View source for Angiotensin II receptor blocker/ja

<languages />
[[Image:Losartan structure.svg|thumb|最初のARBであるロサルタン|250px|right]]

'''アンジオテンシンII受容体拮抗薬'''（'''ARBs'''）は、正式には'''アンジオテンシンII受容体1型（AT<sub>1</sub>）拮抗薬'''であり、'''アンジオテンシン受容体遮断薬'''、または'''AT<sub>1</sub>受容体拮抗薬'''とも呼ばれる。[[angiotensin II receptor type 1/ja|アンジオテンシンII受容体1型]]（AT<sub>1</sub>）に結合して阻害し、それによって[[renin–angiotensin system/ja|レニン・アンジオテンシン系]]の[[Vasoconstriction/ja|動脈管収縮]]および[[sodium retention/ja|ナトリウム貯留]]作用を阻害する一群の医薬品である。

<div lang="en" dir="ltr" class="mw-content-ltr">
Their main uses are in the treatment of [[hypertension]] (high blood pressure), [[diabetic nephropathy]] ([[kidney damage]] due to [[diabetes mellitus|diabetes]]) and [[congestive heart failure]]. They ''selectively'' [[receptor antagonist|block]] the activation of the [[Angiotensin II receptor type 1|AT<sub>1</sub> receptor]], preventing the [[Ligand (biochemistry)|binding]] of [[angiotensin#Angiotensin II|angiotensin II]] compared to [[ACE inhibitors]].
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
ARBs and the similar-attributed ACE inhibitors are both indicated as the first-line [[antihypertensive]]s in patients developing [[hypertension]] along with [[left ventricular|left-sided]] [[heart failure]]. However, ARBs appear to produce less adverse effects compared to ACE inhibitors.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
==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]].  They do not inhibit the breakdown of [[bradykinin]] or other [[kinin]]s, and are thus only rarely associated with the persistent dry cough and/or [[angioedema]] that limit ACE inhibitor therapy.  More recently, they have been used for the treatment of [[heart failure]] in patients intolerant of ACE inhibitor therapy, in particular [[candesartan]]. [[Irbesartan]] and [[losartan]] have trial data showing benefit in hypertensive patients with [[type 2 diabetes]], and may delay the progression of [[diabetic nephropathy]]. A 1998 double-blind study found "that [[lisinopril]] improved [[insulin sensitivity]] whereas losartan did not affect it." [[Candesartan]] is used experimentally in preventive treatment of [[migraine]]. Lisinopril has been found less often effective than candesartan at preventing migraine.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
The angiotensin II receptor blockers have differing potencies in relation to blood pressure control, with statistically differing effects at the maximal doses.  When used in clinical practice, the particular agent used may vary based on the degree of response required.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
Some of these drugs have a [[uricosuric]] effect.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
Angiotensin II, through [[AT1 receptor|AT<sub>1</sub> 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]].
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
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 [[United States Department of Veterans Affairs|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.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
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.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
==Adverse effects==
This class of drugs is usually well tolerated. Common [[adverse drug reaction]]s (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. 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.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
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.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
===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. However, other studies have found ARBs do not increase the risk of MI. To date, with no consensus on whether ARBs have a tendency to increase the risk of myocardial infarction, further investigations are underway.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
Indeed, as a consequence of AT<sub>1</sub> 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 AT<sub>2</sub> receptors, which are, in addition, upregulated. However, recent data suggest AT<sub>2</sub> 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 [[atherogenesis|proatherogenic]] and [[proinflammatory]] effects.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
===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."  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. 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]] or [[prostate cancer]]. 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."
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
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.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
A 2016 meta-analysis including 148,334 patients found no significant differences in cancer incidence associated with ARB use.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
===Kidney failure===
Although ARBs have protective effects against developing kidney diseases for patients with [[diabetes]] and previous [[hypertension]] without administration of ARBs, ARBs may worsen [[kidney function]]s 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]], [[Fibrosis#Heart|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.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
==History==
{{further|Discovery and development of angiotensin receptor blockers}}
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
== 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.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
==Mechanism of action==
These substances are AT<sub>1</sub>-receptor antagonists; that is, they block the activation of [[Angiotensin receptor|angiotensin II AT<sub>1</sub> receptors]]. AT<sub>1</sub> receptors are found in [[smooth muscle]] cells of vessels, cortical cells of the [[adrenal gland]], and [[adrenaline|adrenergic]] nerve synapses. Blockage of AT<sub>1</sub> receptors directly causes [[vasodilation]], reduces secretion of [[vasopressin]], and reduces production and secretion of [[aldosterone]], among other actions. The combined effect reduces blood pressure.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
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.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
===Pressor inhibition===
[[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:
* [[Valsartan]]{{snd}} 30% at 80&nbsp;mg
* [[Telmisartan]]{{snd}} 40% at 80&nbsp;mg
* [[Losartan]]{{snd}} 25–40% at 100&nbsp;mg
* [[Irbesartan]]{{snd}} 40% at 150&nbsp;mg; 60% 300&nbsp;mg
* [[Azilsartan]]{{snd}} 60% at 32&nbsp;mg
* [[Olmesartan]]{{snd}} 61% at 20&nbsp;mg; 74% at 40&nbsp;mg
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
===AT<sub>1</sub> affinity vs AT<sub>2</sub>===
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
The ratios of AT<sub>1</sub> to AT<sub>2</sub> in binding affinities of the specific ARBs are shown as follows. However, AT<sub>1</sub> affinity vs AT<sub>2</sub> is not a meaningful indicator of blood pressure response.
* [[Losartan]]{{snd}} 1000-fold
* [[Telmisartan]]{{snd}} 3000-fold
* [[Irbesartan]]{{snd}} 8500-fold
* [[Candesartan]]{{snd}} greater than 10000-fold
* [[Olmesartan]]{{snd}} 12500-fold
* [[Valsartan]]{{snd}} 30000-fold
* [[Saprisartan]] – ???
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
===Component===
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
Nearly all ARBs contain [[biphenyltetrazole moiety]] except [[telmisartan]] and [[eprosartan]].
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
===Active agent===
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
Losartan carries a [[heterocycle imidazole]] while valsartan carries a nonplanar acylated [[amino acid]].
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
==Pharmacokinetics comparison==
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
{| class="wikitable"
|+ Table 1: Comparison of ARB [[pharmacokinetics]]
|-
! Drug
! Trade name
! [[Biological half-life]] [hrs]
! [[Cmax_(pharmacology)|Peak plasma concentration [Tmax] ]]
! [[Protein binding]] [%]
! [[Bioavailability]] [%]
! Renal/hepatic [[Clearance (medicine)|clearance]] [%]
! Food effect
! Daily dosage [mg]
! [[Metabolism]]/[[Transport protein|transporter]]
|-
| [[Losartan]]
| Cozaar
| 2 h
| 1 hr 
| 98.7%
| 33%
| 10/90%
| Minimal
| 50–100
| [[Sensitive substrates]]: [[CYP2C9]] and [[CYP3A4]]
|-
| [[Losartan#Pharmacokinetics|EXP 3174]] active metabolite of losartan
| -
| 6–9 hrs
| 3–4 hrs after oral losartan administration
| 99.8%
| –
| 50/50%
| –
| –
| AUC reduced by phenytoin and rifampin by 63% and 40% respectively; specific CYP450 isozymes are unknown
|-
| [[Candesartan]]
| Atacand
| 9
| 3–4 hrs
| >99%
| 15%
| 60/40%
| No
| 4–32
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
| [[Moderate sensitive substrate]]: [[CYP2C9]]
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
|-
| [[Valsartan]]
| Diovan
| 6
| 2–4 hrs
| 95%
| 25%
| 30/70%
| Yes
| 80–320
| Substrates: [[Multidrug resistance-associated protein 2|MRP2]] and [[OATP1B1|OATP1B1/SLCO1B1]]
|-
| [[Irbesartan]]
| Avapro
| 11–15
| 1.5–2 hrs
| 90–95%
| 70%
| 20/80%
| No
| 150–300
| Minor substrates of [[CYP2C9]]
|-
| [[Telmisartan]]
| Micardis
| 24
| 0.5–1 hr 
| >99%
| 42–58%
| 1/99%
| No
| 40–80
| None known; >97% via biliary excretion
|-
| [[Eprosartan]]
| Teveten
| 5
| 1–2 hrs 
| 98%
| 13%
| 30/70%
| No
| 400–800
| None known; >90% via renal and biliary excretion
|-
| [[Olmesartan]]
| Benicar/Olmetec
| 14–16
| 1–2 hrs 
| >99%
| 29%
| 40/60%
| No
| 10–40
| Substrates of [[OATP1B1|OATP1B1/SLCO1B1]]
|-
| [[Azilsartan]]
| Edarbi
| 11
| 1.5–3 hrs 
| >99%
| 60%
| 55/42%
| No
| 40–80
| Minor substrates of CYP2C9 
|-
| [[Fimasartan]]
| Kanarb
| 7–11
| 0.5–3 hrs after dosing.
| >97%
| 30–40%
| –
| –
| 30–120
| None known; primarily biliary excretion 
|-
! Drug
! Trade name
! [[Biological half-life]] [hrs]
! [[Cmax_(pharmacology)|Peak plasma concentration [Tmax] ]]
! [[Protein binding]] [%]
! [[Bioavailability]] [%]
! Renal/hepatic [[Clearance (medicine)|clearance]] [%]
! Food effect
! Daily dosage [mg]
! [[Metabolism]]/[[Transport protein|transporter]]
|}
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
{{further|Discovery and development of angiotensin receptor blockers}}
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
==Research==
===Longevity===
Knockout of the Agtr1a gene that encodes AT<sub>1</sub> 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.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
===Fibrosis regression===
ARBs, such as losartan, have been shown to curb or reduce muscular, liver, cardiac, and kidney fibrosis.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
===Dilated aortic root regression===
A 2003 study using candesartan and valsartan demonstrated an ability to regress dilated [[Ascending aorta|aortic root]] size.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
==Impurities==
{{Anchor|recalls}}
{{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]]. The FDA stated "In June 2018, FDA was informed of the presence of an impurity, identified as [[N-Nitrosodimethylamine]] (NDMA), from one [[active ingredient|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." In 2018, the FDA issued guidance to the industry on how to assess and control the impurities.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
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.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
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.
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
These sartan medicines have a specific ring structure (tetrazole) whose synthesis could potentially lead to the formation of nitrosamine impurities. 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.
</div>

===アジド化合物===
{{multiple image | width1 = 200 | image1 = Losartan azide.svg | alt1 = ロサルタンアジドの骨格式 | width2 = 180 | image2 = AZBT.svg | alt2 = アジドメチル-ビフェニル-テトラゾールの骨格式 | footer = ロサルタンアジド（左）とAZBT（右）、サルタンから検出される2つのアジドプロセス不純物。ロサルタンアジドはロサルタンの製造時にのみ発生し、AZBTは同クラスの複数の薬物に含まれる。}}
2021年4月、[[:en:European Directorate for the Quality of Medicines & HealthCare|欧州医薬品品質理事会]]（EDQM）は、テトラゾール含有サルタンに非ニトロソアミン系不純物（具体的には[[azide/ja|アジド化合物]]）が混入するリスクがあることを警告した。2021年9月、EDQMは調査によりロサルタンのみに存在する新規のアジド系不純物（ロサルタンアジドまたはロサルタンアジド不純物）が発見され、[[Ames test/ja|エームス試験]]で変異原性が認められたと発表した。

<div lang="en" dir="ltr" class="mw-content-ltr">
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]], [[Brazil]], and Europe (including Switzerland).
</div>

<div lang="en" dir="ltr" class="mw-content-ltr">
[[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.
</div>

{{clear}}

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

{{Major drug groups/ja}}
{{Receptor agonists and antagonists/ja}}
{{Angiotensin II receptor antagonists/ja}}
{{Angiotensin receptor modulators/ja}}
{{Portal bar | Medicine}}

{{DEFAULTSORT:Angiotensin Ii Receptor Blocker}}
[[Category:Angiotensin II receptor antagonists| ]]