Fibrinolytic Drugs

FIBRINOLYTIC DRUGS


FIBRINOLYTIC DRUGS

  • Also referred as “thrombolytics”.
  • Are drugs activating plasminogen to form plasmin & helping thrombus lysis.

MOA:

  • Insoluble fibrin molecules are broken down to soluble fragments by plasmin.
    • Plasmin is generated from plasminogen, by tissue plasminogen activator (tPA).
    • tPA selectively activates fibrin-bound plasminogen in thrombus.
  • Excess plasmin generated is inactivated by circulating antiplasmins.

Adverse effect:

  • Bleeding (major) – Due to lysis of physiological thrombi & excessive circulating plasmin.

Indication:

  • Treatment of acute myocardial infarction (Stemi)
    • Administered i.v. within 12 hours preferably within 1st 3-6 hours.          
  • In severe, life-threatening pulmonary embolism (Massive Pulmonary Embolism in Shock).

Contra-indications:

  • Mainly increased bleeding risk.
  • Based on various scenarios of bleeding risks divided into, absolute & relative.

Absolute

Relative

Absolute of hemorrhagic stroke at any time

Current use of anticoagulants (INR≥ 2)

History  of non-hemorrhagic stroke within the past year

Recent  (>2weeks) invasive or surgical procedure

Marked hypertension (systolic >180 and/or diastolic > 110mm Hg)

Prolonged (> 10 min.) cardiopulmonary resuscitation.

Suspicion of aortic dissection

Known bleeding diathesis

Active internal bleeding (excluding menses)

Pregnancy

 

Hemorrhagic ophthalmic condition (Eg. hemorrhagic diabetic retinopathy)

 

Active peptic ulcer disease

 

History  of severe hypertension (currently adequately controlled)

Fibrinolytic overdose:

  • Specific antidote: Epsilon amino caproic acid (EACA) & tranexaemic acid.

Important drugs:

  • Streptokinase, anistreplase urokinase, alteplase, reteplase & tenecteplase.
  • Streptokinase, anistreplase & urokinase – 
    • Activate bound fibrin as well as circulating plasminogen
    • Leads to systemic lytic state.
  • Reteplase, alteplase & tenecteplase – Fibrin-specific.

1. Streptokinase:

  • Obtained from β-hemolytic streptococci.
  • Activates fibrin-bound as well as circulating plasminogen.
MOA:
  • Does not directly convert plasminogen to plasmin (unlike other plasminogen activators).
  • Forms complex with plasminogen, exposing its active site.
  • Altered plasminogen acts like tPA & activates other plasminogen molecules to plasmin.
Properties:
  • Antigenic causing allergic reactions.
    • Lead to neutralizing antibody formation.
  • Less effective on repeated usage.
  • Least expensive.

2. Anistreplase:

  • Formed by combining streptokinase with Lys-plasminogen.
  • Active site of exposed plasminogen is masked with anisoyl group.
  • Non-specific for fibrin-bound plasminogen.
Properties:
  • Drug administration:
    • Via a single bolus infusion.
  • Half-life: 
    • 100 minutes.
    • Due to slow removal of anisoyl group by deacylation, on i.v. infusion.
  • Antigenic.

3. Urokinase:

  • Isolated from human urine.
  • MOA: 
    • Directly converts plasminogen to plasmin.
    • Affects both free & circulating plasmin.
    • Induces systemic lytic state.
  • Use: Used for catheter-directed lysis of thrombi in deep veins or peripheral arteries.
  • Property:
    • Not antigenic.
    • Limited availability.

4. Recombinant tPA:

  • Alteplase, reteplase & tenecteplase.
  • Non-antigenic.
  • More efficacious than streptokinase.
  • Cause hemorrhage (similar to streptokinase & urokinase).
  • Longest acting tPA:
    • Reteplase & tenecteplase.
    • Referred as “bolus fibrinolytic”.
    • Because administration does not require prolonged intravenous infusion.

Exam Important

FIBRINOLYTIC DRUGS

  • Fibrinolytic drugs are also referred as “thrombolytics”.
  • Fibrinolytic drugs are drugs activating plasminogen to form plasmin & helping thrombus lysis.
  • Plasmin is generated from plasminogen, by tissue plasminogen activator (tPA).
  • tPA selectively activates fibrin-bound plasminogen in thrombus.
  • Bleeding is the major adverse effect of fibrinolytic, mainly due to lysis of physiological thrombi & excessive circulating plasmin.
  • Fibrinolytic drugs are indicated for treatment of acute myocardial infarction (Stemi) – Administered i.v. within 12 hours preferably within 1st 3-6 hours.
  • Absolute contraindications for fibrinolytic drugs include, 
    • History of non-hemorrhagic stroke within the past year/at any time, 
    • Marked hypertension (systolic >180 and/or diastolic > 110mm Hg),
    • Active internal bleeding (excluding menses).
  • Relative contraindications for fibrinolytic drugs include, 
    • Current use of anticoagulants (INR≥ 2),
    • Recent  (>2weeks) invasive or surgical procedure,
    • Prolonged (> 10 min.) cardiopulmonary resuscitation,
    • Known bleeding diathesis,
    • Pregnancy,
    • Hemorrhagic diabetic retinopathy,
    • Active peptic ulcer disease,
    • History of severe hypertension.
  • Specific antidotes for fibrinolytic drug overdose are Epsilon aminocaproic acid (EACA) & tranexaemic acid.
  • Streptokinase, anistreplase urokinase, alteplase, reteplase & tenecteplase are some of the important fibrinolytic drugs.
  • Streptokinase, anistreplase & urokinase activate bound fibrin as well as circulating plasminogen
  • Reteplase, alteplase & tenecteplase are fibrin-specific drugs.
  • Streptokinase activates fibrin-bound as well as circulating plasminogen.
  • Unlike other plasminogen activators, streptokinase does not directly convert plasminogen to plasmin instead forms complex with plasminogen.
  • Streptokinase is antigenic in nature, causing allergic reactions.
  • Anistreplase is formed by combining streptokinase with Lys-plasminogen.
  • Urokinase directly converts plasminogen to plasmin.
  • Streptokinase & Urokinase are contraindicated in intracranial malignancy.
  • Fibrinolytic drug affecting both free & circulating plasmin is urokinase.
  • Alteplase, reteplase & tenecteplase are recombinant tPA.
  • Recombinant tPA is more efficacious than streptokinase.
  • Reteplase & tenecteplase are longest acting tPA & are referred asbolus fibrinolytic”.
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