Angiotensin II receptor blocker
Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists,
Their main uses are in the treatment of
ARBs and the similar-attributed ACE inhibitors are both indicated as the first-line
Medical uses
Angiotensin II receptor blockers are used primarily for the treatment of
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]
Angiotensin II, through
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.[15][16]
A retrospective study of 1968 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.[17]
Adverse effects
This class of drugs is usually well tolerated. Common
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.[18]
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.[20] However, other studies have found ARBs do not increase the risk of MI.[21] 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
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."
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
A 2016 meta-analysis including 148,334 patients found no significant differences in cancer incidence associated with ARB use.[30]
Kidney failure
Although ARBs have protective effects against developing kidney diseases for patients with
History
Structure
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.
Mechanism of action
These substances are AT1-receptor antagonists; that is, they block the activation of
The specific efficacy of each ARB within this class depends upon a combination of three
Pressor inhibition
- Valsartan – 30% at 80 mg
- Telmisartan – 40% at 80 mg
- Losartan – 25–40% at 100 mg
- Irbesartan – 40% at 150 mg; 60% 300 mg
- Azilsartan – 60% at 32 mg
- Olmesartan – 61% at 20 mg; 74% at 40 mg
AT1 affinity vs AT2
This section needs additional citations for verification. (January 2022) |
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.[38]
- 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[39][40]
- Saprisartan – ???[41]
Binding affinities Ki
This section needs expansion. You can help by adding to it. (May 2019) |
Component
Nearly all ARBs contain biphenyltetrazole moiety except telmisartan and eprosartan.[40]
Active agent
Losartan carries a heterocycle imidazole while valsartan carries a nonplanar acylated amino acid.[40]
Pharmacokinetics comparison
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 [42] | 98.7% | 33% | 10/90% | Minimal | 50–100 | |
EXP 3174 active metabolite of losartan | - | 6–9 hrs | 3–4 hrs after oral losartan administration[42] | 99.8% | – | 50/50% | – | – | AUC reduced by phenytoin and rifampin by 63%[43] and 40%[42] respectively; specific CYP450 isozymes are unknown |
Candesartan | Atacand | 9 | 3–4 hrs[44] | >99% | 15% | 60/40% | No | 4–32 | |
Valsartan | Diovan | 6 | 2–4 hrs[45] | 95% | 25% | 30/70% | Yes | 80–320 | Substrates: OATP1B1/SLCO1B1[45]
|
Irbesartan | Avapro | 11–15 | 1.5–2 hrs[46] | 90–95% | 70% | 20/80% | No | 150–300 | Minor substrates of CYP2C9[46] |
Telmisartan | Micardis | 24 | 0.5–1 hr [47] | >99% | 42–58% | 1/99% | No | 40–80 | None known; >97% via biliary excretion[47] |
Eprosartan | Teveten | 5 | 1–2 hrs [48] | 98% | 13% | 30/70% | No | 400–800 | None known; >90% via renal and biliary excretion[48] |
Olmesartan | Benicar/Olmetec | 14–16 | 1–2 hrs [49] | >99% | 29% | 40/60% | No | 10–40 | Substrates of OATP1B1/SLCO1B1[49]
|
Azilsartan | Edarbi | 11 | 1.5–3 hrs [50] | >99% | 60% | 55/42% | No | 40–80 | Minor substrates of CYP2C9 [50] |
Fimasartan | Kanarb | 7–11 | 0.5–3 hrs after dosing.[51] | >97% | 30–40% | – | – | 30–120 | None known; primarily biliary excretion [52] |
Drug | Trade name | Biological half-life [hrs] | Peak plasma concentration [Tmax] | Protein binding [%]
|
Bioavailability [%] | Renal/hepatic clearance [%]
|
Food effect | Daily dosage [mg] | Metabolism/transporter |
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.[58][59]
Fibrosis regression
ARBs, such as losartan, have been shown to curb or reduce muscular,[60] liver,[61] cardiac,[62] and kidney[63] fibrosis.
Dilated aortic root regression
A 2003 study using candesartan and valsartan demonstrated an ability to regress dilated aortic root size.[64]
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.[65][66][67][68][69] The FDA stated "In June 2018, FDA was informed of the presence of an impurity, identified as N-Nitrosodimethylamine (NDMA), from one[70] 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
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]
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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.
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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.
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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.
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External links
- Angiotensin II Type 1 Receptor Blockers at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- "Nitrosamine impurities in medications: Guidance". Health Canada. 4 April 2022.