tharanga lecture

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Anticoagulant, Antiplatelet, and Thrombolytic Drugs

Dr. Tharanga Kulathilaka

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Objectives

• Normal haemostasis process Plt plug, Clot & Thrombus

• Mechanism of action

• Indications

• Common side effects

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Haemostasis

• Complex process• Interaction between vessel wall, plt, Coagualtion/

fibrinolytic mechanism.

• Vessel wall in normal condition prevents plt adhesion and thrombin formation by negative charge, PC, NO synthesis, Production of plasminogen activator, Expression of thrombomodulin and heparan sulphate.

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Physiology and Pathophysiology of Coagulation

• Hemostasis– Stage 1—formation of platelet plug

• Platelet aggregation– Stage 2—coagulation

• Intrinsic coagulation pathway• Extrinsic coagulation pathway

– Keeping hemostasis under control– Physiologic removal of clots

• Thrombosis– Arterial thrombosis, Venous thrombosis

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• Endothelial injury is caused by Mechanical stresses (HT)

Biochemical abnormalities ( Modified LDL, DM, Plasma homocystein )

Immunological factors

Free radicals

Inflammation

Genetic alteration

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Platelets

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Platelet plug formation

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Clotting pathway

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Thrombus

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Physiological limitations of coagulation

• Rapid blood flow

• Circulating inhibitors of clotting factors

• Antithrombin – Heparin

• Act protein c (-)V ,viii

• Protein S cofactor for protein C

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Fibrinolysis

• Fibrinolysis is the controlled remodeling of a platelet plug. It is the process that dissolves fibrin resulting in the removal of small blot clots. Agents or drugs which promote fibrinolysis are useful therapeutically.

• Plasminogen – Plasmin

• Tpa

• FDP - D dimers

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Overview of DrugsDrug Class Prototype Drug Action

Therapeutic Effect

Anticoagulants: Parenteral

Heparin Fibrin formation (by promoting inactivation of clotting factors)

Prevention of venous thrombosis

Anticoagulants: Oral

Warfarin Fibrin formation (by decreasing synthesis of clotting factors)

Prevention of venous thrombosis

Antiplatelet Drugs

Aspirin Platelet aggregations

Prevention of arterial thrombosis

Thrombolytic Drugs

Streptokinase Promotion of fibrin digestion

Removal of newly formed thrombi

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Antiplatelet Drugs

Two Drugs to know:

ASPIRIN and CLOPIDOGREL

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Antiplatelet Drugs

• Aspirin (ASA)– Irreversible Inhibition of cyclooxygenase

reducing Txa2

Effect lasts for 7 days.– Adverse effects

• Increase risk of GI bleeding• Hypersensitivity• Bronchospasms• Interstitial nephritis and protenuria• Rayes syndrome

• Clopidogrel [Plavix]– Orally active– ADP receptor antagonist– Prevents/reduces thrombotic events (MI, ischemic stroke, vascular

death)

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Cont Anti plt drugs

• Clopidogrel – ADP receptor blocker in plt membrane

• Prevents ADP dependent activation of gpǁb, ǁl a complex

• Prasugrel - Potent and rapid action

• Dipiridamole – Inhibits plt phosphodiesterase activity increses pgi2 action

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Plt llb,llla blockers

• Abciximab

• Eptifibatide

• Tirofiban

• Excessive bleeding

• Its uses yet to indentify

• During pci

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Parenteral Anticoagulants I:Heparin and Related Drugs

Heparin (Unfractionated Heparin)• Sources

– Lungs of cattle– Intestines of pigs

• Rapid-acting anticoagulant• Uses

– Pulmonary embolism (PE)– Stroke evolving– Massive deep venous thrombosis (DVT)

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Parenteral Anticoagulants I:Heparin and Related Drugs

• Adverse effects

– Hemorrhage

– Heparin-induced thrombocytopenia

– Hypersensitivity reactions

• Protamine

• Activated partial thromboplastin time (aPTT)

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Figure 51-3 Mechanism of action of heparin, LMW heparins, and fondaparinux.

Heparin suppresses coagulation by promoting the action of antithrombin (a serine protease inhbitor) to inactivate thrombin and factor Xa.

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Low-Molecular-Weight HeparinsLovenox (enoxaparin)

• Heparin preparations composed of molecules that are shorter than those found in unfractionated heparin. – Lovenox (enoxaparin)

• Therapeutic use– Prevention of DVT following surgery– Treatment of established DVT– Prevention of ischemic complications

• Adverse effects and interactions– Bleeding, immune-mediated thrombocytopenia– Cost

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Fondaparinux [Arixtra]

• Synthetic subQ anticoagulant – like LMW heparin• Selective inhibition of Factor Xa – see Figure 51-3• Therapeutic use

– Prevention of DVT following surgery– Treatment of acute PE (with warfarin)– Treatment of acute DVT (with warfarin)

• Adverse effects– Bleeding is the biggest concern, risk is increased

with advancing age and renal impairment– Patients weighting less than 50 kg. low BW

increases bleeding risk

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Parenteral Anticoagulants II:Direct Thrombin Inhibitors

Bivalirudin [Angiomax]• Therapeutic use

– Prevent clot formation (combined with aspirin)• Mechanism of action

– Direct, reversible inhibitor of thrombin– Prevents the conversion of fibrinogen into fibrin– Prevents factor XIIIa activation

• Adverse effects– Back pain, headache

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Parenteral Anticoagulants II:Direct Thrombin Inhibitors

Bivalirudin [Angiomax]• synthetic peptide,

must be injected IV• short half-life (25

min)• very expensive

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Warfarin• Oral anticoagulant• Antagonist of vitamin K-dependent reactions• Blocks the biosynthesis of four clotting factors:

Factors VII, IX, X, and prothrombin• Reduces production of clotting factors by 30-50%• Therapeutic uses

Long-term prophylaxis of thrombosis• Prevention of venous thrombosis and associated

pulmonary embolism• Prevention of thromboembolism (in patients with

prosthetic heart valves)• Prevention of thrombosis during atrial fibrillation

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Warfarin

• Adverse effects

– Hemorrhage

– Fetal hemorrhage and teratogenesis from use during pregnancy

– Use during lactation – warfarin enters breast milk

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Warfarin

• Drug interactions

– Drugs that increase anticoagulant effects

– Drugs that promote bleeding

– Drugs that decrease anticoagulant effects

– Heparin

– Aspirin

– Acetaminophen

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Thrombolytic Drugs – Clot Busters

• Streptokinase [Streptase]

– Binds plasminogen and facilitates plasmin formation – plasmin digests fibrin of clots

– Most effective when therapy is begun within 6 hours of symptom onset

– Intended for IV or intracoronary administration

• Uses

– Acute coronary thrombosis (acute MI)

– Deep venous thrombosis (DVT)

– Massive pulmonary emboli

• Adverse effects

– Bleeding, hypotension

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tPA

• Alteplase

• Reteplase

• More specific for clot bound plasminogen

• Fewer bleeding episodes

• Expensive

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