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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/08/31 02:37:13」(JST)

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Nicorandil is a vasodilatory drug used to treat angina. It is marketed under the trade names Ikorel (in the United Kingdom, Australia and most of Europe), Angedil (in Romania, Poland), Dancor (in Switzerland), Nikoran,PCA (in India), Aprior (in the Philippines), Nitorubin (in Japan), and Sigmart (in Japan, South Korea and Taiwan). Nicorandil is not available in the United States.

Angina is chest pain that results from episodes of transient myocardial ischemia. This can be caused by diseases such as atherosclerosis, coronary artery disease and aortic stenosis. Angina commonly arises from vasospasm of the coronary arteries. There are multiple mechanisms causing the increased smooth muscle contraction involved in coronary vasospasm, including increased Rho-kinase activity. Increased levels of Rho-kinase inhibit myosin phosphatase activity, leading to increased calcium sensitivity and hypercontraction.^[1] Rho-kinase also decreases nitric oxide synthase activity, which reduces nitric oxide concentrations.^[2] Lower levels of nitric oxide are present in spastic coronary arteries.^[3] L-type calcium channel expression increases in spastic vascular smooth muscle cells, which could result in excessive calcium influx, and hypercontraction.^[4]

Nicorandil is an anti-angina medication that has the dual properties of a nitrate and K+ATP channel agonist.^[5] In humans, the nitrate action of nicorandil dilates the large coronary arteries at low plasma concentrations.^[5] At high plasma concentrations nicorandil reduces coronary vascular resistance, which is associated with increased K+ATP channel opening.^[5]

Mechanism of action

Nitrate: Nicorandil stimulates guanylate cyclase to increase formation of cyclic GMP (cGMP).^[6] cGMP activates protein kinase G (PKG) which phosphorylates and inhibits GTPase RhoA and decreases Rho-kinase activity.^[6] Reduced Rho-kinase activity permits an increase in myosin phosphatase activity, decreasing the calcium sensitivity of the smooth muscle.^[6] PKG also activates the sarcolemma calcium pump to remove activating calcium.^[7] PKG acts on K+ channels to promote K+ efflux and the ensuing hyperpolarization inhibits voltage-gated calcium channels.^[5] Overall, this leads to relaxation of the smooth muscle and coronary vasodilation.

K+ATP channel opener: Nicorandil activates K+ATP channel, causing K+ efflux. This hyperpolarizes the cell, which inactivates voltage-gated calcium channels and reduces free intracellular Ca2+.^[5]

The effect of nicorandil as a vasodilator is mainly attributed to its nitrate property.^[5] Yet, nicorandil is effective in cases where nitrates, such as nitroglycerine, are not effective.^[5] Studies show that this is due to its K+ATP channel agonist action which causes pharmacological preconditioning and provides cardioprotective effects against ischemia.^[5] Nicorandil activates K+ATP channels in the mitochondria of the myocardium, which appears to relay the cardioprotective effects, although the mechanism is still unclear.^[8]

Side effects

Side effects listed in the British National Formulary include flushing, palpitations, weakness and vomiting. More recently, perianal, ileal and peristomal ulceration has been reported as a side effect. Anal ulceration is now included in the British National Formulary as a reported side effect. Other side effects include severe toothache, and nasal congestion.

References

Kukovetz WR, Holzmann S, Pöch G (1992). "Molecular mechanism of action of nicorandil". J. Cardiovasc. Pharmacol. 20 (Suppl 3): S1–7. PMID 1282168.

Tripathi, K.D. Essentials of Medical Pharmacology. Ch. 37. p. 499. ISBN 8180611876.

Dr.Hosny Mohaed, Brief ACSs.

^ Kandabashi, T; Shimokawa, H; Miyata, K; Kunihiro, I; Kawano, Y; Fukata, Y; Higo, T; Egashira, K; Takahashi, S; Kaibuchi, K; Takeshita, A (Mar 21, 2000). "Inhibition of myosin phosphatase by upregulated rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1beta.". Circulation 101 (11): 1319–23. doi:10.1161/01.cir.101.11.1319. PMID 10725293.
^ Takemoto, M; Sun, J; Hiroki, J; Shimokawa, H; Liao, JK (Jul 2, 2002). "Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase.". Circulation 106 (1): 57–62. doi:10.1161/01.cir.0000020682.73694.ab. PMID 12093770.
^ Kugiyama, K; Yasue, H; Okumura, K; Ogawa, H; Fujimoto, K; Nakao, K; Yoshimura, M; Motoyama, T; Inobe, Y; Kawano, H (Aug 1, 1996). "Nitric oxide activity is deficient in spasm arteries of patients with coronary spastic angina.". Circulation 94 (3): 266–71. doi:10.1161/01.cir.94.3.266. PMID 8759065.
^ Kuga, T; Shimokawa, H; Hirakawa, Y; Kadokami, Y; Arai, Y; Fukumoto, Y; Kuwata, K; Kozai, T; Egashira, K; Takeshita, A (May 2000). "Increased expression of L-type calcium channels in vascular smooth muscle cells at spastic site in a porcine model of coronary artery spasm.". Journal of cardiovascular pharmacology 35 (5): 822–8. doi:10.1097/00005344-200005000-00021. PMID 10813387.
^ ^a ^b ^c ^d ^e ^f ^g ^h Nakae, I; Matsumoto, T; Horie, H; Yokohama, H; Omura, T; Minai, K; Matsui, T; Nozawa, M; Takahashi, M; Sugimoto, Y; Ito, M; Izumi, M; Nakamura, Y; Mitsunami, K; Kinoshita, M (Jun 2000). "Effects of intravenous nicorandil on coronary circulation in humans: plasma concentration and action mechanism.". Journal of cardiovascular pharmacology 35 (6): 919–25. doi:10.1097/00005344-200006000-00014. PMID 10836727.
^ ^a ^b ^c Sauzeau, V; Le Jeune, H; Cario-Toumaniantz, C; Smolenski, A; Lohmann, SM; Bertoglio, J; Chardin, P; Pacaud, P; Loirand, G (Jul 14, 2000). "Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle.". The Journal of Biological Chemistry 275 (28): 21722–9. doi:10.1074/jbc.M000753200. PMID 10783386.
^ Vrolix, M; Raeymaekers, L; Wuytack, F; Hofmann, F; Casteels, R (Nov 1, 1988). "Cyclic GMP-dependent protein kinase stimulates the plasmalemmal Ca2+ pump of smooth muscle via phosphorylation of phosphatidylinositol.". The Biochemical journal 255 (3): 855–63. PMC 1135320. PMID 2850801.
^ Liu, Y; Sato, T; O'Rourke, B; Marban, E (Jun 23, 1998). "Mitochondrial ATP-dependent potassium channels: novel effectors of cardioprotection?". Circulation 97 (24): 2463–9. doi:10.1161/01.cir.97.24.2463. PMID 9641699.

UpToDate Contents

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1. 狭心症の新しい治療法 new therapies for angina pectoris
2. 心臓の虚血性再潅流障害 ischemic reperfusion injury of the heart
3. 虚血プレコンディショニングの臨床的意義 clinical implications of ischemic preconditioning
4. 先天性ＱＴ延長症候群の予後およびマネージメント prognosis and management of congenital long qt syndrome
5. クローン病の肛門合併症 perianal complications of crohns disease

English Journal

Nicorandil as a novel therapy for advanced diabetic nephropathy in the eNOS-deficient mouse.

Tanabe K, Lanaspa MA, Kitagawa W, Rivard CJ, Miyazaki M, Klawitter J, Schreiner GF, Saleem MA, Mathieson PW, Makino H, Johnson RJ, Nakagawa T.SourceDiv. of Renal Diseases and Hypertension, Univ. of Colorado Denver, C281, 12900E 19th Ave., Aurora, CO 80045. Takahiko.Nakagawa@ucdenver.edu.
American journal of physiology. Renal physiology.Am J Physiol Renal Physiol.2012 May;302(9):F1151-60. Epub 2012 Feb 15.
Nicorandil is an orally available drug that can act as a nitric oxide donor, an antioxidant, and an ATP-dependent K channel activator. We hypothesized that it may have a beneficial role in treating diabetic nephropathy. We administered nicorandil to a model of advanced diabetic nephropathy (the stre
PMID 22338086

Effects of intravenous nicorandil on the mid-term prognosis of patients with acute heart failure syndrome.

Ishihara S, Koga T, Kaseda S, Nyuta E, Haga Y, Fujishima S, Ishitsuka T, Sadoshima S.SourceDepartment of Cardiology, Steel Memorial Yawata Hospital.
Circulation journal : official journal of the Japanese Circulation Society.Circ J.2012 Apr 25;76(5):1169-76. Epub 2012 Mar 14.
Background: Acute heart failure syndrome (AHFS) remains a major clinical challenge because of its poor prognosis. Nicorandil, a hybrid compound of a potassium-channel opener and nitric oxide donor, has been reported to improve the prognosis of ischemic heart disease. We sought to evaluate the effect
PMID 22447009

Japanese Journal

Effect of Long-Term Nitrate Treatment on Cardiac Events in Patients With Vasospastic Angina

KOSUGI Munenori,NAKAGOMI Akihiro,SHIBUI Toshiyuki,KATO Katsuhito,KUSAMA Yoshiki,ATARASHI Hirotsugu,MIZUNO Kyoichi
Circulation journal : official journal of the Japanese Circulation Society 75(9), 2196-2205, 2011-08-25
… Methods and Results: Two-hundred and thirty-one patients with VSA who had not been receiving any antiischemic drugs, including calcium channel blockers (CCBs), nitrates, nicorandil, or any combination of these medications were prospectively enrolled in the present study. …
NAID 10029339744

In vitro皮膚透過性研究におけるヒト皮膚に代わるラット皮膚の有用性

TAKEUCHI Hiroyuki,MANO Yoko,TERASAKA Shuichi,SAKURAI Takanobu,FURUYA Atsushi,URANO Hidetoshi,SUGIBAYASHI Kenji
Experimental animals 60(4), 373-384, 2011-07-01
… In vitro permeation studies of the three model drugs, nicorandil, isosorbide dinitrate, and flurbiprofen, through human skin and SD rat skin were performed using Franz-type diffusion cells. …
NAID 10029550710

Related Pictures

★リンクテーブル★

リンク元	「ニコランジル」「抗狭心症薬」

「ニコランジル」

Nicorandil
Systematic (IUPAC) name
	2-[(pyridin-3-ylcarbonyl)amino]ethyl nitrate
Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy; category	AU: B3;
Legal status	UK: Prescription-only (POM);
Routes of; administration	Oral
Pharmacokinetic data
Bioavailability	75 to 80%
Protein binding	25%
Metabolism	Hepatic
Biological half-life	1 hour
Excretion	Renal (21%)
Identifiers
CAS Registry Number	65141-46-0
ATC code	C01DX16
PubChem	CID: 47528
IUPHAR/BPS	2411
ChemSpider	43240
UNII	260456HAM0
KEGG	D01810
ChEBI	CHEBI:31905
ChEMBL	CHEMBL284906
Chemical data
Formula	C8H9N3O4
Molecular mass	211.175 g/mol
	SMILES O=C(NCCO[N+]([O-])=O)c1cccnc1 ;
	InChI InChI=1S/C8H9N3O4/c12-8(7-2-1-3-9-6-7)10-4-5-15-11(13)14/h1-3,6H,4-5H2,(H,10,12) ; Key:LBHIOVVIQHSOQN-UHFFFAOYSA-N ;
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　　[★]

英: nicorandil
商: シグマート、シルビノール、ニコランジス、ニコランタ、ニコランマート
関: 抗狭心症薬

狭心症治療薬

構造

硝酸エステル型のニコチン酸アミド系

作用機序

ATP感受性Kチャネルを開き、K+が細胞膜外に流出し過分極、そしてCaチャネルが閉じて(収縮できなくなる)弛緩する。
ニコランジルの摘出血管弛緩作用がATP感受性Kチャネル阻害剤あるいはグアニル酸シクラーゼ阻害剤で抑制されること28)、イヌ急性心不全モデルにおけるニコランジルの大動脈血流量増加作用などの心血行動態改善作用がATP感受性Kチャネル阻害剤で抑制されること29)、及びニコランジルが摘出血管のcGMP含量を増加させること30)から、本薬の血管拡張作用にはATP感受性Kチャネル開口作用とcGMP産生増加作用が関与する。 (シグマート注2mg／シグマート注12mg／シグマート注48mg)

薬理作用

冠血管拡張作用

抗狭心症作用

心収縮力↓→酸素の消費量↓

血管弛緩→末梢血管抵抗↓→心の前後負荷↓ (特に硝酸薬は静脈を弛緩させるので前負荷を軽減させる)

血管弛緩→スパズムを抑制する

冠状動脈攣縮抑制作用

動態

適応

シグマート注2mg／シグマート注12mg／シグマート注48mg

不安定狭心症
急性心不全（慢性心不全の急性増悪期を含む）

注意

禁忌

シグマート注2mg／シグマート注12mg／シグマート注48mg

1. 重篤な肝・腎機能障害のある患者［代謝・排泄機能が障害されるため、本剤は高い血中濃度で推移する可能性がある。］
2. 重篤な脳機能障害のある患者［本剤により過度の血圧低下が生じた場合、脳機能障害に悪影響を及ぼす可能性がある。］
3. 重篤な低血圧又は心原性ショックのある患者［本剤により血圧低下が生じ、これらの症状を悪化させる可能性がある。］
4. Eisenmenger症候群又は原発性肺高血圧症のある患者［本剤により静脈還流量が減少し、血圧低下、心拍出量減少が強くあらわれる可能性がある。］
5. 右室梗塞のある患者［本剤により静脈還流量が減少し、心原性ショックを招来する可能性がある。］
6. 脱水症状のある患者［本剤により静脈還流量が減少し、心拍出量もさらに減少するため、心原性ショックを起こす可能性がある。］
7. 神経循環無力症のある患者［神経的要因により生じる病態であるため、効果は不定である。］
8. 閉塞隅角緑内障のある患者［眼圧を上昇させるおそれがある。］
9. 本剤又は硝酸・亜硝酸エステル系薬剤に対し過敏症の既往歴のある患者
10. ホスホジエステラーゼ５阻害作用を有する薬剤（シルデナフィルクエン酸塩、バルデナフィル塩酸塩水和物、タダラフィル）を投与中の患者（「相互作用」の項参照）

副作用

頭痛、血圧低下

相互作用

参考

シグマート注2mg／シグマート注12mg／シグマート注48mg

http://www.info.pmda.go.jp/go/pack/2171406D1021_1_13/2171406D1021_1_13?view=body

「抗狭心症薬」

　　[★]

英: antianginal agents, antianginal drug
関: 狭心症

種類

硝酸薬

冠血管スパズム緩解→酸素供給↑
末梢血管拡張→心筋仕事量↓→心筋酸素需要↓

特徴

小動脈より静脈を拡張させる　→　前負荷の減少
冠血管では、細い動脈より太い動脈を弛緩させる

β遮断薬

心筋抑制→心筋仕事量↓→心筋酸素需要↓

Ca拮抗薬

冠血管スパズム緩解→酸素供給↑ (SPC.226)
心筋抑制→心筋仕事量↓→心筋酸素需要↓

作用機序

電位依存性型Ca²⁺チャネルのαサブユニットに作用

その他の冠血管拡張薬

抗狭心症薬の使い分け

	労作時狭心症	安静時狭心症	不安定狭心症
硝酸薬	○	○	○
β遮断薬	○
Ca拮抗薬		○

[1] Kandabashi, T; Shimokawa, H; Miyata, K; Kunihiro, I; Kawano, Y; Fukata, Y; Higo, T; Egashira, K; Takahashi, S; Kaibuchi, K; Takeshita, A (Mar 21, 2000). "Inhibition of myosin phosphatase by upregulated rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1beta.". Circulation 101 (11): 1319–23. doi:10.1161/01.cir.101.11.1319. PMID 10725293.

[2] Takemoto, M; Sun, J; Hiroki, J; Shimokawa, H; Liao, JK (Jul 2, 2002). "Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase.". Circulation 106 (1): 57–62. doi:10.1161/01.cir.0000020682.73694.ab. PMID 12093770.

[3] Kugiyama, K; Yasue, H; Okumura, K; Ogawa, H; Fujimoto, K; Nakao, K; Yoshimura, M; Motoyama, T; Inobe, Y; Kawano, H (Aug 1, 1996). "Nitric oxide activity is deficient in spasm arteries of patients with coronary spastic angina.". Circulation 94 (3): 266–71. doi:10.1161/01.cir.94.3.266. PMID 8759065.

[4] Kuga, T; Shimokawa, H; Hirakawa, Y; Kadokami, Y; Arai, Y; Fukumoto, Y; Kuwata, K; Kozai, T; Egashira, K; Takeshita, A (May 2000). "Increased expression of L-type calcium channels in vascular smooth muscle cells at spastic site in a porcine model of coronary artery spasm.". Journal of cardiovascular pharmacology 35 (5): 822–8. doi:10.1097/00005344-200005000-00021. PMID 10813387.

[Nakae-5] ^ ^a ^b ^c ^d ^e ^f ^g ^h Nakae, I; Matsumoto, T; Horie, H; Yokohama, H; Omura, T; Minai, K; Matsui, T; Nozawa, M; Takahashi, M; Sugimoto, Y; Ito, M; Izumi, M; Nakamura, Y; Mitsunami, K; Kinoshita, M (Jun 2000). "Effects of intravenous nicorandil on coronary circulation in humans: plasma concentration and action mechanism.". Journal of cardiovascular pharmacology 35 (6): 919–25. doi:10.1097/00005344-200006000-00014. PMID 10836727.

[Sauzeau-6] Sauzeau, V; Le Jeune, H; Cario-Toumaniantz, C; Smolenski, A; Lohmann, SM; Bertoglio, J; Chardin, P; Pacaud, P; Loirand, G (Jul 14, 2000). "Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle.". The Journal of Biological Chemistry 275 (28): 21722–9. doi:10.1074/jbc.M000753200. PMID 10783386.

[7] Vrolix, M; Raeymaekers, L; Wuytack, F; Hofmann, F; Casteels, R (Nov 1, 1988). "Cyclic GMP-dependent protein kinase stimulates the plasmalemmal Ca2+ pump of smooth muscle via phosphorylation of phosphatidylinositol.". The Biochemical journal 255 (3): 855–63. PMC 1135320. PMID 2850801.

[8] Liu, Y; Sato, T; O'Rourke, B; Marban, E (Jun 23, 1998). "Mitochondrial ATP-dependent potassium channels: novel effectors of cardioprotection?". Circulation 97 (24): 2463–9. doi:10.1161/01.cir.97.24.2463. PMID 9641699.

匿名

検索

案内

案内

nicorandil

Wikipedia preview

wiki en

Contents

Mechanism of action

Side effects

See also

References

UpToDate Contents

English Journal

Japanese Journal

Related Links

Related Pictures

★リンクテーブル★

「ニコランジル」

構造

作用機序

薬理作用

動態

適応

注意

禁忌

副作用

相互作用

参考

「抗狭心症薬」

種類

硝酸薬

特徴

β遮断薬

Ca拮抗薬

作用機序

その他の冠血管拡張薬

抗狭心症薬の使い分け