Thrombolytic MBBS

Fibrinolytics, antifibrinolytics and antiplatelet drugs: 

Dr.Rathnakar U.P MD.DIH.PGDHM www.scribd.com Fibrinolytics , antifibrinolytics and antiplatelet drugs

Blood coagulation: 

Blood coagulation Two contrasting properties of Blood Remains fluid in circulation Solidifies when vessels are injured

Blood Clotting [Pathophysiology] : 

Blood Clotting [ Pathophysiology ] Vascular Phase Platelet Phase Coagulation Phase Fibrinolytic Phase

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Damaged vessel wall Collagen release Platelet activation TXA2 Release ADP release Thrombin Platelet adhesion RECEPTORS Antiplatelets

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Blood Vessel Injury IX IXa XI XIa X Xa XII XIIa Tissue Injury Tissue Factor Thromboplastin VIIa VII X Prothrombin Thrombin Fibrinogen Fribrin monomer Fibrin polymer XIII Intrinsic Pathway Extrinsic Pathway Factors affected By Heparin Vit . K dependent Factors Affected by Oral Anticoagulants 5 Coagulation

Fibrinolysis: 

Fibrinolysis PLASMINOGEN PLASMIN Fibrin [Insoluble ] Fibrin [Soluble]

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1. Anticoagulant Parenteral Heparin Inactivation of clotting factors DVT Oral Warfarin Decrease synthesis of clotting factors DVT 2. Antiplatelet Aspirin Decrease platelet aggregation Prevent arterial thrombosis 3. Thrombolytic Streptokinase Fibinolysis Breakdown of thrombi Drugs used to reduce clotting 7

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Streptokinase Urokinase Rt-PA PLASMINOGEN EACA Tranexaemic acid Aprotinin Activators Inhibitors Factor XIIA Kallikrein T-PA PLASMIN α2Antiplasmin α2Macroglobulin Fibrin [Insoluble] Fibrin [Soluble] EXTRINSIC INTRINSIC EXTRINSIC INTRINSIC Fibrinolytic system 8

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Streptokinase and Urokinase Fibrinolytics Prour o kinase Alteplase Reteplase Tenecteplase Anisstreplace [ Anisoylated purified streptokinase activator complex]

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Source MOA [PA] Antigenic Route[ i.v .] ADE Alteplase [t-PA] Recombinant [I gen] Fibrin specific No Bolus+infusion Less Reteplase [r-PA] Recombinant [II gen] As above No Bolus+Bolus Less Tenecteplase Recombinant As above NO Bolus Less Streptokinase Streptococci Plasminogen complex Non-specific YES Infusion High Urokinase Human urine/Recombinant Directly acts, [Not as complex] NO Bolus+infusion Prourokinase Recombinant Prodrug Non specific NO Anistreplase Synthetic Plasminogen+SK No need to form complex Non specific YES 10

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Charecteristic Streptokinase Urokinase Alteplase t1/2[Minutes] 15-25 15-20 4-8 Fibrin specificity Minimal Moderate Maximum Plasminogen Binding Indirect Direct Direct Antigenicity Yes No NO Dose 1.5 MU 3-4 MU 100mg Administration [MI] 1.5MU i.v . 3L.i.v-10mts 3L/h-12h 15mg bolus 50mg-30mts 35mg-60mts

General properties-Thrombolytic agents: 

General properties-Thrombolytic agents MOA- All are activators of plasminogen PK- Administered by i.v . route USE- MI is the most important use When- To be given in the therapeutic window-6 hours ADE Some are highly antigenic Hemorrhage is the most important complication

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Fibrinolytics- Adverse effects 13

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Streptokinase ADEs Bleeding Antigenic-Anaphylaxis, Rashes

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Streptokinase…. Therapeutic uses: Acute myocardial infarction , Acute pulmonary embolism , Deep-vein thrombosis, Arterial thrombosis [PVD], Route I.V. 15

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Urokinase …. Isolated from human Directly acts on plasminogen Non-antigenic. Adverse action profile same SK 16

Alteplase: 

Alteplase Alteplase ( tPA ) originally derived from cultured human melanoma cells-now recombinant DNA technology. Mechanism of action: Alteplase has a low affinity for free plasminogen in the plasma-rapidly activates plasminogen that is bound to fibrin in a thrombus or a hemostatic plug . Fibrin selective-At low doses, it has the advantage of lysing only fibrin, without unwanted degradation of other proteins- fibrinogen . Streptokinase, which acts on free plasminogen and induces a general fibrinolytic state. [Note: At therapeutic doses, circulating plasminogen may be activated, resulting in hemorrhage .]

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Anistreplase: 

Anistreplase Anisoylated plasminogen streptokinase activator complex Anistreplase is a preformed complex of streptokinase and plasminogen and it is considered to be a prodrug .

Fibrinolytics-Indications: 

Fibrinolytics -Indications Acute MI Acute Ischemic Stroke Deep Vein Thrombosis Pulmonary embolism Peripheral arterial occlusion Administration-STEMI- Within 1 hr[golden hour] Not useful after 6 hours of MI[ Th.window ] Bleeding risk –same with all.

Fibrinolytics-CI: 

Fibrinolytics -CI AbsoluteContraindications 1. Prior ICH 2. Known Cerebral vascular lesion 3. IC malignant neoplasm 4. Ischemic stroke-past 3 months 5. Aortic dissection 6. Active bleeding,bleeding diatehsis [Not menses] 7. Closed head injury/facial trauma-past 3 months Relative Contraindications 1. Poorly controlled/sever HTN 2. Major surgery-3 weeks 3. Recent internal bleeding 4. SK/ Anistreplase -h/o allergy/prior admn . 5. Pregnancy 6. Active peptic ulcer

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Uses of Antifibrinolytics

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ADEs Antifibrinolytics

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Summary: Fibrinolytics

Antiplatelet drugs: 

Antiplatelet drugs

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Damaged vessel wall Collagen release Platelet activation TXA2 Release ADP release Thrombin Platelet adhesion RECEPTORS Aspirin PDE-I GPIIb / IIIa Anta P2Y12 anta Antiplatelets

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Platelet cox-1 inhibitor Aspirin P2y12[Adenosine] receptor blockade Ticlopidine, Clopidogrel , Prasugrel, Elinogrel, Ticagrelor GPIIb/IIIa antagonist Abciximab , Eptifibatide, Tirofiban Phosphodiesterase inhibitor Dipyridamole , Pentoxifylline, Cilostazon Thrombaxane A 2 synthesis inhibitor GR3219 Natural patelet aggregation inhibitor PGI 2 [ Epoprosteno ]l , nitric oxide platelet inhibitors

ASPIRIN: 

ASPIRIN Mechanism of action: Aspirin (acetylsalicylic acid) irreversibly inhibits cyclooxygenase-1 in platelets Blocks the formation of thromboxane A2 (TXA2; a potent vasoconstrictor and platelet aggregant ). Only the parent form, acetylsalicylic acid, which has any significant effect on platelet function .

Aspirin……: 

Aspirin…… Platelets are unable to regenerate cyclooxygenase , antithrombotic effect of aspirin remains for the lifespan of the platelet (8–10 days). After stopping aspirin therapy, normal haemostasis may be regained when about 20% of platelets have normal cyclooxygenase activity, daily aspirin intake is recommended

Aspirin-ADE: 

Aspirin-ADE Adverse effects Dyspepsia Erosive gastritis Peptic ulcer with bleeding and perforation Hepatic and renal toxicities Increase in bleeding tendency

Aspirin-imp/points: 

Aspirin-imp/points 1. Aspirin in low dose inhibits cox-1 of platelets in liver 2. Platelets have no nuclei-hence no regeneration 3. Inhibition irreversible [Other NSAIDs reversible] 4.Higher doses inhibit PGI2 in vessel wall 5. Low dose-can produce peptic ulceration and bleeding 6. Aspirin resistance-Failure to respond.-Genetic,

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Platelet cox-1 inhibitor Aspirin P2y12[Adenosine] receptor blockade Ticlopidine, Clopidogrel , Prasugrel, Elinogrel, Ticagrelor GPIIb/IIIa antagonist Abciximab , Eptifibatide, Tirofiban Phosphodiesterase inhibitor Dipyridamole , Pentoxifylline, Cilostazol Thrombaxane A 2 synthesis inhibitor GR3219 Natural patelet aggregation inhibitor PGI 2 [ Epoprosteno ]l , nitric oxide Platelet inhibitors

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P2Y12 receptor antagonist 250mg twice daily orally Drug interaction Synergestic effect on platelet with aspirin

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Clopidogrel Closely related to ticlopidine 75mg once daily, orally Less than Ticlopidine P2Y12 receptor antagonist

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Platelet cox-1 inhibitor Aspirin P2y12[Adenosine] receptor blockade Ticlopidine, Clopidogrel , Prasugrel, Elinogrel, Ticagrelor GPIIb/IIIa antagonist Abciximab , Eptifibatide, Tirofiban Phosphodiesterase inhibitor Dipyridamole , Pentoxifylline, Cilostazol Thrombaxane A 2 synthesis inhibitor GR3219 Natural patelet aggregation inhibitor PGI 2 [ Epoprosteno ]l , nitric oxide Platelet inhibitors

Glycoprotein IIb/ IIIa receptor antagonist: 

Glycoprotein IIb / IIIa receptor antagonist ABCIXIMAB: A Monoclonal antibody MOA: Inhibition of this receptor blocks binding of fibrin to platelets and platelet aggregation USE: Used with Aspirin+Heparin during coronary artery interventions. i.v.infusion ADE: Bleeding, Thrombocytopinia , constipation

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STEMI NON-STEMI Before During Procedure After Previous MI Previous stroke PVD LL Arterial graft CABG Carotid endarterectomies AF Usually with anticogulants Indications for antiplatelet drugs Acute ischemic event Percutaneous Coronary Interventions High risk of vascular events Revascularization procedures Prosthetic valves Acute ischemic stroke

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Summary: Antiplatelets