Significant controversy surrounds the comparative efficacy of

HCTZ and chlorthalidone. Most clinicians, including the AHA,

assume a class effect for these two drugs.15 However, class effects

can be legitimized only after assurance of equipotent dosing;

for antihypertensives, when they are not directly compared in

a CV event trial, it assumes that if two agents achieve similar

BP lowering then both achieve similar reduction in CV events.

With regard to HCTZ and chlorthalidone, this assumption is

unproven. Chlorthalidone is more potent on a milligram per

milligram basis and has a longer half-life than HCTZ (50–60

hours versus 9–10 hours).128 Based on a comparative study using

24-hour ABPM, it appears that the equipotent dose of chlorthalidone 25 mg daily is HCTZ 50 mg daily, but this dose of HCTZ

is unpopular because of increased side effects. Consequently, it is

believed by some that the antihypertensive efficacy of chlorthalidone is greater than HCTZ when contemporary doses are used;

the 12.5- to 25-mg doses of chlorthalidone do not appear to significantly increase the risk of hypokalemia more so than HCTZ.129

Complicating this issue is evidence demonstrating that office BP

tends to overestimate the response to HCTZ, and the 24-hour

BP lowering with HCTZ is only comparable to other common

agents (ACEI, ARB, CCB, and even β-blocker) when 50 mg daily

is used.130 Recently, data from the Multiple Risk Factor Intervention Trial indicate that chlorthalidone reduces CV events more

than HCTZ.131 Although chlorthalidone is the most optimal

and evidence-based thiazide diuretic for B.A., HCTZ remains

currently accepted in the clinical environment as a reasonable

thiazide diuretic for hypertension assuming her BP goal can be

readily achieved with its use.

LOOP DIURETICS

Loop diuretics produce a more potent diuresis, but a smaller

decrease in PVR, and less vasodilation than thiazide diuretics.

They are subject to a significant postdose antinatriuretic period,

which offsets their antihypertensive effect. Therefore, a thiazide is

more effective at lowering BP than loop diuretics in most patients.

Loop diuretics are usually considered only for patients with severe

CKD (estimated GFR <30 mL/minute/1.73 m2), left ventricular

dysfunction, or severe edema. In these patients potent diuresis

is often needed. Furosemide has a short duration of effect and

should be given twice daily when used in hypertension, whereas

torsemide can be given once daily.

POTASSIUM-SPARING DIURETICS

Potassium-sparing diuretics (triamterene and amiloride) should

be reserved for patients who experience hypokalemia while on

a thiazide diuretic. With low-dose thiazide diuretics, less than

25% of patients develop hypokalemia, and most cases are not

severe. Triamterene and amiloride usually do not provide significant additional BP lowering when added to a thiazide diuretic.

Several fixed-dose products are available that include HCTZ with

triamterene or amiloride. Empirically starting all patients with

hypertension treated with a thiazide diuretic on triamterene or

amiloride to avoid hypokalemia is not rational unless baseline

serum potassium is in the low-normal range.

CASE 14-4, QUESTION 2: How should a thiazide diuretic be

started in B.A.?

B.A. has stage 1 hypertension, and monotherapy with a thiazide diuretic is reasonable. A thiazide diuretic is a first-line option

in primary prevention patients like B.A., and she has no contraindications (Table 14-10). Although B.A. has dyslipidemia, thiazide diuretics are unlikely to have a clinically significant effect on

cholesterol when used in low doses.132,133 An appropriate starting dose of HCTZ is 12.5 or 25 mg daily. B.A. has no additional

risks for orthostatic hypotension, so starting at the higher 25-mg

daily dose is safe, and will have a better chance of lowering her

TABLE 14-10 Side Effects and Contraindications of Antihypertensive Agents Side Effects Innocuous but Sometimes Annoying Potentially Harmful Usually Requires Cessation of Therapy, at Least Temporarily Contraindications Thiazide diuretics Increased urination (at onset of therapy), muscle cramps, hyperuricemia (without gout) Hypokalemia,a hyponatremia, hyperglycemia, hypovolemia, pancreatitis, photosensitivity, hypercholesterolemia, hypertriglyceridemia, hyperuricemia with gout, orthostatic hypotension (more frequent in elderly) Hypercalcemia, azotemia, skin rash (cross-reacts with only certain sulfonamide allergies), purpura, bone marrow depression, lithium toxicity in patients on lithium therapy, hyponatremia Anuria, kidney failure Loop diuretics Increased urination, muscle cramps, hyperuricemia (less than with thiazides) Hypokalemia,a hyperglycemia, hypovolemia, pancreatitis, hypercholesterolemia, hypertriglyceridemia, hearing loss with large IV doses, orthostatic hypotension (more pronounced in elderly) Hyponatremia, hypocalcemia, azotemia, skin rash (cross-reacts with only certain sulfonamide allergies), photosensitivity, lithium toxicity in patients on lithium therapy Anuria ACEI Dizziness, dry cough Orthostatic hypotension (more pronounced in elderly treated with a diuretic), increased serum creatinine, increased potassium Angioedema, severe hyperkalemia, increase in serum creatinine >35% Bilateral renal artery stenosis, volume depletion, hyponatremia, pregnancy, history of angioedema ARB Dizziness Orthostatic hypotension (more pronounced in elderly treated with a diuretic), increased serum creatinine, increased potassium Severe hyperkalemia, increase in serum creatinine >35% Bilateral renal artery stenosis, volume depletion, hyponatremia, pregnancy CCB: dihydropyridines Dizziness, headache, flushing Peripheral edema, tachycardia Significant peripheral edema Left ventricular dysfunction (not with amlodipine or felodipine) CCB: nondihydropyridines Dizziness, headache, constipation Bradycardia Heart block, left ventricular dysfunction, interactions with certain drugs Left ventricular dysfunction, second- or third-degree heart block, sick sinus syndrome β-Blocker Bradycardia, weakness, exercise intolerance Masking the symptoms of hypoglycemia in diabetes, hyperglycemia, aggravation of peripheral arterial disease, erectile dysfunction, increased triglycerides, decreased HDL-C Left ventricular dysfunction (not with carvedilol, metoprolol, bisoprolol), bronchospasm in patients with asthma or COPD (more pronounced with nonselective agents) Severe asthma, second- or third-degree heart block, acute left ventricular dysfunction exacerbation, coronary artery disease for agents with intrinsic sympathomimetic activity Aldosterone antagonist Menstrual irregularities (spironolactone only) or gynecomastia (spironolactone only) Increased potassium Hyperkalemia, hyponatremia Kidney failure. kidney impairment (for eplerenone: CrCl <50 mL/min, or type 2 diabetes with proteinuria, and creatinine >1.8 in women, >2.0 in men), hyperkalemia, hyponatremia aRoutine addition of potassium supplementation or empiric concurrent potassium-sparing diuretics should be discouraged unless hypokalemia is demonstrated, the patient is taking digoxin, or potassium is in the low-normal range. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium-channel blocker; COPD, chronic obstructive pulmonary disease; CrCl, creatinine clearance; HDL-C, high-density lipoprotein cholesterol; IV, intravenous.

313

314 Section 2 Cardiac and Vascular Disorders

BP to goal than the lower 12.5-mg dose because most antihypertensive agents provide a 10-mm Hg reduction in SBP and 5-mm

Hg reduction in DBP with a standard starting dose.81

PATIENT EDUCATION

CASE 14-4, QUESTION 3: B.A. is prescribed HCTZ 25 mg

daily. How should she be counseled regarding this therapy?

Several counseling points are summarized in Table 14-7. Some

patients disregard lifestyle modifications when they start antihypertensive therapy, so B.A. must be encouraged to continue

lifestyle modification to maximize her response to drug therapy.

B.A. should be informed that diuretics lower both BP and risk of

CV events and that taking her dose at about the same time each

morning to minimize nocturia and provide consistent effects is

recommended. B.A. should expect to experience increased urination when starting HCTZ, but should be informed that this

diminishes with time. Inform B.A. that missed doses should be

taken as soon as possible within the same day, but doubling doses

the next day is not recommended. The potential for hypokalemia,

which is easily identified and managed, and the need for routine

monitoring of serum potassium should be reviewed. She should

be counseled on the signs and symptoms of electrolyte abnormalities (e.g., leg cramps, muscle weakness) and encouraged to

report these to her health care provider if they occur. Increasing

dietary intake of potassium-rich foods to minimize electrolyte

depletion is an option to minimize potassium loss. This should

be encouraged only with thiazide and loop diuretics, but not with

potassium-sparing agents.

CASE 14-4, QUESTION 4: After 4 weeks of HCTZ 25 mg

daily, B.A. has no complaints and has not missed a dose.

She is exercising and is following the DASH diet. Her BP

values are 142/86 mm Hg (140/84 mm Hg when repeated).

Her fasting laboratory values are as follows:

Serum potassium, 3.8 mEq/L

Uric acid, 7.3 mg/dL

Glucose, 99 mg/dL

All other values are unchanged. Last month, potassium

was 4.0 mEq/L, uric acid was 6.8 mg/dL, and fasting glucose was 95 mg/dL. What is your assessment regarding the

efficacy and toxicity of B.A.’s antihypertensive therapy?

Despite improvements with lifestyle modifications and

reported adherence with HCTZ, B.A.’s goal BP of less than 140/90

mm Hg has not been met (her BP average is 141/83 mm Hg).

No new signs of hypertension-associated complications are seen.

She should be encouraged to continue with her current efforts,

but other interventions are warranted.

POTASSIUM LOSS

Adverse reactions with low-dose thiazide diuretics (e.g., HCTZ

12.5–25 mg daily) are minimal compared with higher-dose therapy (HCTZ>25 mg daily). Moreover, side effects and tolerability

with low-dose thiazide diuretic therapy are similar to other firstline drug therapy options and not much higher than what is

seen with placebo.41,43,44,57 Regardless, signs and symptoms of

electrolyte and metabolic changes, such as hypokalemia, hyponatremia, hyperglycemia, or hyperuricemia, should be evaluated

in all patients treated with thiazide diuretics. B.A. has experienced

small changes in serum potassium and uric acid, which are typical

thiazide-induced abnormalities. B.A. should be questioned about

muscle cramps or weakness, which can be caused by decreased

potassium.

CASE 14-4, QUESTION 5: Is B.A.’s potassium decrease concerning? If so, how should this be managed?

Most total body potassium is intracellular (∼98%). Thiazide

diuretics can cause potassium loss and can result in potassium

serum concentrations in the low end of the normal range.

However, with low-dose therapy overt hypokalemia is not common. HCTZ in doses of 12.5, 25, and 50 mg daily can decrease

serum potassium by an average of 0.21, 0.34, and 0.5 mEq/L,

respectively.41,132,133 This is usually considered mild, with serum

potassium concentrations reaching a nadir within the first month

of therapy and remaining stable thereafter. Restriction of dietary

sodium in patients receiving diuretic therapy has been shown

to reduce the loss of potassium, and should be encouraged in

B.A.134

SUBCLINICAL POTASSIUM DECREASES

The clinical significance of small potassium decreases when

serum potassium concentrations are still in the normal range

is controversial. B.A.’s potassium has dropped slightly, and her

current serum concentration is in the low end of the normal

range. Low serum potassium values have been cited as an independent predictor of development of diabetes.135 Some data suggest that patients treated with a thiazide diuretic who experience

the greatest decreases in potassium also experience the greatest

increases in glucose values,136 although this is not consistently

demonstrated in other analyses.137

Large outcome trials have demonstrated that thiazide

diuretic-based treatment results in a higher incidence of developing type 2 diabetes compared with other antihypertensive

therapies.34,138,139 Because of the possible association between

potassium decreases and development of diabetes, some clinicians believe that it is optimal to maintain serum potassium in

the middle to high end of the normal range (e.g., between 4.0

and 5.0 mEq/L) in patients treated with thiazide diuretics.140 This

may minimize the risk, albeit small, of increasing fasting glucose

concentrations, and possibly development of type 2 diabetes.

Although this is not necessarily a universally accepted recommendation to mitigate risk of developing type 2 diabetes in patients

treated with thiazide diuretics, keeping serum potassium concentrations in the 4.0 to 5.0 mEq/L range can be accomplished by

combining the thiazide diuretic with a potassium-sparing diuretic

(including an aldosterone antagonist), or an ACEI, ARB. These

strategies are particularly attractive when additional BP lowering is needed. Moreover, lifestyle modifications remain the best