Lecture Notes on Thrombolytics/Fibrinolytics (Streptokinase, Urokinase & Alteplase)

Overview of the Topics
Thrombolytic Drugs 

Thrombolytic Drugs 

Thrombolytic/Fibrinolytic agents lyse the formed clots (thrombi) by catalyzing the activation of endogenous fibrinolytic protein (Plasminogen to Active Plasmin). The clinically important thrombolytics include streptokinase, urokinase, and other recombinant forms (Alteplase, Reteplase & Tenecteplase)

Indication for Thrombolytics
Used intravenously for short-term emergency management of 
- Acute Myocardial Infarction & recanalization of the thrombosed artery
- Deep vein thrombosis
- Pulmonary embolism
- Stroke 

Mechanism of action
- serve as plasminogen activators
- the first generation thrombolytics such as streptokinase (from bacteria- beta-hemolytic Streptococcus) acts on both bound and free plasminogen
- Second generation thrombolytics such as Alteplase (tPA) mainly act on the fibrin bound plasminogen, resulting in fibrinolysis 
- Third-generation agents (Retavase & Tenecteplase)  have improved fibrin specificity & pharmacokinetics


 

Toxicity
- Bleeding due to fibrinogenolysis or fibrinolysis at the site of vascular injury
- Intracranial bleeding can be life-threatening, and thrombolytic therapy should be stopped

Contraindications 
- Active bleeding
- Intracranial trauma
- Vascular disease 
- Uncontrolled Hypertension

Streptokinase

- Protein derived from beta-hemolytic streptococcus that activates plasminogen 
- Streptokinase binds to plasminogen, resulting in conformation change, and exposure of an active site, and activation of additional plasminogen
- Non-selective fibrinogenolysis and fibrinolysis
- Half-life: faster (11-23 minutes)- drug distribution, slower (23-29 minutes)- loss of enzyme activity
- Complications include hemorrhage, pyrexia, or anaphylactic reactions
- Preexisting streptokinase induced antibodies
 

Urokinase

- Derived from human cells 
two polypeptide chain serine protease that does not bind  avidly to fibrin
- directly activates both circulating and fibrin bound plasminogen
- Half-life 10 to 20 minutes

Alteplase (tissue-type plasminogen activator, t-PA)

- Recombinant t-PA, consisting of two polypeptide chain
- t-PA is a principal physiological activator of plasminogen in the blood
- has a high affinity for fibrin and produces fibrin selective activation of plasminogen


Reteplase

- better pharmacological properties than alteplase
- contains only peptide chan domain required for fibrin binding and activity 
- greater potency and activity 


Tenecteplase

- Better half life than alteplase and reteplase
- may be administerd as an  IV bolus