(2002) 16, S9 S16 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh AT 1 -receptor blockers: differences that matter Division of Cardiovascular Diseases, The Western Pennsylvania Hospital, Pittsburgh, Pennsylvania, USA The available angiotensin II type 1 (AT 1 )-receptor blockers differ markedly in their pharmacological properties and clinical efficacy. Losartan shifts the dose-response curve for angiotensin II to the right without affecting the maximal response; this antagonism can be overcome by increasing concentrations of angiotensin II and thus losartan acts as a surmountable antagonist. By contrast, other agents suppress the maximal response to angiotensin II to varying extents; this can not be overcome by increasing angiotensin concentrations and hence these agents are insurmountable antagonists. Receptor binding studies have shown that candesartan has the highest affinity for the AT 1 -receptor, followed by irbesartan, valsartan and losartan, and that candesartan dissociates from the receptor more slowly than other antagonists. A meta-analysis using an E Max model has shown that differences in receptor binding activity are reflected in differences in maximal antihypertensive effect, and this finding is supported by the results of comparative clinical trials. Moreover, the prolonged binding of candesartan to the receptor is reflected in a longer duration of action, compared with losartan; the antihypertensive effect of candesartan persists for 48 h after dosing, compared with approximately 24 h with losartan. Candesartan thus offers extended therapeutic coverage, an important consideration since a majority of patients miss occasional doses of antihypertensive medication. There is currently no evidence that differences in receptor binding between AT 1 -receptor blockers translate into differences in tolerability. In summary, therefore, pharmacological differences between AT 1 - receptor blockers are reflected in clinically important differences in maximal antihypertensive effect, response rate, and duration of action. (2002) 16, S9 S16. doi:10.1038/sj.jhh.1001434 Keywords: AT 1 -receptor blockers; blood pressure control; candesartan; irbesartan; losartan; receptor binding studies; valsartan Introduction Angiotensin II is the principal effector peptide of the renin-angiotensin system and has a variety of biological effects, including vasoconstriction, promotion of growth in vascular smooth muscle and cardiac myocytes, stimulation of aldosterone release, thrombosis, myocardial fibrosis, and promotion of vascular inflammation. 1 The deleterious effects of angiotensin II on blood pressure and cardiovascular remodelling are mediated via angiotensin II type 1 (AT 1 ) receptors. 1,2 The AT 2 -receptor subtype is also activated by angiotensin II, and has been shown in experimental studies to counteract the detrimental effects of AT 1 -receptor stimulation. 3,4 Selective blockade of the AT 1 receptor thus represents a rational therapeutic target in hypertension and cardiovascular disease. 5 Since the introduction of the prototype AT 1 - receptor blocker, losartan, in 1994 five others have been introduced into clinical practice: candesartan, eprosartan, irbesartan, telmisartan and valsartan; a number of others are currently undergoing develop- Correspondence: Professor MD, The Western Pennsylvania Hospital, 4800 Friendship Avenue, Pittsburgh, Pennsylvania 15224, USA ment. Each of these compounds selectively blocks the AT 1 -receptor, and as a class these agents have been shown to be at least as effective in lowering blood pressure as other antihypertensive agents and to offer a tolerability profile comparable with that of placebo. 6 There are, however, marked differences in the pharmacological properties of these agents, and these may be reflected in important differences in clinical performance. Pharmacological differences between AT 1 -receptor blockers AT 1 -receptor blockers bind selectively to AT 1 - receptors and thus inhibit the deleterious effects of angiotensin II, irrespective of whether angiotensin II is produced via angiotensin converting enzyme (ACE) or by non-ace pathways. 2 As a result, they produce more complete blockade of the renin-angiotensin system than ACE inhibitors. However, the binding kinetics of AT 1 -receptor blockers vary considerably, both in terms of the type of antagonism seen at the receptor and the affinity of the antagonist for the receptor (Figure 1).
Pharmacology of AT 1 -receptor blockers S10 Affinity of AT 1 -receptor blockers for the receptor and duration of binding Figure 1 Differences in receptor (R) binding kinetics of AT 1 - receptor blockers, exemplified by losartan and candesartan. 7 Reproduced with permission from Morsing P, Vauquelin G. How can the differences among AT 1 -receptor antagonists be explained? Cell Biochem Biophys 2001; 35: 89 102. Nature of angiotensin II antagonism: surmountable vs insurmountable Some agents, such as losartan, only produce a parallel shift of the dose-response curve to the right without reducing the maximal response to angiotensin II. This inhibition can therefore be overcome by increasing concentrations of angiotensin II, and hence these agents are described as surmountable antagonists. By contrast, other agents also depress the maximal response to angiotensin II; the extent to which these agents depress the response ranges from a partial decrease with irbesartan, valsartan and EXP3174 (the active metabolite of losartan) to almost complete suppression with candesartan. This inhibition can not be overcome by increasing concentrations of angiotensin II and hence is described as insurmountable antagonism. 8,9 These differences in the antagonist properties of different AT 1 -receptor blockers have been demonstrated in a series of studies with isolated blood vessel preparations. 10 In one set of experiments, for example, rabbit aortic strips were preincubated with various concentrations of candesartan, irbesartan, losartan and EXP3174, and the contractile response to increasing concentrations of angiotensin II was assessed (Figure 2). Candesartan produced a progressive reduction in the response to angiotensin II, with a concentration of 1 nmol/l producing complete inhibition. Irbesartan and EXP3174 produced less marked reductions in the maximal response, while losartan had no effect on the maximal response at concentrations of up to 100 nmol/l. AT 1 -receptor blockers differ markedly in their affinity for the receptor. Experiments in animals have shown that the affinity of candesartan for the AT 1 -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 AT 1 -receptor blockers. 11 13 In other experiments, rat portal vein preparations were incubated with various concentrations of AT 1 -receptor blocker, which was washed out after different times to determine the duration of AT 1 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 the human AT 1 -receptor. 14 In these experiments, cells were preincubated with unlabelled candesartan, irbesartan, EXP3174, or losartan and subsequently incubated with [ 3 H]-candesartan to determine the rate at which the unlabelled AT 1 -receptor blockers dissociated from the receptor and were replaced by [ 3 H]- candesartan. The dissociation rate constant for candesartan was markedly lower than that of other AT 1 - receptor blockers, and the half life for dissociation of candesartan from the receptor was several-fold longer (Table 1). Together, therefore, these studies show that candesartan binds to the AT 1 -receptor with greater affinity than other AT 1 -receptor blockers, and dissociates from the receptor more slowly. These differences in affinity and duration of binding probably reflect the nature of the receptor-antagonist complex formed following binding of the antagonist to the receptor. Further evidence for this comes from the studies in transfected CHO cells, which suggest that with candesartan a higher proportion of this complex exists in a particularly tightly bound form than with losartan, EXP3174, or irbesartan; 15,16 more than 90% of candesartan is present in this form, compared with 70% for EXP3174 and 44% for irbesartan, whereas no tight binding is detectable with losartan. 16 This prolonged binding of candesartan to the AT 1 - receptor is associated with a long duration of biological activity in vivo. In studies in conscious rats, treatment with candesartan inhibited the increase in blood pressure induced by angiotensin II by approximately 80%; this effect was maintained for at least 24 h after dosing, despite the fact that plasma concentrations of candesartan declined rapidly and were undetectable at 24 h. 10 In other studies, increases in plasma renin were measured as a marker of inhibition of the renin-angiotensin system after administration of candesartan and other AT 1 - receptor blockers to healthy, salt-depleted, volunteers. Candesartan, 16 mg, produced greater increases in plasma renin over 24 h than losartan, 50 mg, or valsartan, 80 or 160 mg. 17,18
Pharmacology of AT 1 -receptor blockers 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 dissociation of antagonist from the AT 1 -receptor (T. ), measured in Chinese hamster ovary cells transfected with the human AT 1 - receptor. Dissociation rates were calculated from the slowing of the association rate for [ 3 H]-candesartan following pretreatment of cells with AT 1 -receptor antagonists, washing, and further incubation 8,14 K 1 (min 1 ) T. (min) Candesartan (1.5 nmol/l) 0.0046 ± 0.0017 152 ± 58 EXP3174 (5 nmol/l) 0.022 ± 0.004 31 ± 6 Irbesartan (100 nmol/l) 0.041 ± 0.009 17 ± 4 Losartan (10 mol/l) 0.13 ± 0.03 5.2 ± 1.1 Differences in antihypertensive efficacy between AT 1 -receptor blockers These differences in pharmacological properties between AT 1 -receptor blockers may translate into marked differences in antihypertensive potency and duration of action. The clinical evidence suggests that this is indeed the case. Dose-response relationship Most drugs show dose-dependent efficacy, but in some cases the recommended clinical doses lie near the top of the dose-response range and increasing the dose produces little further effect. For example, in a randomised parallel-group study, patients with essential hypertension were treated for 8 weeks with losartan, at daily doses of between 10 mg and 150 mg. 19 Losartan, 50 mg, was more effective than 10 mg or 25 mg, producing a placebo-corrected reduction in diastolic blood pressure of 4.5 mm Hg. 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 normal recommended dose for this agent lies near the top of the dose-response range. By contrast, studies with other AT 1 -receptor blockers have shown dose-response relationships that extend across the therapeutic range. For example, six randomised, placebo-controlled, parallel-group dose-response studies, involving a total of 1482 patients, have investigated the antihyperten-
S12 Pharmacology of AT 1 -receptor blockers sive efficacy of candesartan cilexetil (the prodrug of candesartan) in patients with essential hypertension. A meta-analysis of these studies 20 showed that the placebo-corrected mean reductions in sitting diastolic blood pressure were approximately 4.5 mm Hg with 4 mg, 6 mm Hg with 8 mg, and 8 mm Hg with 16 mg; the corresponding reductions in systolic blood pressure were approximately 7, 10 and 12 mm Hg, respectively. Similar studies have been performed with other AT 1 -receptor blockers. The pooled data from eight studies with irbesartan, involving a total of 2955 patients, showed placebo-corrected reductions in diastolic blood pressure ranging from approximately 4.2 mm Hg at a dose of 75 mg to 6.2 mm Hg at doses of 300 mg and above. 21 Similarly, a meta-analysis of nine studies with valsartan, involving 4117 patients, showed mean reductions in diastolic blood pressure of between 2.5 mm Hg and 5.1 mm Hg at doses of 40 160 mg. 22 A recent meta-analysis has compared the doseresponse relationships for candesartan, irbesartan, valsartan and losartan. 23 The analysis included all double-blind, placebo-controlled, fixed dose, parallel-group studies, with a duration of 4 weeks or longer, in patients with mild-to-moderate hypertension, that had been submitted to the US Food and Drug Administration (FDA). For each drug, mean placebo-corrected reductions in trough diastolic blood pressure were calculated at each dose and a mathematical model fitted to the data to allow the maximum achievable reduction in trough diastolic blood pressure (E Max ) to be calculated. The results showed that candesartan produced the greatest reductions in diastolic blood pressure (Figure 3), with an E Max of 8.1 mm Hg. Irbesartan was the next most potent agent, with an E Max of 7.1 mm Hg, followed by valsartan (E Max 6.4 mm Hg) and losartan (E Max 5.2 mm Hg). Thus, in this analysis, differences in receptor binding properties were reflected in differences in maximal antihypertensive efficacy. Comparative studies A number of studies have compared the antihypertensive efficacies of different AT 1 -receptor blockers. In one study, for example, 334 patients with essential hypertension (sitting diastolic blood pressure 95 114 mm Hg) were randomised to receive candesartan cilexetil, 8 mg or 16 mg, losartan, 50 mg, or placebo once daily for 8 weeks. 24 Compared with placebo, candesartan cilexetil, 8 mg and 16 mg, reduced trough diastolic blood pressure (measured 24 h after the last dose) by a mean of 8.9 and 10.3 mm Hg, respectively (both P 0.001); the effect of the 8 mg dose was comparable with that of losartan, 50 mg (mean treatment difference 2.3 mm Hg in favour of candesartan, P = 0.115), whereas the 16 mg dose was significantly more effective than losartan (mean treatment difference 3.7 mm Hg, P = 0.013) (Figure 4). Similar results were obtained in the recent CLAIM Study, which involved 654 hypertensive patients (diastolic blood pressure 95 114 mm Hg) recruited from 72 centres in the United States. 25 In this study, patients were randomised to receive candesartan cilexetil, 16 mg, or losartan, 50 mg, and doses were doubled after 2 weeks; these high doses were used to ensure that maximal blood pressure responses were achieved. At 8 weeks after randomisation, trough blood pressures were reduced to a significantly greater extent with candesartan than with losartan (mean reductions 13.3/10.9 mm Hg vs 9.8/8.7 mm Hg, respectively, P 0.001). Candesartan was also significantly more effective than losartan in Figure 3 Dose-response relationships for candesartan, irbesartan, valsartan and losartan, derived from an E Max model fitted to pooled clinical trial data. 23 Reproduced with permission from Hansson L. The relationship between dose and antihypertensive effect for different AT 1 -receptor blockers. Blood Pressure 2001; 10 (Suppl 3): 33 39. Figure 4 Placebo-corrected reductions in diastolic blood pressure (DBP) in 334 hypertensive patients treated for 8 weeks with candesartan cilexetil, 8 mg or 16 mg, losartan, 50 mg, or placebo. 24 *P 0.001 vs placebo; na: not assessed. Reproduced with permission from Andersson OK, Neldam S. The antihypertensive effect and tolerability of candesartan cilexetil, a new generation angiotensin II antagonist, in comparison with losartan. Blood Press 1998; 7: 53 59.
lowering blood pressure at peak (mean reductions 15.2/11.6 mm Hg vs 12.6/10.1 mm Hg, P 0.05). These differences in blood pressure reductions were reflected in significant differences in response rates (defined in this study as the proportion of patients achieving a diastolic blood pressure of below 90 mm Hg or a reduction in diastolic blood pressure of at least 10 mm Hg). Among patients receiving candesartan cilexetil, the response rate was 62.4%, compared with 54.0% in the losartan group (P 0.05). Similarly, the proportion of patients in whom blood pressure was considered to be controlled (diastolic blood pressure less than 90 mm Hg) was significantly higher in the candesartan cilexetil group than in the losartan group (56.0% vs 46.9%, respectively, P 0.05). Comparative studies have consistently shown that candesartan, 8 16 mg, is significantly more effective than losartan, 50 mg, reflecting the greater affinity and duration of receptor binding seen with candesartan. Irbesartan also appears to be a potent AT 1 - receptor blocker, with doses of 150 300 mg being more effective than losartan, 50 100 mg, 26,27 while valsartan, 80 160 mg, appears to be comparable in efficacy to losartan, 50 100 mg. 28 These findings are consistent with those of the E Max analysis described above, 23 reinforcing the view that differences in receptor binding between AT 1 -receptor blockers translate into differences in antihypertensive effect. Duration of antihypertensive efficacy International hypertension management guidelines recommend the use of long-acting formulations that provide 24-h blood pressure control for a number of reasons, including: smooth and persistent, rather than intermittent, blood pressure control; potentially better patient adherence to therapy with once-daily dosing; possible protection against the risk of sudden death, myocardial infarction or stroke associated with abrupt increases in blood pressure on waking. 29 Trough-to-peak ratios are a widely used measure of the duration of antihypertensive efficacy. In this approach, blood pressure is measured approximately 4 h after drug administration, when the effect would be expected to be maximal, and again after 24 h. Current guidelines recommend that longacting formulations should provide a trough-to-peak ratio of at least 50%. 29 In the study comparing candesartan cilexetil and losartan, described above, 24 candesartan, 8 mg and 16 mg, produced mean trough-to-peak ratios of 108% and 89%, respectively, for systolic blood pressure and 110% and 86%, respectively, for diastolic blood pressure. By contrast, losartan, 50 mg, produced trough-to-peak ratios of 71% for systolic blood pressure and 67% for diastolic blood press- Pharmacology of AT 1 -receptor blockers ure. Furthermore, the lower limits of the 95% confidence intervals for these measurements were 65 71% with candesartan, compared with 48 51% with losartan. Thus, in contrast to losartan, candesartan consistently produced trough-to-peak ratios that were higher than the minimum recommended in current management guidelines. This study showed, therefore, that candesartan cilexetil produces smoother blood pressure control over 24 h than losartan, reflecting its longer duration of action. The antihypertensive efficacies of different AT 1 - receptor blockers have also been compared in studies using 24-h ambulatory blood pressure monitoring. In one study, for example, 268 hypertensive patients (mean sitting diastolic blood pressure 95 110 mm Hg and mean ambulatory diastolic blood pressure 85 mm Hg or above) were randomised to receive candesartan cilexetil, 8 mg, losartan, 50 mg, or placebo for 4 weeks, after which doses were doubled and treatment continued for a further 4 weeks. 30 Candesartan reduced both systolic and diastolic blood pressure to a significantly greater extent than losartan over 36 h after dosing (Figure 5); indeed, by 36 h after dosing, blood pressure had returned almost to baseline levels in losartan-treated patients, but remained significantly lower than baseline in patients receiving candesartan. Blood pressure was also measured in the clinic at 24 and 48 h 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 after dosing with candesartan, whereas in losartantreated patients blood pressures were not significantly different from baseline values at this time (Figure 6). Indeed, the effect on blood pressure seen 48 h after dosing with candesartan was comparable with that seen with losartan after 24 h. Similar results were obtained in a second study with ambulatory blood pressure monitoring, in which the antihypertensive effect over 36 h of candesartan cilexetil, 8 mg, was significantly greater than that of losartan, 50 mg. 31 Other studies have shown that irbesartan, 150 mg, and telmisartan, 40 80 mg, appear to have greater effects on ambulatory blood pressure than valsartan, 80 mg, or losartan, 50 mg. 32 36 The available studies thus indicate that the therapeutic effect of candesartan is maintained even if a dose is delayed or missed, and hence candesartan offers extended therapeutic coverage. The potential importance of this extended therapeutic coverage is underlined by studies of adherence with antihypertensive medication. In one such study, approximately 50% of patients showed between 60 and 90% compliance. 37 Thus, even in patients in whom adherence is usually satisfactory, a high proportion may miss occasional doses, resulting in a risk of suboptimal blood pressure control. Tolerability of AT 1 -receptor blockers In contrast to other classes of antihypertensive drugs, where the incidence of adverse events S13
Pharmacology of AT 1 -receptor blockers 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 Lacourcière 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. 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 Lacourcière 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 AT 1 -receptor blockers show placebo-like tolerability at all doses evaluated in clinical trials. There is currently no evidence of significant differences in tolerability profiles between members of the class. 6 Conclusions There is increasing evidence that differences in receptor binding kinetics between AT 1 -receptor blockers are reflected in marked differences in antihypertensive efficacy. Agents such as candesartan, that bind tightly to the AT 1 -receptor and act as insurmountable antagonists, produce a greater maximum reduction in blood pressure, higher response rates, and a longer duration of action, compared to agents that bind less tightly to the receptor. These pharmacological differences do not, however, appear to affect the placebo-like tolerability associated with AT 1 -receptor blockers. References 1 Timmermans PB et al. Angiotensin II receptors and functional correlates. Am J Hypertens 1992; 5 (12 Pt 2): 221S 235S.
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S16 Pharmacology of AT 1 -receptor blockers 36 Littlejohn T et al. A prospective, randomized, openlabel trial comparing telmisartan 80 mg with valsartan 80 mg in patients with mild to moderate hypertension using ambulatory blood pressure monitoring. Can J Cardiol 2000; 16: 1123 1132. 37 Rudd P et al. Issues in patient compliance: the search for therapeutic sufficiency. Cardiology 1992; 80 (Suppl 1): 2 10.