Lihat sumber Itrakonazol

{{Short description|Medication used to treat fungal infections}}
{{Use dmy dates|date=March 2024}}
{{Drugbox
| Watchedfields = changed
| verifiedrevid = 459522522
| image = Itraconazole.svg
| width =
| alt = 
| chirality = [[Racemic mixture]]

<!-- Clinical data -->
| tradename = Sporanox, Sporaz, Orungal, dll
| Drugs.com = {{drugs.com|monograph|itraconazole}}
| MedlinePlus = a692049
| DailyMedID = Itraconazole
| pregnancy_AU = B3
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Itraconazole Use During Pregnancy | website=Drugs.com | date=20 March 2019 | url=https://www.drugs.com/pregnancy/itraconazole.html | access-date=15 May 2020}}</ref>
| routes_of_administration = Oral, [[larutan]]), [[supositoria]] vaginal, [[infus]]
| ATC_prefix = J02
| ATC_suffix = AC02

| legal_AU = S4
| legal_CA = Rx-only
| legal_UK = POM
| legal_UK_comment = <ref>{{cite web | title=Sporanox 10 mg/mL Oral Solution - Summary of Product Characteristics (SmPC) | website=(emc) | date=1 February 2018 | url=https://www.medicines.org.uk/emc/product/1522/smpc | access-date=15 May 2020}}</ref>
| legal_US = Rx-only

<!-- Pharmacokinetic data -->
| bioavailability = ~55%, maksimal jika dikonsumsi bersamaan dengan makanan lengkap
| protein_bound = 99.8%
| metabolism = Secara luas di [[Hati]] ([[CYP3A4]])
| metabolites = Hidroksi-itrakonazol, keto-itrakonazol,<br />''N''-desalkil-itrakonazol<ref>{{cite journal | vauthors = Isoherranen N, Kunze KL, Allen KE, Nelson WL, Thummel KE | title = Role of itraconazole metabolites in CYP3A4 inhibition | journal = Drug Metabolism and Disposition | volume = 32 | issue = 10 | pages = 1121–1131 | date = October 2004 | pmid = 15242978 | doi = 10.1124/dmd.104.000315 | s2cid = 6941636 }}</ref>
| elimination_half-life = 21 jam
| excretion = [[Ginjal]] (35%), [[feses]] (54%)<ref name="Sporanox PI">{{cite web|title=Sporanox (itraconazole) Capsules. Full Prescribing Information|url=http://www.janssen.com/us/sites/www_janssen_com_usa/files/products-documents/pi-sporanoxcapsules.pdf|publisher=Janssen Pharmaceuticals, Inc.|access-date=28 August 2016|archive-date=17 May 2018|archive-url=https://web.archive.org/web/20180517073659/http://www.janssen.com/us/sites/www_janssen_com_usa/files/products-documents/pi-sporanoxcapsules.pdf|url-status=dead}}</ref>

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 84625-61-6
| PubChem = 55283
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01167
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 49927
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 304NUG5GF4
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00350
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 6076
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 22587
| synonyms = ITZ

<!--Chemical data-->
| IUPAC_name = (±)-1-[(''RS'')-''sek''-butil]-4-[''p''-[4-[''p''-<nowiki>[[</nowiki>(2''R'',4''S'')-''rel''-2-(2,4-diklorofenil)-2-(1''H''-1,2,4-triazol-1-ilmetil)-1,3-dioksolan-4-il]metoksi]fenil]-1-piperazinil]fenil]-Δ<sup>2</sup>-1,2,4-triazolin-5-ona
| C=35 | H=38 | Cl=2 | N=8 | O=4
| smiles = O=C1N(/N=C\N1c2ccc(cc2)N7CCN(c6ccc(OC[C@@H]3O[C@](OC3)(c4ccc(Cl)cc4Cl)Cn5ncnc5)cc6)CC7)C(C)CC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C35H38Cl2N8O4/c1-3-25(2)45-34(46)44(24-40-45)29-7-5-27(6-8-29)41-14-16-42(17-15-41)28-9-11-30(12-10-28)47-19-31-20-48-35(49-31,21-43-23-38-22-39-43)32-13-4-26(36)18-33(32)37/h4-13,18,22-25,31H,3,14-17,19-21H2,1-2H3/t25?,31-,35-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = VHVPQPYKVGDNFY-ZPGVKDDISA-N
| melting_point = 165 <ref name="NikitaVas">{{cite journal | vauthors = Vasilev NA, Surov AO, Voronin AP, Drozd KV, Perlovich GL | title = Novel cocrystals of itraconazole: Insights from phase diagrams, formation thermodynamics and solubility | journal = International Journal of Pharmaceutics | volume = 599 | pages = 120441 | date = April 2021 | pmid = 33675927 | doi = 10.1016/j.ijpharm.2021.120441 | s2cid = 232135660 }}</ref>
| solubility = 7.8 ± 0.4 × 10<sup>−6</sup> mol/L (pH 1.6)<ref name="NikitaVas"/>
}}

'''Itrakonazol''' (terkadang disingkat '''ITZ''') adalah obat [[antijamur]] yang digunakan untuk mengobati sejumlah [[Mikosis|infeksi jamur]] termasuk [[aspergilosis]], [[blastomikosis]], [[koksidioidomikosis]], [[histoplasmosis]], dan [[parakoksidioidomikosis]]. Obat ini dapat diberikan secara [[Oral (rute pemberian obat)|oral]] atau [[infus]].<ref name=AHFS2017/>

Efek samping yang umum termasuk [[mual]], [[diare]], [[mulas]], ruam, dan sakit kepala. Efek samping yang parah mungkin termasuk masalah hati, [[gagal jantung]], [[sindrom Stevens-Johnson]] dan reaksi alergi termasuk [[anafilaksis]].<ref name=AHFS2017/> Tidak jelas apakah penggunaan selama [[kehamilan]] atau [[menyusui]] aman.<ref name="Drugs.com pregnancy" /> Obat ini termasuk dalam kelompok obat triazol. Obat ini menghentikan pertumbuhan jamur dengan mempengaruhi [[membran]] sel atau mempengaruhi [[metabolisme]] mereka.<ref name=AHFS2017/> 

Itrakonazol dipatenkan pada tahun 1978 dan disetujui untuk penggunaan medis di Amerika Serikat pada tahun 1992.<ref name=AHFS2017>{{cite web|title=Itraconazole|url=https://www.drugs.com/monograph/itraconazole.html|publisher=The American Society of Health-System Pharmacists|access-date= 8 December 2017}}</ref><ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=503 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA503 |language=en}}</ref> Obat ini ada dalam [[Daftar Obat Esensial Organisasi Kesehatan Dunia]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> 

Penelitian terbaru menunjukkan itrakonazol juga dapat digunakan dalam pengobatan kanker dengan menghambat "jalur [[landak susu]]"<ref name="LiFang2019">{{cite journal | vauthors = Li K, Fang D, Xiong Z, Luo R | title = Inhibition of the hedgehog pathway for the treatment of cancer using Itraconazole | journal = OncoTargets and Therapy | volume = 12 | pages = 6875–6886 | year = 2019 | pmid = 31692536 | pmc = 6711563 | doi = 10.2147/OTT.S223119 | doi-access = free }}</ref> dengan cara yang mirip dengan sonidegib.
==Sejarah==
Itrakonazol disetujui untuk penggunaan medis di Amerika Serikat pada tahun 1992.<ref>{{cite web | title=Itraconazole: FDA-Approved Drugs | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020083 | access-date=15 May 2020}}</ref> Obat ini ditetapkan sebagai ''orphan drug'' oleh [[Badan Pengawas Obat dan Makanan Amerika Serikat]] (FDA) dan [[Badan Pengawas Obat Eropa]] (EMA).
== Kegunaan dalam Medis ==
==Efek Samping==
Itrakonazol adalah obat yang relatif dapat ditoleransi dengan baik (walaupun tidak dapat ditoleransi dengan baik seperti [[flukonazol]] atau vorikonazol) dan kisaran efek samping yang ditimbulkannya mirip dengan antijamur [[azola]] lainnya:

*peningkatan kadar [[alanina aminotransferase]] ditemukan pada 4% orang yang memakai itrakonazol 
*"risiko kecil namun nyata" terjadinya [[gagal jantung]] kongestif<ref name="FDA">{{cite web | title=The Safety of Sporanox Capsules and Lamisil Tablets for the Treatment of Onychomycosis | url=https://www.fda.gov/CDER/drug/advisory/sporanox-lamisil/advisory.htm | publisher=FDA Public Health Advisory | date=9 May 2001 | access-date=10 August 2006 | archive-url = https://web.archive.org/web/20090528160344/https://www.fda.gov/cder/drug/advisory/sporanox-lamisil/advisory.htm | archive-date=28 May 2009}}</ref> 
*gagal hati, terkadang berakibat fatal 

Siklodekstrin yang digunakan untuk membuat sediaan sirup itrakonazol dapat menyebabkan diare. Efek samping yang mungkin mengindikasikan masalah yang lebih besar meliputi:{{cn|date=December 2022}} 

*[[mual]] 
*[[muntah]] 
*[[mulas]]
*[[kelelahan]] 
*Anoreksia 
*kulit kuning ([[Jaundis|penyakit kuning]]) 
*mata kuning 
*[[gatal]] 
*urin berwarna gelap 
*feses pucat 
*[[sakit kepala]]

==Interaksi==
Obat-obatan berikut tidak boleh dikonsumsi bersamaan dengan itrakonazol karena dapat menyebabkan interaksi:<ref name="urlSporanox (Itraconazole) Capsules">{{cite web | url = https://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm303524.htm | title = Sporanox (Itraconazole) Capsules | work = Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research | publisher = U.S. [[Food and Drug Administration]] (FDA) | access-date = 16 December 2019 | archive-date = 26 October 2016 | archive-url = https://web.archive.org/web/20161026050954/http://www.fda.gov/safety/medwatch/safetyinformation/ucm303524.htm | url-status = dead }}</ref> 
*[[amiodaron]]<ref name="urlCardiac arrest provoked by itraconazole and amiodarone interaction: a case report">{{cite journal | vauthors = Tsimogianni AM, Andrianakis I, Betrosian A, Douzinas E | title = Cardiac arrest provoked by itraconazole and amiodarone interaction: a case report | journal = Journal of Medical Case Reports | volume = 5 | pages = 333 | date = July 2011 | pmid = 21801420 | pmc = 3161953 | doi = 10.1186/1752-1947-5-333 | doi-access = free }}</ref>
*[[kisaprida]] 
*dofetilid 
*nisoldipin 
*[[alkohol]] 
*pimozid 
*kuinidin 
*lurasidon 
*lovastatin atau [[simvastatin]]
*[[midazolam]] atau triazolam 
*obat-obat [[ergot]] seperti dihidroergotamin, ergometrin, [[ergotamin]], dan [[metilergometrin]]

==Farmakologi==
===Farmakodinamik=== 
Mekanisme kerja itrakonazol sama dengan [[antijamur]] [[azola]] lainnya yakni menghambat sintesis [[ergosterol]] yang dimediasi jamur, melalui penghambatan lanosterol 14α-demetilase. Karena kemampuannya menghambat sitokrom P450 3A4 CC-3, kehati-hatian harus digunakan ketika mempertimbangkan interaksi dengan obat lain.<ref>{{cite book | vauthors = Trevor AJ, Katzung BG, Kruidering-Hall M |title=Katzung & Trevor's Pharmacology: Examination & Board Review |date=2015 |publisher=McGraw Hill Medical |location=New York |isbn=978-0-07-182635-8 |edition=Eleventh |pages=397}}</ref>

Itrakonazol secara farmakologi berbeda dari agen antijamur azola lainnya karena merupakan satu-satunya inhibitor di kelas ini yang telah terbukti menghambat "jalur sinyal [[landak susu]]"<ref>{{cite journal |vauthors=Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, Chong CR, Chang KS, Fereshteh M, Gardner D, Reya T, Liu JO, Epstein EH, Stevens DA, Beachy PA | title = Itraconazole, a Commonly Used Antifungal that Inhibits Hedgehog Pathway Activity and Cancer Growth | journal = Cancer Cell | volume = 17 | issue = 4 | pages = 388–99 | year = 2010 | pmid = 20385363 | doi = 10.1016/j.ccr.2010.02.027  | pmc = 4039177 }}</ref><ref name="Kim, Aftab">{{cite journal |vauthors=Kim J, Aftab BT, Tang JY, Kim D, Lee AH, Rezaee M, Kim J, Chen B, King EM, Borodovsky A, Riggins GJ, Epstein EH, Beachy PA, Rudin CM | title = Itraconazole and arsenic trioxide inhibit hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists | journal = Cancer Cell | volume = 23 | issue = 1 | pages = 23–34 | year = 2013 | pmid = 23291299 | pmc = 3548977 | doi = 10.1016/j.ccr.2012.11.017 }}</ref> dan [[angiogenesis]].<ref name="Chong">{{cite journal |vauthors=Chong CR, Xu J, Lu J, Bhat S, Sullivan DJ, Liu JO | title = Inhibition of Angiogenesis by the Antifungal Drug Itraconazole | journal = ACS Chemical Biology | volume = 2 | issue = 4 | pages = 263–70 | year = 2007 | pmid = 17432820 | doi = 10.1021/cb600362d }}</ref><ref name="Aftab">{{cite journal |vauthors=Aftab BT, Dobromilskaya I, Liu JO, Rudin CM | title = Itraconazole Inhibits Angiogenesis and Tumor Growth in Non-Small Cell Lung Cancer | journal = Cancer Research | volume = 71 | issue = 21 | pages = 6764–72 | year = 2011 | pmid = 21896639 | pmc = 3206167 | doi = 10.1158/0008-5472.CAN-11-0691 }}</ref> Aktivitas berbeda ini tidak berhubungan dengan penghambatan [[sitokrom P450]] lanosterol 14 alfa-demetilase dan target molekuler pasti yang bertanggung jawab masih belum teridentifikasi. Secara fungsional, aktivitas antiangiogenik itrakonazol telah terbukti terkait dengan penghambatan glikosilasi, fosforilasi VEGFR2,<ref name="Aftab" /> penyelundupan,<ref>{{cite journal |vauthors=Xu J, Dang Y, Ren YR, Liu JO | title = Cholesterol trafficking is required for mTOR activation in endothelial cells | journal = Proceedings of the National Academy of Sciences | volume = 107 | issue = 10 | pages = 4764–9 | year = 2010 | pmid = 20176935 | pmc = 2842052 | doi = 10.1073/pnas.0910872107 | bibcode = 2010PNAS..107.4764X | doi-access = free }}</ref> dan jalur biosintesis kolesterol.<ref name="Chong" /> Bukti menunjukkan bahwa faktor penentu struktural penghambatan "sinyal landak susu" oleh itrakonazol sangat berbeda dengan faktor yang terkait dengan aktivitas antiangiogenik.<ref>{{cite journal |vauthors=Shi W, Nacev BA, Aftab BT, Head S, Rudin CM, Liu JO | title = Itraconazole Side Chain Analogues: Structure–Activity Relationship Studies for Inhibition of Endothelial Cell Proliferation, Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Glycosylation, and Hedgehog Signaling | journal = Journal of Medicinal Chemistry | volume = 54 | issue = 20 | pages = 7363–74 | year = 2011 | pmid = 21936514 | pmc = 3307530 | doi = 10.1021/jm200944b }}</ref>

===Farmakokinetik=== 
Itrakonazol, seperti [[siklosporin]], kuinidin, dan [[klaritromisin]], dapat menghambat P-glikoprotein, menyebabkan [[interaksi obat]] dengan mengurangi eliminasi dan meningkatkan penyerapan obat kation organik. Pada sediaan itrakonazol konvensional, kadar serum dapat sangat bervariasi antar pasien, seringkali mengakibatkan konsentrasi serum lebih rendah dari indeks terapeutik.<ref name="pmid8878612">{{cite journal |vauthors=Patterson TF, Peters J, Levine SM, Anzueto A, Bryan CL, Sako EY, Miller OL, Calhoon JH, Rinaldi MG | title = Systemic availability of itraconazole in lung transplantation | journal = Antimicrob. Agents Chemother. | volume = 40 | issue = 9 | pages = 2217–20 | year = 1996 | pmid = 8878612 | pmc = 163504 | doi = 10.1128/AAC.40.9.2217}}</ref> Oleh karena itu, secara konvensional disarankan agar pasien mengonsumsi itrakonazol setelah makan berlemak, bukan sebelum makan.<ref name="pmid9477653">{{cite journal |vauthors=Fraga Fuentes MD, García Díaz B, de Juana Velasco P, Bermejo Vicedo MT | title = [Influence of foods on the absorption of antimicrobial agents] | language = es| journal = Nutr Hosp | volume = 12 | issue = 6 | pages = 277–88 | year = 1997 | pmid = 9477653 }}</ref><ref name="pmid8388198">{{cite journal |vauthors=Barone JA, Koh JG, Bierman RH, Colaizzi JL, Swanson KA, Gaffar MC, Moskovitz BL, Mechlinski W, Van de Velde V | title = Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers | journal = Antimicrob. Agents Chemother. | volume = 37 | issue = 4 | pages = 778–84 | year = 1993 | pmid = 8388198 | pmc = 187759 | doi = 10.1128/aac.37.4.778}}</ref>

Produk (Lozanoc) yang dilisensikan melalui prosedur desentralisasi Uni Eropa<ref name="urlwww.mhra.gov.uk">{{cite web | url = http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con249676.pdf | title = Lozanoc 50 Mg Hard Capsules (Itraconazole) | work = Public Assessment Report Decentralised Procedure | publisher = UK Medicines and Health Care Products Regulatory Agency }}</ref> telah meningkatkan [[bioavailabilitas]], menurunkan sensitivitas terhadap konsumsi makanan secara bersamaan, dan karenanya menurunkan variabilitas kadar serum.

==Kimia==
[[File:Itraconazole chiral carbons.svg|thumb|right|300px|Pusat kiral ditandai dengan tanda bintang]]

Molekul itrakonazol memiliki tiga karbon kiral. Dua pusat kiral pada cincin dioksolana terikat satu sama lain, dan substituen cincin triazolometilen dan ariloksimetilen dioksolana selalu saling ''[[Isomerisme cis–trans|cis]]''. Formulasi klinisnya adalah campuran 1:1:1:1 dari empat stereoisomer (dua pasangan enansiomer).<ref>{{cite journal | vauthors = Kunze KL, Nelson WL, Kharasch ED, Thummel KE, Isoherranen N | title = Stereochemical aspects of itraconazole metabolism in vitro and in vivo | journal = Drug Metabolism and Disposition | volume = 34 | issue = 4 | pages = 583–590 | date = April 2006 | pmid = 16415110 | doi = 10.1124/dmd.105.008508 | s2cid = 189994 }}</ref><ref>{{cite web|title=Itraconazole on Drugs.com|url=https://www.drugs.com/pro/itraconazole.html|website=Drugs.com|access-date=28 August 2016}}</ref>

[[File:Itraconazole enantiomers.svg|thumb|right|300px|Empat diastereomer itrakonazol]]

==Referensi ==
{{Reflist}}
[[Kategori:Obat]]
[[Kategori:Antijamur]]
[[Kategori:Obat Esensial Organisasi Kesehatan Dunia]]
==Pranala Luar==
* {{commonscatinline}}