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Identification
NameHeparin
Accession NumberDB01109  (APRD00056)
Typesmall molecule
Groupsapproved, investigational
Description

Unfractionated heparin (UH) is a heterogenous preparation of anionic, sulfated glycosaminoglycan polymers with weights ranging from 3000 to 30,000 Da. It is a naturally occurring anticoagulant released from mast cells. It binds reversibly to antithrombin III (ATIII) and greatly accelerates the rate at which ATIII inactivates coagulation enzymes thrombin (factor IIa) and factor Xa. UH is different from low molecular weight heparin (LMWH) in the following ways: the average molecular weight of LMWH is about 4.5 kDa whereas it is 15 kDa for UH; UH requires continuous infusions; activated partial prothrombin time (aPTT) monitoring is required when using UH; and UH has a higher risk of bleeding and higher risk of osteoporosis in long term use. Unfractionated heparin is more specific than LMWH for thrombin. Furthermore, the effects of UH can typically be reversed by using protamine sulfate.

Structure
Thumb
Synonyms
SynonymLanguageCode
CalciparineNot AvailableNot Available
EparinaItalianDCIT
Hep-lockNot AvailableNot Available
HeparinateNot AvailableNot Available
Heparinic acidNot AvailableNot Available
LiquaeminNot AvailableNot Available
PanheprinNot AvailableNot Available
Salts
Name/CAS Structure Properties
Heparin sodium
Thumb Not applicable DBSALT000417
Brand names
NameCompany
CalcileanNot Available
CalciparineNot Available
HepaleanNot Available
Heparin LEONot Available
Heparin Lock FlushNot Available
LiquaeminNot Available
LiqueminNot Available
MultiparinNot Available
NovoheparinNot Available
Brand mixturesNot Available
Categories
CAS number9005-49-6
WeightAverage:
Monoisotopic:
Chemical FormulaNot Available
InChI KeyNot Available
InChI
IUPAC Name
SMILES
Mass SpecNot Available
Taxonomy
KingdomNot Available
SuperclassNot Available
ClassNot Available
SubclassNot Available
Direct parentNot Available
Alternative parentsNot Available
SubstituentsNot Available
Classification descriptionNot Available
Pharmacology
IndicationUnfractionated heparin is indicated for prophylaxis and treatment of venous thrombosis and its extension, prevention of post-operative deep venous thrombosis and pulmonary embolism and prevention of clotting in arterial and cardiac surgery. In cardiology, it is used to prevent embolisms in patients with atrial fibrillation and as an adjunct antithrombin therapy in patients with unstable angina and/or non-Q wave myocardial infarctions (i.e. non-ST elevated acute coronary artery syndrome) who are on platelet glycoprotein (IIb/IIIa) receptor inhibitors. Additionally, it is used to prevent clotting during dialysis and surgical procedures, maintain the patency of intravenous injection devices and prevent in vitro coagulation of blood transfusions and in blood samples drawn for laboratory values.
PharmacodynamicsUnfractionated heparin is a highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from 3000 to 30,000 daltons. Heparin is obtained from liver, lung, mast cells, and other cells of vertebrates. Heparin is a well-known and commonly used anticoagulant which has antithrombotic properties. Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo. Small amounts of heparin in combination with antithrombin III, a heparin cofactor,) can inhibit thrombosis by inactivating Factor Xa and thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor. Heparin prolongs several coagulation tests. Of all the coagulation tests, activated partial prothrombin time (aPTT) is the most clinically important value.
Mechanism of actionUnder normal circumstances, antithrombin III (ATIII) inactivates thrombin (factor IIa) and factor Xa. This process occurs at a slow rate. Administered heparin binds reversibly to ATIII and leads to almost instantaneous inactivation of factors IIa and Xa The heparin-ATIII complex can also inactivate factors IX, XI, XII and plasmin. The mechanism of action of heparin is ATIII-dependent. It acts mainly by accelerating the rate of the neutralization of certain activated coagulation factors by antithrombin, but other mechanisms may also be involved. The antithrombotic effect of heparin is well correlated to the inhibition of factor Xa. Heparin is not a thrombolytic or fibrinolytic. It prevents progression of existing clots by inhibiting further clotting. The lysis of existing clots relies on endogenous thrombolytics.
AbsorptionHeparin must be given parenterally as it is not absorbed through the gastrointestinal mucosa. It is usually given by iv infusion or deep sc injection. The onset of action is immediate after iv injection but can be delayed 20 to 60 minutes following sc injection. Plasma heparin concentrations may be increased and activated partial thromboplastin times (aPTTs) may be more prolonged in geriatric adults (older than 60 years of age) compared with younger adults.
Volume of distribution

40-70 mL/min (approximately the same as blood volume)
Although heparin does not distribute into adipose tissues, clinicians should use actual body weight in obese patients to account for extra vasculature.

Protein bindingVery high, mostly to low-density lipoproteins. It is also extensively bound by globulins and fibrinogens.
Metabolism

Liver and the reticulo-endothelial system are the sites of biotransformation. The metabolic fate of heparin is not well understood.

Route of eliminationThe drug appears to be removed mainly by the reticuloendothelial system. A small fraction of unchanged heparin also appears to be excreted in urine. Heparin cannot be eliminated by hemodialysis.
Half life1.5 hours. The plasma half-life of heparin increases from about 60 minutes with a 100 unit/kg dose to about 150 minutes with a 400 unit/kg dose.
Clearance

Adult Clearance = 0.43 ml/kg/min
25-28 weeks gestation = 1.49 ml/kg/min

ToxicityIn mouse, the median lethal dose is greater than 5000 mg/kg. Another side effect is heparin-induced thrombocytopenia (HIT syndrome). Platelet counts usually do not fall until between days 5 and 12 of heparin therapy. HIT is caused by an immunological reaction that makes platelets form clots within the blood vessels, thereby using up coagulation factors. It can progress to thrombotic complications such as arterial thrombosis, gangrene, stroke, myocardial infarction and disseminated intravascular coagulation. Symptoms of overdose may show excessive prolongation of aPTT or by bleeding, which may be internal or external, major or minor. Therapeutic doses of heparin give for at least 4 months have been associated with osteoporosis and spontaneous vertebral fractures. Osteoporosis may be reversible once heparin is discontinued. Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates. Toxicity appears to have resulted from administration of large amounts (i.e., about 100–400 mg/kg daily) of benzyl alcohol in these neonates. Its use is principally associated with the use of bacteriostatic 0.9% sodium chloride intravascular flush or endotracheal tube lavage solutions.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Heparin Action PathwayDrug actionSMP00274
Fc Epsilon Receptor I Signaling in Mast CellsSignalingSMP00358
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption Not Available Not Available
Blood Brain Barrier Not Available Not Available
Caco-2 permeable Not Available Not Available
P-glycoprotein substrate Not Available Not Available
P-glycoprotein inhibitor I Not Available Not Available
P-glycoprotein inhibitor II Not Available Not Available
Renal organic cation transporter Not Available Not Available
CYP450 2C9 substrate Not Available Not Available
CYP450 2D6 substrate Not Available Not Available
CYP450 3A4 substrate Not Available Not Available
CYP450 1A2 substrate Not Available Not Available
CYP450 2C9 substrate Not Available Not Available
CYP450 2D6 substrate Not Available Not Available
CYP450 2C19 substrate Not Available Not Available
CYP450 3A4 substrate Not Available Not Available
CYP450 inhibitory promiscuity Not Available Not Available
Ames test Not Available Not Available
Carcinogenicity Not Available Not Available
Biodegradation Not Available Not Available
Rat acute toxicity Not Available Not applicable
hERG inhibition (predictor I) Not Available Not Available
hERG inhibition (predictor II) Not Available Not Available
Pharmacoeconomics
Manufacturers
  • Sanofi aventis us llc
  • Hospira inc
  • International medication systems ltd
  • Luitpold pharmaceuticals inc
  • Parke davis div warner lambert co
  • Smith and nephew solopak div smith and nephew
  • Solopak medical products inc
  • Abraxis pharmaceutical products
  • Akorn inc
  • App pharmaceuticals llc
  • Baxter healthcare corp anesthesia and critical care
  • Baxter healthcare corp anesthesia critical care
  • Chamberlin parenteral corp
  • Dell laboratories inc
  • Eli lilly and co
  • Marsam pharmaceuticals llc
  • Organon usa inc
  • Pharmaceutical specialist assoc
  • Pharmacia and upjohn co
  • Sagent pharmaceuticals inc
  • Watson laboratories inc
  • Baxter healthcare corp
  • Mcgaw inc
  • B braun medical inc
  • Pharma serve inc sub torigian laboratories
  • 3m pharmaceuticals inc
Packagers
Dosage forms
FormRouteStrength
LiquidIntravenous
LiquidIrrigation
SolutionIntraperitoneal
SolutionIntravenous
SolutionSubcutaneous
Prices
Unit descriptionCostUnit
Heparin sod 1000000 unit powder1318.63USDeach
Heparin sod 100000 unit powder256.73USDeach
Heparin Sodium (Porcine) 1000 unit/ml Solution 10ml Vial188.99USDvial
Heparin sod 25000 unit powder58.8USDeach
Heparin Sodium (Porcine) 10000 unit/ml Solution 5ml Vial29.99USDvial
Heparin Sodium (Porcine) 10000 unit/ml vial10.37USDvial
Hep-lock flush 100 unit/ml kit10.08USDkit
Hep-lock flush 10 unit/ml kit8.91USDkit
Heparin Leo 25000 unit/ml8.42USDml
Heparin sod 1000 unit/ml vial7.92USDml
Heparin sod 5000 unit/ml syringe3.08USDml
Heparin iv flush 100 unit/ml2.71USDml
Hepalean 10000 unit/ml2.32USDml
Heparin Leo 10000 unit/ml2.03USDml
Heparin lock flush 10 unit/ml1.21USDml
Heparin lock flush 100 unit/ml1.13USDml
Hep-lock u-p 10 unit/ml vial0.98USDml
Hepalean 1000 unit/ml0.98USDml
Hep-lock u-p 100 unit/ml vial0.96USDml
Heparin Leo 1000 unit/ml0.43USDml
Heparin Leo 100 unit/ml Lock Flush0.36USDml
Heparin Lock Flush 100 unit/ml Lock Flush0.3USDml
Heparin Lock Flush 10 unit/ml Lock Flush0.29USDml
Heparin iv flush 1 unit/ml syr0.19USDml
Heparin iv flush 2 unit/ml syr0.19USDml
Heparin lock 100 unit/ml vial0.13USDml
Heparin lock 10 unit/ml vial0.1USDml
Heparin-1/2ns 25000 unit/2500.03USDml
Heparin-1/2ns 12500 unit/2500.02USDml
Heparin-ns 2000 unit/1000 ml0.01USDml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubilitySolubleNot Available
logP-13.2Not Available
Predicted Properties
PropertyValueSource
Spectra
SpectraNot Available
References
Synthesis Reference

Fernando Fussi, Gianfranco Fedeli, “Oligo-heteropolysaccharides having a heparin-like activity method for their preparation and pharmaceutical compositions based thereon.” U.S. Patent US4757057, issued June, 1952.

US4757057
General Reference
  1. Linhardt RJ, Gunay NS: Production and chemical processing of low molecular weight heparins. Semin Thromb Hemost. 1999;25 Suppl 3:5-16. Pubmed
  2. Ferro DR, Provasoli A, Ragazzi M, Casu B, Torri G, Bossennec V, Perly B, Sinay P, Petitou M, Choay J: Conformer populations of L-iduronic acid residues in glycosaminoglycan sequences. Carbohydr Res. 1990 Jan 15;195(2):157-67. Pubmed
  3. Mulloy B, Forster MJ, Jones C, Davies DB: N.m.r. and molecular-modelling studies of the solution conformation of heparin. Biochem J. 1993 Aug 1;293 ( Pt 3):849-58. Pubmed
  4. Hirsh J, Raschke R: Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 Sep;126(3 Suppl):188S-203S. Pubmed
  5. Petitou M, Herault JP, Bernat A, Driguez PA, Duchaussoy P, Lormeau JC, Herbert JM: Synthesis of thrombin-inhibiting heparin mimetics without side effects. Nature. 1999 Apr 1;398(6726):417-22. Pubmed
  6. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics. 1983; 72:356-8. [PubMed] [IDIS 175725]
  7. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull. 1982; 12:10-1. [PubMed]
  8. Anon. Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982; 31:290-1. [PubMed] [IDIS 150868]
  9. Abbott Laboratories. Heparin lock flush solution, USP 100 USP units/mL prescribing information. North Chicago, IL; 1998 Jul.
  10. Spruill WJ, Wade WE, Huckaby WG, Leslie RB: Achievement of anticoagulation by using a weight-based heparin dosing protocol for obese and nonobese patients. Am J Health Syst Pharm. 2001 Nov 15;58(22):2143-6. Pubmed
  11. McDonald MM, Jacobson LJ, Hay WW Jr, Hathaway WE: Heparin clearance in the newborn. Pediatr Res. 1981 Jul;15(7):1015-8. Pubmed
External Links
ResourceLink
KEGG CompoundC00374
PubChem Substance46507594
ChemSpider751
ChEBI28304
ChEMBLCHEMBL1909300
Therapeutic Targets DatabaseDAP000189
PharmGKBPA449855
Drug Product Database453781
RxListhttp://www.rxlist.com/cgi/generic/heparin.htm
Drugs.comhttp://www.drugs.com/heparin.html
WikipediaHeparin
ATC CodesC05BA01C05BA03S01XA09S01XA14
AHFS Codes
  • 20:12.04.16
  • 92:00.00
PDB Entries
FDA labelshow(198 KB)
MSDSshow(72.1 KB)
Interactions
Drug Interactions
Drug
Acetylsalicylic acidIncreased risk of bleeding.
AprotininAprotinin, in the presence of heparin, has been found to prolong the activated clotting time (ACT) as measured by a celite surface activation method. The kaolin activated clotting time appears to be much less affected.
corticotropin-releasing factorContraindication: Heparin may enhance the adverse/toxic effect of Corticorelin. Significant hypotension and bradycardia have been previously attributed to this combination. Corticorelin prescribing information describes a case in which a patient experienced a substantial fall in blood pressure and heart rate, resulting in asystole and requiring resuscitation.
DrospirenoneHeparin can increase risk of hyperkalemia for patients on drospirenone
Drotrecogin alfaThe potential benefits of drotrecogin alfa should be weighed against an increased risk of bleeding in patients receiving therapeutic doses of heparin. Monitor for bleeding during concomitant therapy, and immediately stop infusion of drotrecogin if clinically important bleeding occurs. In patients receiving prophylactic heparin doses, consider continuing this during drotrecogin.
Ginkgo bilobaAdditive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.
TiclopidineIncreased bleeding risk. Monitor aPTT.
TobramycinIncreased risk of nephrotoxicity
TreprostinilThe prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the anticoagulant, Heparin. Monitor for increased bleeding during concomitant thearpy.
Food Interactions
  • Adequate calcium intake is recommended, needs increased with long term use, supplement recommended.
  • Many herbs with anticoagulant properties (e.g. ginger, garlic, ginseng, green tea, evening primrose) may increase the risk of bleeding in patients on anticoagulant therapy such as heparin

Targets

1. Antithrombin-III

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: potentiator

Components

Name UniProt ID Details
Antithrombin-III P01008 Details

References:

  1. Mirow N, Zimmermann B, Maleszka A, Knobl H, Tenderich G, Koerfer R, Herberg FW: Plasma protein binding properties to immobilized heparin and heparin-albumin conjugate. Artif Organs. 2007 Jun;31(6):466-71. Pubmed
    Pubmed
  2. Pappalardo F, Franco A, Crescenzi G, De Simone F, Torracca L, Zangrillo A: Anticoagulation management in patients undergoing open heart surgery by activated clotting time and whole blood heparin concentration. Perfusion. 2006 Dec;21(5):285-90. Pubmed
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  4. Chuang YJ, Swanson R, Raja SM, Olson ST: Heparin enhances the specificity of antithrombin for thrombin and factor Xa independent of the reactive center loop sequence. Evidence for an exosite determinant of factor Xa specificity in heparin-activated antithrombin. J Biol Chem. 2001 May 4;276(18):14961-71. Epub 2001 Feb 7. Pubmed
  5. Petitou M, Herault JP, Bernat A, Driguez PA, Duchaussoy P, Lormeau JC, Herbert JM: Synthesis of thrombin-inhibiting heparin mimetics without side effects. Nature. 1999 Apr 1;398(6726):417-22. Pubmed
  6. Schedin-Weiss S, Richard B, Olson ST: Kinetic evidence that allosteric activation of antithrombin by heparin is mediated by two sequential conformational changes. Arch Biochem Biophys. 2010 Dec 15;504(2):169-76. Epub 2010 Sep 15. Pubmed
  7. Gettins PG, Olson ST: Activation of antithrombin as a factor IXa and Xa inhibitor involves mitigation of repression rather than positive enhancement. FEBS Lett. 2009 Nov 3;583(21):3397-400. Epub 2009 Oct 9. Pubmed

2. Coagulation factor X

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Coagulation factor X P00742 Details

References:

  1. Ignjatovic V, Summerhayes R, Gan A, Than J, Chan A, Cochrane A, Bennett M, Horton S, Shann F, Lane G, Ross-Smith M, Monagle P: Monitoring Unfractionated Heparin (UFH) therapy: which Anti-Factor Xa assay is appropriate? Thromb Res. 2007;120(3):347-51. Epub 2006 Nov 21. Pubmed
  2. Patey SJ, Edwards EA, Yates EA, Turnbull JE: Heparin derivatives as inhibitors of BACE-1, the Alzheimer’s beta-secretase, with reduced activity against factor Xa and other proteases. J Med Chem. 2006 Oct 5;49(20):6129-32. Pubmed
  3. Rezaie AR: Heparin-binding exosite of factor Xa. Trends Cardiovasc Med. 2000 Nov;10(8):333-8. Pubmed
  4. Rosenberg RD: Role of heparin and heparinlike molecules in thrombosis and atherosclerosis. Fed Proc. 1985 Feb;44(2):404-9. Pubmed

3. P-selectin

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
P-selectin P16109 Details

References:

  1. Simonis D, Fritzsche J, Alban S, Bendas G: Kinetic analysis of heparin and glucan sulfates binding to P-selectin and its impact on the general understanding of selectin inhibition. Biochemistry. 2007 May 22;46(20):6156-64. Epub 2007 Apr 26. Pubmed
  2. Maugeri N, Di Fabio G, Barbanti M, de Gaetano G, Donati MB, Cerletti C: Parnaparin, a low-molecular-weight heparin, prevents P-selectin-dependent formation of platelet-leukocyte aggregates in human whole blood. Thromb Haemost. 2007 Jun;97(6):965-73. Pubmed
  3. Simonis D, Christ K, Alban S, Bendas G: Affinity and kinetics of different heparins binding to P- and L-selectin. Semin Thromb Hemost. 2007 Jul;33(5):534-9. Pubmed
  4. Asberg AE, Videm V: Inhibition of platelet receptors involved in neutrophil-platelet interaction in model cardiopulmonary bypass. Artif Organs. 2007 Aug;31(8):617-26. Pubmed
  5. Gao Y, Li N, Fei R, Chen Z, Zheng S, Zeng X: P-Selectin-mediated acute inflammation can be blocked by chemically modified heparin, RO-heparin. Mol Cells. 2005 Jun 30;19(3):350-5. Pubmed
  6. Koenig A, Norgard-Sumnicht K, Linhardt R, Varki A: Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents. J Clin Invest. 1998 Feb 15;101(4):877-89. Pubmed
  7. Nelson RM, Cecconi O, Roberts WG, Aruffo A, Linhardt RJ, Bevilacqua MP: Heparin oligosaccharides bind L- and P-selectin and inhibit acute inflammation. Blood. 1993 Dec 1;82(11):3253-8. Pubmed

Enzymes

1. Heparanase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Heparanase Q9Y251 Details

References:

  1. Wang B, Jia J, Zhang X, Zcharia E, Vlodavsky I, Pejler G, Li JP: Heparanase affects secretory granule homeostasis of murine mast cells through degrading heparin. J Allergy Clin Immunol. 2011 May 14. Pubmed
  2. Nadir Y, Brenner B: Heparanase procoagulant effects and inhibition by heparins. Thromb Res. 2010 Apr;125 Suppl 2:S72-6. Pubmed
  3. Levy-Adam F, Feld S, Suss-Toby E, Vlodavsky I, Ilan N: Heparanase facilitates cell adhesion and spreading by clustering of cell surface heparan sulfate proteoglycans. PLoS One. 2008 Jun 11;3(6):e2319. Pubmed
  4. Vlodavsky I, Ilan N, Naggi A, Casu B: Heparanase: structure, biological functions, and inhibition by heparin-derived mimetics of heparan sulfate. Curr Pharm Des. 2007;13(20):2057-73. Pubmed
  5. Katz BZ, Muhl L, Zwang E, Ilan N, Herishanu Y, Deutsch V, Naparstek E, Vlodavsky I, Preissner KT: Heparanase modulates heparinoids anticoagulant activities via non-enzymatic mechanisms. Thromb Haemost. 2007 Dec;98(6):1193-9. Pubmed
  6. Nasser NJ, Sarig G, Brenner B, Nevo E, Goldshmidt O, Zcharia E, Li JP, Vlodavsky I: Heparanase neutralizes the anticoagulation properties of heparin and low-molecular-weight heparin. J Thromb Haemost. 2006 Mar;4(3):560-5. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 13, 2013 11:03