SPECIAL ARTICLE
Angiotensin
11
(ATI blockers,
receptor antagonists ARBs, sartans): similarities
and differences PA. van Zwieten
A survey is presented of the registered nonpeptidergic angiotensin II receptor antagonists (AT1 blockers, ARBs, sartans) and their general properties and similarities. Accordingly, their receptor profile, pharmacokinetic and therapeutic applications are discussed. In addition, attention is paid to the individual characteristics of the AT1 blockers now available. A few components of this category offer additional potentially beneficial properties, owing to their pharmacological or metabolic characteristics. Such additional properties are critically discussed for eprosartan, losartan, tehnisartan and valsartan. (Net/ Heart J 2006: 14:381-7.)
Keywords: renin-angiotensin system, angiotensin II receptor antagonists, AT1 receptors, insulin sensitisation
on-peptidergic angiotensin II receptor antagonists I (AT1 blockers, ARBs, sartans) were introduced in the treatment of cardiovascular diseases more than a decade ago. They have acquired and maintained an important position in the treatment of hypertensive disease, including diabetic nephropathy. More recently, some of these agents, in particular candesartan and valsartan, were introduced for the management of congestive heart failure, as an alternative to ACE inhibitors. The AT1 blockers can also be considered for add-on therapy in heart failure, and possibly for the management of renal dysfunction and/or microalbuminuria.
PA. van Zwleten Departments of Pharmacotherapy, Cardiology and Cardiothoracic Surgery, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
Correspondence to: P.A. van Zwieten Departments of Pharmacotherapy, Cardiology and Cardiothoracic Surgery, Academic Medical Centre, University of Amsterdam, P0 Box 22660 1100 DD Amsterdam, the Netherlands
Netherlands Heart Journal, Volume 14, Number 11, November 2006
Losartan, developed by Timmermans et al. in the USA, was the first ofthe clinically useful AT1 blockers. Since then, several related compounds have been introduced and registered in the Netherlands. Seven AT1 blockers are now available. For several ofthese agents substantial clinical experience has been acquired. Although rather similar and comparable in many respects some potentially interesting differences and peculiarities of certain AT1 blockers are beginning to emerge. It therefore seems of interest to briefly discuss these differential properties in a comparative manner, after a synopsis of the most relevant backgrounds of the AT1 blockers in more general terms. General aspects It has long been recognised that the suppression of the renin-angiotensin system (RAS) would be desirable from a therapeutic point ofview in conditions such as hypertension and congestive heart failure. Angiotensin II, the major effector peptide of the RAS, has several detrimental actions, such as vasoconstriction and a rise in blood pressure, enhanced release of aldosterone from the adrenal cortex, retention of sodium and water via the kidney, synergistic activity with respect to the catecholamines (noradrenaline, adrenaline) released by sympathetic neurons, and the stimulation of cell proliferation, and left ventricular and vascular hypertrophy.'3 Several possibilities aiming at the suppression of these deleterious activities have been explored (figure 1), such as ACE inhibitors, renin inhibitors4 and angiotensin II receptor antagonists. Since the 1970s several peptidergic angiotensin II receptor antagonists have been synthesised and some ofthem have been made available for research purposes, such as saralasin, sarile and sarmesin. Saralasin was shown to antagonise the pressor effects of angiotensin II in rats and to lower blood pressure in renin-dependent hypertensive patients and animals.5 However, the therapeutic potential of these peptide antagonists is greatly hampered by their low bioavailability, short duration of action and partial agonistic activity. A major improvement has been obtained by the development of non-peptidergic angiotensin II re381
Angiotensin 11 receptor antagonists (AT1 blockers, ARBs, sartans): similarities and differences
Angiotensinogen (circulating and loce Tissue renin and circulating renin
Renal renin
Candosartan
Angiotensin I Tissue ACE& other proteases e.g. Chymase
Lung ACE
Angiotensin 11 Protease
Irbesartan Protease
CCH, Ct 3
Inactive fragments
Inactive fragments eg
N
Nc-N
H~~~~
Valsartan
c H
N
CH3
Losartan COOOH
Angiotensin receptors
HOOCI1
Eprosartan
Figure 1. The renin-angiomensin system (RAS). ACE inhibitors, renin inhibitors and angiotensin II receptor antagonists (AT, blockers, ARBs, sartans) are the drugs that can counteract the activity of the RAS. Their targets in the system are shown.
Figure 2. Chemicalstructures ofvariousAT1-receptorantagonists. Losartan, candesartan and olmesartan are prodrugs, which are converted after oral ingestion into their active metabolites.
ceptor antagonists, of which losartan has become the prototype. Losartan was developed by Timmermans and his co-workers6-8 on the basis of the inhibitory effects of some ofthe imidazole analogues (S8307 and S8308) against angiotensin II induced vasoconstriction.9 The introduction oflosartan as a non-peptidergic AT,-receptor antagonist was followed up by an impressive series ofcompounds with comparable pharmacological and chemical properties.'0 The following AT, blockers have been developed clinically and registered as antihypertensive drugs in various countries: losartan, irbesartan, valsartan, candesartan, telmisartan, eprosartan, and olmesartan.
irbesartan, olmesartan and eprosartan contain an imidazole substituent. In candesartan and telmisartan this imidazole moiety is condensated with a phenyl ring. A tetrazolium component was initially thought to be essential, but it is only found in losartan, candesartan, oLnesartan and irbesartan, not in the other agents. Losartan, a prodrug, is converted in vivo (after oral ingestion) into its more active metabolite EXP3174. Candesartan cilexetil is also a prodrug. In vivo it is converted into its more active metabolite CVI 1974, the active drug candesartan. Olmesartan medoxomil is a prodrug too.
The common properties of the registered angiotensin-receptor antagonists are summarised in general terms below. Some of these aspects merit more detailed discussion, which they will receive later in this article.
Receptor profile All ofthe registered angiotensin II receptor antagonists (losartan, irbesartan, candesartan, eprosartan, olmesartan, telmisartan, valsartan) are highly selective for the AT, receptor. This selectivity has been established by means of radioligand experiments. The highly selective affinity for the AT, receptor is reflected by IC50 values in the range of 1 to 2 nmol/l; the affinity for AT, receptor is usually 10,000 to 20,000 times higher than that for the AT2 receptor.
Chemical structures As shown in figure 2 the majority of the registered angiotensin II receptor antagonists possess a biphenyl component, with the exception of eprosartan. Losartan, 382
Netherlands Heart Journal, Volume 14, Number 11, November 2006
cQpc
Angiotensin 11 receptor antagonists (AT1 blockers, ARBs, sartans): similarties and differences
The AT1 selectivity for the AT1 implies that during treatment with these drugs the AT2 receptor is exposed to high concentrations of angiotensin II. The functional role of the AT2 receptor still remains unknown, although it is believed to counteract cell proliferation when stimulated with angiotensin 11.11 Accordingly, it may be possible that the stimulated AT2 receptor can inhibit and perhaps even reverse the growth-promoting effects of angiotensin II indirectly, via the blockade of the AT1 receptor. Furthermore, AT2-receptor stimulation has been shown to cause vasodilatation in experimental models, thus counteracting the vasoconstriction caused by AT1-receptor stimulation."1-'3 A few years ago the detailed mechanism of the interaction between the various AT1 blockers and the AT1 receptor was subject to intense debate. In this connection, a differentiation between surmountable versus insurmountable antagonism was discussed for the various available AT1 blockers. The terms surmountable/insurmountable antagonism largely correspond (although not in all details) to the classical pharmacological terms competitive/non-competitive antagonism, respectively. Accordingly, ifanAT,-receptor antagonist bound to the AT1 receptor can be displaced by adding the agonist (Ang II) it can be considered as surmountable. If high concentrations of angiotensin II cannot displace the AT, antagonist from the AT, receptor it is considered to be an insurmountable antagonist. Insurmountable antagonism indicates strong binding of an antagonist to its receptor. This issue requires some critical consideration. First of all it should be realised that the finding of surmountable versus insurmountable antagonism depends greatly upon the pharmacological model used. For instance, losartan is a surmountable antagonist in certain models (e.g. isolated rat aorta), but it behaves like an insur-
mountable antagonist in other models, such as the rabbit isolated renal artery'4"15 or the vascular bed of the human forearm.'6 Similarly, irbesartan may either behave as a surmountable or as an insurmountable antagonist.'7 Candesartan has been put forward as a typically insurmountable AT,-receptor antagonist.'8 In conclusion, the issue of 'surmountable versus insurmountable' antagonism is oftheoretical interest but so far it is by no means relevant for the clinical application ofAT,-receptor antagonists. This issue has been overemphasised for marketing purposes. Haemodynamic profile All ofthe compounds are vasodilators, in particular of the resistance vessels, and hence reduce peripheral vascular resistance. Venous dilatation can be demonstrated to occur, but it is much weaker than the dilator effects upon the arterial system. The haemodynamic profile of the AT, antagonists is very similar to that of the ACE inhibitors. Heart rate remains unchanged (no reflex tachycardia). Kinetic profile and biological inactivation In clinical terms the kinetic properties of the various compounds are rather similar. After oral ingestion all of the various AT, blockers are readily absorbed and display their haemodynamic actions after a few hours. Virtually all available AT, blockers have a long duration of action, thus allowing satisfactory control ofblood pressure over 24 hours after a single oral dose. Most agents are lipophilic and display a very high degree of plasma protein binding. Elimination/inactivation of the various AT, blockers occurs either by hepatic biodegradation and/or renal elimination. The major pathways of elimination/inactivation ofthe various AT, blockers are summarised in table 1.
Table 1 Pharmacokinetic characteristics of various AT1-receptor antagonists
Compound*
Prodrug
Losartan (Cozaar)
Yes
Candesartan (cilexetil) (Atacand) Eprosartan (Teveten) Irbesartan (Aprovel) Olmesartan (medoxomil) (Olmetec) Telmisartan (Micardis), (Kinzal) Valsartan (Diovan)
Yes No No Yes No No
*
Inactivation
Liver > kidney active metabolite, first pass effect Kidney + liver Liver > kidney Liver > kidney Liver > kidney Liver >> kidney Liver > kidney
adaptation In dysfunction
Dosage
Renal
Hepatic
No
Yes
Yes No No Yes No No
Yes No No No Yes Yes
Duration of action (blood pressure 4)
70-80% of the maximal effect after 24 h .24 h .24 h >24 h .24 h >24 h .24 h
Commercial names as in the Netherlands.
qC
Netherlands Heart Journal, Volume 14, Number 11, November 2006
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Angiotensin 11 receptor antagonists (AT1 blockers, ARBs, sartans): similarities and differences
Side effects So far all registered compounds display a very favourable side effect profile that does not significantly differ from that ofplacebo treatment. In contrast to the ACE inhibitors, cough is not a common adverse reaction to AT,-receptor antagonists. Angioneurotic oedema has been described for losartan in highly exceptional cases. Contraindications Hypersensitivity, although rare, is a contraindication. Hypotension caused by the angiotensin II receptor antagonists is a drawback in the use of these compounds in patients with hypovolaemia (use of diuretics, vomiting, diarrhoea) or with severe symptomatic heart failure. Caution is advised in patients with aortic stenosis, renal artery stenosis or primary hyperaldosteronism. Since data are not yet available on use in pregnancy or lactation, angiotensin II receptor antagonists should then be avoided.
Drug interactions Used together with diuretics, symptomatic hypotension may be problematic. When combined with potassium-sparing diuretics, clinically significant retention of potassium may occur.
Efficacy in the treatment of hypertension The efficacy of the various registered compounds as antihypertensives is very similar, although a few reports would seem to indicate that some of the newer agents are somewhat more effective than losartan.'0 This may be a matter of dosage. It is generally felt that the once daily dose of 50 mg per tablet oflosartan is rather low for the adequate treatment ofhypertension. In relevant clinical trials the required daily dose of losartan was in the range of 80 mg. Efficacy in the treatment of congestive heart failure On theoretical grounds one would expect a beneficial effect ofAT1 blockers in congestive heart failure, similar to that of the ACE inhibitors. However, it should be realised that the ACE inhibitors, developed many years before the AT1 blockers, have been studied much more
thoroughly. Clinical data, including those from randomised studies, are now beginning to emerge and strongly suggest that the AT1 blockers are beneficial and potentially useful in the management of congestive heart failure. Candesartan and valsartan have been registered for the treatment ofheart failure in various countnes. Characteristics of Individual AT1-receptor antagonists The various AT,-receptor antagonists have now matured as therapeutically useful agents. The question therefore arises to which degree the various agents now available can be compared and differentiated. 384
Globally speaking the various AT1 blockers are rather similar with respect to their chemical structures, receptor profile, and haemodynamic and pharmacokinetic properties. A few differences, however, are beginning to emerge and some of these may be clinically relevant. It is not surprising that pharmaceutical companies manufacturing an AT1 blocker preparation attempt to emphasise the peculiarity of their agent in order to differentiate it from the other registered compounds. In the present survey, we will critically discuss the claims made for the individual AT1 blockers and their possible clinical relevance. Losartan This was the first AT,-receptor antagonist developed clinically and then applied on a large scale in antihypertensive treatment. Its safety and efficacy appear to be beyond doubt. A selective AT,-receptor antagonist, losartan is, as mentioned earlier, a prodrug which after oral administration is converted into its metabolite EXP3174. This is a more potent AT1 antagonist than losartan and, in reality, underlies most ofthe antihypertensive activity of the 'parent' compound.2 Like all other angiotensin II receptor antagonists that have been clinically introduced so far, losartan is well tolerated and accepted by patients. Angioneurotic oedema and pancreatitis have been reported in a few exceptional cases. The antihypertensive efficacy of losartan is well established and documented by various studies, including large-scale randomised trials. In the LIFE study, carried out in hypertensives with an additional risk factor, losartan showed the same antihypertensive activity as atenolol, but it was significantly more protective against the sequelae of hypertension, in particular stroke.22 Patients treated with losartan developed significantly less diabetes (type 2) than those receiving atenolol. The renoprotective activity of losartan has been demonstrated in hypertensive patients with diabetic nephropathy (RENAAL study).23 Losartan may also be beneficial in the treatment of congestive heart failure (CHF). In the ELITE-I study24 it was shown to reduce mortality in CHF patients significantly more than the ACE inhibitor captopril. This issue was pursued in the ELI lE-II study, where captopril and losartan did not differ. In addition, losartan appears to display significant uricosuric activity in the dosage used for antihypertensive treatment. This effect is limited to losartan, it is not a class effect ofthe AT1-receptor blockers.'9 This may be a potentially beneficial effect when losartan is combined with a thiazide diuretic which will increase plasma uric acid levels.
Candesartan cilexetil This is a prodrug and, after oral ingestion, it is converted into candesartan, the active compound. Candesartan Netherlands Heart Journal, Volume 14, Number 11, November 2006
Angiotensin 11 receptor antagonists (AT1 blockers, ARBs, sartans): similarities and differences
had been put forward as the prototype of an insurmountable AT,-selective receptor antagonist, but as such it is not unique. Its long duration of action (>24 hours) may be partly explained by strong and persistent binding to the AT1 receptor, but pharmacokinetic characteristics also contribute to its long-lasting antihypertensive effect. Candesartan is tolerated as well as the other AT,-receptor antagonists. In the SCOPE study25 the antihypertensive activity ofcandesartan was documented in elderly patients and compared with classical drugs (diuretics or 5-blockers). The protective effect ofcandesartan against stroke and other endpoints was significant. In the recently published CHARM studies, the beneficial effect of candesartan in congestive heart failure has been clearly demonstrated.26 Accordingly, candesartan has recently been registered in a few countries for the treatment of congestive heart failure. For reviews see Andersson et al. and Sever et al.27,28 Eprosartan This is a selective AT,-receptor antagonist. Its haemodynamic profile, antihypertensive efficacy and tolerability are comparable with those of the other AT1receptor antagonists. Excretion of eprosartan, in the unchanged form, predominantly occurs via the bile and faeces (approximately 90%), and much less so via the kidney (approximately 10%). Since eprosartan is not metabolised by the cytochrome P450 system, it has a low potential for drug interactions. In pithed rats29 eposartan inhibits the stimulated release of noradrenaline from presynaptic sites, probablyvia the blockade ofpresynaptic angiotensin receptors (AT1 type) at the sympathetic nerve endings. These experiments with eposartan have validated this agent as an experimental tool in the research on presynaptic AT1 receptors. Presynaptic AT,-receptor blockade can be demonstrated for a few other ARBs, but there are (at least in experimental models) major quantitative differences and exprosartan appears to be one of the most active compounds. The clinical relevance ofthe inhibition of sympathetic outflow by eprosartan is still unclear, although it may be potentially beneficial, in particular in congestive heart failure patients, where the sympathetic nervous system is usually activated. For a review on eprosartan see McCellan et al.30
Irbesartan This is an AT,-selective agent with a long duration of action (at least 24 hours after one oral dose). The side effect profile does not differ from that ofplacebo. The occurrence of side effects does not appear to be clearly dose dependent. Its antihypertensive efficacy is well established. Irbesartan has been shown to display protective activity in hypertensive patients with microalbuminuria3l and with diabetic nephropathy.32 For reviews on irbesartan see Gillis et al. and Man in 't Veld.33' 34
Netierlands Heart Journal, Volume 14, Number 11, November 2006
Olmesartan Recently introduced for the treatment of essential hypertension, olmesartan medoxomil is a prodrug which is converted after oral ingestion by various esterases into the active metabolite olmesartan. The efficacy and safety of olmesartan appear to be similar to those of otherAT, blockers. Large-scale intervention studies such as OLMEBEST are ongoing. The bioavailability ofolmesartan is increased in the elderly and in patients with impaired renal and/or hepatic functions. For reviews see Brunner et al. and Unger et al.35,36 Telmisartan This is a lipophilic, selective, unsurmountable ATrreceptor antagonist with a very long duration of action. Its haemodynamic profile, antihypertensive activity and tolerability are comparable to those of the other AT1 blockers. Telmisartan is inactivated almost entirely via hepatic degradation. Hepatic dysfunction requires dose adaptation. In the recently published DETAIL study the renoprotective properties of telmisartan and the ACE inhibitor enalapril were found to be equivalent in patients with type 2 diabetes.37 Telmisartan appears to display interesting metabolic properties. Telmisartan, probably also in doses and concentrations as used in the treatment of hypertension, acts as an insulin sensitiser, owing to the activation of peroxisomeproliferator activated receptor subtype y (PPAR-y).38'39 Accordingly, telmisartanr's metabolic actions resemble those of the glitazones, such as pioglitazone or rosiglitazone. Telmisartan has been evaluated in large intervention studies, such as ONTARGET and TRANSCEND. For a review see Chrysant et al.40
Valsartan This is a highly selective AT1-receptor antagonist that displays competitive antagonism at the level of the AT1 receptor in isolated tissues. It is conceivable that the high AT,-receptor selectivity is associated with a stronger activation of the AT2 receptor. As discussed previously AT2-receptor stimulation is assumed to be a favourable activity, since it brings aboutvasodilatation and decreased cellular proliferation. In the recently published VALUE study valsartan, used for the treatment ofhypertensive patients, was associated with a significantly lower incidence of cases ofnew diabetes when compared with amlodipine.4' Valsartan displays beneficial activity in patients with congestive heart failure. Its registration for the treatment ofheart failure has occurred in several countnes. In the VALIANT study42 it was shown that valsartan is a suitable alternative for an ACE inhibitor in patients after an acute myocardial infarction with signs or evidence for heart failure. Combination therapy (ACE inhibitor + valsartan) did not add benefit to monotherapy. Renoprotective activity ofvalsartan was recently demonstrated by the MARVAL study.43 For a review on valsartan see Markham et al.44 385
Angiotensin 11 receptor antagonists (AT1 blockers, ARBs, sartans): similarities and differences
Conclusions and perspectives The development of olly active, non-peptidergic ATrreceptor antagonists is a good example of rational medicinal chemistry and subsequent phannacological investigation, and the angiotensin-receptor antagonists have enriched our therapeutic armamentarium for antihypertensive treatment. They are characterised by a satisfactory antihypertensive activity, acceptable pharmacokinetic profiles and so far, excellent tolerability. In particular, the absence of cough is a clinical advantage. Long-term randomised clinical trials are ongoing, and a few such studies (LIFE, VALUE, SCOPE) have demonstrated the antihypertensive effect of the AT1 blockers, as well as their protective actions on the well-known complications ofhypertensive disease. The AT,-receptor antagonists are of potential interest in the protection against diabetic nephropathy and in the treatment of congestive heart failure, as demonstrated in a limited number of clinical trials. Much more clinical experience will be required to judge the validity of these therapeutic approaches. So far the AT,-receptor antagonists that have been developed clinically are similar in many respects. Most ofthem are chemically related (biphenylderivatives) and selective for the AT, receptor.
References 1
2 3 4
5 6 7
8
9
10 11 12
13
In most cases the pharmacokinetic profile of the AT,receptor antagonists is satisfactory or even very good, enabling control of blood pressure over 24 hours by means of a single dose. The kinetic differences between the various agents are not impressive and hardly influence the pattern of treatment or the choice of a particular drug. A few newer data, both experimental and clinical, appear to indicate that certain AT1 blockers may offer metabolic and other effects which are potentially beneficial in addition to their haemodynamic actions. Examples ofsuch effects are for instance: * Losartan: uricosuric activity; * Eprosartan: inhibition ofnoradrenaline release from the sympathetic nerve endings (mediated by presynaptic AT1 receptors); * Telmisartan: insulin-sensitising activity (mediated by stimulation ofthe PPAR-y receptor); * Valsartan: very high selectivity for the AT1 receptor - stronger stimulation of the AT2 receptor by angiotensin II.
Many more new AT,-receptor antagonists may be expected to be introduced in the forthcoming years, but it seems unlikely that new agents will offer substantial advantages over those that are available at present.45 It can be speculated that the AT2 receptor may offer a novel target for drug design, but the approach would be directed towards modulation of cell proliferation or metabolic effects rather than towards the lowering of blood pressure per se. *
386
14
15 16
17
18
19 20 21 22
23
24
Goodfriend TL, Elliot ME, Catt KJ. Angiotensin receptors and their antagonists. NEnglJMed 1996;334:1649-54. Johnston CI. Renin-angiotensin system: a dual tissue and hormonal system for cardiovascular control. JHypertens 1992;1O:S13-26. Peach MJ, Dostal DE. The angiotensin II receptor and the actions of angiotensin II. J Cardiovasc Pharmacol 1990;16:S25-30. Gradman AH, Schmeider PR, Lins RL, Nussberger J, Chiang Y, Bedigian MP. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 2005;111:1012-8. Streeten DHP. Outpatient experience with saralasin. Kidney Int 1979;159(Suppl 9):44-52. Timmermans PBMWM, Wong PC, Chin AT, et al. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 1993;45:205-51. Johnston CI, Naitoh M, Burrell LM. Rationale and pharmacology of angiotensin II receptor antagonists: current status and future issues. JHypertens 1997;15(Suppl 8):3-6. Unger T, Culman J, Gohike P. Angiotensin II receptor blockade and end-organ protection: pharmacological rationale and evidence. JHypertens 1998;16(Suppl 17):3-9. Wong PC, Chui AT, Price WA, et al. Non-peptide angiotensin II receptor antagonists. I. Pharmacological characterization of 2-nbutyl-4-chloro-1-2(2-chlorobenzyl)imidazole-5-acetic acid sodium salt (S8307). JPharmacol Exp Ther 1988;247:1-10. Baan J. Functional role of angiotensin II andAT1-receptor antagonists in human arteries and veins. PhD Thesis (ISBN 909011397-5), University ofAmsterdam;1998:18. Johnston CI, Risvanis J. Preclinical pharmacology of angiotensin II receptor antagonists. AmJHypertens 1997;10:S306-10. Unger T, Chung O, Csikos T, et al. Angiotensin receptors. JHypertens 1996;14(Suppl):95-103. Kivlighn S, Zingaro GJ, Gabel RA, et al. In vivo pharmacology of an angiotensin AT,-receptor antagonist with balanced affinity for angiotensin AT2-receptors. EurJPharmacol 1995;294:439-50. Zhang J. Pharmacological effects of angiotensin II and nonpeptidergic receptor antagonists. PhD Thesis (ISBN 90-90083774), University ofAmsterdam 1995:145. Zhang J, Pfaffendorf M, Zhang JS, van Zwieten PA. A non-competitive type of angiotensin II receptor antagonism by losartan in renal artery preparations. EurJPharmacol 1994;252:337-40. Baan J, Chang PC, Vermeij P, Pfaffendorf M, van Zwieten PA. Effects of losartan on vasoconstrictor responses to angiotensin II in the human forearm vascular bed of healthy volunteers. Cardiovasc Res 1996;32:973-9. Cazaubon C, Gougat J, Bousquet F, et al. Pharmacological characterization of SR 47436, a new non-peptide AT,-subtype angiotensin II receptor antagonist. JPharmacol Exp Ther 1993; 265:826-34. Shibouta Y, Inada Y, Ogima, et al. Pharmacological profile of a highly potent and long-acting angiotensin II receptor antagonist,
2-ethoxy-1-[2-(IH tetrazol-5-yl)biphenyl-4-yl]-methyl]-lH benzimidazole-7 -carboxylic acid (CV 11974), and its prodrug, (±)-1-(cyclohexyloxycarbonyloxy]-ethyl-2-ethoxy-1 -[[2-(1Htetrazol-5-yl)biphenyl-4-yl]-methyl]-1H benzimidazole-7 carboxylate (TCY-116). JPharmacolExp Ther 1993;266:114-20. Burnier M. Angiotensin II type 1 receptor blockers. Circulation 2001;103:904-912. Dzielak DJ. Comparative pharmacology of the angiotensin II receptor antagonists. Exp Opin Invest Drugs 1998;7:741-51 Acker CG, Greenberg A. Angioedema induced by the angiotensin II blocker losartan. NEnglJMed 1995;333:1572. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet2002;359:995-1003. Brenner BM, Cooper ME, de Zeeuw D, et al. RENAAL-study investigations. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl JMed 2001;345:861-9. Pitt B, Segal R, Matinez FA, et al. On behalf ofthe ELITE Study Investigators. Randomized trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan In The Elderly Study, ELITE). Lancet 1997;349:747-52.
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Angiotensin 11 receptor antagonists (AT1 blockers, ARBs, sartans): similarities and differences
25 Lithell H, Hansson L, Skoog I, et al. The study on cognition and prognosis in the elderly (SCOPE): principal results of a randomized double blind intervention trial. JHypertens2003;21:875-86. 26 White HD. Candesartan and heart failure: the allure of CHARM. Lancet 2003;362:754-5. 27 Andersson OK, Neldman S. The antihypertensive effect and tolerability of candesartan cilexetil, a new generation angiotensin II antagonist, in comparison with losartan. Blood Pressure 1998;7: 53-9. 28 Sever P, Menard J. Angiotensin II antagonism refined: candesartan cilexetil. A novel long-acting AT, -receptor blocker. JHum Hypertens 1997;11(Suppl 2):1-95. 29 Nap A, Balt JC, Mathy MJ, van Zwieten PA. AT,-receptor blockade and sympathetic neurotransmission in cardiovascular disease. Auton Autacoid Pharmacol 2004;23:285-96. 30 McCellan KJ, Balfour JA. Eprosartan. Drugs 1998;55:713-8. 31 Parring HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. NEnglJMed 2001;345:870-8. 32 Lewis EJ, Huusicker LG, Clarke WR, et al. Renoprotective effects of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. NEnglJMed 2001;345:85160. 33 Gillis JC, Markham A. Irbesartan. A review ofits pharmacodynamic and pharmacokinetic properties and therapeutic use in the management of hypertension. Drugs 1997;54:885-902. 34 Man in 't Veld AJ. Clinical overview ofirbesartan: expanding the therapeutic window in hypertension. J Hypertension 1997;15 (Suppl 7):27-33. 35 Brunner HR, Laers P. Clinical efficacy of olmesartan medoxomil. JHypertens2003;21(Suppl 2):543-6. 36 Unger T, McInnes GT, Neutel JM, Bohm M. The role of olmesartan medoxomil in the management of hypertension. Drugs 2004;64:2731-9.
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37 Barnett AH, Bain SC, Bouter P, et al. Angiotensin receptor blockade versus converting enzyme inhibition in type 2 diabetes and nephropathy. NEnglJMed 2004;351:1952-61. 38 Benson SC, Perchadsingh HA, Ho CI, et al. Identification of telmisartan as an unique angiotensin II receptor antagonist with selective PPAR-ymodulating activity. Hypertension 2004;43:9931002. 39 Schupp M, Janke J, Clasen R, Unger T, Kintschen U. Angiotensin type I receptor include peroxizome proliferator activated receptoryactivity. Circulation 2004;109:2054-7. 40 Chrysant SG, Chrysant GS, Desai A. Current status of angiotensin receptor blockers for the treatment ofcardiovascular diseases: focus on telmisartan. JHum Hypertens2005;19:173-83. 41 Julius S, Kjeldsen SE, Weber M, et al. VALUE Trial Group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimes based on valsartan or amlodipine: the VALUE randomised trial. Lancet2004;363:2022-31. 42 Pfeffer MA, Mc Murray JJ, Velasquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. NEnglJMed 2003;349:1893906. 43 Viberti GC, Wheeldon MN. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressureindependent effect. Circulation 2002;106:672-8. 44 Markham A, Goa KL. Valsartan. Areview of its pharmacology and therapeutic use in essential hypertension. Drugs 1997;54:299-331. 45 Weber AM. Angiotensin II receptor blockers and cardiovascular outcomes: what does the future hold? JReninAngAld Syst2003; 4:62-73. 46 Ruilope LM, Agabite Rosei E, Bakris GL, et al. Angiotensin receptor blockers: therapeutic targets and cardiovascular protection. Blood Pressure 2005;14:196-209.
387
Angiotensin
11
(ATI blockers,
receptor antagonists ARBs, sartans): similarities
and differences PA. van Zwieten
A survey is presented of the registered nonpeptidergic angiotensin II receptor antagonists (AT1 blockers, ARBs, sartans) and their general properties and similarities. Accordingly, their receptor profile, pharmacokinetic and therapeutic applications are discussed. In addition, attention is paid to the individual characteristics of the AT1 blockers now available. A few components of this category offer additional potentially beneficial properties, owing to their pharmacological or metabolic characteristics. Such additional properties are critically discussed for eprosartan, losartan, tehnisartan and valsartan. (Net/ Heart J 2006: 14:381-7.)
Keywords: renin-angiotensin system, angiotensin II receptor antagonists, AT1 receptors, insulin sensitisation
on-peptidergic angiotensin II receptor antagonists I (AT1 blockers, ARBs, sartans) were introduced in the treatment of cardiovascular diseases more than a decade ago. They have acquired and maintained an important position in the treatment of hypertensive disease, including diabetic nephropathy. More recently, some of these agents, in particular candesartan and valsartan, were introduced for the management of congestive heart failure, as an alternative to ACE inhibitors. The AT1 blockers can also be considered for add-on therapy in heart failure, and possibly for the management of renal dysfunction and/or microalbuminuria.
PA. van Zwleten Departments of Pharmacotherapy, Cardiology and Cardiothoracic Surgery, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
Correspondence to: P.A. van Zwieten Departments of Pharmacotherapy, Cardiology and Cardiothoracic Surgery, Academic Medical Centre, University of Amsterdam, P0 Box 22660 1100 DD Amsterdam, the Netherlands
Netherlands Heart Journal, Volume 14, Number 11, November 2006
Losartan, developed by Timmermans et al. in the USA, was the first ofthe clinically useful AT1 blockers. Since then, several related compounds have been introduced and registered in the Netherlands. Seven AT1 blockers are now available. For several ofthese agents substantial clinical experience has been acquired. Although rather similar and comparable in many respects some potentially interesting differences and peculiarities of certain AT1 blockers are beginning to emerge. It therefore seems of interest to briefly discuss these differential properties in a comparative manner, after a synopsis of the most relevant backgrounds of the AT1 blockers in more general terms. General aspects It has long been recognised that the suppression of the renin-angiotensin system (RAS) would be desirable from a therapeutic point ofview in conditions such as hypertension and congestive heart failure. Angiotensin II, the major effector peptide of the RAS, has several detrimental actions, such as vasoconstriction and a rise in blood pressure, enhanced release of aldosterone from the adrenal cortex, retention of sodium and water via the kidney, synergistic activity with respect to the catecholamines (noradrenaline, adrenaline) released by sympathetic neurons, and the stimulation of cell proliferation, and left ventricular and vascular hypertrophy.'3 Several possibilities aiming at the suppression of these deleterious activities have been explored (figure 1), such as ACE inhibitors, renin inhibitors4 and angiotensin II receptor antagonists. Since the 1970s several peptidergic angiotensin II receptor antagonists have been synthesised and some ofthem have been made available for research purposes, such as saralasin, sarile and sarmesin. Saralasin was shown to antagonise the pressor effects of angiotensin II in rats and to lower blood pressure in renin-dependent hypertensive patients and animals.5 However, the therapeutic potential of these peptide antagonists is greatly hampered by their low bioavailability, short duration of action and partial agonistic activity. A major improvement has been obtained by the development of non-peptidergic angiotensin II re381
Angiotensin 11 receptor antagonists (AT1 blockers, ARBs, sartans): similarities and differences
Angiotensinogen (circulating and loce Tissue renin and circulating renin
Renal renin
Candosartan
Angiotensin I Tissue ACE& other proteases e.g. Chymase
Lung ACE
Angiotensin 11 Protease
Irbesartan Protease
CCH, Ct 3
Inactive fragments
Inactive fragments eg
N
Nc-N
H~~~~
Valsartan
c H
N
CH3
Losartan COOOH
Angiotensin receptors
HOOCI1
Eprosartan
Figure 1. The renin-angiomensin system (RAS). ACE inhibitors, renin inhibitors and angiotensin II receptor antagonists (AT, blockers, ARBs, sartans) are the drugs that can counteract the activity of the RAS. Their targets in the system are shown.
Figure 2. Chemicalstructures ofvariousAT1-receptorantagonists. Losartan, candesartan and olmesartan are prodrugs, which are converted after oral ingestion into their active metabolites.
ceptor antagonists, of which losartan has become the prototype. Losartan was developed by Timmermans and his co-workers6-8 on the basis of the inhibitory effects of some ofthe imidazole analogues (S8307 and S8308) against angiotensin II induced vasoconstriction.9 The introduction oflosartan as a non-peptidergic AT,-receptor antagonist was followed up by an impressive series ofcompounds with comparable pharmacological and chemical properties.'0 The following AT, blockers have been developed clinically and registered as antihypertensive drugs in various countries: losartan, irbesartan, valsartan, candesartan, telmisartan, eprosartan, and olmesartan.
irbesartan, olmesartan and eprosartan contain an imidazole substituent. In candesartan and telmisartan this imidazole moiety is condensated with a phenyl ring. A tetrazolium component was initially thought to be essential, but it is only found in losartan, candesartan, oLnesartan and irbesartan, not in the other agents. Losartan, a prodrug, is converted in vivo (after oral ingestion) into its more active metabolite EXP3174. Candesartan cilexetil is also a prodrug. In vivo it is converted into its more active metabolite CVI 1974, the active drug candesartan. Olmesartan medoxomil is a prodrug too.
The common properties of the registered angiotensin-receptor antagonists are summarised in general terms below. Some of these aspects merit more detailed discussion, which they will receive later in this article.
Receptor profile All ofthe registered angiotensin II receptor antagonists (losartan, irbesartan, candesartan, eprosartan, olmesartan, telmisartan, valsartan) are highly selective for the AT, receptor. This selectivity has been established by means of radioligand experiments. The highly selective affinity for the AT, receptor is reflected by IC50 values in the range of 1 to 2 nmol/l; the affinity for AT, receptor is usually 10,000 to 20,000 times higher than that for the AT2 receptor.
Chemical structures As shown in figure 2 the majority of the registered angiotensin II receptor antagonists possess a biphenyl component, with the exception of eprosartan. Losartan, 382
Netherlands Heart Journal, Volume 14, Number 11, November 2006
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Angiotensin 11 receptor antagonists (AT1 blockers, ARBs, sartans): similarties and differences
The AT1 selectivity for the AT1 implies that during treatment with these drugs the AT2 receptor is exposed to high concentrations of angiotensin II. The functional role of the AT2 receptor still remains unknown, although it is believed to counteract cell proliferation when stimulated with angiotensin 11.11 Accordingly, it may be possible that the stimulated AT2 receptor can inhibit and perhaps even reverse the growth-promoting effects of angiotensin II indirectly, via the blockade of the AT1 receptor. Furthermore, AT2-receptor stimulation has been shown to cause vasodilatation in experimental models, thus counteracting the vasoconstriction caused by AT1-receptor stimulation."1-'3 A few years ago the detailed mechanism of the interaction between the various AT1 blockers and the AT1 receptor was subject to intense debate. In this connection, a differentiation between surmountable versus insurmountable antagonism was discussed for the various available AT1 blockers. The terms surmountable/insurmountable antagonism largely correspond (although not in all details) to the classical pharmacological terms competitive/non-competitive antagonism, respectively. Accordingly, ifanAT,-receptor antagonist bound to the AT1 receptor can be displaced by adding the agonist (Ang II) it can be considered as surmountable. If high concentrations of angiotensin II cannot displace the AT, antagonist from the AT, receptor it is considered to be an insurmountable antagonist. Insurmountable antagonism indicates strong binding of an antagonist to its receptor. This issue requires some critical consideration. First of all it should be realised that the finding of surmountable versus insurmountable antagonism depends greatly upon the pharmacological model used. For instance, losartan is a surmountable antagonist in certain models (e.g. isolated rat aorta), but it behaves like an insur-
mountable antagonist in other models, such as the rabbit isolated renal artery'4"15 or the vascular bed of the human forearm.'6 Similarly, irbesartan may either behave as a surmountable or as an insurmountable antagonist.'7 Candesartan has been put forward as a typically insurmountable AT,-receptor antagonist.'8 In conclusion, the issue of 'surmountable versus insurmountable' antagonism is oftheoretical interest but so far it is by no means relevant for the clinical application ofAT,-receptor antagonists. This issue has been overemphasised for marketing purposes. Haemodynamic profile All ofthe compounds are vasodilators, in particular of the resistance vessels, and hence reduce peripheral vascular resistance. Venous dilatation can be demonstrated to occur, but it is much weaker than the dilator effects upon the arterial system. The haemodynamic profile of the AT, antagonists is very similar to that of the ACE inhibitors. Heart rate remains unchanged (no reflex tachycardia). Kinetic profile and biological inactivation In clinical terms the kinetic properties of the various compounds are rather similar. After oral ingestion all of the various AT, blockers are readily absorbed and display their haemodynamic actions after a few hours. Virtually all available AT, blockers have a long duration of action, thus allowing satisfactory control ofblood pressure over 24 hours after a single oral dose. Most agents are lipophilic and display a very high degree of plasma protein binding. Elimination/inactivation of the various AT, blockers occurs either by hepatic biodegradation and/or renal elimination. The major pathways of elimination/inactivation ofthe various AT, blockers are summarised in table 1.
Table 1 Pharmacokinetic characteristics of various AT1-receptor antagonists
Compound*
Prodrug
Losartan (Cozaar)
Yes
Candesartan (cilexetil) (Atacand) Eprosartan (Teveten) Irbesartan (Aprovel) Olmesartan (medoxomil) (Olmetec) Telmisartan (Micardis), (Kinzal) Valsartan (Diovan)
Yes No No Yes No No
*
Inactivation
Liver > kidney active metabolite, first pass effect Kidney + liver Liver > kidney Liver > kidney Liver > kidney Liver >> kidney Liver > kidney
adaptation In dysfunction
Dosage
Renal
Hepatic
No
Yes
Yes No No Yes No No
Yes No No No Yes Yes
Duration of action (blood pressure 4)
70-80% of the maximal effect after 24 h .24 h .24 h >24 h .24 h >24 h .24 h
Commercial names as in the Netherlands.
qC
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Side effects So far all registered compounds display a very favourable side effect profile that does not significantly differ from that ofplacebo treatment. In contrast to the ACE inhibitors, cough is not a common adverse reaction to AT,-receptor antagonists. Angioneurotic oedema has been described for losartan in highly exceptional cases. Contraindications Hypersensitivity, although rare, is a contraindication. Hypotension caused by the angiotensin II receptor antagonists is a drawback in the use of these compounds in patients with hypovolaemia (use of diuretics, vomiting, diarrhoea) or with severe symptomatic heart failure. Caution is advised in patients with aortic stenosis, renal artery stenosis or primary hyperaldosteronism. Since data are not yet available on use in pregnancy or lactation, angiotensin II receptor antagonists should then be avoided.
Drug interactions Used together with diuretics, symptomatic hypotension may be problematic. When combined with potassium-sparing diuretics, clinically significant retention of potassium may occur.
Efficacy in the treatment of hypertension The efficacy of the various registered compounds as antihypertensives is very similar, although a few reports would seem to indicate that some of the newer agents are somewhat more effective than losartan.'0 This may be a matter of dosage. It is generally felt that the once daily dose of 50 mg per tablet oflosartan is rather low for the adequate treatment ofhypertension. In relevant clinical trials the required daily dose of losartan was in the range of 80 mg. Efficacy in the treatment of congestive heart failure On theoretical grounds one would expect a beneficial effect ofAT1 blockers in congestive heart failure, similar to that of the ACE inhibitors. However, it should be realised that the ACE inhibitors, developed many years before the AT1 blockers, have been studied much more
thoroughly. Clinical data, including those from randomised studies, are now beginning to emerge and strongly suggest that the AT1 blockers are beneficial and potentially useful in the management of congestive heart failure. Candesartan and valsartan have been registered for the treatment ofheart failure in various countnes. Characteristics of Individual AT1-receptor antagonists The various AT,-receptor antagonists have now matured as therapeutically useful agents. The question therefore arises to which degree the various agents now available can be compared and differentiated. 384
Globally speaking the various AT1 blockers are rather similar with respect to their chemical structures, receptor profile, and haemodynamic and pharmacokinetic properties. A few differences, however, are beginning to emerge and some of these may be clinically relevant. It is not surprising that pharmaceutical companies manufacturing an AT1 blocker preparation attempt to emphasise the peculiarity of their agent in order to differentiate it from the other registered compounds. In the present survey, we will critically discuss the claims made for the individual AT1 blockers and their possible clinical relevance. Losartan This was the first AT,-receptor antagonist developed clinically and then applied on a large scale in antihypertensive treatment. Its safety and efficacy appear to be beyond doubt. A selective AT,-receptor antagonist, losartan is, as mentioned earlier, a prodrug which after oral administration is converted into its metabolite EXP3174. This is a more potent AT1 antagonist than losartan and, in reality, underlies most ofthe antihypertensive activity of the 'parent' compound.2 Like all other angiotensin II receptor antagonists that have been clinically introduced so far, losartan is well tolerated and accepted by patients. Angioneurotic oedema and pancreatitis have been reported in a few exceptional cases. The antihypertensive efficacy of losartan is well established and documented by various studies, including large-scale randomised trials. In the LIFE study, carried out in hypertensives with an additional risk factor, losartan showed the same antihypertensive activity as atenolol, but it was significantly more protective against the sequelae of hypertension, in particular stroke.22 Patients treated with losartan developed significantly less diabetes (type 2) than those receiving atenolol. The renoprotective activity of losartan has been demonstrated in hypertensive patients with diabetic nephropathy (RENAAL study).23 Losartan may also be beneficial in the treatment of congestive heart failure (CHF). In the ELITE-I study24 it was shown to reduce mortality in CHF patients significantly more than the ACE inhibitor captopril. This issue was pursued in the ELI lE-II study, where captopril and losartan did not differ. In addition, losartan appears to display significant uricosuric activity in the dosage used for antihypertensive treatment. This effect is limited to losartan, it is not a class effect ofthe AT1-receptor blockers.'9 This may be a potentially beneficial effect when losartan is combined with a thiazide diuretic which will increase plasma uric acid levels.
Candesartan cilexetil This is a prodrug and, after oral ingestion, it is converted into candesartan, the active compound. Candesartan Netherlands Heart Journal, Volume 14, Number 11, November 2006
Angiotensin 11 receptor antagonists (AT1 blockers, ARBs, sartans): similarities and differences
had been put forward as the prototype of an insurmountable AT,-selective receptor antagonist, but as such it is not unique. Its long duration of action (>24 hours) may be partly explained by strong and persistent binding to the AT1 receptor, but pharmacokinetic characteristics also contribute to its long-lasting antihypertensive effect. Candesartan is tolerated as well as the other AT,-receptor antagonists. In the SCOPE study25 the antihypertensive activity ofcandesartan was documented in elderly patients and compared with classical drugs (diuretics or 5-blockers). The protective effect ofcandesartan against stroke and other endpoints was significant. In the recently published CHARM studies, the beneficial effect of candesartan in congestive heart failure has been clearly demonstrated.26 Accordingly, candesartan has recently been registered in a few countries for the treatment of congestive heart failure. For reviews see Andersson et al. and Sever et al.27,28 Eprosartan This is a selective AT,-receptor antagonist. Its haemodynamic profile, antihypertensive efficacy and tolerability are comparable with those of the other AT1receptor antagonists. Excretion of eprosartan, in the unchanged form, predominantly occurs via the bile and faeces (approximately 90%), and much less so via the kidney (approximately 10%). Since eprosartan is not metabolised by the cytochrome P450 system, it has a low potential for drug interactions. In pithed rats29 eposartan inhibits the stimulated release of noradrenaline from presynaptic sites, probablyvia the blockade ofpresynaptic angiotensin receptors (AT1 type) at the sympathetic nerve endings. These experiments with eposartan have validated this agent as an experimental tool in the research on presynaptic AT1 receptors. Presynaptic AT,-receptor blockade can be demonstrated for a few other ARBs, but there are (at least in experimental models) major quantitative differences and exprosartan appears to be one of the most active compounds. The clinical relevance ofthe inhibition of sympathetic outflow by eprosartan is still unclear, although it may be potentially beneficial, in particular in congestive heart failure patients, where the sympathetic nervous system is usually activated. For a review on eprosartan see McCellan et al.30
Irbesartan This is an AT,-selective agent with a long duration of action (at least 24 hours after one oral dose). The side effect profile does not differ from that ofplacebo. The occurrence of side effects does not appear to be clearly dose dependent. Its antihypertensive efficacy is well established. Irbesartan has been shown to display protective activity in hypertensive patients with microalbuminuria3l and with diabetic nephropathy.32 For reviews on irbesartan see Gillis et al. and Man in 't Veld.33' 34
Netierlands Heart Journal, Volume 14, Number 11, November 2006
Olmesartan Recently introduced for the treatment of essential hypertension, olmesartan medoxomil is a prodrug which is converted after oral ingestion by various esterases into the active metabolite olmesartan. The efficacy and safety of olmesartan appear to be similar to those of otherAT, blockers. Large-scale intervention studies such as OLMEBEST are ongoing. The bioavailability ofolmesartan is increased in the elderly and in patients with impaired renal and/or hepatic functions. For reviews see Brunner et al. and Unger et al.35,36 Telmisartan This is a lipophilic, selective, unsurmountable ATrreceptor antagonist with a very long duration of action. Its haemodynamic profile, antihypertensive activity and tolerability are comparable to those of the other AT1 blockers. Telmisartan is inactivated almost entirely via hepatic degradation. Hepatic dysfunction requires dose adaptation. In the recently published DETAIL study the renoprotective properties of telmisartan and the ACE inhibitor enalapril were found to be equivalent in patients with type 2 diabetes.37 Telmisartan appears to display interesting metabolic properties. Telmisartan, probably also in doses and concentrations as used in the treatment of hypertension, acts as an insulin sensitiser, owing to the activation of peroxisomeproliferator activated receptor subtype y (PPAR-y).38'39 Accordingly, telmisartanr's metabolic actions resemble those of the glitazones, such as pioglitazone or rosiglitazone. Telmisartan has been evaluated in large intervention studies, such as ONTARGET and TRANSCEND. For a review see Chrysant et al.40
Valsartan This is a highly selective AT1-receptor antagonist that displays competitive antagonism at the level of the AT1 receptor in isolated tissues. It is conceivable that the high AT,-receptor selectivity is associated with a stronger activation of the AT2 receptor. As discussed previously AT2-receptor stimulation is assumed to be a favourable activity, since it brings aboutvasodilatation and decreased cellular proliferation. In the recently published VALUE study valsartan, used for the treatment ofhypertensive patients, was associated with a significantly lower incidence of cases ofnew diabetes when compared with amlodipine.4' Valsartan displays beneficial activity in patients with congestive heart failure. Its registration for the treatment ofheart failure has occurred in several countnes. In the VALIANT study42 it was shown that valsartan is a suitable alternative for an ACE inhibitor in patients after an acute myocardial infarction with signs or evidence for heart failure. Combination therapy (ACE inhibitor + valsartan) did not add benefit to monotherapy. Renoprotective activity ofvalsartan was recently demonstrated by the MARVAL study.43 For a review on valsartan see Markham et al.44 385
Angiotensin 11 receptor antagonists (AT1 blockers, ARBs, sartans): similarities and differences
Conclusions and perspectives The development of olly active, non-peptidergic ATrreceptor antagonists is a good example of rational medicinal chemistry and subsequent phannacological investigation, and the angiotensin-receptor antagonists have enriched our therapeutic armamentarium for antihypertensive treatment. They are characterised by a satisfactory antihypertensive activity, acceptable pharmacokinetic profiles and so far, excellent tolerability. In particular, the absence of cough is a clinical advantage. Long-term randomised clinical trials are ongoing, and a few such studies (LIFE, VALUE, SCOPE) have demonstrated the antihypertensive effect of the AT1 blockers, as well as their protective actions on the well-known complications ofhypertensive disease. The AT,-receptor antagonists are of potential interest in the protection against diabetic nephropathy and in the treatment of congestive heart failure, as demonstrated in a limited number of clinical trials. Much more clinical experience will be required to judge the validity of these therapeutic approaches. So far the AT,-receptor antagonists that have been developed clinically are similar in many respects. Most ofthem are chemically related (biphenylderivatives) and selective for the AT, receptor.
References 1
2 3 4
5 6 7
8
9
10 11 12
13
In most cases the pharmacokinetic profile of the AT,receptor antagonists is satisfactory or even very good, enabling control of blood pressure over 24 hours by means of a single dose. The kinetic differences between the various agents are not impressive and hardly influence the pattern of treatment or the choice of a particular drug. A few newer data, both experimental and clinical, appear to indicate that certain AT1 blockers may offer metabolic and other effects which are potentially beneficial in addition to their haemodynamic actions. Examples ofsuch effects are for instance: * Losartan: uricosuric activity; * Eprosartan: inhibition ofnoradrenaline release from the sympathetic nerve endings (mediated by presynaptic AT1 receptors); * Telmisartan: insulin-sensitising activity (mediated by stimulation ofthe PPAR-y receptor); * Valsartan: very high selectivity for the AT1 receptor - stronger stimulation of the AT2 receptor by angiotensin II.
Many more new AT,-receptor antagonists may be expected to be introduced in the forthcoming years, but it seems unlikely that new agents will offer substantial advantages over those that are available at present.45 It can be speculated that the AT2 receptor may offer a novel target for drug design, but the approach would be directed towards modulation of cell proliferation or metabolic effects rather than towards the lowering of blood pressure per se. *
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15 16
17
18
19 20 21 22
23
24
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37 Barnett AH, Bain SC, Bouter P, et al. Angiotensin receptor blockade versus converting enzyme inhibition in type 2 diabetes and nephropathy. NEnglJMed 2004;351:1952-61. 38 Benson SC, Perchadsingh HA, Ho CI, et al. Identification of telmisartan as an unique angiotensin II receptor antagonist with selective PPAR-ymodulating activity. Hypertension 2004;43:9931002. 39 Schupp M, Janke J, Clasen R, Unger T, Kintschen U. Angiotensin type I receptor include peroxizome proliferator activated receptoryactivity. Circulation 2004;109:2054-7. 40 Chrysant SG, Chrysant GS, Desai A. Current status of angiotensin receptor blockers for the treatment ofcardiovascular diseases: focus on telmisartan. JHum Hypertens2005;19:173-83. 41 Julius S, Kjeldsen SE, Weber M, et al. VALUE Trial Group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimes based on valsartan or amlodipine: the VALUE randomised trial. Lancet2004;363:2022-31. 42 Pfeffer MA, Mc Murray JJ, Velasquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. NEnglJMed 2003;349:1893906. 43 Viberti GC, Wheeldon MN. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressureindependent effect. Circulation 2002;106:672-8. 44 Markham A, Goa KL. Valsartan. Areview of its pharmacology and therapeutic use in essential hypertension. Drugs 1997;54:299-331. 45 Weber AM. Angiotensin II receptor blockers and cardiovascular outcomes: what does the future hold? JReninAngAld Syst2003; 4:62-73. 46 Ruilope LM, Agabite Rosei E, Bakris GL, et al. Angiotensin receptor blockers: therapeutic targets and cardiovascular protection. Blood Pressure 2005;14:196-209.
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