Angiotensin II receptor blocker

Angiotensin II receptor blockers (ARBs), also known as angiotensin II receptor antagonists, AT1 receptor antagonists or sartans, are a group of pharmaceuticals that modulate the renin–angiotensin system. Their main uses are in the treatment of hypertension (high blood pressure), diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure. They selectively block the activation of AT1 receptors, preventing the binding of angiotensin II compared to ACE inhibitors.

ARBs and the similar-attributed ACE inhibitors are both indicated as the first-line antihypertensives in patients developing hypertension along the left-sided heart failure.[1] However, ARBs appear to produce less adverse effects compared to ACE inhibitors.[1]

Medical uses

Angiotensin II receptor blockers are used primarily for the treatment of hypertension where the patient is intolerant of ACE inhibitor therapy primarily because of cough.[2] 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, 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. A 1998 double-blind study found "that lisinopril improved insulin sensitivity whereas losartan did not affect it."[3] Candesartan is used experimentally in preventive treatment of migraine.[4][5] Lisinopril has been found less often effective than candesartan at preventing migraine.[6]

The angiotensin II receptor blockers have differing potencies in relation to blood pressure control, with statistically differing effects at the maximal doses.[7] 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.[8][9]

In one study after 10 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%.[10] 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.[11] Other ARBs include candesartan (Atacand), telmisartan (Micardis), and Valsartan (Diovan), fimasartan (Kanarb).

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.[12]

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.[13][14]

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.[15] A 2014 Cochrane systematic review based on randomized controlled trials reported that when comparing patients taking ACE inhibitors to patients taking ARBs, fewer ARB patients withdrew from the study due to adverse events compared to ACE inhibitor patients.[16]

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.[15]

Myocardial infarction

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.[17] However, other studies have found ARBs do not increase the risk of MI.[18] 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.[19][20][21]


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." [22] A later meta-analysis by the U.S. Food and Drug Administration (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.[23] In 2013, comparative effectiveness research from the United States Department of Veterans Affairs on the experience of more than a million Veterans found no increased risks for either lung cancer [24] (original article in Journal of Hypertension) or prostate cancer.[25] The researchers concluded "In this large nationwide cohort of United States Veterans, we found no evidence to support any concern of increased risk of lung cancer among new users of ARBs compared with nonusers. Our findings were consistent with a protective effect of ARBs."[24]

In May 2013, a senior regulator at the Food & Drug Administration, Medical Team Leader Thomas A. Marciniak, revealed publicly that contrary to the FDA's official conclusion that there was no increased cancer risk, after a patient by patient examination of the available FDA data he had concluded that there was a lung-cancer risk increase of about 24% in ARB patients, compared with patients taking a placebo or other drugs. One of the criticisms Marciniak made was that the earlier FDA meta-analysis did not count lung carcinomas as cancers. In ten of the eleven studies he examined, Marciniak said that there were more lung cancer cases in the ARB group than the control group. Ellis Unger, chief of the drug-evaluation division that includes Dr. Marciniak, was quoted as calling the complaints a "diversion," and saying in an interview, "We have no reason to tell the public anything new." In an article about the dispute, the Wall Street Journal interviewed three other doctors to get their views; one had "no doubt" ARBs increased cancer risk, one was concerned and wanted to see more data, and the third thought there was either no relationship or a hard to detect, low-frequency relationship.[26]

A 2016 meta-analysis including 148,334 patients found no significant differences in cancer incidence associated with ARB use.[27]

Renal failure

ARB inhibitors, although have protective effects against developing kidney diseases for patients with diabetes and previously hypertension without administration of ARBs, may worsen kidney functions such as causing further reduction of glomerular filtration rate associated with rise of serum creatinine in patients suffering practically clinical or already clinically present proteinuria, renal artery stenosis, hypertensive nephrosclerosis, heart failure, polycystic kidney disease, chronic kidney disease, interstitial fibrosis, focal segmental glomerulosclerosis, or any conditions such as ARBs-treated but still clinically hypertension that lead to abnormal narrowing of blood vessels to the kidney that interrupts oxygen and nutrients supply to the organ.[28][29][30][31][32][33]



Losartan, irbesartan, olmesartan, candesartan, valsartan, fimasartan and azilsartan 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. AT1 receptors are found in smooth muscle cells of vessels, cortical cells of the adrenal gland, and adrenergic nerve synapses. 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 (PD) and pharmacokinetic (PK) 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 U.S. Food and Drug Administration (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 affinity vs AT2

The ratios of AT1 to AT2 in binding affinities of the specific ARBs are shown as follows. Whereas, AT1 affinity vs AT2 is not a meaningful efficacy measurement of BP response.

Binding affinities Ki


Nearly all ARBs contain biphenyltetrazole moiety except telmisartan and eprosartan.[35]

Active agent

Losartan carries a heterocycle imidazole while valsartan carries a nonplanar acylated amino acid.[35]

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 U.S. Food and Drug Administration (FDA) Package Inserts (PIs) are as follows:

Comparison and pharmacokinetics

Table 1: Comparison of ARB pharmacokinetics
Drug Trade Name Biological half-life [h] Peak plasma concentration [Tmax] Protein binding [%] Bioavailability [%] Renal/hepatic clearance [%] Food effect Daily dosage [mg] Metabolism/transporter
Losartan Cozaar 6–9 h
  • Losartan: 1 h
  • active metabolite: 3-4 hrs


98.7% 33% 10/90% Minimal 50–100 mg Sensitive substrates: CYP2C9 and CYP3A4[37]
EXP 3174 6–9 h 99.8% 50/50%
Candesartan Atacand 9h 3-4 hrs[38] >99% 15% 60/40% No 4–32 mg Moderate sensitive substrate: CYP2C9[38]
Valsartan Diovan 6 h 2-4 hrs[39] 95% 25% 30/70% No 80–320 mg Substrates:MRP2 and OATP1B1/SLCO1B1[39]
Irbesartan Avapro 11–15 h 1.5 to 2 hrs[40] 90–95% 70% 20/80% No 150–300 mg Minor substrates of CYP2C9[40]
Telmisartan Micardis 24 h 0.5 to 1 hour [41] >99% 42–58% 1/99% No 40–80 mg Unknown[41]
Eprosartan Teveten 5 h 1 to 2 hours [42] 98% 13% 30/70% No 400–800 mg None known [42]
Olmesartan Benicar/Olmetec 14–16 h 1 to 2 hours [43] >99% 29% 40/60% No 10–40 mg Substrates of OATP1B1/SLCO1B1[43]
Azilsartan Edarbi 11 h 1.5 to 3 hours [44] >99% 60% 55/42% No 40–80 mg Minor substrates of CYP2C9 [44]
Fimasartan Kanarb 7–11 h 30 mins to 3 hrs after dosing.[45] >97% 30–40% - - 30–120 mg No related research as of February 2019.


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.[51][52]

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.[53]


In 2018 and in 2019, the U.S Food and Drug Administration (FDA) found traces of NDMA and NDEA impurities in the ARB drug products valsartan, losartan, and irbesartan.[54][55][56][57][58] The FDA stated "In June 2018, FDA was informed of the presence of an impurity, identified as N-Nitrosodimethylamine (NDMA), from one valsartan API producer. Since then, FDA has determined that other types of nitrosamine compounds, e.g., N-Nitrosodiethylamine (NDEA), are present at unacceptable levels in APIs from multiple API producers of valsartan and other drugs in the ARB class."[59] In 2018, the FDA issued guidance to the industry on how to assess and control the impurities.[60]


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