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 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 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