarteritis nodosa may occur. Cross-photosensitivity has been reported in a patient who received quinethazone after previously having photosensitivity reactions with 2 thiazides. Allergic reactions are most likely to occur in patients with a history of allergy or bronchial asthma, and the possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

Most information reporting cross-reactivity among sulfonamide derivatives is based on case reports. The mechanism of sulfonamide sensitivity is poorly understood, and the contribution of allergens, haptens, and/or other immune mechanisms remains to be established. Although there is an association between hypersensitivity to sulfonamide anti-infectives and subsequent sensitivity reactions to non-anti-infective sulfonamides such as thiazides and thiazide manufacturers state that use of the diuretics is contraindicated in patients who are allergic to any sulfonamide derivative, this association appears to result from a predisposition to allergic reactions in general rather than to cross-reactivity to the sulfa moiety per se. In fact, a retrospective cohort study using the UK General Practice Research Database found that the risk of associated allergic reactions in sulfonamide anti-infective-sensitive patients was even greater following exposure to penicillins than following exposure to non-anti-infective sulfonamides such as thiazides. In addition, the risk of an allergic reaction following administration of a non-anti-infective sulfonamide (e.g., thiazides, sulfonylurea antidiabetic agents, furosemide, dapsone, probenecid) was lower in patients with a history of sensitivity to sulfonamide anti-infectives than in those with a history of penicillin sensitivity. There also is other evidence, including a pooled analysis of data from clinical trails with celecoxib (an arylsulfonamide) and a cohort study of the risk of cross-sensitivity between co-trimoxazole and dapsone (a sulfone), to support the apparent lack of chemical cross-reactivity among sulfa derivatives. Therefore, based on current evidence from cohort studies and pooled analyses, some researchers suggest that clinicians should understand that patients with a history of any allergic reaction to sulfonamides or penicillins may be at increased risk for reactions to other drugs in general, and a history of sensitivity to sulfonamide anti-infectives should not be considered an absolute contraindication to subsequent use of non-anti-infective sulfonamides.

Cardiovascular Effects

Orthostatic hypotension may occur rarely, and hypotensive episodes have occurred during surgery in patients receiving thiazides. The hypotensive effect of the drugs may be enhanced in postsympathectomy patients. Transient cerebral ischemic attacks related to thiazide-induced hypotension have been reported.

GI Effects

GI adverse effects reported with the thiazides include anorexia, gastric irritation, nausea, vomiting, sialadenitis, cramping, diarrhea, constipation, intrahepatic cholestatic jaundice, and pancreatitis.

CNS Effects

CNS reactions associated with thiazides include dizziness, vertigo, paresthesia, headache, and xanthopsia.

Hematologic Effects

Infrequently, hematologic reactions including leukopenia, hemolytic anemia, thrombocytopenic purpura, agranulocytosis, and aplastic anemia have been reported with some of the thiazides.

Other Adverse Effects

Muscle spasms, impotence, renal failure, renal dysfunction, interstitial nephritis, weakness, restlessness, transient blurred vision, fever, respiratory distress, necrotizing angiitis (vasculitis and cutaneous vasculitis), and anaphylactic reactions have also been reported with thiazides.

Rarely, pulmonary edema and allergic pneumonitis have been reported with hydrochlorothiazide. Hematuria has been reported in at least one patient receiving IV chlorothiazide.

Precautions and Contraindications

Electrolyte disturbances may occur during thiazide therapy, and patients should be observed for signs of electrolyte imbalance such as dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, oliguria, or muscle pains or cramps, muscular fatigue, hypotension, tachycardia, or GI disturbances such as nausea and vomiting. Periodic determination of serum electrolyte concentrations (particularly potassium, sodium, chloride, and bicarbonate) should be performed and measures to maintain normal serum concentrations should be instituted if necessary. Serum and urinary electrolyte measurements are especially important in diabetic patients and in patients who are vomiting, have diarrhea, are receiving parenteral fluids, or are expected to undergo excessive diuresis. It has been recommended that electrolytes be measured weekly or more frequently early in the course of therapy. Once the electrolyte response has stabilized, it may be possible to extend the interval between electrolyte determinations to 3 months or longer.

Thiazides should be used with caution in patients with severe renal disease because the drugs decrease the glomerular filtration rate (GFR) and may precipitate azotemia. The effects of thiazides may be cumulative in patients with impaired renal function. If progressive renal impairment becomes evident as indicated by rising nonprotein nitrogen, BUN, or serum creatinine concentrations, careful reappraisal of therapy is necessary with consideration given to interrupting or discontinuing thiazide therapy. The drugs should also be used with caution in patients with impaired hepatic function or progressive liver disease, particularly when potassium deficiency exists, because they may precipitate hepatic coma as a result of alterations in electrolyte balance. Thiazides should be discontinued immediately if signs of impending hepatic coma appear.

Thiazides are contraindicated in patients with anuria and in those who are allergic to any of the thiazides. The manufacturers state that thiazides are contraindicated in patients who are allergic to other sulfonamide derivatives. However, there currently is limited evidence to support this latter contraindication, and some suggest that a history of sensitivity to sulfonamide anti-infectives (“sulfa sensitivity”) should not be considered an absolute contraindication to non-anti-infective sulfonamides such as thiazides. (See Uncommon Adverse Effects: Dermatologic and Sensitivity Reactions, in Cautions.)

Pregnancy and Lactation

Pregnancy

The routine use of thiazides is contraindicated in pregnant women with mild edema who are otherwise healthy. Thiazides cross the placenta and appear in cord blood. Thrombocytopenia has been reported in newborn infants of women receiving thiazides; however, this appears to be an unpredictable idiosyncratic reaction. Amniotic fluid concentrations of uric acid and creatinine are elevated in women receiving thiazides near term. Jaundice may also occur in the fetus or neonate. These risks and the possibility that other effects of the thiazides may occur in the fetus or neonate must be weighed against the potential benefits of therapy.

Although some evidence suggests that thiazide use during pregnancy may be associated with an increased risk of fetal abnormalities, other data do not support such an association. Some experts have considered thiazide diuretics to be contraindicated during pregnancy, except in patients with heart disease or chronic hypertension, because of the theoretical fetal risk associated with plasma volume reduction. The American College of Obstetricians and Gynecologists (ACOG) states that thiazide diuretics may be used as second-line antihypertensive agents and may be particularly useful in women who are sodium sensitive. The goal of antihypertensive treatment in pregnant women with hypertension is to minimize the acute complications of maternal hypertension while avoiding therapy that could compromise fetal well-being. Antihypertensive therapy is recommended in pregnant women with chronic hypertension who have persistent, severely elevated blood pressure (e.g., systolic blood pressure [SBP] of 160 mm Hg or higher or diastolic blood pressure [DBP] of 105 mm Hg or higher); it is less clear whether antihypertensive therapy should be initiated in women with mild to moderate chronic hypertension. If initiation of antihypertensive therapy is necessary in a pregnant woman, use of labetalol, nifedipine, or methyldopa is recommended. Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and aldosterone antagonists should not be used in pregnant women. In women who are already receiving antihypertensive therapy prior to pregnancy, ACOG states there are insufficient data to make recommendations regarding the continuance or discontinuance of such therapy; treatment decisions should be individualized in these situations. Thiazide diuretics are not recommended for the prevention or management of gestational hypertension or preeclampsia.

Lactation

Thiazides are distributed into the milk of nursing women in low concentrations; however, the drug is considered to be compatible with breastfeeding. The potential for idiosyncratic or allergic reactions in the infant should be considered, however, and some manufacturers state that women receiving thiazides should not nurse their infants.

Drug Interactions

Drugs Affected by or Causing Potassium Depletion

In patients receiving digitalis glycosides, electrolyte disturbances produced by the thiazides (principally hypokalemia, but also hypomagnesemia and hypercalcemia) predispose the patient to digitalis toxicity. Periodic electrolyte determinations should be performed in patients receiving a thiazide and a digitalis glycoside, and correction of hypokalemia should be undertaken if warranted. (See Cautions: Electrolyte, Fluid, and Renal Effects.)

It has been stated that the thiazides and related diuretics may cause prolonged neuromuscular blockade in patients receiving nondepolarizing neuromuscular blocking agents, such as tubocurarine chloride or gallamine triethiodide (no longer commercially available in the US), presumably because of potassium depletion. Actual case reports are lacking, however.

Some drugs such as corticosteroids, corticotropin, and amphotericin B also cause potassium loss, and severe potassium depletion may occur when one of these drugs is administered during thiazide therapy.

Lithium

Thiazides, sometimes used in combination with lithium to reduce lithium-induced polyuria, will reduce renal lithium clearance within several days. The reduced lithium clearance has resulted in increased serum lithium concentrations and several cases of lithium intoxication. When thiazide diuretics are used to treat lithium-induced polyuria, most clinicians recommend reducing lithium dosage by about 50% and carefully monitoring serum lithium concentrations. Thiazides and lithium should generally not be used concomitantly because of the increased risk of lithium toxicity.

Antidiabetic Agents

The hyperglycemic effect of the thiazides may exacerbate diabetes mellitus, resulting in increased requirements of insulin or sulfonylurea antidiabetic agents, temporary loss of diabetic control, or secondary failure to the antidiabetic agent.

Hypotensive Agents

The hypotensive effects of most other hypotensive agents are increased by the thiazide diuretics. This effect is usually used to therapeutic advantage in antihypertensive therapy, but severe postural hypotension may result if a thiazide is added to the regimen of a patient stabilized on a potent hypotensive agent such as guanethidine sulfate, methyldopa, or a ganglionic blocking agent. The hyperglycemic, hypotensive, and hyperuricemic effects of diazoxide may be potentiated by the thiazide diuretics. Caution should be used in administering the thiazides with diazoxide.

Probenecid

Probenecid blocks thiazide-induced uric acid retention when administered concomitantly with the thiazides. It appears that probenecid enhances excretion of calcium, magnesium, and citrate during thiazide therapy, but urinary calcium concentrations remain below normal. The excretion of sodium, potassium, ammonia, chloride, bicarbonate, phosphate, and titratable acid during thiazide therapy do not seem to be affected by concomitant probenecid therapy. Probenecid also blocks the renal tubular secretion of the thiazides, but its effect on the duration of action of the thiazides has apparently not been studied.

Nonsteroidal Anti-inflammatory Agents

Diuretics may increase the risk of nonsteroidal anti-inflammatory agent (NSAIA)-induced renal failure. Such NSAIA-induced renal failure appears to be secondary to decreased renal blood flow resulting from prostaglandin inhibition by the drugs. In addition, NSAIAs may interfere with the natriuretic, diuretic, and antihypertensive response to diuretics. Therefore, patients receiving the drugs concomitantly should be observed closely for possible adverse effects and/or attenuation of diuretic-induced therapeutic effects.

Other Drugs

Since the pH of the urine becomes slightly more alkaline during thiazide therapy, the urinary excretion of some amines such as amphetamine and quinidine may be decreased somewhat when given concurrently with the thiazides; however, since the change in urine pH is not great during thiazide therapy, toxic blood concentrations of these drugs usually do not occur. Patients receiving amines (e.g., amphetamine, quinidine) should be monitored for signs of toxicity following initiation of thiazide therapy. Urinary alkalinization may decrease the effectiveness of methenamine compounds which require a urinary pH of 5.5 or less for optimal activity. The pH of the urine should be monitored during concurrent therapy with a thiazide and a methenamine compound.

Alcohol, barbiturates, and opiates are reported to increase the postural hypotensive effect of the thiazides.

It has been proposed that the thiazides may antagonize the effects of oral anticoagulants; however, studies which demonstrate this effect are lacking.

Cholestyramine or colestipol resin may bind thiazides and reduce their absorption from the GI tract, with cholestyramine reportedly producing greater binding in vitro. Thiazides should be administered at least 2 hours before cholestyramine or colestipol when these drugs are used concomitantly.

A decrease in arterial responsiveness to vasopressors has been reported during thiazide therapy; however, the clinical importance of this interaction has not been established.

Laboratory Test Interferences

In addition to alterations in laboratory test values resulting from the metabolic changes caused by the thiazides, the drugs may affect the results of a number of other tests. Thiazides may cause false-negative results in both the tyramine and phentolamine tests and probably the histamine test for pheochromocytoma. Protein-bound iodine values may be decreased during thiazide therapy, although usually not to subnormal levels. Triiodothyronine resin uptake may be decreased slightly, but the 24-hour I 131 uptake is not affected. Thyroid function is not affected by the thiazides.

Since thiazides may cause elevations in serum calcium in the absence of known disorders of calcium metabolism, the drugs should be discontinued prior to performing tests of parathyroid function.

It has been reported that hydrochlorothiazide causes falsely decreased values in the spectrophotometric assay of total urinary estrogen by interfering with formation of the Kober chromogen, and with the assay of estriol by degrading estriol at the acid hydrolytic stage of the assay. These interferences apparently do not occur with chlorothiazide.

Serum amylase values may be increased substantially in both asymptomatic patients and in patients developing acute pancreatitis who are receiving thiazides. Thiazides have been reported to decrease urinary corticosteroid values by interfering in vitro with the absorbance in the modified Glenn-Nelson technique for urinary 17-hydroxycorticosteroids. The drugs may also decrease urinary excretion of cortisol. The importance of the effect of thiazides on urinary corticosteroids is not clear.

Thiazides compete with phenolsulfonphthalein (PSP) for secretion by the proximal renal tubules, but the importance of this effect on PSP excretion is unknown.

Acute Toxicity

Manifestations

In addition to diuresis and resultant dehydration, overdosage of thiazides may produce lethargy, nausea, weakness, and electrolyte imbalance; lethargy may progress to coma within a few hours with minimal depression of respiratory and cardiovascular function and without evidence of dehydration or serum electrolyte changes. The mechanism of thiazide-induced CNS depression is unknown. GI irritation and hypermotility may occur, and temporary elevation of the BUN has been reported. Serum electrolyte changes (e.g., hypokalemia, hypochloremia, hyponatremia) may occur, especially in patients with impaired renal function.

Treatment

In the treatment of thiazide overdosage, gastric contents may be evacuated taking caution to avoid aspiration, especially in unconscious patients. If the patient is conscious, induction of vomiting with ipecac syrup is effective in removing the drug from the stomach. Cathartics should not be administered because they tend to promote loss of fluid and electrolytes. Treatment is generally supportive. Serum electrolytes and renal function should be monitored, and replacement of fluid and electrolytes may be indicated. Measures may be required to maintain respiratory, cardiovascular, and renal function. GI irritation is usually of short duration, but may be treated symptomatically.

Pharmacology

Thiazides and related diuretics enhance excretion of sodium, chloride, and water by interfering with the transport of sodium ions across the renal tubular epithelium. Their primary site of action appears to be the cortical diluting segment of the nephron. The exact mechanism of action of the thiazides is unclear; however, they may act by altering metabolism of the tubular cells.

Thiazides decrease the glomerular filtration rate (GFR), but whether this results from a direct effect on renal vasculature or is secondary to the decrease in intravascular fluid volume or an increase in tubular pressure caused by the inhibition of sodium and water reabsorption is unclear. The fall in GFR is not important in the mechanism of action of the drugs, but contributes to their decreased efficacy in patients with impaired renal function. Thiazides also exhibit a carbonic anhydrase inhibiting effect which varies considerably among the various agents.

In addition to increasing sodium and chloride excretion, thiazides affect excretion of other electrolytes. Potassium excretion is substantially increased because of the increased amount of sodium reaching the distal tubular site of sodium-potassium exchange. The ratio of potassium to sodium excreted may vary among the thiazides and related diuretics and at different dosages of the drugs; however, the differences in excretion are generally clinically insignificant. Long-term thiazide therapy can cause mild metabolic alkalosis associated with hypokalemia and hypochloremia.

Thiazides increase bicarbonate excretion (although to a lesser extent than chloride excretion) but change in urinary pH is usually minimal. The diuretic efficacy of the thiazides is not affected by the acid-base balance of the patient. Magnesium, phosphate, bromide, and iodide excretion are also increased. Excretion of ammonia may decrease slightly, and blood ammonia concentrations may be increased. Urinary calcium excretion may increase transiently when therapy is initiated; however, during long-term administration, it is substantially decreased. The hypocalciuric effect is thought to result from a decrease in extracellular fluid (ECF) volume, although calcium reabsorption in the nephron may be increased. Thiazides also have been reported to cause slight or intermittent elevations in serum calcium concentration. The rate of excretion of uric acid is decreased, probably because of competitive inhibition of uric acid secretion or a decrease in ECF volume and a secondary increase in uric acid reabsorption. Lithium excretion may also be decreased.

Thiazides have hypotensive activity in hypertensive patients, and they augment the action of other hypotensive agents. The precise mechanism of hypotensive action has not been determined, but it has been postulated that part of this effect is caused by direct arteriolar dilation. Initially, thiazides cause appreciable decreases in ECF volume, plasma volume, and cardiac output which may account for the decrease in blood pressure. After several weeks of therapy, however, plasma and ECF volumes approach, but remain slightly below, normal. Cardiac output returns to normal or slightly above, and peripheral vascular resistance remains decreased. Total body sodium also remains slightly below pretreatment values, which may be due to chronic depletion of sodium. Slight decreases in plasma and ECF volumes and total body sodium during prolonged thiazide therapy are not sufficient to explain the long-term decrease in blood pressure, but may explain the efficacy of thiazides in combination with most other hypotensive agents which tend to increase sodium retention and plasma volume.

Plasma renin activity is considerably elevated during thiazide therapy, probably because of plasma volume changes. The aldosterone secretion rate is slightly but substantially increased and contributes to the hypokalemia caused by thiazides.

Paradoxically, thiazides decrease urine volume in patients with diabetes insipidus. The urine becomes less hypotonic, but not hypertonic, and thirst and water consumption are decreased. This effect is thought to result mainly from the decrease in plasma volume and from sodium depletion with a resultant increase in renal water and sodium reabsorption, although other factors may play a role.

Thiazides can induce hyperglycemia, exacerbate preexisting diabetes mellitus, or precipitate diabetes in prediabetic patients. The mechanism of this action of the thiazides is not known, but there is evidence that the drugs act at both pancreatic and peripheral sites and that potassium depletion may decrease glucose tolerance.

Thiazides General Statement Pharmacokinetics

Absorption

Thiazides are absorbed from the GI tract in varying degrees. The onset of diuretic action of the thiazides following oral administration occurs within 2 hours, and the peak effect occurs 3–6 hours after administration. Following IV administration, chlorothiazide sodium has an onset of action within 15 minutes and a peak effect in 30 minutes. The duration of diuretic action of the individual agent is determined by the rate of its excretion. The approximate duration of diuretic action of a single dose of the thiazides and related diuretics is as follows:

The onset of hypotensive action is generally 3 or 4 days, and the hypotensive action dissipates during the first week after discontinuing chronic therapy.

Distribution

Thiazides are distributed in the extracellular space and cross the placenta. Thiazides also are distributed into milk.

Elimination

Most thiazides are excreted in urine, principally unchanged. The drugs are excreted by glomerular filtration and active secretion in the proximal tubule. The renal clearance of the thiazides varies; those with the lowest renal clearance generally require the lowest dosage for therapeutic effect. In patients with uncompensated heart failure or impaired renal function, excretion of the drugs may be delayed.

Chemistry

Thiazide (benzothiadiazine) diuretics are derivatives of 1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Substitution in the R² and R³ positions of the thiazide nucleus increases the activity of the compound. In most thiazides, the 3-4 bond is saturated and all presently marketed compounds have a chloride or CF₃ substituent at the 6 position of the thiazide nucleus. Quinethazone and metolazone, which are pharmacologically similar to the thiazides, are quinazoline derivatives and differ from the thiazides in having a carbonyl group rather than a sulfoxide group at the 1 position. Chlorthalidone is also pharmacologically and structurally similar to the thiazides, but is a phthalimidine derivative of benzenesulfonamide. Diazoxide, a nondiuretic hypotensive agent, is structurally related to the thiazides, but lacks the 7-sulfamyl group common to the thiazide diuretics.

In general, thiazides occur as white or nearly white, crystalline powders and are very slightly soluble or practically insoluble in water.

Related Monographs

For further information on chemistry and stability, pharmacology, pharmacokinetics, and dosage and administration of thiazides, see the individual monographs in 40:28.

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