Angiotensin II receptor blocker

Angiotensin II receptor blockers are used primarily for the treatment of hypertension where the patient is intolerant of ACE inhibitor therapy primarily because of persistent and/or dry cough.{{Cite web |title=Choice of drug therapy in primary (essential) hypertension |url=https://www.uptodate.com/contents/choice-of-drug-therapy-in-primary-essential-hypertension |access-date=2019-02-03 |website=UpToDate}}{{Cite journal |last=Hu |first=Yiyun |title=Angiotensin-converting enzyme inhibitor induced cough compared with placebo, and other antihypertensives: A systematic review, and network meta-analysis |journal=Journal of Clinical Hypertension (Greenwich, Conn.) |date=2023 |volume=25 |issue=8 |pages=661–688 |doi=10.1111/jch.14695 |pmid=37417783 |pmc=10423763 }} 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|date=August 2012}} 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 2 diabetes,{{citation needed|date=November 2013}} and may delay the progression of diabetic nephropathy.{{citation needed|date=November 2013}} A 1998 double-blind study found "that lisinopril improved insulin sensitivity whereas losartan did not affect it."{{Cite journal |vauthors=Fogari R, Zoppi A, Corradi L, Lazzari P, Mugellini A, Lusardi P |date=November 1998 |title=Comparative effects of lisinopril and losartan on insulin sensitivity in the treatment of non diabetic hypertensive patients |journal=British Journal of Clinical Pharmacology |volume=46 |issue=5 |pages=467–71 |doi=10.1046/j.1365-2125.1998.00811.x |pmc=1873694 |pmid=9833600}} Candesartan is used experimentally in preventive treatment of migraine.{{Cite journal |vauthors=Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G |date=January 2003 |title=Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial |journal=JAMA |volume=289 |issue=1 |pages=65–9 |doi=10.1001/jama.289.1.65 |pmid=12503978 |s2cid=35939042}}{{Cite journal |vauthors=Cernes R, Mashavi M, Zimlichman R |year=2011 |title=Differential clinical profile of candesartan compared to other angiotensin receptor blockers |journal=Vascular Health and Risk Management |volume=7 |pages=749–59 |doi=10.2147/VHRM.S22591 |pmc=3253768 |pmid=22241949 |doi-access=free}} Lisinopril has been found less often effective than candesartan at preventing migraine.{{Cite journal |vauthors=Gales BJ, Bailey EK, Reed AN, Gales MA |date=February 2010 |title=Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for the prevention of migraines |journal=The Annals of Pharmacotherapy |volume=44 |issue=2 |pages=360–6 |doi=10.1345/aph.1M312 |pmid=20086184 |s2cid=207263658}}

The angiotensin II receptor blockers have differing potencies in relation to blood pressure control, with statistically differing effects at the maximal doses.{{Cite journal |vauthors=Kassler-Taub K, Littlejohn T, Elliott W, Ruddy T, Adler E |date=April 1998 |title=Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan in mild-to-moderate hypertension. Irbesartan/Losartan Study Investigators |journal=American Journal of Hypertension |volume=11 |issue=4 Pt 1 |pages=445–53 |doi=10.1016/S0895-7061(97)00491-3 |pmid=9607383 |doi-access=free}} When used in clinical practice, the particular agent used may vary based on the degree of response required.{{cn|date=February 2025}}

Some of these drugs have a uricosuric effect.{{Cite journal |vauthors=Dang A, Zhang Y, Liu G, Chen G, Song W, Wang B |date=January 2006 |title=Effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia in Chinese population |journal=Journal of Human Hypertension |volume=20 |issue=1 |pages=45–50 |doi=10.1038/sj.jhh.1001941 |pmid=16281062 |s2cid=25534200}}{{Cite journal |vauthors=Daskalopoulou SS, Tzovaras V, Mikhailidis DP, Elisaf M |year=2005 |title=Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia |journal=Current Pharmaceutical Design |volume=11 |issue=32 |pages=4161–75 |doi=10.2174/138161205774913309 |pmid=16375738}}

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.{{Cite journal |vauthors=Pavel J, Benicky J, Murakami Y, Sanchez-Lemus E, Saavedra JM |date=December 2008 |title=Peripherally administered angiotensin II AT1 receptor antagonists are anti-stress compounds in vivo |journal=Annals of the New York Academy of Sciences |volume=1148 |issue=1 |pages=360–6 |bibcode=2008NYASA1148..360P |doi=10.1196/annals.1410.006 |pmc=2659765 |pmid=19120129}}

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 to 40% less likely to develop AD than those using other antihypertensives.{{Cite journal |author-link7=Benjamin Wolozin |vauthors=Li NC, Lee A, Whitmer RA, Kivipelto M, Lawler E, Kazis LE, Wolozin B |date=January 2010 |title=Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis |journal=BMJ |volume=340 |issue=9 |pages=b5465 |doi=10.1136/bmj.b5465 |pmc=2806632 |pmid=20068258}}{{Cite journal |date=September 2008 |title=Potential of antihypertensive drugs for the prevention and treatment of Alzheimer's disease |journal=Expert Review of Neurotherapeutics |volume=8 |issue=9 |pages=1285–1287 |doi=10.1586/14737175.8.9.1285 |doi-access=free}}

A retrospective study of 1,968 stroke patients revealed that prestroke treatment with ARB may be associated with both reduced stroke severity and better outcome. This finding agrees with experimental data that suggest that ARB's exert a cerebral protective effect.{{Cite journal |last=Fuentes |first=Blanca |date=2010 |title=Treatment with angiotensin receptor blockers before stroke could exert a favourable effect in acute cerebral infarction |journal=Journal of Hypertension |volume=28 |issue=3 |pages=575–581 |doi=10.1097/HJH.0b013e3283350f50 |pmid=20090554 |s2cid=28972688}}

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.Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. 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.{{Cite journal |vauthors=Li EC, Heran BS, Wright JM |date=August 2014 |title=Angiotensin converting enzyme (ACE) inhibitors versus angiotensin receptor blockers for primary hypertension |journal=The Cochrane Database of Systematic Reviews |volume=2014 |issue=8 |pages=CD009096 |doi=10.1002/14651858.CD009096.pub2 |pmc=6486121 |pmid=25148386}}

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.

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.{{Cite journal |vauthors=Strauss MH, Hall AS |date=August 2006 |title=Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox |journal=Circulation |volume=114 |issue=8 |pages=838–54 |doi=10.1161/CIRCULATIONAHA.105.594986 |pmid=16923768 |doi-access=free}} However, other studies have found ARBs do not increase the risk of MI.{{Cite journal |vauthors=Tsuyuki RT, McDonald MA |date=August 2006 |title=Angiotensin receptor blockers do not increase risk of myocardial infarction |journal=Circulation |volume=114 |issue=8 |pages=855–60 |doi=10.1161/CIRCULATIONAHA.105.594978 |pmid=16923769 |doi-access=free}} To date, with no consensus on whether ARBs have a tendency to increase the risk of myocardial infarction, further investigations are underway.{{old fact|2022|7|26}}

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.{{Cite journal |vauthors=Levy BI |date=September 2005 |title=How to explain the differences between renin angiotensin system modulators |journal=American Journal of Hypertension |volume=18 |issue=9 Pt 2 |pages=134S–141S |doi=10.1016/j.amjhyper.2005.05.005 |pmid=16125050 |doi-access=free}}{{Cite journal |vauthors=Lévy BI |date=January 2004 |title=Can angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? Implications for therapeutic blockade of the renin-angiotensin system |journal=Circulation |volume=109 |issue=1 |pages=8–13 |doi=10.1161/01.CIR.0000096609.73772.C5 |pmid=14707017 |doi-access=free}}{{Cite journal |vauthors=Reudelhuber TL |date=December 2005 |title=The continuing saga of the AT2 receptor: a case of the good, the bad, and the innocuous |journal=Hypertension |volume=46 |issue=6 |pages=1261–2 |doi=10.1161/01.HYP.0000193498.07087.83 |pmid=16286568}}

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."{{Cite journal |vauthors=Sipahi I, Debanne SM, Rowland DY, Simon DI, Fang JC |date=July 2010 |title=Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials |journal=The Lancet. Oncology |volume=11 |issue=7 |pages=627–36 |doi=10.1016/S1470-2045(10)70106-6 |pmc=4070221 |pmid=20542468}} 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.{{Cite web |date=2 June 2011 |title=Angiotensin FDA Drug Safety Communication: No increase in risk of cancer with certain blood pressure drugs – Angiotensin Receptor Blockers (ARBs) |url=https://www.fda.gov/Drugs/DrugSafety/ucm257516.htm |url-status=dead |archive-url=https://web.archive.org/web/20111208185025/https://www.fda.gov/Drugs/DrugSafety/ucm257516.htm |archive-date=8 December 2011 |publisher=Food and Drug Administration (FDA)}} 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{{Cite journal |display-authors=6 |vauthors=Rao GA, Mann JR, Shoaibi A, Pai SG, Bottai M, Sutton SS, Haddock KS, Bennett CL, Hebert JR |date=August 2013 |title=Angiotensin receptor blockers: are they related to lung cancer? |journal=Journal of Hypertension |volume=31 |issue=8 |pages=1669–75 |doi=10.1097/HJH.0b013e3283621ea3 |pmc=3879726 |pmid=23822929}} or prostate cancer.{{Cite journal |display-authors=6 |vauthors=Rao GA, Mann JR, Bottai M, Uemura H, Burch JB, Bennett CL, Haddock KS, Hébert JR |date=July 2013 |title=Angiotensin receptor blockers and risk of prostate cancer among United States veterans |journal=Journal of Clinical Pharmacology |volume=53 |issue=7 |pages=773–8 |doi=10.1002/jcph.98 |pmc=3768141 |pmid=23686462}} 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."

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 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.{{Cite news |last=Burton |first=Thomas M. |date=31 May 2013 |title=Dispute Flares Inside FDA Over Safety of Popular Blood-Pressure Drugs |url=https://www.wsj.com/articles/SB10001424127887324682204578515172395384146 |url-status=live |archive-url=https://web.archive.org/web/20180215023701/https://www.wsj.com/articles/SB10001424127887324682204578515172395384146 |archive-date=15 February 2018 |access-date=1 May 2018 |work=The Wall Street Journal}}

A 2016 meta-analysis including 148,334 patients found no significant differences in cancer incidence associated with ARB use.{{Cite journal |vauthors=Zhao YT, Li PY, Zhang JQ, Wang L, Yi Z |date=May 2016 |title=Angiotensin II Receptor Blockers and Cancer Risk: A Meta-Analysis of Randomized Controlled Trials |journal=Medicine |volume=95 |issue=18 |pages=e3600 |doi=10.1097/MD.0000000000003600 |pmc=4863811 |pmid=27149494}}

Although ARBs have protective effects against developing kidney diseases for patients with diabetes and previous hypertension without administration of ARBs, 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.{{Cite journal |vauthors=Toto RD, Mitchell HC, Lee HC, Milam C, Pettinger WA |date=October 1991 |title=Reversible renal insufficiency due to angiotensin converting enzyme inhibitors in hypertensive nephrosclerosis |journal=Annals of Internal Medicine |volume=115 |issue=7 |pages=513–9 |doi=10.7326/0003-4819-115-7-513 |pmid=1883120}}{{Cite journal |vauthors=Bakris GL, Weir MR |date=March 2000 |title=Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? |journal=Archives of Internal Medicine |volume=160 |issue=5 |pages=685–93 |doi=10.1001/archinte.160.5.685 |pmid=10724055}}{{Cite journal |vauthors=Remuzzi G, Ruggenenti P, Perico N |date=April 2002 |title=Chronic renal diseases: renoprotective benefits of renin-angiotensin system inhibition |journal=Annals of Internal Medicine |volume=136 |issue=8 |pages=604–15 |doi=10.7326/0003-4819-136-8-200204160-00010 |pmid=11955029 |s2cid=24795760}}{{Cite journal |vauthors=Sarafidis PA, Khosla N, Bakris GL |date=January 2007 |title=Antihypertensive therapy in the presence of proteinuria |journal=American Journal of Kidney Diseases |volume=49 |issue=1 |pages=12–26 |doi=10.1053/j.ajkd.2006.10.014 |pmid=17185142 |s2cid=18337587}}{{Cite journal |vauthors=Weir MR |date=October 2002 |title=Progressive renal and cardiovascular disease: optimal treatment strategies |journal=Kidney International |volume=62 |issue=4 |pages=1482–92 |doi=10.1111/j.1523-1755.2002.kid591.x |pmid=12234333 |doi-access=free}}{{Cite journal |last=Tom Hostetter |first=M. D. |date=June 2004 |title=ACE Inhibitors and ARBs in Patients with Kidney Disease |url=https://www.pharmacytimes.com/publications/issue/2004/2004-06/2004-06-8008 |journal=Pharmacy Times |access-date=2019-02-05}}{{Cite book |last1=Tucker |first1=Bryan M. |title=Nephrology Secrets |last2=Perazella |first2=Mark A. |publisher=Elsevier |year=2019 |isbn=978-0-323-47871-7 |pages=78–83 |chapter=Medications: 3. What are the major adverse effects on the kidney of ACE inhibitors and ARBs? |doi=10.1016/b978-0-323-47871-7.00019-8 |quote=due to inhibition of angiotensin II production by ACE inhibitors or competitive antagonism of the angiotensin II receptor by ARBs... results in loss of angiotensin II–induced efferent arteriolar tone, leading to a drop in glomerular filtration fraction and GFR. The efferent arteriolal vasodilation reduces intraglomerular hypertension (and pressure-related injury) and maintains perfusion (and oxygenation) of the peritubular capillaries. |s2cid=239423283}}{{citation overkill|date=March 2023}}

{{further|Discovery and development of angiotensin receptor blockers}}

Losartan, irbesartan, olmesartan, candesartan, valsartan, fimasartan include the tetrazole group (a ring with four nitrogen and one carbon). Losartan, irbesartan, olmesartan, candesartan, and telmisartan include one or two imidazole groups.{{cn|date=February 2025}}

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.{{cn|date=March 2023}}

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.{{cn|date=March 2023}}

Pressor inhibition at trough level {{emdash}} 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:{{cn|date=February 2025}}

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

The ratios of AT₁ to AT₂ in binding affinities of the specific ARBs are shown as follows. However, AT₁ affinity vs AT₂ is not a meaningful indicator of blood pressure response.{{Cite journal |last1=Miura |first1=S |last2=Karnik |first2=SS |last3=Saku |first3=K |date=March 2011 |title=Review: angiotensin II type 1 receptor blockers: class effects versus molecular effects. |journal=Journal of the Renin-Angiotensin-Aldosterone System |volume=12 |issue=1 |pages=1–7 |doi=10.1177/1470320310370852 |pmc=3891529 |pmid=20603272}}

• Losartan{{snd}} 1000-fold{{Citation needed|date=March 2021}}
• Telmisartan{{snd}} 3000-fold{{Citation needed|date=March 2021}}
• Irbesartan{{snd}} 8500-fold{{Citation needed|date=March 2021}}
• Candesartan{{snd}} greater than 10000-fold{{Citation needed|date=March 2021}}
• Olmesartan{{snd}} 12500-fold{{Citation needed|date=March 2021}}
• Valsartan{{snd}} 30000-fold{{Cite journal |last1=Kjeldsen |first1=Sverre E |last2=Brunner |first2=Hans R |last3=McInnes |first3=Gordon T |last4=Stolt |first4=Pelle |year=2005 |title=Valsartan in the treatment of hypertension |journal=Aging Health |publisher=Future Medicine Ltd |volume=1 |issue=1 |pages=27–36 |doi=10.2217/1745509x.1.1.27}}{{Cite journal |vauthors=Siragy HM |date=November 2002 |title=Angiotensin receptor blockers: how important is selectivity? |journal=American Journal of Hypertension |volume=15 |issue=11 |pages=1006–14 |doi=10.1016/s0895-7061(02)02280-x |pmid=12441224 |doi-access=free}}
• Saprisartan – ???{{Cite web |title=Saprisartan |url=http://www.drugbank.ca/drugs/DB01347 |url-status=live |archive-url=https://web.archive.org/web/20160928101722/http://www.drugbank.ca/drugs/DB01347 |archive-date=28 September 2016 |access-date=1 May 2018 |website=drugbank.ca}}

{{expand section|date=May 2019}}

Nearly all ARBs contain biphenyltetrazole moiety except telmisartan and eprosartan.

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

File:Angiotensin II Type 1 Receptor.png

In one report, to determine the structure and binding mode of AT₁R blockers a small molecule antagonist (ZD7155) was used. This antihypertensive compound is a precursor to the drug candesartan, and as such, possess a biphenyl-tetrazole moiety similar to other AT₁R blockers. ZD7155 was shown to make several key interactions within the active sight, revealing the binding mode of AT₁R blockers.

File:AT1 active site pp labels.png

Through X-Ray Crystallography, one studied showed that there are three key side chains involved in the inhibition of AT₁R. Arg167, Trp84, and Tyr35 were shown to interact with AT₁R blocker compounds through ionic bonding, hydrogen bonding, and π-π interactions within the active site of AT₁R. Then through competitive inhibition these antihypertensive compounds render the AT₁R inactive and therefore produce the intended therapeutic effects.

{{Citation |last1=Burnier |first1=M. |title=Angiotensin II receptor antagonists |journal=Lancet |volume=355 |issue=9204 |pages=637–645 |year=2000 |doi=10.1016/S0140-6736(99)10365-9 |pmid=10696996 |s2cid=18835715 |last2=Brunner |first2=H. R.}}Analogue-based Drug Discovery (Optimizing Antihypertensive Therapy by Angiotensin Receptor Blockers; Farsang, C., Fisher, J., p.157–167) Editors; Fischer, J., Ganellin, R. Wiley-VCH 2006. {{ISBN|978-3-527-31257-3}}{{Citation |last1=Brousil |first1=J. A. |title=Olmesartan Medoxomil: An Angiotensin II-Receptor Blocker |journal=Clinical Therapeutics |volume=25 |issue=4 |pages=1041–1055 |year=2003 |doi=10.1016/S0149-2918(03)80066-8 |pmid=12809956 |last2=Burke |first2=J. M.}}{{Citation |last=Brunner |first=H. R. |title=The new oral angiotensin II antagonist olmesartan medoxomil: a concise overview |journal=Journal of Human Hypertension |volume=16 |issue=2 |pages=13–16 |year=2002 |doi=10.1038/sj.jhh.1001391 |pmid=11967728 |s2cid=24382600 |id={{ProQuest|219966061}}}}{{Citation |last1=Zusman |first1=R. M. |title=Are There Differences Among Angiotensin Receptor Blockers? |journal=American Journal of Hypertension |volume=12 |issue=2 Pt 1 |pages=231–235 |year=1999 |doi=10.1016/S0895-7061(99)00116-8 |pmid=10090354 |last2=Jullien |first2=V. |last3=Lemetayer |first3=P. |last4=Jarnier |first4=P. |last5=Clementy |first5=J. |doi-access=free}}

{{further|Discovery and development of angiotensin receptor blockers}}

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.{{Cite journal |display-authors=6 |vauthors=Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M, Conti S, Rottoli D, Longaretti L, Cassis P, Morigi M, Coffman TM, Remuzzi G |date=March 2009 |title=Disruption of the Ang II type 1 receptor promotes longevity in mice |journal=The Journal of Clinical Investigation |volume=119 |issue=3 |pages=524–30 |doi=10.1172/JCI36703 |pmc=2648681 |pmid=19197138}}{{Cite journal |vauthors=Cassis P, Conti S, Remuzzi G, Benigni A |date=January 2010 |title=Angiotensin receptors as determinants of life span |journal=Pflügers Archiv |volume=459 |issue=2 |pages=325–32 |doi=10.1007/s00424-009-0725-4 |pmid=19763608 |s2cid=24404339}}

ARBs, such as losartan, have been shown to curb or reduce muscular,{{Cite journal |last1=Hubbert |first1=Katherine |last2=Clement |first2=Ryan |date=April 2021 |title=Losartan: A Novel Treatment for Acute Skeletal Muscle Injury |url=https://journals.lww.com/jbjsjopa/Abstract/2021/06000/Losartan__A_Novel_Treatment_for_Acute_Skeletal.2.aspx |journal=JBJS Journal of Orthopaedics for Physician Assistants |volume=9 |issue=2 |doi=10.2106/JBJS.JOPA.20.00030 |issn=2470-1122 |s2cid=242846521 |access-date=14 April 2022|url-access=subscription }} liver,{{Cite journal |last1=Salama |first1=Zakaria A. |last2=Sadek |first2=Ahmed |last3=Abdelhady |first3=Ahmed M. |last4=Darweesh |first4=Samar Kamal |last5=Morsy |first5=Shereif Ahmed |last6=Esmat |first6=Gamal |date=June 2016 |title=Losartan may inhibit the progression of liver fibrosis in chronic HCV patients |journal=Hepatobiliary Surgery and Nutrition |volume=5 |issue=3 |pages=249–255 |doi=10.21037/hbsn.2016.02.06 |issn=2304-3881 |pmc=4876242 |pmid=27275467 |doi-access=free}} cardiac,{{Cite journal |last1=Wang |first1=J |last2=Duan |first2=L |last3=Gao |first3=Y |last4=Zhou |first4=S |last5=Liu |first5=Y |last6=Wei |first6=S |last7=An |first7=S |last8=Liu |first8=J |last9=Tian |first9=L |last10=Wang |first10=S |date=5 September 2018 |title=Angiotensin II receptor blocker valsartan ameliorates cardiac fibrosis partly by inhibiting miR-21 expression in diabetic nephropathy mice. |url=https://doi.org/10.1016/j.mce.2017.12.005 |journal=Molecular and Cellular Endocrinology |volume=472 |pages=149–158 |doi=10.1016/j.mce.2017.12.005 |pmid=29233785 |s2cid=6615686 |access-date=14 April 2022|url-access=subscription }} and kidney{{Cite journal |last1=Naito |first1=T |last2=Ma |first2=LJ |last3=Yang |first3=H |last4=Zuo |first4=Y |last5=Tang |first5=Y |last6=Han |first6=JY |last7=Kon |first7=V |last8=Fogo |first8=AB |date=March 2010 |title=Angiotensin type 2 receptor actions contribute to angiotensin type 1 receptor blocker effects on kidney fibrosis. |journal=American Journal of Physiology. Renal Physiology |volume=298 |issue=3 |pages=F683-91 |doi=10.1152/ajprenal.00503.2009 |pmc=2838584 |pmid=20042458}} fibrosis.

A 2003 study using candesartan and valsartan demonstrated an ability to regress dilated aortic root size.{{Cite journal |vauthors=Weinberg MS, Weinberg AJ, Cord RB, Martin H |date=1 May 2003 |title=P-609: Regression of dilated aortic roots using supramaximal and usual doses of angiotensin receptor blockers |journal=American Journal of Hypertension |volume=16 |issue=S1 |pages=259A |doi=10.1016/S0895-7061(03)00782-9 |issn=0895-7061 |quote=In conclusion, we demonstrated regression of DAR using ARBs at moderate and supramaximal doses. Intensive ARB therapy offers a promise to reduce the natural progression of disease in patients with DARs. |doi-access=free}}

{{Anchor|recalls}}

{{See also|Ranitidine#impurities}}

In June 2018, the US 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.{{Cite web |date=20 August 2018 |title=FDA Updates and Press Announcements on Angiotensin II Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan) |url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-angiotensin-ii-receptor-blocker-arb-recalls-valsartan-losartan |archive-url=https://web.archive.org/web/20190428204904/https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-angiotensin-ii-receptor-blocker-arb-recalls-valsartan-losartan |url-status=dead |archive-date=April 28, 2019 |access-date=17 September 2019 |website=Food and Drug Administration (FDA)}}{{Cite web |date=28 August 2019 |title=Statement on the agency's ongoing efforts to resolve safety issue with ARB medications |url=https://www.fda.gov/news-events/press-announcements/statement-agencys-ongoing-efforts-resolve-safety-issue-arb-medications |archive-url=https://web.archive.org/web/20190828154612/https://www.fda.gov/news-events/press-announcements/statement-agencys-ongoing-efforts-resolve-safety-issue-arb-medications |url-status=dead |archive-date=August 28, 2019 |access-date=17 September 2019 |website=Food and Drug Administration (FDA)}}{{Cite web |date=4 April 2019 |title=FDA's Assessment of Currently Marketed ARB Drug Products |url=https://www.fda.gov/drugs/drug-safety-and-availability/fdas-assessment-currently-marketed-arb-drug-products |url-status=dead |archive-url=https://web.archive.org/web/20191230180654/https://www.fda.gov/drugs/drug-safety-and-availability/fdas-assessment-currently-marketed-arb-drug-products |archive-date=30 December 2019 |access-date=17 September 2019 |website=Food and Drug Administration (FDA)}}{{Cite web |date=28 June 2019 |title=Search List of Recalled Angiotensin II Receptor Blockers (ARBs) including Valsartan, Losartan and Irbesartan |url=https://www.fda.gov/drugs/drug-safety-and-availability/search-list-recalled-angiotensin-ii-receptor-blockers-arbs-including-valsartan-losartan-and |access-date=17 September 2019 |website=Food and Drug Administration (FDA)}}{{Cite web |date=23 September 2019 |title=Updated: Torrent Pharmaceuticals Limited Expands Voluntary Nationwide Recall of Losartan Potassium Tablets, USP and Losartan Potassium / Hydrochlorothiazide Tablets, USP |url=https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/updated-torrent-pharmaceuticals-limited-expands-voluntary-nationwide-recall-losartan-potassium-0 |archive-url=https://web.archive.org/web/20190924062123/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/updated-torrent-pharmaceuticals-limited-expands-voluntary-nationwide-recall-losartan-potassium-0 |url-status=dead |archive-date=September 24, 2019 |access-date=24 September 2019 |website=U.S. Food and Drug Administration}} The FDA stated "In June 2018, FDA was informed of the presence of an impurity, identified as N-Nitrosodimethylamine (NDMA), from onevalsartan 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."{{Cite web |title=General Advice ARB |url=https://www.fda.gov/media/122643/download |archive-url=https://web.archive.org/web/20191112235059/https://www.fda.gov/media/122643/download |url-status=dead |archive-date=November 12, 2019 |access-date=17 September 2019 |website=Food and Drug Administration (FDA) |format=PDF}} {{PD-notice}} In 2018, the FDA issued guidance to the industry on how to assess and control the impurities.{{Cite web |date=30 August 2018 |title=M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk |url=https://www.fda.gov/media/85885/download |archive-url=https://web.archive.org/web/20190828154728/https://www.fda.gov/media/85885/download |url-status=dead |archive-date=August 28, 2019 |access-date=17 September 2019 |website=Food and Drug Administration (FDA) |format=PDF}}

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.{{Cite web |date=23 October 2019 |title=Nitrosamine impurities |url=https://www.ema.europa.eu/en/human-regulatory/post-authorisation/referral-procedures/nitrosamine-impurities |access-date=6 August 2020 |website=European Medicines Agency}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

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. 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). 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.{{Cite press release |title=Nitrosamines: EMA aligns recommendations for sartans with those other medicines |date=12 November 2020 |url=https://www.ema.europa.eu/en/news/nitrosamines-ema-aligns-recommendations-sartans-those-other-medicines |access-date=13 November 2020 |website=European Medicines Agency (EMA)}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

These sartan medicines have a specific ring structure (tetrazole) whose synthesis could potentially lead to the formation of nitrosamine impurities.{{Cite web |date=17 September 2018 |title=Angiotensin-II-receptor antagonists (sartans) containing a tetrazole group |url=https://www.ema.europa.eu/en/medicines/human/referrals/angiotensin-ii-receptor-antagonists-sartans-containing-tetrazole-group |access-date=13 November 2020 |website=European Medicines Agency (EMA)}} 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.

The FDA issued revised guidelines about nitrosamine impurities in September 2024.{{Cite web |date=24 February 2021 |title=Control of Nitrosamine Impurities in Human Drugs |url=https://www.fda.gov/regulatory-information/search-fda-guidance-documents/control-nitrosamine-impurities-human-drugs |archive-url=https://web.archive.org/web/20200901235726/https://www.fda.gov/regulatory-information/search-fda-guidance-documents/control-nitrosamine-impurities-human-drugs |url-status=dead |archive-date=September 1, 2020 |access-date=6 September 2024 |website=U.S. Food and Drug Administration}}

{{multiple image | width1 = 200 | image1 = Losartan azide.svg | alt1 = Skeletal formula of losartan azide | width2 = 180 | image2 = AZBT.svg | alt2 = Skeletal formula of azidomethyl-biphenyl-tetrazole | footer = Losartan azide (left) and AZBT (right), two azido process impurities detected in sartans. Losartan azide occurs exclusively during manufacture of losartan, while AZBT can be found in several drugs in the class.}}

In April 2021, the European Directorate for the Quality of Medicines (EDQM) warned of the risk of contamination with non-nitrosamine impurities (specifically, azido compounds) in tetrazole-containing sartans.{{Cite press release |title=Risk of presence of mutagenic azido impurities in sartan active substances with a tetrazole ring |date=29 April 2021 |publisher=European Directorate for the Quality of Medicines & HealthCare |url=https://www.edqm.eu/en/-/risk-of-presence-of-mutagenic-azido-impurities-in-sartan-active-substances-with-a-tetrazole-ring |accessdate=26 June 2022}} In September 2021, the EDQM announced that investigations had revealed a novel azido contaminant which occurs only in losartan (losartan azide or losartan azido impurity) and which was found to be mutagenic on Ames testing.{{Cite press release |title=Risk of the presence of mutagenic azido impurities in losartan active substance |date=29 September 2021 |publisher=European Directorate for the Quality of Medicines & HealthCare |url=https://www.edqm.eu/en/-/risk-of-the-presence-of-mutagenic-azido-impurities-in-losartan-active-substance |accessdate=26 June 2022}}

Later in 2021 and 2022, several cases of contamination with azido impurities were detected in losartan, irbesartan, and valsartan, prompting regulatory responses ranging from investigation to market withdrawals and precautionary recalls in Australia,{{Cite web |last=Therapeutic Goods Administration (TGA) |author-link=Therapeutic Goods Administration |date=20 August 2021 |title=Azide impurity in 'sartan' blood pressure medicines |url=https://www.tga.gov.au/alert/azide-impurity-sartan-blood-pressure-medicines#:~:text=What%20is%20the%20azide%20impurity,individual's%20risk%20of%20developing%20cancer. |access-date=26 June 2022}} Brazil,{{Cite web |date=23 June 2022 |title=Losartana: Anvisa determina recolhimento e interdição de lotes; veja o que fazer |url=https://g1.globo.com/saude/noticia/2022/06/23/losartana-anvisa-determina-recolhimento-de-lotes-veja-o-que-fazer.ghtml |access-date=26 June 2022 |website=g1 |publisher=Grupo Globo |language=Portuguese}} and Europe (including Switzerland).{{Cite web |last=Chapman |first=Kit |date=29 June 2021 |title=Sartan contaminant recall hits generics manufacturers |url=https://www.chemistryworld.com/news/sartan-contaminant-recall-hits-generics-manufacturers/4013911.article |access-date=26 June 2022 |website=Chemistry World}}{{Cite web |last=Swissmedic |date=1 July 2021 |title=Monitoring of sartan medicines stepped up: traces of a new foreign substance detected |url=https://www.swissmedic.ch/swissmedic/en/home/news/mitteilungen/intensivierte-ueberwachung-sartan-arzneimittel.html |access-date=26 June 2022}}

Teva Pharmaceuticals announced that it would change its losartan manufacturing process to prevent future contamination with these impurities, and the Indian API manufacturer IOL Chemicals and Pharmaceuticals applied for a patent on a new synthesis of losartan designed to be free of azido contaminants.{{Cite web |date=5 April 2022 |title=Process For The Preparation Of Carcinogenic Azido Impurities Free Losartan And Salts Thereof |url=https://www.quickcompany.in/patents/process-for-the-preparation-of-carcinogenic-azido-impurities-free-losartan-and-salts-thereof |access-date=26 June 2022}}

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{{reflist}}

• {{MeshName|Angiotensin II Type 1 Receptor Blockers}}
• {{Cite web |date=4 April 2022 |title=Nitrosamine impurities in medications: Guidance |url=https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/information-health-product/drugs/nitrosamine-impurities/medications-guidance.html |website=Health Canada}}

{{Major drug groups}}

{{Receptor agonists and antagonists}}

{{Angiotensin II receptor antagonists}}

{{Angiotensin receptor modulators}}

{{Portal bar | Medicine}}

{{DEFAULTSORT:Angiotensin Ii Receptor Blocker}}