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.

• 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.

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.

• 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.

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