Pharmacology Lecture Slides on Thrombolytic Medications by Sanjaya Mani Dixit Assistant Professor of Pharmacology at Kathmandu Medical College

1. Thrombolytic Medications
Sanjaya Mani Dixit
Assistant Prof of Pharmacology

2. Topics under Discussion
• Thromboembolic Diseases
• Why Thrombolytic Therapy??
• Thrombolytics/ Fibrinolytics
– Blood clotting stages
– Thrombus-Thrombolytics
– Thrombolytic Medications
• Streptokinase
• Urokinase
• Alteplase (rt-PA)
• Clinical Uses
• Pharmacological Basis
• Adverse Effects
• Contraindications

3. Thromboembolic Diseases
Abnormal blood clotting (thrombosis) is one of the major cause of
death and a leading cause of morbidity worldwide. Blood clots can
develop in the arterial circulation (arterial thrombosis) or venous
circulation (venous thrombosis).
Arterial thrombi usually develop in
arteries diseased by
atherosclerosis.
Venous thrombosis is possibly due
to inactivity and small injuries to
the veins.

5. Thromboembolic Disorders

7. Why Thrombolytic Therapy??
• Thrombolytic therapy is also known as clot busting
drug.
• This therapy has saved many untold lives.
• Critical in the treatment of arterial and venous
thrombosis, which if left untreated can even lead to
death.
• Thrombolytic drugs currently available are Alteplase,
Anistreplase, Urokinase, Streptokinase, Tenecteplase,
etc.
• Often a combination of drug therapy is employed for
effective thrombolysis.

8. History of Thrombolytic Therapy??
• The streptokinase era dates back to 1933, while Tillett and
Garner discovered the agent through sheer serendipity, who
called it fibrolysin.
• But first test was carried out on human in 1947 to lyse chronic
thoracic empyemas with considerable success.
• Due to difficulties in purifying the protein the intravenous
administration of streptokinase was delayed.
• In the 1960s, Behringwerke AG and Kabi Pharmacia made the
drug accessible for prevalent therapeutic use.
• A significant success came during first trial using streptokinase
with acute myocardial infarction, published between 1978 and
1988, compared with conservative treatment or placebo.
https://www.hindawi.com/journals/tswj/2014/586510/

9. Therapy of Thromboembolic Disorders:
Thrombolytics:
• Preparations, pharmacological basis for their actions and related
usefulness.
Anticoagulants :
• Introduction, General principles- Classification, Mechanism of action,
Adverse effects, Contraindications,
• Therapeutic Uses and Drug interactions.
Antiplatelet agents:
• Classification, Mechanism of action, Adverse effects,
Contraindications, Therapeutic Uses.

10. Darwinism and Risk of Cardiovascular
Disease

11. 1. Vascular Phase
2. Platelet Phase
3. Coagulation Phase
4. Fibrinolytic Phase
Blood Clotting

12. Thrombosis Vs Fibrinolysis

13. Drug Class Prototype Action Effect
1. Anticoagulant
Parenteral Heparin Inactivation of clotting
factors
Prevent DVT
Oral Warfarin Decrease synthesis of
clotting factors
Prevent DVT
2.
Antiplatelet
Aspirin Decrease platelet
aggregation
Prevent arterial
thrombosis
3. Thrombolytic Streptokinase Fibrinolysis Breakdown of
thrombi
Drugs used to reduce clotting

14. Thrombus
Thrombus is a stationary blood clot along the wall of a blood
vessel, frequently causing vascular obstruction.
During the formation of thrombus, plasminogen in its inactive
form is bound to the fibrin, this binding renders fibrin bound
plasminogen more susceptible to activation than plasma
plasminogen, hence selective action of thrombolytic agents.
Thrombus are of different constitution
when they are formed in different BVs
– Artery (White)
– Vein (Red)

15. Thrombus
According to location & composition
Arterial (White)
• Occur in areas of rapid
flow (arteries)
• In response to an
injured or abnormal
vessel wall
• Composed:
primarily of platelets,
also fibrin & occasional
leukocytes
• Associated with
MI
Stroke
ischemia
Venous (Red)
• Occur primarily in the venous
circulation
• In response to venous stasis
or vascular injury
• Composed
almost entirely of fibrin &
erythrocytes (Red)
• Associated with
Congestive Heart Failure,
Cancer
Surgery

16. Fibrinolysis
• Enhance degradation of clots
• Activation of endogenous protease
• Plasminogen (inactive form) is converted to
Plasmin (active form)
• Plasmin breaks down fibrin clots

17. Thrombolytics
• These are drugs used to lyse thrombi/clot to
reopen the occluded blood vessels.
• They are curative rather than prophylactic.
• The primary action of all thrombolytic agents is to
convert plasminogen (precursor zymogen) to
plasmin (serine protease).
• Plasmin possess enzymatic activity that brings about
the degradation of fibrin (fibrinolysis) that results in
the lysis of clots.

18. Plasmin is the active fibrinolytic
enzyme.
Anistreplase is a combination of
streptokinase and the
proactivator plasminogen.
Aminocaproic acid (right) inhibits
the activation of plasminogen to
plasmin and is useful in some
bleeding disorders.
Thrombolytic System

19. Thrombolytics/
Fibrinolytics
• Streptokinase
• Urokinase
• Alteplase (rt-PA)
• Reteplase
• Tenecteplase

20. Thrombolytic Agents
Mechanism:
• Rapid lysis of thrombi by catalyzing the formation of plasmin from
plasminogen
• Endogenous plasmin breaks down fibrin promoting clot dissolution
Use:
• Emergency treatment of coronary artery thrombosis in M.I.
• IV or intracoronary injection
• DVT: rapid recanalization of occluded vessels
Toxicity:
• Bleeding (intracranial, G.I.)
• Allergic reactions (i.e. streptokinase)

21. Streptokinase (STK)
• Streptokinase is a non-enzyme protein produced by several
bacterial strains of hemolytic streptococci.
• Streptokinase cannot directly cleave peptide bonds. It combines
with circulating plasminogen to form an activator complex
which then causes limited proteolysis of other plasminogen
molecules to plasmin.
• T½ 30-80 mins
• Anti-streptococcal antibodies present due to past infections
inactivate considerable fraction of the initial dose of STK: a
loading dose is necessary in the beginning.

22. Streptokinase (STK)
• Streptokinase is antigenic; can cause
hypersensitivity reactions and anaphylaxis,
especially when used second time in a patient.
• Fever is common, hypotension and arrhythmias
are reported.
• STK is infrequently used now in developed
countries, owing to antigenicity.

23. Urokinase
• Its an enzyme, initially isolated from human urine[Uro-],
later prepared from cultured human kidney cells.
• Non-antigenic, expensive
• Indicated in whom Streptokinase have been tried earlier.
• M/A:
• Activates plasminogen directly, T1/2 10-15 mins.
S/Es
• Fever
• Hypotension and Allergy (Rarely)

24. Alteplase (rt-PA)
• Recombinant tissue plasminogen activator
• Non-antigenic, Expensive
• Co-prescribed with Heparin
• M/A
• Activates gel phase plasminogen already bound to fibrin and
has little action on circulating plasminogen.
• Rapidly cleared by liver, T1/2 4-8 mins (slow IV infusion)
• S/Es
– Nausea
– Mild hypotension and fever
Reteplase modified rt-PA; long acting form.

25. Aspect of Thrombolytic Therapy: A Review

26. Clinical Uses
• Acute Myocardial Infarction
– First line agents, however, should be given within 3hrs of MI. The first hour in
MI is still called the “Golden Hour”.
[New-Ultrasound enhanced systemic thrombolysis(SonoLysis)]
• Stroke
– Therapy controversial, no decrease in mortality (fatal intracranial bleeding)
– rt-PA is approved for Ischemic stroke, T ½ being 4-8 mins
• Deep Vein Thrombosis
– Upto 60% success, DVT in leg, pelvis, and shoulder
[New technique-Catheter directed thrombolysis for DVT]
• Pulmonary Embolism
– Lung function may be preserved, but mortality is not reduced.
• Peripheral artery occlusion
– Recanalize arteries if therapy started within 72 hrs.

28. Pharmacological Basis
• Thrombolytic drugs are used to dissolve blood clots or the
thrombi.
• Blood clots can occur in any vascular bed; however, when
they occur in coronary, cerebral or pulmonary vessels,
they tend to be immediately life-threatening –
– coronary thrombi are the cause of myocardial infarctions,
– cerebrovascular thrombi produce strokes, and
– pulmonary thromboemboli can lead to respiratory and cardiac
failure.
• Therefore, it is important to rapidly diagnose and treat
blood clots.

29. Adverse Effects
Bleeding complications
• The bleeding is often noted at a catheterization site.
• Gastrointestinal and cerebral hemorrhages may
occur.
Allergic reactions
• More with streptokinase (bacterial origin)
Hypotension
Seen more with Streptokinase

30. Re-thrombosis
• Re-thrombosis can occur following thrombolysis,
and therefore anticoagulants such as heparin are
usually co-administered, and continued after
thrombolytic therapy for a period of time.
• Re-thrombosis, following re-perfusion occurs
roughly inverse proportion to the length of plasma
T ½ of drugs, and therefore is highest with rt-PA
and lowest with Streptokinase and Urokinase.

31. Contraindications
• Thrombolytic therapy requires careful patient
selection.
• It is contraindicated in all situations where the risk
of bleeding is increased, such as-
– Recent trauma, surgery, biopsies,
– Hemorrhagic stroke or
– Peptic ulcer,
– Severe hypertension,
– Aneurysms,
– Bleeding disorders,
– Acute pancreatitis, etc.

32. Aspect of Thrombolytic
Therapy: A Review

33. www.medipuzzle.com
Trusted by
10K + Students

34. That’s All
ENJOY
34