In haemostasis pharmacology we have antiplatelet drugs, anticoagulant drugs, and fibrinolytic drugs. Aren’t they similar? What are the differences? It’s easy to become somewhat confused with the terminology – not least because all three classes are involved, to some extent or another, in the prevention or treatment of thromboembolism, and myocardial infarctions etc. Before we turn to the pharmacology of fibrinolytic drugs, let’s first discuss what each of these three classes of drug aim to achieve:
- Antiplatelet drugs decrease platelet aggregation; decreasing thrombus formation. They are effective in the arterial circulation.
- Anticoagulant drugs prevent the coagulation, or clotting, of blood. Anticoagulants have little effect in the arterial circulation.
- Fibrinolytic drugs, also known as thrombolytic drugs, are drugs that promote the dissolution of blood clots.
Fibrinolytic drugs, then, are useful when the patient has suffered a heart attack where a thrombus blocks a coronary artery. Dissolving the thrombus restores blood supply to the heart, while arresting the death of cardiac cells. Fibrinolytic drugs are also effective in the treatment of thromboembolic strokes, but are contraindicated in patients with haemorrhagic strokes (itself a complication of thrombolytic therapy). These drugs are also used in the treatment of deep vein thrombosis and pulmonary embolism.
Pharmacology of Fibrinolytic Drugs
The mechanism of action of fibrinolytic drugs is simple, as all fibrinolytic drugs work by activating the enzyme plasminogen – an enzyme that breaks down the fibrin formation of blood clots. The fibrin formation acts as the backbone of the clot, its dissolution helping to usher in other enzymes to break the clot down even further. Fibrinolytic drugs reduce the size of the blood clot, whereas anticoagulant drugs (eg. Heparin) prevent its growth.
For this reason, fibrinolytic drugs (except streptokinase) are commonly administered with anticoagulant drugs – such as heparin – in the short term, boosting the therapeutic effect. The fibrinolytic drugs we study here are either derived from Streptococcus species, or they are recombinant versions of tissue plasminogen activator (t-PA). These include:
Alteplase is a genetically engineered version of t-PA – a drug that binds to fibrinogen and fibrin. Reteplase is a deletion-modified version of t-PA, a drug which binds less to fibrinogen and fibrin than alteplase, but has a longer duration of action. Tenecteplase is also an engineered version of t-PA, this time with greater fibrin specificity and less sensitivity to inhibitors of plasminogen activators. It, too, has a longer duration of action than natural t-PA.
Streptokinase is secreted by several species of haemolytic streptococci. Streptokinase is, unlike the recombinant versions of t-PA, inactive until it binds to circulating plasminogen – a complex that causes greater plasminogen activation. The effectiveness of any of these thrombolytic drugs is dependent on several factors – such as the size of the clot and how long the clot has existed (younger clots are most susceptible to thrombolytic therapy).
Pharmacokinetics and Unwanted Effects
The pharmacology of fibrinolytics is quite simple – as thrombolytic therapy is centred around, in some form or other, the activation of plasminogen. But how do fibrinolytic drugs fare in terms of pharmacokinetics and unwanted effects? Let’s find out:
- All fibrinolytic drugs are administered intravenously.
- Alteplase and related compounds are metabolised in the liver.
- The streptokinase-plasminogen complex is broken down by enzymes in the circulation.
- Due to the presence of antibodies, the effectiveness of streptokinase declines with subsequent doses (for several years).
- Due to the time taken to complex with plasminogen, streptokinase has a slower onset of action than alteplase (and related compounds).
- Due to the short duration of action of alteplase, it is commonly administered with heparin (for at least 48 hours) to reduce the risk of reocclusion.
Unwanted effects with fibrinolytic drugs include haemorrhage, hypotension, and allergic reactions. Intracerebral haemorrhage, though rare, occurs in about 1 percent of patients (more common in patients taking alteplase as opposed to streptokinase). Hypotension is more common with streptokinase (and is dose related). Due to their bacterial origin, allergic reactions can occur with streptokinase but these are, admittedly, quite rare. Thrombolytic therapy should not be given to patients with haemorrhagic stroke.
Excessive blood loss – such as through injury or trauma – may need to be halted with antifibrinolytic drugs, medicines that promote the bleeding cessation process. Examples of antifibrinolytic drugs include:
- Tranexamic acid
- Aminocaproic acid
Tranexamic acid competitively inhibits the activation of plasminogen – inhibiting fibrinolysis. The drug is completely absorbed from the gut, though it can also be administered intravenously. Tranexamic acid is excreted unchanged by the kidney and has a short half-life of between 1 and 2 hours. Unwanted effects include headache, back ache, nasal sinus difficulties, diarrhoea, fatigue, nausea, and anaemia.
Desmopressin increases the plasma concentration of clotting factor VIII and von Willebrand factor. Factor VIII is responsible for fibrin formation, whereas von Willebrand factor promotes platelet adhesion onto subendothelial tissue. Unwanted effects with desmopressin include headache, facial flushing, nausea, hyponatremia, and seizures. It has a biological half-life of 1.5-2.5 hours and is primarily eliminated via the renal route.
Aminocaproic acid is a derivative of the amino acid lysine, making it an effective inhibitor for enzymes relying on this amino acid residue – enzymes that include plasmin. It is used in the treatment of postoperative bleeding, and can be administered via the oral or intravenous route – and has a half-life of around 2 hours. Unwanted effects with aminocaproic acid include nausea, headache, muscle pain, stuffy nose, watery eyes, vision problems, and mild skin rash.
That’s about it for the pharmacology of fibrinolytic drugs. Test your knowledge of everything covered in this summary here – ten questions covering just about everything you need to know.