Transcript thrombolytic drugs

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
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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 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
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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
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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
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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