Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Aliskiren: Difference between pages
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Saving copy of the {{drugbox}} taken from revid 474928777 of page Aliskiren for the Chem/Drugbox validation project (updated: 'ChemSpiderID', 'ChEMBL', 'ChEBI', 'StdInChI', 'StdInChIKey'). |
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{{Short description|Medication}} |
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{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid [{{fullurl:Aliskiren|oldid=474928777}} 474928777] of page [[Aliskiren]] with values updated to verified values.}} |
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{{Drugbox |
{{Drugbox |
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| |
| Verifiedfields = changed |
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| verifiedrevid = |
| verifiedrevid = 477317502 |
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| IUPAC_name = (2''S'',4''S'',5''S'',7''S'')-5-amino-''N''-(2-carbamoyl-2,2-dimethylethyl)-4-hydroxy-7-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-8-methyl-2-(propan-2-yl)nonanamide |
| IUPAC_name = (2''S'',4''S'',5''S'',7''S'')-5-amino-''N''-(2-carbamoyl-2,2-dimethylethyl)-4-hydroxy-7-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-8-methyl-2-(propan-2-yl)nonanamide |
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| image = Aliskiren.svg |
| image = Aliskiren.svg |
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| width = 275 |
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<!--Clinical data--> |
<!--Clinical data--> |
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| tradename = |
| tradename = Tekturna, Rasilez |
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| Drugs.com = {{drugs.com|monograph|aliskiren-hemifumarate}} |
| Drugs.com = {{drugs.com|monograph|aliskiren-hemifumarate}} |
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| MedlinePlus = a607039 |
| MedlinePlus = a607039 |
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| |
| DailyMedID = Aliskiren |
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| licence_EU = yes |
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| licence_US = Tekturna |
| licence_US = Tekturna |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = <!-- A / B |
| pregnancy_US = <!-- A / B / C / D / X --> |
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| pregnancy_category = C in first trimester<br />D in second and third trimesters |
| pregnancy_category = C in first trimester<br />D in second and third trimesters |
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| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> |
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> |
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| legal_CA = <!-- |
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_UK = POM |
| legal_UK = POM |
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| legal_US = Rx-only |
| legal_US = Rx-only |
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| routes_of_administration = |
| routes_of_administration = By mouth ([[Tablet (pharmacy)|tablets]]) |
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<!--Pharmacokinetic data--> |
<!--Pharmacokinetic data--> |
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<!--Identifiers--> |
<!--Identifiers--> |
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| IUPHAR_ligand = 4812 |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 173334-57-1 |
| CAS_number = 173334-57-1 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = DB01258 |
| DrugBank = DB01258 |
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| ChemSpiderID_Ref = {{chemspidercite| |
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} |
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| ChemSpiderID = |
| ChemSpiderID = 4591452 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = 502FWN4Q32 |
| UNII = 502FWN4Q32 |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D03208 |
| KEGG = D03208 |
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| ChEBI_Ref = {{ebicite| |
| ChEBI_Ref = {{ebicite|changed|EBI}} |
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| ChEBI = |
| ChEBI = 601027 |
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| ChEMBL_Ref = {{ebicite| |
| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = |
| ChEMBL = 1639 |
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| PDB_ligand = C41 |
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⚫ | |||
| molecular_weight = 551.758 g/mol |
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<!--Chemical data--> |
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⚫ | |||
| smiles = O=C(N)C(C)(C)CNC(=O)[C@H](C(C)C)C[C@H](O)[C@@H](N)C[C@@H](C(C)C)Cc1cc(OCCCOC)c(OC)cc1 |
| smiles = O=C(N)C(C)(C)CNC(=O)[C@H](C(C)C)C[C@H](O)[C@@H](N)C[C@@H](C(C)C)Cc1cc(OCCCOC)c(OC)cc1 |
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| StdInChI_Ref = {{stdinchicite| |
| StdInChI_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChI = 1S/ |
| StdInChI = 1S/C30H53N3O6/c1-19(2)22(14-21-10-11-26(38-8)27(15-21)39-13-9-12-37-7)16-24(31)25(34)17-23(20(3)4)28(35)33-18-30(5,6)29(32)36/h10-11,15,19-20,22-25,34H,9,12-14,16-18,31H2,1-8H3,(H2,32,36)(H,33,35)/t22-,23-,24-,25-/m0/s1 |
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| StdInChIKey_Ref = {{stdinchicite| |
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChIKey = |
| StdInChIKey = UXOWGYHJODZGMF-QORCZRPOSA-N |
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}} |
}} |
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'''Aliskiren''' (brand names '''Tekturna''' and '''Rasilez''') is the first in a class of drugs called direct [[renin inhibitor]]s. It is used for [[essential hypertension|essential (primary) hypertension]].<ref>{{cite news | url = http://www.cbc.ca/cp/HealthScout/070306/6030611AU.html | title = First Hypertension Drug to Inhibit Kidney Enzyme Approved | date = 2007-03-06 | access-date = 2007-03-14 | publisher = [[Canadian Broadcasting Corporation|CBC]] | archive-url = https://web.archive.org/web/20070322214927/http://www.cbc.ca/cp/HealthScout/070306/6030611AU.html | archive-date = 2007-03-22 | url-status = dead }}</ref> While used for high blood pressure, other better studied medications are typically recommended due to concerns of higher side effects and less evidence of benefit.<ref name=Pres2014/> |
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In December 2011, Novartis halted a trial of the drug after discovering increased nonfatal [[stroke]], kidney complications, [[hyperkalemia|high blood potassium]], and [[hypotension|low blood pressure]] in people with [[Diabetes mellitus|diabetes]] and [[Chronic kidney disease|kidney problems]].<ref>Healthzone.ca: [http://www.healthzone.ca/health/newsfeatures/article/1105900--blood-pressure-drug-reviewed-amid-dangerous-side-effects?bn=1 Blood-pressure drug reviewed amid dangerous side effects]</ref><ref name = "Parving_2012">{{cite journal | vauthors = Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, Chaturvedi N, Persson F, Desai AS, Nicolaides M, Richard A, Xiang Z, Brunel P, Pfeffer MA | display-authors = 6 | title = Cardiorenal end points in a trial of aliskiren for type 2 diabetes | journal = The New England Journal of Medicine | volume = 367 | issue = 23 | pages = 2204–13 | date = December 2012 | pmid = 23121378 | doi = 10.1056/NEJMoa1208799 | url = https://boris.unibe.ch/15598/1/nejmoa1208799.pdf }}</ref> |
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As a result, in 2012: |
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* A new contraindication was added to the product label concerning the use of aliskiren with [[angiotensin receptor blocker]]s (ARBs) or [[angiotensin-converting enzyme inhibitor]]s (ACEIs) in patients with diabetes because of the risk of kidney impairment, low blood pressure, and high levels of potassium in the blood.<ref name="FDA safety">{{cite web | title=FDA Drug Safety Communication: New Warning and Contraindication for blood pressure medicines containing aliskiren (Tekturna) | website=U.S. [[Food and Drug Administration]] (FDA) | date=19 January 2016 | url=http://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-new-warning-and-contraindication-blood-pressure-medicines-containing | access-date=12 February 2020}}</ref> |
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* A warning to avoid use of aliskiren with ARBs or ACEIs was also added for patients with moderate to severe kidney impairment (i.e., where glomerular filtration rate is less than 60 ml/min).<ref name="FDA safety" /> |
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* Novartis decided to stop marketing Valturna (aliskiren/[[valsartan]]).<ref>{{cite web | title=Aliskiren Information | website=U.S. Food and Drug Administration | date=8 July 2015 | url=http://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/aliskiren-information | access-date=12 February 2020}}</ref> |
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Aliskiren was co-developed by the Swiss pharmaceutical companies [[Novartis]] and Speedel.<ref>{{cite journal | vauthors = Gradman AH, Schmieder RE, Lins RL, Nussberger J, Chiang Y, Bedigian MP | title = Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients | journal = Circulation | volume = 111 | issue = 8 | pages = 1012–8 | date = March 2005 | pmid = 15723979 | doi = 10.1161/01.CIR.0000156466.02908.ED | doi-access = free }}</ref><ref>{{cite journal | vauthors = Staessen JA, Li Y, Richart T | title = Oral renin inhibitors | journal = Lancet | volume = 368 | issue = 9545 | pages = 1449–56 | date = October 2006 | pmid = 17055947 | doi = 10.1016/S0140-6736(06)69442-7 | s2cid = 20729350 }}</ref><!----> |
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==Medical uses== |
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While used for high blood pressure, other better-studied medications are typically recommended.<ref name=Pres2014/> ''[[Prescrire]]'' has stated that aliskiren is potentially more harmful than beneficial and thus list it as a drug to avoid (as of 2014).<ref name=Pres2014>{{cite journal | title = Towards better patient care: drugs to avoid in 2014 | journal = Prescrire International | volume = 23 | issue = 150 | pages = 161–5 | date = June 2014 | pmid = 25121155 | url = http://english.prescrire.org/en/81/168/49342/0/NewsDetails.aspx }}</ref> |
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==Adverse effects== |
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* [[Angioedema]] - The ADE of angioedema found in patients using Aliskiren is due to the inhibition of bradykinin degradation which occurs within the Renin-Angiotensin System (RAAS) |
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* [[Hyperkalemia|High blood potassium level]] (particularly when used with ACE inhibitors in diabetic patients) |
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* [[Hypotension|Low blood pressure]] (particularly in volume-depleted patients) |
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* Diarrhea and other GI symptoms |
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* Headache |
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* Dizziness |
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* Cough |
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==Contraindications== |
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* Pregnancy: Other drugs such as [[angiotensin-converting enzyme|ACE]] inhibitors, also acting on the [[renin–angiotensin system]], have been associated with fetal malformations and neonatal death.<ref name="drugs.com">Drugs.com: [https://www.drugs.com/pro/tekturna.html Tekturna]</ref> Angiotensin cannot be used in patients who are pregnant because it will result in disruption of normal fetal kidney development. |
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* Breastfeeding: During animal studies, the drug has been found present in milk.<ref name="drugs.com" /> |
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* Aliskiren has been shown to increase the likelihood of adverse cardiovascular outcomes in patients with diabetes and kidney or heart disease.<ref name = "Parving_2012" /> |
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==Drug interactions== |
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Aliskiren is a minor inhibitor of substrate [[CYP3A4]] and, more importantly, [[P-glycoprotein]]: |
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* It reduces [[furosemide]] blood concentration. |
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* [[Atorvastatin]] may increase aliskiren's blood concentration, but no dose adjustment is needed. |
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* Due to possible interaction with [[ciclosporin]], the use of ciclosporin and aliskiren at the same time is contraindicated. |
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* Caution should be exercised when aliskiren is administered with [[ketoconazole]] and other moderate P-glycoprotein inhibitors such as [[itraconazole]], [[clarithromycin]], [[telithromycin]], [[erythromycin]], or [[amiodarone]]. |
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* Recommendations have been made to stop prescribing aliskiren-containing medicines to patients with diabetes (type 1 or type 2) or with moderate to severe kidney impairment who are also taking an ACE inhibitor or ARB. Such patients should consider alternative antihypertensive treatment as necessary.<ref>{{Cite web |last=EMA |date=2018-09-17 |title=European Medicines Agency recommends new contraindications and warnings for aliskiren-containing medicines |url=https://www.ema.europa.eu/en/news/european-medicines-agency-recommends-new-contraindications-warnings-aliskiren-containing-medicines |access-date=2023-11-05 |website=European Medicines Agency |language=en}}</ref> |
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==Mechanism of action== |
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Aliskiren is an inhibitor of renin.<ref name="structure">{{cite journal | vauthors = Rahuel J, Rasetti V, Maibaum J, Rüeger H, Göschke R, Cohen NC, Stutz S, Cumin F, Fuhrer W, Wood JM, Grütter MG | display-authors = 6 | title = Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin | journal = Chemistry & Biology | volume = 7 | issue = 7 | pages = 493–504 | date = July 2000 | pmid = 10903938 | doi = 10.1016/S1074-5521(00)00134-4 | doi-access = free }}</ref> Renin, the first enzyme in the [[renin–angiotensin–aldosterone system]], plays a role in blood pressure control. It cleaves [[angiotensinogen]] to [[angiotensin I]], which is in turn converted by [[angiotensin-converting enzyme]] (ACE) to [[angiotensin II]]. Angiotensin II has both direct and indirect effects on blood pressure. It directly causes arterial [[smooth muscle]] to contract, leading to [[vasoconstriction]] and increased blood pressure. Angiotensin II also stimulates the production of [[aldosterone]] from the adrenal cortex, which causes the tubules of the kidneys to increase reabsorption of sodium, with water following, thereby increasing plasma volume, and thus blood pressure. Aliskiren binds to the S3<sup>bp</sup> binding site of renin, essential for its activity.<ref name="structure" /> Binding to this pocket prevents the conversion of angiotensinogen to angiotensin I. |
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Aliskiren is also available as combination therapy with [[hydrochlorothiazide]].<ref name="aliskhydro">{{cite journal | vauthors = Baldwin CM, Plosker GL | title = Aliskiren/hydrochlorothiazide combination: in mild to moderate hypertension | journal = Drugs | volume = 69 | issue = 7 | pages = 833–41 | year = 2009 | pmid = 19441870 | doi = 10.2165/00003495-200969070-00004 | s2cid = 26512682 }}</ref> |
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==Chemistry== |
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The chemical name for aliskiren is (2 S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7-[ 4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide.<ref>{{cite journal|title=Recommended INN List 45|journal=WHO Drug Information|date=2001|volume=15|issue=1|url=https://www.who.int/medicines/publications/druginformation/innlists/RL45.pdf?ua=1}}</ref> |
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==Rationale for design== |
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Many drugs control blood pressure by interfering with angiotensin or [[aldosterone]]. However, when these drugs are used chronically, the body increases renin production, which drives blood pressure up again. Therefore, pharmacologists have been looking for a drug to inhibit renin directly. Aliskiren is the first drug to do so.<ref name="pmid18525047">{{cite journal | vauthors = Ingelfinger JR | title = Aliskiren and dual therapy in type 2 diabetes mellitus | journal = The New England Journal of Medicine | volume = 358 | issue = 23 | pages = 2503–5 | date = June 2008 | pmid = 18525047 | doi = 10.1056/NEJMe0803375 }}</ref><ref>PharmaXChange: [http://pharmaxchange.info/presentations/dri.html Direct Renin Inhibitors as Antihypertensive Drugs] {{Webarchive|url=https://web.archive.org/web/20101207071030/http://pharmaxchange.info/presentations/dri.html |date=2010-12-07 }}</ref> |
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==References== |
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{{reflist}} |
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==External links== |
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* {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/Aliskiren | publisher = U.S. National Library of Medicine| work = Drug Information Portal | title = Aliskiren }} |
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* {{MeshName|Aliskiren}} |
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{{Agents acting on the renin–angiotensin system}} |
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{{Angiotensin receptor modulators}} |
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{{portal bar|Medicine}} |
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[[Category:Renin inhibitors]] |
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[[Category:Catechol ethers]] |
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[[Category:Drugs developed by Novartis]] |