Blopress Mechanism of Action

Pharmacology: Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension, heart failure and other cardiovascular disorders. It is also has an important role in the pathogenesis of end organ hypertrophy and damage.
The major physiological effects of angiotensin II, such as vasoconstriction, aldosterone stimulation, regulation of salt and water homeostasis and stimulation of cell growth, are mediated via the type I (AT₁) receptor.
Blopress is a prodrug suitable for oral use. It is rapidly converted to the active drug, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Blopress is an angiotensin II receptor antagonist, selective for AT₁ receptor, with tight binding to and slow dissociation from the receptor. It has no agonist activity.
Candesartan does not inhibit ACE, which convert angiotensin I to angiotensin II and degrades bradykinin. There is no effect on ACE and no potentiation of bradykinin or substance P. In controlled clinical trials comparing Blopress with ACE-inhibitor, the incidence of cough was lower in patients receiving Blopress. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Hypertension: In hypertension, Blopress causes a dose-dependent, long lasting reduction in arterial blood pressure. The antihypertensive action is due to decreased systemic peripheral resistance, while heart rate, stroke volume and cardiac output are not affected. There is no indication of serious exaggerate first-dose hypotension or rebound effect after cessation of treatment.
Blopress is effective in all grades of hypertension.
After administration of a single dose. Onset of antihypertensive effect generally occurs within 2 hours. With continuous treatment, the maximum reduction in blood pressure with any dose generally attained within 4 weeks and is sustained during long-term treatment. It provides effective and smooth blood pressure reduction over the 24-hr with little difference between maximum and trough effects during the dosing interval.
When Blopress is used together with hydrochlorothiazide, the reduction in blood pressure is additive. Blopress is similarly effective in patients irrespective of age and gender.
Blopress increases renal blood flow and either has no effect on, or increases glomerular filtration rate while renal vascular resistance and filtration fraction are reduced. Blopress has no adverse effect on blood glucose or lipid profile.
Heart Failure: Treatment with candesartan cilexetil reduces mortality, reduces hospitalization due to heart failure and improves symptoms in patients with left ventricular systolic dysfunction as shown in the Candesartan in Heart Failure - Assessment of Reduction in Mortality and Morbidity (CHARM) programme.
This multinational, placebo controlled, double-blind study programme in chronic heart failure (CHF) patients with NYHA functional class II to IV consisted of three separate studies: CHARM-Alternative (n=2,028) in patients with LVEF ≤40% not treated with an ACE inhibitor because of intolerance (mainly due to cough, 72%), CHARM-Added (n=2,548) in patients with LVEF ≤40% and treated with an ACE inhibitor, and CHARM-Preserved (n=3,023) in patients with LVEF >40%. Patients on optimal CHF therapy at baseline were randomised to placebo or candesartan cilexetil (titrated from 4 mg or 8 mg once daily to 32 mg once daily or the highest tolerated dose, mean dose 24 mg) and followed for a median of 37.7 months. After 6 months of treatment, 63% of the patients still taking candesartan cilexetil (89%) were at the target dose of 32 mg.
In CHARM-Alternative, the composite endpoint of cardiovascular mortality or first CHF hospitalisation was significantly reduced with candesartan in comparison with placebo [hazard ratio (HR) 0.77, 95% CI 0.67-0.89, p <0.001]. This corresponds to a relative risk reduction of 23%. Fourteen patients needed to be treated for the duration of the study to prevent one patient from dying of a cardiovascular event or being hospitalised for treatment of heart failure. The composite endpoint of all-cause mortality or first CHF hospitalisation was also significantly reduced with candesartan (HR 0.80, 95% CI 0.70-0.92, p=0.001). Both the mortality and morbidity (CHF hospitalisation) components of these composite endpoints contributed to the favourable effects of candesartan. Treatment with candesartan cilexetil resulted in improved NYHA functional class (p=0.008).
In CHARM-Added, the composite endpoint of cardiovascular mortality or first CHF hospitalisation was significantly reduced with candesartan in comparison with placebo (HR 0.85, 95% CI 0.75-0.96, p=0.011). This corresponds to a relative risk reduction of 15%. Twenty-three patients needed to be treated for the duration of the study to prevent one patient from dying of a cardiovascular event or being hospitalised for treatment of heart failure. The composite endpoint of all-cause mortality or first CHF hospitalisation was also significantly reduced with candesartan (HR 0.87, 95% CI 0.78-0.98, p=0.021). Both the mortality and morbidity components of these composite endpoints contributed to the favourable effects of candesartan. Treatment with candesartan cilexetil resulted in improved NYHA functional class (p=0.020).
In CHARM-Preserved, no statistically significant reduction was achieved in the composite endpoint of cardiovascular mortality or first CHF hospitalisation (HR 0.89, 95% CI 0.77-1.03, p=0.118). The numerical reduction was attributable to reduced CHF hospitalisation. There was no evidence of effect on mortality in this study.
All-cause mortality was not statistically significant when examined separately in each of the three CHARM studies. However, all-cause mortality was also assessed in pooled populations, CHARM-Alternative and CHARM-Added (HR 0.88, 95% CI 0.79-0.98, p=0.018) and all three studies (HR 0.91, 95% CI 0.83-1.00, p=0.055).
The beneficial effects of candesartan on cardiovascular mortality and CHF hospitalization were consistent irrespective of age, gender and concomitant medication. Candesartan was effective also in patients taking both beta-blockers and ACE inhibitors at the same time, and the benefit was obtained whether or not patients were taking ACE inhibitors at the target dose recommended by treatment guidelines.
In patients with CHF and depressed left ventricular systolic function (left ventricular ejection fraction, LVEF ≤40%), candesartan decreases systemic vascular resistance and pulmonary capillary wedge pressure, increases plasma renin activity and angiotensin II concentration, and decreases aldosterone levels.