Coagulant & Anticoagulants

Coagulant & Anticoagulants

1. BY
Prof.Bhavesh.B. Amrute
(M.Pharmacy, Pharmaceutical Chemistry)
Sub-Medicinal Chemistry II (BP501T)
Third Year B.Pharmacy

2. Bloodmustremainfluidwithinthevesselsandyetclotquicklywhenexposedtosubendothelial
surfacesatsitesofvascularinjury.Undernormalcircumstances,adelicatebalancebetweencoagulation
andfibrinolysispreventsboththrombosisandhemorrhage.Alterationofthisbalanceinfavorof
coagulationresultsinthrombosis.
Blood Coagulation
It is a complex process of enzymatic reactions in which clotting factors activate other clotting factors in a
fixed sequence until a clot is formed. It depends on the existence of a complex system of reactions
involving plasma proteins, platelets, tissue factors and calcium ion. The coagulation process can be
activated and proceed through one of two possible sequential pathways:
•Intrinsic system path: components present within the circulating blood,
•Extrinsic system: components present in the extravascular and intravascular compartment.

3. Stages and mechanism of blood clotting.

4. Coagulants
Coagulants are substances which promote coagulation indicated in hemorrhagic states like
Haemophilia,Vonwillibrandsdisease etc.
Classification of anticoagulants

5. Menadione
Menadioneisasyntheticnaphthoquinone
ItisalsocalledasvitaminK
Itisaprothrombinactivator.
Mechanism of action
Menadione(vitaminK3)isinvolvedasacofactorintheposttranslationalgamma-
carboxylationofglutamicacidresiduesofcertainproteinsinthebody.Theseproteins
includethevitaminK-dependentcoagulationfactorsII(prothrombin),VII
(proconvertin),IX(Christmasfactor),X(Stuartfactor),proteinC,proteinS,proteinZv
andagrowth-arrest-specificfactor(Gas6).IncontrasttotheothervitaminK-dependent
proteinsinthebloodcoagulationcascade,proteinCandproteinSserveanticoagulant
roles.ThetwovitaminK-dependentproteinsfoundinboneareosteocalcin,alsoknown
asboneG1a(gamma-carboxyglutamate)proteinorBGP,andthematrixG1aproteinor
MGP.Gamma-carboxylationiscatalyzedbythevitaminK-dependentgamma-
carboxylases.ThereducedformofvitaminK,vitaminKhydroquinone,istheactual
cofactorforthegamma-carboxylases.Proteinscontaininggamma-carboxyglutamateare
calledG1aproteins
Uses
It is used in the treatment
of hypoprothrombinemia.
It may also play a role in
normal bone calcification

6. Acetomenadione
Acetomenadioneisamemberofnaphthalenes.
Itisasyntheticvitamin.
Itisalsoknownasdavitamon-Koracetomenaphthone.
Acetomenaphthoneisanextremelyweakbasic
Mechanismofaction–AssameasMenadione
Uses
Acetomenadioneisusedforthetreatment,control,prevention,&improvementofthe
followingdiseases,conditionsandsymptoms:
CoagulationdisordersduetovitaminKdeficiency
Anticoagulant-inducedprothrombindeficiency

7. Anticoagulants
Drugsthatinterferewithbloodcoagulation(anticoagulants)areknownasanticoagulants.Theyarethe
mainstayofcardiovasculartherapy.Anticoagulantseliminateorreducetheriskofbloodclots.They’reoften
calledbloodthinners,butthesemedicationsdon’treallythinyourblood.Instead,theyhelppreventorbreak
updangerousbloodclotsthatforminyourbloodvesselsorheart.
Classification
1. Used in vivo
a. Parenteral anticoagulants
i. Indirect thrombin inhibitors Ex. Heparin, Danaparoid, Fondaparinux
ii. Direct thrombin inhibitors Ex. Lepirudin, Bivalirudin, Argatroban

8. b. Oral anticoagulants
i.Coumarinderivatives Ex. Warfarin, Bishydroxycoumarin,
Acenocoumarol
ii.Indanedione derivatives Ex. Phenindione
iii.Direct factor Xainhibitors Ex. Rivaroxaban
iv.Oral direct thrombin inhibitors Ex.Dabigatran
2.Usedinvitro
Heparin
Calciumcomplexingagents
i.OxalatecompoundsEx.Calciumoxalate
ii.CitratecompoundsExSodiumcitrate

9. Warfarin
4-hydroxy-3-(3-oxo-1-
phenylbutyl)chromen-2-one
Warfarinisasyntheticanticoagulant
ThenamewarfarincamefromitsdiscoveryattheWARF(WisconsinAlumniResearch
Foundation)andtheending-arin,indicatesitslinkwithcoumarin
Warfarinexistsintautomericform.
Hemiketalmusttautomerisetothe4-hydroxylforminorderforwarfarintobeactive.
WarfarincontainsastereocenterandconsistsoftwoenantiomersThisisaracemate.
AnticoagulantactivityofS-warfarinis2–5timesmorethantheR-isomer

10. Mechanismofaction
WarfarinactsbyantagonizingvitaminKandreductionofthefactorsinvolveddirectlyorindirectlyinbloodclotting.
WarfarininhibitsvitaminKreductaseenzyme,whichresultsindecreaseamountofreducedformofvitaminK.
ReductioninvitaminK(reduced)lowersdowntheglutamateresiduescarboxylationintheN-terminalregionsof
coagulantproteins.
ThisinhibitsthesynthesisofvitaminK-dependentcoagulationfactors(factorsII,VII,IX,andX)andanticoagulant
proteins(regulatoryfactors)CandSbytheliver.
Decreaseinthecoagulationfactorscausesloweringintheprothrombinlevels.
Reduceprothrombinaffectsproductionofthrombinandfibrinboundthrombin,whichultimatelyreducesbloodclotting

11. Mechanism of action of warfarin

12. Synthesis
Base/acidcatalysedMichaelcondensationreactionof4-hydroxycoumarinwithbenzalacetone.
Pyridineisusuallyusedasthecatalystforthisreactiontoaffordracemicwarfarin.

13. Uses
Prophylaxisandtreatmentofvenousthromboembolismandrelatedpulmonaryembolism.
Prophylaxisandtreatmentofthromboembolismassociatedwithatrialfibrillation.
Prophylaxisandtreatmentofthromboembolismassociatedwithcardiacvalve
replacement.
Usedasadjuncttherapytoreducemortality,recurrentmyocardialinfarction,and
thromboemboliceventspostmyocardialinfarction.
Secondarypreventionofstrokeandtransientischemicattacksinpatientswithrheumatic
mitralvalvediseasebutwithoutatrialfibrillation.

14. Anisindione
Anisindioneis a synthetic indanedioneanticoagulant.
Mechanismofaction
AnisindioneinhibitsthevitaminK–mediatedgamma-carboxylationofprecursorproteins.
ThispreventstheformationofactiveprocoagulationfactorsII,VII,IX,andX,aswellastheanticoagulantproteins
CandS.
Theconsequentialeffectsofthisinhibitionincludeareducedactivityoftheseclottingfactorsandprolongedblood
clottingtime.
Anisindionehasnodirectthrombolyticeffectanddoesnotreverseischemictissuedamage,althoughitmaylimit
extensionofexistingthrombiandpreventsecondarythromboemboliccomplications.
Uses
Fortheprophylaxisandtreatmentofvenousthrombosisanditsextension,thetreatment
ofatrialfibrillationwithembolization,theprophylaxisandtreatmentofpulmonary
embolism,andasanadjunctinthetreatmentofcoronaryocclusion.
Itisprescribedonlyifcoumarin-typeanticoagulantscannotbetaken.

15. Clopidogrel
Clopidogrelisaprodrugofthethienopyridinefamily
Mechanismofaction
Clopidogrelisaprodruganditsthiolmetaboliteisaplateletinhibitor.
Clopidogrelismetabolizedtoitsactiveformintwostepsintheliverbycytochrome
P450enzymes.
TheactivethiolmetaboliteirreversiblyinhibitstheP2Y12subtypeofADP(adenosine
diphosphate)receptorontheplateletsurface.
Thisleadstodisruptionofresultinginplateletaggregation..
Mechanism of action of clopidogrel
Uses
Used to reduce the risk of heart disease and stroke in those at high risk.
It is also used together with aspirin in heart attacks and following the
placement of a coronary artery stent (dual antiplatelet therapy).