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Anticoagulant, Fibrinolytic andAntiplatelet Drugs
Introduction to Pharmacology I
Kishore Pasumarthi([email protected])
Oct 29, 2008
NB: This handout does not have ALL the......
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Overview
• Describe basic physiology of blood coagulation
- Anticoagulant drugs
• Describe basic physiology of fibrinolysis
- Fibrinolytic drugs
• Describe role of platelets in blood coagulation
- Antiplatelet drugs
• Management of clotting disorders
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Background
• Hemostasis is a highly regulated process:
- maintains the fluidity of the blood,
- m s oss o oo rom a amage oo vesse ,
- prevents vessel occlusion (thrombosis)
• Failure of hemostasis mechanisms can lead to:
- excessive bleeding (or)- vessel occlusion by excessive blood clot formation(thrombosis)
• Drugs used to prevent thrombosis are classified asanticoagulant, fibrinolytic and antiplatelet drugs.
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Clinical significance of thrombosis
• Damage to vessel wall can initiate the formation of ablood clot (thrombus).-
• oo c ot can occ u e oo ow caus ng sc em a nvarious organs such as heart, brain and kidney.
- this can lead to:
• A blood clot formed in one site can break off and travelto remote sites and occlude smaller blood vessels. Thisprocess is called thromboembolism.
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Blood Clotting
• Highly regulated process involving platelets aswell as various cellular and blood clotting factors.
• Two physiological steps involved:
1) Thrombogenesis
2) Blood coagulation
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Thrombogenesis
• Platelet adhesion and aggregation:
• Platelet plug:
• r n e n orcement:
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EndotheliumVessel walldamage
Collagen
ADP
TXA2
5-HT
and aggregation2) Formation of weakPlatelet
p a e e p ug
3) Fibrin
+Platelet
ReinforcementIntrinsicExtrinsic
Xa
+
+
Fibrinogen
+ Blood
CoagulationProthrombin Thrombin
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Blood Clot
Yuri Veklich and John W. Weisel, University of Pennsylvania School of Medicine
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Blood Coagulation
• Transformation of soluble fibrinogen into insoluble fibrin.
• Many blood clotting factors interact in a cascading seriesof limited proteolytic reactions.
• Extrinsic and intrinsic pathways: converge at factor X toproduce thrombin which catalyses the transformation ofsoluble fibrinogen to insoluble fibrin.
• Extrinsic pathway (The main initiator of blood coagulation) –
• Intrinsic pathway – ac va e y sur ace con ac w a ore gn o y
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Schematic of Blood Coagulation
Extrinsic
Tissue injuryAbnormal
vessel wall
VII + TF VIIaIntrinsic
XIIXIIa
XIa
Ix IXa IX
X Xa
IIaII
ThrombinProthrombin
Ia
Fibrinogen Fibrin Clot
NOT ON EXAM
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Anticoagulant Drugs
• Heparin (Enoxaparin) (LMWH):• Binds to and stabilizes antithrombin which inhibits many
clotting factor proteases (1000x enhanced activity)
• 1st line therapy (acts quickly)
• m n n: y . . or . . n ec on
• Indications: embolisms, prophylactic (low dose. . ,
• Toxicity: excessive bleeding therefore closely
,patients, thrombocytopenia occurs in 25% ormore of atients
• Antidote: protamine sulfate a specific antagonist
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xtr ns c
clotting cascadeIntrinsic
clotting cascade
Xa
ThrombinProthrombin
Heparin
Fibrinogen Fibrin Clot 1000X
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Anticoagulant Drugs
• Hirudin –
the leech available as recombinant form (lepirudin)
–
– Indications: for patients who have developed-thrombocytopenia
– : up o o pa en s on ong- erminfusions can develop allergy (forming antibodiesto thrombin-lepirudin complex), no antidote
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Extrinsic
clotting cascadeIntrinsic
clotting cascade
Xa
Thrombin
Prothrombin Hirudin
Fibrinogen Fibrin Clot
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Anticoagulant Drugs
• Warfarin member of coumarin family
– blocks γ−carboxylation of glutamate residues inrothrombin and factors VII IX X leavin them
biologically inactive
– : a en ora y, - ours un onse oaction, long half life (~36 hours)
– Indications: Treatment of thromboembolisms,Prophylactic (often given after MI), rodent infestations
– Toxicity: Can cross placental barrier, several druginteractions leading to increased bleeding.
– Antidote: vitamin K
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Mechanism of Warfarin Action
Descarboxy-
prothrombin Prothrombin
CO2
carboxylase
Coupled
O2
vitamin Kct ve
Vitamin K
(catalyst)
Epoxide
Antidote:Vitamin K
Supplementation
hydrolase
Warfarin
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Regulation of Coagulation
• Fibrin Inhibition: Plasma protease inhibitors (such,
fibrin formation.
• Fibrinolytic Enzymes: Thrombus is digested by
proteolytic enzymes (tissue plasminogenact vator t- , uro nase etc.
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Fibrinolysis
Plasminogen
t-PA, urokinase + Aminocaproic acid
Plasmin
DegradationThrombin
FibrinFibrin split
products products
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Fibrinolytic Drugs (Clot-Busters)
• Streptokinase – is a bacterial protein that combines with
p asm nogen to cata yze t e convers on o
plasminogen to plasmin (not selective for fibrin-bound plasminogen)
• Urokinase – uman enzyme conver s p asm nogen o p asm n• very expensive, thousands of dollars
• Alteplase – recombinant human t-PA (tissue plasminogen
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Fibrinolytic Drugs (cont)
• MOA: – Lyse thrombi by catalyzing the formation of plasmin
– -
fibrin confining fibrinolysis to formed thrombus avoidssystemic activation
• Administration: I.V. (5 min-12 hrs)
• Indications: – mu p e pu monary em o , cen ra eep ve nthrombosis
– acute myocardial infarction (can reduce mortality by
20% in MI patients) – patients presenting with acute stroke symptoms given
within 3 hours of onset
• Toxicity: allergies and bleeding
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Platelet Function
• Platelet function can be regulated 3 ways:
autocr ne st mu at on - ma e y p ate ets tointeract with their own receptors (ADP, PG, 5-
.
2) agents made by platelets which function2+ 2, , .
3) external agents that interact with their, ,
prostacyclin)
*Antagonists exist for all 3 levels of platelet activation*
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EndotheliumVessel walldamage
Collagen
ADP
TXA2
5-HT
and aggregation2) Formation of weakPlatelet
p a e e p ug
3) Fibrin
+Platelet
ReinforcementIntrinsicExtrinsic
Xa
+
+
Fibrinogen
+ Blood
CoagulationProthrombin Thrombin
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Antiplatelet Drugs
• Aspirin (acetylsalicylic acid)
• MOA: irreversibly acetylates cyclooxygenase-,
(TXA2), therefore blocking its platelet-
aggregating action
• Indications: Pro h laxis of MI 350m /d
•
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Anti latelet Dru s• Thienopyridines (Clopidogrel)
• MOA: inhibit ADP pathway by irreversiblyinhibiting binding to its receptor (reducing itsp a e e aggrega ng e ec s
• Administration: Oral dose (300mg then
• Indications: prohylaxis in stroke, MI patients
• ox c y: s omac rr a on, arr ea,hemorrage, leukopenia (rare)
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Antiplatelet Drugs
• Glycoprotein IIb/IIIa inhibitors:• Abciximab (Ab),
– MOA: bind GPIIb/IIIa receptors inhibits thefinal common pathway in plateletaggregation
– Administration: I.V.
Platelet
FibrinogenIIb/IIIa
Platelet
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EndotheliumVessel walldamage
Collagen
PlateletTXA2
5-HT
(Aspirin,
Thienopyridines,
Platelet
+a oc ers
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Arterial Thrombosis
• ,
strokes, unstable angina, or myocardial
– Treatment with aspirin, clopidogrel
– fibrinolytic drug such as urokinase, orl l
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– rop y ac c rea men ma n y w• Anticoagulants
– LWMH Warfarin
• Antiplatelets – Aspirin, Clopidogrel
– Acute treatment with one or in combination• Anticoa ulant, Anti latelet, and /or Fibrinol tic
Drugs