Thrombolytics, anticoagulants & antiplatelets

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1. ANTICOAGULANTS
Ravish Yadav

2. Outline
•General Overview of
Anticoagulants
•Overview of Blood Coagulation
•Anticoagulant Drugs
•History of Anticoagulant Drugs
•Use of Anticoagulants Today,
Prevention
•Future Outlook

3. Anticoagulants –General Overview
•Drugs that help prevent the clotting (coagulation) of blood
•Coagulation will occur instantaneously once a blood vessel has been
severed
•Blood begins to solidify to prevent
excessive blood loss and to prevent
invasive substances from entering
the bloodstream

4. A Blood Clot
•Consists of platelets
meshed into fibrin
•A web-like accumulation
of strands with RBCs
•There are two major
facets of the clotting
mechanism –the
platelets, and the
thrombin system

5. Platelets
•Tiny cellular elements, made in the bone marrow, that travel in the
bloodstream waiting for a bleeding problem to develop
•When bleeding occurs, chemical reactions change the surface of
the platelet to make it activated and become “sticky”
•These activated platelets begin adhering to the wall of the blood
vessel at the site of bleeding

6. Thrombin System
•Calcium ions must be present for the
thrombin system to begin
•The thrombin system consists of
several blood proteins that activate
when bleeding occurs
•The activated clotting proteins engage
in a cascade of chemical reactions that
finally produce a substance called
fibrin
•Fibrin strands stick to the exposed
vessel wall, clumping together and
forming a web-like complex of strands
•Red blood cells become caught up in
the web, causing a clot

7. Coagulation Factors
FactorName
IFibrinogen
IIProthrombin
III Tissue Factor or
thromboplastin
IV Ca++
VProaccelerin
VII Proconvertin
VIIIAntihemophilic A factor
IX Antihemophilic B
factor or Christmas
factor
FactorName
X Stuart or Stuart-
Prower factor
XI Plasma thomboplastin
antecedent
XIIHageman factor,
contact factor
XIIIFibrin stabilizing factor
Prekallikrein factor
High-molecular-weight
kininogen

8. Heparin
•Heparin is a naturally-occurring anticoagulant
produced by basophils and mast cells to
prevent formation and extension of blood
clots
•Heparin does not disintegrate clots that have
already formed. It permits the body's natural
clot lysis mechanisms, i.e. fibrinolysis,to work
normally to break down previously formed
clots
•As the thrombokinase is released, it
neutralizes the action of heparin to allow
clotting to occur

9. Anticoagulant Use
•Anticoagulant drugs help prevent the development of
harmful clots in the blood vessels by lessening the blood's
ability to cluster together
•The function of these drugs is often misunderstood because
they are sometimes referred to as blood thinners; they do
not in fact thin the blood
•These drugs will not dissolve clots that already have formed,
but it will stop an existing clot from becoming worse and
prevent future clots

10. Anticoagulant Drugs
•Heparin and warfarin are the two traditional anticoagulants
•Anticoagulants are used for acute coronary syndromes, deep-
vein thrombosis (DVT), pulmonary embolism (PE), and heart
surgery
•Thrombus -A blood clot that forms abnormally within the
blood vessels
•Embolus -When a blood clot becomes dislodged from the
vessel wall and travels through the bloodstream
•It is also given to certain people at risk for forming blood
clots, such as those with artificial heart valves or who have
atrial fibrillation (AF)

11. Warfarin
•Warfarin is an oral medication
•It is a synthetic derivative of coumarin, a
chemical found naturally in many plants --it
decreases blood coagulation by interfering
with vitamin K metabolism
•It stops the blood from clotting within the
blood vessels and is used to stop existing clots
from getting bigger (as in DVT) and to stop
parts of clots breaking off and forming emboli
(as in PE)
IUPAC Name: 4-hydroxy-3-(3-oxo-1-phenylbutyl)chromen-2-one

12. Warfarin
•The most common side effects of warfarin are bleeding and
bruising
•The bleeding can be in the form of prolonged bleeding from
cuts; bleeding that does not stop by itself
•Treatment is monitored by regular blood testing using the
International Normalized Ratio (INR), which is a measure of
how much longer it takes the blood to clot when oral
anticoagulant drug is used

13. Warfarin
•Warfarin inhibits the effective synthesis of biologically active
forms of the vitamin K-dependent clotting factors: II, VII, IX and X,
as well as the regulatory factors protein C, protein S and protein Z

15. Dicoumarol
Dicoumarolis a naturally occurringanticoagulantthat
functions as a functionalvitamin Kdepleter (similar towarfarin,
a drug that dicoumarol inspired). It is also used in biochemical
experiments as an inhibitor of reductases.
4-hydroxycoumarin drugs it is acompetitive
inhibitorofvitamin K epoxide reductase, an enzyme that
recyclesvitamin K, thus causing depletion of active vitamin K in
blood. This prevents the formation of the active form
ofprothrombinand several other coagulant enzymes.
IUPAC Name: 4-hydroxy-3-[(4-hydroxy-2-oxochromen-3-
yl)methyl]chromen-2-one

16. Anisindione
•Anisindione (brand name Miradon) is a synthetic oral anticoagulant and
an indanedione derivative
•Reduces the prothrombin activity of the blood
•It prevents the formation of active procoagulation factors II, VII, IX, and
X, as well as the anticoagulant proteins C and S, in the liver by
inhibiting the vitamin K–mediated gamma-carboxylation of precursor
proteins.
IUPAC Name: 2-(4-methoxyphenyl)indene-1,3-dione

17. PHENINDIONE
Phenindioneis an Indanedione that has been used as an
anticoagulantwhich functions as aVitamin K antagonist.
It is anindandionethat has been used as an
anticoagulant.Phenindionehas actions similar towarfarin, but it
is now rarely employed because of its higher incidence of severe
adverse effects.
IUPAC Name: 2-phenylindene-1,3-dione

18. Classification of antiplatelet drugs
Arachidonicacid pathway inhibitors
e.gAspirin
Phosphodiesterase inhibitors
e.g.Triflusal, Dipyridamole, cilostazol
ADP pathway inhibitors
e.g. Ticlopidine -Clopidogrel
Glycoprotein IIb/IIIainhibitors
e.g. Abciximab –Eptifibatide , Tirofiban, Indobufen
Antiplatelet drugs

19. Vascular Injury
Exposure of collagen and vWF Tissue factor exposure
Platelet adhesion and release Activation of coagulation
Platelet recruitment and activation Thrombin generation
Fibrin formation
Platelet aggregation
Platelet –fibrin thrombus

20. Plaque Disruption
Collagen vWF
Platelet adhesion and secretion
Aspirin
Ticlopidine
Clopidogrel
Abciximab
Eptifibatide
Tirofiban
Platelet aggregation
Platelet recruitment and activation
COX-1
ADP
GPllb/ lllaactivation
X
Mechanisms of action
of antiplatelet drugs
X
TXA2

21. Mechanism of action
Irreversible inhibition of cyclooxygenase enzyme ( COX-1 ) via
acetylation.
Small dose inhibits thromboxane (TXA2) synthesis in platelets But
not prostacyclin (PGI
2) synthesis in endothelium (larger dose).
Uses of aspirin
Prophylaxis of thromboembolism e.g. prevention of transient ischemic
attack, ischemic stroke and myocardial infarction.
Prevention of ischemic events in patients with unstable angina pectoris.
Can be combined with other antiplatelet drugs (clopidogrel) or
anticoagulants (heparin).
Arachidonicacid pathway inhibitors
Aspirin (Acetylsalicylic Acid)

22. Cilostazol
Cilostazolis a Phosphodiesterase 3 Inhibitor.
Cilostazolis aquinolinonederivative and cellular
phosphodiesterase inhibitor, more specific for phosphodiesterase III
(PDE III).
Although the exact mechanism of action of is
unknown,cilostazoland its metabolites appears to inhibit PDE III
activity, thereby suppressing cyclic adenosine monophosphate
(cAMP) degradation. This results in an increase incAMPin platelets
and blood vessels, leading to inhibition of platelet aggregation and
vasodilation.
IUPAC: 6-[4-(1-cyclohexyltetrazol-5-yl)butoxy]-3,4-dihydro-1H-quinolin-
2-one

24. Dipyridamol
Dipyridamoleis amedicationthat inhibitsblood
clotformationwhen given chronically and causesblood vessel
dilationwhen given at high doses over a short time.
Dipyridamoleis a synthetic agent derivative ofpyrimido-
pyrimidine, with antiplatelet properties.
Dipyridamoleinhibitsadenosineuptake by platelets and
endothelial cells, triggering an accumulation of cyclic adenosine
monophosphate (cAMP), and inhibiting the stimulation of
platelet aggregation by agents such asplatelet activating
factorand collagen.
Iupac Name: 2-[[2-[bis(2-hydroxyethyl)amino]-4,8-di(piperidin-1-
yl)pyrimido[5,4-d]pyrimidin-6-yl]-(2-hydroxyethyl)amino]ethanol

25. Triflusal
IUPAC Name: 2-acetyloxy-4-(trifluoromethyl)benzoic acid
Triflusal is a selective platelet antiaggregant through;
Blockscyclooxygenaseinhibitingthromboxane A2,
preventing aggregation
Preserves vascularprostacyclin, thus promoting anti-
aggregant effect
Blocksphosphodiesterasethereby
increasingcAMPconcentration, thereby promoting anti-
aggregant effect due to inhibition of calcium mobilization

26. Indobufen
Indobufenis aplatelet aggregation inhibitor.
It acts as a reversiblecyclooxygenase inhibitor
IUPAC Name: 2-[4-(3-oxo-1H-isoindol-2-yl)phenyl]butanoic acid

27. Ticlopidine
Ticlopidineis an antiplatelet drug in
thethienopyridinefamily which is anadenosine
diphosphate(ADP) receptor inhibitor.
Ticlopidine is a thienopyridine which, when metabolized by
the body, irreversibly blocks the ADP receptor on the surface of
platelets. Without ADP, fibrinogen does not bind to the platelet
surface, preventing platelets from sticking to each other.[12]By
interfering with platelet function, ticlopidine prevents clots from
forming on the inside of blood vessels.
IUPAC Name:5-[(2-chlorophenyl)methyl]-6,7-dihydro-4H-thieno[3,2-
c]pyridine

28. Clopidogrel
Clopidogrel acts by inhibiting the ADP receptor onplateletcell membranes.
It is aprodrug, which requires CYP2C19 for its activation.
The drug specifically and irreversibly inhibits theP2Y
12subtype of ADP
receptor, which is important in activation of platelets and eventual cross-
linking by the proteinfibrin.
Platelet inhibition can be demonstrated two hours after a single dose of oral
clopidogrel, but the onset of action is slow, so a loading dose of either 600 or
300mg is administered when a rapid effect is needed
IUPAC Name: methyl (2S)-2-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-
c]pyridin-5-yl)acetate

29. Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a
member of the integrin family of adhesion receptors and the major
platelet surface receptor involved in platelet aggregation. This binding is
thought to involve steric hindrance and/or conformational alterations
which block access of large molecules to the receptor rather than direct
interaction with the RGD (arginine-glycine-aspartic acid) binding site of
GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3
integrin), abciximab blocks effects mediated by this integrin which
include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on
monocytes and neutrophils thus inhibiting monocyte adhesion.
Abciximab

30. STRUCTURE

31. The future for anticoagulants
•Limitations of warfarin have fostered a great interest in the
development of novel anticoagulants for oral use to potentially
replace warfarin
•The design of specific inhibitors against molecular targets that play a
pivotal role in the coagulation cascade are in development

32. The future for anticoagulants
•Molecular targets are factor IIa (thrombin) and factor Xa
•The two candidate compounds, one direct thrombin inhibitor
(dabigatran etexilate) and one direct factor Xa inhibitor (rivaroxaban)
are hoping to be approved as new oral anticoagulants in the near
future

33. The future for anticoagulants
•Factor Xa is an attractive
target for the design of new
oral anticoagulants because
of the unique role factor Xa
plays in the coagulation
cascade as a connection
between the extrinsic and
intrinsic pathways

34. The future for anticoagulants
•Factor Xa also regulates
thrombin generation via binding
to factor Va followed by
activation of prothrombin to
thrombin

35. The future for anticoagulants
•It is hypothesized that
anticoagulants targeting factor
Xa might be more effective than
those targeting coagulation
factors located lower down in
the cascade, such as thrombin

36. The future for anticoagulants
•This concept has been
partially proved when
the first indirect factor Xa
inhibitor, fondaparinux,
received FDA approval
for the prevention and
treatment of VTE.

37. References
•http://science.jrank.org/pages/419/Anticoagulants-How-works.html
•http://www.rxlist.com/cgi/generic/heparin.htm
•http://asheducationbook.hematologylibrary.org/cgi/reprint/2006/1/450
•http://www.medic8.com/healthguide/articles/warfarin.html
•http://www.wikipedia.com
•http://www.drugs.com
•http://www.pharmgkb.org/do/serve