Fludrocortisone: Difference between revisions

{{Short description|Mineralocorticoid hormone medication}}

| Watchedfields = changed

| verifiedrevid = 457636417

| drug_name = Fludrocortisone

| image = Fludrocortisone.svg

| width = 200px

| image2 = Fludrocortisone-from-xtal-1972-3D-balls.png

| width2 = 225px

| tradename = Astonin, Astonin-H, others

| legal_US = Rx-only

| routes_of_administration = [[Oral administration|By mouth]]

| class = [[Corticosteroid]]; [[glucocorticoid]]; [[mineralocorticoid]]

| ATC_prefix = H02

| ATC_suffix = AA02

| ATC_supplemental =

| bioavailability =

| metabolism = [[Liver]]

| index2_label = Acetate

| CAS_number2_Ref = {{cascite|correct|CAS}}

| CAS_number2 = U0476M545B

| PubChemSubstance = 46508616

| IUPHAR_ligand = 2873

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 1201388

| PDB_ligand = ZK5

| synonyms = StC-1400; 9α-Fluorohydrocortisone; 9α-Fluorocortisol; 9α-Fluoro-17α-hydroxycorticosterone; 9α-Fluoro-11β,17α,21-trihydroxypregn-4-ene-3,20-dione

<!--Chemical data-->

| IUPAC_name = (8''S'',9''R'',10''S'',11''S'',13''S'',14''S'',17''R'')-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[''a'']phenanthren-3-one

| C=21 | H=29 | F=1 | O=5

| SMILES = O=C(CO)[C@]3(O)[C@]2(C[C@H](O)[C@]4(F)[C@@]1(/C(=C\C(=O)CC1)CC[C@H]4[C@@H]2CC3)C)C

{{Drugbox

| Verifiedfields =

| Watchedfields =

| verifiedrevid =

| drug_name = Fludrocortisone acetate

| image = Fludrocortisone acetate.svg

| width =

<!--Clinical data-->

| tradename = Cortineff, Florinef, Florinefe, Fludrocortison, others

| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->

| pregnancy_US = <!-- A / B / C / D / X -->

| pregnancy_category =

| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->

| legal_CA =

| legal_UK =

| legal_US =

| legal_status =

| routes_of_administration = [[Oral administration|By mouth]]

| class = [[Corticosteroid]]; [[glucocorticoid]]; [[mineralocorticoid]]

| ATC_prefix =

| ATC_suffix =

| ATC_supplemental =

<!--Pharmacokinetic data-->

| bioavailability =

| protein_bound =

| metabolism = [[Liver]]

| elimination_half-life =

| excretion =

<!-- Identifiers -->

| CAS_number_Ref =

| CAS_number = 514-36-3

| CAS_supplemental =

| PubChem = 225609

| IUPHAR_ligand =

| DrugBank_Ref =

| DrugBank =

| ChemSpiderID_Ref =

| ChemSpiderID = 196144

| UNII = V47IF0PVH4

| KEGG = D00986

| ChEBI = 5102

| ChEMBL = 1201010

| synonyms = Fluorohydrocortisone acetate; 9α-Fluorohydrocortisone 21-acetate; 9α-Fluoro-17α-hydroxycorticosterone 21-acetate; 9α-Fluoro-11β,17α,21-trihydroxypregn-4-ene-3,20-dione 21-acetate

<!--Chemical data-->

| IUPAC_name = [2-[(8''S'',9''R'',10''S'',11''S'',13''S'',14''S'',17''R'')-9-fluoro-11,17-dihydroxy-10,13-dimethyl-3-oxo-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[''a'']phenanthren-17-yl]-2-oxoethyl] acetate

| C=23 | H=31 | F=1 | O=6

| SMILES = CC(=O)OCC(=O)[C@]1(CC[C@@H]2[C@@]1(C[C@@H]([C@]3([C@H]2CCC4=CC(=O)CC[C@@]43C)F)O)C)O

| StdInChI_Ref =

| StdInChI = 1S/C23H31FO6/c1-13(25)30-12-19(28)22(29)9-7-16-17-5-4-14-10-15(26)6-8-20(14,2)23(17,24)18(27)11-21(16,22)3/h10,16-18,27,29H,4-9,11-12H2,1-3H3/t16-,17-,18-,20-,21-,22-,23-/m0/s1

| StdInChIKey_Ref =

| StdInChIKey = SYWHXTATXSMDSB-GSLJADNHSA-N

<!--Physical data-->

| melting_point = 260

| melting_high = 262

| melting_notes = (dec.)

}}

<!-- Definition and medical uses -->

'''Fludrocortisone''', sold under the brand name '''Florinef''', among others, is a [[corticosteroid]] used to treat [[adrenogenital syndrome]], [[postural hypotension]], and [[adrenal insufficiency]].<ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA558|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=558–|url-status=live|archive-url=https://web.archive.org/web/20171105200659/https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA558|archive-date=5 November 2017}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA450|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=450–|url-status=live|archive-url=https://web.archive.org/web/20171105200659/https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA450|archive-date=2017-11-05}}</ref><ref name=AHFS2016/> In adrenal insufficiency, it is generally taken together with [[hydrocortisone]].<ref name=AHFS2016/> Fludrocortisone is taken by mouth<ref name=AHFS2016>{{cite web|title=Fludrocortisone Acetate|url=https://www.drugs.com/monograph/fludrocortisone-acetate.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20170705084019/https://www.drugs.com/monograph/fludrocortisone-acetate.html|archive-date=5 July 2017}}</ref> and is most commonly used in its [[acetate]] form.<ref name=DayFurst2010>{{cite book| vauthors = | chapter = Medicinal Chemistry of the Disease Modifying Antirheumatic Drugs | veditors = Day RO, Furst DE, van Riel PL, Bresnihan B |title=Antirheumatic Therapy: Actions and Outcomes| chapter-url=https://books.google.com/books?id=OqKTuL9ePhsC&pg=PA21|date=30 May 2010|publisher=Springer Science & Business Media|isbn=978-3-7643-7726-7|pages=21–|url-status=live|archive-url=https://web.archive.org/web/20171105200659/https://books.google.com/books?id=OqKTuL9ePhsC&pg=PA21|archive-date=5 November 2017}}</ref>

<!-- Side effects and mechanism -->

Common side effects of fludrocortisone include [[high blood pressure]], swelling, [[heart failure]], and [[low blood potassium]].<ref name=AHFS2016/> Other serious side effects can include [[immunosuppression|low immune-system function]], [[cataracts]], muscle weakness, and mood changes.<ref name=AHFS2016/> Whether use of fludrocortisone during [[pregnancy]] is safe for the fetus is unknown.<ref>{{cite web|title=Fludrocortisone Use During Pregnancy |url=https://www.drugs.com/pregnancy/fludrocortisone.html|website=Drugs.com |access-date=24 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161224235323/https://www.drugs.com/pregnancy/fludrocortisone.html|archive-date=24 December 2016}}</ref> Fludrocortisone is mostly a [[mineralocorticoid]], but it also has [[glucocorticoid]] effects.<ref name=AHFS2016/>

<!-- Society and culture -->

Fludrocortisone was patented in 1953.<ref name=Fis2006>{{cite book| vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons|isbn=9783527607495|page=484|url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA484|language=en|url-status=live|archive-url=https://web.archive.org/web/20171105200659/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA484|archive-date=2017-11-05}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<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>

==Medical uses==

Fludrocortisone has been used in the treatment of [[cerebral salt wasting|cerebral salt-wasting syndrome]].<ref name="pmid17101713">{{cite journal | vauthors = Taplin CE, Cowell CT, Silink M, Ambler GR | title = Fludrocortisone therapy in cerebral salt wasting | journal = Pediatrics | volume = 118 | issue = 6 | pages = e1904–e1908 | date = December 2006 | pmid = 17101713 | doi = 10.1542/peds.2006-0702 | s2cid = 28871495 }}</ref> It is used primarily to replace the missing hormone [[aldosterone]] in various forms of [[adrenal insufficiency]] such as [[Addison's disease]] and the classic salt-wasting ([[21-hydroxylase deficiency]]) form of [[congenital adrenal hyperplasia]]. Due to its effects on increasing Na+ levels, and therefore blood volume, fludrocortisone is the first-line of treatment for [[orthostatic intolerance]], and [[postural orthostatic tachycardia syndrome]] (POTS).<ref>{{cite journal | vauthors = Freitas J, Santos R, Azevedo E, Costa O, Carvalho M, de Freitas AF | title = Clinical improvement in patients with orthostatic intolerance after treatment with bisoprolol and fludrocortisone | journal = Clinical Autonomic Research | volume = 10 | issue = 5 | pages = 293–299 | date = October 2000 | pmid = 11198485 | doi = 10.1007/BF02281112 | s2cid = 20843222 }}</ref> It can be used to treat low blood pressure.<ref>{{cite journal | vauthors = Veazie S, Peterson K, Ansari Y, Chung KA, Gibbons CH, Raj SR, Helfand M | title = Fludrocortisone for orthostatic hypotension | journal = The Cochrane Database of Systematic Reviews | volume = 2021 | issue = 5 | pages = CD012868 | date = May 2021 | doi = 10.1002/14651858.CD012868.pub2 | pmid = 34000076 | pmc = 8128337 }}</ref>

Fludrocortisone is also a confirmation test for diagnosing [[Conn's syndrome]] (aldosterone-producing adrenal adenoma), the fludrocortisone suppression test. Loading the patient with fludrocortisone would ''suppress'' serum aldosterone level in a normal patient, whereas the level would remain ''elevated'' in a Conn's patient. The fludrocortisone suppression test is an alternative to the NaCl challenge (which would use normal saline or salt tablets).{{medcn|date=August 2020}}

Use of fludrocortisone can lead to one or more of the following side effects:<ref>{{Cite web |title=Fludrocortisone Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD |url=https://www.webmd.com/drugs/2/drug-6802/fludrocortisone-oral/details |access-date=2023-09-05 |website=www.webmd.com |language=en}}</ref>

==Pharmacology==

{{see also|Glucocorticoid#Pharmacology}}

Fludrocortisone is a [[corticosteroid]] and acts as a powerful [[mineralocorticoid]], along with some additional but comparatively very weak [[glucocorticoid]] activity.<ref name="pmid25905379">{{cite book | vauthors = De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, Chrousos, Pavlaki AN, Magiakou MA | display-authors = 6 | chapter = Glucocorticoid Therapy and Adrenal Suppression | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK279156/ | year = 2000 | pmid = 25905379 | veditors = Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP | display-editors = 6 | title = Endotext [Internet]. | location = South Dartmouth (MA) | publisher = MDText.com, Inc. }}</ref> Relative to cortisol, it is said to have 10&nbsp;times the glucocorticoid [[potency (pharmacology)|potency]] but 250 to 800&nbsp;times the mineralocorticoid potency.<ref name="pmid25905379" /><ref name="LemkeWilliams2008" /> Fludrocortisone acetate is a [[prodrug]] of fludrocortisone, which is the active form of the drug.<ref name="pmid27416887">{{cite journal | vauthors = Polito A, Hamitouche N, Ribot M, Polito A, Laviolle B, Bellissant E, Annane D, Alvarez JC | display-authors = 6 | title = Pharmacokinetics of oral fludrocortisone in septic shock | journal = British Journal of Clinical Pharmacology | volume = 82 | issue = 6 | pages = 1509–1516 | date = December 2016 | pmid = 27416887 | pmc = 5099539 | doi = 10.1111/bcp.13065 }}</ref>

Plasma renin, sodium, and potassium are checked through blood tests to verify that the correct dosage is reached.{{medcn|date=August 2020}}

==Chemistry==

Fludrocortisone, also known as 9α-fluorocortisol (9α-fluorohydrocortisone) or as 9α-fluoro-11β,17α,21-trihydroxypregn-4-ene-3,20-dione, is a [[synthetic compound|synthetic]] [[pregnane]] [[steroid]] and a [[halogen]]ated [[chemical derivative|derivative]] of [[cortisol]] (11β,17α,21-trihydroxypregn-4-ene-3,20-dione).<ref name="Elks2014" /><ref name="IndexNominum2000" /> Specifically, it is a modification of cortisol with a [[fluorine]] atom [[substituent|substituted]] in place of one [[hydrogen]] atom at the C9α position.<ref name="Elks2014" /><ref name="IndexNominum2000" /> Fluorine is a good [[bioisostere]] for hydrogen because it is similar in size, with the major difference being in its [[electronegativity]]. The acetate form of fludrocortisone, fludrocortisone acetate, is the C21 [[acetate]] [[ester]] of fludrocortisone,<ref name="Elks2014" /><ref name="IndexNominum2000" /> and is [[hydrolysis|hydrolyzed]] into fludrocortisone in the body.<ref name="pmid27416887" />

==History==

Fludrocortisone was described in the literature in 1953<ref name="pmid13875857">{{cite journal | vauthors = Calvert DN | title = Anti-inflammatory steroids | journal = Wisconsin Medical Journal | volume = 61 | pages = 403–404 | date = August 1962 | pmid = 13875857 }}</ref> and was introduced for medical use (as the acetate ester) in 1954.<ref name="LemkeWilliams2008">{{cite book| vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=R0W1ErpsQpkC&pg=PA890|year=2008|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6879-5|pages=890–|url-status=live|archive-url=https://web.archive.org/web/20171105200659/https://books.google.com/books?id=R0W1ErpsQpkC&pg=PA890|archive-date=2017-11-05}}</ref><ref name="Publishing2013">{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia, 3rd Edition|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1642|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=1642–|url-status=live|archive-url=https://web.archive.org/web/20171105200659/https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1642|archive-date=5 November 2017}}</ref> It was the first synthetic corticosteroid to be marketed, and followed the introduction of [[cortisone]] in 1948 and [[hydrocortisone]] (cortisol) in 1951.<ref name="pmid13875857" /><ref name="pmid16178782">{{cite journal | vauthors = Khan MO, Park KK, Lee HJ | title = Antedrugs: an approach to safer drugs | journal = Current Medicinal Chemistry | volume = 12 | issue = 19 | pages = 2227–2239 | year = 2005 | pmid = 16178782 | doi = 10.2174/0929867054864840 }}</ref> Fludrocortisone was also the first fluorine-containing pharmaceutical drug to be marketed.<ref name="pmid24776946">{{cite journal | vauthors = Walker MC, Chang MC | title = Natural and engineered biosynthesis of fluorinated natural products | journal = Chemical Society Reviews | volume = 43 | issue = 18 | pages = 6527–6536 | date = September 2014 | pmid = 24776946 | doi = 10.1039/c4cs00027g | s2cid = 205904152 }}</ref>

==Society and culture==

===Generic name===

Fludrocortisone is the [[generic term|generic name]] of fludrocortisone and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|BAN|British Approved Name}}, {{abbrlink|DCF|Dénomination Commune Française}}, and {{abbrlink|DCIT|Denominazione Comune Italiana}}, whereas ''fludrocortisone acetate'' is the generic name of fludrocortisone acetate and its {{abbrlink|USP|United States Pharmacopeia}}, {{abbrlink|BANM|British Approved Name}} and {{abbrlink|JAN|Japanese Accepted Name}}.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Drugs.com">{{cite web |url=https://www.drugs.com/international/fludrocortisone.html |title=Fludrocortisone Uses, Side Effects & Warnings |access-date=2017-07-16 |url-status=live |archive-url=https://web.archive.org/web/20150513235052/http://www.drugs.com/international/fludrocortisone.html |archive-date=2015-05-13 }}</ref>

===Brand names===

Fludrocortisone is marketed mainly under the brand names Astonin and Astonin-H, whereas the more widely used fludrocortisone acetate is sold mainly as Florinef, but also under several other brand names including Cortineff, Florinefe, and Fludrocortison.<ref name="IndexNominum2000" /><ref name="Drugs.com" />

===Availability===

Fludrocortisone is marketed in [[Austria]], [[Croatia]], [[Denmark]], [[Germany]], [[Luxembourg]], [[Romania]], and [[Spain]], whereas fludrocortisone acetate is more widely available throughout the world and is marketed in the [[United States]], [[Canada]], the [[United Kingdom]], various other [[Europe]]an countries, [[Australia]], [[Japan]], [[China]], [[Brazil]], and many other countries.<ref name="IndexNominum2000" /><ref name="Drugs.com" />

== References ==

== External links ==

* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/fludrocortisone | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Fludrocortisone }}

{{Glucocorticoids and antiglucocorticoids}}

{{Mineralocorticoids and antimineralocorticoids}}

{{Glucocorticoid receptor modulators}}

{{Mineralocorticoid receptor modulators}}

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[[Category:Acetate esters]]

[[Category:Antihypotensive agents]]

[[Category:Corticosteroid esters]]

[[Category:Corticosteroids]]

[[Category:Diketones]]

[[Category:Glucocorticoids]]

[[Category:Halohydrins]]

[[Category:Pregnanes]]

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[[Category:World Health Organization essential medicines]]

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