anticoagulant anti platelet fibrinolytic drugs08 black and white

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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......



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



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.



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.



Blood Clotting

• Highly regulated process involving platelets aswell as various cellular and blood clotting factors.

• Two physiological steps involved:

1) Thrombogenesis

2) Blood coagulation



Thrombogenesis

• Platelet adhesion and aggregation:

• Platelet plug:

• r n e n orcement:



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



Blood Clot

Yuri Veklich and John W. Weisel, University of Pennsylvania School of Medicine



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



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



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



xtr ns c

clotting cascadeIntrinsic

clotting cascade

Xa

ThrombinProthrombin

Heparin

Fibrinogen Fibrin Clot 1000X



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



Extrinsic

clotting cascadeIntrinsic

clotting cascade

Xa

Thrombin

Prothrombin Hirudin

Fibrinogen Fibrin Clot



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



Mechanism of Warfarin Action

Descarboxy-

prothrombin Prothrombin

CO2

carboxylase

Coupled

O2

vitamin Kct ve

Vitamin K

(catalyst)

Epoxide

Antidote:Vitamin K

Supplementation

hydrolase

Warfarin



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.



Fibrinolysis

Plasminogen

t-PA, urokinase + Aminocaproic acid

Plasmin

DegradationThrombin

FibrinFibrin split

products products



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



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



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*




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



Antiplatelet Drugs

• Aspirin (acetylsalicylic acid)

• MOA: irreversibly acetylates cyclooxygenase-,

(TXA2), therefore blocking its platelet-

aggregating action

• Indications: Pro h laxis of MI 350m /d

•



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)



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




Collagen

PlateletTXA2

5-HT

(Aspirin,

Thienopyridines,

Platelet

+a oc ers



Arterial Thrombosis

• ,

strokes, unstable angina, or myocardial

– Treatment with aspirin, clopidogrel

– fibrinolytic drug such as urokinase, orl l



– 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

anticoagulant anti platelet fibrinolytic drugs08 black and white

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