THERAPY

Angiotensin II antagonists lead the way in hypertension management

-Manin Gallagher-

Angiotensin n receptor antagonists (AIlRAs) represent a major advance in the treatment of cardiovascular disease. This new therapeutic class appears to combine a placebo-like tolerability profile with proven antihypertensive efficacy. Recently, AURAs have also shown encouraging results in the treatment of heart failure. The irrst 'sartan', losartan potassium, was initially marketed less than 4 years ago and has since been joined by a number of other agents. Attention is now focusing on the individual characteristics of each new compound. An abundance of data were presented on the latest of these agents, candesartan cilexetil, at a Takeda Chemical Industries-sponsored satellite symposium at the 17th Scientific Meeting of the International Society of Hypertension [Amsterdam, The Netherlmuls; June 1998]. These included data suggesting possible end-organ protective effects that may be independent of the drug's BP lowering effects.

The past decade has witnessed many significant advances in our understanding of the renin-angiotensin system (RAS) and its role in the pathophysiology of hypertension. Similar to the angiotensin converting enzyme (ACE) inhibitors that preceded them. AURAs are accepted as effective antihypertensives. However, unlike ACE inhibitors, AURAs are not associated with adverse effects that are treatment-limiting. such as cough, or serious, such as angioneurotic oedema.

Because AURAs act at the receptor level, they produce a more complete blockade of the effects of angiotensin II, compared with agents that interfere with the production of angiotensin II. Several lines of new research suggest that AIlRAs may offer additional benefits in cardiovascular disorders.

Important differences in ADRAs The RAS has a diverse array of effects, explained

Professor Thomas Unger from the University of Kiel, Germany. Haemodynarnic effects include increases in extracellular volume, peripheral vascular resistance and BP. The RAS also influences cell proliferation and differentiation. Most if not all of the cardiovascular effects of angiotensin II are mediated by the angiotensin II type l (ATl) receptor subtype [see boxed text on next page].

Despite the fact that all AIIRAs act at ATl receptors, there are substantial differences in their binding characteristics. For example. candesartan cilexetil has a higher affinity (about 80-fold higher) for ATl receptors than losartan potassium. Candesartan cilexetil is highly selective for ATl over AT2 receptor SUbtypes and displays high-affinity binding and slow dissociation

from the receptor. Consequently. candesartan cilexetil acts as an insurmountable (noncompetitive) antagonist. This is in contrast to the surmountable (competitive) antagonism of losartan potassium and other AURAs. Thus, the effects of candesartan cilexetil are unlikely to be overcome by elevated levels of endogenous angiotensin II.

A plateau in the antihypertensive effect is seen with several of the AURAs (e.g. losartan potassium and valsartan) when used as monotherapy at recom­mended dosages. This means that patients having an unsatisfactory BP-Iowering effect with monotherapy must switch to combination therapy or an alternative agent.

Clinical data from numerous multicentre studies, conducted throughout Europe and the Far East. indicating that once-daily candesartan cilexetil 4-16mg produces dose-dependent and sustained reductions in both systolic and diastolic BP were presented by Professor Peter Sever from St Mary's Hospital Medical School, London. UK, and Professor Toshio Ogihara of Osaka University Medical School. Japan.

Rapid BP lowering The magnitude of the BP-Iowering effect of

candesartan cilexetil is at least equivalent to that seen with several commonly used antihypertensives such as enalapril, amlodipine and hydrochlorothiazide.

Professor Sever presented a meta-analysis of controlled clinical trials involving 1187 patients with hypertension. The analysis shows that candesartan cilexetil 8-16 mg/day has a rapid onset of action. In addition. clinically relevant reductions in BP

occurred within 2 weeks of starting therapy; about two-thirds of the BP-lowering effect achieved by week 8 had occurred at week 1, and about 80% of the effect had occurred by week 2 [see figure 1].

Total BP control and tolerability

An important consider­ation with once-daily anti­hypertensive therapy is that BP control is maintained over 24 hours. Ambulatory

• BaseIne dastoIlc BP was 102.3 and 102.5rrm Hg for condesatan and placebo recipients. respectively, BP monitoring has con-L-lhe __ COIT_ espond ___ ng_ vOOes __ for_ boseIne ___ syst_oIIc_BP_~_e_160_,l_and __ 16_1_,()rm __ Hg_._respectIIIeIy _ ___ ' _____ -' firmed that once-daily

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14 THERAPY

candesartan cilexetil produces a smooth and effective reduction in diastolic BP throughout the entire 24-hour dose interval at all dose levels, explained Professor Giuseppe Mancia from the University of Milan, Italy.

Candesartan cilexetil has a similar tolerability profile to that of placebo over its entire once-daily dose range of 4-16mg, according to data from> 3000 patients enrolled in clinical trials with the agent. Importantly, it is equally well tolerated by men and women and by elderly and younger patients.

End-organ protection possible Results from preclinical studies indicated that

candesartan cilexetil has cardioprotective, cerebro­protective and renoprotective effects.

Similar beneficial effects of AIIRAs and ACE inhibitors on proteinuria and glomerulosclerosis have been seen in a number of models of chronic renal disease in rats, said Professor Barry Brenner from Brigham and Women's Hospital, Boston, US. Results from a long-tenn preclinical study in rats, suggested that candesartan cilexetil had greater inhibitory effects than enalapril on glomerulosclerosis, interstitial fibrosis and transforming growth factor-[3 synthesis.

Positive effects on end-organ protection obtained in studies conducted in animals appear to translate into marked benefits in the clinical setting, according to Professor Kiyoshi Kurokawa and colleagues from Tokai University School of Medicine, Kanagawa, Japan. In a pilot study involving 22 patients with chronic glomerulonephritis, about one-third of patients treated with candesartan cilexetil 8 mg/day for 12 weeks experienced> 50% reduction in urinary protein excretion.

Effects of angiotensin mediated by ATl receptors

• Vascular smooth muscle vasoconstriction • Vascular smooth muscle proliferation • Catecholamine release • Aldosterone release • Vagal inhibition • Central sympathetic activation • Sodium and water retention • Thirst stimulation

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~ Editorial comment: Candesartan cilexetil was launched in its first market Sweden in 1997 and is now available in several other European countries as 'Elopress' and 'Amias' by Takeda and as 'A tacand , by Astra Merr::k. Candesartan cilexetil received US FDA approval at the beginning of June this year and will be marketed in the US as 'Atacand' by Astra Merr::k {see Inpharma 1141: 22, 13 Jun 1998; 800632090].

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