Angiotensin Receptor Blockers: New Considerations in Their Mechanism of Action

Abstract

Angiotensin receptor blockers are one of several drug classes that act by hindering activity of the renin–angiotensin axis. Angiotensin receptor blockers act by selectively blocking the binding of angiotensin II to the angiotensin type 1 receptor but not the angiotensin type 2 receptor. Compounds in this class are as effective as most other antihypertensive drug classes in reducing blood pressure in the patient with hypertension. The mechanism of action of an angiotensin receptor blocker, which seemed a straightforward proposition early on, has of late become more convoluted with a host of class and compound‐specific concerns having emerged. As the mechanistic basis for the action(s) of angiotensin receptor blockers more completely unfolds, added credence may ultimately be lent to widely touted and often overstated intraclass differences.

Angiotensin‐converting enzyme (ACE) inhibitors have earned an important place in medical therapy since captopril, the first compound in this class, was released in 1981. Captopril proved to be an extremely effective blood pressure (BP)‐lowering agent, as demonstrated in a wide range of renin‐dependent models of hypertension. The ACE inhibitor field quickly mushroomed thereafter to the degree that there are currently 10 ACE inhibitors available in the United States. ¹ The first angiotensin receptor blocker (ARB), losartan, was released in 1995 and now there are currently seven ARBs available in the US market. The mechanistic basis for ARB action—blocking the angiotensin type 1 (AT₁) receptor—seemed at first to be clear‐cut. As treatment experience grew and novel experimental observations surfaced, however, the question of how an ARB works has become much more unsettled. As such, multiple neurohumoral, cellular, and tissue‐based considerations have been added to the mix of how an ARB works. ² , ³ , ⁴ , ⁵ , ⁶ , ⁷

PHARMACOLOGIC CONSIDERATIONS

The pharmacology of ARBs has engendered much discussion. Despite the sometimes intense nature of such dialogue, the pharmacologic differences between the several compounds in this class are of modest practical significance for the most part. This would seem to apply to the issues of absolute bioavailability, rate of absorption, volume of distribution, lipid solubility, plasma half‐life, mode of metabolism (CYP₄₅₀ or not), and route of elimination (liver and liver/kidney). Several of the ARBs are administered as prodrugs (candesartan cilexetil and olmesartan medoxomil) or a less‐active parent compound (losartan). ⁸ , ⁹ , ¹⁰ To date, there does not appear to be any meaningful difference in efficacy attributable to prodrug considerations between candesartan cilexetil and olmesartan medoxomil and those ARBs not being administered as a pro‐drug. Among the ARBs, candesartan, olmesartan, and the E‐3174 active metabolite of losartan undergo modest renal clearance; however, this is of no particular advantage (or disadvantage) when these drugs are given to patients with moderate‐to‐severe chronic kidney disease. ¹¹ ARBs do not require dose adjustment in renal failure on the basis of their pharmacokinetics; rather, dose reduction in this setting should be empirically dictated by having reached or exceeded the goal established for BP reduction.

RECEPTOR OCCUPANCY

Duration of receptor occupancy is of most significance when low‐end doses of ARBs are being given. At high‐end doses for drugs in this class, the surfeit of drug reduces the impact of compound‐specific differences in receptor occupancy and/or elimination half‐life. ¹² Duration of receptor occupancy does, however, become important in the setting of a missed dose of medication; therein, with long‐acting compounds such as telmisartan and candesartan, BP reduction can persist 24 hours hence from the prior day's dose. ¹³ , ¹⁴

On the basis of in vitro binding studies, ARBs have been divided into two categories: surmountable antagonists (losartan and eprosartan) and insurmountable antagonists (valsartan, irbesartan, candesartan, telmisartan, olmesartan, and the E‐3174 metabolite of losartan) (Figure 1). Surmountable antagonists produce a rightward parallel shift of the agonist concentration‐response curve with no change in the maximal response (Figure 1A). Insurmountable antagonists elicit relatively parallel shifts of the agonist‐concentration response curve, but can be accompanied by a depression of the maximal response to the agonist that cannot be overcome with increasing agonist concentrations (Figure 1B). Candesartan represents an insurmountable antagonist that can produce nonparallel agonist‐concentration response curve shifts, again depressing the maximal response in such a way that it cannot be overcome with increasing concentrations of the agonist (Figure 1C). Although the specific mode of receptor occupancy has not been clearly linked with the BP response to an ARB, it is likely that a slow off rate from the AT₁ receptor may extend the time of occupancy of the receptor protein and lengthen the duration of antagonism.

Figure 1.

Feature of surmountable and insurmountable angiotensin receptor antagonists. (See text for details.) Reproduced with permission from J Clin Pharmacol. 1999;39:547–559. ¹⁵

DOSE‐RESPONSE RELATIONSHIPS

A patient with hypertension can be a full, partial, or nonresponder to ARB therapy. Responders typically require no more than mid‐range doses of an ARB, such as 40 mg of telmisartan, 8–16 mg of candesartan, or 80–160 mg of valsartan. In such patients, increasing the dose of an ARB does not typically increase the peak effect; rather, it prolongs the response. ¹² 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 ensures receptor blockade at trough (24 hours), thereby extending the duration of antihypertensive action.

Circumstances are somewhat different for partial responders to an ARB. If the BP response to an ARB is modest, one can increase the dose. This can be done by administering the total dose once daily or by split‐dosing. Split‐dosing, per se, does not ensure a better overall response than full‐dose once‐daily administration. Any increase in the ARB dose in partial responders should be done with the understanding that the dose‐response curve for ARBs is relatively flat in such patients. ¹⁶ In nonresponders, the BP reduction is negligible with an ARB. In such patients, there is little to be gained from a within‐class switch.

Acute and chronic BP reduction often activates an interlinked series of mechanisms designed to restore BP. Reflex increases in cardiac output, peripheral vasoconstriction, and salt/water retention can result from baroreflex‐mediated activation of the sympathetic and renin–angiotensin systems. ARBs do not interfere with circulatory reflexes and/or baroreceptor function; thus, they will not reflexly increase heart rate when BP is reduced. ⁸ ARBs also do not prompt sodium and water retention in the setting of BP reduction. ¹⁷ Accordingly, pseudotolerance does not develop with long‐term ARB administration.

TIME‐OF‐DAY DOSING

No ARB therapy is indicated per se for nocturnal dosing. If bedtime dosing occurs with an ARB, it is at the discretion of the prescriber and most times relates to evening and/or early morning BP values being above goal. An additional consideration for bedtime dosing of an ARB, however, is to reduce overnight BP values in nondipper patients. In this regard, 148 nondipper patients were randomly assigned to receive monotherapy with valsartan (160 mg/d) either on awakening or at bedtime. The 24‐hour mean systolic and diastolic BP reduction after 3 months of valsartan was similar for both treatment times (13.1/8.5 mm Hg [morning] vs. 14.7/10.3 mm Hg [bedtime]); however, in those receiving valsartan at bedtime, 75% became nocturnal dippers while only 23.6% of the treated hypertensives did so with morning dosing of valsartan. ¹⁸ Of note, urinary albumin excretion was significantly reduced by 41% after bedtime treatment with valsartan. This reduction was independent of the 24‐hour BP decrease but correlated with both the decrease in nocturnal BP and more so with the increase in the ratio of diurnal/nocturnal BP. ¹⁹

SYMPATHETIC NERVOUS SYSTEM

The ARB eprosartan has been observed in preclinical studies to be a potent inhibitor of neural presynaptic AT₁ receptors. It has been hypothesized that this effect may be greater than that observed with other ARBs at pharmacologically relevant doses. ² , ²⁰ This theory was tested in a prospective, randomized, three‐way, placebo‐controlled crossover study of eprosartan (600 mg/d), losartan (50 mg/d), or placebo. Multiunit firing rates in efferent sympathetic nerves distributed to skeletal muscle vasculature (muscle sympathetic nerve activity) were determined with microneurography, testing whether ARBs inhibit central sympathetic outflow. In parallel, isotope dilution methodology was used to measure whole body norepinephrine spillover to plasma. Both muscle sympathetic nerve activity and whole body norepinephrine spillover were unchanged by ARB administration (Figure 2), indicating that the tested ARBs did not materially inhibit central sympathetic outflow or act presynaptically to reduce norepinephrine release at existing rates of nerve firing. Thus, it would appear that sympathetic nervous system inhibition is not a relevant component of the BP‐lowering action of ARBs in essential hypertension. ²

Figure 2.

Microneurographic assessment of efferent sympathetic nerve traffic to the skeletal muscle vasculature (muscle sympathetic nerve activity), indicative of central sympathetic outflow, assessed as bursts/minute and bursts/100 beats after 4‐week therapy with eprosartan, losartan, or placebo. Data are presented as mean ± SD. Reproduced with permission from Am J Physiol Heart Circ Physiol. 2006;290:H1706–H1712. ²

ALDOSTERONE EFFECTS

Although conventional belief holds that plasma aldosterone (PA) and/or aldosterone secretion diminishes with drugs that interfere with renin–angiotensin system activity, such is not the case in practice. Losartan may be the best studied of the ARBs relative to its effect on plasma aldosterone. As such, there is a very high intersubject and interstudy variability in PA values, following losartan, with interpretation of PA values necessitating consideration of the time of day of sampling since PA exhibits a diurnal secretion pattern. ²¹ , ²² At most, approximately a 50% decrement in PA is seen within the first several hours of losartan dosing, with a return toward baseline at the end of the dosing interval. Long‐term PA responses to losartan (as is the case with other ARBs) tend to disappear, possibly as a consequence of aldosterone escape. ²³ In regard to the latter, small increases in serum potassium values brought about by an ARB (and likewise for an ACE inhibitor) can independently stimulate aldosterone secretion and thereby offset the suppressive effect of renin–angiotensin system interruption on aldosterone secretion.

STIMULATION OF AT₂ RECEPTORS

A decrease in angiotensin II (Ang II) production at the level of juxtaglomerular cells induced by an ACE inhibitor or the displacement of Ang II from AT₁ receptors by an ARB interrupts the permanent feedback inhibition of renin release mediated by Ang II. Accordingly, administration of an ARB will result in a time‐wise elevation of plasma renin activity (and thereby Ang II) and AT₂‐receptor stimulation, being that this receptor is one that is not blocked by an ARB.

In contrast to the well established physiologic roles of the AT₁ receptor, the significance of the AT₂ remains largely unclear, particularly as it relates to its stimulation effecting a positive change in BP. Studies do, however, demonstrate that the AT₂ receptor mediates cellular differentiation and growth, opposing the actions of Ang II through the AT₁ receptor. ²⁴ More recently, accumulating experimental evidence suggests that AT₂‐receptor stimulation elicits a vasodilator response, which involves the bradykinin‐nitric oxide‐cGMP pathway. ²⁵ AT₂‐receptor stimulation dilates both small resistance arteries and large capacitance vessels. It remains to be determined, however, whether the vasodilator aspect of AT₂‐receptor stimulation can be maintained chronically and to what extent it occurs in humans.

CENTRAL HEMODYNAMICS/VASCULAR REMODELING

Despite similar effects on peripheral BP and a greater effect on aortic stiffness, atenolol has been observed to have less impact on central systolic BP than the ARB eprosartan, in that the β blocker failed to reduce wave reflection. ²⁶ This provides one potential explanation for the failure of atenolol to improve outcome in older patients with essential hypertension (when compared with an ARB), as was the case in the Losartan Intervention for Endpoint reduction in hypertension (LIFE) study. ²⁷ The central BP effect of full‐dose ARB therapy has not been carefully studied; however, there is little to suggest that there would be major intraclass differences in how this hemodynamic parameter is affected.

The ARBs losartan and irbesartan have also both been studied as to their effect on the structure and function of small arteries. ²⁸ , ²⁹ In the case of each of these ARBs, their use is followed by normalization of the structure and endothelial function of small resistance arteries (100–350 μm in diameter) when compared with the β blocker atenolol. This vascular remodeling occurs at equivalent levels of BP reduction for each of the two drug classes. The advantages derived from corrected structural remodeling and enhanced endothelial function are uncertain at this time. It is also unclear as to how long such structure/function improvement must be present to afford a survival benefit (if such is even the case) and whether it is unique to ARBs alone, which is unlikely. ³⁰

MISCELLANEOUS ARB EFFECTS

The number of circulating endothelial progenitor cells (EPCs) correlates with endothelial dysfunction and cardiovascular risk in humans. As such, ARBs increase the number of regenerative EPCs in patients with type 2 diabetes mellitus. This effect occurs within a matter of 4 weeks and is more completely expressed at 12 weeks of ARB therapy. ³ This seems to be a class effect, because it has been demonstrated with standard doses of two long‐acting ARBs, olmesartan and irbesartan. It is unclear, however, whether the increase of EPC number with an ARB is a result of EPC mobilization from the bone marrow, whether ARBs stimulate EPC proliferation and differentiation, or both. The relevance of an increase in EPC numbers is unclear in terms of its effect on systemic BP and outcomes. ³¹

CONCLUSIONS

The primary mechanism of action of an ARB involves its blocking the untoward effects of Ang II at the AT₁ receptor. In so doing, significant BP reduction will occur. Of late, an overabundance of new considerations has emerged as to the actions of ARBs. Although many of these newly evolved effects are conceptually intriguing, they still remain untested as to their clinical relevance at the bedside. Issues of intraclass differences and dose relationships for non‐BP parameters such as these still remain on the table. Whether these unique attributes of ARB therapy can further the primary BP reduction seen with these drugs remains a work in progress.