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Angiotensin ll receptor antagonist

Angiotensin II receptor antagonist

Angiotensin II receptor antagonists, also known as angiotensin receptor blockers (ARBs), AT1-receptor antagonists or sartans, are a group of pharmaceuticals which 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.


Losartan, the first ARB




  • 1 Discovery and development
  • 2 Structure
  • 3 Mechanism of action
    • 3.1 Pressor inhibition
    • 3.2 AT1 affinity
    • 3.3 Biological half-life
  • 4 Drug comparison and pharmacokinetics
  • 5 Uses
  • 6 Adverse effects
    • 6.1 Myocardial infarction: the controversy
    • 6.2 Cancer risk factors
  • 7 Longevity promotion
  • 8 Fibrosis regression
  • 9 Dilated aortic root regression
  • Discovery and development?


    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 action

    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, amongst 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 inhibition

    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)

    • Valsartan 80 mg 30%
    • Telmisartan 80 mg 40%
    • Losartan 100 mg 25–40%
    • Irbesartan 150 mg 40%
    • Irbesartan 300 mg 60%
    • Azilsartan 32 mg 60%
    • Olmesartan 20 mg 61%
    • Olmesartan 40 mg 74%

    AT1 affinity

    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:

    • Losartan 1000 fold
    • Telmisartan 3000 fold
    • Irbesartan 8500 fold
    • Azilsartan greater than 10000 fold
    • Olmesartan 12500 fold
    • Valsartan 20000 fold

    Biological half-life

    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:

    • Valsartan 6 hours
    • Losartan 6–9 hours
    • Azilsartan 11 hours
    • Irbesartan 11–15 hours
    • Olmesartan 13 hours
    • Telmisartan 24 hours


    Drug comparison and pharmacokinetics

    Table 1: Comparison of ARB pharmacokinetics
    DrugTrade NameBiological half-life [h]Protein binding [%]Bioavailability [%]Renal/hepaticclearance [%]Food effectDaily 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



    Angiotensin II receptor antagonists are primarily used for the treatment of hypertension where the patient is intolerant of ACE inhibitortherapy. 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. More recently, they have been used for the treatment of heart failure in patients intolerant of ACE inhibitor therapy, particularly 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.

    The angiotensin II receptor blockers have differing potencies in relation to BP control, with statistically differing BP effects at the maximal doses. 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.

    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.

    Adverse effects

    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.

    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. Additionally, there is also a small risk of cross-reactivity in patients who have experienced angioedemawith ACE inhibitor therapy.

    Myocardial infarction: the controversy

    The issue of whether angiotensin II receptor antagonists slightly increase the risk of heart attack (myocardial infarction - MI) is currently being investigated. Some studies suggest ARBs can increase the risk of myocardial infarction.However, other studies have found that ARBs do not increase the risk of MI.To date, there is no consensus on whether ARBs have a tendency to increase the risk of myocardial infarction, and 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. Unfortunately, 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 proatherogenic andproinflammatory effects.

    Cancer risk factors

    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." 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.

    Longevity promotion

    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.

    Fibrosis regression

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

    Dilated aortic root regression

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

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