THROMBOLYTIC DRUGS Pathophysiologic Rationale

1. THROMBOLYTIC DRUGSPathophysiologic Rationale • When an atherosclerotic plaque ruptures  thrombosis  occlusion of the artery  myocardial infarction  necrosis • If we can breakdown the thrombus then we can save the myocardial cells from necrosis. • Clinical trials of thrombolytic drugs showed beneficial in patient with MI with ST segment elevation. • But they weren’t as beneficial when it came to unstable angina or MI with non ST segment elevation • The treatment should be initiated rapidly (less than 6 hours)

2. Fibrinolysis TPA: tissue plasminogen activator

3. Mechanism of Thrombolytic Drugs • They convert plasminogen  plasmin which lyses blood clots • Plasmin, is a nonspecificserine protease(capable of breaking down fibrin as well as fibrinogen (main action)and factors V and VIII)

4. Mechanism of Thrombolytic Drugs • The plasmin(ogen) molecule has lysine binding sites, which bind to fibrin $2200 $280 prodrug Secreted from kidney

6. I- Streptokinase (SK) • It is a bacterialprotein (not an enzyme)produced by group C β-hemolytic streptococci. SK activator complex (SK+plasminogen) Plasminogen Activator complex Plasminogen Plasmin Lysis of fibrin clot N.B. Plasmin degrades fibrin clots as well as fibrinogen and other plasma proteins (non-fibrin specific)

7. Cont’d activate degrade

8. Cont’d • Pharmacokinetics: • The t½ of the activator complex= 23 minutes • The complex is inactivated by anti-streptococcal antibodies & by hepatic clearance • It produces hyperfibrinolytic effect, which decreases plasma fibrinogen levels for 24-36 hrs • A prolonged bleeding time may persist for up to 24 hours due to the decrease in plasma levels of fibrinogen

9. Cont’d • Efficacy: reduces mortality: • 47 % reduction after one hour of chest pain. • 23% within 3 hours • 17% between 3-6 hours • No significant reduction between 6-12 hours • Hospital cost per day is minimal 280 $ • The advantages are more when take rapidly (at the onset of chest pain)

10. Cont’d

11. Cont’d • Clinical Uses: • Acute Myocardial Infarction: administered IV or intracoronary  ↓ infarct size and congestive heart failure. • Arterial Thrombosis or Embolism: It is not indicated for arterial emboli originating from the left side of the heart due to the risk of new embolic phenomena such as cerebral embolism. • Occlusion of Arteriovenous Cannulae: for clearing totally or partially occluded arteriovenous cannulae.

12. Cont’d • Side-Effects: • Bleeding due to activation of circulating plasminogen • Hypersensitivity: because it is of bacterial products so, it is antigenic & can produce allergic reactions like rashes & fever (occurs in 3% of patients)

13. II- Anistreplase (APSAC) • Anisoylated Plasminogen Streptokinase Activator Complex (APSAC) purified human plasminogen combined with bacterial streptokinase that has been acylated to protect the enzyme’s active site. • It is a prodrug: APSAC SK-plasminogen complex • Similar to SK, it has minimal fibrin specificity & is antigenic • T1/2 is more than SK (70-120 min ) • Hospital cost per day is 1700 $ deacylation

14. III-Alteplase (rt.PA) • Formerly known as tissue plasminogen activator (t-PA). • Mechanism of action: • It is an enzyme. • rt.PA binds to fibrin  conversion of plasminogen to plasmin (inside the clot)  fibrinolysis • It acts only on fibrin inside the clot (not free fibrin) It’s fibrin selective (specific)

15. cont’d • Pharmacokinetics: t1/2 = 5 minutes • produced by recombinant DNA technology. • Cost per day is around 2200 $ (expensive)

16. Cont’d Therapeutic Uses • Acute Myocardial Infarction: • Reduces mortality • Improve ventricular function  ↓ CHF • Acute Ischemic Stroke • improves neurological recovery • reduces the incidence of disability. • Treatment of acute massive Embolism • Treatment should only be initiated within 3 hours after the onset of stroke symptoms. • You have to exclude cerebral hemorrhage to use alteplase (see adverse effect in the next slide)

17. Cont’d • Side-Effects: • Bleeding including GIT & cerebral hemorrhage • Allergic reactions: rare (< 0.02% of patients) (minor effect)

18. IV-Urokinase • It is an enzyme produced by the kidney of human & also animal ( yet no allergic reaction) and is found in urine. • It is mainly used in the low molecular weight form of urokinase obtained from human neonatal kidney cells grown in tissue culture. • Mechanism: It acts on the endogenous fibrinolytic system converting plasminogen to plasmin that degrades fibrin clots as well as fibrinogen and some other plasma proteins (Non-fibrin selective).

19. Cont’d • (IV) administration • rapidly cleared by the liver • t1/2 = 12-20 minutes Clinical Uses: • For the lyses of acute massive pulmonary emboli Pharmacokinetics

20. Cont’d Contraindications to Thrombolytic Therapy

21. Fibrinolytic Inhibitors • Aminocaproic Acid & tranexamic acid • They have lysine-like structure • They inhibit fibrinolysis by competitive inhibition of plasminogen activation • ِِِAdjuvant therapy in hemophilia, fibrinolytic therapy-induced bleeding & postsurgical bleeding • Aprotinin is a serine protease inhibitor • It inhibits fibrinolysis by blocking free plasmin • Used to stop bleeding in some surgical procedures

22. ZuBDAS, in other words: (butter of the lecture) 1- All thrombolytic drugs cannot be used in case of unstable angina (could mobilize the thrombus  embolism) 2- All thrombolytic drugs can be used in case of acute MI (more effective in the first 6 hours). 3- SK & Anistriplase have same MOA, ADR & selectivity. The only difference between them is that the anistriplase has relatively longer duration of action. 4- All thrombolytic drugs are non-selective except Alteplase. 5- All thrombolytic drugs have short duration of action except anistreplase (relatively) 6- All non-selective thrombolytic drugs cause more bleeding tendency than selective. Yet in general all cause bleeding 7-Streptokinase may cause hypersensitivity reaction 8-Urokinase is used primarily in pulmonary embolism treatment