Pharmacology of Thrombolytic Drugs

Thrombolytic drugs are used to initiate thrombolysis – the destruction of blood clots. With this mechanism, thrombolytic drugs are used in conditions such as stroke, heart attack and pulmonary embolism to eliminate blood clots and restore normal blood flow.

Thrombolytic drugs are also known as fibrinolytic drugs.

Regardless of their name, the medicines are used to eliminate clot formations within blood vessels.

For this reason, they are used to treat:

  • Acute ischemic stroke
  • ST-elevation myocardial infarction
  • Massive pulmonary embolism

The purpose of treatment is to eliminate the clot and restore normal blood flow.

For acute ischemic stroke, thrombolytic therapy is most effective when administered within the first few hours of the stroke. Benefits of treatment decline with time.

For acute ST-elevation myocardial infarction, thrombolytic drugs may be used though they have largely been superseded by other therapeutic means – such as percutaneous coronary intervention (PCI).

Nonetheless, thrombolytic drugs can reduce mortality and so their use can be considered under defined circumstances.

Examples of thrombolytic drugs include:

  • Alteplase
  • Reteplase
  • Tenecteplase
  • Streptokinase

Streptokinase is an exceptional case – it is used only once, not for repeat dosing. That’s because antibodies within the body can develop to combat its effects.

Mechanism of action

The purpose of thrombolytic drugs is to reduce clot size and formation.

They achieve this by catalysing conversion of plasminogen to plasmin. Plasmin acts to dissolve blood clots and restore normal blood flow to the affected infarcted – or blood-deprived – part of the body.

Circulating plasminogen (PLG), from the liver into the systemic circulation, adopts a closed position. Once plasminogen binds to a clot, it adopts an open form that is readily converted into plasmin; the serine protease that degrades and destroys blood clots.

Plasminogen is converted to plasmin by:

  • Tissue plasminogen activator (tPA)
  • Kallikrein
  • Factor XII (Hageman factor)
  • Urokinase plasminogen activator (uPA)

tPA can now be manufactured using recombinant means – what’s known as recombinant tissue plasminogen activator (rTPA).

Examples of rTPAs include the exact medicines we discuss here –  namely, alteplase, reteplase and tenecteplase.

Side effects

Side effects with thrombolytic drugs include:

  • Bleeding
  • Hypotension
  • Nausea
  • Vomiting
  • Bruising at injection sites

Serious bleeding may occur, though it is rare. If it occurs, an antifibrinolytic drug such as tranexamic acid – may be used to limit bleeding.

Serious side effects include allergic reactions, cardiogenic shock and cardiac arrest.

Clinical considerations

When we talk about the clinical pharmacology of thrombolytic drugs, we need to think about the following factors:

  • That aminocaproic acid may be used as an antidote for tPA toxicity.
  • That heparin is routinely administered with thrombolytic drugs for the first 24-48 hours (except streptokinase).
  • That the risk of bleeding increases when patients are taking anticoagulant or antiplatelet medicines.
  • That the risk of bleeding also increases if patients consume / have consumed alcohol.
  • That thrombolytic drugs are linked to many, specific contraindications. Many of these contraindications relate to bleeding risks. For example – thrombolysis should not be commenced in patients who have recently undergone surgery, or who have recently experienced hemorrhage. Similarly, intracranial bleeding must be ruled out – via CT scan, for example – before thrombolysis is used in stroke patients.
  • That streptokinase use is limited. It is avoided for multiple dosing due to the risk of allergy / development of antibodies that render redundant its thrombolytic powers.

Thrombolytic therapy carries serious risks and should, then, only be initiated by experienced clinical personnel.

The likely benefits of thrombolysis decrease with time and, where these drugs are used, close monitoring is required – particularly for the first few hours.

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