FIBRINOLYTICS(THROMBOLYTICS)

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• Plasmin: It is the protease enzyme present in our blood

which brings about lysis of clot or fibrin • Plasminogen: It is the inactive precursor of plasmin On activation it gets converted to active plasmin

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Tissue plasminogen activator:• It is the enzyme in the body which activates & converts

plasminogen to plasmin • It is released when there is stasis of blood

formation of clots in blood t plasminogen activator

Plasminogen Plasmin• α 2 Antiplasmin :

It terminates the action of t PA after dissolution of pathological clots in our blood.

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Drugs Affecting Fibrinolytic System

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• Thrombolytic drugs:• All these drugs are plasminogen activators -

When given in large doses they overcome the action of anti-plasmin and dissolve thrombi

• The fibrin degradation products also inactivate anti-plasmin

• When plasminogen activators are administered for thrombolytic therapy massive fibrinolysis is initiated and the inhibitory controls are overwhelmed

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• Streptokinase:• It is a protein (protease enzyme) produced by ß

hemolytic streptococci• It has no intrinsic enzymatic activity • But forms a stable non-covalent complex with

proactivator plasminogen• This produces a conformational change that

catalyzes the following conversion plasminogen plasmin

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• It has to be given in a loading dose of 250,000 units to overcome plasma antibodies (from prior streptococcal infection)

• ½ life is 40-80 minutes• The streptokinase - plasminogen complex is not

inhibited by α 2 antiplasmin• ADRs: Allergic reactions Fever AnaphylaxisPrior presence of antistreptococcal antibodies may

↓ efficacy. Hence it cannot be repeated before one year of prior strep. Infection.

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• Urokinase:• A protease enzyme isolated from cultured

human kidney cells. It is a direct plasminogen activator.

• ½ life is 15-20 minutes. • It is non antigenic, non pyrogenic, non allergic,

does not produce hypotension. • It is given in a loading dose of 300,000 U over 10

minutes followed by maintenance dose of 300,000 units/hour over 12 hrs

• Used instead of streptokinase and in whom streptokinase cannot be repeated.

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Recombinant tissue plasminogen activator (Alteplase):

• It is manufactured by recombinant DNA technology.

• It is a poor plasminogen activator in the absence of fibrin.

• It preferentially activates bound plasminogen several hundred fold more rapidly than plasminogen in the circulation.

• It is effective in lysing thrombi during ACUTE MYOCARDIAL INFARCTION.

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• Seems superior to streptokinase and urokinase in dissolving old clots.

• As effective as streptokinase but safer (more expensive). Minimal antigenicity.

• It is given as a bolus intravenously• 15 mg followed by 0.75 mg/kg over 30

minutes.

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Anistreplase (APSAC):• It consists of a complex of purified human plasminogen

and bacterial streptokinase that has been acetylated to protect the active site of plasminogen.

• When administered the acyl group spontaneously hydrolyses freeing the activated streptokinase proactivator complex to perform fibrinolysis.

• This allows for rapid IV injection, greater clot selectivity i.e. more active on plasminogen associated with clots than free plasminogen – more thrombolytic activity

• Dose: 30 units as a single intravenous injection given over 3-5 minutes

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Therapeutic uses:• Myocardial infarction• Severe pulmonary embolism• Deep vein thrombosis• Acute peripheral arterial occlusion

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ADRs:• Bleeding - commonest ADR• Less with selective agents – r tPA• Allergic reactions: Streptokinase – bacterial protein antigenic Rarely anaphylactic reactions seen • Hypotension: with rapid administration of streptokinase.• Hemorrhagic stroke

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Absolute contraindications to thrombolytic therapy:

• Prior intracranial hemorrhage• Known structural cerebral vascular lesion• Known malignant intracranial neoplasm• Ischemic stroke within 3 months• Suspected aortic dissection• Active bleeding or bleeding diathesis• Significant head trauma or facial trauma

within 3 months.

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Relative contraindications to thrombolytic therapy:

-Major surgery, traumatic or prolonged CPR within 3 weeks.

-Recent (within 2-4 weeks)internal bleeding-pregnancy - Non compressible vascular punctures- Severe uncontrolled hypertension (SBP > 180

mmHg or DBP> 110mmHg) Active pepetic ulcer Current use of warfarin and INR > 1.7

ANTIFIBRINOLYTIC DRUGS

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Epsilon aminocaproic acid (EACA):• It is chemically similar to the amino acid lysine• It is a synthetic inhibitor of fibrinolysis• It competitively inhibits plasminogen activation • Rapidly absorbed orally• Cleared by the kidneys• Dosage: 6 g four times daily

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Tranexamic acid:• It is an analog of aminocaproic acid and has

the same properties • It is administered orally with a 15mg/kg

loading dose followed by 30 mg/kg every 6 hours

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Uses:1. Adjuvant therapy in hemophilia2. Treatment of bleeding from fibrinolytic

therapy 3. Prophylaxis for re-bleeding from intracranial

aneurysms 4. Post surgical GI bleeding5. Post prostatectomy bleeding6. Bladder hemorrhages secondary to radiation

or drug induced cystitis

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Aprotinin: (Serine protease inhibitor)It is a serine protease inhibitorIt inhibits fibrinolysis by free plasminIt may have other anti-hemorrhagic effects as wellIt ↓ bleeding by 50% from many types of surgery - heart procedures

- liver transplantationIt is currently approved for patients undergoing CABG

who are at high risk of excessive bleedingADRs: Recent studies have shown - ↑ risk of MI, stroke & renal damageAssociation with anaphylaxis also noted - test dose

required

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LOCAL HAEMOSTATICS (STYPTICS)

• These drugs are used to stop bleeding from oozing locations

• eg. tooth sockets, open wounds.• They are meant only for local application • Most of them provide a network of fibrin

which promotes coagulation

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Thrombin:• Obtained from bovine plasma. • Applied topically it is a good haemostaticFibrin sealant:• Obtained from human plasma• Used to stop microbleeding & oozing in dental

procedures Gelatin foams:• Soaked with saline, fibrin or thrombin to cover or pack

bleeding surfaces.Vasoconstrictors: • 1% adrenaline soaked gauze effective haemostatic