Thrombolytics ppt

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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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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
Risk Factors

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Plasminogen,aninactiveprecursor
Itisconvertedtoplasminbycleavageofasingle
peptidebond.
Plasminisarelativelynonspecificprotease
itdigestsfibrinclotsandotherplasmaproteins,
includingseveralcoagulationfactors.

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Plasminisanendogenousfibrinolyticenzymethat
degradesclotsbysplittingfibrinintofragments
Plasminitselfcannotbeusedbecausenaturallyoccurring
inhibitorsinplasmapreventitseffects
Fibrinolyticdrugscatalyzetheconversionofprecursor
plasminogenintoactiveplasmin
Rapidlylyseorbreakdownthrombi
Somedrugsaremoreclotspecificastheyonlyactonfibrin
boundplasminogen.

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PLASMINOGEN
PLASMIN
FIBRINDEGRADATIONPRODUCTS
CLOTDISSOLUTION
PLASMINOGEN
ACTIVATOR

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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.
◦SocancreateageneralizedlyticstatewhenadministeredI/V.
◦Thus,bothprotectivehaemostaticthrombiandtarget
thromboemboliarebrokendown.
◦Hemorrhage---mostseriouscerebralhemorrhage
◦Allergicreactions,rarelyanaphylaxisandfever.
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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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A two chain serine protease containing 411 amino acid
residues isolated from cultured human kidney cells.
It is an enzymeproduced by the kidney, and found in
the urine
MOA:
It converts plasminogen to active plasmin.
It is not clot specific:
◦SocancreateageneralizedlyticstatewhenadministeredI/V.
◦Thus,bothprotectivehaemostaticthrombiandtarget
thromboemboliarebrokendown.

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

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Pharmacokinetics:
It has very short t
1/2of 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 Infarctionin 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 Strokefor 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
Aprotininis 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 caranialtumor
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