The pharmacological potency of various AT1 antagonists assessed by Schild regression technique in man

Abstract

Consistent with results from experimental pharmacology, candesartan cilexetil displayed the highest pharmacological potency (i.e. antagonistic activity per mg substance) of the AIIAs tested. Apparent K(i)-doses at 24 hours were within the dose range recommended for clinical use in patients with hypertension.

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…Antagonism of AT1R by various ARBs has also been tested in vivo in humans, mostly healthy volunteers, and, similar to the above animal studies, this was largely done for ANGinduced blood pressure elevations. Following the original study with losartan (Christen et al, 1991), such studies have been performed with candesartan (Delacretaz et al, 1995;Ogihara et al, 1995;Belz et al, 1997Belz et al, , 2000Malerczyk et al, 1998;Fuchs et al, 2000;Gleiter et al, 2004), irbesartan (Belz et al, 1999Maillard et al, 1999;Mazzolai et al, 1999), losartan (Munafo et al, 1992;Belz et al, 1997Belz et al, , 1999Belz et al, , 2000Maillard et al, 1999;Mazzolai et al, 1999;Fuchs et al, 2000;Gleiter et al, 2004), telmisartan Stangier et al, 2001), and valsartan (Müller et al, 1994;Morgan et al, 1997;Belz et al, 1999Belz et al, , 2000Maillard et al, 1999;Mazzolai et al, 1999).…”

Comparison of angiotensin II receptor antagonists

“…2, the half-maximal effect is obtained with 5 mg candesartan and 60 mg irbesartan. As previously mentioned, the antagonistic properties of most available AT 1 receptor antagonists have been shown clear parallels in Schild plots, though the substances differed in their potency and time kinetics [21].…”

“…Although serum trough levels of candesartan at a dose of 8 mg day 21 increased with repeated administration, and the half-life was higher in patients with impaired renal function, it did not lead to drug accumulation [15]. At doses exceeding 12 mg day 21 , the elimination of candesartan was delayed in patients with severe renal dysfunction, leading to possible accumulation [3].…”

“…A steady-state is already achieved after the first dose, without accumulation, except for irbesartan. The latter accumulates by approximately 20% due to its longer elimination half-life, reaching a steady-state concentration within 24 h. For telmisartan, clinically relevant accumulation is not evident upon 7-day repeat daily dosing with 80 mg day 21 , and a steady-state condition is achieved after one week [5]. Higher plasma concentrations of irbesartan and telmisartan have been documented in female patients [6].…”

Current perspectives for AT1-receptor blockers in the management of heart failure

“…As noted above, the patients included in this trial tend to be more symptomatic, in terms of NYHA class, than those in ValHeFT, and a higher proportion are receiving ␤-blockers or spironolactone. Furthermore, candesartan has been shown to provide more complete and prolonged blockade of the renin-angiotensin system than valsartan and other AT 1 -receptor blockers, [19][20][21] and thus may be expected to produce a greater clinical effect than that achieved with valsartan in Val-HeFT.…”