Combination Antihypertensive Drugs:

Recommendations for Use

NEIL S. SKOLNIK, M.D., JONATHAN D. BECK, M.D., MATHEW CLARK, M.D., Abington
Memorial Hospital, Jenkintown, Pennsylvania.
The recommendation for first-line therapy for hypertension remains a beta
blocker or diuretic given in a low dosage. A target blood pressure of less than
140/90 mm Hg is achieved in about 50 percent of patients treated with
monotherapy; two or more agents from different pharmacologic classes are often
needed to achieve adequate blood pressure control. Single-dose combination
antihypertension therapy is an important option that combines efficacy of blood
pressure reduction and a low side effect profile with convenient once-daily dosing
to enhance compliance. Combination antihypertensives include combined agents
from the following pharmacologic classes: diuretics and potassium-sparing
diuretics, beta blockers and diuretics, angiotensin-converting enzyme (ACE)
inhibitors and diuretics, angiotensin-II antagonists and diuretics, and calcium
channel blockers and ACE inhibitors.

The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure (JNC VI)1 recommends that patients with hypertension
and no comorbid illness begin antihypertensive drug therapy with a low dosage of a diuretic
or beta blocker. This recommendation is supported by the results of a meta-analysis
demonstrating that diuretics and beta blockers are the only agents shown to decrease the
incidence of stroke and congestive heart failure in patients with hypertension.2 Diuretics
administered in a low dosage have also been shown to decrease the incidence of coronary
artery disease and total cardiovascular mortality.2
Although the documented decreases in morbidity and mortality make adequate treatment of
hypertension important, the National Health and Nutrition Examination Survey (NHANES)
report3 showed that blood pressure is controlled to a level below 140/90 mm Hg in only 27
percent of patients diagnosed with hypertension. Because monotherapy is effective in
achieving this target goal in only about 50 percent of patients, treatment with two or more
agents from different pharmacologic classes is often necessary to achieve adequate blood
pressure control.4
The rationale for using fixed-dose combination therapy is to obtain increased blood pressure
control by employing two antihypertensive agents with different modes of action and to
enhance compliance by using a single tablet that is taken once or twice daily.5 Using low
doses of two different agents can also minimize the clinical and metabolic effects that occur
with maximal dosages of the individual components of the combined tablet.6 These potential
advantages are such that some investigators have recommended using combination
antihypertensive therapy as initial treatment, particularly in patients with target-organ damage

or more severe initial levels of hypertension.79 Combination antihypertensive drugs are

listed in Table 1.10
Combination Drugs for the Treatment of Hypertension

Drug

Brand name

Cost
(generic)
*

Diuretic combinations
Amiloride and hydrochlorothiazide (5 mg/50 mg)

Moduretic

$18 (9 to
12)

Spironolactone and hydrochlorothiazide (25 mg/50 mg, 50

mg/50 mg)

Aldactazide

15 (1 to 13)

Triamterene and hydrochlorothiazide (37.5 mg/25 mg, 50

mg/25 mg)

Dyazide

14 (9 to 11)

Triamterene and hydrochlorothiazide (37.5 mg/25 mg, 75

mg/50 mg)

Maxzide-25 mg,
Maxzide

15 (4 to 10)

Beta blockers and diuretics

Atenolol and chlorthalidone (50 mg/25 mg, 100 mg/25 mg) Tenoretic

36 (4 to 27)

Bisoprolol and hydrochlorothiazide (2.5 mg/6.25 mg, 5

mg/6.25 mg, 10 mg/6.5 mg)

Ziac

33

Metoprolol and hydrochlorothiazide (50 mg/25 mg, 100

mg/25 mg, 100 mg/50 mg)

Lopressor HCT

23

Nadolol and bendroflumethazide (40 mg/5 mg, 80 mg/5 mg) Corzide

47

Propranolol and hydrochlorothiazide (40 mg/25 mg, 80

mg/25 mg)

35 (6 to 10)

Inderide

Propranolol ER and hydrochlorothiazide (80 mg/50 mg, 120 Inderide LA

mg/50 mg, 160 mg/50 mg)

50

Timolol and hydrochlorothiazide (10 mg/25 mg)

Timolide

22

Lotensin HCT

24

ACE inhibitors and diuretics

Benazepril and hydrochlorothiazide (5 mg/6.25 mg, 10
mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg)

Drug

Brand name

Cost
(generic)
*

Captopril and hydrochlorothiazide (25 mg/15 mg, 25 mg/25 Capozide

mg, 50 mg/15 mg, 50 mg/25 mg)

28 (22)

Enalapril and hydrochlorothiazide (5 mg/12.5 mg, 10 mg/25 Vaseretic

mg)

33

Lisinopril and hydrochlorothiazide (10 mg/12.5 mg, 20

mg/12.5 mg, 20 mg/25 mg)

Prinzide

30

Lisinopril and hydrochlorothiazide (10 mg/12.5 mg, 20

mg/12.5 mg, 20 mg/25 mg)

Zestoretic

31

Moexipril and hydrochlorothiazide (7.5 mg/12.5 mg, 15

mg/25 mg)

Uniretic

17

Losartan and hydrochlorothiazide (50 mg/12.5 mg, 100

mg/25 mg)

Hyzaar

38

Valsartan and hydrochlorothiazide (80 mg/12.5 mg, 160

mg/12.5 mg)

Diovan HCT

36

Amlodipine and benazepril (2.5 mg/10 mg, 5 mg/10 mg, 5

mg/20 mg)

Lotrel

48

Diltiazem and enalapril (180 mg/5 mg)

Teczem

51

Felodipine and enalapril (5 mg/5 mg)

Lexxel

37

Angiotensin-II receptor antagonists and diuretics

Calcium channel blockers and ACE inhibitors

Verapamil and trandolapril (180 mg/2 mg, 240 mg/1 mg, 240 Tarka
mg/2 mg, 240 mg/4 mg)

43

Miscellaneous combinations
Clonidine and chlorthalidone (0.1 mg/15 mg, 0.2 mg/15 mg, Combipres
0.3 mg/15 mg)

26 (11)

Hydralazine and hydrochlorothiazide (25 mg/25 mg, 50

mg/50 mg, 100 mg/50 mg)

15 (3 to 5)

Apresazide

Drug

Brand name

Cost
(generic)
*

Methyldopa and hydrochlorothiazide (250 mg/15 mg, 250

mg/25 mg, 500 mg/30 mg, 500 mg/50 mg)

Aldoril

16 (6 to 14)

Prazosin and polythiazide (1 mg/0.5 mg, 2 mg/0.5 mg, 5

mg/0.5 mg)

Minizide

21

Diuretics in Combination Antihypertensive Therapy

Diuretics are effective antihypertensive drugs. Treatment with a diuretic such as
hydrochlorothiazide results in a dose-dependent blood pressure reduction that levels off with
higher dosages (Table 2).11 In long-term trials, diuretics have been shown to reduce the
incidence of stroke, congestive heart failure, coronary artery disease and total mortality from
cardiovascular disease.
Blood Pressure Reductions Achieved with Hydrochlorothiazide
Monotherapy
Blood pressure reduction (mm Hg)
Dosage (mg per day)

Systolic

Diastolic

50

23

17

25

21

14

12.5

14

11

6.25

Unfortunately, the degree of improvement in cardiovascular mortality is less than would have
been expected based on epidemiologic data. One postulated but not yet proven explanation is
that the higher diuretic dosages used in the large trials cause relative hypokalemia, as well as
increased serum lipid levels, insulin resistance and uric acid levels. These adverse metabolic
effects counteract the positive cardiovascular benefits of blood pressure reduction. Such
effects do not occur when diuretics are administered in a low dosage, such as 6.25 or 12.5 mg
per day of hydrochlorothiazide.11
Because diuretics blunt the sodium- and water-retaining effects of many other
antihypertensive drugs, they are the most commonly used medication in combination
antihypertensive agents. The JNC VI states clearly, If a diuretic is not chosen as the first
drug, it is usually indicated as a second-step agent because its addition will enhance the
effects of other agents.

POTASSIUM-SPARING AND THIAZIDE DIURETICS

The discrepancy between the JNC VI recommendations for first-line use of thiazide diuretics
and the actual use of these agents in clinical practice may be attributable to physicians'
concerns about the development of hypokalemia and hypomagnesemia, as well as the
marketing of newer agents by pharmaceutical companies. Combination therapy with a
potassium-sparing diuretic and a thiazide diuretic attempts to reduce the risk of adverse
metabolic effects. Combination therapy does not obviate the need for serial monitoring of
serum electrolyte levels, but it does decrease the incidence of thiazide-induced hypokalemia
without an increased risk of hyperkalemia.12
Fixed-dose potassium-sparingthiazide diuretic combinations have been in use for more than
20 years. Current combinations include spironolactone-hydrochlorothiazide (Aldactazide),
triamterene-hydrochlorothiazide (Dyazide, Maxzide) and amiloride-hydrochlorothiazide
(Moduretic). These combination drugs do not appear to differ significantly in efficacy or
adverse effects.13 The described improvement in the bioavailability of Maxzide over
Dyazide has not been shown to yield improved blood pressure control.14
All potassium-sparingthiazide diuretic combinations seem to reduce blood pressure to the
same degree as thiazide diuretics alone.15-18 In one large postmarketing surveillance study
of patients treated with triamterene-hydrochlorothiazide,12 the incidence of hypokalemia was
approximately one half to one third that expected in hydrochlorothiazide monotherapy. In
addition, the amiloride-hydrochlorothiazide combination caused significantly less alteration
of serum potassium levels than did hydrochlorothiazide given alone in dosages of 25 to 100
mg per day.15 The clinical applicability of the findings may be questionable because the
studies used hydrochlorothiazide dosages that were significantly higher than those currently
recommended.
The low dosages of hydrochlorothiazide (12.5 to 25 mg per day) advocated in the JNC VI
provide significant blood pressure reduction while minimizing electrolyte abnormalities.19 It
remains unclear whether the addition of a potassium-sparing agent confers additional benefit
compared with a low dosage of hydrochlorothiazide alone.
BETA BLOCKERS AND DIURETICS

Beta blockers cause retention of sodium and water. Diuretics can cause mild volume
reduction that leads to an increase in renin secretion by the kidney. The rationale for
combining beta blockers with diuretics is twofold: beta blockers blunt the increase in the
plasma renin level that is induced by diuretics, and diuretics decrease the sodium and water
retention that is caused by beta blockers.6,20
The combination of a beta blocker and a diuretic produces additive effects compared with
monotherapy using either agent alone. A recent study21 assessed the safety and efficacy of
antihypertensive therapy using the cardioselective beta blocker bisoprolol alone and in
combination with low dosages of hydrochlorothiazide. The dosages of bisoprolol were 2.5, 5
and 10 mg per day. The hydrochlorothiazide dosages were 6.25 and 25 mg per day. The study

showed that monotherapy with either agent was more effective than placebo, but that when
combination therapy was used, the beneficial effects were greater than when either agent was
used alone (Figure 1).21

In the same study,21 combination therapy was associated with a low incidence
of adverse effects. Side effects for combined hydrochlorothiazide in a dosage of
6.5 mg per day and bisoprolol in all dosages included fatigue (9 percent of
recipients), dizziness (6 percent), somnolence (3 percent), impotence (2 percent)
and diarrhea (4 percent). When used in combination with bisoprolol,
hydrochlorothiazide (6.25 mg) did not cause hypokalemia or any adverse effects
on the lipid profile. Side effects increased with the use of higher dosages of
bisoprolol or hydrochlorothiazide. The incidence of hypokalemia and
hyperuricemia was greater for 25 mg per day of hydrochlorothiazide than for
6.25 mg per day. With higher bisoprolol dosages, the frequency and severity of
asthenia, diarrhea, dyspepsia and somnolence increased significantly.
ACE INHIBITORS AND DIURETICS

Angiotensin-converting enzyme (ACE) inhibitors are among the best tolerated

antihypertensive drugs and have been used extensively as initial agents in the treatment of
hypertension. The JNC VI1 recommends ACE inhibitors as second-line agents in most
patients with hypertension and as first-line choices only in selected patients, including those
with left ventricular systolic dysfunction and those with diabetes and microalbuminuria or
proteinuria.
The reninangiotensin-aldosterone axis is important in the maintenance of systemic blood
pressure. By causing volume and sodium depletion, thiazide diuretics stimulate the
production of renin and angiotensin. This leads to a relative increase in blood pressure and
sodium retention, which counteracts some of the other antihypertensive effects of the thiazide
diuretics. ACE inhibitors interfere with the conversion of angiotensin I to angiotensin II and
thereby decrease angiotensin II levels. These effects lead to decreased sodium retention and
an enhanced antihypertensive effect.

Synergism between ACE inhibitors and diuretics is especially prominent in black patients, a
population in whom monotherapy with ACE inhibitors has been shown to be less effective
than it is in white patients. One small study22 of black patients with hypertension (N= 38)
compared monotherapy using 20 mg per day of enalapril with combination therapy consisting
of 20 mg of enalapril plus 12.5 mg of hydrochlorothiazide per day. Combination therapy
significantly reduced systolic, diastolic and 24-hour ambulatory blood pressure measurements
compared with monotherapy. Combination therapy controlled blood pressure to a level of less
than 140/90 mm Hg in 74 percent of patients.
Studies have shown that ACE inhibitordiuretic combinations achieve blood pressure control
in approximately 80 percent of patients.20,23-25 Typical results were obtained in one of the
larger double-blind, placebo-controlled trials.23
In this study,23 505 patients with diastolic blood pressures of 100 to 114 mm Hg received
placebo, lisinopril (10 mg per day), hydrochlorothiazide (12.5 or 25 mg per day) or the
combination of lisinopril (10 mg per day) and hydrochlorothiazide (12.5 or 25 mg per day).
All drug therapies were more effective than placebo in lowering blood pressure, but the
combination antihypertensive therapies produced the greatest effect (Figure 2).23

The study23 found that the combination consisting of 10 mg per day of lisinopril and 12.5 mg
per day of hydrochlorothiazide was well tolerated. The most commonly observed side effects
were pharyngitis (14 percent of recipients), increased cough (6 percent), dizziness (2
percent), headache (12 percent) and asthenia (4 percent). Cough was the only side effect that
was more prevalent in this group than in the placebo group.
Based on this large study,23 antihypertensive drug combinations containing an ACE inhibitor
and a lower dose of hydrochlorothiazide are more desirable. It is important to be aware that
the doses of ACE inhibitor in the antihypertensive drug combinations do not reach the target
doses of ACE inhibitors recommended for the treatment of congestive heart failure, which
may be a limitation in these patients.26

ANGIOTENSIN-II ANTAGONISTS AND DIURETICS

In patients for whom ACE inhibitordiuretic combinations are indicated but not tolerated
because of cough, angiotensin-II receptor antagonistdiuretic combinations are available.
Angiotensin-II receptor antagonists work by blocking specific angiotensin II subtype I,
thereby selectively inhibiting the vasoactive properties of angiotensin II.
One study27 evaluated the efficacies of losartan in a dosage of 50 mg per day,
hydrochlorothiazide in a dosage of 12.5 mg per day and combination therapy
with 50 mg per day of losartan and 6.25 or 12.5 mg per day of
hydrochlorothiazide. The treatments were compared with each other and with
placebo (Figure 3).27 The greatest antihypertensive effect occurred with the
combination of 50 mg of losartan and 12.5 mg of hydrochlorothiazide. This
treatment reduced diastolic blood pressure to less than 90 mm Hg (or a
reduction of 10 mm Hg or greater) in 78 percent of patients. The combination of
losartan with the lower hydrochlorothiazide dose (6.25 mg) demonstrated no
benefit over monotherapy with losartan. No significant differences in adverse
events were attributable to the combination of losartan (50 mg) and
hydrochlorothiazide (12.5 mg) compared with placebo.

Calcium Channel Blockers and ACE Inhibitors

The combination of a calcium channel blocker and an ACE inhibitor is appealing on theoretic
grounds. Although calcium antagonists exert much of their antihypertensive effect through a
vasodilatory action, they also have diuretic and natriuretic properties.28 ACE inhibitors blunt
the stimulation of the reninangiotensin-aldosterone axis that may result from this diuretic
effect. These agents also inhibit the central sympathetic stimulation that may result from
calcium antagonistassociated vasodilatation, although both classes of drugs are potent
vasodilators.29
ACE inhibitors and calcium channel blockers work effectively in combination to lower blood
pressure.3032 In one representative study,33 diastolic blood pressures were reduced by 3.6
mm Hg more with a trandolapril-verapamil combination than with monotherapy using either
agent. No increase in side effects was observed for treatment with combined trandolapril and
verapamil.
Calcium antagonists and ACE inhibitors may also work together to favorably influence
target-organ disease independent of their effect on blood pressure. Together they appear to
have a renal-protective effect,34 to promote reduction of left ventricular mass35 and to
decrease mediators of vascular disease.36 The relatively low dose of ACE inhibitor in some
combinations may not confer the same degree of renal or cardiac protection that has been
demonstrated for higher doses.
Calcium channel blockerACE inhibitor combinations may result in fewer or milder side
effects than occur with either agent alone. The addition of an ACE inhibitor to therapy with a
dihydropyridine calcium antagonist significantly reduces the incidence of peripheral edema

and reflex tachycardia. Neither class of medications has prominent metabolic side effects, an
advantage in patients with diabetes and renal disease.
Four fixed-dose combinations of calcium channel blockers and ACE inhibitors are currently
available in the United States. These combinations have yet to be proved more efficacious
than antihypertensive combinations containing diuretics.

Miscellaneous Combination Agents

Other combination antihypertensive agents that have existed for many years include diuretics
with a direct-acting vasodilator (hydralazine-hydrochlorothiazide [Apresazide]), a central
alpha-adrenergic agonist (methyldopa-hydrochlorothiazide [Aldoril] and clonidinechlorthalidone [Combipres]) or a peripheral alpha-adrenergic blocker (prazosin-polythiazide
[Minizide]). No trials have indicated survival benefit with their use.
The JNC VI specifically mentioned that the three nondiuretic classes represented in these
combinations are not well suited for initial monotherapy because they produce annoying
adverse effects in many patients.1(p2426) No studies have provided conclusive evidence of
increased tolerance when these agents are taken orally in combination with a diuretic.
Therefore, these combinations are not indicated for first-line therapy.

Final Comment
The JNC VI1 continues to recommend monotherapy with a diuretic or beta blocker as initial
treatment for the undifferentiated patient with hypertension. At the same time, it is recognized
that monotherapy will not provide adequate blood pressure control in a large proportion of
patients, and that many patients will experience unacceptable side effects with higher dosages
of a single agent. Fixed-dose combination antihypertensive medications are a useful and
appropriate treatment option in this large group of patients.