Thrombolytic Medications

Sanjaya Mani Dixit

Assistant Prof of Pharmacology
 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
 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.
Thromboembolic Disorders
 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.
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/
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.
Darwinism and Risk of
Cardiovascular Disease
 Blood Clotting
1. Vascular Phase
2. Platelet Phase
3. Coagulation Phase
4. Fibrinolytic Phase
Thrombosis Vs Fibrinolysis
 Drugs used to reduce clotting

Drug Class Prototype Action Effect

1. Anticoagulant Heparin Inactivation of clotting Prevent DVT

Parenteral
factors

Oral Warfarin Decrease synthesis of Prevent DVT

clotting factors

2. Antiplatelet Aspirin Decrease platelet Prevent arterial

aggregation thrombosis

3. Thrombolytic Streptokinase Fibrinolysis Breakdown of

thrombi
 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)
 Thrombus
According to location & composition
Arterial (White)
• Occur in areas of rapid Venous (Red)
flow (arteries) • Occur primarily in the venous
• In response to an circulation
injured or abnormal • In response to venous stasis
vessel wall
• Composed: or vascular injury
primarily of platelets, • Composed
also fibrin & occasional almost entirely of fibrin &
leukocytes erythrocytes (Red)
• Associated with • Associated with
MI Congestive Heart Failure,
Stroke Cancer
ischemia Surgery
 Fibrinolysis
• Enhance degradation of clots
• Activation of endogenous protease
• Plasminogen (inactive form) is converted to
Plasmin (active form)
• Plasmin breaks down fibrin clots
 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.
 Thrombolytic System
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.
Thrombolytics/
Fibrinolytics
• Streptokinase
• Urokinase
• Alteplase (rt-PA)
• Reteplase
• Tenecteplase
 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)
 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.
 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.
 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)
 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.

Aspect of Thrombolytic Therapy: A Review
 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.
 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.
 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
 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.
 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.
Aspect of Thrombolytic
Therapy: A Review
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