Pharmacotherapy Review: Angiotensin Receptor Antagonists

Abstract

Angiotensin receptor blockers are one of several drug classes that act by interfering with activity of the renin‐angiotensin axis. Drugs in this class are as effective as angiotensin‐converting enzyme inhibitors in the reduction of blood pressure in hypertensive patients. Results from a series of outcomes trials increasingly support the use of drugs in this class as cardioprotective and renoprotective agents in patients with heart failure, diabetic nephropathy, and post‐myocardial infarction.

Each of the seven angiotensin receptor blockers (ARBs) available in the United States is indicated for the management of hypertension. The Seventh Report of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and numerous other international hypertension organizations endorse ARBs as a first‐line therapy option in patients with essential hypertension. However, despite the inclusion of ARBs as a first‐step therapy in virtually all treatment guidelines, restrictions still exist in a number of formularies, limiting their use to angiotensin‐converting enzyme (ACE) inhibitor‐intolerant patients. For example, the 2005 National Formulary for the Federal Bureau of Prisons states that ARBs are “reserved for patients unable to tolerate an ACE inhibitor due to cough (even after a trial of fosinopril) or angioedema.”

Restrictions on ARB use are not founded on matters of efficacy or tolerability; rather, since ARBs are not generically available, their cost has become the basis for formulary restrictions, particularly when their cost is compared with that of generic ACE inhibitors. Although there are established indications for ARB therapy in patients with heart failure, diabetes with renal disease/proteinuria, and/or those who are post‐myocardial infarction, treatment algorithms for these disease states do not routinely position drugs in this class ahead of ACE inhibitors; rather, they are more frequently seen as efficacious substitutes if ACE inhibitor intolerance occurs.

ARB MONOTHERAPY

ARBs are considered a suitable first‐step option in a diversity of hypertensive phenotypes. The enthusiasm for the use of ARBs goes beyond the issue of effectiveness, since drugs in this class are, at best, comparably as effective as monotherapy with diuretics, β blockers, ACE inhibitors, and calcium channel blockers. The underpinnings of support for this drug class reside in their ability to diminish the rate at which new‐onset diabetes develops in at‐risk patients as well as to decrease renal end‐event rates in excess of what might be expected from blood pressure (BP) reduction alone. It is unclear at the current time whether ARB therapy reduces cardiac end‐event rate in high‐risk coronary artery disease patients in a “beyond‐the‐numbers” fashion.

Response rates with ARBs range from 40% to 70% in stage I or II hypertension, with level of sodium intake and ethnicity having some bearing on the overall effect. In the interpretation of clinical trial results with ARBs, the mean reduction in BP (which is typically significant) should be distinguished from the percentage of individuals who are poor, average, or excellent responders (which may vary considerably in different studies).

The pharmacology of ARBs has been a matter of some considerable discussion; however, for the most part, the pharmacologic differences between the several compounds in this class are of little practical consequence. This would seem to apply to the issues of bioavailability, rate of absorption, volume of distribution, mode of metabolism (cytochrome P‐450 or not), and route of elimination. Duration of receptor occupancy, a surrogate for the BP lowering of drugs in this class, is a consideration only when a low‐end dose ARB is being administered. At high‐end doses of drugs in this class, the surfeit of drug reduces the impact of drug‐specific differences in receptor occupancy and/or elimination half‐life.

PREDICTORS OF RESPONSE

There are no reliable predictors of the magnitude of the BP reduction with an ARB. There has been an inconsistent relationship between the pretreatment and/or post‐treatment plasma renin activity values (used as markers of renin‐angiotensin axis activity) and the decrease in BP with an ARB; however, when hypertension is marked by significant renin‐angiotensin axis activation, such as in the presence of renal arterial disease and/or significant volume contraction, the initial response to an ARB can be considerable.

Certain patient groups are recognized as being responsive (high‐renin and young hypertensives [age 6–16 years]) and others less responsive to ARB monotherapy, including low‐renin, salt‐sensitive, volume‐expanded individuals such as the diabetic and the black hypertensive. However, the BP response to ARB monotherapy can be highly variable in African‐American and diabetic patients, with some individuals in these groups experiencing significant falls in BP.

The elderly generally respond well to ARBs, although for several of the ARBs, full dose‐ranging studies have not been undertaken in this population. Since ARBs are in large measure hepatically cleared (ranging from 40% to 99%), senescencerelated renal failure would not be expected to modify the systemic clearance of these drugs in a meaningful fashion. This is in contradistinction to ACE inhibitors, which typically undergo significant renal clearance and have their effect influenced by this pharmacokinetic characteristic in the elderly.

DOSING CONSIDERATIONS

An often‐posed question is what to do when ARB monotherapy does not bring BP to the desired goal. The answer to this question depends on the initial response. If there is minimal BP reduction with an ARB, a switch to a different drug class is a consideration; however, since many hypertensive patients require more than one drug to reach BP goal, a more expedient step is to add either a diuretic or a calcium channel blocker to the ARB. In doing so, ARB “nonresponders” (or partial responders) typically then become “responders.” This latter observation would suppose that a minority of patients should have an ARB discontinued solely on the basis of a failure to initially respond.

If the BP response to an ARB is modest, one can increase the total daily dose. This can be done by administering the total dose once daily or by split dosing. Split dosing, however, does not necessarily ensure a better overall response than full‐dose once‐daily administration. Any increase in the dose of an ARB should be done with the understanding that the dose‐response curve for ARBs, like many antihypertensive agents, is relatively steep (in responders) at typical beginning doses and flattens thereafter.

Increasing the dose of an ARB typically does not increase the peak effect; rather, it prolongs the response. For example, increasing the dose of valsartan from 80 mg to 320 mg minimally impacts its peak antihypertensive effect; however, a dose increment of this order of magnitude clearly augments receptor blockade at trough (24 hours), prolonging the duration of antihypertensive action. This example with valsartan can be extended to several of the ARBs.

It is clear that current starting doses of many ARBs (as recommended by package inserts) do not sustain maximal blockade of angiotensin II effect for a 24‐hour dose interval. It would seem a fairly straightforward proposition to advise that ARB therapy be started at “higher” doses; however, once the concept of a low starting dose of an antihypertensive medication has taken hold it is difficult to uproot from prescription practice. Another undesirable consequence of low‐end recommended starting doses arises from head‐to‐head studies comparing different ARBs. These studies can prove quite difficult to interpret when full dose‐ranging comparisons have not been undertaken and may unfairly favor one drug in the class over another. There is little that separates one ARB from another, with the exception of losartan, which does not produce as significant a BP reduction as longeracting drugs such as candesartan and irbesartan. The FDA views the difference between candesartan and losartan (systolic and diastolic BP 2–3 mm Hg decrease for 32 mg of candesartan vs. 100 mg of losartan) as significant enough for the difference to be cited in the package insert for candesartan.

COMBINATION THERAPY

The BP‐lowering ability of an ARB is bettered when a diuretic is coadministered, particularly when a salt‐sensitive form of hypertension is present. This pattern of response served as the basis for the development of fixed‐dose combination products, consisting of an ARB and hydrochlorothiazide. The underlying principle for combining these two drug classes is one of renin‐angiotensin axis activation by diuretic‐induced sodium depletion and, in so doing, shifting BP to an angiotensin‐II dependent mode. Even minimally natriuretic doses of hydrochlorothiazide (12.5 mg/d) can boost the BP‐reducing effect of an ARB (Table).

If the response to the addition of other drug classes to an ACE inhibitor holds true for ARBs, it can be expected that the addition of a β blocker to an ARB would have a minimal additional effect on BP unless a significant decrease in pulse rate occurs with the β blockade. Alternatively, adding a peripheral α antagonist, a calcium channel blocker, or an aldosterone receptor antagonist to an ARB (with or without a diuretic) is likely to lead to a significant additional reduction in BP.

The observation that angiotensin II escape occurs with extended ACE inhibitor therapy provides the theoretic basis for addition of an ARB to an ACE inhibitor. It is presumed that if an incremental reduction in BP occurs with addition of an ARB to an ACE inhibitor that it derives from blocking the effect of angiotensin II generated during this neurohumoral escape. However, the combination of an ARB with an ACE inhibitor does not generally lead to a significant additional reduction in BP. The occasional patient who responds to the combination of these two drug classes may do so based on a more long‐acting compound having been added and/or that the dosing of the drugs being administered is split with an evening dose of one added to a morning dose of the other.

CONCLUSIONS

ARB therapy has an emerging role in the management of hypertension either as monotherapy or in combination with a thiazide‐type diuretic. ARBs are comparable to most other drug classes—including ACE inhibitors—in their ability to reduce BP. Within the ARB class, their appear to be some differences in the relative efficacy of the compounds comprising the class. The greatest difference appears to occur when losartan is being compared with other ARBs, such as candesartan and irbesartan. Other assertions of intraclass differences (derived from head‐to‐head studies) oftentimes represent little more than the nuances of study design. ARBs are mechanistically distinct from ACE inhibitors; therefore, they are not simply an “ACE inhibitor without the potential for cough.” Based on their tolerability and favorable outcomes data, drugs in the ARB class can (and have) actively competed with ACE inhibitors in the hypertension market, notwithstanding their higher cost compared with generic ACE inhibitors.