2. OBJECTIVES
īŽ To know mechanism of action of thrombolytic
therapy.
īŽ To differentiate between different types of
thrombolytic drugs.
īŽ To describe Indications, side effects and
contraindications of thrombolytic drugs.
īŽ To recognize the mechanisms, uses and side
effects of antiplasmins.
3. Definition of Thrombolytics
Thrombolytic agents are used to lyse
already formed blood clots in clinical
settings where ischemia may be fatal.
Thrombolytic drugs needs to be given
immediately to the patient after MI ,
delay in administration will be of no
value.
4. thrombolytic therapy
īŽ The goal of thrombolytic therapy is rapid
restoration of flow in an occluded vessel by
accelerating fibrinolytic proteolysis of the
thrombus
īŽ Thrombolytic therapy is one part of an
overall antithrombotic plan that frequently
includes anticoagulants, antiplatelet agents
and mechanical approaches to rapidly
restore flow and prevent reocclusion.
5. Mechanism of Action
of thrombolytic drugs
They have common mechanism of action by
converting the proenzyme (plasminogen) to
active enzyme (plasmin) īŽ lysis of fibrin clot.
Plasmin: is a nonspecific protease capable of
breaking down fibrin as well as other circulating
proteins, including fibrinogen, factor V, and factor VIII.
plasmin, degrades the insoluble fibrin clot matrix into
soluble derivatives
6. Mechanism of Action
of thrombolytic drugs
Plasminogen
Plasmin
Fibrin
Soluble degradation
products
Thrombolytics
Activates
degrades
8. Types of thrombolytic drugs
Non-fibrin specific
Streptokinase
Anistreplase
Urokinase
Remember (USA)
for their names
Fibrin specific
Tissue plasminogen
Activators (t-PA)
īAlteplase
īReteplase
īTenecteplase
Remember (ART)
for their names
9. Types of thrombolytic drugs
Non fibrin-specific agents:
īUrokinase -Streptokinase â Anistreplase â
ībinds equally to circulating and non-circulating
plasminogen.
īproduces breakdown of clot (fibrinolysis) and
circulating fibrinogen (fibrinogenolysis), cause
systemic fibrinolytic state leading to bleeding.
10. Types of thrombolytic drugs
Fibrin-specific agents:
ī are tissue plaminogen activators
ī e.g. Alteplase â Reteplase -Tenecteplase
ī selective in action (clot-specific fibrin)
ī Activity is enhanced upon binding to fibrin.
ībinds preferentially to plasminogen at the fibrin
surface (non-circulating) rather than circulating
plasminogen.
ī risk of bleeding is less than non specific agents
12. Contraindications to Thrombolytics
īActive internal bleeding
īRecent intracranial trauma or neoplasm
īCerebral hemorrhagic stroke
īCerebrovascular disease
īMajor surgery within two weeks
īActive peptic ulcer
īdiabetic retinopathy
īPregnancy
13. Streptokinase (SK)
ī Is a bacterial protein produced by B-hemolytic
streptococci.
ī It acts indirectly by forming plasminogen-
streptokinase complex "activator complex"
which converts other inactive plasminogen into
active plasmin.
īPlasmin degrades fibrin clots as well as
fibrinogen and other plasma proteins (non-fibrin
specific).
14. Streptokinase
īT 1/2 = less than 20 minutes.
īgiven as intravenous infusion (250,000U then
100,000U/h for 24-72 h).
īIt is the least expensive.
ī used for venous or arterial thrombosis
īLife threatening pulmonary embolism.
15. Side effects of streptokinase
ī Bleeding due to activation of circulating
plasminogen (systemic fibrinolysis)
ī Antigenicity and high-titer antibodies develop 1
to 2 weeks after use, retreatment until the titer
declines.
ī Allergic reaction: like rashes, fever, hypotension
ī Prior exposure to the streptokinase or infection
can cause sever allergic reaction.
16. Precautions
Not used in patients with:
īRecent streptococcal infections or pharyngits
īPrevious administration of the drug
īThese patients may develop fever, allergic
reactions and resistance upon treatment with
streptokinase due to antistreptococcal antibodies
17. Anistreplase (APSAC)
īŽ Anisoylated Plasminogen Streptokinase
Activator Complex (APSAC) acylated
plasminogen combined with streptokinase
īŽ It is a prodrug, de-acylated in circulation into
the active plasminogen-streptokinase complex.
īŽ T1/2 is 70-120 min
18. Advantages
īŽ Given as a bolus I.V. injection (30 U over 3 -
5 min.).
īŽ Longer duration of action than SK.
īŽ More thrombolytic activity than SK.
īŽ Greater clot selectivity than SK.
19. Disadvantages
Similar but less than streptokinase alone in:
īą Antigenicity.
īą Allergic reactions.
īą Minimal fibrin specificity
īą Systemic lysis.
But more expensive than SK
20. Urokinase
ī Human enzyme synthesized by the kidney
ī obtained from either urine or cultures of
human embryonic kidney cells.
ī acts directly to convert plasminogen to
active plasmin.
ī Given by intravenous infusion.
ī 300,000U over 10 min then 300,000U/h for
12h.
21. Urokinase
īŽ Has an elimination half-life of 12-20 minutes.
īŽ Used for the lyses of acute massive pulmonary
emboli
Disadvantages
īą Minimal fibrin specificity
īą Systemic lysis (Because it does not discriminate between
fibrin-bound and circulating plasminogen..
īą Expensive (its use is now limited)
Advantages
īŽ No anaphylaxis (not antigenic).
22. Tissue Plasminogen Activators (t - PA)
âĸ All are recombinant tissue plasminogen
activators (t âPA).
âĸ Prepared by recombinant DNA technology.
âĸ Include drugs as
īAlteplase
īReteplase
īTenecteplase
23. Mechanism of t-PA
ī Direct action: They activate fibrin-bound
plasminogen rather than free plasminogen in
blood.
ī Their action is enhanced by the presence of
fibrin.
ī It binds to fibrin in a thrombus and converts the
entrapped plasminogen to plasmin. limited
systemic fibrinolysis.
24. Advantages of t-PA
ī Fibrin-specific drugs (clot specific).
ī Works at the site of thrombus.
ī Limited systemic fibrinolysis.
ī Reduced risk of bleeding
ī T-PA produced by human endothelium so
Not -antigenic (Can be used in patients with
antistreptococcal antibodies).
25. Alteplase
ī is a recombinant form of human tPA.
ī has very short half life (~5 min)
ī is usually administered as an intravenous
bolus followed by an infusion.
ī (60 mg i.v. bolus + 40 mg infusion over 2 h).
26. Reteplase
ī A variant of recombinant tPA
ī It has longer duration than alteplase (15 min.)
ī Has enhanced fibrin specificity
ī Given as two I.V. bolus injections of 10 U each
Uses
ī In ST-elevation myocardial infarction (STEMI);
improvement of ventricular function; reduction of the
incidence of CHF and the reduction of mortality
following AMI.
ī Pulmonary embolism.
27. Tenecteplase (TNK-tPA)
ī Is another genetically modified human t-PA.
ī prepared by recombinant technology
ī It is more fibrin-specific & longer duration than
alteplase.
ī It has half life of more than 30 min.
ī It can be administered as a single IV bolus.
ī It is only approved for use in acute myocardial
infarction.
29. Fibrinolytic Inhibitors
Antiplasmin
īą Aminocaproic Acid & tranexamic cid
īŧ acts by competitive inhibition of plasminogen
activation
īŧ ŲŲŲGiven orally
īą Aprotinin
īŧ It inhibits fibrinolysis by blocking plasmin
īŧ Gien orally or i.v.
30. Uses of Fibrinolytic Inhibitors
īŧ Adjuvant therapy in hemophilia
īŧ Fibrinolytic therapy-induced bleeding (antidote).
īŧ Postsurgical bleeding
īŧThese drugs work like antidotes for
fibrinolytic drugs. Similar to Protamine
(Antidote of heparin) orVit K (Antidote
of Warfarin)
Editor's Notes
extensive systemic plasminogen activation, with degradation of several plasma proteins including fibrinogen, factor V,
and factor VIII.
Active internal bleeding; history of cerebrovascular accident; recent intracranial or intraspinal surgery or trauma; intracranial neoplasm, arteriovenous malformations, or aneurysm; known bleeding diathesis; severe uncontrolled hypertension