THROMBOLYTIC DRUGS Pathophysiologic Rationale

1. THROMBOLYTIC DRUGSPathophysiologic Rationale • Re-establishing coronary flow during a period of occlusion will limit myocardial infarct (MI) size was first demonstrated in a dog model of MI by Reimer et al. in 1977 • These experiments demonstrated that after coronary occlusion there was a wavefront of ischemic cell death, which progressed over time from the subendocardium toward the epicardium • The time frame for this process was quite short, in the range of 3 to 4 hours • Thus these studies provided the basis for the rationale that re-canalization and reperfusion early in the course of MI would limit myocardial necrosis, improve left ventricular function, & improve patient outcome

2. Wave-front Phenomenon of Ischemic Cell Death

3. THROMBOLYTIC DRUGSPathophysiologic Rationale • Angiographic studies in the early 1980s showed that early in the course of MI with ST-segment elevation, most patients had complete coronary occlusion • Pathologic studies established the importance of plaque rupture in the pathogenesis of acute coronary syndromes

4. THROMBOLYTIC DRUGSPathophysiologic Rationale • Acute coronary syndromes varies with the degree of thrombus-induced obstruction, ranging from a persistent complete occlusion corresponding to ST-segment elevation MI to a subocclusive thrombus corresponding to unstable angina

5. Thrombolytic Therapy Benefit • The ability of streptokinase to lyse clots was first recognized in the 1930s • Thrombolytic therapy was not applied to acute MI until the early 1980s after the establishment of the central role of acute thrombotic coronary occlusion in the pathogenesis of acute MI • Clinical trials have firmly established the benefit of thrombolytic therapy for patients with acute MI with ST-segment elevationwithin 12 hours of symptom onset • Patients with unstable angina or MI without ST elevation do not benefit from thrombolytic therapy • Rapid initiation of thrombolytic therapy is essential to optimize patient outcome because each additional hour of delay from symptom onset to treatment corresponds to a 0.5% to 1% increase in mortality

6. Fibrinolysis

7. Mechanism of Thrombolytic Drugs • They have a common mechanism of converting the proenzyme plasminogen to the active enzyme plasmin, which lyses fibrin clot • Plasminogen is converted to plasmin by cleavage of the Arg-Val (560-561) peptide bond • Plasmin, the active two-chain polypeptide, is a nonspecific serine protease capable of breaking down fibrin as well as fibrinogen and factors V and VIII

8. Mechanism of Thrombolytic Drugs • The plasmin(ogen) molecule has lysine binding sites, which bind to and degrade fibrin • Fibrin-specific agents are much more active upon binding to fibrin, thereby increasing the affinity for plasminogen at the clot surface

9. Thrombolytic Drugs Streptokinase • It is a bacterialprotein produced by group C (beta)-hemolytic streptococci • Mechanism: It binds to plasminogen producing an "activator complex" that lyses free plasminogen to the proteolytic enzyme plasmin • Plasmin degrades fibrin clots as well as fibrinogen and other plasma proteins (non-fibrin specific) • Pharmacokinetics: • The t½ of the activator complex is about 23 minutes • The complex is inactivated by anti-streptococcal antibodies & by hepatic clearance

10. Thrombolytic Drugs Streptokinase • It produces hyperfibrinolytic effect, which decreases plasma fibrinogen levels for 24-36 hrs • A prolonged thrombin time may persist for up to 24 hours due to the decrease in plasma levels of fibrinogen • Efficacy: In the GISSI study the reduction in mortality was time dependent; 47% reduction in mortality in patients treated within one hour of the onset of chest pain, 23% within three hours, & a 17% reduction between three and six hours • The reduction was not statistically significant between 6-12 hrs • Hospital cost per day is minimal 280 $

11. Thrombolytic DrugsStreptokinase • Clinical Uses: • Acute Myocardial Infarction: administered by either the intravenous or the intracoronary route for the reduction of infarct size & congestive heart failure associated with AMI • Pulmonary Embolism • Deep Vein Thrombosis • 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 when acceptable flow cannot be achieved

12. Thrombolytic DrugsStreptokinase • Side-Effects: • Bleeding due to activation of circulating plasminogen • Hypersensitivity: It is antigenic & can produce allergic reactions like rashes & fever (possibly via already present Streptococcal antibodies)

13. Anistreplase (APSAC) • Anisoylated Plasminogen Streptokinase Activator Complex (APSAC) IS acylated plasminogen combined with streptokinase • It is a prodrug, de-acylated in circulation into the active plasminogen-SK complex • Similar to SK, it has minimal fibrin specificity & is antigenic • T1/2 is 70-120 min • Hospital cost per day is 1700 $

14. Thrombolytic Drugs Alteplase (rt.PA) • It is a tissue plasminogen activator (t.PA) produced by recombinant DNA technology of 527 amino acids • Cost per day is around 2200 $ • Mechanism: • It is an enzyme which has the property of fibrin-enhanced conversion of plasminogen to plasmin • It produces limited conversion of free plasminogen in the absence of fibrin • When introduced into the systemic circulation it binds to fibrin in a thrombus and converts the entrapped plasminogen to plasmin followed by activated local fibrinolysis with limited systemic proteolysis

15. Thrombolytic DrugsAlteplase Therapeutic Uses • Acute Myocardial Infarction in adults for the improvement of ventricular function following AMI the reduction of the incidence of congestive heart failure, and the reduction of mortality associated with AMI • Acute Ischemic Stroke for improving neurological recovery and reducing the incidence of disability. Treatment should only be initiated within 3 hours after the onset of stroke symptoms, and after exclusion of intracranial hemorrhage • Pulmonary Embolism: Treatment of acute massive pulmonary embolism

16. Thrombolytic DrugsAlteplase • Pharmacokinetics: It has very short t1/2 of 5 minutes • Side-Effects: • Bleeding including GIT & cerebral hemorrhage • Allergic reactions, e.g., anaphylactoid reaction, laryngeal edema, rash, and urticaria have been reported very rarely (<0.02%)

17. Reteplase & Tenectaplase • Reteplase is another human t-PA prepared by recombinant mutation technology • It is fibrin-specific • It has longer duration than alteplase • Tenectaplase is another genetically modified human t-PA prepared by recombinant technology • It is more fibrin-specific & longer duration than alteplase

18. Thrombolytic Drugs Urokinase • It is an enzyme produced by the kidney, and found in the 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 the enzyme plasmin that degrades fibrin clots as well as fibrinogen and some other plasma proteins (Non-fibrin selective)

19. Thrombolytic DrugsUrokinase • Urokinase administered by intravenous infusion is rapidly cleared by the liver with an elimination half-life for biologic activity of 12-20 minutes • Clinical Uses: • For the lyses of acute massive pulmonary emboli

20. Contraindications to Thrombolytic Therapy • Absolute contraindications include: • Recent head trauma or caranial tumor • Previous hemorrhagic shock • Stroke or cerebro-vascular events 1 year old • Active internal bleeding • Major surgery within two weeks • Relative contraindications include: • Active peptic ulcer, diabetic retinopathy, pregnancy, uncontrolled HTN

21. Fibrinolytic Inhibitors • Aminocaproic Acid & tranexamic cid • 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 free plasmin • Used to stop bleeding in some surgical procedures