THROMBOLYTIC DRUGS Pathophysiologic 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

Wave-front Phenomenon of Ischemic Cell Death

THROMBOLYTIC DRUGS Pathophysiologic 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

THROMBOLYTIC DRUGS Pathophysiologic Rationale

Acute coronary

syndromes varies with the degree of thrombusinduced obstruction, ranging from a persistent complete occlusion corresponding to STsegment elevation MI to a subocclusive thrombus corresponding to unstable angina

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 STsegment elevation within 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

Fibrinolysis

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

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

Thrombolytic Drugs Streptokinase

It is a bacterial protein 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 t of the activator complex is about 23 minutes The complex is inactivated by anti-streptococcal antibodies & by hepatic clearance

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 $

Thrombolytic Drugs Streptokinase

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

Thrombolytic Drugs Streptokinase

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)

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 $

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

Thrombolytic Drugs

Alteplase
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

Thrombolytic Drugs Alteplase

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%)

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

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)

Thrombolytic Drugs Urokinase

Urokinase administered by intravenous infusion is

rapidly cleared by the liver with an elimination halflife for biologic activity of 12-20 minutes Clinical Uses: For the lyses of acute massive pulmonary emboli

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

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