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Angiotensin II receptor antagonist

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File:Losartan structure.png

Angiotensin II receptor antagonists, also known as angiotensin receptor blockers (ARBs), AT1-receptor antagonists or sartans, are a group of pharmaceuticals that modulate the renin-angiotensin-aldosterone system. Their main uses are in the treatment of hypertension (high blood pressure), diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure.

Medical usesEdit

Angiotensin II receptor blockers are used primarily for the treatment of hypertension where the patient is intolerant of ACE inhibitor therapy. They do not inhibit the breakdown of bradykinin or other kinins, and are thus only rarely associated with the persistent dry cough and/or angioedema that limit ACE inhibitor therapy[citation needed]. More recently, they have been used for the treatment of heart failure in patients intolerant of ACE inhibitor therapy, in particular candesartan. Irbesartan and losartan have trial data showing benefit in hypertensive patients with type II diabetes, and may delay the progression of diabetic nephropathy. Candesartan is used experimentally in preventive treatment of migraine.[1][2] Lisinopril has been found less often effective than candesartan at preventing migraine.[3]

The angiotensin II receptor blockers have differing potencies in relation to blood pressure control, with statistically differing effects at the maximal doses.[4] When used in clinical practice, the particular agent used may vary based on the degree of response required.

Some of these drugs have a uricosuric effect.[5][6]

In one study after 12 weeks of treatment with an ARB called losartan (Cozaar), 88% of hypertensive males with sexual dysfunction reported improvement in at least one area of sexuality, and overall sexual satisfaction improved from 7.3% to 58.5%.[7] In a study comparing beta-blocker carvedilol with valsartan, the angiotensin II receptor blocker not only had no deleterious effect on sexual function, but actually improved it.[8] Other ARBs include candesartan (Atacand), telmisartan (Micardis), and Valsartan (Diovan).

Angiotensin II, through AT1 receptor stimulation, is a major stress hormone and, because (ARBs) block these receptors, in addition to their eliciting anti-hypertensive effects, may be considered for the treatment of stress-related disorders.[9]

In 2008, they were reported to have a remarkable negative association with Alzheimer's disease (AD). A retrospective analysis of five million patient records with the US Department of Veterans Affairs system found different types of commonly used antihypertensive medications had very different AD outcomes. Those patients taking angiotensin receptor blockers (ARBs) were 35—40% less likely to develop AD than those using other antihypertensives.[10][11]

Discovery and developmentEdit

For more details on this topic, see Discovery and development of angiotensin receptor blockers.


Losartan, irbesartan, olmesartan, candesartan and valsartan include the tetrazole group (a ring with four nitrogen and one carbon). Losartan, irbesartan, olmesartan, candesartan, and telmisartan include one or two imidazole groups.

Mechanism of actionEdit

These substances are AT1-receptor antagonists; that is, they block the activation of angiotensin II AT1 receptors. Blockage of AT1 receptors directly causes vasodilation, reduces secretion of vasopressin, and reduces production and secretion of aldosterone, among other actions. The combined effect reduces blood pressure.

The specific efficacy of each ARB within this class depends upon a combination of three pharmacodynamic and pharmacokinetic parameters. Efficacy requires three key PD/PK areas at an effective level; the parameters of the three characteristics will need to be compiled into a table similar to one below, eliminating duplications and arriving at consensus values; the latter are at variance now.

Pressor inhibitionEdit

Pressor inhibition at trough level - this relates to the degree of blockade or inhibition of the blood pressure-raising ("pressor") effect of angiotensin II. However, pressor inhibition is not a measure of blood pressure-lowering (BP) efficacy per se. The rates as listed in the US FDA Package Inserts (PIs) for inhibition of this effect at the 24th hour for the ARBs are as follows: (all doses listed in PI are included)

AT1 affinityEdit

AT1 affinity vs AT2 is not a meaningful efficacy measurement of BP response. The specific AT1 affinity relates to how specifically attracted the medicine is for the correct receptor, the US FDA PI rates for AT1 affinity are as follows:

*Irbesartan 8500-fold

Biological half-lifeEdit

The third area needed to complete the overall efficacy picture of an ARB is its biological half-life. The half-lives from the US FDA PIs are as follows:

Drug comparison and pharmacokineticsEdit

Table 1: Comparison of ARB pharmacokinetics
Drug Trade Name Biological half-life [h] Protein binding [%] Bioavailability [%] Renal/hepatic clearance [%] Food effect Daily dosage [mg]
Losartan Cozaar 2 h 98.7% 33% 10%/90% Minimal 50–100 mg
EXP 3174 6–9 h 99.8% 50%/50%
Candesartan Atacand 9h >99% 15% 60%/40% No 4–32 mg
Valsartan Diovan 6 h 95% 25% 30%/70% No 80–320 mg
Irbesartan Avapro 11–15 h 90–95% 70% 1%/99% No 150–300 mg
Telmisartan Micardis 24 h >99% 42–58% 1%/99% No 40–80 mg
Eprosartan Teveten 5 h 98% 13% 30%/70% No 400–800 mg
Olmesartan Benicar 14–16 h >99% 29% 40%/60% No 10–40 mg
Azilsartan Edarbi 11 h >99% 60% 55%/42% No 40–80 mg
For more details on this topic, see Discovery and development of angiotensin receptor blockers.

Adverse effectsEdit

This class of drugs is usually well tolerated. Common adverse drug reactions (ADRs) include: dizziness, headache, and/or hyperkalemia. Infrequent ADRs associated with therapy include: first dose orthostatic hypotension, rash, diarrhea, dyspepsia, abnormal liver function, muscle cramp, myalgia, back pain, insomnia, decreased hemoglobin levels, renal impairment, pharyngitis, and/or nasal congestion.[12]

While one of the main rationales for the use of this class is the avoidance of dry cough and/or angioedema associated with ACE inhibitor therapy, rarely they may still occur. In addition, there is also a small risk of cross-reactivity in patients having experienced angioedema with ACE inhibitor therapy.[12]

Myocardial infarction: the controversyEdit

The issue of whether angiotensin II receptor antagonists slightly increase the risk of myocardial infarction (MI or heart attack) is currently being investigated. Some studies suggest ARBs can increase the risk of MI.[13] However, other studies have found ARBs do not increase the risk of MI.[14] To date, with no consensus on whether ARBs have a tendency to increase the risk of myocardial infarction, further investigations are underway.

Indeed, as a consequence of AT1 blockade, ARBs increase angiotensin II levels several-fold above baseline by uncoupling a negative-feedback loop. Increased levels of circulating angiotensin II result in unopposed stimulation of the AT2 receptors, which are, in addition, upregulated. However, recent data suggest AT2 receptor stimulation may be less beneficial than previously proposed, and may even be harmful under certain circumstances through mediation of growth promotion, fibrosis, and hypertrophy, as well as eliciting proatherogenic and proinflammatory effects.[15][16][17]

Cancer risk factorsEdit

A study published in 2010 determined that "...meta-analysis of randomised controlled trials suggests that ARBs are associated with a modestly increased risk of new cancer diagnosis. Given the limited data, it is not possible to draw conclusions about the exact risk of cancer associated with each particular drug. These findings warrant further investigation." [18] A later meta-analysis by the FDA of 31 randomized controlled trials comparing ARBs to other treatment found no evidence of an increased risk of incident (new) cancer, cancer-related death, breast cancer, lung cancer, or prostate cancer in patients receiving ARBs.[19]

Longevity promotionEdit

Knockout of the Agtr1a gene that encodes AT1 results in marked prolongation of the life-span of mice by 26% compared to controls. The likely mechanism is reduction of oxidative damage (especially to mitochondria) and overexpression of renal prosurvival genes. The ARBs seem to have the same effect.[20][21]

Fibrosis regressionEdit

Losartan and other ARBs regress liver, heart, lung and kidney fibrosis.

Dilated aortic root regressionEdit

A 2003 study using candesartan and valsartan demonstrated an ability to regress dilated aortic root size.[22]


  1. Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G. (2003). Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA 1 (289 Pt 1): 65–9.
  2. Cernes R, Mashavi M, Zimlichman R (2011). Differential clinical profile of candesartan compared to other angiotensin receptor blockers. Vasc Health Risk Manag 7: 749–59.
  3. Gales BJ, Bailey EK, Reed AN, Gales MA (2010 Feb). Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for the prevention of migraines. Ann Pharmacother 44 (2): 360–6.
  4. Kassler-Taub K, Littlejohn T, Elliott W, Ruddy T, Adler E. (1998). Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan in mild-to-moderate hypertension. Irbesartan/Losartan Study Investigators. Am J Hypertens 11 (4 Pt 1): 445–53.
  5. Dang A, Zhang Y, Liu G, Chen G, Song W, Wang B (January 2006). Effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia in Chinese population. J Hum Hypertens 20 (1): 45–50.
  6. Daskalopoulou SS, Tzovaras V, Mikhailidis DP, Elisaf M (2005). Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia. Curr. Pharm. Des. 11 (32): 4161–75.
  7. (2001). Sexual dysfunction in hypertensive patients treated with losartan. The American journal of the medical sciences 321 (5): 336–41.
  8. (2001). Sexual activity in hypertensive men treated with valsartan or carvedilol: A crossover study. American journal of hypertension 14 (1): 27–31.
  9. (2008). Peripherally administered Angiotensin II AT1 receptor antagonists are anti-stress compounds in vivo. Annals of the New York Academy of Sciences 1148: 360–366.
  10. Li NC, Lee A, Whitmer RA, Kivipelto M, Lawler E, Kazis LE, Wolozin B (2010). Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ 340 (9): b5465.
  11. (September 2008) Potential of antihypertensive drugs for the prevention and treatment of Alzheimer's disease. Expert Review of Neurotherapeutics 8 (9): 1286.
  12. 12.0 12.1 Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
  13. Strauss MH, Hall AS (2006). Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox. Circulation 114 (8): 838–54.
  14. Tsuyuki RT, McDonald MA (2006). Angiotensin receptor blockers do not increase risk of myocardial infarction. Circulation 114 (8): 855–60.
  15. Levy BI (2005). How to explain the differences between renin angiotensin system modulators. Am. J. Hypertens. 18 (9 Pt 2): 134S–141S.
  16. Lévy BI (2004). Can angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? Implications for therapeutic blockade of the renin-angiotensin system. Circulation 109 (1): 8–13.
  17. Reudelhuber TL (2005). The continuing saga of the AT2 receptor: a case of the good, the bad, and the innocuous. Hypertension 46 (6): 1261–2.
  18. Sipahi I (2010). Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol 11 (7): 627–36.
  19. Angiotensin FDA Drug Safety Communication: No increase in risk of cancer with certain blood pressure drugs--Angiotensin Receptor Blockers (ARBs). U.S. Food and Drug Administration.
  20. Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M, Conti S, Rottoli D, Longaretti L, Cassis P, Morigi M, Coffman T, Remuzzi G (2009). Disruption of the Ang II type 1 receptor promotes longevity in mice. J. Clin. Invest. 119 (3): 524–30.
  21. Cassis P, Conti S, Remuzzi G, Benigni A (2010 Jan). Angiotensin receptors as determinants of life span. Pflugers Arch. 459 (2): 325–32.
  22. Weinberg, Marc S., Adam J. Weinberg, Raymond B Cord, Horace Martin (2003). P-609: Regression of dilated aortic roots using supramaximal and usual doses of angiotensin receptor blockers. American Journal of Hypertension 16 (5): A259.

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