Pharmacy Division Ramathibodi Hospital


Beyond the Usual Strategies for Blood Pressure Reduction: Therapeutic Considerations and Combination Therapies

Thomas D. Giles, MD, and Gary E. Sander, MD, PhD, from The Section of Cardiology, Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA

[J Clin Hypertens 3(6):346-353, 2001. © 2001 Le Jacq Communications, Inc.]

Abstract and Introduction


Rapidly accumulating clinical data have repeatedly demonstrated not only the critical importance of even small increases in blood pressure as a pathophysiologic factor in the development of cardiovascular disease, particularly in individuals with diabetes mellitus, but also the therapeutic necessity of more aggressive blood pressure reduction and the achievement of progressively lower blood pressure targets in reducing cardiovascular event rates. JNC VI has defined optimal blood pressure as lt_equal120/80 mm Hg, and Stage 1 hypertension as gt_equal140/80 mm Hg. Target blood pressures are now lt_equal130/80 mm Hg in patients with diabetes and <125/75 mm Hg for patients with hypertensive renal disease with proteinuria of >1 gm/24 hours. Achieving such target pressures is increasingly difficult, particularly in diabetic patients with chronic renal disease, who require complex multidrug antihypertensive regimens. This review attempts to provide some suggestions for constructing such antihypertensive regimens, and provides considerations for the appropriate use of diuretics and the most effective drug combinations. Factors potentially contributing to drug resistant hypertension include such problems as failure to maximize drug dosing, suboptimal diuretic use, noncompliance, and possible confounding effects of such concomitant medications as nonsteroidal and anti-inflammatory drugs or decongestants. The issues underlying drug-resistant hypertension are listed, together with strategies for overcoming this problem.


The critical importance of lowering blood pressure in the prevention of cardiovascular events, including angina, myocardial infarction, and stroke, has been demonstrated by numerous clinical trials. It has now become apparent, on the basis of clinical trial evidence, that reduction should be carried out to lower levels of blood pressure than have been previously recommended. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood pressure (JNC VI)[1] defines optimal blood pressure as lt_equal120/80 mm Hg, normal as lt_equal130/85 mm Hg, and high-normal as 130-139/85-89 mm Hg, using the higher number of the systolic and diastolic pressures to define the category. A blood pressure of 140/90 mm Hg would be considered to represent stage 1 hypertension.

The Hypertension Optimal Treatment (HOT) trial[2] results suggest that blood pressure reduction to mean levels of <140/85 mm Hg appears to produce the maximum protection against cardiovascular morbidity and mortality events in treated, nondiabetic hypertensives, at least over the 3.8-year average duration of the study. Clearly, some patients benefited from lower levels. Earlier concern over a J-curve relationship, which would suggest that lowering diastolic blood pressure below 80-85 mm Hg in patients with evidence of ischemic heart disease would increase cardiovascular event rates, now appears less warranted,[1,3] although not totally unjustified.[4] Isolated systolic hypertension, which is particularly common in the elderly, is associated with a dramatic increase in the risk of cardiovascular events.[5] The elderly should be treated to the same goal (lt_equal140/90 mm Hg) as younger patients, although a more gradual reduction in pressure to this level, with perhaps an intermediate goal of systolic blood pressure of <160 mm Hg, may be advisable.[1] However, in the presence of certain comorbidities, lower target blood pressures are clearly indicated. The blood pressure target in diabetes mellitus is lt_equal130/85 mm Hg, according to the JNC VI criteria, but a diastolic level of <80 mm Hg is suggested in the HOT trial report[2] and is now more widely advocated.[3] In patients with hypertensive renal disease and proteinuria of >1 g/24 hr, blood pressure should be controlled to 130/85 mm Hg (125/75 mm Hg, if possible).[1] Data from the HOT trial[2] and the United Kingdom Prospective Diabetes Study (UKPDS)[6] demonstrate that the desired blood pressure reduction will not likely be achieved without resort to use of multiple drugs. An average of 3.2 drugs has been reported to be necessary in hypertensive diabetic patients with renal disease.[3]

There are numerous effective antihypertensive drugs, and many protocols for combining those drugs have been devised since the initial JNC recommendation for "stepped care." Although considerable interest and effort have been invested to establish the presence or absence of genuine therapeutic differences in clinical outcomes among individual drugs and multidrug regimens, no such data have yet been reported for patients with uncomplicated hypertension.[7] This review will highlight certain considerations and "pearls" that may assist clinicians in designing pharmacologic regimens for their patients. JNC VI lists "compelling" indications for utilizing certain classes of drugs as initial therapy, e.g., angiotensin-converting enzyme (ACE) inhibitors in patients with diabetes, and advises building on this foundation with addition of other classes of drugs until control is achieved. The JNC suggests that if two or more classes of drugs are necessary, a diuretic should be included. Alternatively, protocols may be selected from those used in clinical trials. Regardless of which approach is used, many patients simply do not respond satisfactorily. In the discussion to follow, we will review certain pharmacologic properties of individual drugs that are often not considered because of the implications of such properties relative to multidrug regimens. We will also suggest alternative combinations that may improve control of blood pressure, as well as some combinations to be avoided. These suggestions are, of course, based on a desire to achieve lower blood pressures and have not been the subject of clinical outcome trials; they may be particularly appropriate for patients who have received drugs from four of the major classes -- diuretics, beta blockers, ACE inhibitors/angiotensin II receptor (AT1) blockers (ARBs), and calcium channel blockers (CCBs), since clinical trials have shown that multiple drugs may be required to achieve target blood pressure levels.

Diuretics: All Are Not the Same


Hydrochlorothiazide and chlorthalidone are the thiazide diuretics most commonly used in the United States for the treatment of hypertension. These drugs have produced remarkable results in lowering blood pressure and reducing morbidity and mortality associated with hypertension, particularly in the elderly population, as demonstrated in such trials as the Systolic Hypertension in the Elderly Program (SHEP)[8] and the Systolic Hypertension-Europe (Syst-Eur) [9] trial. Diuretic doses used in earlier studies (50-100 mg of hydrochlorothiazide or chlorthalidone) caused salt and water loss with a reduction in vascular volume, which contributed to the hypotensive mechanism. The antihypertensive effect of low-dose diuretics may result from alterations in intracellular calcium concentrations and modulation of potassium channels with resultant vasodilation.[10,11] Higher doses of thiazide diuretics result in secondary activation of the sympathetic nervous system and the renin-angiotensin system, hypokalemia, hypomagnesemia, and increased serum glucose concentrations. The low thiazide doses currently advocated for hypertension (for example, 6.25-25 mg of hydrochlorothiazide) cause little diuresis and minimal activation of the sympathetic nervous system and renin-angiotensin system and minimal, if any, alterations in electrolyte concentrations or glucose metabolism.[12] However, closer evaluation of the SHEP data reveal that after 1 year of treatment, 7.2% of patients randomized to active treatment with 12.5 mg of chlorthalidone had a serum potassium of <3.5 mg/dL, compared to only 1% of those receiving placebo.[13]

The synergistic effects of low-dose diuretic combinations with ACE inhibitors, ARBs, and beta blockers represent the additive effect of multiple drug mechanisms. Addition of low-dose thiazides to ACE inhibitors or ARBs markedly increases the antihypertensive efficacy of these drugs in black patients,[14] thus providing effective blood pressure reduction together with vascular protection that is independent of blood pressure reduction.[15] If actual diuresis is necessary, either higher thiazide doses or loop diuretics must be used. Thiazides are generally ineffective when serum creatinine exceeds 2.5 mg/dL.[1] Thiazides have also been noted to increase bone density,[16] which may represent another benefit of their use in the elderly population.[17]

Two "thiazide-like" drugs deserve mention. The indole derivative indapamide may be used in individuals intolerant of thiazides; mechanistically, it appears to block the L-calcium channel in a fashion similar to that of CCBs[11] and has been reported to be more effective than 25 mg of hydrochlorothiazide in regressing left ventricular hypertrophy.[18] Metolazone appears to be effective even in the presence of reduced renal function[19]; however, outcome data are lacking for this drug.

Potassium-Sparing Diuretics

Drugs of this class (including spironolactone, amiloride, and triamterene) have minimal antihypertensive effects alone but were commonly used in the past, particularly in combination with thiazides, to minimize potassium and magnesium loss. However, in recent years, probably due to the lower doses of thiazides used together with the abundance of newer drugs developed for the treatment of hypertension, interest in these drugs waned. Interest was reawakened in the use of spironolactone in the treatment of advanced heart failure when its markedly favorable effect on survival was demonstrated in the Randomized Aldactone Evaluation Study (RALES).[20] Now, evidence is emerging that primary hyperaldosteronism may account for 10%-20% of cases of previously diagnosed primary hypertension.[21-23] Thus, for these patients, antagonism of the mineralocorticoid receptor provides dramatic blood pressure reduction. Furthermore, spironolactone may reduce the extent of myocardial fibrosis.[24] Perhaps even more importantly, the patients in the SHEP trial who developed hypokalemia did not experience the reduction in cardiovascular events achieved among those who maintained normal serum potassium levels,[13] emphasizing the importance of aldosterone antagonists in preventing potassium and magnesium depletion[25] and possibly reducing the incidence of cardiovascular complications. Spironolactone doses of 12.5-25.0 mg daily are effective and inexpensive.

Loop Diuretics

The loop diuretics, including furosemide, bu-metanide, torsemide, and ethacrynic acid, while not infrequently employed in the management of hypertension, are short-acting and produce brief periods of natriuresis, followed by periods of sodium reabsorption. These drugs are not approved by the US Food and Drug Administration for use in the treatment of hypertension and should not be routinely used as monotherapy. However, loop diuretics are clearly beneficial for patients with edema, particularly under conditions of decreased renal function or poor renal blood flow, e.g., heart failure. They may be useful additions for patients not adequately controlled with other two-drug combinations, particularly if both drugs are vasodilators. "Resistance" in such patients is often the result of secondary salt and water retention with resultant vascular volume expansion. Thus, the role of loop diuretics is in the treatment of fluid retention and edema, whether secondary to the use of other hypertensive agents or to concomitant disease states, especially renal disease.

Drugs That Inhibit the Renin-Angiotensin System ACE Inhibitors

It was originally believed that ACE inhibitors reduce blood pressure by inhibiting the formation of angiotensin II. However, it is now apparent that plasma angiotensin II levels return to near or even above baseline levels during chronic ACE inhibitor treatment, despite the fact that blood pressure reduction is maintained.[26] In fact, in humans, tissue production of angiotensin II occurs primarily by non-ACE pathways, and is catalyzed by enzymes such as chymase.[27] Data now indicate that it is the attenuation of bradykinin and angiotensin-(1-7) degradation by the inhibition of ACE that is important in achieving blood pressure reduction and other ACE inhibitor effects, including inhibition of myocardial remodeling.[28-30]

ACE inhibitors are useful as initial therapy in many hypertensive individuals with a wide variety of concomitant disease states. There has been a reluctance to utilize ACE inhibitors in patients with renal insufficiency, based upon the concern that the use of ACE inhibitors may lead to renal failure. It has now been demonstrated that ACE inhibitors (usually with a diuretic) are more effective than other antihypertensive agents in reducing the development of both diabetic and nondiabetic end-stage renal disease, and they do not increase mortality.[31-33] In nondiabetic nephropathies, ACE inhibition confers renoprotection even to patients with non-nephrotic proteinuria.[34] Individuals with serum creatinine levels of gt_equal1.4 mg/dL who were randomized to an ACE inhibitor experienced a 55%-75% risk reduction in renal disease progression compared to those with normal renal function randomized to an ACE inhibitor. Acute increases in serum creatinine of up to 30% stabilized within the first 2 months of therapy, and this was followed by long-term preservation of renal function. ACE inhibitor therapy should be withdrawn only when the rise in creatinine exceeds 30% above baseline within the first 2 months of ACE inhibitor initiation, or if hyperkalemia (serum potassium of gt_equal5.6 mmol/L) develops.[35]

Angiotensin II (AT1) Receptor Blockers

The ARBs specifically inhibit the binding of angiotensin II to the AT1 receptor, with subsequent interruption of the vasoconstrictive and smooth muscle proliferative effects of angiotensin II.[36] ARBs are similar to ACE inhibitors in antihypertensive efficacy; their combination with thiazide diuretics is particularly efficacious. Since the ARBs are newer drugs, there is less experience and fewer long-term outcome data than with the ACE inhibitors. ARB therapy results in little, if any, hyperkalemia, and may be particularly useful in situations in which an ACE inhibitor is indicated but its use is restricted by the presence of increased potassium. Furthermore, the ARBs do not cause cough and have very rarely been associated with angioedema. Initial data suggest that the ARBs exert renoprotective effects, and may offer a lesser risk of functional renal insufficiency and hyperkalemia.[37] The ARBs have an increasingly important role in the management of high-risk hypertension complicated by diabetes, as demonstrated in multiple recent trials.[38]

Combination of ACE Inhibitors and ARBs
Since ARBs inhibit the activation of the AT1 receptor by angiotensin II, while ACE inhibitors increase the concentration of vasodilator peptides, such as bradykinin, this combination should provide a higher degree of blockade of the renin-angiotensin system than either agent alone, and thus represents an attractive possibility for therapy in patients requiring multiple drugs for blood pressure control. ACE inhibitor/ARB combination has been evaluated primarily in heart failure trials for determination of clinical outcome.[39,40] However, in a small study of patients with chronic renal disease,[41] the reductions in both systolic and diastolic blood pressure were greater with the combination than with an ARB alone. The combination did not cause further deterioration of renal function, and it may also have additive antiproteinuric effects.[42]

Sympathetic Nervous System Attenuation

Beta Blockers

The use of beta blockers has achieved success in hypertension, particularly in patients with associated coronary artery disease. A meta-analysis to evaluate the effects of treatment with beta blockers in the elderly suggested that thiazides are superior to beta blockers in this population in the control of blood pressure and reduction of the cardiovascular event rate.[43] However, this meta-analysis has been questioned because the majority of patients received both diuretics and beta blockers, and much of the difference between agents occurred in a single trial with a high drop-out rate.[44] Although beta blockers are still advocated by some as a suitable first-line therapy for elderly patients,[45] some experts would not use beta blockers as monotherapy for the elderly hypertensive patient despite the fact that their use reduces strokes and congestive heart failure in this population.[44] Beta blockers remain important in the secondary prevention of cardiovascular events following myocardial infarction and are significantly underutilized in this regard.[46] Beta blockers reduce the processing of prorenin to renin, thus suppressing plasma angiotensin II levels in parallel with marked reductions in plasma renin activity and urinary aldosterone levels, in normotensive as well as hypertensive subjects; the suppression of angiotensin II levels is comparable to that produced during ACE inhibition.[47] Up-regulation of renin by antihypertensive treatment can largely be prevented by concomitant beta blockers treatment.[48]

Combination beta-Blocker/ACE Inhibitor Therapy
This combination is widely thought not to be rational, but it may have some utility.[49] Combination of enalapril with atenolol was found to provide an additional hypotensive response, but the full potential for an additive effect was attenuated by 30%-50%.[50] It has been reported that atenolol is significantly more effective than enalapril in reducing systolic blood pressure during exercise, and the addition of atenolol to enalapril produces a significant supplementary antihypertensive effect.[51] The addition of a beta blockers also seems to prolong the blood pressure-lowering effect of the short-acting ACE inhibitor captopril.[52] The combination of a beta blockers with a nondihydropyridine CCB should be attempted with caution, particularly in the elderly and those with conduction system disorders, due to the possibility of excessive bradycardia or heart block.

Combination alpha/beta Blockade
This approach may be very effective, and may avoid the potential increase in peripheral vascular resistance that can result from nonselective b blockade. Although the recent results of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)[53] suggest that utilization of an alpha1 blocker alone may not be particularly efficacious because of the resultant salt and water retention, the use of the combination would offset the action of the catecholamine increase that results from peripheral vasodilatory effects of the alpha1 blocker alone.

Calcium Channel Blockers

The CCBs are an unusual class of drugs, in that they are structurally diverse and related only by their ability to inhibit the flow of calcium ions through the L-type calcium channel during the action potential.[54,55] Those with negative chronotropic and inotropic effects (verapamil, diltiazem) should be used carefully in situations of bradycardia, conduction abnormalities, or decreased left ventricular systolic function.

Dihydropyridine CCBs are less effective than ACE inhibitors in reducing cardiovascular events in diabetic patients[56,57]; however, the combination of an ACE inhibitor and a long-acting dihydropyridine was found, in a small trial, to reduce cardiovascular events to a greater degree than does ACE inhibition alone.[58,59] Interestingly, the antihypertensive effect of CCBs is less dependent upon dietary sodium restriction, at least in salt-sensitive black patients, than is the antihypertensive effect of ACE inhibitors.[60] Thus, CCBs may be particularly useful in patients who cannot or will not restrict sodium intake. The peripheral edema that frequently occurs with higher doses of the dihydropyridines as a result of vasodilatation and reduction in precapillary resistance, may be reduced by concomitant use of an ACE inhibitor, which lowers postcapillary resistance.[61] The use of older, short-acting formulations of the CCBs has been associated with an increase in the rate of cardiovascular complications.[62,63] These formulations should not be used as initial therapy.

Dihydropyridine and Nondihydropyridine CCB Combinations
Combined use is predicated on the information that the dihydropyridine diltiazem and verapamil binding proteins or receptors occupy different areas of the L-type calcium channel and that they are allosterically linked such that occupation of multiple sites confers additional blockade of calcium entry.[54,55] Use of these combinations has been related to the treatment of resistant coronary arterial vasospasm.[64] Combination use has recently been suggested as a means to achieve blood pressure control in hypertensive patients with diabetes or chronic renal failure who are not at target (<130/80 mm Hg) despite treatment with an ACE inhibitor, a diuretic, and a long-acting CCB,[3] and who do not respond to the addition of a beta blockers.

Centrally Acting Drugs

The most commonly used centrally acting antihypertensive drug in the United States is clonidine, a central alpha2 agonist. Clonidine increases parasympathetic activity and decreases sympathetic activity, and thus may significantly reduce heart rate.[65] It may be particularly useful in patients with increased resting heart rates, but conversely, problematic in those with bradycardia or if used in combination with negatively chronotropic CCBs or beta blockers. Side effects often limit the use of this drug. Clonidine is the only antihypertensive drug available as a transdermal preparation, which makes it uniquely useful as an alternative to parenteral therapy when oral medication is not feasible.[66] The 7-day efficacy of each patch may also offer an alternative to daily medication in appropriate clinical situations. It is essential to remember that therapeutic plasma levels are not achieved until 48 hours after initial application of the patch, and steady state is attained at 48-96 hours; also, clonidine effects persist for similar durations after the patch is removed.

Combinations of clonidine and beta blockers should be avoided if at all possible, not only because of the additive bradycardic effect, but also because b blockade converts the (usually weak) peripheral alpha2 action of clonidine to a pressor effect.[65]

Drug-Resistant Hypertension

According to the JNC VI definition, hypertension should be considered resistant if blood pressure cannot be reduced below 140/90 mm Hg (below 160 mm Hg systolic blood pressure for the elderly patient with isolated systolic hypertension) with near-maximal doses of a triple-drug regimen that includes a diuretic. The prevalence of resistant hypertension has been reported to be 20% or higher.[67,68] Common causes include pseudoresistance resulting from inaccurate blood pressure measurement, problems with the antihypertensive regimen, associated medical conditions, and unrecognized secondary hypertension.[67] Suboptimal medication regimens are the most common cause. The major medication-related issues are summarized in the Table.

Apparent resistance to antihypertensive medications is often the result of noncompliance, either with the medications themselves or with reasonable dietary sodium restriction. Often, medication is not changed or added to by the physician, despite failure to achieve goal blood pressure levels. It is logical that noncompliance, either intentional or inadvertent, will increase in proportion to the complexity and expense of the pharmacologic regimen. Combination drug regimens may not only be therapeutically more effective than single-drug therapy, but also may contribute to patient compliance by simplifying and reducing the cost of the treatment regimen. Multiple-drug regimens should include drugs from different classes.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been demonstrated, in numerous clinical trials, to produce a statistically significant rise in blood pressure of 3-6 mm Hg -- a blood pressure change that has been associated with an increase in the cardiovascular event rate. Piroxicam, naproxen, and indomethacin have the greatest negative impact upon blood pressure control, although central alpha2 agonists and CCBs appear relatively resistant to NSAID effects. The mechanism appears to result from inhibition of the production of vasodilatory prostaglandins.[69-71] Other, more subtle considerations include the vascular volume expansion that may result from use of multiple nondiuretic agents.

The possible confounding role of NSAIDs and decongestants, either prescribed or over-the-counter, and a high-sodium diet should always be considered when resistance is encountered. However, most problems result from non-use, or inappropriate use, of diuretics. As discussed earlier, an understanding of the pharmacology of the various diuretics and their appropriate use is critical to blood pressure reduction.[68] Low-dose thiazides do not achieve significant volume diuresis; in order to achieve sodium and water diuresis, it is necessary to use either a loop diuretic or higher doses of a thiazide (gt_equal50 mg daily), while presumably lowering blood pressure by vasodilation. Thiazides are ineffective in the presence of renal insufficiency (glomerular filtration rate of <15-20 mL/min); either a loop diuretic or metolazone is indicated in such situations.[72] Loop diuretics are not appropriate as initial therapy, particularly in patients with normal renal function. The total duration of action of the loop diuretics furosemide and bumetanide is <5 hours; these may require b.i.d. or t.i.d. dosing. More than one half of "resistant" patients can be controlled by careful adjustment of the antihypertensive regimen or the addition of a diuretic, if one is not being used.

Figure 1 illustrates a "Round 1" approach for developing logical combination therapy to reach target blood pressure levels. As has been described, optimal blood pressure control may require use of multiple drugs, particularly in hypertensive diabetic patients with renal insufficiency. Figure 2 provides some suggestions for situations in which blood pressure remains elevated after "Round 1." Once adequate control is achieved, particularly after addition of the second round of drugs, thought may be given to eliminating one or two of the initial drugs that appeared less efficacious.

Figure 1. Initial or "Round 1" therapy for the hypertensive subject usually begins with one of the four major classes of drugs. An angiotensin receptor blocker (ARB) may be used in place of an angiotensin-converting enzyme (ACE) inhibitor for avoidance of ACE intolerance or ACE side effects. A calcium channel blocker (CCB) may also be appropriate in certain clinical situations. When a second drug is necessary, the most useful combinations are connected by solid lines.

Figure 2. "Round 2" illustrates drug combinations that may be particularly useful in the difficult-to-control patient. It may occasionally prove necessary to combine a dihydropyridine (DHPD) calcium channel blocker (CCB) with a non-DHPD, such as diltiazem or verapamil. Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACE/ARB) combinations and alpha1/beta blocker combinations may be helpful, as may be the addition of a central alpha2 agonist, such as clonidine. Spironolactone may be especially efficacious for patients with increased plasma aldosterone levels (see text). CNS=central nervous system

Table. Medication-Related Causes of Resistant Hypertension

  • Failure to use maximal recommended doses of each medication

  • Failure to dose in accordance with duration of action of each medication

  • Inappropriate use, or lack of use, of diuretics

  • Inappropriate drug combinations

  • Patient noncompliance with medication regimen

  • Patient noncompliance with dietary sodium restriction

  • Concomitant medications, including nonsteroidal anti-inflammatory drugs and decongestants


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Address for correspondence/reprint requests: Thomas D. Giles, MD, Section Cardiology, Department of Medicine, Louisiana State University Health Sciences Center, 1524 Tulane Avenue, New Orleans, LA 70112

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