Angiotensin receptor blockers: the story continues................

Angiotensin receptors are protein molecules that mediate the effect of the hormone angiotensin 2. These receptors are found in various parts of the body. The existence of angiotensin in the body was recognised by the work of people like Tigerstedt, Bergman and Goldblatt who, in different experiments in the late nineteenth and early twentieth centuries, showed the presence of a vasoconstrictor substance released by the kidneys¹. This substance was named renin and it was soon determined that renin led to the formation of angiotensin 1 and that angiotensin 1 had to be changed to angiotensin 2 in order to be effective. The conversion of angiotensin 1 to angiotensin 2 is facilitated by the enzyme called angiotensin – converting enzyme. Angiotensin 2 exerts its effects on blood vessels and other tissues through receptors called angiotensin receptors. These receptors are also of two types: angiotensin receptor 1 (AT1) and angiotensin receptor 2(AT2). The vasoconstrictor effect of angiotensin 2 is mediated through the AT1 receptor and the angiotensin receptor blockers used clinically are all AT1 receptor blockers.

Angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI) are both used in medicine for patients with hypertension, cardiac failure, ischemic heart disease and proteinuric-renal disease. Angiotensin receptor blockers score over angiotensin converting enzyme inhibitors in a few ways: they provide a more comprehensive blockade of the renin angiotensin system and they do not affect the serum levels of bradykinin. Hence the effect of angiotensin receptor blockers is more consistent with dose, and bradykinin-related side effects – like cough and angioedema – are not seen².

Angiotensin Receptor Blockers have been shown to protect against myocardial infarctions and strokes in patients who are at high risk for these vascular events. A study reported in 2008 showed the benefit of these drugs in preventing cardiovascular events in patients undergoing long-term hemodialysis ³. A meta-analysis had also shown that ARB can prevent the development of atrial fibrillation in patients with heart failure⁴ and another meta-analysis had shown that these drugs could prevent new onset diabetes in patients who are predisposed to developing diabetes⁵. Hence angiotensin receptor blockers not only reduce blood pressure but also favourably influence cardiovascular risk factors.

There may however be differences in clinical benefit between various angiotensin receptor blockers. A study comparing Losartan, Irbesartan, Valsartan, Candesartan and Telmisartan in patients with heart failure found that Losartan showed poorer survival rates in elderly people with heart failure compared to the other drugs⁶.

Alzheimer’s disease is a common cause of dementia. A pathological finding in this disease is amyloid deposition in the brain.  There is very new evidence, based on autopsies, that those who take angiotensin receptor blockers for hypertension have less amyloid deposition in their brains than those who are on other kinds of antihypertensive drugs⁷ and this actually confirms some earlier anecdotal reports that treatment with angiotensin receptor blockers reduces the likelihood of developing Alzheimer’s disease.  It appears that angiotensin receptor blockers are able to reduce amyloid deposition in the brain by reducing inflammation within the brain.

In conclusion, we have learnt a great deal about the clinical benefits of blocking the renin-angiotensin-aldosterone system (RAAS) in the last decade. Since the ARB class of drugs are more expensive than the ACEI class of drugs, doctors are encouraged to use angiotensin-converting enzyme inhibitors wherever RAAS inhibition is needed and to use angiotensin receptor blockers only when patients are intolerant to ACEI. However, if the recent evidence of the possible benefit of angiotensin receptor blockers in preventing dementia can be verified through other studies, then the drugs in this class will have a distinct edge over their first cousins – the ACE inhibitors.

References:

1. Discovery and development of angiotensin receptor blockers, Wikipedia: http://en.wikipedia.org/wiki/Discovery_and_development_of_angiotensin_receptor_blockers

2. Amy Barreras, et al.Angiotensin 2 receptor blockers. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1200815/

3. Effect of angiotensin receptor blockers in patients undergoing hemodialysis http://www.ajkd.org/article/S0272-6386(08)00955-4/abstract

4. Prevention of atrial fibrillation with angiotensin converting enzyme inhibitors and angiotensin receptor blockers http://content.onlinejacc.org/article.aspx?articleid=1136655

5. Angiotensin converting enzyme inhibitors or angiotensin receptor blockers for prevention of Type 2 diabetes http://content.onlinejacc.org/article.aspx?articleid=1136856

6. Angiotensin 2 receptors for the treatment of heart failure http://www.ncbi.nlm.nih.gov/pubmed/17381379

7. Ihab Hajjar, et al. Impact of Angiotensin Receptor Blockers on Alzheimer Disease Neuropathology in a Large Brain Autopsy Series. Arch Neurol 2012; Published online Sept 2012. http://archneur.jamanetwork.com/article.aspx?articleid=1356776#METHODS