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FIBRINOLYTIC DRUGS VIJAYA LECHIMI RAJ. Learning Outcomes. On completing this lecture, you should be able to: Classify the fibrinolytic drugs Discuss the mechanism of action of fibrinolytic drugs e.g streptokinase, alteplase Discuss briefly the pharmacology of streptokinase and alteplase - PowerPoint PPT Presentation
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FIBRINOLYTIC DRUGS
VIJAYA LECHIMI RAJ
On completing this lecture, you should be able to:
Classify the fibrinolytic drugsDiscuss the mechanism of action of
fibrinolytic drugs e.g streptokinase, alteplaseDiscuss briefly the pharmacology of
streptokinase and alteplaseContents:Classification of fibrinolytic drugsPharmacology of streptokinase and alteplase
Acute thromboembolic disease maybe treated by administration of agents that activate the conversion of plasminogen to plasmin
Plasmin is a serine protease that hydrolyses fibrin and thus dissolves clots
Streptokinase – first to be approvedCauses systemic fibrinolytic state that can lead
to bleeding problemsAlteplase – acts more locally on the thrombotic
fibrin to produce fibrinolysis <fig>Nearly equal efficacy between streptokinase and
alteplaseThrombolytic therapy is unsuccessful in 20% of
infarcted arteries and 15% will close again laterIn MI:
When angioplasty is not an optionUntil pt can be taken to facility that performs
percutaneous coronary interventionsMay lyse both normal and pathologic
thrombi<next>
<back>
1. Mechanism of action: All act directly or indirectly to convert
plasminogen to plasmin cleaves fibrin lyses thrombi
Clot dissolution and reperfusion occur with higher frequency when therapy is initiated early after clot formation
Clots become more resistant to lysis as they age
Increased local thrombi may occur as clot dissolves
Enhanced platelet aggregability and thrombosis Strategy:
Include administration of antiplatelet drugs (aspirin) or antithrombotics (heparin)
2. Therapeutic uses: Originally for deep vein thrombosis (DVT),
serious pulmonary embolism - Now less frequently
Tendency to cause bleeding has blunted their use in acute MI or peripheral arterial thrombosis
Helpful in restoring catheter and shunt function By lysing clots that cause occlusions
Also used to dissolve clots that result in strokes3. Pharmacokinetics: Usually administered IV Rapid Inexpensive Does not have risks of catheterization
4. Adverse effects: Do not distinguish between fibrin of
unwanted thrombus and of a beneficial hemostatic plug
Hemorrhage is a major side effect E.g. a peptic ulcer may hemorrhage after
injection of a thrombolytic agent<diag>
C/I in pts with healing wounds, pregnancy, history of cerebrovascular accident, metastatic cancer
presence of thrombogenic stimuli may cause rethrombosis after lysis of the initial clot<next>
<back><cont>
Formerly known as tissue plasminogen activator (tPA)Is a serine protease originally derived from human melanoma
cellsNow – product of recombinant DNA technologyMechanism of action:Low affinity for free plasminogen but rapidly activates
plasminogen bound to fibrin in a thrombus or hemostatic plugFibrin selective and at low doses lyses only fibrinContrasts with streptokinase
Acts on free plasminogen Induces a general fibrinolytic state
2. Therapeutic uses: Approved for treatment of myocardial infarction,
massive pulmonary embolism and acute ischemic stroke
Superior to streptokinase in dissolving older clots Administered within 3 hours of onset of ischemic
stroke can significantly improve clinical outcome
3. Pharmacokinetics: Very short half-life – about 5 mins Usually 10% of total dose is injected IV as a bolus
and remaining drug is administered over 60 minutes
4. Adverse effects Bleeding complications including GI and cerebral
hemorrhages may occur
An extracellular protein purified from culture broths of Group C β-hemolytic streptococci
1.Mechanism of action:No enzymic activityForms an active one-to-one complex with
plasminogenConverts uncomplexed plasminogen to the active
enzyme plasmin
In addition to the hydrolysis of fibrin plugs, the complex also catalyses the degradation of fibrinogen as well as clotting Factors V and VII
2. Therapeutic uses: Acute pulmonary embolism, deep vein
thrombosis, acute myocardial infarction, arterial thrombosis and occluded access shunt
3. Pharmacokinetics: Is instituted within 4 hours of a MI and is
infused for 1 hour Half-life is less than half an hour Thromboplastin time is monitored and
maintained at 2-5 fold the control value On discontinuation of treatment, either
heparin or oral anticoagulants may be administered
4. Adverse effects:a) Bleeding disorders Activation of circulating plasminogen
leads to elevated levels of plasmin May precipitated bleeding by
dissolving hemostatic plugs<fig> In the rare instance of life-threatening
hemorrhage, aminocaproic acid may be administered
4. Adverse effects:
b) Hypersensitivity
Streptokinase is a foreign protein and is
antigenic
Rashes, fever and rarely, anaphylaxis occur
Circulating antibodies against streptokinase
are likely to be present in most patients
These antibodies can combine with streptokinase and neutralize its fibrinolytic properties
Sufficient quantities must be administered to overwhelm the antibodies and provide a therapeutic concentration of plasmin
Fever, allergic reaction and therapeutic failure may be associated with the presence of antistreptococcal antibodies
Incidence of allergic reactions – 3%