Key Features of Candesartan Cilexetil and a Comparison with Other Angiotensin II Receptor Antagonists
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Journal of Human Hypertension (1999) 13, (Suppl 1), S3–S10 1999 Stockton Press. All rights reserved 0950-9240/99 $12.00 Key features of candesartan cilexetil and a comparison with other angiotensin II receptor antagonists PS Sever Imperial College of Science, Technology & Medicine at St Mary’s Hospital, London, UK Current research on angiotensin II AT1-receptor antag- in patients with essential hypertension. Candesartan onists (AIIRAs) and selected studies presented at the cilexetil has a rapid onset of action (approximately 80% recent symposium held in Amsterdam, The Netherlands, of total blood pressure reduction within the first 2 on 6 June 1998, titled ‘Angiotensin II Receptor Antagon- weeks) and dose-dependent effects on blood pressure, ists are NOT all the Same’ are reviewed. AIIRAs offer a is comparable in efficacy to a number of classes of anti- number of potential advantages over alternative antihy- hypertensives, and is effective in combination therapy pertensive agents acting via the renin-angiotensin-aldo- (eg, with hydrochlorothiazide and amlodipine). This sterone system. They combine blood pressure-lowering favourable profile may be due in part to the highly selec- effects at least equivalent to those of angiotensin-con- tive, tight binding to and slow dissociation of candesar- verting enzyme (ACE) inhibitors, coupled with placebo- tan from the AT1 receptor. Preliminary studies suggest like tolerability. Candesartan cilexetil is a novel AIIRA that candesartan cilexetil also protects end organs that has demonstrated clinical efficacy superior to losar- (kidney, heart, vasculature, and brain) beyond blood tan, has a sustained duration of action over 24 hours pressure control. (trough:peak ratio close to 100%) and is well tolerated Keywords: candesartan cilexetil; angiotensin II AT1-receptor antagonist; organ protection; review Antihypertensive therapy associated adverse consequences.3 There is growing evidence from a wide variety of clinical trials that Non-peptide angiotensin II AT1-receptor antagonists the AIIRAs are able to combine or even to exceed (AIIRAs) are a new class of drugs that represent a the considerable benefits of ACE inhibition with the major advance in therapeutics for the treatment of added bonus of improved tolerability. With parti- cardiovascular disease. Members of this new class cular attention to candesartan cilexetil, this article have been proved effective in the treatment of gives an overview of the antihypertensive potential hypertension and have recently also shown promise of AIIRAs reviewed in this supplement which sum- for the treatment of heart failure. AIIRAs attenuate marises the recent symposium held in Amsterdam, the effects of angiotensin II by blocking its action, The Netherlands, on 6 June 1998, titled ‘Angiotensin competitively or non-competitively, at the AT1 II Receptor Antagonists are NOT all the Same’. receptor. This receptor subtype mediates the cardio- vascular and metabolic activities of angiotensin II.1 This mode of action contrasts with that of angio- Criteria for selecting an antihypertensive agent tensin-converting enzyme (ACE) inhibitors, which partially inhibit the conversion of angiotensin I to The main criteria that need to be considered in mak- angiotensin II. One of the disadvantages of ACE ing choices between different antihypertensive inhibitors is that angiotensin II is also produced by agents, particularly in the context of the AIIRAs, are non-ACE-dependent pathways, notably those the following: (1) efficacy in lowering blood press- involving chymase in the heart and other tissues.2 ure; (2) onset and duration of action; (3) organ-pro- The more specific mechanism of action of AIIRAs tective effects; and (4) the side effects profile. The means that the actions of angiotensin II are com- sustained efficacy of any new antihypertensive agent pletely blocked at the effector site, independently of in lowering blood pressure over the full 24-h period the route of its production. Moreover, because ACE is particularly important, since existing therapies is identical to the enzyme kininase II, which inhibits have only achieved relatively small reductions, bradykinin formation, AIIRAs avoid the bradykinin averaging approximately 7%,4 which equate to only potentiation induced by ACE inhibitors and the a small reduction in risk. This outcome for hyper- tension management compares unfavourably with the situation for cardiovascular disease in general, where the 40% reduction in plasma cholesterol Correspondence: Professor Peter S Sever, Department of Clinical 5 Pharmacology and Therapeutics, Imperial College School of levels now attainable with some statins represents Science, Technology & Medicine at St Mary’s Hospital, London a very considerable reduction of risk for ischaemic W2 1NY, UK heart disease. The organ-protective effects of antihy- Angiotensin II AT1-receptor antagonists PS Sever S4 pertensive agents, as demonstrated with ACE inhibi- antagonist. The active losartan metabolite EXP 3174 tors, are of special interest, since they offer opport- in this model acts as a mixed antagonist. The obser- unities for preventing the long-term progression of vations are not easily reproduced in in vivo studies hypertension. A major problem with many contem- and to what extent they relate to differences in porary treatments is poor compliance that mainly apparent clinical efficacy and duration of action of results from intolerance and efficacy deficiencies of these drugs remain at present conjectural. many currently available agents. Duration of action Candesartan cilexetil—a novel A key efficacy criterion of choice of any given anti- hypertensive agent is the degree to which these angiotensin II AT1-receptor antagonist blood pressure-lowering effects are maintained Pharmacology throughout the 24-h period. Although sophisticated Candesartan cilexetil is a new, once-daily oral anti- measures of the 24-h profiles of antihypertensive hypertensive, which is completely hydrolysed drugs are being developed (Mancia G et al, unpub- during gastrointestinal absorption to the only active lished data), a widely recognised parameter is the compound, candesartan, a potent, long-acting AIIRA simple trough:peak blood pressure ratio. On this selective for the type 1 receptor subtype.6,7 The basis, candesartan cilexetil demonstrates an excel- lent 24-h blood pressure profile, with a trough:peak pharmacokinetics of candesartan cilexetil are not 13 affected by administration in the presence of food,8 ratio close to unity. This compares favourably with which simplifies treatment, and no clinically sig- lower trough:peak values for losartan and other nificant drug–drug interactions have been reported.9 AIIRAs. The prolonged antihypertensive activity of The pharmacology of angiotensin II receptors and candesartan cilexetil is likely related to its specific binding characteristics to the AT1 receptor at the AT1-receptor blockers, including candesartan cilexe- 14 til, is reviewed in this supplement by Dr Oliver tissue level. Chung and colleagues from the Institute of Pharma- Dr Inada’s group, of Pharmaceutical Research, cology, Christian-Albrechts-University, Kiel, Ger- Takeda Chemical Industries Ltd, Osaka, Japan, many. It is now known that drugs like ACE inhibi- report in this supplement on potent and long-lasting antihypertensive effects of candesartan cilexetil in tors or angiotensin AT1-receptor antagonists can exert further beneficial actions independent of a clinical trials and in several animal models of hyper- reduction in blood pressure. Dr Chung et al’s study tension. They confirm that the insurmountable reviews the literature, and reports on a reduction antagonism of candesartan cilexetil in vascular con- in vascular- and post-myocardial-infarction re- traction is likely the result of its tight binding and slow dissociation from angiotensin II AT1 receptors. modelling, and a preservation of kidney function in 15 the presence of diabetic nephropathy, in hyperten- In a 12-month study, mean sitting diastolic sive patients taking candesartan cilexetil. blood pressure was progressively reduced from Preclinical and early clinical studies of the lead- approximately 100 mm Hg at baseline to approxi- ing group of AIIRAs that are currently available or mately 85 mm Hg with candesartan cilexetil, and a at advanced stages of development have been perfor- response rate of more than 80% was achieved med to explore the impact of the distinct differences (Figure 1). These data indicate that candesartan in mode of action from ACE inhibitors, particularly cilexetil is effective in a large proportion of hyper- with regard to their clinical benefits in terms of ACE- tensive patients and that blood pressure response is inhibitor-associated cough10 and angioneurotic oed- maintained long-term. ema.11 As predicted, the lack of bradykinin potenti- ation with AIIRA does indeed translate into placebo- Time-to-effect relationship like levels of these troublesome adverse effects. In a report by the author and colleagues, which was However, as our experience of using AIIRAs in the summarised in a poster session at the proceedings, clinic grows it is also increasingly apparent that a total of 1187 patients received 8 or 16 mg of cande- individual compounds display significant differ- sartan cilexetil or placebo once daily for 4 to 12 ences in their pharmacology and clinical behaviour weeks. The results of a meta-analysis showed that within the AIIRA class, which should be taken into approximately two-thirds of the total reduction