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>

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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>

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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%