AT1-Receptor Blockers: Differences That Matter

Home , Candesartan, Eprosartan, Losartan, Receptor antagonist

AT1-receptor blockers: differences that matter

AH Gradman Division of Cardiovascular Diseases, The Western Pennsylvania Hospital, Pittsburgh, Pennsylvania, USA

The available angiotensin II type 1 (AT1)-receptor block- effect, and this finding is supported by the results of ers differ markedly in their pharmacological properties comparative clinical trials. Moreover, the prolonged and clinical efficacy. Losartan shifts the dose-response binding of candesartan to the receptor is reflected in a curve for angiotensin II to the right without affecting the longer duration of action, compared with losartan; the maximal response; this antagonism can be overcome by antihypertensive effect of candesartan persists for 48 h increasing concentrations of angiotensin II and thus los- after dosing, compared with approximately 24 h with artan acts as a surmountable antagonist. By contrast, losartan. Candesartan thus offers extended therapeutic other agents suppress the maximal response to angio- coverage, an important consideration since a majority tensin II to varying extents; this can not be overcome by of patients miss occasional doses of antihypertensive increasing angiotensin concentrations and hence these medication. There is currently no evidence that differ- agents are insurmountable antagonists. Receptor bind- ences in receptor binding between AT1-receptor block- ing studies have shown that candesartan has the high- ers translate into differences in tolerability. In summary, est affinity for the AT1-receptor, followed by irbesartan, therefore, pharmacological differences between AT1- valsartan and losartan, and that candesartan dis- receptor blockers are reflected in clinically important sociates from the receptor more slowly than other differences in maximal antihypertensive effect, antagonists. A meta-analysis using an EMax model has response rate, and duration of action. shown that differences in receptor binding activity are Journal of Human Hypertension (2002) 16, S9–S16. reflected in differences in maximal antihypertensive doi:10.1038/sj.jhh.1001434

Keywords: AT1-receptor blockers; blood pressure control; candesartan; irbesartan; losartan; receptor binding studies; valsartan

Introduction ment. Each of these compounds selectively blocks the AT1-receptor, and as a class these agents have Angiotensin II is the principal effector peptide of the been shown to be at least as effective in lowering renin-angiotensin system and has a variety of bio- blood pressure as other antihypertensive agents and logical effects, including vasoconstriction, pro- to offer a tolerability profile comparable with that of motion of growth in vascular smooth muscle and placebo.6 There are, however, marked differences in cardiac myocytes, stimulation of aldosterone the pharmacological properties of these agents, and release, thrombosis, myocardial fibrosis, and pro- these may be reflected in important differences in motion of vascular inflammation.1 The deleterious clinical performance. effects of angiotensin II on blood pressure and cardiovascular remodelling are mediated via angioten- 1,2 sin II type 1 (AT1) receptors. The AT2-receptor subtype is also activated by angiotensin II, and has Pharmacological differences between been shown in experimental studies to counteract AT1-receptor blockers the detrimental effects of AT1-receptor stimu- 3,4 lation. Selective blockade of the AT1 receptor thus represents a rational therapeutic target in hyperten- AT1-receptor blockers bind selectively to AT1- sion and cardiovascular disease.5 receptors and thus inhibit the deleterious effects of angiotensin II, irrespective of whether angiotensin II Since the introduction of the prototype AT1- receptor blocker, losartan, in 1994 five others have is produced via angiotensin converting enzyme 2 been introduced into clinical practice: candesartan, (ACE) or by non-ACE pathways. As a result, they eprosartan, irbesartan, telmisartan and valsartan; a produce more complete blockade of the renin-angio- number of others are currently undergoing develop- tensin system than ACE inhibitors. However, the binding kinetics of AT1-receptor blockers vary con- siderably, both in terms of the type of antagonism Correspondence: Professor AH Gradman MD, The Western seen at the receptor and the affinity of the antagonist Pennsylvania Hospital, 4800 Friendship Avenue, Pittsburgh, for the receptor (Figure 1). Pennsylvania 15224, USA Pharmacology of AT1-receptor blockers AH Gradman S10 Affinity of AT1-receptor blockers for the receptor and duration of binding

AT1-receptor blockers differ markedly in their affinity for the receptor. Experiments in animals have shown that the affinity of candesartan for the AT1-receptor is 10 and 80 times greater than that of EXP3174 and losartan, respectively, and that candesartan dissociates more slowly from the receptor than other AT1-receptor blockers.11–13 In other experiments, rat portal vein preparations were incubated with various concentrations of AT1-receptor blocker, which was washed out after different times to determine the duration of AT1 receptor blockade. The inhibition with candesartan persisted despite repeated washing for 2 h, whereas the effects of losartan, EXP3174 and irbesartan were significantly reduced 30–60 min after washing.10 These findings are supported by studies with Chinese hamster ovary (CHO) cells transfected with Figure 1 Differences in receptor (R) binding kinetics of AT1- 14 receptor blockers, exemplified by losartan and candesartan.7 the human AT1-receptor. In these experiments, cells Reproduced with permission from Morsing P, Vauquelin G. How were preincubated with unlabelled candesartan, irbes- can the differences among AT1-receptor antagonists be explained? artan, EXP3174, or losartan and subsequently incu- Cell Biochem Biophys 2001; 35: 89–102. bated with [3H]-candesartan to determine the rate at which the unlabelled AT1-receptor blockers dis- sociated from the receptor and were replaced by [3H]- candesartan. The dissociation rate constant for candesartan was markedly lower than that of other AT1- receptor blockers, and the half life for dissociation of Nature of angiotensin II antagonism: candesartan from the receptor was several-fold longer surmountable vs insurmountable (Table 1). Some agents, such as losartan, only produce a paral- Together, therefore, these studies show that candes- lel shift of the dose-response curve to the right with- artan binds to the AT1-receptor with greater affinity out reducing the maximal response to angiotensin than other AT1-receptor blockers, and dissociates from II. This inhibition can therefore be overcome by the receptor more slowly. These differences in affinity increasing concentrations of angiotensin II, and and duration of binding probably reflect the nature of hence these agents are described as surmountable the receptor-antagonist complex formed following antagonists. By contrast, other agents also depress binding of the antagonist to the receptor. Further evi- the maximal response to angiotensin II; the extent dence for this comes from the studies in transfected to which these agents depress the response ranges CHO cells, which suggest that with candesartan a from a partial decrease with irbesartan, valsartan higher proportion of this complex exists in a parti- and EXP3174 (the active metabolite of losartan) to cularly tightly bound form than with losartan, almost complete suppression with candesartan. This EXP3174, or irbesartan;15,16 more than 90% of candes- inhibition can not be overcome by increasing con- artan is present in this form, compared with 70% for centrations of angiotensin II and hence is described EXP3174 and 44% for irbesartan, whereas no tight as insurmountable antagonism.8,9 binding is detectable with losartan.16 These differences in the antagonist properties of This prolonged binding of candesartan to the AT1- different AT1-receptor blockers have been demon- receptor is associated with a long duration of bio- strated in a series of studies with isolated blood logical activity in vivo. In studies in conscious rats, vessel preparations.10 In one set of experiments, treatment with candesartan inhibited the increase in for example, rabbit aortic strips were preincubated blood pressure induced by angiotensin II by with various concentrations of candesartan, irbes- approximately 80%; this effect was maintained for artan, losartan and EXP3174, and the contractile at least 24 h after dosing, despite the fact that plasma response to increasing concentrations of angioten- concentrations of candesartan declined rapidly and sin II was assessed (Figure 2). Candesartan pro- were undetectable at 24 h.10 In other studies, duced a progressive reduction in the response to increases in plasma renin were measured as a angiotensin II, with a concentration of 1 nmol/L marker of inhibition of the renin-angiotensin system producing complete inhibition. Irbesartan and after administration of candesartan and other AT1- EXP3174 produced less marked reductions in the receptor blockers to healthy, salt-depleted, volun- maximal response, while losartan had no effect on teers. Candesartan, 16 mg, produced greater the maximal response at concentrations of up to increases in plasma renin over 24 h than losartan, 100 nmol/L. 50 mg, or valsartan, 80 or 160 mg.17,18

Journal of Human Hypertension Pharmacology of AT1-receptor blockers AH Gradman S11

Figure 2 Response to angiotensin II, expressed as percentage of maximum contraction, in rabbit aortic strips preincubated with various concentrations of candesartan, irbesartan, losartan and EXP3174.10 Reproduced with permission from Morsing P et al. Mechanistic differences of various AT1-receptor blockers in isolated vessels of different origin. Hypertension 1999; 33: 1406–1413.

Table 1 Dissociation rate constants (K−1) and half life for dis- Dose-response relationship sociation of antagonist from the AT1-receptor (T.), measured in Chinese hamster ovary cells transfected with the human AT1- Most drugs show dose-dependent efﬁcacy, but in receptor. Dissociation rates were calculated from the slowing of some cases the recommended clinical doses lie near the association rate for [3H]-candesartan following pretreatment the top of the dose-response range and increasing of cells with AT1-receptor antagonists, washing, and further incubation8,14 the dose produces little further effect. For example, in a randomised parallel-group study, patients with −1 essential hypertension were treated for 8 weeks with K−1 (min )T. (min) losartan, at daily doses of between 10 mg and 150 19 Candesartan (1.5 nmol/L) 0.0046 ± 0.0017 152 ± 58 mg. Losartan, 50 mg, was more effective than 10 EXP3174 (5 nmol/L) 0.022 ± 0.004 31 ± 6 mg or 25 mg, producing a placebo-corrected Irbesartan (100 nmol/L) 0.041 ± 0.009 17 ± 4 reduction in diastolic blood pressure of 4.5 mm Hg. ␮ ± ± Losartan (10 mol/L) 0.13 0.03 5.2 1.1 However, higher doses (100 mg and 150 mg) did not result in any further antihypertensive effect, producing mean reductions in diastolic blood pressure of 4.3 mm Hg and 4.1 mm Hg, respectively. Thus, the Differences in antihypertensive efﬁcacy normal recommended dose for this agent lies near the top of the dose-response range. between AT1-receptor blockers By contrast, studies with other AT1-receptor These differences in pharmacological properties blockers have shown dose-response relationships between AT1-receptor blockers may translate into that extend across the therapeutic range. For marked differences in antihypertensive potency and example, six randomised, placebo-controlled, paral- duration of action. The clinical evidence suggests lel-group dose-response studies, involving a total of that this is indeed the case. 1482 patients, have investigated the antihyperten-

Journal of Human Hypertension Pharmacology of AT1-receptor blockers AH Gradman S12 sive efficacy of candesartan cilexetil (the prodrug of Comparative studies candesartan) in patients with essential hyperten- A number of studies have compared the antihyper- sion. A meta-analysis of these studies20 showed that tensive efficacies of different AT -receptor blockers. the placebo-corrected mean reductions in sitting 1 In one study, for example, 334 patients with essen- diastolic blood pressure were approximately 4.5 tial hypertension (sitting diastolic blood pressure mm Hg with 4 mg, 6 mm Hg with 8 mg, and 8 95–114 mm Hg) were randomised to receive candes- mm Hg with 16 mg; the corresponding reductions in artan cilexetil, 8 mg or 16 mg, losartan, 50 mg, or systolic blood pressure were approximately 7, 10 placebo once daily for 8 weeks.24 Compared with and 12 mm Hg, respectively. placebo, candesartan cilexetil, 8 mg and 16 mg, Similar studies have been performed with other reduced trough diastolic blood pressure (measured AT -receptor blockers. The pooled data from eight 1 24 h after the last dose) by a mean of 8.9 and 10.3 studies with irbesartan, involving a total of 2955 mm Hg, respectively (both P Ͻ 0.001); the effect of patients, showed placebo-corrected reductions in the 8 mg dose was comparable with that of losartan, diastolic blood pressure ranging from approximately 50 mg (mean treatment difference 2.3 mm Hg in fav- 4.2 mm Hg at a dose of 75 mg to 6.2 mm Hg at doses our of candesartan, P = 0.115), whereas the 16 mg of 300 mg and above.21 Similarly, a meta-analysis of dose was significantly more effective than losartan nine studies with valsartan, involving 4117 patients, (mean treatment difference 3.7 mm Hg, P = 0.013) showed mean reductions in diastolic blood pressure (Figure 4). of between 2.5 mm Hg and 5.1 mm Hg at doses of Similar results were obtained in the recent CLAIM 40–160 mg.22 Study, which involved 654 hypertensive patients A recent meta-analysis has compared the dose- (diastolic blood pressure 95–114 mm Hg) recruited response relationships for candesartan, irbesartan, from 72 centres in the United States.25 In this study, valsartan and losartan.23 The analysis included all patients were randomised to receive candesartan double-blind, placebo-controlled, fixed dose, paral- cilexetil, 16 mg, or losartan, 50 mg, and doses were lel-group studies, with a duration of 4 weeks or doubled after 2 weeks; these high doses were used to longer, in patients with mild-to-moderate hyperten- ensure that maximal blood pressure responses were sion, that had been submitted to the US Food and achieved. At 8 weeks after randomisation, trough Drug Administration (FDA). For each drug, mean blood pressures were reduced to a significantly placebo-corrected reductions in trough diastolic greater extent with candesartan than with losartan blood pressure were calculated at each dose and a (mean reductions 13.3/10.9 mm Hg vs 9.8/8.7 mathematical model fitted to the data to allow the mm Hg, respectively, P Ͻ 0.001). Candesartan was maximum achievable reduction in trough diastolic also significantly more effective than losartan in blood pressure (EMax) to be calculated. The results showed that candesartan produced the greatest reductions in diastolic blood pressure (Figure 3), with an EMax of 8.1 mm Hg. Irbesartan was the next most potent agent, with an EMax of 7.1 mm Hg, followed by valsartan (EMax 6.4 mm Hg) and losartan (EMax 5.2 mm Hg). Thus, in this analysis, differences in receptor binding properties were reflected in differences in maximal antihypertensive efficacy.

Figure 4 Placebo-corrected reductions in diastolic blood pressure (DBP) in 334 hypertensive patients treated for 8 weeks with can- Figure 3 Dose-response relationships for candesartan, irbesartan, desartan cilexetil, 8 mg or 16 mg, losartan, 50 mg, or placebo.24 Ͻ valsartan and losartan, derived from an EMax model ﬁtted to *P 0.001 vs placebo; na: not assessed. Reproduced with per- pooled clinical trial data.23 Reproduced with permission from mission from Andersson OK, Neldam S. The antihypertensive Hansson L. The relationship between dose and antihypertensive effect and tolerability of candesartan cilexetil, a new generation

effect for different AT1-receptor blockers. Blood Pressure 2001; angiotensin II antagonist, in comparison with losartan. Blood 10 (Suppl 3): 33–39. Press 1998; 7: 53–59.

Journal of Human Hypertension Pharmacology of AT1-receptor blockers AH Gradman S13 lowering blood pressure at peak (mean reductions ure. Furthermore, the lower limits of the 95% con- 15.2/11.6 mm Hg vs 12.6/10.1 mm Hg, P Ͻ 0.05). fidence intervals for these measurements were 65– These differences in blood pressure reductions were 71% with candesartan, compared with 48–51% with reflected in significant differences in response rates losartan. Thus, in contrast to losartan, candesartan (defined in this study as the proportion of patients consistently produced trough-to-peak ratios that achieving a diastolic blood pressure of below 90 were higher than the minimum recommended in mm Hg or a reduction in diastolic blood pressure of current management guidelines. This study showed, at least 10 mm Hg). Among patients receiving cande- therefore, that candesartan cilexetil produces sartan cilexetil, the response rate was 62.4%, com- smoother blood pressure control over 24 h than los- pared with 54.0% in the losartan group (P Ͻ 0.05). artan, reflecting its longer duration of action. Similarly, the proportion of patients in whom blood The antihypertensive efficacies of different AT1- pressure was considered to be controlled (diastolic receptor blockers have also been compared in stud- blood pressure less than 90 mm Hg) was signifi- ies using 24-h ambulatory blood pressure monitor- cantly higher in the candesartan cilexetil group than ing. In one study, for example, 268 hypertensive in the losartan group (56.0% vs 46.9%, respectively, patients (mean sitting diastolic blood pressure 95– P Ͻ 0.05). 110 mm Hg and mean ambulatory diastolic blood Comparative studies have consistently shown that pressure 85 mm Hg or above) were randomised to candesartan, 8–16 mg, is significantly more effective receive candesartan cilexetil, 8 mg, losartan, 50 mg, than losartan, 50 mg, reflecting the greater affinity or placebo for 4 weeks, after which doses were and duration of receptor binding seen with candes- doubled and treatment continued for a further 4 30 artan. Irbesartan also appears to be a potent AT1- weeks. Candesartan reduced both systolic and receptor blocker, with doses of 150–300 mg being diastolic blood pressure to a significantly greater more effective than losartan, 50–100 mg,26,27 while extent than losartan over 36 h after dosing (Figure valsartan, 80–160 mg, appears to be comparable in 5); indeed, by 36 h after dosing, blood pressure had efficacy to losartan, 50–100 mg.28 These findings are returned almost to baseline levels in losartan-treated consistent with those of the EMax analysis described patients, but remained significantly lower than base- above,23 reinforcing the view that differences in line in patients receiving candesartan. Blood press- receptor binding between AT1-receptor blockers ure was also measured in the clinic at 24 and 48 h translate into differences in antihypertensive effect. after the last dose of candesartan cilexetil, 16 mg, and losartan, 100 mg. Significant reductions in both systolic and diastolic blood pressure were seen 48 h Duration of antihypertensive efficacy after dosing with candesartan, whereas in losartan- International hypertension management guidelines treated patients blood pressures were not signifi- recommend the use of long-acting formulations that cantly different from baseline values at this time provide 24-h blood pressure control for a number of (Figure 6). Indeed, the effect on blood pressure seen reasons, including: 48 h after dosing with candesartan was comparable with that seen with losartan after 24 h. • smooth and persistent, rather than intermittent, Similar results were obtained in a second study blood pressure control; with ambulatory blood pressure monitoring, in which • potentially better patient adherence to therapy the antihypertensive effect over 36 h of candesartan with once-daily dosing; cilexetil, 8 mg, was significantly greater than that of • possible protection against the risk of sudden losartan, 50 mg.31 Other studies have shown that death, myocardial infarction or stroke associated irbesartan, 150 mg, and telmisartan, 40–80 mg, appear with abrupt increases in blood pressure on wak- to have greater effects on ambulatory blood pressure ing.29 than valsartan, 80 mg, or losartan, 50 mg.32–36 Trough-to-peak ratios are a widely used measure of The available studies thus indicate that the thera- the duration of antihypertensive efficacy. In this peutic effect of candesartan is maintained even if a approach, blood pressure is measured approxi- dose is delayed or missed, and hence candesartan mately 4 h after drug administration, when the effect offers extended therapeutic coverage. The potential would be expected to be maximal, and again after importance of this extended therapeutic coverage is 24 h. Current guidelines recommend that long- underlined by studies of adherence with antihyper- acting formulations should provide a trough-to-peak tensive medication. In one such study, approxi- ratio of at least 50%.29 mately 50% of patients showed between 60 and In the study comparing candesartan cilexetil and 90% compliance.37 Thus, even in patients in whom losartan, described above,24 candesartan, 8 mg and adherence is usually satisfactory, a high proportion 16 mg, produced mean trough-to-peak ratios of may miss occasional doses, resulting in a risk of 108% and 89%, respectively, for systolic blood suboptimal blood pressure control. pressure and 110% and 86%, respectively, for diastolic blood pressure. By contrast, losartan, 50 mg, Tolerability of AT1-receptor blockers produced trough-to-peak ratios of 71% for systolic In contrast to other classes of antihypertensive blood pressure and 67% for diastolic blood press- drugs, where the incidence of adverse events

Journal of Human Hypertension Pharmacology of AT1-receptor blockers AH Gradman S14

Figure 5 Mean change from baseline in systolic (SBP) (a) and diastolic (DBP) (b) blood pressures in 268 patients treated with candesartan cilexetil, 16 mg, or losartan, 100 mg.30 Reproduced by permission of Elsevier Science from Lacourcie`re Y, Asmar R. A comparison of the efﬁcacy and duration of action of candesartan cilexetil and losartan as assessed by clinic and ambulatory blood pressure after a missed dose, in truly hypertensive patients. A placebo-controlled, forced titration study. Am J Hypertens 1999; 12: 1181–1187. Copy- right 1999 by American Journal of Hypertension Ltd.

Figure 6 Mean changes in blood pressure 24 and 48 h after the last dose in patients treated with candesartan cilexetil, 16 mg, and losartan, 100 mg.30 Reproduced by permission of Elsevier Science from Lacourcie`re Y, Asmar R. A comparison of the efﬁcacy and duration of action of candesartan cilexetil and losartan as assessed by clinic and ambulatory blood pressure after a missed dose, in truly hypertensive patients. A placebo-controlled, forced titration study. Am J Hypertens 1999; 12: 1181–1187. Copyright 1999 by American Journal of Hypertension Ltd.

increases with dose, the AT1-receptor blockers show insurmountable antagonists, produce a greater placebo-like tolerability at all doses evaluated in maximum reduction in blood pressure, higher clinical trials. There is currently no evidence of sig- response rates, and a longer duration of action, com- nificant differences in tolerability profiles between pared to agents that bind less tightly to the receptor. members of the class.6 These pharmacological differences do not, however, appear to affect the placebo-like tolerability associa- Conclusions ted with AT1-receptor blockers. There is increasing evidence that differences in References receptor binding kinetics between AT1-receptor blockers are reflected in marked differences in anti- 1 Timmermans PB et al. Angiotensin II receptors and hypertensive efficacy. Agents such as candesartan, functional correlates. Am J Hypertens 1992; 5 (12 Pt that bind tightly to the AT1-receptor and act as 2): 221S–235S.

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