Angiotensin II receptor blocker

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Angiotensin II receptor blocker
Drug class
Losartan, the first ARB
Other namesAngiotensin receptor blockers, angiotensin II receptor type 1 (AT1) antagonists,[1] angiotensin II receptor antagonists, AT1 receptor antagonists
Clinical data
UsesHigh blood pressure, heart failure, coronary heart disease, kidney disease[3]
Side effectsLow blood pressure, high potassium, kidney problems[3]
Common typesCandesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan[4]
External links
Drugs.comDrug Classes

Angiotensin II receptor blockers (ARBs), also known as angiotensin receptor blockers, are a class of medication primarily used to treat high blood pressure, heart failure, coronary heart disease, and kidney disease.[3] They are taken by mouth.[3] Their use with ACE inhibitors is not recommended.[5]

Side effects can include low blood pressure, high potassium, and kidney problems.[3] Kidney problems are more likely in those with renal artery stenosis.[3] Compared to ACE inhibitors they are less likely to cause cough or angioedema.[3] Use during pregnancy can harm the baby.[6] They work by blocking the angiotensin II receptor type 1 (AT1) thereby preventing the effects of angiotensin II.[7] This results in dilation of blood vessels and increased release of water and sodium by the kidneys.[4]

ARBs, specifically losartan, came into medical use in 1995.[8] Some are available as generic medication and are not very expensive.[3] In the United States losartan and irbesartan were the least expensive at about 90 USD per month in 2016.[9] In the United States they are a first line treatment for high blood pressure, along with calcium channel blockers, thiazide diuretics, and ACE inhibitors.[10]


ARBs include candesartan (Atacand), lisinopril, telmisartan (Micardis), and valsartan (Diovan), fimasartan (Kanarb).

A number are also available in combination with HCTZ, chlorthalidone, or amlodipine within a single pill.[9]

Medical uses

Angiotensin II receptor blockers are used primarily for the treatment of hypertension where the person is intolerant of ACE inhibitor therapy primarily because of persistent cough.[11] More recently, they have been used for the treatment of heart failure in people intolerant of ACE inhibitor therapy, in particular candesartan. Irbesartan and losartan have trial data showing benefit in hypertensive patients with type 2 diabetes,[citation needed] and may delay the progression of diabetic nephropathy.[citation needed]

Candesartan is used experimentally in preventive treatment of migraine.[12][13] Lisinopril has been found less often effective than candesartan at preventing migraine.[14]

The angiotensin II receptor blockers have differing potencies in relation to blood pressure control, with statistically differing effects at the maximal doses.[15]

Some of these drugs have a uricosuric effect.[16][17]

In 2008, they were reported to have a negative association with Alzheimer's disease (AD). Those people taking angiotensin receptor blockers (ARBs) were 35–40% less likely to develop AD than those using other antihypertensives.[18][19]

Side 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.[20] 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.[21]

While one of the main rationales for the use of this class is the avoidance of a persistent 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.[20]

Heart attack

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.[22] However, other studies have found ARBs do not increase the risk of MI.[23] 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.[24][25][26]


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." [27] 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.[28] 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 [29] (original article Archived 2014-12-10 at the Wayback Machine in Journal of Hypertension) or prostate cancer.[30] 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."[29]

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.[31]

A 2016 meta-analysis including 148,334 patients found no significant differences in cancer incidence associated with ARB use.[32]

Kidney failure

Although ARBs have protective effects against developing kidney diseases for patients with diabetes and previous hypertension without administration of ARBs,[33] ARBs may worsen kidney functions such as reducing glomerular filtration rate associated with a rise of serum creatinine in patients with pre-existing 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 present hypertension that lead to abnormal narrowing of blood vessels to the kidney that interrupts oxygen and nutrient supply to the organ.[34][35][36][37][38][39][33]

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.[citation needed]


Nearly all ARBs contain biphenyltetrazole moiety except telmisartan and eprosartan.[41]

Active agent

Losartan carries a heterocycle imidazole while valsartan carries a nonplanar acylated amino acid.[41]

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)[clarification needed] are as follows:[citation needed]


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.


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


98.7% 33% 10/90% Minimal 50–100 Sensitive substrates: CYP2C9 and CYP3A4[43]
EXP 3174 6–9 99.8% 50/50%
Candesartan Atacand 9 3–4 hrs[44] >99% 15% 60/40% No 4–32 Moderate sensitive substrate: CYP2C9[44]
Valsartan Diovan 6 2–4 hrs[45] 95% 25% 30/70% No 80–320 Substrates:MRP2 and OATP1B1/SLCO1B1[45]
Irbesartan Avapro 11–15 1.5–2 hrs[46] 90–95% 70% 20/80% No 150–300 Minor substrates of CYP2C9[46]
Telmisartan Micardis 24 0.5–1 hr [47] >99% 42–58% 1/99% No 40–80 Unknown[47]
Eprosartan Teveten 5 1–2 hrs [48] 98% 13% 30/70% No 400–800 None known [48]
Olmesartan Benicar/Olmetec 14–16 1–2 hrs [49] >99% 29% 40/60% No 10–40 Substrates of OATP1B1/SLCO1B1[49]
Azilsartan Edarbi 11 1.5–3 hrs [50] >99% 60% 55/42% No 40–80 Minor substrates of CYP2C9 [50]
Fimasartan Kanarb 7–11 0.5–3 hrs after dosing.[51] >97% 30–40% 30–120 No related research as of February 2019.
Drug Trade name Biological half-life [hrs] Peak plasma concentration [Tmax] Protein binding [%] Bioavailability [%] Renal/hepatic clearance [%] Food effect Daily dosage [mg] Metabolism/transporter



Society and culture


In 2018 and in 2019, the U.S Food and Drug Administration (FDA) found traces of NDMA and NDEA impurities in the angiotensin II receptor blocker (ARB) drug products valsartan, losartan, and irbesartan.[57][58][59][60][61] 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."[62] In 2018, the FDA issued guidance to the industry on how to assess and control the impurities.[63]

In August 2020, the European Medicines Agency (EMA) provided guidance to marketing authorization holders on how to avoid the presence of nitrosamine impurities in human medicines and asked them to review all chemical and biological human medicines for the possible presence of nitrosamines and to test the products at risk.[64]

In November 2020, the Committee for Medicinal Products for Human Use (CHMP) of the EMA aligned recommendations for limiting nitrosamine impurities in sartan medicines with recommendations it issued for other classes of medicines.[65] The main change concerns the limits for nitrosamines, which previously applied to the active ingredients but now apply instead to the finished products (e.g. tablets).[65] These limits, based on internationally agreed standards (ICH M7(R1)), should ensure that the excess risk of cancer from nitrosamines in any sartan medicines is below 1 in 100,000 for a person taking the medicine for lifelong treatment.[65]

These sartan medicines have a specific ring structure (tetrazole) whose synthesis could potentially lead to the formation of nitrosamine impurities.[65][66] Other sartan medicines which do not have this ring, such as azilsartan, eprosartan and telmisartan, were not included in this review but are covered by the subsequent review of other medicines.[65]


Knockout of the Agtr1a gene that encodes AT1 results in 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.[67][68]


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