Blood clots can cause serious medical issues if they block arteries or veins. Thrombolytic drugs work by activating plasminogen into plasmin, an enzyme that breaks down fibrin in clots. The three main types of thrombolytic drugs are streptokinase, urokinase, and tissue plasminogen activators (TPA). While all three work to break down clots, TPA is more specific to clots and has fewer side effects than the other drugs. Thrombolytic drugs are used to treat conditions like heart attacks, strokes, and pulmonary embolisms but have risks of bleeding if overused or in the wrong patients.

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3.  Blood clots (thrombus/thrombi)
 Vascular bed/Blood vessels
 Coronary thrombi cause myocardial infarctions
 cerebrovascular thrombi produce strokes
 pulmonary thromboemboli can lead to respiratory
and cardiac failure
 So it is important to rapidly diagnose and treat blood clots.
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Risk Factors
 Major Risk Factors That Cannot Be Changed
 Heredity
 Gender
 Age
 Major Risk Factors That Can Be Controlled or Changed
 Smoking
 High Blood Pressure
 Blood Cholesterol Levels
 Stress
 Contributing Factors
 Obesity
 Lack of Exercise
 Diabetes

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 Plasminogen, an inactive precursor
 It is converted to plasmin by cleavage of a single
peptide bond.
 Plasmin is a relatively nonspecific protease
 it digests fibrin clots and other plasma proteins,
including several coagulation factors.

6.  Plasmin is an endogenous fibrinolytic enzyme that
degrades clots by splitting fibrin into fragments
 Plasmin itself can not be used because naturally occurring
inhibitors in plasma prevent its effects
 Fibrinolytic drugs catalyze the conversion of precursor
plasminogen into active plasmin
 Rapidly lyse or break down thrombi
 Some drugs are more clot specific as they only act on fibrin
bound plasminogen.
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PLASMINOGEN
PLASMIN
PLASMINOGEN
ACTIVATOR
FIBRIN DEGRADATION PRODUCTS
CLOT DISSOLUTION

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9.  Thrombolytic drugs dissolve blood clots by activating
plasminogen
 which forms a cleaved product called plasmin.
 Plasmin is a proteolytic enzyme that is capable of breaking
cross-links between fibrin molecules
 which provide the structural integrity of blood clots.
 Because of these actions, thrombolytic drugs are also called
"plasminogen activators" and "fibrinolytic drugs.”
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10.  Streptokinase
 Urokinase
 Anistreplase
 tissue Plasminogen Activators (t-PA)
◦ Alteplase
◦ Reteplase
◦ Tenecteplase
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11. Source:
 It is a protein produced by beta-hemolytic streptococci.
It has no intrinsic enzymatic activity.
MOA:
 It combines with proactivator plasminogen to form a
complex.
 This complex catalyzes the conversion of plasminogen
to active plasmin.
 So rapid lysis of the clot by plasmin.
 This complex also catalyzes the clotting factor V and VII.
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12. Plasma half life: (t ½) 40-80 minutes
◦ The streptokinase-plasminogen complex is not inhibited by natural
alpha 2-antiplasmin
Adverse effects: Not clot specific.
◦ So can create a generalized lytic state when administered I/V.
◦ Thus, both protective haemostatic thrombi and target
thromboemboli are broken down.
◦ Hemorrhage --- most serious cerebral hemorrhage
◦ Allergic reactions, rarely anaphylaxis and fever.
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13. Clinical Uses of streptokinase
 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
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14. A two chain serine protease containing 411 amino acid
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residues isolated from cultured human kidney cells.
It is an enzyme produced by the kidney, and found in
the urine
MOA:
 It converts plasminogen to active plasmin.
 It is not clot specific:
◦ So can create a generalized lytic state when administered I/V.
◦ Thus, both protective haemostatic thrombi and target
thromboemboli are broken down.

15.  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
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 A complex of purified human plasminogen & bacterial
streptokinase that has been acylated to protect the
enzymes active site.
 On I/V administration, the acyl group spontaneously
hydrolyzes.
 Free activated streptokinase - proactivator complex
produces lysis of clots also degrades fibrinogen.

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Advantages:
 Rapid I/V injection may be given.
 Greater clot selectivity .
 More thrombolytic activity.
Dose: A single I/V injection of 30 units over 3-5 minutes.

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Alteplase (rt.PA)
 It is a tissue plasminogen activator (t.PA) produced by
recombinant DNA technology of 527 amino acids
 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

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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%)

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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

21. Reteplase:
 Recombinant human t-PA. from which several amino
acid sequences have been deleted.
 Faster OOA & slighter longer DOA.
 Less expensive
 Less fibrin specific than t-PA.
Tenecteplase:
 Mutant form of t-PA with a longer DOA.
 Slightly more fibrin-specific than t-PA.
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Aminocaproic Acid & tranexamic acid
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

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24.  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
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By
Raman