The pharmacological potency of various AT(1) antagonists assessed by Schild regression technique in man.
BACKGROUND
A quantitative technique was used to compare the pharmacological potency in healthy volunteers of angiotensin II receptor antagonists (AIIA): candesartan cilexetil, losartan, irbesartan, valsartan, and telmisartan.


METHODS
In a randomised, double-blind, parallel-group (4x12 subjects) study, single oral doses of candesartan cilexetil 4, 8 and 16 mg, losartan potassium 25, 50 and 100 mg, valsartan 40, 80 and 160 mg, and irbesartan 75, 150 and 300 mg were administered on three consecutive days. Telmisartan 20, 40 and 80 mg was similarly evaluated in 12 volunteers in an open amendment. Angiotensin II (Ang II) antagonistic effects were determined in vivo from rightward shifts in Ang II dose-response curves for diastolic blood pressure (BP) and dose ratios were calculated. Apparent K(i)-doses, i.e. doses (in mg) required to induce a two-fold shift in Ang II dose-response curves (equivalent to approx. 50% blockade of receptors) were determined, using Schild regression analysis.


RESULTS
All treatments dose-dependently attenuated increases in diastolic BP induced by infusion of exogenous Ang II. Candesartan cilexetil appeared to have a more pronounced increase in effect following cumulative dosing. At 24 hours, apparent K(i)-doses were: candesartan cilexetil 6 mg, irbesartan 123 mg, valsartan 93.5 mg, and telmisartan 54 mg. It was not possible to determine an apparent K(i)-dose for losartan at 24 hours.


CONCLUSIONS
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.
Belz
G G
GG
Centre for Cardiovascular Pharmacology, ZeKaPha GmbH, Mainz, D-55116, Germany.
Breithaupt-Grögler
K
K
Butzer
R
R
Fuchs
W
W
Hausdorf
C
C
Mang
C
C
D000328:Adult; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000494:pharmacology*; D001562:Benzimidazoles / Q000009:adverse effects / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D000077405:Irbesartan; D019808:Losartan / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D044140:Receptor, Angiotensin, Type 1; D012016:Reference Values; D013777:Tetrazoles / Q000009:adverse effects / Q000494:pharmacology*; D014633:Valine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology*; D000068756:Valsartan
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine; D000077405:Irbesartan; D019808:Losartan; C077793:candesartan cilexetil