The Expanding Role of Angiotensin Receptor Blockers
Author: John A. Brose, DO, FAAFP, Professor of Family Medicine and Assistant Dean, Clinical Research, Ohio University, College of Osteopathic Medicine, Athens, OH.
Peer Reviewer: Michael H. Crawford, MD, Robert S. Flinn Professor, Chief of Cardiology, University of New Mexico, Albuquerque.
Editor's Note-Phone calls and clinic visits for antihypertensive medication side effects are a part of every primary care physician's life. Fatigue, cough, cold feet, loss of exercise tolerance, sexual dysfunction-the list of patient complaints is all too familiar. Patients now rightfully demand medications that are both effective and do not interfere with their quality of life.
Treatment decisions in hypertensive therapy are also influenced by the presence of coexisting diseases. Primary care physicians have long noted the association of hypertension with disorders such as hyperlipidemia, obesity, and glucose intolerance. When these disorders occur along with hypertension, choosing a medication becomes complicated. If the patient has heart failure, what is the inotropic effect of the antihypertensive? If the patient has diabetes, is the medication also going to protect the kidneys? If the patient has hyperlipidemia, is the medication going to raise the lipid levels?
A class of antihypertensives called angiotensin receptor blockers (ARBs), introduced recently and boasting a side effect profile similar to placebo, provides some possible answers to these concerns. For 30 years, animal studies have been suggesting that the renin-angiotensin system is intimately related to hypertension, heart failure, and kidney disease. Building upon these studies, scientists developed angiotensin converting enzyme (ACE) inhibitors to block formation of angiotensin II. Clinical benefits of angiotensin converting enzyme (ACE) inhibitors in heart and kidney failure have further indicted the renin-angiotensin system in these diseases. The ACE inhibitors, while highly effective, not only block the formation of angiotensin II but also increase bradykinin. This fact has both positive and negative consequences. Now there is preliminary evidence suggesting that the angiotensin receptor blockers may share some of the positive effects of ACE inhibitors, while lacking some of the troubling side effects.
In 1995, the first oral angiotensin II receptor blocker, losartan, was introduced. The ARB class provides a more complete blockade of angiotensin II than ACE inhibitors but lack the effects on bradykinin. Is this group of medications equally effective to other antihypertensive classes? Do they currently have a place in the treatment of heart failure and nephropathy? Are there situations in which they should not be used? Can they be safely used with other hypertensives?
To answer these questions, an understanding of the renin-angiotensin system and the mechanism of action of angiotensin II receptor blockers is required. This article provides an overview of the renin-angiotensin system and examines the mechanism of action of the ARBs. It will contrast the ARBs to each other and look at their efficacy compared to other drug classes. While the ARBs are currently indicated only for hypertension, this article reviews growing evidence that the class may eventually prove useful in heart failure and diabetic nephropathy.
Angiotensin II receptor blockers provide a new and specific approach to the treatment of hypertension. Their efficacy, specificity, and safety profile provide primary care physicians with a new alternative for first-line hypertensive therapy.
Introduction
Hypertension is the most prevalent cardiovascular disease in the United States. One in four American adults has hypertension, defined as either a diastolic blood pressure of 90 mmHg or greater or a systolic blood pressure of 140 mmHg or higher.1
Both the risks of hypertension and the benefits of improved recognition and treatment are clear. After adjusting for age, blood cholesterol, and smoking, a 7.5 mmHg difference in usual diastolic blood pressure is associated with a 46% difference in the risk of stroke and a 29% difference in the risk of coronary heart disease.2 The public campaign to lower blood pressure has clearly affected the sequelae of hypertension. With aggressive public and professional awareness programs, increased attention to lifestyle issues, and improved medications, the age-adjusted death rates from stroke and coronary artery disease declined by nearly 60% and 53%, respectively.3
The identification and treatment of patients with hypertension are also improving. Public awareness programs, continuing medical education for physicians, and improved blood pressure lowering medications have each had a positive effect on the treatment of this disease. Contrasting data from 1976-1980 to 1988-1991, The National Health and Nutrition Examination Survey (NHANES) demonstrated an increase in patients' awareness of their hypertension from 51% to 73%. The treatment percentage of Americans with hypertension increased during that same period from 31% to 55%, and the number of hypertensive patients with blood pressure controlled to below 140/90 mmHg increased from 10% to 29%.2,4
Changing Goals of Treatment
With the availability of highly effective medications and an improved understanding of the long-term effects of hypertension, the goals of therapy have changed. While previous therapy was aimed almost entirely at reducing blood pressure to target levels, physicians are now equally concerned with issues of compliance, cost, and prevention of target organ damage. In addition, the focus is on using a single medication to treat more than one disease at a time. Thus, the cookbook method of attacking hypertension has been replaced by tailored medication choices matching individual patient characteristics. Antihypertensive medications previously available only partially met these goals. They often exhibited unwanted side effects, drug interactions, or other adverse effects. (See Table 1.) The ideal antihypertensive would be cost-effective, have minimal side effects, avoid drug interactions, and provide end organ protection.
A relatively recent class of antihypertensive medications, the angiotensin II receptor blockers (also known as angiotensin II receptor antagonists), attempts to address the new treatment paradigms. Until recently, many physicians viewed this class of medications as useful primarily in patients who cannot tolerate angiotensin converting enzyme inhibitors. The Joint National Committee's sixth report (JNC6) supports this view for patients with concurrent heart failure and diabetes.3 However, the ARBs may offer some unique advantages over other classes of antihypertensive medications. If future studies confirm their theoretical advantages, this drug class may emerge as a preferred first-line antihypertensive therapy.
This discussion will review the mechanism of action, existing indications, and potential future uses of the angiotensin receptor blocking agents (ARBs). The ARBs currently available will be contrasted with each other and with other classes of antihypertensive medications.
The Renin-Angiotensin System (RAS)
While the exact etiology of essential hypertension remains unclear, important contributors have been identified. One of these is the renin-angiotensin system (RAS). It is well recognized that pharmacological interference with the RAS system can significantly improve hypertension. To fully understand the proven and potential benefits of medications that affect this system, a basic knowledge of RAS physiology and the vasoconstrictor angiotensin II is necessary.
The Case Against Angiotensin II
The primary vasoactive substance in the RAS relating to blood pressure is angiotensin II. This octapeptide activates receptors in the vascular endothelium, kidney, lung, heart, liver, brain, adrenal glands, and pituitary gland.5 It has diverse effects including induction of cell hypertrophy and/or hyperplasia and stimulation of hormone synthesis and ion transport in the heart, kidney, and adrenal gland.6 Two main subtypes of angiotensin II receptors have been described. These are referred to as AT1 and AT2. The pharmacological effects of angiotensin II are primarily mediated by the AT1 receptor.7
Angiotensin elevates blood pressure directly and indirectly. Activation of receptors in blood vessel smooth muscle cells causes vasoconstriction and increases in peripheral resistance. Sodium and water are reabsorbed by the direct action of angiotensin II on AT1 receptors in the cells of the proximal tubules. Adding to the resulting volume overload, angiotensin II stimulates vasopressin release and initiates the thirst reflex.8 In addition, it causes the adrenal cortex to increase the production and secretion of aldosterone, which in turn, causes sodium retention and secretion of potassium and hydrogen ions.9
Another effect of angiotensin II that has attracted a good deal of recent attention is cardiovascular remodeling (redistribution of mass). One mechanism for this involves an increase in blood volume and peripheral resistance resulting in increased cardiac workload. This can lead to cardiac hypertrophy, fibrosis, thickening of the intimal surface of the blood vessel wall, and increased wall-to-lumen ratio in the blood vessels. In addition, angiotensin II stimulates proliferation and hypertrophy of cardiac myocytes through its action on AT1 receptors in these cells.9 Smooth muscle growth and migration is stimulated, resulting in synthesis of extracellular matrix protein by fibroblasts.10 These changes may contribute to the cardiac sequelae associated with hypertension. (See Figure 1.)
Other problems result from these changes in morphology, as well. First, the reduction in the size of the lumen in blood vessels increases the wall sheer stress.10 This may be critical in the development of atherosclerosis. Second, angiotensin II activates macrophages. During plaque formation, these macrophages produce even more local angiotensin II. Angiotensin at the tissue level may then increase the risk of thrombosis by preventing thrombolysis and taking part in platelet activation and aggregation.11
The resulting remodeling of blood vessels increases peripheral resistance, increases blood pressure, and may lead to atherosclerosis and thrombosis. In this way, a dangerous cycle of increasing hypertension and remodeling occurs, with each worsening the other. (See Figure 2.)
Finally, angiotensin II has an important role in the development of diabetic nephropathy. There is evidence that it acts synergistically with hyperglycemia to promote cellular injury in the kidney.12 This will be discussed later in more detail.
Table 1. Side Effects of Commonly Used Antihypertensives
DIURETICS BETA BLOCKERS CALCIUM CHANNEL BLOCKERS ALPHA BLOCKERS ACE INHIBITORS
Glucose intolerance Decreased Peripheral edema Dizziness Cough exercise tolerance
Sexual dysfunction Depression Constipation Orthostatic hypotension Angioneurotic edema
Increased uric acid Sexual dysfunction Headache Weakness
Hypokalemia Cold extremities Heart rhythm abnormalities
Low magnesium Exacerbated bronchospasm Dizziness
The production of angiotensin II
The primary pathway for the production of angiotensin II begins with renin, which is released from the renal juxtaglomerular cells in response to hemodynamic and sympathetic stimuli. Renin is a protease that bonds in angiotensinogen, an abundant circulating alpha2-globulin produced in the liver. The result is a weak vasodilator called angiotensin I. Angiotensin I, in turn, is converted to angiotensin II by angiotensin converting enzyme (ACE), found in plasma, pulmonary endothelium, and other tissues. While angiotensin I has weak vasoconstrictive capabilities (< 1% as potent as angiotensin II), angiotensin II is a powerful vasoconstrictor with multiple actions. ACE is identical to kininase II, which is responsible for inactivating bradykinin and other potent vasodilator peptides.9 This characteristic accounts for the increase in bradykinin levels seen in patients using ACE inhibitors. Increased bradykinin levels can have both positive and negative effects, as discussed below.
Why block the AT1 receptors? The non-renin production of Angiotensin II
In addition to production through the renin-angiotensin system, angiotensin II is produced through alternative enzymatic pathways. Angiotensin-processing enzymes exist in some tissues that can convert angiotensinogen either to angiotensin I or directly to angiotensin II. While the significance of this production is still being determined, alternative pathways may be important at the local tissue (endothelial) level. Enzymes other than ACE that catalyze the conversion of angiotensin I to angiotensin II include cathepsin G, chymostatin-sensitive A II-generating enzyme (CAGE), and heart chymase.9
Feedback Mechanisms
Angiotensin II self regulates in two ways. First, it acts directly upon receptors found in the renal juxtaglomerular cells to inhibit the production of renin. Second, raising the blood pressure provides negative feedback by restricting renin production.9 A properly functioning feedback mechanism is essential in maintaining normal blood pressure.
Other angiotensins
In addition to its conversion to angiotensin II, angiotensin I can be cleaved to angiotensin 1-7, which may have vasodilatory properties. Similarly, angiotensin II catabolism yields angiotensin III.13 Research is currently underway to determine the significance of these other forms of angiotensin. The roles of other types of angiotensin and the AT2 receptors in the feedback mechanism are currently under investigation.
Attack on Angiotensin II: The ACE inhibitors
As a better understanding of the renin-angiotensin system developed, researchers sought medications that could interfere in the production of angiotensin II. While beta-blockers were known to have some effects on the renin-angiotensin system, a medication to act more specifically on angiotensin II was required. In the 1960s, venom from pit vipers was found to contain factors that intensified response to bradykinin. This led to the synthesis of first ACE inhibitor, teprotide. This medication lowered blood pressure and had positive effects on heart failure in humans, but it had to be administered parenterally. The search then ensued for an orally active ACE inhibitor. A group of compounds was found, the most active of which was captopril.9
ACE inhibitors lower the blood pressure by several mechanisms. First, they block the conversion of angiotensin I to angiotensin II by the competitive inhibition of ACE. As noted previously, however, tissues synthesize angiotensin II using enzymes unassociated with angiotensin converting enzyme. This inhibition of angiotensin II is, therefore, incomplete.
A second mechanism for blood pressure reduction with ACE inhibitors involves impeding the degradation of bradykinin and substance P, which, in turn, stimulates prostaglandin biosynthesis. ACE is identical to kininase II, which is responsible for degrading bradykinin. By blocking ACE, the ACE inhibitors are also increasing bradykinin levels. Bradykinin is a potent vasodilator and may be a significant contributor to the efficacy of ACE inhibitors.
Unfortunately, bradykinin and substance P may also be partially responsible for the side effects seen with ACE inhibitor use, including cough.14 Cough is seen in 5-20% of patients on ACE inhibitor therapy. It is usually dry, persistent, and tends to linger for the duration of therapy. Over time, it can change the tone of the voice; when severe, it can result in vomiting. The cough tends to be resistant to antitussive agents and is a significant reason for discontinuation of ACE inhibitor therapy.9
While the exact mechanism of ACE inhibitor cough is not known, bradykinin is strongly suspected as a major factor. Bradykinin can induce cough by activating sensory C fibers. It can also increase the production of prostaglandins and leukotrienes, resulting in irritation of the lung. Finally, ACE inhibitors potentiate a neuropeptide known as substance P (tachykinin), which may increase sensitivity to the cough reflex.14
Thus, a search began for medications that prevent the detrimental effects of angiotensin II but that spare patients from the side effects associated with increased bradykinin levels.
The Angiotensin II receptor blockers
Alternative metabolic pathways of angiotensin production and the side effects of ACE inhibitors lead to a search for an alternative method of blocking angiotensin II. Since all known pressor effects of angiotensin II are mediated through the AT1 receptor, a medication that blocked these receptors would theoretically share therapeutic effects of the ACE inhibitors. This new approach yielded the angiotensin II receptor blockers (ARBs). The first blockade of the angiotensin II receptors was achieved in the 1970s with saralasin acetate, which had a short duration and had to be given parenterally. Losartan, the first orally administered angiotensin II type 1 receptor blocker, became available in 1995.
ARBs lower blood pressure by interfering with the action of angiotensin II, blockading the AT1 receptor site. This obstructs the action of angiotensin II regardless of its site or mechanism of production. (See Figure 3.) ARBs do not interfere with ACE; therefore, they do not result in increased bradykinin or substance P. They have no effect on glomerular filtration rate, triglycerides, total or HDL cholesterol, or fasting glucose concentrations.15
Treatment with ARBs has a number of beneficial effects. By blocking the AT1 receptor site, ARBs decrease all of angiotensin II's known effects, including slow and fast pressor responses, sympathetic nervous system stimulation, CNS effects including thirst, release of adrenal catecholamines, secretion of aldosterone, direct and indirect effects on the kidneys, and growth-promoting actions.9
Unlike the ACE inhibitors, ARBs do not decrease the levels of angiotensin II. Indeed, because ARBs disrupt the negative feedback mechanism of angiotensin II synthesis, renin and angiotensin II levels increase. Because the ARBs are specific for the AT1 receptors only, the AT2 receptors are increasingly activated by the rise in angiotensin II. While the exact physiologic role of AT2 receptors is not known, animal studies suggest that stimulation may inhibit vasopressin release, counteract angiotensin II's pressor effects, and mediate an antiproliferative mechanism.16-19 (See Table 2.)
Currently available ARBs
At the time of writing, three angiotensin II receptor blockers were available. At least several others will probably receive FDA approval this year.
Losartan (Cozaar) was the first available orally active ARB. It is available alone or in combination with low-dose hydrochlorothiazide (Hyzaar). Subsequently, valsartan (Diovan) was brought out in 1996 and irbesartan (Avapro) in 1997. Many other ARBs are in various stages of clinical development. The most important part of each structure is the biphenyl tetrazole moiety, which is necessary for AT1 receptor binding.7 Variance in molecular structure causes differences primarily in the bioavailability and pharmacokinetics of the medications.
ARBs and Hypertension
All of the currently available ARBs have been shown to be clinically effective in hypertension. Since losartan was the first ARB introduced, it is the most extensively studied. Multiple clinical trials have demonstrated losartan's efficacy in hypertension.20-25 Losartan has both an active parent and an active metabolite. Dosage in otherwise healthy patients is started at 50 mg/d and can be increased to 100 mg daily in a single or twice daily dose. Because there is little proven advantage to increasing the dose of losartan above 50 mg, it is often advantageous to add low-dose hydrochlorothiazide when increased efficacy is required. Losartan can be given with or between meals, as food has only minimal effects on bioavailability. A small uricosuric effect with chronic oral administration that is due to losartan's active parent.26
Table 2. Benefits of Angiotensin II Receptor Blockers
· Block all of angiotensin II's known effects, including:
Pressor responses
Sympathetic nerve stimulation
CNS effects including thirst
Secretion of aldosterone
Direct effects on the kidneys
Growth promoting actions
· No effects on bradykinin or substance P
· Block angiotensin II regardless of the site of production
· Side effect profile similar to placebo
Valsartan has demonstrated effectiveness in hypertension in at least seven placebo-controlled, randomized clinical trials with more than 2000 patients.27-29 The dose of valsartan is started at 80 mg once daily and can be titrated to 320 mg/d. Adding a low-dose diuretic such as hydrochlorothiazide to valsartan improves efficacy more than increasing dose above 80 mg. Although food decreases the peak plasma concentration by about 50%, it can be taken with or without food.30
The efficacy of irbesartan, the newest ARB, has been demonstrated in seven randomized, double-blind, placebo-controlled trials with more than 1900 patients. Irbesartan has a dose-dependent reduction in blood pressure at doses of 75 mg qd and greater that plateaus at doses of more than 300 mg.31 The dose of irbesartan is generally started at 150 mg, then titrated to 300 mg once daily if necessary. Like the other ARBs, irbesartan demonstrates a significant increase in efficacy when combined with low-dose hydrochlorothiazide.32 Taking irbesartan with food has no effect on bioavailability.15
Unlike the ACE inhibitors, cough is not a major problem with the ARB drug class. Three studies have compared ARBs with the ACE inhibitor enalapril. Comparing the incidence of cough in patients treated with losartan to those treated with enalapril, Tikkanen found a 3% incidence of cough with losartan compared to a 15.1% incidence with enalapril.33 Larochelle found a 2.5% incidence with irbesartan compared to 13.1% for enalapril, and Holwerda found a 0.7% incidence in valsartan compared to 4.3% in enalapril.27,34
There is some indication that ARBs may not be as effective in black patients as in white patients.35,36 Patients over age 65 generally respond well to the ARBs.20,24,36
Several unpublished trials suggest that there may be some differences in efficacy, response rate, and side effect profile among the three currently available ARBs.23,37 However, to date there are insufficient data to conclude that one ARB is clearly superior to the others for controlling hypertension. (See Table 3.)
Comparison of ARBs to other drug classes in hypertension
Currently available ARBs have been compared in head-to-head studies against drugs in other antihypertensive classes. Attention has focused on comparisons with ACE inhibitors due to hope that the ARBs will share ACE inhibitors' positive effects in hypertension, congestive heart failure, and nephropathy.
Losartan vs. enalapril, atenolol, nifedipine, amlodipine, and hydrochlorothiazide. In a study by Tikkanen, losartan was compared to enalapril after 12 weeks of treatment. The difference in blood pressure response between the two medications was not significant.33 In two other studies, losartan (up to 100 mg) and atenolol (up to 100 mg) had comparable blood pressure response rates.22,36 Two trials compared losartan (with or without hydrochlorothiazide) to nifedipine and amlodipine and found that, particularly when combined with hydro-chlorothiazide, losartan and these calcium channel blockers had comparable efficacy.20,24
Valsartan vs. lisinopril, enalapril, amlodipine. Black et al compared valsartan 80 mg once daily, titrated to 160 mg once daily if necessary, to lisinopril 10 mg, titrated if necessary to 20 mg once daily. No significant differences in efficacy at 12 weeks were found.28 In another study, 80 mg of valsartan was compared to enalapril 20 mg once daily over an eight-week period; the two drugs showed no statistical difference in blood pressure response.27 Corea et al compared valsartan to amlodipine and found no statistical difference in blood pressure control at 12 weeks.38
Irbesartan vs. enalapril, atenolol, hydrochlorothiazide. In a study by Mimran et al, irbesartan, titrated over 12 weeks to 300 mg if necessary, was compared to enalapril, titrated to 40 mg if necessary. At week 12, reduction in diastolic blood pressure was not statistically different between the two medications.39 Stumpe, in a recent trial of irbesartan vs. atenolol, showed similar efficacy of 150 mg of irbesartan to 100 mg of atenolol.40 Kochar et al, comparing irbesartan to hydrochlorothiazide, found that irbesartan lowered diastolic blood pressure by a mean of 10.2 mmHg compared to 8.3 mmHg of hydrochlorothiazide.32
The use of ARBs in diseases otherthan hypertension
Currently, the ARBs are only indicated for treatment of hypertension. However, there is increasing evidence that they may also be effective in the treatment of other disorders, particularly congestive heart failure and diabetic nephropathy. Because losartan has been available the longest, most of the available studies were done with this medication.
ARBs and heart failure
Between one and two million adults in the United States are affected by heart failure.41 Based on strong evidence citing improvement in heart failure with ACE inhibitors, JNC 6 recommends using angiotensin II receptor blockers for patients in whom ACE inhibitors are indicated but who are unable to tolerate them. Studies showing a similar benefit of ARBs to ACE inhibitors are accumulating but are as yet inconclusive.
ACE inhibitors are beneficial for decreasing symptoms and increasing survival in heart failure. Their mechanism of that protection, however, is not completely understood.42,43 Some authorities have postulated that part of the positive effect of ACE inhibitors may be due to the increased effects of bradykinin. Since ARBs do not raise bradykinin levels, they theoretically may lack some of the efficacy seen with ACE inhibitors.44,45 The significance of elevated bradykinin levels and their potential benefit is not yet clear.
Recent studies suggest that losartan can improve hemodynamics and exercise performance in patients with heart failure to a similar extent as ACE inhibitors.25,46,47 In the Evaluation of Losartan in the Elderly trial (ELITE) study, 722 patients with NYHA class II-IV heart failure and ejection fractions of 40% or less were placed on losartan (352 patients) or captopril (370 patients). End points were persisting increase in serum creatinine on therapy, death and/or hospital admission for heart failure, total mortality, admission for heart failure, NYHA class, and admission for myocardial infarction or unstable angina. Results showed that persisting increases in serum creatinine were the same in both groups (10.5%), and fewer losartan patients discontinued therapy for adverse experiences. Death and/or hospital admission for heart failure was 9.4% in the losartan group compared to 13.2% in the captopril patients, primarily due to a reduction in all-cause mortality (4.8% vs 8.7%). Admissions with heart failure were the same for both groups, as was the improvement in NYHA functional class. The authors concluded that losartan was associated with an unexpected lower mortality rate than captopril and that losartan was generally better tolerated.48 Further studies evaluating morbidity and mortality are ongoing, and additional evidence is required before recommending the use of ARBs for heart failure. In addition, specific drug studies are required to determine whether any beneficial effects are unique to losartan or common to the entire class of ARBs.
An interesting concept currently under study is the combination of an ARB with an ACE inhibitor. As mentioned earlier, some investigators feel that the beneficial effects of ACE inhibitors on heart failure are not only from angiotensin II inhibition, but also from the increase in bradykinin. Combining an ARB with an ACE inhibitor would theoretically block both the ACE- and non-ACE-dependent systems of angiotensin II formation. In addition, the increase in bradykinin caused by the ACE inhibitor would be preserved. This raises speculation that combining the two medications might be more effective for heart failure than either drug alone. Trials are currently underway to evaluate this hypothesis.49
Finally, ARBs are also being evaluated in hypoxemic cor pulmonale, and early results suggest that they may play a future role in therapy.50
Table 3. Currently Available ARBs
Losartan Valsartan Irbesartan
Usual dose 50-100 mg/d 80-320 mg/d 150-300 mg/d
Clinical Approved Approved Approved experience 1995 1996 1997
Side Similar to Similar to Similar toeffects placebo placebo placebo
Dosing QD or BID QD QD
Effect Minimal 50% decreased oneof food peak plasma concentration
Dosage one Use carefully Noneadjustmentfor renalfailure
Use with With With o difference liver failure caution caution in pharmaco- kinetics
ARBs and diabetic nephropathy
Diabetic nephropathy is the major cause of end-stage renal failure in the Western world. It is a major cause of morbidity and mortality in patients with diabetes. Roughly 40% of all diabetics, whether insulin-dependent or not, develop diabetic nephropathy.51 ACE inhibitors, calcium antagonists, and low-dose diuretics (JNC 6) have emerged as preferred drugs in the hypertensive diabetic patient.3,51,52 In addition, data support the use of ACE inhibitors or nondihydropyridine calcium-channel antagonists in nonhypertensive diabetics with proteinuria.53
Recent studies have implicated the renin-angiotensin system as an important contributor to renal disease and diabetic nephropathy.12,54 It has been shown that antagonism of angiotensin II improves the hemodynamics of the glomerular capillary and modulates cellular components, resulting in preservation of the glomerular capillary cell wall function.55 The protective effects of inhibition of the RAS also correlate with the suppression of transforming growth factor-ß production, which may induce renal fibrosis.56
ACE inhibitors have been shown to reduce proteinuria in a variety of proteinuric renal diseases, primarily mediated through a reduction of glomerular capillary pressure.57 There is experimental evidence that the positive effect of ACE inhibitors in preventing diabetic nephropathy is directly related to effects on angiotensin II, rather than their effects on bradykinin.58-60 Since ARBs appear to have similar effects on renal vasculature to ACE inhibitors, it seems reasonable that they may have a similar protective effect for preventing nephropathy, particularly in diabetic patients.61 Preliminary animal and human studies support this hypothesis.
In diabetic rats treated either with insulin alone or insulin with losartan, losartan significantly prevented proteinuria and glomerulosclerosis. This effect seems to be a direct result of angiotensin II inhibition.62,63 In a small study from Hong Kong, 12 elderly hypertensive patients with Type 2 diabetes were placed on either losartan or felodipine. Urinary albumin excretion was reduced by 27% in the losartan group, compared to no change in the felodipine-treated group.64 While initial results are promising, further studies of ARBs are required before recommending their use to prevent diabetic nephropathy. As in the treatment of heart failure, it is currently unclear whether these beneficial effects are unique to losartan or are common to the entire ARB class.
Side effects and precautions for ARBs
One of the most notable benefits of the angiotensin II receptor blockers is their side effect profile. In non-pregnant patients with normal hepatic and renal function, multiple trials have shown the ARBs to have a side effect profile equal to or better than placebo.27,33,34 ARBs have a neutral effect on levels of serum lipids and lipoproteins.65 As discussed previously, ARBs are not associated with cough, an advantage over ACE inhibitors.
Despite an excellent side effect profile, there are some precautions for specific ARBs. Losartan and valsartan should be used with caution in patients with liver failure. The manufacturer of losartan recommends consideration of a decreased starting dose in patients with impaired liver function.66 In seven-day studies, healthy subjects and patients with hepatic cirrhosis placed on irbesartan showed no significant differences in pharmacokinetics.35
When possible, volume depletion should be corrected prior to starting ARBs. Patients with severe renal failure should followed very carefully when started on valsartan; no dosage adjustment is necessary with irbesartan or losartan.
Like the ACE inhibitors, none of the ARBs should be used during pregnancy and should be discontinued as soon as possible if a patient becomes pregnant while taking the medication. When used during pregnancy, they can cause serious fetal problems, including renal failure and death.67
ACE inhibitors have been shown to markedly reduce renal perfusion in patients with bilateral renal artery stenosis or in patients with a single kidney renal artery stenosis.70 Since there is a similar effect on the renal vasculature with ARBs, these medications must be monitored in a similar fashion.3 If there is a persistent elevation in potassium or creatinine after starting an ARB, the diagnosis of renal artery stenosis should be entertained and the medication discontinued. Angioedema has been rarely reported with ARB use.66
Drug interactions are rare with the ARB class. There are no clinically significant interactions with digoxin or warfarin. They can be used with other antihypertensive medications with careful monitoring of the blood pressure. Levels of losartan are increased with cimetidine and decreased with phenobarbital, but the clinical effect is unclear.53
There are very few available data on overdosage with the ARBs. Treatment for overdosage is supportive, as they cannot be removed by hemodialysis.53
Studies have compared the side effects of ARBs with other classes of antihypertensives. These studies consistently demonstrated that ARBs have a side effect profile that is equal to or better than any other antihypertensive drug class.20-22,27,28,32-34,38-40
The treatment costs of ARBs have not yet been defined. While the cost of antihypertensive therapy was once based solely upon the cost of medication, it is now recognized that many other economic factors must be considered.69 Clinic visits related to medication changes, treatment of side effects, and monitoring end organ effects greatly add to the cost of treatment. Similarly, laboratory testing to monitor glucose, lipids, electrolytes, uric acid, etc., can escalate the hidden costs of medication. Finally, the economic effect of non-compliance to treatment regimens is significant.70 The excellent side effect profile, lack of metabolic effects, and preliminary evidence of end organ benefit in the ARB class suggest that the long-term cost of these medications will compare favorably to other antihypertensive agents. This is only speculative, however, and studies examining many of these issues are underway.
Summary
The goals of treatment in hypertension have been expanded to include control of blood pressure, protection against end-organ damage, limitation of medication adverse effects and drug interactions, and simultaneous treatment of other diseases. While a great deal more study is needed, angiotensin receptor blockers may address many of these goals. Angiotensin II receptor blockers interfere with the action of angiotensin II at the AT1 receptor, but they do not affect ACE or bradykinin.
For treatment of hypertension, ARBs have an efficacy similar to other drug classes but a side effect profile similar to placebo. If necessary, adding a low dose of hydrochlorothiazide can potentiate the antihypertensive effects of ARBs with minimal adverse effects. ARBs should not be used in pregnant patients, nor in patients with suspected renal artery stenosis.
While early studies indicate that they may share ACE inhibitors' beneficial effects in heart failure and diabetic nephropathy, more studies are needed before use in for these indications can be recommended.
Because of their efficacy, specificity, and safety profile, angiotensin II receptor blockers provide an alternative as first-line therapy for the treatment of patients with hypertension.
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Physician CME Questions
35. Which of the following angiotensin II receptors are blocked by the angiotensin II receptor blockers?
a. AT1
b. AT2
c. AT3
d. AT4
e. AT3A
36. The cough seen with ACE inhibitors is probably caused primarily by an increase in bradykinin. The cough seen in a significant number of patients treated with ARBs is associated with:
a. increased bradykinin levels.
b. increased prostaglandin levels.
c. increased substance P.
d. increased seritonin levels.
e. cough is not a serious problem with ARBs.
37. Angiotensin II is produced through a single mechanism involving:
a. angiotensin converting enzyme
b. cathepsin G
c. heart chymase
d. angiotensin deoxidification peptide
e. the statement is false. Angiotensin is produced through more than one pathway.
38. Which of the following statements regarding ARBs is not true?
a. They are useful in hypertensive patients over the age of 65.
b. They can be used safely in pregnancy.
c. Studies show that they are equally effective to ACE inhibitors in hypertension.
d. Cough is not a significant problem with the angiotensin II receptor blockers.
e. They have very few drug interactions.
39. Which of the following is true regarding the angiotensin II receptor blockers?
a. They have significant side effects that limit their use.
b. Their have significant side effects when combined with low dose hydrochlorothiazide.
c. They interfere with other blood pressure medications and should be used only in monotherapy.
d. They have a side effect profile similar to placebo.
e. They are much less effective than calcium channel blockers.
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