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Angiotensin II receptor blocker/ja: Difference between revisions

Angiotensin II receptor blocker/ja
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Created page with "===線維症の退縮=== ロサルタンなどのARBは、筋肉、肝臓、心臓、腎臓の線維化を抑制または軽減することが示されている。"
 
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{{main/ja|Discovery and development of angiotensin receptor blockers/ja}}
{{main/ja|Discovery and development of angiotensin receptor blockers/ja}}


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== 構造 ==
== Structure ==
{{Anchor|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.
[[Losartan/ja|ロサルタン]]、[[irbesartan/ja|イルベサルタン]]、[[olmesartan/ja|オルメサルタン]]、[[candesartan/ja|カンデサルタン]]、[[valsartan/ja|バルサルタン]]、[[fimasartan/ja|フィマサルタン]]は[[tetrazole/ja|テトラゾール]]基（4つの窒素と1つの炭素を持つ環）を含む。ロサルタン、イルベサルタン、オルメサルタン、カンデサルタン、[[telmisartan/ja|テルミサルタン]]は、1つまたは2つの[[imidazole/ja|イミダゾール]]基を含む。
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==作用機序==
==Mechanism of action==
{{Anchor|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.
これらの物質はAT<sub>1</sub>受容体拮抗薬である；すなわち、[[Angiotensin receptor/ja|アンジオテンシンⅡAT<sub>1</sub>受容体]]の活性化を阻害する。AT<sub>1</sub>受容体は、血管の[[smooth muscle/ja|平滑筋]]細胞、[[adrenal gland/ja|副腎]]の皮質細胞、および[[adrenaline/ja|副腎皮質]]神経シナプスに存在する。AT<sub>1</sub>受容体の遮断は、他の作用の中でも、直接的に[[vasodilation/ja|血管拡張]]を引き起こし、[[vasopressin/ja|バソプレシン]]の分泌を減少させ、[[aldosterone/ja|アルドステロン]]の産生と分泌を減少させる。この複合作用により血圧が低下する。
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このクラスの各ARBの具体的な有効性は、3つの[[pharmacodynamic/ja|薬力学的]]（PD）と[[pharmacokinetic/ja|薬物動態学的]]（PK）パラメータの組み合わせに依存する。有効性には、有効なレベルでの3つの主要なPD/PK領域が必要である。3つの特性のパラメータを以下のような表にまとめ、重複を排除し、コンセンサス値を得る必要がある。
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.
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===プレッサー阻害===
===Pressor inhibition===
[[trough level/ja|トラフレベル]]における[[pressor/ja|プレッサー]]抑制作用。これは、アンジオテンシンIIの血圧上昇（「プレッサー」）作用の遮断または阻害の程度に関係する。 しかし、プレッサー抑制は血圧降下（BP）効果の''それ自体''の指標ではない。 米国[[Food and Drug Administration/ja|食品医薬品局]]（FDA）の添付文書（PI）に記載されているARBの24時間目におけるこの作用の抑制率は以下の通りである：
[[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/ja|バルサルタン]]{{snd}}80&nbsp;mgで30％
* [[Valsartan]]{{snd}} 30% at 80&nbsp;mg
* [[Telmisartan/ja|テルミサルタン]]{{snd}}80&nbsp;mgで40%
* [[Telmisartan]]{{snd}} 40% at 80&nbsp;mg
* [[Losartan/ja|ロサルタン]]{{snd}} 100&nbsp;mgで25～40%。100&nbsp;mgで25-40%
* [[Losartan]]{{snd}} 25–40% at 100&nbsp;mg
* [[Irbesartan/ja|イルベサルタン]]{{snd}}150&nbsp;mgで40%; 300&nbsp;mgで60
* [[Irbesartan]]{{snd}} 40% at 150&nbsp;mg; 60% 300&nbsp;mg
* [[Azilsartan/ja|アジルサルタン]]{{snd}}32&nbsp;mgで60%
* [[Azilsartan]]{{snd}} 60% at 32&nbsp;mg
* [[Olmesartan/ja|オルメサルタン]]{{snd}}20&nbsp;mgで61%; 40&nbsp;mgで74%
* [[Olmesartan]]{{snd}} 61% at 20&nbsp;mg; 74% at 40&nbsp;mg
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===AT<sub>1</sub>親和性 vs AT<sub>2</sub>親和性===
===AT<sub>1</sub> affinity vs AT<sub>2</sub>===
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特定のARBの結合親和性におけるAT<sub>1</sub>とAT<sub>2</sub>の比を以下に示す。しかし、AT<sub>1</sub>親和性対AT<sub>2</sub>親和性は血圧反応の指標としては意味がない。
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/ja|ロサルタン]]{{snd}} 1000倍
* [[Losartan]]{{snd}} 1000-fold
* [[Telmisartan/ja|テルミサルタン]]{{snd}} 3000倍
* [[Telmisartan]]{{snd}} 3000-fold
* [[Irbesartan/ja|イルベサルタン]]{{snd}} 8500倍
* [[Irbesartan]]{{snd}} 8500-fold
* [[Candesartan/ja|カンデサルタン]]{{snd}} 10000倍以上
* [[Candesartan]]{{snd}} greater than 10000-fold
* [[Olmesartan/ja|オルメサルタン]]{{snd}} 12500倍
* [[Olmesartan]]{{snd}} 12500-fold
* [[Valsartan/ja|バルサルタン]]{{snd}} 30000倍
* [[Valsartan]]{{snd}} 30000-fold
* [[Saprisartan/ja|サプリサルタン]] – ???
* [[Saprisartan]] – ???
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===構成要素===
===Component===
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[[telmisartan/ja|テルミサルタン]]と[[eprosartan/ja|エプロサルタン]]を除くほぼすべてのARBは[[biphenyltetrazole moiety/ja|ビフェニルテトラゾール部位]]を含む。
Nearly all ARBs contain [[biphenyltetrazole moiety]] except [[telmisartan]] and [[eprosartan]].
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===有効成分===
===Active agent===
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ロサルタンは[[heterocycle imidazole/ja|複素環イミダゾール]]を持つが、バルサルタンは非平面アシル化[[amino acid/ja|アミノ酸]]を持つ。
Losartan carries a [[heterocycle imidazole]] while valsartan carries a nonplanar acylated [[amino acid]].
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==薬物動態の比較==
==Pharmacokinetics comparison==
{{Anchor|Pharmacokinetics comparison}}
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{| class="wikitable"
{| class="wikitable"
|+ Table 1: Comparison of ARB [[pharmacokinetics]]
|+ 表1: ARB[[pharmacokinetics/ja|薬物動態]]の比較
|-
|-
! Drug
! 薬剤
! Trade name
! 製品名
! [[Biological half-life]] [hrs]
! [[Biological half-life/ja|半減期]] [時間]
! [[Cmax_(pharmacology)|Peak plasma concentration [Tmax] ]]
! [[Cmax_(pharmacology)/ja|ピーク血漿中濃度[Tmax]]]
! [[Protein binding]] [%]
! [[Protein binding/ja|タンパク質結合率]] [%]
! [[Bioavailability]] [%]
! [[Bioavailability/ja|生物学的利用能]] [%]
! Renal/hepatic [[Clearance (medicine)|clearance]] [%]
! 腎／肝[[Clearance (medicine)/ja|クリアランス]] [%]
! Food effect
! 食べ物の影響
! Daily dosage [mg]
! 容量/日 [mg]
! [[Metabolism]]/[[Transport protein|transporter]]
! [[Metabolism/ja|代謝]]/[[Transport protein/ja|トランスポーター]]
|-
|-
| [[Losartan]]
| [[Losartan/ja|ロサルタン]]
| Cozaar
| Cozaar
| 2 h
| 2H
| 1 hr
| 1H
| 98.7%
| 98.7%
| 33%
| 33%
| 10/90%
| 10/90%
| Minimal
| ミネラル
| 50–100
| 50–100
| [[Sensitive substrates]]: [[CYP2C9]] and [[CYP3A4]]
| [[Sensitive substrates/ja|センシティブ基質]]: [[CYP2C9/ja|CYP2C9]]と[[CYP3A4/ja|CYP3A4]]
|-
|-
| [[Losartan#Pharmacokinetics|EXP 3174]] active metabolite of losartan
| [[Losartan/ja#Pharmacokinetics|EXP 3174]] ロサルタンの活性代謝物
| -
| -
| 6–9 hrs
| 6–9H
| 3–4 hrs after oral losartan administration
| ロサルタン経口投与3–4H後
| 99.8%
| 99.8%
| –
| –
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| –
| –
| –
| –
| AUC reduced by phenytoin and rifampin by 63% and 40% respectively; specific CYP450 isozymes are unknown
| AUCはフェニトインで63％、リファンピンで40％減少する；特定のCYP450アイソザイムは不明
|-
|-
| [[Candesartan]]
| [[Candesartan/ja|カンデサルタン]]
| Atacand
| Atacand
| 9
| 9
| 3–4 hrs
| 3–4H
| >99%
| >99%
| 15%
| 15%
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| No
| No
| 4–32
| 4–32
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| [[Moderate sensitive substrate/ja|中程度のセンシティブ基質]]: [[CYP2C9/ja|CYP2C9]]
| [[Moderate sensitive substrate]]: [[CYP2C9]]
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|-
|-
| [[Valsartan]]
| [[Valsartan/ja|バルサルタン]]
| Diovan
| Diovan
| 6
| 6
| 2–4 hrs
| 2–4H
| 95%
| 95%
| 25%
| 25%
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| Yes
| Yes
| 80–320
| 80–320
| Substrates: [[Multidrug resistance-associated protein 2|MRP2]] and [[OATP1B1|OATP1B1/SLCO1B1]]
| 基質: [[Multidrug resistance-associated protein 2/ja|MRP2]]と[[OATP1B1/ja|OATP1B1/SLCO1B1]]
|-
|-
| [[Irbesartan]]
| [[Irbesartan/ja|イルベサルタン]]
| Avapro
| Avapro
| 11–15
| 11–15
| 1.5–2 hrs
| 1.5–2H
| 90–95%
| 90–95%
| 70%
| 70%
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| No
| No
| 150–300
| 150–300
| Minor substrates of [[CYP2C9]]
| [[CYP2C9/ja|CYP2C9]]のマイナー基質
|-
|-
| [[Telmisartan]]
| [[Telmisartan/ja|テルミサルタン]]
| Micardis
| Micardis
| 24
| 24
| 0.5–1 hr
| 0.5–1H
| >99%
| >99%
| 42–58%
| 42–58%
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| No
| No
| 40–80
| 40–80
| None known; >97% via biliary excretion
| 不明; >97% 胆汁排泄
|-
|-
| [[Eprosartan]]
| [[Eprosartan/ja|エプロサルタン]]
| Teveten
| Teveten
| 5
| 5
| 1–2 hrs
| 1–2H
| 98%
| 98%
| 13%
| 13%
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| No
| No
| 400–800
| 400–800
| None known; >90% via renal and biliary excretion
| 不明; >90% 腎と胆汁排泄
|-
|-
| [[Olmesartan]]
| [[Olmesartan/ja|オルメサルタン]]
| Benicar/Olmetec
| Benicar/Olmetec
| 14–16
| 14–16
| 1–2 hrs
| 1–2H
| >99%
| >99%
| 29%
| 29%
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| No
| No
| 10–40
| 10–40
| Substrates of [[OATP1B1|OATP1B1/SLCO1B1]]
| [[OATP1B1/ja|OATP1B1/SLCO1B1]]の基質
|-
|-
| [[Azilsartan]]
| [[Azilsartan/jaZ|アジルサルタン]]
| Edarbi
| Edarbi
| 11
| 11
| 1.5–3 hrs
| 1.5–3H
| >99%
| >99%
| 60%
| 60%
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| No
| No
| 40–80
| 40–80
| Minor substrates of CYP2C9
| CYP2C9のマイナー基質
|-
|-
| [[Fimasartan]]
| [[Fimasartan/ja|フィマサルタン]]
| Kanarb
| Kanarb
| 7–11
| 7–11
| 0.5–3 hrs after dosing.
| 服用後0.5–3H
| >97%
| >97%
| 30–40%
| 30–40%
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| –
| –
| 30–120
| 30–120
| None known; primarily biliary excretion
| 不明; 主に胆汁性排泄
|-
|-
! Drug
! 薬剤
! Trade name
! 製品名
! [[Biological half-life]] [hrs]
! [[Biological half-life/ja|半減期]] [時間]
! [[Cmax_(pharmacology)|Peak plasma concentration [Tmax] ]]
! [[Cmax_(pharmacology)/ja|ピーク血漿中濃度[Tmax]]]
! [[Protein binding]] [%]
! [[Protein binding/ja|タンパク質結合率]] [%]
! [[Bioavailability]] [%]
! [[Bioavailability/ja|生物学的利用能]] [%]
! Renal/hepatic [[Clearance (medicine)|clearance]] [%]
! 腎／肝[[Clearance (medicine)/ja|クリアランス]] [%]
! Food effect
! 食べ物の影響
! Daily dosage [mg]
! 容量/日 [mg]
! [[Metabolism]]/[[Transport protein|transporter]]
! [[Metabolism/ja|代謝]]/[[Transport protein/ja|トランスポーター]]
|}
|}
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{{further/ja|Discovery and development of angiotensin receptor blockers/ja}}
{{further|Discovery and development of angiotensin receptor blockers}}
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==研究==
==Research==
{{Anchor|Research}}
===Longevity===
===寿命===
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.
AT<sub>1</sub>をコードするAgtr1a遺伝子をノックアウトすると、マウスの寿命は対照と比較して26％著しく延長する。 そのメカニズムとしては、酸化的損傷（特にミトコンドリア）の軽減と腎臓の生存促進遺伝子の過剰発現が考えられる。ARBにも同様の効果があるようだ。
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===線維症の退縮===
===Fibrosis regression===
ロサルタンなどのARBは、筋肉、肝臓、心臓、腎臓の線維化を抑制または軽減することが示されている。
ARBs, such as losartan, have been shown to curb or reduce muscular, liver, cardiac, and kidney fibrosis.
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===大動脈基部拡張の退縮===
===Dilated aortic root regression===
カンデサルタンとバルサルタンを用いた2003年の研究では、拡張した[[Ascending aorta/ja|大動脈起始部]]のサイズを退縮させる能力が示された。
A 2003 study using candesartan and valsartan demonstrated an ability to regress dilated [[Ascending aorta|aortic root]] size.
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==不純物==
==不純物==
Retrieved from "https://wiki.tiffa.net/wiki/Angiotensin_II_receptor_blocker/ja"