Azilsartan newer ARB, is it pleiotropic?

 Nowadays in pharma industry pleiotropic effect has become a trend. New molecules come with feather stating they have special extra advantage over previous class counterparts. Newer Angiotensin receptor blockers are being added to their group day by day. In the year 2011, 8th ARB i.e. Azilsartan was launched with FDA approval. In India this molecule is being introduced this year i.e. 2016 .
I was asked to by Emcure (pharma company) to give talk on azilsartan with brand name Zilarbi a couple days ago. Zilarbi pronunciation sounds more like Indian sweet “Jilebi”. Emcure gave me slides for the talk, as it was more like promotional lecture. I went through the slides where in there was mention of MAS pathway which comes along with RAAS pathway.
MAS pathway has its receptor MasR.  Blockage of  AT1 receptor  diverts the Ang-I and Ang –II towards MAS pathway see Figure 1to form angiotensin 1–7, this has protective effect on heart and blood vessel thus they have a protective effect on ischemic heart disease, heart failure , hypertension, renal disease and diabeties1. 
Figure 1 MAS pathway
Azilsartan protection against cardiac hypertrophy and renal damage by  high blood pressure was studied  in Sprague-Dawley rats. ANG II infused in rats, the one who received Azilsartan showed decreased cardiac hypertrophy and kidney damage compared to rats who did not receive azilsartan. So this study concluded that azilsartan  has beneficial effect beyond BP reduction2.
Dahlöf et al showed Losartan a first ARB had decreased events of stroke, cardiac mortality and cardiac hypertrophy compared to beta-blocker atenalol3  from this it appears that ARB as groups are associated with benefits beyond BP reduction “class effect rather than specific Azilsartan”.
Olmesartan is considered to be the most potent antihypertensive among other ARBs4, but Azilsartan medoxomil at 80 mg is  superior in terms of 24 hour  systolic BP reduction to both valsartan at 320 mg and olmesartan at 40 mg and  Azilsartan medoxomil 40 mg is noninferior to olmesartan medoxomil 40mg5,6. This higher potency of azilsartan is due its higher affinity towards AT1 receptors as compared to other ARBs
Azilsartan has 10,000 times more affinity towards  AT1 receptor compared to  AT2 receptor7. Azilsartan has higher and longer time antagonist activity  towards AT1 receptor as compared to rest of ARBs8. Azilsartan has plasma half life of 11 hours, but its prolonged binding to AT1 receptors may prove beneficial in patients who are irregular with antihypertensive drug treatment9.
References

1. Jiang F, Yang J, Zhang Y, Dong M, Wang S, Zhang Q, et al. Angiotensin-converting enzyme 2 and angiotensin 1-7: novel therapeutic targets. Nat Rev Cardiol [Internet]. 2014 Jul;11(7):413–26. Available from: http://dx.doi.org/10.1038/nrcardio.2014.59

2. Carroll MA, Kang Y, Chander PN, Stier CTJ. Azilsartan is associated with increased circulating angiotensin-(1-7) levels and  reduced renovascular 20-HETE levels. Am J Hypertens. 2015 May;28(5):664–71.

3. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint  reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet (London, England). 2002 Mar;359(9311):995–1003.

4. Zannad F, Fay R. Blood pressure-lowering efficacy of olmesartan relative to other angiotensin II receptor antagonists: an overview of randomized controlled studies. Fundam Clin Pharmacol [Internet]. 2007;21(2):181–90. Available from: http://dx.doi.org/10.1111/j.1472-8206.2007.00464.x

5. White WB, Weber MA, Sica D, Bakris GL, Perez A, Cao C, et al. Effects of the Angiotensin Receptor Blocker Azilsartan Medoxomil Versus Olmesartan and Valsartan on Ambulatory and Clinic Blood Pressure in Patients With Stages 1 and 2 Hypertension. Hypertens  [Internet]. 2011 Mar 1;57 (3 ):413–20. Available from: http://hyper.ahajournals.org/content/57/3/413.abstract

6. Bakris GL, Sica D, Weber M, White WB, Roberts A, Perez A, et al. The Comparative Effects of Azilsartan Medoxomil and Olmesartan on Ambulatory and Clinic Blood Pressure. J Clin Hypertens [Internet]. 2011;13(2):81–8. Available from: http://dx.doi.org/10.1111/j.1751-7176.2010.00425.x

7. Zaiken K, Cheng J. Azilsartan medoxomil: a new angiotensin receptor blocker. Clin Ther. 2011;33(11).

8. Ojima M, Igata H, Tanaka M, Sakamoto H, Kuroita T, Kohara Y, et al. In vitro antagonistic properties of a new angiotensin type 1 receptor blocker, azilsartan, in receptor binding and function studies. J Pharmacol Exp Ther. 2011 Mar;336(3):801–8.

9.  Kurtz TW, Kajiya T. Differential pharmacology and benefit/risk of azilsartan compared to other sartans. Vasc Health Risk Manag. 2012;8(1):133–43.

Author: Dr Umesh Bilagi

MBBS, MD, DM (cardiology). I am Interventional cardiologist. Blogging is my passion. Associate professor of cardiology KIMS Hubli. Director and consultant at Tatwadarsha Hospital Hubli. Owner of Jeevan Jyoti Hospital Hubli. Mobile +91 9343403620.

5 thoughts on “Azilsartan newer ARB, is it pleiotropic?”

  1. Zilarbi acts effectively on systolic reduction but increases the heart rate sometime to 90 +. Why

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