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 thrombus-induced obstruction, ranging from a persistent complete occlusion corresponding to ST-segment 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 ST-segment 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 t½ 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 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)

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 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

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%)

Reteplase & Tenectaplase

ReteplaseReteplase is another human t-PA prepared by recombinant mutation technology

It is fibrin-specific It has longer duration than alteplase TenectaplaseTenectaplase is another genetically modified

human t-PA prepared by recombinant technology It is more fibrin-specific & longer duration than

alteplase

Thrombolytic Drugs Urokinase 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 half-life 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