Pharmacology of Thrombolytics and Fibrinolytics

1. -RVS CHAITANYA KOPPALA
Drugs Used in Clotting
Disorders

3. Coagulation Cascade

4. Basic Pharmacology
• Anticoagulants
• limit the ability of the blood to clot
• venous thrombosis fibrin rich
• Antiplatelet drugs
• limit the migration or aggregation of platelets
• arterial thrombosis platelet rich
• Thrombolytics / Fibrinolytics
• drugs act to dissolve clots after they have formed
• venous thrombosis fibrin rich

5. Anticoagulant drugs
Oral anticoagulants
• Vitamin K antagonism :
• Direct thrombin inhibition :
• Direct Xa inhibition :
Warfarin/coumarins
Dabigatran Rivaroxaban,
Apixaban
Injectable anticoagulants
• Antithrombin-dependent inhibition of thrombin and Xa: Heparin
• Antithrombin-dependent inhibition of Xa :Fondaparinux, Idraparinux
• Direct thrombin inhibition : Lepirudin, Argatroban,Bivalirudin

6. Heparin
• MOA: promotes the action of antithrombin III to inactivate thrombin and
factor Xa and suppresses coagulation. Affects factor IIa, IXa, Xa, Xia,XIIa
and VIIa
• Uses: pulmonary embolism, DVT
• Mode of administration: only IV or deep s.c.
• Adverse effect
Hemorrhage
Heparin-induced thrombocytopenia
Hypersensitivity reaction
Osteoporosis(long term use)
Safe in pregnency
• Contraindication
- Active bleeding
- Hypertension
- Tuberculosis
- Renal disease
- Recent surgery of brain, spinal
cord, eye.
- Ulcerative lesions in GIT
• Half life 1-5 hrs
• Antidote: protamine sulfate

7. Warfarin

8. • Clearance is slow = 36 hrs
• Delayed onset
• Oral Administration
• 5-10 mg daily
• Antidote
• Vitamin K infusion
• Can cross placenta
• do not use during late pregnancies
Warfarin
Monitoring of Warfarin Therapy
• INR ( International Normalized Ratio )
• INR=(PT patient/PT normal)ISI
• Target INR= 2.0 TO 3.0
• Every 2-3 weeks

9. Contraindications to Anticoagulant use
• Previous Heparin-induced thrombocytopenia syndrome (HITS)
• Coagulopathies
• Hemophilia
• thrombocytopenia
• Active bleeding
• intracranial hemorrhage
• gastrointestinal (GI) ulcers
• certain cancers
Adverse effects of Warfarin
• Bleeding
• Skin necrosis
• Fetal abnormalities, bleeding

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11. • Blood clots (thrombus/thrombi)
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• 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.
Introduction

12.  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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13. 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.
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Thrombolysis

14. 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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Mechanism of action

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16.  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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Thrombolytic drugs

17. Streptokinase
• Urokinase
• Anistreplase
• tissue Plasminogen Activators (t-PA)
◦ Alteplase
◦ Reteplase
◦ Tenecteplase
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Thrombolytic drugs

18. 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 andVII.
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Streptokinase

19. Plasma half life: (t ½) 40-80 minutes
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◦ 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.
and target◦ Thus, both protective haemostatic thrombi
thromboemboli are broken down.
◦ Hemorrhage --- most serious cerebral hemorrhage
◦ Allergic reactions, rarely anaphylaxis and fever.

20.  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 VeinThrombosis
 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 ofArteriovenous Cannulae: for clearing totally or
partially occluded arteriovenous cannulae when acceptable flow cannot
be achieved
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21. A two chain serine protease containing 411 amino acid residues
isolated from cultured human kidney cells.
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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.
Urokinase

22. 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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Urokinase

23. 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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Anistreplase (APSAC)
(Anisolyted Plasminogen Streptokinase Activator)
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.

24.  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
Alteplase (rt.PA)
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Tissue Plasminogen Activator (t-PA)

25. 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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26. 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
withAMI
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
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27. 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-PAwith a longer DOA.
Slightly more fibrin-specific than t-PA.
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28.  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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30. 9
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31.  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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Contraindications to Thrombolytic Therapy