fbpx
Wikipedia

Angiotensin II receptor blocker

January 20, 2023

"Sartan" redirects here. For the village in Iran, see Sartan, Iran.

Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists,[1] also known as angiotensin receptor blockers,[2][3] angiotensin II receptor antagonists, or AT1 receptor antagonists, are a group of pharmaceuticals that bind to and inhibit the angiotensin II receptor type 1 (AT1) and thereby block the arteriolar contraction and sodium retention effects of renin–angiotensin system.[4]

Losartan, the first ARB

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 the AT1 receptor, preventing the binding of angiotensin II compared to ACE inhibitors.[4]

ARBs and the similar-attributed ACE inhibitors are both indicated as the first-line antihypertensives in patients developing hypertension along with left-sided heart failure.[5] However, ARBs appear to produce less adverse effects compared to ACE inhibitors.[5]

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 persistent and/or dry cough.[6] 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 2 diabetes,[citation needed] and may delay the progression of diabetic nephropathy.[citation needed] A 1998 double-blind study found "that lisinopril improved insulin sensitivity whereas losartan did not affect it."[7] Candesartan is used experimentally in preventive treatment of migraine.[8][9] Lisinopril has been found less often effective than candesartan at preventing migraine.[10]

The angiotensin II receptor blockers have differing potencies in relation to blood pressure control, with statistically differing effects at the maximal doses.[11] 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.[12][13]

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%.[14] 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.[15] 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.[16]

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.[17][18]

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.[19] 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.[20]

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.[19]

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.[21] However, other studies have found ARBs do not increase the risk of MI.[22] To date, with no consensus on whether ARBs have a tendency to increase the risk of myocardial infarction, further investigations are underway.[needs update]

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.[23][24][25]

Cancer

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."[26] 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.[27] 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[28] (original article in Journal of Hypertension) or prostate cancer.[29] 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."[28]

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.[30]

A 2016 meta-analysis including 148,334 patients found no significant differences in cancer incidence associated with ARB use.[31]

Kidney failure

Although ARBs have protective effects against developing kidney diseases for patients with diabetes and previous hypertension without administration of ARBs,[32] 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.[33][34][35][36][37][38][32]

History

Further information: Discovery and development of angiotensin receptor blockers

Structure

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. However, AT1 affinity vs AT2 is not a meaningful indicator of blood pressure response.[39]

Binding affinities Ki

Component

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]

Pharmacokinetics comparison

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 2 h 1 hr [43] 98.7% 33% 10/90% Minimal 50–100 Sensitive substrates: CYP2C9 and CYP3A4[43]
EXP 3174 active metabolite of losartan - 6–9 hrs 3–4 hrs after oral losartan administration[43] 99.8% – 50/50% – – AUC reduced by phenytoin and rifampin by 63%[44] and 40%[43] respectively; specific CYP450 isozymes are unknown
Candesartan Atacand 9 3–4 hrs[45] >99% 15% 60/40% No 4–32 Moderate sensitive substrate: CYP2C9[45]
Valsartan Diovan 6 2–4 hrs[46] 95% 25% 30/70% Yes 80–320 Substrates: MRP2 and OATP1B1/SLCO1B1[46]
Irbesartan Avapro 11–15 1.5–2 hrs[47] 90–95% 70% 20/80% No 150–300 Minor substrates of CYP2C9[47]
Telmisartan Micardis 24 0.5–1 hr [48] >99% 42–58% 1/99% No 40–80 None known; >97% via biliary excretion[48]
Eprosartan Teveten 5 1–2 hrs [49] 98% 13% 30/70% No 400–800 None known; >90% via renal and biliary excretion[49]
Olmesartan Benicar/Olmetec 14–16 1–2 hrs [50] >99% 29% 40/60% No 10–40 Substrates of OATP1B1/SLCO1B1[50]
Azilsartan Edarbi 11 1.5–3 hrs [51] >99% 60% 55/42% No 40–80 Minor substrates of CYP2C9 [51]
Fimasartan Kanarb 7–11 0.5–3 hrs after dosing.[52] >97% 30–40% – – 30–120 None known; primarily biliary excretion [53]
Drug Trade name Biological half-life [hrs] Peak plasma concentration [Tmax] Protein binding [%] Bioavailability [%] Renal/hepatic clearance [%] Food effect Daily dosage [mg] Metabolism/transporter

[54][55][56][57][58]

Further information: Discovery and development of angiotensin receptor blockers

Research

Longevity

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.[59][60]

Fibrosis regression

ARBs, such as losartan, have been shown to curb or reduce muscular,[61] liver,[62] cardiac,[63] and kidney[64] fibrosis.

Dilated aortic root regression

A 2003 study using candesartan and valsartan demonstrated an ability to regress dilated aortic root size.[65]

Impurities

See also: Ranitidine § impurities

Nitrosamines

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.[66][67][68][69][70] 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."[71] In 2018, the FDA issued guidance to the industry on how to assess and control the impurities.[72]

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.[73]

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.[74] 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).[74] 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.[74]

These sartan medicines have a specific ring structure (tetrazole) whose synthesis could potentially lead to the formation of nitrosamine impurities.[74][75] 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.[74]

Azides

 
 
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.[76] 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.[77]

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,[78] Brazil,[79] and Europe (including Switzerland).[80][81]

Teva Pharmaceuticals announced that it would change its losartan manufacturing process to prevent future contamination with these impurities,[80] 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.[82]

References

  1. ^ Mirabito Colafella, Katrina M.; Uijl, Estrellita; Jan Danser, A.H. (2019). "Interference With the Renin–Angiotensin System (RAS): Classical Inhibitors and Novel Approaches". Encyclopedia of Endocrine Diseases. Elsevier. pp. 523–530. doi:10.1016/b978-0-12-801238-3.65341-2. ISBN 978-0-12-812200-6. S2CID 86384280.
  2. ^ "List of Angiotensin receptor blockers (angiotensin II inhibitors)". Drugs.com. 2020-02-28. Retrieved 2020-03-21.
  3. ^ . blood pressure medication. Archived from the original on 2012-12-14. Retrieved 2020-03-21.
  4. ^ a b "ARBs", Angiotensin II Receptor Antagonists, Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, 2012, PMID 31643954, retrieved 2020-03-21, The angiotensin II receptor antagonists, also known as angiotensin receptor blockers (ARBs), are a family of agents that bind to and inhibit the angiotensin II type 1 receptor (AT1) and thus inhibit the renin-angiotensin system and its cascade of effects in causing arteriolar contraction and sodium retention. While angiotensin converting enzyme (ACE) inhibitors block the cleavage of angiotensin I to angiotensin II, the active peptide that causes a pressor response, the ARBs inhibit its peripheral action.
  5. ^ a b "Management of Hypertension in Chronic Heart Failure". Today on Medscape. Retrieved 2019-02-03.
  6. ^ "Choice of drug therapy in primary (essential) hypertension". UpToDate. Retrieved 2019-02-03.
  7. ^ Fogari R, Zoppi A, Corradi L, Lazzari P, Mugellini A, Lusardi P (November 1998). "Comparative effects of lisinopril and losartan on insulin sensitivity in the treatment of non diabetic hypertensive patients". British Journal of Clinical Pharmacology. 46 (5): 467–71. doi:10.1046/j.1365-2125.1998.00811.x. PMC 1873694. PMID 9833600.
  8. ^ Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G (January 2003). "Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial". JAMA. 289 (1): 65–9. doi:10.1001/jama.289.1.65. PMID 12503978. S2CID 35939042.
  9. ^ Cernes R, Mashavi M, Zimlichman R (2011). "Differential clinical profile of candesartan compared to other angiotensin receptor blockers". Vascular Health and Risk Management. 7: 749–59. doi:10.2147/VHRM.S22591. PMC 3253768. PMID 22241949.
  10. ^ Gales BJ, Bailey EK, Reed AN, Gales MA (February 2010). "Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for the prevention of migraines". The Annals of Pharmacotherapy. 44 (2): 360–6. doi:10.1345/aph.1M312. PMID 20086184. S2CID 207263658.
  11. ^ Kassler-Taub K, Littlejohn T, Elliott W, Ruddy T, Adler E (April 1998). "Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan in mild-to-moderate hypertension. Irbesartan/Losartan Study Investigators". American Journal of Hypertension. 11 (4 Pt 1): 445–53. doi:10.1016/S0895-7061(97)00491-3. PMID 9607383.
  12. ^ 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". Journal of Human Hypertension. 20 (1): 45–50. doi:10.1038/sj.jhh.1001941. PMID 16281062.
  13. ^ Daskalopoulou SS, Tzovaras V, Mikhailidis DP, Elisaf M (2005). "Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia". Current Pharmaceutical Design. 11 (32): 4161–75. doi:10.2174/138161205774913309. PMID 16375738.
  14. ^ Llisterri JL, Lozano Vidal JV, Aznar Vicente J, Argaya Roca M, Pol Bravo C, Sanchez Zamorano MA, Ferrario CM (May 2001). "Sexual dysfunction in hypertensive patients treated with losartan". The American Journal of the Medical Sciences. 321 (5): 336–41. doi:10.1097/00000441-200105000-00006. PMID 11370797. S2CID 6983215.
  15. ^ Fogari R, Zoppi A, Poletti L, Marasi G, Mugellini A, Corradi L (January 2001). "Sexual activity in hypertensive men treated with valsartan or carvedilol: a crossover study". American Journal of Hypertension. 14 (1): 27–31. doi:10.1016/S0895-7061(00)01214-0. PMID 11206674.
  16. ^ Pavel J, Benicky J, Murakami Y, Sanchez-Lemus E, Saavedra JM (December 2008). "Peripherally administered angiotensin II AT1 receptor antagonists are anti-stress compounds in vivo". Annals of the New York Academy of Sciences. 1148 (1): 360–6. Bibcode:2008NYASA1148..360P. doi:10.1196/annals.1410.006. PMC 2659765. PMID 19120129.
  17. ^ Li NC, Lee A, Whitmer RA, Kivipelto M, Lawler E, Kazis LE, Wolozin B (January 2010). "Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis". BMJ. 340 (9): b5465. doi:10.1136/bmj.b5465. PMC 2806632. PMID 20068258.
  18. ^ "Potential of antihypertensive drugs for the prevention and treatment of Alzheimer's disease". Expert Review of Neurotherapeutics. 8 (9): 1285–1287. September 2008. doi:10.1586/14737175.8.9.1285.
  19. ^ a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
  20. ^ Li EC, Heran BS, Wright JM (August 2014). "Angiotensin converting enzyme (ACE) inhibitors versus angiotensin receptor blockers for primary hypertension". The Cochrane Database of Systematic Reviews (8): CD009096. doi:10.1002/14651858.CD009096.pub2. PMC 6486121. PMID 25148386.
  21. ^ Strauss MH, Hall AS (August 2006). "Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox". Circulation. 114 (8): 838–54. doi:10.1161/CIRCULATIONAHA.105.594986. PMID 16923768.
  22. ^ Tsuyuki RT, McDonald MA (August 2006). "Angiotensin receptor blockers do not increase risk of myocardial infarction". Circulation. 114 (8): 855–60. doi:10.1161/CIRCULATIONAHA.105.594978. PMID 16923769.
  23. ^ Levy BI (September 2005). "How to explain the differences between renin angiotensin system modulators". American Journal of Hypertension. 18 (9 Pt 2): 134S–141S. doi:10.1016/j.amjhyper.2005.05.005. PMID 16125050.
  24. ^ Lévy BI (January 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. doi:10.1161/01.CIR.0000096609.73772.C5. PMID 14707017.
  25. ^ Reudelhuber TL (December 2005). "The continuing saga of the AT2 receptor: a case of the good, the bad, and the innocuous". Hypertension. 46 (6): 1261–2. doi:10.1161/01.HYP.0000193498.07087.83. PMID 16286568.
  26. ^ Sipahi I, Debanne SM, Rowland DY, Simon DI, Fang JC (July 2010). "Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials". The Lancet. Oncology. 11 (7): 627–36. doi:10.1016/S1470-2045(10)70106-6. PMC 4070221. PMID 20542468.
  27. ^ "Angiotensin FDA Drug Safety Communication: No increase in risk of cancer with certain blood pressure drugs – Angiotensin Receptor Blockers (ARBs)". Food and Drug Administration (FDA). 2 June 2011. from the original on 8 December 2011.
  28. ^ a b Rao GA, Mann JR, Shoaibi A, Pai SG, Bottai M, Sutton SS, et al. (August 2013). "Angiotensin receptor blockers: are they related to lung cancer?". Journal of Hypertension. 31 (8): 1669–75. doi:10.1097/HJH.0b013e3283621ea3. PMC 3879726. PMID 23822929.
  29. ^ Rao GA, Mann JR, Bottai M, Uemura H, Burch JB, Bennett CL, et al. (July 2013). "Angiotensin receptor blockers and risk of prostate cancer among United States veterans". Journal of Clinical Pharmacology. 53 (7): 773–8. doi:10.1002/jcph.98. PMC 3768141. PMID 23686462.
  30. ^ Burton, Thomas M. (31 May 2013). "Dispute Flares Inside FDA Over Safety of Popular Blood-Pressure Drugs". The Wall Street Journal. from the original on 15 February 2018. Retrieved 1 May 2018.
  31. ^ Zhao YT, Li PY, Zhang JQ, Wang L, Yi Z (May 2016). "Angiotensin II Receptor Blockers and Cancer Risk: A Meta-Analysis of Randomized Controlled Trials". Medicine. 95 (18): e3600. doi:10.1097/MD.0000000000003600. PMC 4863811. PMID 27149494.
  32. ^ a b Tucker, Bryan M.; Perazella, Mark A. (2019). "Medications: 3. What are the major adverse effects on the kidney of ACE inhibitors and ARBs?". Nephrology Secrets. Elsevier. pp. 78–83. doi:10.1016/b978-0-323-47871-7.00019-8. ISBN 978-0-323-47871-7. 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.
  33. ^ Toto RD, Mitchell HC, Lee HC, Milam C, Pettinger WA (October 1991). "Reversible renal insufficiency due to angiotensin converting enzyme inhibitors in hypertensive nephrosclerosis". Annals of Internal Medicine. 115 (7): 513–9. doi:10.7326/0003-4819-115-7-513. PMID 1883120.
  34. ^ Bakris GL, Weir MR (March 2000). "Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern?". Archives of Internal Medicine. 160 (5): 685–93. doi:10.1001/archinte.160.5.685. PMID 10724055.
  35. ^ Remuzzi G, Ruggenenti P, Perico N (April 2002). "Chronic renal diseases: renoprotective benefits of renin-angiotensin system inhibition". Annals of Internal Medicine. 136 (8): 604–15. doi:10.7326/0003-4819-136-8-200204160-00010. PMID 11955029. S2CID 24795760.
  36. ^ Sarafidis PA, Khosla N, Bakris GL (January 2007). "Antihypertensive therapy in the presence of proteinuria". American Journal of Kidney Diseases. 49 (1): 12–26. doi:10.1053/j.ajkd.2006.10.014. PMID 17185142. S2CID 18337587.
  37. ^ Weir MR (October 2002). "Progressive renal and cardiovascular disease: optimal treatment strategies". Kidney International. 62 (4): 1482–92. doi:10.1111/j.1523-1755.2002.kid591.x. PMID 12234333.
  38. ^ Tom Hostetter, M. D. (June 2004). "ACE Inhibitors and ARBs in Patients with Kidney Disease". Pharmacy Times. Retrieved 2019-02-05.
  39. ^ Miura, S; Karnik, SS; Saku, K (March 2011). "Review: angiotensin II type 1 receptor blockers: class effects versus molecular effects". Journal of the Renin-Angiotensin-Aldosterone System. 12 (1): 1–7. doi:10.1177/1470320310370852. PMC 3891529. PMID 20603272.
  40. ^ Kjeldsen, Sverre E; Brunner, Hans R; McInnes, Gordon T; Stolt, Pelle (2005). "Valsartan in the treatment of hypertension". Aging Health. Future Medicine Ltd. 1 (1): 27–36. doi:10.2217/1745509x.1.1.27.
  41. ^ a b c Siragy HM (November 2002). "Angiotensin receptor blockers: how important is selectivity?". American Journal of Hypertension. 15 (11): 1006–14. doi:10.1016/s0895-7061(02)02280-x. PMID 12441224.
  42. ^ "Saprisartan". drugbank.ca. from the original on 28 September 2016. Retrieved 1 May 2018.
  43. ^ a b c d "LOSARTAN- losartan potassium tablet, film coated". DailyMed. 2018-12-26. Retrieved 2019-02-06. 12.3 Pharmacokinetics/ Absorption: Following oral administration, the systemic bioavailability of losartan is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3 to 4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC (area under the curve) of the metabolite is about 4 times as great as that of losartan. A meal slows absorption of losartan and decreases its Cmax but has only minor effects on losartan AUC or on the AUC of the metabolite (≈10% decrease). The pharmacokinetics of losartan and its active metabolite are linear with oral losartan doses up to 200 mg and do not change over time.
  44. ^ Fischer, Tracy L.; Pieper, John A.; Graff, Donald W.; Rodgers, Jo E.; Fischer, Jeffrey D.; Parnell, Kimberly J.; Goldstein, Joyce A.; Greenwood, Robert; Patterson, J. Herbert (September 2002). "Evaluation of potential losartan-phenytoin drug interactions in healthy volunteers". Clinical Pharmacology and Therapeutics. 72 (3): 238–246. doi:10.1067/mcp.2002.127945. ISSN 0009-9236. PMID 12235444. S2CID 28606328.
  45. ^ a b "CANDESARTAN - candesartan tablet". DailyMed. 2017-06-27. Retrieved 2019-02-06.
  46. ^ a b "VALSARTAN - valsartan tablet". DailyMed. 2017-12-07. Retrieved 2019-02-06.
  47. ^ a b "IRBESARTAN - irbesartan tablet". DailyMed. 2018-09-04. Retrieved 2019-02-06.
  48. ^ a b "TELMISARTAN - telmisartan tablet". DailyMed. 2018-11-01. Retrieved 2019-02-06.
  49. ^ a b "EPROSARTAN MESYLATE- eprosartan mesylate tablet, film coated". DailyMed. 2014-12-05. Retrieved 2019-02-06.
  50. ^ a b "OLMESARTAN MEDOXOMIL - olmesartan medoxomil tablet, film coated". DailyMed. 2017-05-04. Retrieved 2019-02-06.
  51. ^ a b "EDARBI- azilsartan kamedoxomil tablet". DailyMed. 2018-01-25. Retrieved 2019-02-06.
  52. ^ Gu, N., Kim, B., Kyoung, S.L., Kim, S.E., Nam, W.S., Yoon, S.H., Cho, J., Shin, S., Jang, I., Yu, K. The Effect of Fimasartan, an Angiotensin Receptor Type 1 Blocker, on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Korean Male Volunteers: A One- Sequence, Two-Period Crossover Clinical Trial. (2012). Clinical Therapeutics. 34(7): 1592–1600.
  53. ^ Chi, Yong Ha; Lee, Howard; Paik, Soo Heui; Lee, Joo Han; Yoo, Byoung Wook; Kim, Ji Han; Tan, Hyun Kwang; Kim, Sang Lin (2011-10-01). "Safety, tolerability, pharmacokinetics, and pharmacodynamics of fimasartan following single and repeated oral administration in the fasted and fed states in healthy subjects". American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions. 11 (5): 335–346. doi:10.2165/11593840-000000000-00000. ISSN 1179-187X. PMID 21910510. S2CID 207300735.
  54. ^ Burnier, M.; Brunner, H. R. (2000), "Angiotensin II receptor antagonists", Lancet, 355 (9204): 637–645, doi:10.1016/S0140-6736(99)10365-9, PMID 10696996, S2CID 18835715
  55. ^ 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
  56. ^ Brousil, J. A.; Burke, J. M. (2003), "Olmesartan Medoxomil: An Angiotensin II-Receptor Blocker", Clinical Therapeutics, 25 (4): 1041–1055, doi:10.1016/S0149-2918(03)80066-8, PMID 12809956
  57. ^ Brunner, H. R. (2002), "The new oral angiotensin II antagonist olmesartan medoxomil: a concise overview", Journal of Human Hypertension, 16 (2): 13–16, doi:10.1038/sj.jhh.1001391, PMID 11967728, ProQuest 219966061
  58. ^ Zusman, R. M.; Jullien, V.; Lemetayer, P.; Jarnier, P.; Clementy, J. (1999), "Are There Differences Among Angiotensin Receptor Blockers?", American Journal of Hypertension, 12 (2 Pt 1): 231–235, doi:10.1016/S0895-7061(99)00116-8, PMID 10090354
  59. ^ Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M, et al. (March 2009). "Disruption of the Ang II type 1 receptor promotes longevity in mice". The Journal of Clinical Investigation. 119 (3): 524–30. doi:10.1172/JCI36703. PMC 2648681. PMID 19197138.
  60. ^ Cassis P, Conti S, Remuzzi G, Benigni A (January 2010). "Angiotensin receptors as determinants of life span". Pflügers Archiv. 459 (2): 325–32. doi:10.1007/s00424-009-0725-4. PMID 19763608. S2CID 24404339.
  61. ^ Hubbert, Katherine; Clement, Ryan (April 2021). "Losartan: A Novel Treatment for Acute Skeletal Muscle Injury". JBJS Journal of Orthopaedics for Physician Assistants. 9 (2). doi:10.2106/JBJS.JOPA.20.00030. ISSN 2470-1122. S2CID 242846521. Retrieved 14 April 2022.
  62. ^ Salama, Zakaria A.; Sadek, Ahmed; Abdelhady, Ahmed M.; Darweesh, Samar Kamal; Morsy, Shereif Ahmed; Esmat, Gamal (June 2016). "Losartan may inhibit the progression of liver fibrosis in chronic HCV patients". Hepatobiliary Surgery and Nutrition. 5 (3): 249–255. doi:10.21037/hbsn.2016.02.06. ISSN 2304-3881. PMC 4876242. PMID 27275467.
  63. ^ Wang, J; Duan, L; Gao, Y; Zhou, S; Liu, Y; Wei, S; An, S; Liu, J; Tian, L; Wang, S (5 September 2018). "Angiotensin II receptor blocker valsartan ameliorates cardiac fibrosis partly by inhibiting miR-21 expression in diabetic nephropathy mice". Molecular and Cellular Endocrinology. 472: 149–158. doi:10.1016/j.mce.2017.12.005. PMID 29233785. S2CID 6615686. Retrieved 14 April 2022.
  64. ^ Naito, T; Ma, LJ; Yang, H; Zuo, Y; Tang, Y; Han, JY; Kon, V; Fogo, AB (March 2010). "Angiotensin type 2 receptor actions contribute to angiotensin type 1 receptor blocker effects on kidney fibrosis". American Journal of Physiology. Renal Physiology. 298 (3): F683-91. doi:10.1152/ajprenal.00503.2009. PMC 2838584. PMID 20042458.
  65. ^ Weinberg MS, Weinberg AJ, Cord RB, Martin H (1 May 2003). "P-609: Regression of dilated aortic roots using supramaximal and usual doses of angiotensin receptor blockers". American Journal of Hypertension. 16 (S1): 259A. doi:10.1016/S0895-7061(03)00782-9. ISSN 0895-7061. 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.
  66. ^ "FDA Updates and Press Announcements on Angiotensin II Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan)". Food and Drug Administration (FDA). 20 August 2018. Retrieved 17 September 2019.
  67. ^ "Statement on the agency's ongoing efforts to resolve safety issue with ARB medications". Food and Drug Administration (FDA). 28 August 2019. Retrieved 17 September 2019.
  68. ^ "FDA's Assessment of Currently Marketed ARB Drug Products". Food and Drug Administration (FDA). 4 April 2019. Retrieved 17 September 2019.
  69. ^ "Search List of Recalled Angiotensin II Receptor Blockers (ARBs) including Valsartan, Losartan and Irbesartan". Food and Drug Administration (FDA). 28 June 2019. Retrieved 17 September 2019.
  70. ^ "Updated: Torrent Pharmaceuticals Limited Expands Voluntary Nationwide Recall of Losartan Potassium Tablets, USP and Losartan Potassium / Hydrochlorothiazide Tablets, USP". U.S. Food and Drug Administration. 23 September 2019. Retrieved 24 September 2019.
  71. ^ "General Advice ARB" (PDF). Food and Drug Administration (FDA). Retrieved 17 September 2019.  This article incorporates text from this source, which is in the public domain.
  72. ^ "M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk" (PDF). Food and Drug Administration (FDA). 30 August 2018. Retrieved 17 September 2019.
  73. ^ "Nitrosamine impurities". European Medicines Agency. 23 October 2019. Retrieved 6 August 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  74. ^ a b c d e "Nitrosamines: EMA aligns recommendations for sartans with those other medicines". European Medicines Agency (EMA) (Press release). 12 November 2020. Retrieved 13 November 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  75. ^ "Angiotensin-II-receptor antagonists (sartans) containing a tetrazole group". European Medicines Agency (EMA). Retrieved 13 November 2020.
  76. ^ "Risk of presence of mutagenic azido impurities in sartan active substances with a tetrazole ring" (Press release). European Directorate for the Quality of Medicines & HealthCare. 29 April 2021. Retrieved 26 June 2022.
  77. ^ "Risk of the presence of mutagenic azido impurities in losartan active substance" (Press release). European Directorate for the Quality of Medicines & HealthCare. 29 September 2021. Retrieved 26 June 2022.
  78. ^ Therapeutic Goods Administration (TGA) (20 August 2021). "Azide impurity in 'sartan' blood pressure medicines". Retrieved 26 June 2022.
  79. ^ "Losartana: Anvisa determina recolhimento e interdição de lotes; veja o que fazer". g1 (in Portuguese). Grupo Globo. 23 June 2022. Retrieved 26 June 2022.
  80. ^ a b Chapman, Kit (29 June 2021). "Sartan contaminant recall hits generics manufacturers". Chemistry World. Retrieved 26 June 2022.
  81. ^ Swissmedic (1 July 2021). "Monitoring of sartan medicines stepped up: traces of a new foreign substance detected". Retrieved 26 June 2022.
  82. ^ "Process For The Preparation Of Carcinogenic Azido Impurities Free Losartan And Salts Thereof". 5 April 2022. Retrieved 26 June 2022.

External links

January 20, 2023
angiotensin, receptor, blocker, sartan, redirects, here, village, iran, sartan, iran, arbs, formally, angiotensin, receptor, type, antagonists, also, known, angiotensin, receptor, blockers, angiotensin, receptor, antagonists, receptor, antagonists, group, phar. Sartan redirects here For the village in Iran see Sartan Iran Angiotensin II receptor blockers ARBs formally angiotensin II receptor type 1 AT1 antagonists 1 also known as angiotensin receptor blockers 2 3 angiotensin II receptor antagonists or AT1 receptor antagonists are a group of pharmaceuticals that bind to and inhibit the angiotensin II receptor type 1 AT1 and thereby block the arteriolar contraction and sodium retention effects of renin angiotensin system 4 Losartan the first ARB 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 the AT1 receptor preventing the binding of angiotensin II compared to ACE inhibitors 4 ARBs and the similar attributed ACE inhibitors are both indicated as the first line antihypertensives in patients developing hypertension along with left sided heart failure 5 However ARBs appear to produce less adverse effects compared to ACE inhibitors 5 Contents 1 Medical uses 2 Adverse effects 2 1 Myocardial infarction 2 2 Cancer 2 3 Kidney failure 3 History 4 Structure 5 Mechanism of action 5 1 Pressor inhibition 5 2 AT1 affinity vs AT2 5 3 Binding affinities Ki 5 4 Component 5 5 Active agent 5 6 Biological half life 6 Pharmacokinetics comparison 7 Research 7 1 Longevity 7 2 Fibrosis regression 7 3 Dilated aortic root regression 8 Impurities 8 1 Nitrosamines 8 2 Azides 9 References 10 External linksMedical uses EditAngiotensin 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 6 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 2 diabetes citation needed and may delay the progression of diabetic nephropathy citation needed A 1998 double blind study found that lisinopril improved insulin sensitivity whereas losartan did not affect it 7 Candesartan is used experimentally in preventive treatment of migraine 8 9 Lisinopril has been found less often effective than candesartan at preventing migraine 10 The angiotensin II receptor blockers have differing potencies in relation to blood pressure control with statistically differing effects at the maximal doses 11 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 12 13 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 14 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 15 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 16 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 17 18 Adverse effects EditThis 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 19 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 20 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 19 Myocardial infarction Edit 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 21 However other studies have found ARBs do not increase the risk of MI 22 To date with no consensus on whether ARBs have a tendency to increase the risk of myocardial infarction further investigations are underway needs update 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 23 24 25 Cancer Edit 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 26 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 27 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 28 original article in Journal of Hypertension or prostate cancer 29 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 28 In May 2013 a senior regulator at the Food amp 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 30 A 2016 meta analysis including 148 334 patients found no significant differences in cancer incidence associated with ARB use 31 Kidney failure Edit Although ARBs have protective effects against developing kidney diseases for patients with diabetes and previous hypertension without administration of ARBs 32 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 33 34 35 36 37 38 32 History EditFurther information Discovery and development of angiotensin receptor blockersStructure EditLosartan 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 EditThese 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 Edit 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 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 vs AT2 Edit This section needs additional citations for verification Please help improve this article by adding citations to reliable sources Unsourced material may be challenged and removed January 2022 Learn how and when to remove this template message 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 39 Losartan 1000 fold citation needed Telmisartan 3000 fold citation needed Irbesartan 8500 fold citation needed Candesartan greater than 10000 fold citation needed Olmesartan 12500 fold citation needed Valsartan 30000 fold higher than AT2 the ratio of binding affinities of valsartan to AT1 and AT2 is 30000 1 40 41 Saprisartan 42 Binding affinities Ki Edit This section needs expansion You can help by adding to it May 2019 Component Edit Nearly all ARBs contain biphenyltetrazole moiety except telmisartan and eprosartan 41 Active agent Edit Losartan carries a heterocycle imidazole while valsartan carries a nonplanar acylated amino acid 41 Biological half life Edit 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 Valsartan 6 hours Losartan 6 9 hours Azilsartan 11 hours Irbesartan 11 15 hours Olmesartan 13 hours Telmisartan 24 hours Fimasartan 7 11 hoursPharmacokinetics comparison EditTable 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 transporterLosartan Cozaar 2 h 1 hr 43 98 7 33 10 90 Minimal 50 100 Sensitive substrates CYP2C9 and CYP3A4 43 EXP 3174 active metabolite of losartan 6 9 hrs 3 4 hrs after oral losartan administration 43 99 8 50 50 AUC reduced by phenytoin and rifampin by 63 44 and 40 43 respectively specific CYP450 isozymes are unknownCandesartan Atacand 9 3 4 hrs 45 gt 99 15 60 40 No 4 32 Moderate sensitive substrate CYP2C9 45 Valsartan Diovan 6 2 4 hrs 46 95 25 30 70 Yes 80 320 Substrates MRP2 and OATP1B1 SLCO1B1 46 Irbesartan Avapro 11 15 1 5 2 hrs 47 90 95 70 20 80 No 150 300 Minor substrates of CYP2C9 47 Telmisartan Micardis 24 0 5 1 hr 48 gt 99 42 58 1 99 No 40 80 None known gt 97 via biliary excretion 48 Eprosartan Teveten 5 1 2 hrs 49 98 13 30 70 No 400 800 None known gt 90 via renal and biliary excretion 49 Olmesartan Benicar Olmetec 14 16 1 2 hrs 50 gt 99 29 40 60 No 10 40 Substrates of OATP1B1 SLCO1B1 50 Azilsartan Edarbi 11 1 5 3 hrs 51 gt 99 60 55 42 No 40 80 Minor substrates of CYP2C9 51 Fimasartan Kanarb 7 11 0 5 3 hrs after dosing 52 gt 97 30 40 30 120 None known primarily biliary excretion 53 Drug Trade name Biological half life hrs Peak plasma concentration Tmax Protein binding Bioavailability Renal hepatic clearance Food effect Daily dosage mg Metabolism transporter 54 55 56 57 58 Further information Discovery and development of angiotensin receptor blockersResearch EditLongevity Edit 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 59 60 Fibrosis regression Edit ARBs such as losartan have been shown to curb or reduce muscular 61 liver 62 cardiac 63 and kidney 64 fibrosis Dilated aortic root regression Edit A 2003 study using candesartan and valsartan demonstrated an ability to regress dilated aortic root size 65 Impurities EditSee also Ranitidine impurities Nitrosamines Edit 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 66 67 68 69 70 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 71 In 2018 the FDA issued guidance to the industry on how to assess and control the impurities 72 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 73 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 74 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 74 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 74 These sartan medicines have a specific ring structure tetrazole whose synthesis could potentially lead to the formation of nitrosamine impurities 74 75 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 74 Azides Edit 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 76 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 77 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 78 Brazil 79 and Europe including Switzerland 80 81 Teva Pharmaceuticals announced that it would change its losartan manufacturing process to prevent future contamination with these impurities 80 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 82 References Edit Mirabito Colafella Katrina M Uijl Estrellita Jan Danser A H 2019 Interference With the Renin Angiotensin System RAS Classical Inhibitors and Novel Approaches Encyclopedia of Endocrine Diseases Elsevier pp 523 530 doi 10 1016 b978 0 12 801238 3 65341 2 ISBN 978 0 12 812200 6 S2CID 86384280 List of Angiotensin receptor blockers angiotensin II inhibitors Drugs com 2020 02 28 Retrieved 2020 03 21 Blood Pressure Angiotensin receptor blockers ARBs blood pressure medication Archived from the original on 2012 12 14 Retrieved 2020 03 21 a b ARBs Angiotensin II Receptor Antagonists Bethesda MD National Institute of Diabetes and Digestive and Kidney Diseases 2012 PMID 31643954 retrieved 2020 03 21 The angiotensin II receptor antagonists also known as angiotensin receptor blockers ARBs are a family of agents that bind to and inhibit the angiotensin II type 1 receptor AT1 and thus inhibit the renin angiotensin system and its cascade of effects in causing arteriolar contraction and sodium retention While angiotensin converting enzyme ACE inhibitors block the cleavage of angiotensin I to angiotensin II the active peptide that causes a pressor response the ARBs inhibit its peripheral action a b Management of Hypertension in Chronic Heart Failure Today on Medscape Retrieved 2019 02 03 Choice of drug therapy in primary essential hypertension UpToDate Retrieved 2019 02 03 Fogari R Zoppi A Corradi L Lazzari P Mugellini A Lusardi P November 1998 Comparative effects of lisinopril and losartan on insulin sensitivity in the treatment of non diabetic hypertensive patients British Journal of Clinical Pharmacology 46 5 467 71 doi 10 1046 j 1365 2125 1998 00811 x PMC 1873694 PMID 9833600 Tronvik E Stovner LJ Helde G Sand T Bovim G January 2003 Prophylactic treatment of migraine with an angiotensin II receptor blocker a randomized controlled trial JAMA 289 1 65 9 doi 10 1001 jama 289 1 65 PMID 12503978 S2CID 35939042 Cernes R Mashavi M Zimlichman R 2011 Differential clinical profile of candesartan compared to other angiotensin receptor blockers Vascular Health and Risk Management 7 749 59 doi 10 2147 VHRM S22591 PMC 3253768 PMID 22241949 Gales BJ Bailey EK Reed AN Gales MA February 2010 Angiotensin converting enzyme inhibitors and angiotensin receptor blockers for the prevention of migraines The Annals of Pharmacotherapy 44 2 360 6 doi 10 1345 aph 1M312 PMID 20086184 S2CID 207263658 Kassler Taub K Littlejohn T Elliott W Ruddy T Adler E April 1998 Comparative efficacy of two angiotensin II receptor antagonists irbesartan and losartan in mild to moderate hypertension Irbesartan Losartan Study Investigators American Journal of Hypertension 11 4 Pt 1 445 53 doi 10 1016 S0895 7061 97 00491 3 PMID 9607383 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 Journal of Human Hypertension 20 1 45 50 doi 10 1038 sj jhh 1001941 PMID 16281062 Daskalopoulou SS Tzovaras V Mikhailidis DP Elisaf M 2005 Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia Current Pharmaceutical Design 11 32 4161 75 doi 10 2174 138161205774913309 PMID 16375738 Llisterri JL Lozano Vidal JV Aznar Vicente J Argaya Roca M Pol Bravo C Sanchez Zamorano MA Ferrario CM May 2001 Sexual dysfunction in hypertensive patients treated with losartan The American Journal of the Medical Sciences 321 5 336 41 doi 10 1097 00000441 200105000 00006 PMID 11370797 S2CID 6983215 Fogari R Zoppi A Poletti L Marasi G Mugellini A Corradi L January 2001 Sexual activity in hypertensive men treated with valsartan or carvedilol a crossover study American Journal of Hypertension 14 1 27 31 doi 10 1016 S0895 7061 00 01214 0 PMID 11206674 Pavel J Benicky J Murakami Y Sanchez Lemus E Saavedra JM December 2008 Peripherally administered angiotensin II AT1 receptor antagonists are anti stress compounds in vivo Annals of the New York Academy of Sciences 1148 1 360 6 Bibcode 2008NYASA1148 360P doi 10 1196 annals 1410 006 PMC 2659765 PMID 19120129 Li NC Lee A Whitmer RA Kivipelto M Lawler E Kazis LE Wolozin B January 2010 Use of angiotensin receptor blockers and risk of dementia in a predominantly male population prospective cohort analysis BMJ 340 9 b5465 doi 10 1136 bmj b5465 PMC 2806632 PMID 20068258 Potential of antihypertensive drugs for the prevention and treatment of Alzheimer s disease Expert Review of Neurotherapeutics 8 9 1285 1287 September 2008 doi 10 1586 14737175 8 9 1285 a b Rossi S editor Australian Medicines Handbook 2006 Adelaide Australian Medicines Handbook 2006 Li EC Heran BS Wright JM August 2014 Angiotensin converting enzyme ACE inhibitors versus angiotensin receptor blockers for primary hypertension The Cochrane Database of Systematic Reviews 8 CD009096 doi 10 1002 14651858 CD009096 pub2 PMC 6486121 PMID 25148386 Strauss MH Hall AS August 2006 Angiotensin receptor blockers may increase risk of myocardial infarction unraveling the ARB MI paradox Circulation 114 8 838 54 doi 10 1161 CIRCULATIONAHA 105 594986 PMID 16923768 Tsuyuki RT McDonald MA August 2006 Angiotensin receptor blockers do not increase risk of myocardial infarction Circulation 114 8 855 60 doi 10 1161 CIRCULATIONAHA 105 594978 PMID 16923769 Levy BI September 2005 How to explain the differences between renin angiotensin system modulators American Journal of Hypertension 18 9 Pt 2 134S 141S doi 10 1016 j amjhyper 2005 05 005 PMID 16125050 Levy BI January 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 doi 10 1161 01 CIR 0000096609 73772 C5 PMID 14707017 Reudelhuber TL December 2005 The continuing saga of the AT2 receptor a case of the good the bad and the innocuous Hypertension 46 6 1261 2 doi 10 1161 01 HYP 0000193498 07087 83 PMID 16286568 Sipahi I Debanne SM Rowland DY Simon DI Fang JC July 2010 Angiotensin receptor blockade and risk of cancer meta analysis of randomised controlled trials The Lancet Oncology 11 7 627 36 doi 10 1016 S1470 2045 10 70106 6 PMC 4070221 PMID 20542468 Angiotensin FDA Drug Safety Communication No increase in risk of cancer with certain blood pressure drugs Angiotensin Receptor Blockers ARBs Food and Drug Administration FDA 2 June 2011 Archived from the original on 8 December 2011 a b Rao GA Mann JR Shoaibi A Pai SG Bottai M Sutton SS et al August 2013 Angiotensin receptor blockers are they related to lung cancer Journal of Hypertension 31 8 1669 75 doi 10 1097 HJH 0b013e3283621ea3 PMC 3879726 PMID 23822929 Rao GA Mann JR Bottai M Uemura H Burch JB Bennett CL et al July 2013 Angiotensin receptor blockers and risk of prostate cancer among United States veterans Journal of Clinical Pharmacology 53 7 773 8 doi 10 1002 jcph 98 PMC 3768141 PMID 23686462 Burton Thomas M 31 May 2013 Dispute Flares Inside FDA Over Safety of Popular Blood Pressure Drugs The Wall Street Journal Archived from the original on 15 February 2018 Retrieved 1 May 2018 Zhao YT Li PY Zhang JQ Wang L Yi Z May 2016 Angiotensin II Receptor Blockers and Cancer Risk A Meta Analysis of Randomized Controlled Trials Medicine 95 18 e3600 doi 10 1097 MD 0000000000003600 PMC 4863811 PMID 27149494 a b Tucker Bryan M Perazella Mark A 2019 Medications 3 What are the major adverse effects on the kidney of ACE inhibitors and ARBs Nephrology Secrets Elsevier pp 78 83 doi 10 1016 b978 0 323 47871 7 00019 8 ISBN 978 0 323 47871 7 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 Toto RD Mitchell HC Lee HC Milam C Pettinger WA October 1991 Reversible renal insufficiency due to angiotensin converting enzyme inhibitors in hypertensive nephrosclerosis Annals of Internal Medicine 115 7 513 9 doi 10 7326 0003 4819 115 7 513 PMID 1883120 Bakris GL Weir MR March 2000 Angiotensin converting enzyme inhibitor associated elevations in serum creatinine is this a cause for concern Archives of Internal Medicine 160 5 685 93 doi 10 1001 archinte 160 5 685 PMID 10724055 Remuzzi G Ruggenenti P Perico N April 2002 Chronic renal diseases renoprotective benefits of renin angiotensin system inhibition Annals of Internal Medicine 136 8 604 15 doi 10 7326 0003 4819 136 8 200204160 00010 PMID 11955029 S2CID 24795760 Sarafidis PA Khosla N Bakris GL January 2007 Antihypertensive therapy in the presence of proteinuria American Journal of Kidney Diseases 49 1 12 26 doi 10 1053 j ajkd 2006 10 014 PMID 17185142 S2CID 18337587 Weir MR October 2002 Progressive renal and cardiovascular disease optimal treatment strategies Kidney International 62 4 1482 92 doi 10 1111 j 1523 1755 2002 kid591 x PMID 12234333 Tom Hostetter M D June 2004 ACE Inhibitors and ARBs in Patients with Kidney Disease Pharmacy Times Retrieved 2019 02 05 Miura S Karnik SS Saku K March 2011 Review angiotensin II type 1 receptor blockers class effects versus molecular effects Journal of the Renin Angiotensin Aldosterone System 12 1 1 7 doi 10 1177 1470320310370852 PMC 3891529 PMID 20603272 Kjeldsen Sverre E Brunner Hans R McInnes Gordon T Stolt Pelle 2005 Valsartan in the treatment of hypertension Aging Health Future Medicine Ltd 1 1 27 36 doi 10 2217 1745509x 1 1 27 a b c Siragy HM November 2002 Angiotensin receptor blockers how important is selectivity American Journal of Hypertension 15 11 1006 14 doi 10 1016 s0895 7061 02 02280 x PMID 12441224 Saprisartan drugbank ca Archived from the original on 28 September 2016 Retrieved 1 May 2018 a b c d LOSARTAN losartan potassium tablet film coated DailyMed 2018 12 26 Retrieved 2019 02 06 12 3 Pharmacokinetics Absorption Following oral administration the systemic bioavailability of losartan is approximately 33 Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3 to 4 hours respectively While maximum plasma concentrations of losartan and its active metabolite are approximately equal the AUC area under the curve of the metabolite is about 4 times as great as that of losartan A meal slows absorption of losartan and decreases its Cmax but has only minor effects on losartan AUC or on the AUC of the metabolite 10 decrease The pharmacokinetics of losartan and its active metabolite are linear with oral losartan doses up to 200 mg and do not change over time Fischer Tracy L Pieper John A Graff Donald W Rodgers Jo E Fischer Jeffrey D Parnell Kimberly J Goldstein Joyce A Greenwood Robert Patterson J Herbert September 2002 Evaluation of potential losartan phenytoin drug interactions in healthy volunteers Clinical Pharmacology and Therapeutics 72 3 238 246 doi 10 1067 mcp 2002 127945 ISSN 0009 9236 PMID 12235444 S2CID 28606328 a b CANDESARTAN candesartan tablet DailyMed 2017 06 27 Retrieved 2019 02 06 a b VALSARTAN valsartan tablet DailyMed 2017 12 07 Retrieved 2019 02 06 a b IRBESARTAN irbesartan tablet DailyMed 2018 09 04 Retrieved 2019 02 06 a b TELMISARTAN telmisartan tablet DailyMed 2018 11 01 Retrieved 2019 02 06 a b EPROSARTAN MESYLATE eprosartan mesylate tablet film coated DailyMed 2014 12 05 Retrieved 2019 02 06 a b OLMESARTAN MEDOXOMIL olmesartan medoxomil tablet film coated DailyMed 2017 05 04 Retrieved 2019 02 06 a b EDARBI azilsartan kamedoxomil tablet DailyMed 2018 01 25 Retrieved 2019 02 06 Gu N Kim B Kyoung S L Kim S E Nam W S Yoon S H Cho J Shin S Jang I Yu K The Effect of Fimasartan an Angiotensin Receptor Type 1 Blocker on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Korean Male Volunteers A One Sequence Two Period Crossover Clinical Trial 2012 Clinical Therapeutics 34 7 1592 1600 Chi Yong Ha Lee Howard Paik Soo Heui Lee Joo Han Yoo Byoung Wook Kim Ji Han Tan Hyun Kwang Kim Sang Lin 2011 10 01 Safety tolerability pharmacokinetics and pharmacodynamics of fimasartan following single and repeated oral administration in the fasted and fed states in healthy subjects American Journal of Cardiovascular Drugs Drugs Devices and Other Interventions 11 5 335 346 doi 10 2165 11593840 000000000 00000 ISSN 1179 187X PMID 21910510 S2CID 207300735 Burnier M Brunner H R 2000 Angiotensin II receptor antagonists Lancet 355 9204 637 645 doi 10 1016 S0140 6736 99 10365 9 PMID 10696996 S2CID 18835715 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 Brousil J A Burke J M 2003 Olmesartan Medoxomil An Angiotensin II Receptor Blocker Clinical Therapeutics 25 4 1041 1055 doi 10 1016 S0149 2918 03 80066 8 PMID 12809956 Brunner H R 2002 The new oral angiotensin II antagonist olmesartan medoxomil a concise overview Journal of Human Hypertension 16 2 13 16 doi 10 1038 sj jhh 1001391 PMID 11967728 ProQuest 219966061 Zusman R M Jullien V Lemetayer P Jarnier P Clementy J 1999 Are There Differences Among Angiotensin Receptor Blockers American Journal of Hypertension 12 2 Pt 1 231 235 doi 10 1016 S0895 7061 99 00116 8 PMID 10090354 Benigni A Corna D Zoja C Sonzogni A Latini R Salio M et al March 2009 Disruption of the Ang II type 1 receptor promotes longevity in mice The Journal of Clinical Investigation 119 3 524 30 doi 10 1172 JCI36703 PMC 2648681 PMID 19197138 Cassis P Conti S Remuzzi G Benigni A January 2010 Angiotensin receptors as determinants of life span Pflugers Archiv 459 2 325 32 doi 10 1007 s00424 009 0725 4 PMID 19763608 S2CID 24404339 Hubbert Katherine Clement Ryan April 2021 Losartan A Novel Treatment for Acute Skeletal Muscle Injury JBJS Journal of Orthopaedics for Physician Assistants 9 2 doi 10 2106 JBJS JOPA 20 00030 ISSN 2470 1122 S2CID 242846521 Retrieved 14 April 2022 Salama Zakaria A Sadek Ahmed Abdelhady Ahmed M Darweesh Samar Kamal Morsy Shereif Ahmed Esmat Gamal June 2016 Losartan may inhibit the progression of liver fibrosis in chronic HCV patients Hepatobiliary Surgery and Nutrition 5 3 249 255 doi 10 21037 hbsn 2016 02 06 ISSN 2304 3881 PMC 4876242 PMID 27275467 Wang J Duan L Gao Y Zhou S Liu Y Wei S An S Liu J Tian L Wang S 5 September 2018 Angiotensin II receptor blocker valsartan ameliorates cardiac fibrosis partly by inhibiting miR 21 expression in diabetic nephropathy mice Molecular and Cellular Endocrinology 472 149 158 doi 10 1016 j mce 2017 12 005 PMID 29233785 S2CID 6615686 Retrieved 14 April 2022 Naito T Ma LJ Yang H Zuo Y Tang Y Han JY Kon V Fogo AB March 2010 Angiotensin type 2 receptor actions contribute to angiotensin type 1 receptor blocker effects on kidney fibrosis American Journal of Physiology Renal Physiology 298 3 F683 91 doi 10 1152 ajprenal 00503 2009 PMC 2838584 PMID 20042458 Weinberg MS Weinberg AJ Cord RB Martin H 1 May 2003 P 609 Regression of dilated aortic roots using supramaximal and usual doses of angiotensin receptor blockers American Journal of Hypertension 16 S1 259A doi 10 1016 S0895 7061 03 00782 9 ISSN 0895 7061 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 FDA Updates and Press Announcements on Angiotensin II Receptor Blocker ARB Recalls Valsartan Losartan and Irbesartan Food and Drug Administration FDA 20 August 2018 Retrieved 17 September 2019 Statement on the agency s ongoing efforts to resolve safety issue with ARB medications Food and Drug Administration FDA 28 August 2019 Retrieved 17 September 2019 FDA s Assessment of Currently Marketed ARB Drug Products Food and Drug Administration FDA 4 April 2019 Retrieved 17 September 2019 Search List of Recalled Angiotensin II Receptor Blockers ARBs including Valsartan Losartan and Irbesartan Food and Drug Administration FDA 28 June 2019 Retrieved 17 September 2019 Updated Torrent Pharmaceuticals Limited Expands Voluntary Nationwide Recall of Losartan Potassium Tablets USP and Losartan Potassium Hydrochlorothiazide Tablets USP U S Food and Drug Administration 23 September 2019 Retrieved 24 September 2019 General Advice ARB PDF Food and Drug Administration FDA Retrieved 17 September 2019 This article incorporates text from this source which is in the public domain M7 R1 Assessment and Control of DNA Reactive Mutagenic Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk PDF Food and Drug Administration FDA 30 August 2018 Retrieved 17 September 2019 Nitrosamine impurities European Medicines Agency 23 October 2019 Retrieved 6 August 2020 Text was copied from this source which is c European Medicines Agency Reproduction is authorized provided the source is acknowledged a b c d e Nitrosamines EMA aligns recommendations for sartans with those other medicines European Medicines Agency EMA Press release 12 November 2020 Retrieved 13 November 2020 Text was copied from this source which is c European Medicines Agency Reproduction is authorized provided the source is acknowledged Angiotensin II receptor antagonists sartans containing a tetrazole group European Medicines Agency EMA Retrieved 13 November 2020 Risk of presence of mutagenic azido impurities in sartan active substances with a tetrazole ring Press release European Directorate for the Quality of Medicines amp HealthCare 29 April 2021 Retrieved 26 June 2022 Risk of the presence of mutagenic azido impurities in losartan active substance Press release European Directorate for the Quality of Medicines amp HealthCare 29 September 2021 Retrieved 26 June 2022 Therapeutic Goods Administration TGA 20 August 2021 Azide impurity in sartan blood pressure medicines Retrieved 26 June 2022 Losartana Anvisa determina recolhimento e interdicao de lotes veja o que fazer g1 in Portuguese Grupo Globo 23 June 2022 Retrieved 26 June 2022 a b Chapman Kit 29 June 2021 Sartan contaminant recall hits generics manufacturers Chemistry World Retrieved 26 June 2022 Swissmedic 1 July 2021 Monitoring of sartan medicines stepped up traces of a new foreign substance detected Retrieved 26 June 2022 Process For The Preparation Of Carcinogenic Azido Impurities Free Losartan And Salts Thereof 5 April 2022 Retrieved 26 June 2022 External links EditAngiotensin II Type 1 Receptor Blockers at the US National Library of Medicine Medical Subject Headings MeSH Portal Medicine Retrieved from https en wikipedia org w index php title Angiotensin II receptor blocker amp oldid 1133203215, wikipedia, wiki, book, books, library,

article

, read, download, free, free download, mp3, video, mp4, 3gp, jpg, jpeg, gif, png, picture, music, song, movie, book, game, games.