THROMBOLYTIC DRUGS

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Thrombolytic / Fibrinolytics drugs: 

1 Thrombolytic / Fibrinolytics drugs

Thrombolytic / Fibrinolytics drugs: 

2 Thrombolytic / Fibrinolytics drugs Thrombolytic drugs are used to dissolve (lyse) blood clots (thrombi). Blood clots can occur in any vascular bed; however, when they occur in coronary, cerebral or pulmonary vessels, they can be immediately life-threatening - coronary thrombi are the cause of myocardial infarctions, cerebrovascular thrombi produce strokes, and pulmonary thromboemboli can lead to respiratory and cardiac failure. Therefore, it is important to rapidly diagnose and treat blood clots.

Fibrinolysis and Thrombolysis: 

3 Fibrinolysis and Thrombolysis Introduction The fibrinolytic system dissolves intravascular clots as a result of the action of plasmin, an enzyme that digests fibrin. Plasminogen, an inactive precursor, is converted to plasmin by cleavage of a single peptide bond. Plasmin is a relatively nonspecific protease; it digests fibrin clots and other plasma proteins, including several coagulation factors.

Thrombolytic drugs: 

4 Thrombolytic drugs Thrombolytic drugs dissolve blood clots by activating plasminogen, which forms a cleaved product called plasmin. Plasmin is a proteolytic enzyme that is capable of breaking cross-links between fibrin molecules, which provide the structural integrity of blood clots. Because of these actions, thrombolytic drugs are also called "plasminogen activators" and "fibrinolytic drugs."

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Thrombolytic drugs: 

6 Thrombolytic drugs Streptokinase Urokinase Anistreplase tissue Plasminogen Activators (t-PA) Alteplase Reteplase Tenecteplase

MOA - Thrombolytic drugs : 

7 MOA - Thrombolytic drugs Plasmin is an endogenous fibrinolytic enzyme that degrades clots by splitting fibrin into fragments. Plasmin itself can not be used because naturally occurring inhibitors in plasma prevent its effects. Fibrinolytic drugs catalyze the conversion of precursor plasminogen into active plasmin. Rapidly lyse or break down thrombi.

MOA-Thrombolytic drugs…: 

8 MOA-Thrombolytic drugs… Some drugs are more clot specific as they only act on fibrin bound plasminogen. Streptokinase & urokinase are not clot specific. So can create a generalized lytic state when administered I/V. Thus, both protective haemostatic thrombi and target thromboemboli are broken down.

Streptokinase: 

9 Streptokinase Source: It is a protein produced by beta-hemolytic streptococci. It has no intrinsic enzymatic activity. MOA : It combines with proactivator plasminogen to form a complex. This complex catalyzes the conversion of plasminogen to active plasmin. So rapid lysis of the clot by plasmin. This complex also catalyzes the clotting factor V and VII.

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10 Plasma half life: (t ½ ) 40-80 minutes The streptokinase-plasminogen complex is not inhibited by natural alpha 2-antiplasmin Adverse effects: Not clot specific. So can create a generalized lytic state when administered I/V. Thus, both protective haemostatic thrombi and target thromboemboli are broken down. Hemorrhage --- most serious cerebral hemorrhage Allergic reactions, rarely anaphylaxis and fever.

Urokinase: 

11 Urokinase A two chain serine protease containing 411 amino acid residues isolated from cultured human kidney cells. MOA: It converts plasminogen to active plasmin. It is not clot specific: So can create a generalized lytic state when administered I/V. Thus, both protective haemostatic thrombi and target thromboemboli are broken down.

Urokinase…: 

12 Urokinase… Ph. K Given I/V. t ½ : 15-20 minutes Metabolized by liver.

Anistreplase (Anisolyted Plasminogen Streptokinase Activator Complex; APSAC) : 

13 Anistreplase (Anisolyted Plasminogen Streptokinase Activator Complex; APSAC) A complex of purified human plasminogen & bacterial streptokinase that has been acylated to protect the enzymes active site. On I/V administration, the acyl group spontaneously hydrolyzes. Free activated streptokinase - proactivator complex produces lysis of clots also degrades fibrinogen.

Anistreplase: 

14 Anistreplase Advantages: Rapid I/V injection may be given. Greater clot selectivity . More thrombolytic activity. Dose: A single I/V injection of 30 units over 3-5 minutes.

tissue Plasminogen Activator (t-PA) : 

15 tissue Plasminogen Activator (t-PA) t-PA is a natural serine protease. It preferentially activates fibrin bound plasminogen. Human t-PA has been manufactured by recombinant DNA technology for therapeutic use. Alteplase: Recombinant form of t-PA.

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16 Reteplase: Recombinant human t-PA. from which several amino acid sequences have been deleted. Faster OOA & slighter longer DOA. Less expensive Less fibrin specific than t-PA. Tenecteplase: Mutant form of t-PA with a longer DOA. Slightly more fibrin-specific than t-PA.

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Clinical Indications for thrombolytic therapy: 

18 Clinical Indications for thrombolytic therapy Acute myocardial infarction: due to coronary artery thrombosis. Best given within 6 hrs. Pulmonary embolism: with hemodynamic instability. Severe deep vein thrombosis: Ascending thrombophlebitis: of the iliofemoral Acute ischemic stroke: (only t-PA)

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19 Adverse Effects: Bleeding: the most serious is cerebral hemorrhage . Allergic reactions: even anaphylactic shock with streptokinase, urokinase, anistreplase

Antiplatelet Drugs: 

20 Antiplatelet Drugs These drugs inhibit the platelet aggregation (PA). PA contributes to the clotting process specially important in arterial circulation. Platelets have a central role in pathologic coronary and cerebral artery occlusion.

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21 Platelet function is regulated by three categories of agents: First group : agents generated outside the platelets that interact with platelet membrane receptors e.g. Catecholamines Collagen Thrombin Prostacyclin.

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22 Second group : agents generated within the platelets that interact with membrane receptors, e.g. ADP Prostaglandin D 2 Prostaglandin E 2 Serotonin.

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23 Third group : agents generated within the platelets that act within the platelets, e.g. Thromboxane A 2 cAMP cGMP Calcium ion.

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25 Anti-platelet drugs: Prostaglandin synthesis inhibitors / COX inhibitors: Aspirin. ADP Antagonists: Ticlopidine & Clopidogrel Glycoprotein IIb / IIIa inhibitor: Abciximab, Eptifibatide & Tirofiban PDE / adenosine uptake inhibitors: Diapyridamole & Cilostazol

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Aspirin : 

28 Aspirin MOA: Thromboxane A 2 is a potent stimulator of PA. Aspirin inhibits Platelet aggregation in low doses. It inhibits thromboxane A 2 synthesis in platelets by irreversible acetylation of COX-1 enzyme in platelets. Platelets are aneuclear & can not synthesize new proteins so inhibition persists for 7-10 days until new platelets are found. Inhibition of platelet aggregation leads to prolongation of bleeding time.

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29 Rational of low dose Aspirin TXA 2 & PGI 2 (Prostacycline) constitutes a mutually antagonistic system. TXA 2 produced locally by platelets is a potent inducer of aggregation & release reaction on injury when plugging & thrombosis are needed. PGI 2 generated by vascular endothelium is a potent inhibitor of platelet aggregation while in circulation .

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30 Aspirin in low doses selectively inhibits TXA 2 in platelets. In high doses it inhibits both TXA 2 & PGI 2 , hence can reverse the beneficial effects. So for anti-platelet effect aspirin is used in low doses only 100-325mg/day.

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Therapeutic Uses: : 

32 Therapeutic Uses: For primary & secondary prevention of myocardial infraction due to coronary thrombosis. To prevent coronary thrombosis in patients with unstable angina. To prevent transient ischemic attacks & recurrence of ischemic stroke & other thrombotic events. Dose: A single loading oral dose of 325 mg of aspirin followed by a daily dose of 75 - 100mg.

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33 Main Adverse Effects: 1. ↑ incidence of hemorrhagic stroke. 2. Aspirin ↑ the incidence of peptic ulcer disease & gastrointestinal bleeding.

Clopidogrel & Ticlopidine (ADP receptor antagonists): 

34 MOA: They reduce the platelet aggregation by irreversibly blocking ADP receptors on platelets. They have no effect on prostaglandin metabolism. Clopidogrel & Ticlopidine (ADP receptor antagonists)

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35 Therapeutic Uses: Transient ischemic attacks. Unstable angina pectoris. Patients undergoing placement of coronary stents. Stroke.

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Adverse effects:: 

37 Adverse effects: Nausea, dyspepsia and diarrhea --- upto 20% of patients. Haemorrhage in 5% of patients. Leukopenia in 1% of patients (ticlopidine). Thrombotic thrombocytopenic purpura (Clopidogrel) Dosage: 250 mg twice daily. It is useful in patients who cannot tolerate aspirin.

Glycoprotein IIb/IIIa receptors inhibitor: 

38 Glycoprotein IIb/IIIa receptors inhibitor MOA: They inhibit platelet aggregation by blocking the IIb/IIIa receptor complex. The IIb/IIIa complex functions as a receptor mainly for fibrinogen, vibronectin also for fibronectin & von willebrand factor. Activation of this complex is the “final common pathway” for platelet aggregation Persons lacking this receptor have a bleeding disorder called Glanz manns thrombasthenia.

Abciximab: 

39 Abciximab A chimeric monoclonal antibody directed against IIb/IIIa complex including the vibronectin receptor. So inhibits platelet aggregation due to blockade of these receptors. Th. Uses: Percutaneous coronary intervention. Acute coronary syndromes.

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40 Eptifibatide & Tirofiban: Block the ligand binding fibrinogen to the GP IIa/ IIIb receptors but do not block the vibronectin receptor. These drugs are given parenterally.

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Additional anti platelets –directed drugs: 

42 Additional anti platelets –directed drugs Dipyridamole: (Phosphodiesterase inhibitor) MOA: It inhibit platelets function by inhibiting phosphodiesterase (PDE). Inactivation of cAMP is prevented. Levels of cAMP ↑ ;  ↓ intracellular Ca ++ So there is inhibition of platelet aggregation. It is a coronary vasodilator.

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43 Th. Uses: Prevention of cerebrovascular ischemia. (Along with aspirin) Prophylaxis of thromboemboli in patients with prosthetic heart valves. A/E: Headache & palpitations.

Cilostazol: 

44 Cilostazol Newer Phosphodiesterase inhibitor. Promotes vasodilation and inhibition of platelet aggregation. Used to treat intermittent claudication. A/E: Headache & palpitations.

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45 Drugs used in bleeding Disorders Vitamin K Clotting factors and desmopressin Antiplasmin agents.

Vitamin K : 

46 Vitamin K Deficiency of vit. K, prones to bleeding , it is most common in: Older individuals with abnormality of fat absorption. New borns. Th. Use: of phytonadiaone (Vit. K 1 ) Treatment of deficiency (oral or parenteral) Large doses I/V to reverse the bleeding due to warfarin excess.

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47 Clotting factors and desmopressin: They are useful in bleeding disorders. In hemophilia: Fresh plasma . Purified human blood clotting factors specially factor VIII for hemophilia A & factor IX for hemophilia B. Source of clotting factors: Purified from blood products Recombinant DNA technology. These products are expensive, risk of immunologics reactions or infections.

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48 To prepare patients with mild hemophilia A or von Willebrand disease for elective surgery desmopressin acetate is used. Desmopressin is vasopressin V 2 receptor agonist ↑ the concentration of von Willebrand factor & factor VIII.

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49 Antiplasmin agents : Aminocaproic acid & tranexamic acid. Orally active Inhibit fibrinolysis by inhibiting plasminogen activation. Th. use: For prevention or management of acute bleeding episodes in hemophilia & other bleeding disorders.

Aprotinin : 

50 Aprotinin Inhibits fibrinolysis by plasmin & by the plasmin streptokinase complex. Th. use: In coronary artery bypass grafting who are at high risk of excessive blood loss.