The Role of Angiotensin II Receptorbr
Blockers for the Treatment of Hypertension

by Martin Couret, MSN, NP

Angiotensin II receptor blockers (ARBs) are a new class of antihypertensive medications. Also known as angiotensin II receptor antagonists, these medications selectively bind the angiotensin II type 1 receptor preventing the effects of angiotensin II. Presently there are five ARBs on the market: losartan, valsartan, irbesartan, candesartan cilexetil, and telmisartan.

Approximately 1.8 million people in the U.S. develop hypertension every year. To diagnose hypertension, a patient must have their blood pressure taken two or more times on at least two or more visits. If the average systolic blood pressure (BP) is >= 140mm Hg or a diastolic BP of >= 90mm Hg, then the diagnosis of hypertension is appropriate (JNC VI, 1997). These cut off points are significant given that consistent blood pressures above these levels have been shown to increase the risk of stroke, coronary artery disease (CAD), congestive heart failure (CHF), and renal insufficiency. The correlation of these risk factors is more significant with elevated systolic blood pressure than elevated diastolic (Cutler, 1996). Nurse practitioners have the ability to reduce mortality and morbidity in their patients simply by managing their hypertension.

While the etiology of essential hypertension remains unknown, there are many factors that have been proven to contribute to the elevation of blood pressure. While it has been shown that there is a genetic predisposition to hypertension, the actual genetic variations or genes are not completely understood (Luft, 1998). Other factors including obesity, insulin resistance, high alcohol intake, aging, sedentary lifestyle, stress, low potassium or calcium, have been shown to increase blood pressure (Carretero & Oparil, 2000).

The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VI) contains recommendations for the treatment of hypertension depending on the level of hypertension. These recommendations begin with lifestyle modifications such as, exercising 30 minutes three days a week, losing weight if necessary, decreasing dietary sodium, increasing dietary fiber, cessation of smoking, and moderate alcohol consumption. If the goal hypertension is not reached after a three to six month trial of these recommendations, pharmacotherapy is warranted.  

Patients with uncomplicated hypertension should be started on either a diuretic or a beta-blocker. The JNC VI guidelines also include recommendations for patients with certain comorbidities. Patients with a history of heart failure should be started on an angiotensin converting enzyme (ACE) inhibitor, or a diuretic. Following a myocardial infarction (MI), patients should receive a beta-blocker unless they have systolic dysfunction, in which case they should take an ACE inhibitor. Type I diabetics with proteinuria should receive an ACE inhibitor, preferably with a diuretic. Presently, the only indication for ARBs made by the JNC VI is for patients whom ACE inhibitors are indicated, but not well tolerated.

In order to understand how ARBs function, one must understand the renin-angiotensin system (RAS). The RAS is integral in the pathophysiology of hypertension because it regulates fluid volume, electrolyte balance, and the vascular bed. Renin is produced primarily by the juxtaglomerular cells in the kidneys in response to decreased fluid volume. Renin catalyzes the conversion of angiotensinogen to angiotensin I. Angiotensin I can also be generated by the non-renin enzymes tonin and cathepsin (Burnier & Brunner, 2000). Angiotensin I is then converted into angiotensin II primarily by angiotensin converting enzymes (ACE). ACE is not the only enzyme capable of this conversion; trypsin, cathepsin, and heart chymase can also convert angiotensin I into angiotensin II. ACE inhibitors, like accupril, partially block this process by inhibiting ACE. Angiotensin II binds to AT1 and AT2 receptor sites. AT1 receptor sites are located in the kidney, heart, brain, vascular smooth muscle cells, placenta, platelets and in fat cells ( Timmermans, 1993). AT2 receptor sites are important in fetal development and are not well understood.  

All of the understood clinical effects of angiotensin II are mediated at the AT1 receptor sites. Some of the responses to AT1 stimulation are coronary, efferent arteriole, and cerebral vasoconstriction. Angiotensin II also binds to the zona glomerulosa, stimulating secretion of aldosterone. Aldosterone then stimulates sodium retention and water resorption in the kidney. Angiotensin II also binds to AT1 receptor sites in the heart, mounting positive ionotropic and chronotropic effects. In addition angiotensin II can activate the sympathetic nervous system. ACE inhibition prevents some of these events from taking place and reduces blood pressure. Unfortunately, ACE inhibitors do not completely block the production of angiotensin II. In addition, ACE inhibitors also prevent the breakdown of bradykinin. While bradykinin is a vasodilator and may add to the antihypertensive effect of ACE inhibitors, it also may be responsible for the adverse effects of cough and angioedema (Kaufman, Coleridge, & Coleridge, 1980; Israili & Hall, 1992). ARBs create an insurmountable blockade of angiotensin II at the AT1 receptors forming a more complete blockade of the renin-angiotensin system without affecting bradykinin. This complete blockade causes a decrease in blood pressure. ARBs have almost no affinity for the AT2 receptor site. 

There are five orally active AT1 receptor antagonists available in the US and in Europe. All of the agents are based on the prototype losartan. All of them create an insurmountable blockade of angiotensin II by binding to the AT1 receptor, but there are some differences.

Losartan is the prototype from which all the other ARBs were derived. It is the only ARB with an active metabolite, E3174. E3174 has a higher affinity for the AT1 receptor and contributes to the antihypertensive effects. The 10 fold greater affinity of E3174 contributes to losartan's 24 hour duration of action. Losartan has been found to have the same antihypertensive effect as enalapril (Gradman, 1995), atenolol (Dahlof et al., 1997), and felodipine ER (Chan et al., 1995). The starting dose of losartan is 50mg daily. However, the medication is not dose dependent; increasing the dose greater than 50mg does not significantly reduce blood pressure (Gradman, 1995). Unique to losartan is the fact that it is the only ARB to cause uric acid excretion. Both losartan and E3174 are excreted in the kidney and bile.

Valsartan is another potent AT1 antagonist. The 80mg starting dose has been found to provide persistent angiotensin II blockade for 24 hours (Morgan et al., 1997). Valsartan's efficacy has been tested, enalapril (Halwerda et al., 1996), lisinopril (Black et al., 1997), and amlodipine (Corea et al., 1996), all showed similar reductions in BP. Unique to valsartan is its 40% decrease in absorption in the presence of food.

Irbesartan is a longer acting ARB (Gillis & Markham, 1997). It binds the AT1 receptor non-competitively (Burnier & Brunner, 2000), and has no affinity for the AT2 receptor. The starting dose of irbesartan is 150mg once a day. Increasing the dose to 300mg a day has been shown to increase its antihypertensive effect significantly. However, the response relationship curve suggests that doses >300mg will not significantly increase efficacy. Nonetheless, irbesartan has been shown to be safe with doses up to 900mg. In a study with type 2 diabetics, irbesartan was shown to reduce urinary protein levels 8.5% (Gillis & Markham, 1997). Compared to other antihypertensives, irbesartan has shown BP reduction similar to that of enalapril (Mimran et al., 1998) and atenolol (Stumpe et al., 1998). In terms of safety, there is no dosage adjustment needed for the elderly or for those with renal or hepatic failure (Vachharajani et al. 1995; Marino et al., 1998; Sica et al., 1997). 

Candesartan cilexetil is another long acting ARB (Sever, 1997). Candesartan is a prodrug that is activated during gastrointestinal absorption. It binds tightly to the AT1 receptor, prolonging activity and allowing once a day dosing. The tight binding and slow dissociation produces a 9 hour half life, 12 hours for the elderly. Sixty percent of candesartan is eliminated by the kidneys and 40% in the bile. Mild renal impairment has not shown any drug accumulation, however doses of >12mg a day may cause accumulation in severe renal impairment. Candesartan is one of the few ARBs that shows a dose dependant antihypertensive effect (Hubner et al., 1997). Bell et al. (1999) found that candesartan cilexetil 32mg was significantly more effective than the starting dose of 16mg. However, a dose of 64mg had no additional BP reduction.

Telmisartan was approved by the FDA for the treatment of hypertension in November 1998. Like other ARBs it provides an insurmountable blockade of angiotensin II by means of once a day dosing. It has an exceptionally long half-life of 24 hours in patients with mild to moderate hypertension. Ninety-eight percent of telmisartan is excreted in the feces with minimal transformation (Burnier & Brunner, 2000). While three times normal plasma concentrations were found to accumulate in women, there was no increase in adverse effects or excessive changes in blood pressure. In addition, administration to the elderly showed no changes in safety, efficacy, or tolerability. Consequently, no changes need to be made based on gender or age. However, telmisartan has been shown to be less effective in the Black population due to the decrease secretion of renin compared to Caucasians. Telmisartan should be avoided if patients are taking digoxin or coumadin, as this drug has the tendency to increase digoxin levels and decrease coumadins efficacy. Caution should also be taken when giving to patients with liver disease.

There are more similarities of all five medications than there are differences. All five medications significantly reduce BP more than placebo. Several long-term studies have also demonstrated that ARBs and ACE inhibitors have comparable efficacy. The significant finding, however, is the lack of side effects of ARBs (Holwerda et al., 1996). ARBs have continually been shown to have a side effect profile equal to that of placebo. Similar to ACE inhibitors, ARBs have the tendency to make blood pressure sodium dependent. Addition of a thiazide diuretic results in additional lowering of the blood pressure (McClellan & Markham, 1998; Sever, 1997; MacKay et. al., 1996). Other studies have shown similar blood pressure reduction compared to ACE inhibitors, calcium channel blockers, beta-blockers, and diuretics (McClellan, & Markham, 1998; Stumpe et. al., 1998; Severe, 1997; Gillis & Markham 1997; Corea et. al., 1996; Goldberg et. al., 1995).

As explained above, ARBs and ACE inhibitors operate by inhibiting RAS. The major difference is that ACE inhibitors do not provide a complete blockade of the system, and have the tendency to cause adverse side effects like cough (Kaufman, Coleridge, & Coleridge, 1980; Singer & McGregor, 1986; Morice et al. 1987). Because of their similar method of action, several studies have compared the two antihypertensives. Black et al. (1997) completed a multicenter, placebo controlled, double blind, randomly assigned, titration study of 734 patients comparing valsartan and lisinopril. After a 2 - 4 week placebo trial, patients with a sitting diastolic blood pressure (SDBP) of >95 and <115mm Hg were randomized to valsartan 80mg, lisinopril 10mg, or placebo. If after four weeks goal BPs were not obtained, the valsartan group either received an increase to 160mg or they received 80mg twice a day. If the BP of the lisinopril group needed further titration, they were put on 20mg of lisinopril. The study concluded that valsartan, despite differences in administration, had a lower incidence of side effects including cough while providing similar BP reduction to lisinopril. Halwerda et al. (1996) completed a double blind, parallel study of 348 randomly assigned patients comparing 80mg valsartan to 20mg of enalapril. Patients with mild to moderate hypertension were defined as having SDBP >95 and <115. BPs were checked for baseline information, at four weeks, and at 8 weeks. Like Black, Halwerda concluded that there were no therapeutic differences, between the two medications after eight weeks of therapy. One study found losartan to significantly reduce diastolic blood pressure over captopril (Mallion et al., 1999). However, captopril was given once a day, and the doses throughout the study are not considered therapeutically equivalent. Captopril is usually dosed twice a day, consequently it required titration to a higher dose.

The Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) study compared candesartan and enalapril independently and in combination to examine the effects on congestive heart failure (McKelvie et al., 1999). This multicenter, double blind, placebo controlled pilot study randomized 768 patients to one of three doses of candesartan cilexetil, enalapril 10mg twice a day, or a combination of candesartan cilexetil 4mg or 8 mg with enalapril 10mg twice a day. Unfortunately, the study terminated six weeks early due to an increasing trend in mortality with the combination group. At the study's end, 90% of the participants had completed their follow-up assessments. While the study lacked the power to determine differences in mortality and morbidity, there was noticeable increase in the ejection fraction of patients on the combination therapy.

As stated earlier, ARBs have the tendency to make blood pressure sodium dependent. This state makes diuretics more effective. Weber et al.(1995) found that patients unresponsive to losartan would benefit by the addition of hydrochlorothiazide (HCTZ). The study found that 12.5mg HCTZ would decrease diastolic blood pressure further by 6.1 to 7.8mm Hg. However, the same decrease was noted in patients taking a placebo an addition to a diuretic. Additional studies confirm these findings (McClellan & Markham, 1998; Sever, 1997; MacKay et al., 1996).

ARBs have also been compared to calcium channel blockers. Corea et al. (1996) completed a seven center, double blind, comparative study of 162 patients. After a two week placebo, patients with SDBP >95 and <120mm Hg were randomized to eight weeks of monotherapy with 80mg valsartan or 5mg amlodipine. If SDBP was still >95mm Hg then 5mg of amlodipine was added for the remaining four weeks. The study found "valsartan is as least as effective as amlodipine in the treatment of mild to moderate hypertension." The results also showed valsartan to be well tolerated, and did not have the associated side effects of calcium channel blockers. Chan et al. (1995) compared felodipine ER and losartan in patients greater than 65. This randomized double blind, parallel study of the antihypertensive efficacy found the two medications to have equivalent efficacy in blood pressure reduction.

Two of studies have been completed comparing atenolol, the gold standard of beta-blockers, to ARBs. Stumpe et al. (1998) compared irbesartan to atenolol and found them equivalent in both systolic and diastolic trough blood pressure reduction. Another study compared 50mg of losartan to 50mg of atenolol (Dahlof et al., 1997). Atenolol and losartan were found to be approximately equal. Nonetheless, the average mean systolic and diastolic BPs for atenolol were slightly lower than that of losartan.

With five ARBs to choose from, it maybe difficult to make a decision on which one to use. Losartan, being the oldest ARB, is often used to compare the efficacy of the newer ARBs. One report evaluated losartan, irbesartan, and valsartan at their recommended starting doses (Mazzolai et al.,1999). This study compared the ability of these ARBs to block exogenous angiotensin II in healthy volunteers. Irbesartan demonstrated the greatest inhibition at the AT1 receptor site. Two additional experiments revealed irbesartan to be superior to losartan. Kassler-Taub et al. (1997) performed a double blind placebo controlled study of 567 randomized patients. Losartan 100mg and Irbesartan 150 and 300mg were compared to placebo. Seated trough BPs were measured 24 +/- 3 hours after medication administration. BP was measured on day 2 and weeks 1, 2, 4, and 8. Irbesartan 300mg produced the greatest reduction in trough seated systolic and diastolic BP. It also produced a significant reduction in BP compared to 100mg of losartan. Oparil et al. (1998) completed a randomized, double-masked, elective titration study comparing losartan and irbesartan. This experiment allowed the researchers the ability titrate up the dose in order to reach goal BP. If the goal BP was not achieved by the fourth week, the losartan 50mg was increased to 100mg and irbesartan 150mg was increased to 300mg. During the eighth week of the study if goal BPs were still not reached researchers were allowed to add HCTZ according to the recommendations of the package insert (PI). Unfortunately, the PI for losartan recommends that losartan be reduced to 50mg when HCTZ is added. The outcome of this study showed irbesartan to be the best of the two ARBs for monotherapy.

Mallion et al.(1999) completed a study on ambulatory BP reduction between telmisartan and losartan. Telmisartan 40 and 80mg were compared to losartan 50mg in a multicenter, double-blind, placebo controlled, parallel-group study of 223 randomized patients. Compared to losartan 50mg, 80mg of telmisartan significantly reduced ambulatory systolic and diastolic BP during all monitored periods. However, telmisartan 40mg only produced significant reductions during evening and morning periods. This study neglected to test telmisartan against losartan 100mg.

Candesartan cilexetil has been compared to losartan in a double blind, multicenter study of 337 randomized patients (Anderson & Neldam, 1998). At peak, there was no significant difference between the two medications. However, at trough concentrations candesartan 16mg produced a significant BP reduction over 50mg of losartan.

Multiple studies scrutinize the safety and tolerability of this new class of medications. The majority of studies have found ARB's side effect profile equal to that of placebo groups. Gradman et al. (1995) found that, "there were no dose related trends for losartan potassium with respect to the percentage of patients with any adverse experience, serious adverse experience, or drug-related adverse experiences, or withdrawal because of an adverse experience." Goldberg et al. (1995) reported the most frequent adverse events experienced while taking losartan were headache 14.1%, upper respiratory infection 6.5%, and dizziness 4.1%. All of these adverse events were comparable to placebo. Even with the addition of HCTZ all of the adverse events were decreased except dizziness which increased to 5.7%. In addition, withdrawal events were lower for losartan than HCTZ, placebo, beta-blockers, or calcium channel blockers, and comparable to ACE inhibitors. Losartan also has a rare occurrence of first dose hypotension and there was no evidence of BP rebound (Goa & Wagstaff, 1996; Gillis & Markham, 1997). Hyperkalemia has been seen in about 1.5% of the patients taking losartan.

Because cough is considered a class effect of ACE inhibitors, cough related to ARBs has been measured in several studies (Goa & Wagstaff, 1996; Gillis & Markham, 1997; Sever, 1997). Cough is a rare adverse effect usually equal to placebo in those taking ARBs. Angioedema, another side effect of ACE inhibition has been reported with losartan administration (Acker & Greenberg, 1995). However, this study did not control well for other substances that may cause angioedema, so it is still unclear if the edema is drug related. Like ACE inhibitors, ARBs should be avoided in pregnant or breastfeeding patients and patients with renal artery stenosis (Diovan package insert, 1997).

Reviewing all of this research, a few conclusions can be reached for the applications of ARBs for practice. The primary indication for ARBs made by the JNC VI is for the patients for whom ACE inhibitors are indicated, but are unable to tolerate them. This means that in the event that a patient has CHF, history of a previous MI with systolic dysfunction, or type I diabetes with proteinuria and cannot tolerate an ACE inhibitor, they should be started on an ARB. Another possible indication is for hypertension with a co-morbidity of gout. Losartan does not have an indication for the treatment of gout, but has been shown repeatedly to excrete uric acid. ARBs have consistently been shown to have a side effect profile equal to that of placebo, so they may be the drugs of choice for patients who are prone to adverse effects. In addition to monotherapy, ARBs should be considered as adjunctive therapy for patients that are already on one class of antihypertensive and require the addition of another.

ARBs are still considered a new drug class, and therefore have not worked their way into the education and training system of health care providers. Unfortunately, there is not a simple way to disseminate this research to nurse practitioners. The majority of nurse practitioners education on these medications comes from pharmaceutical representatives. This needs to change due to the bias of pharmaceutical representatives and their tendency cast their company's drug in a wholly positive light. The education needs to come from more credible, nonbiased sources. Journals need to offer continuing education on the various new methods of treatment for hypertension. Continuing education should also be offered at conferences, so that nurse practitioners can be better informed on the latest options in hypertension management.

Research still needs to be competed at full dose strengths looking at the accumulative affect of ACE inhibitors and ARBs used concurrently. This is important since research has not looked at the reactive rise in angiotensin II and the possibility of a subsequent decrease in the effectiveness of ARBs. Using the two medications together would hypothetically reduce this possibility.

The majority of the research available is on the oldest ARB losartan. Unfortunately, multiple studies have shown losartan to be less effective than the newer ARBs. This suggests that some research may need to be done using the newer ARBs. Additional research should compare the efficacy of all of the ARBs. There is plenty of research comparing each ARB to losartan, but there are no comprehensive studies comparing all of the ARBs. The studies need to include peak and trough BP data, ambulatory and seated BP data, and long term efficacy. More titration research is necessary to compare other classes of anti-hypertensives to adequately reflect clinical practice.

Further research needs to be completed as to ARB's role in the treatment of severe hypertension. It has been shown that ARBs are not helpful as monotherapy in severe hypertension. However, their role as an adjunctive therapy has not been determined.

ARBs are an effective new medication for the treatment of hypertension. In order to better manage their patients, nurse practitioners need to be educated on the role ARBs play in hypertension management. However, further research needs to be completed to clarify ARBs exact niche in treatment of hypertension.

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Updated May 14, 2001


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