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{{Short description|Chemical compound}}
{{Drugbox
{{Drugbox
| Verifiedfields = changed
| Verifiedfields = changed
Line 9: Line 10:
| Drugs.com = {{drugs.com|monograph|arixtra}}
| Drugs.com = {{drugs.com|monograph|arixtra}}
| licence_EU = yes
| licence_EU = yes
| licence_US = Fondaparinux
| DailyMedID = Fondaparinux
| pregnancy_category =
| pregnancy_category =
⚫
| routes_of_administration = [[Subcutaneous injection|Subcutaneous]]
⚫
| ATC_prefix = B01
⚫
| ATC_suffix = AX05
⚫
| ATC_supplemental =

| legal_AU = S4
| legal_UK = POM
| legal_UK = POM
| legal_US = Rx-only
| legal_US = Rx-only
| legal_status =
| legal_EU = Rx-only
| legal_status =
⚫
| routes_of_administration = subcutaneous


<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
Line 20: Line 27:
| protein_bound = 94%
| protein_bound = 94%
| metabolism = renally excreted unchanged
| metabolism = renally excreted unchanged
| elimination_half-life = 17-21 hours<ref name="Walenga Jeske Fareed 2005 pp. 143–177">{{cite book | vauthors = Walenga JM, Jeske WP, Fareed J | title=Chemistry and Biology of Heparin and Heparan Sulfate | chapter=Biochemical and Pharmacologic Rationale for Synthetic Heparin Polysaccharides | publisher=Elsevier | year=2005 | isbn=978-0-08-044859-6 | doi=10.1016/b978-008044859-6/50006-x | pages=143–177|quote=The elimination half-life of AT-bound fondaparinux is 17–21 h (171,172). The subcutaneous bioavailability of fondaparinux is nearly 100% and it is distributed mainly in the blood (165,173).}}</ref>
| elimination_half-life = 17-21 hours


<!--Identifiers-->
<!--Identifiers-->
| CAS_number_Ref = {{cascite|changed|CAS}}
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 104993-28-4
| CAS_number = 104993-28-4
| CAS_number2_Ref = {{cascite|changed|CAS}}
| CAS_number2_Ref = {{cascite|correct|CAS}}
| CAS_number2 = 114870-03-0
| CAS_number2 = 114870-03-0
⚫
| ATC_prefix = B01
⚫
| ATC_suffix = AX05
⚫
| ATC_supplemental =
| PubChem = 636380
| PubChem = 636380
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
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| UNII_Ref = {{fdacite|correct|FDA}}
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = J177FOW5JL
| UNII = J177FOW5JL
| UNII2_Ref = {{fdacite|changed|FDA}}
| UNII2_Ref = {{fdacite|correct|FDA}}
| UNII2 = X0Q6N9USOZ
| UNII2 = X0Q6N9USOZ
| index2_label= decasodium salt
| index2_label= decasodium salt
Line 45: Line 49:
<!--Chemical data-->
<!--Chemical data-->
| C=31 | H=43 | N=3 | Na=10 | O=49 | S=8
| C=31 | H=43 | N=3 | Na=10 | O=49 | S=8
| molecular_weight = 1726.77 g/mol
| SMILES = [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[O-]S(=O)(=O)N[C@@H]5[C@@H](O)[C@H](O)[C@@H](COS([O-])(=O)=O)O[C@@H]5O[C@H]1[C@H](O)[C@@H](O)[C@@H](O[C@@H]1C([O-])=O)O[C@@H]4[C@@H](COS([O-])(=O)=O)O[C@H](O[C@H]3[C@H](O)[C@@H](OS([O-])(=O)=O)[C@H](O[C@H]2[C@H](O)[C@@H](NS([O-])(=O)=O)[C@@H](OC)O[C@@H]2COS([O-])(=O)=O)O[C@H]3C([O-])=O)[C@H](NS([O-])(=O)=O)[C@H]4OS([O-])(=O)=O
| SMILES = [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[O-]S(=O)(=O)N[C@@H]5[C@@H](O)[C@H](O)[C@@H](COS([O-])(=O)=O)O[C@@H]5O[C@H]1[C@H](O)[C@@H](O)[C@@H](O[C@@H]1C([O-])=O)O[C@@H]4[C@@H](COS([O-])(=O)=O)O[C@H](O[C@H]3[C@H](O)[C@@H](OS([O-])(=O)=O)[C@H](O[C@H]2[C@H](O)[C@@H](NS([O-])(=O)=O)[C@@H](OC)O[C@@H]2COS([O-])(=O)=O)O[C@H]3C([O-])=O)[C@H](NS([O-])(=O)=O)[C@H]4OS([O-])(=O)=O
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
Line 52: Line 55:
| StdInChIKey = XEKSTYNIJLDDAZ-JASSWCPGSA-D
| StdInChIKey = XEKSTYNIJLDDAZ-JASSWCPGSA-D
}}
}}
'''Fondaparinux''' (trade name '''Arixtra''') is an [[anticoagulant]] medication chemically related to [[low molecular weight heparin]]s. It is marketed by [[GlaxoSmithKline]]. A generic version developed by Alchemia is marketed within the US by [[Dr. Reddy's Laboratories]].
'''Fondaparinux''' (trade name '''Arixtra''') is an [[anticoagulant]] medication chemically related to [[low molecular weight heparin]]s. It is marketed by [[Viatris]]. A generic version developed by Alchemia is marketed within the US by [[Dr. Reddy's Laboratories]].


==Uses==
==Medical uses==
Clinically, it is used for the prevention of [[deep vein thrombosis]] in patients who have had orthopedic surgery<ref>{{cite journal | vauthors = Fuji T, Fujita S, Ochi T | title = Fondaparinux prevents venous thromboembolism after joint replacement surgery in Japanese patients | journal = International Orthopaedics | volume = 32 | issue = 4 | pages = 443–451 | date = August 2008 | pmid = 17468868 | pmc = 2532275 | doi = 10.1007/s00264-007-0360-7 }}</ref> as well as for the treatment of deep vein thrombosis and [[pulmonary embolism]].<ref>{{Cite web |date=2018-09-17 |title=Arixtra |url=https://www.ema.europa.eu/en/medicines/human/EPAR/arixtra |access-date=2023-04-03 | work = European Medicines Agency |language=en}}</ref>
Fondaparinux is similar to [[enoxaparin]] in reducing the risk of ischemic events at nine days, but it substantially reduces major bleeding and improves long-term mortality and morbidity.<ref name="urlNEJM -- Comparison of Fondaparinux and Enoxaparin in Acute Coronary Syndromes">{{cite web |url=http://content.nejm.org/cgi/content/abstract/354/14/1464 |title=NEJM -- Comparison of Fondaparinux and Enoxaparin in Acute Coronary Syndromes |format= |work= |accessdate=2009-01-23}}</ref>


Fondaparinux is similar to [[enoxaparin]] in reducing the risk of ischemic events at nine days, but it substantially reduces major bleeding and improves long-term mortality and morbidity.<ref name="urlNEJM -- Comparison of Fondaparinux and Enoxaparin in Acute Coronary Syndromes">{{cite journal | vauthors = Yusuf S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, Granger CB, Budaj A, Peters RJ, Bassand JP, Wallentin L, Joyner C, Fox KA | collaboration = Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators | display-authors = 6 | title = Comparison of fondaparinux and enoxaparin in acute coronary syndromes | journal = The New England Journal of Medicine | volume = 354 | issue = 14 | pages = 1464–1476 | date = April 2006 | pmid = 16537663 | doi = 10.1056/NEJMoa055443 | hdl-access = free | hdl = 2437/113091 }}</ref>
⚫
It has been investigated for use in conjunction with [[streptokinase]].<ref name="pmid18245119">{{cite journal |vauthors=Peters RJ, Joyner C, Bassand JP, etal |title=The role of fondaparinux as an adjunct to thrombolytic therapy in acute myocardial infarction: a subgroup analysis of the OASIS-6 trial |journal=Eur. Heart J. |volume=29 |issue=3 |pages=324–31 |date=February 2008 |pmid=18245119 |doi=10.1093/eurheartj/ehm616 |url=http://eurheartj.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18245119}}</ref>


⚫
It has been investigated for use in conjunction with [[streptokinase]].<ref name="Peters_2008">{{cite journal | vauthors = Peters RJ, Joyner C, Bassand JP, Afzal R, Chrolavicius S, Mehta SR, Oldgren J, Wallentin L, Budaj A, Fox KA, Yusuf S | display-authors = 6 | title = The role of fondaparinux as an adjunct to thrombolytic therapy in acute myocardial infarction: a subgroup analysis of the OASIS-6 trial | journal = European Heart Journal | volume = 29 | issue = 3 | pages = 324–331 | date = February 2008 | pmid = 18245119 | doi = 10.1093/eurheartj/ehm616 | doi-access = }}</ref>
===Administration===
Fondaparinux is given subcutaneously daily. Clinically, it is used for the prevention of [[deep vein thrombosis]] in patients who have had orthopedic surgery as well as for the treatment of deep vein thrombosis and [[pulmonary embolism]].


===Comparison to other agents===
===Comparison to other agents===
One potential advantage of fondaparinux over LMWH or unfractionated heparin is that the risk for [[heparin-induced thrombocytopenia]] (HIT) is substantially lower. Furthermore, there have been case reports of fondaparinux being used to anti-coagulate patients with established HIT as it has no affinity to PF-4. However, its renal excretion precludes its use in patients with renal dysfunction.
One potential advantage of fondaparinux over LMWH or unfractionated heparin is that the risk for [[heparin-induced thrombocytopenia]] (HIT) is substantially lower. Furthermore, there have been case reports of fondaparinux being used to anti-coagulate patients with established HIT as it has no affinity for [[Platelet factor 4|PF4]]. However, its renal excretion precludes its use in patients with renal dysfunction.


Unlike [[direct factor Xa inhibitor]]s, it mediates its effects indirectly through [[antithrombin III]], but unlike [[heparin]], it is selective for [[factor X]]a.<ref>{{cite web |url=http://www.medscape.com/viewarticle/456874_5 |title=Medscape.com |format= |work= |accessdate=2009-01-23}}</ref>
Unlike [[direct factor Xa inhibitor]]s, it mediates its effects indirectly through [[antithrombin III]], but unlike [[heparin]], it is selective for [[factor X]]a.<ref name="pmid12820819">{{cite journal | vauthors = Comp PC | title = Selective factor Xa inhibition improves efficacy of venous thromboembolism prophylaxis in orthopedic surgery | journal = Pharmacotherapy | volume = 23 | issue = 6 | pages = 772–87 | date = June 2003 | pmid = 12820819 | doi = 10.1592/phco.23.6.772.32190 | s2cid = 19516097 | url = http://www.medscape.com/viewarticle/456874_5 }}</ref>


== Pharmacology ==
==Structure and mechanism==

=== Mechanism of action ===
{{see also|Heparin#Mechanism of action}}
{{see also|Heparin#Mechanism of action}}


Fondaparinux is a synthetic pentasaccharide [[factor Xa]] inhibitor. Fondaparinux binds [[antithrombin]] and accelerates its inhibition of factor Xa.
⚫
Fondaparinux is a synthetic pentasaccharide [[factor Xa]] inhibitor. Apart from the O-methyl group at the reducing end of the molecule, the identity and sequence of the five monomeric sugar units contained in fondaparinux is identical to a sequence of five monomeric sugar units that can be isolated after either chemical or enzymatic cleavage of the polymeric [[glycosaminoglycan]]s [[heparin]] and [[heparin sulfate]] (HS). Within heparin and heparin sulfate this monomeric sequence is thought to form the high-affinity binding site for the anti-coagulant factor [[antithrombin III]] (ATIII). Binding of heparin/HS to ATIII has been shown to increase the anti-coagulant activity of antithrombin III 1000 fold. In contrast to heparin, fondaparinux does not inhibit [[thrombin]].


⚫
Apart from the O-methyl group at the reducing end of the molecule, the identity and sequence of the five monomeric sugar units contained in fondaparinux is identical to a sequence of five monomeric sugar units that can be isolated after either chemical or enzymatic cleavage of the polymeric [[glycosaminoglycan]]s [[heparin]] and [[heparan sulfate]] (HS). Within heparin and heparan sulfate this monomeric sequence is thought to form the high-affinity binding site for the anti-coagulant factor [[antithrombin]] (AT). Binding of heparin or HS to AT has been shown to increase the anti-coagulant activity of antithrombin 1000 fold. In contrast to heparin, fondaparinux does not inhibit [[thrombin]].


==Chemistry==
==Chemical structure==
===Abbreviations===
===Abbreviations===
* '''GlcNS6S''' = 2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranoside
* '''GlcNS6S''' = 2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranoside
Line 80: Line 85:
* '''IdoA2S''' = [[iduronic acid|2-O-sulfo-α-L-idopyranuronoside]]
* '''IdoA2S''' = [[iduronic acid|2-O-sulfo-α-L-idopyranuronoside]]
* '''GlcNS6SOMe''' = methyl-O-2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranoside
* '''GlcNS6SOMe''' = methyl-O-2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranoside

Fondaparinux is only accessible by chemical synthesis. Recently, Supriya Dey ''et al''. reported an effective and scalable one-pot synthesis of Fondaparinux.<ref name="pmid32496799">{{cite journal | vauthors = Dey S, Lo HJ, Wong CH | title = Programmable One-Pot Synthesis of Heparin Pentasaccharide Fondaparinux | journal = Organic Letters | volume = 22 | issue = 12 | pages = 4638–4642 | date = June 2020 | pmid = 32496799 | doi = 10.1021/acs.orglett.0c01386 | pmc = 7347301 | doi-access = free }}</ref>


The sequence of monosaccharides is D-GlcNS6S-α-(1,4)-D-GlcA-β-(1,4)-D-GlcNS3,6S-α-(1,4)-L-IdoA2S-α-(1,4)-D-GlcNS6S-OMe, as shown in the following structure:
The sequence of monosaccharides is D-GlcNS6S-α-(1,4)-D-GlcA-β-(1,4)-D-GlcNS3,6S-α-(1,4)-L-IdoA2S-α-(1,4)-D-GlcNS6S-OMe, as shown in the following structure:
Line 85: Line 92:
[[Image:Fondaparinux.svg|400px|center|Fondaparinux]]
[[Image:Fondaparinux.svg|400px|center|Fondaparinux]]


==References==
== References ==
{{reflist}}
{{reflist}}


==External links==
== External links ==
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/fondaparinux | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Fondaparinux }}
* [http://www.arixtra.com/ Arixtra home page]
* [https://web.archive.org/web/20120321025944/http://www.alchemia.com.au/irm/content/home.html Alchemia home page]


{{Antithrombotics}}
{{Antithrombotics}}
{{GlaxoSmithKline}}
{{GlaxoSmithKline}}
{{Portal bar | Medicine}}

[[Category:Heparins]]
[[Category:Heparins]]
[[Category:Sulfamates]]
[[Category:Sulfamates]]

Latest revision as of 10:19, 16 August 2023

Fondaparinux
Clinical data
Trade namesArixtra
AHFS/Drugs.comMonograph
License data
Routes of
administration		Subcutaneous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • EU: Rx-only
Pharmacokinetic data
BioavailabilityN/A
Protein binding94%
Metabolismrenally excreted unchanged
Elimination half-life17-21 hours[1]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC31H43N3Na10O49S8
Molar mass1728.03 g·mol−1
3D model (JSmol)
  • [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[O-]S(=O)(=O)N[C@@H]5[C@@H](O)[C@H](O)[C@@H](COS([O-])(=O)=O)O[C@@H]5O[C@H]1[C@H](O)[C@@H](O)[C@@H](O[C@@H]1C([O-])=O)O[C@@H]4[C@@H](COS([O-])(=O)=O)O[C@H](O[C@H]3[C@H](O)[C@@H](OS([O-])(=O)=O)[C@H](O[C@H]2[C@H](O)[C@@H](NS([O-])(=O)=O)[C@@H](OC)O[C@@H]2COS([O-])(=O)=O)O[C@H]3C([O-])=O)[C@H](NS([O-])(=O)=O)[C@H]4OS([O-])(=O)=O
  • InChI=1S/C31H53N3O49S8.10Na/c1-69-27-9(33-85(48,49)50)13(37)17(6(74-27)3-71-88(57,58)59)76-31-22(83-91(66,67)68)16(40)21(24(81-31)26(43)44)79-29-10(34-86(51,52)53)19(82-90(63,64)65)18(7(75-29)4-72-89(60,61)62)77-30-15(39)14(38)20(23(80-30)25(41)42)78-28-8(32-84(45,46)47)12(36)11(35)5(73-28)2-70-87(54,55)56;;;;;;;;;;/h5-24,27-40H,2-4H2,1H3,(H,41,42)(H,43,44)(H,45,46,47)(H,48,49,50)(H,51,52,53)(H,54,55,56)(H,57,58,59)(H,60,61,62)(H,63,64,65)(H,66,67,68);;;;;;;;;;/q;10*+1/p-10/t5-,6-,7-,8-,9-,10-,11-,12-,13-,14-,15-,16+,17-,18-,19-,20+,21+,22-,23+,24-,27+,28-,29-,30-,31-;;;;;;;;;;/m1........../s1 checkY
  • Key:XEKSTYNIJLDDAZ-JASSWCPGSA-D checkY
 ☒NcheckY (what is this?)  (verify)

Fondaparinux (trade name Arixtra) is an anticoagulant medication chemically related to low molecular weight heparins. It is marketed by Viatris. A generic version developed by Alchemia is marketed within the US by Dr. Reddy's Laboratories.

Medical uses

[edit]

Clinically, it is used for the prevention of deep vein thrombosis in patients who have had orthopedic surgery[2] as well as for the treatment of deep vein thrombosis and pulmonary embolism.[3]

Fondaparinux is similar to enoxaparin in reducing the risk of ischemic events at nine days, but it substantially reduces major bleeding and improves long-term mortality and morbidity.[4]

It has been investigated for use in conjunction with streptokinase.[5]

Comparison to other agents

[edit]

One potential advantage of fondaparinux over LMWH or unfractionated heparin is that the risk for heparin-induced thrombocytopenia (HIT) is substantially lower. Furthermore, there have been case reports of fondaparinux being used to anti-coagulate patients with established HIT as it has no affinity for PF4. However, its renal excretion precludes its use in patients with renal dysfunction.

Unlike direct factor Xa inhibitors, it mediates its effects indirectly through antithrombin III, but unlike heparin, it is selective for factor Xa.[6]

Pharmacology

[edit]

Mechanism of action

[edit]
See also: Heparin § Mechanism of action

Fondaparinux is a synthetic pentasaccharide factor Xa inhibitor. Fondaparinux binds antithrombin and accelerates its inhibition of factor Xa.

Apart from the O-methyl group at the reducing end of the molecule, the identity and sequence of the five monomeric sugar units contained in fondaparinux is identical to a sequence of five monomeric sugar units that can be isolated after either chemical or enzymatic cleavage of the polymeric glycosaminoglycans heparin and heparan sulfate (HS). Within heparin and heparan sulfate this monomeric sequence is thought to form the high-affinity binding site for the anti-coagulant factor antithrombin (AT). Binding of heparin or HS to AT has been shown to increase the anti-coagulant activity of antithrombin 1000 fold. In contrast to heparin, fondaparinux does not inhibit thrombin.

Chemistry

[edit]

Abbreviations

[edit]
  • GlcNS6S = 2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranoside
  • GlcA = β-D-glucopyranuronoside
  • GlcNS3,6S = 2-deoxy-3,6-di-O-sulfo-2-(sulfoamino)-α-D-glucopyranosyl
  • IdoA2S = 2-O-sulfo-α-L-idopyranuronoside
  • GlcNS6SOMe = methyl-O-2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranoside

Fondaparinux is only accessible by chemical synthesis. Recently, Supriya Dey et al. reported an effective and scalable one-pot synthesis of Fondaparinux.[7]

The sequence of monosaccharides is D-GlcNS6S-α-(1,4)-D-GlcA-β-(1,4)-D-GlcNS3,6S-α-(1,4)-L-IdoA2S-α-(1,4)-D-GlcNS6S-OMe, as shown in the following structure:

Fondaparinux
Fondaparinux

References

[edit]
  1. ^ Walenga JM, Jeske WP, Fareed J (2005). "Biochemical and Pharmacologic Rationale for Synthetic Heparin Polysaccharides". Chemistry and Biology of Heparin and Heparan Sulfate. Elsevier. pp. 143–177. doi:10.1016/b978-008044859-6/50006-x. ISBN 978-0-08-044859-6. The elimination half-life of AT-bound fondaparinux is 17–21 h (171,172). The subcutaneous bioavailability of fondaparinux is nearly 100% and it is distributed mainly in the blood (165,173).
  2. ^ Fuji T, Fujita S, Ochi T (August 2008). "Fondaparinux prevents venous thromboembolism after joint replacement surgery in Japanese patients". International Orthopaedics. 32 (4): 443–451. doi:10.1007/s00264-007-0360-7. PMC 2532275. PMID 17468868.
  3. ^ "Arixtra". European Medicines Agency. 2018-09-17. Retrieved 2023-04-03.
  4. ^ Yusuf S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, Granger CB, et al. (Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators) (April 2006). "Comparison of fondaparinux and enoxaparin in acute coronary syndromes". The New England Journal of Medicine. 354 (14): 1464–1476. doi:10.1056/NEJMoa055443. hdl:2437/113091. PMID 16537663.
  5. ^ Peters RJ, Joyner C, Bassand JP, Afzal R, Chrolavicius S, Mehta SR, et al. (February 2008). "The role of fondaparinux as an adjunct to thrombolytic therapy in acute myocardial infarction: a subgroup analysis of the OASIS-6 trial". European Heart Journal. 29 (3): 324–331. doi:10.1093/eurheartj/ehm616. PMID 18245119.
  6. ^ Comp PC (June 2003). "Selective factor Xa inhibition improves efficacy of venous thromboembolism prophylaxis in orthopedic surgery". Pharmacotherapy. 23 (6): 772–87. doi:10.1592/phco.23.6.772.32190. PMID 12820819. S2CID 19516097.
  7. ^ Dey S, Lo HJ, Wong CH (June 2020). "Programmable One-Pot Synthesis of Heparin Pentasaccharide Fondaparinux". Organic Letters. 22 (12): 4638–4642. doi:10.1021/acs.orglett.0c01386. PMC 7347301. PMID 32496799.
[edit]
  • "Fondaparinux". Drug Information Portal. U.S. National Library of Medicine.
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