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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