Circulation. 2005;112:e127-e129
doi: 10.1161/CIRCULATIONAHA.105.570192
(Circulation. 2005;112:e127-e129.)
© 2005 American Heart Association, Inc.
Diuretics for Hypertension
Lawrence R. Krakoff, MD
From Englewood Hospital and Medical Center, Englewood, NJ.
Correspondence to Lawrence R. Krakoff, MD, Chief of Medicine, Englewood Hospital and Medical Center, Englewood, NJ 07631. E-mail Lawrence.Krakoff{at}ehmc.com or Lawrence.Krakoff@mssm.edu
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Introduction
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A 67-year-old African-American woman was referred to a hypertension
specialty clinic for refractory hypertension and intermittent
hypokalemia. Evaluations for primary aldosteronism and renal
artery stenosis were negative; plasma renin was low. She had
been hypertensive for 15 years. Most recently, she had taken
chlorthalidone 25 mg, amlodipine 5 mg, and metoprolol 50 mg
twice daily. She was not diabetic and had never smoked. Her
blood pressures were in the range of 160 to 170/95 to 100 mm
Hg. Except for her being mildly overweight (body mass index,
28), the physical examination was unremarkable, with no sign
of target organ damage. Voltage criteria for left ventricular
enlargement were present on the ECG. She was considered to be
adherent to medication. Spironolactone 50 mg/d was prescribed,
and her dose of chlorthalidone was reduced to 12.5 mg/d. Over
the next year, her blood pressure fell to the range of 135 to
145/85 mm Hg, and serum potassium was consistently normal.
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Comment
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This patient was taking three antihypertensive drugs, including
a diuretic, which is considered by many as a necessary component
for her management, yet remained uncontrolled, with an especially
high risk of stroke. The addition of another diuretic was successful
in bringing her pressure into an acceptable range and reversed
the tendency toward hypokalemia that was caused by the thiazide-type
diuretic. What is the lesson here? First, diuretic combinations
from different subclasses play an important role in the management
of hypertension. Second, salt-sensitive refractory hypertension
in the African-American population, reflected clinically by
low renin levels, can provide a clue to optimal management.
1,2
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Role of Diuretics in Management of Hypertension
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Treatment of hypertension that uses a diuretic-based strategy
has been effective in preventing stroke and cardiac disease
in the earliest randomized clinical trials in the 1960s, with
a consistently successful "track record" extending to contemporary
trials, as emphasized in ALLHAT.
3 A very high fraction of all
hypertensives, but especially African-Americans, can be well
controlled on simple two-drug regimens, combining a thiazide-type
diuretic with either a ß-blocker or an ACE inhibitor,
each given once a day. Cost is minimal, control rates are high,
and adherence to medication is probably optimum. There is a
substantial argument that a thiazide-type diuretic should be
the initial treatment for all hypertensives.
4 A side issue related
to that argument is that there is no detectable difference between
chlorthalidone (used in ALLHAT and SHEP) and other thiazides.
5 That said, diuretics are not a single drug class but rather
can be divided into three distinct subclasses, and each of these
has an important role to play in the management of most hypertensive
patients. Although most diuretics have been in clinical use
for many years, there has been drug development within this
class. We will focus on the three diuretic classes used to treat
hypertension: (1) thiazide-type, (2) loop-active agents, and
(3) the potassium-sparing agents, which act as either mineralocorticoid
antagonists or inhibitors of the epithelial sodium channel of
the late distal renal tubule or collecting duct. Another subclass,
the carbonic anhydrase inhibitors, is not used to treat hypertension.
The
Figure displays the sites at which the diuretic subclasses
have their major effects on electrolyte and water resorption
in the nephron after glomerular filtration has occurred.
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A nephron depicting locations for effect of the diuretic subclasses. After glomerular filtration, there is resorption of fluid and electrolytes in the proximal tubule (site of action of carbonic anhydrase inhibitors, eg, Diamox), ascending limb of the loop of Henle and early distal tubule (site of action of furosemide-type agents), late distal tubule (site of action of thiazide-like agents, and collecting duct (site of action of aldosterone receptor antagonists and inhibitors of the epithelial sodium channel (amiloride and triamterene).
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Thiazide-Type Diuretics
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As monotherapy and in combination with ß-blockers,
ACE inhibitors, or angiotensin receptor blockers, hydrochlorothiazide
and its many variants lower blood pressure. There remains some
controversy as to whether a thiazide-type diuretic should be
the initial treatment for all hypertensives. The evidence from
the SHEP study emphasizes the value of a low-dose thiazide-type
drug as initial therapy for isolated systolic hypertension in
older patients,
6 and ALLHAT strongly supports that choice for
African-American hypertensives.
3 For others, who are started
on a ß-blocker, ACE inhibitor, or angiotensin receptor
blocker and whose pressure remains above goal, there is a convincing
argument that a diuretic should be the next step.
7 Either way,
most hypertensives placed on one of these two drug combinations
can be well controlled. Using a thiazide-type drug requires
baseline serum electrolyte measurement and monitoring of serum
potassium. Gout remains an occasional adverse reaction as a
consequence of diuretic-induced hyperuricemia, and infrequently,
hypercalcemia may occur. These effects are the result of thiazide-related
reductions in urinary urate or calcium excretion. Type 2 diabetes
may develop during the course of thiazide-type diuretic treatment,
yet in elderly patients, there seems to be little added risk
for cardiovascular events compared with preexisting diabetes.
6 For those patients who develop hypokalemia on low-dose thiazide-type
diuretics, a diagnosis of primary aldosteronism may be considered.
Addition of potassium-sparing drugs, spironolactone, eplerenone,
or amiloride, may achieve effective control of hypertension
and correct hypokalemia without the need for extensive diagnostic
assessment or consideration of adrenalectomy. No study has clearly
shown that surgical treatment for primary aldosteronism is superior
to effective medical management.
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Loop-Active Agents
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As indicated by the
Figure, furosemide and its analogs (bumetanide
or torsemide) interrupt resorption of sodium, calcium, and potassium
in the distal renal tubule at the ascending limb of the loop
of Henle at sites distinct from the thiazide-sensitive loci.
These loop-active agents have a short duration of action and,
for treatment of hypertension, must be given twice daily. Renal
insufficiency reflected by reduced creatinine clearance limits
the effectiveness of thiazide-type diuretics. In contrast, furosemide
is highly effective despite renal impairment, although high
doses are often needed when serum creatinine increases. The
loop-active diuretics may cause hypokalemia, which can be countered
by potassium supplementation or potassium-sparing diuretics.
Close monitoring of serum potassium is necessary in these circumstances.
Unlike the thiazide-type agents, the loop-active diuretics increase
calcium excretion and can reduce serum calcium as a treatment
for hypercalcemia.
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Potassium-Sparing Diuretics: Mineralocorticoid Antagonists and Sodium Channel Antagonists
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Spironolactone, an inhibitor of the mineralocorticoid receptor,
has been used for many years. Although once quite popular, especially
in combination with a thiazide diuretic, spironolactone nearly
fell out of view (except for its use as a medical treatment
for primary aldosteronism) until it was resurrected for its
value in the treatment of congestive heart failure. As indicated
by the comments related to our case study, spironolactone can
be highly effective in many patients with refractory hypertension
in combination with a thiazide-type diuretic and can correct
hypokalemia as well. However, gynecomastia is a limiting adverse
reaction for men treated with spironolactone because of the
antiandrogen effect of this drug. Premenopausal women treated
with spironolactone may develop menstrual irregularities, so
that spironolactone is most likely to have sustained acceptance
only by postmenopausal women. Eplerenone has recently been developed
as a selective mineralocorticoid antagonist whose adverse effect
profile is far more acceptable to a broader range of patients
compared with spironolactone.
8 Eplerenone should be considered
an alternative for those who have a good clinical response to
spironolactone but who develop unacceptable adverse reactions.
Amiloride and triamterene are also customarily used drugs that inhibit the epithelial sodium transport channel (ENaC) of the collecting duct. The overall activity of this channel is controlled by the action of aldosterone. The ENaC inhibitors reduce potassium excretion as a consequence of their inhibition of the ENaC in preventing sodium resorption. The ENaC inhibitors have, in general, a minimal effect on blood pressure as monotherapy and are most effective for their potassium-sparing effects. The combination of a thiazide-type diuretic and amiloride (Co-amilizide) as initial treatment has been directly compared in a large randomized outcome trial (INSIGHT) with the long-acting calcium channel blocker, nifedipine GITS. The results of this trial found no statistically significant difference between the two treatments. However, a nonsignificant trend favored the diuretic combination.9 It is likely that, in the United States, the combination of a thiazide-type diuretic and a potassium-sparing agent, such as amiloride (which is a very-well-tolerated, inexpensive, and generic drug), is underused.
Rarely, salt-sensitive hypertensives may have gain-of-function mutations of the ENaC, resulting in an autosomal recessive trait (Liddle’s syndrome), which conveys a curative role for amiloride in this setting. It has been suggested that heterozygotic patterns may account for salt-sensitive and amiloride-responsive hypertension in some larger population groups.10
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Conclusions
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Contrary to the rumors of only a few years ago, diuretics have
not fallen into disuse but have a highly important and multifaceted
role to play in the treatment of hypertension. Identifiable
but large subgroups within the hypertensive population (isolated
systolic hypertension of the elderly and African-American hypertensives)
are those for whom diuretic treatment as initial management
may achieve the most benefit. Combinations of the thiazide-type
and potassium-sparing subclasses may be highly effective, providing
nearly optimal therapy for some, and might be considered more
often in the treatment of hypertension.
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