Basic Pharmacology of the Fibrinolytic Drugs

BASIC PHARMACOLOGY OF THE FIBRINOLYTIC DRUGS

Fibrinolytic drugs rapidly lyse thrombi by catalyzing the for-mation of the serine protease plasmin from its precursor zymo-gen, plasminogen (Figure 34–3). These drugs create a generalized lytic state when administered intravenously. Thus, both protective hemostatic thrombi and target thromboemboli are broken down. The Box: Thrombolytic Drugs for Acute Myocardial Infarction describes the use of these drugs in one major application.

Pharmacology

Streptokinase is a protein (but not an enzyme in itself ) synthe-sized by streptococci that combines with the proactivator plasmi-nogen. This enzymatic complex catalyzes the conversion of inactive plasminogen to active plasmin. Urokinase is a human enzyme synthesized by the kidney that directly converts plasmi-nogen to active plasmin. Plasmin itself cannot be used because naturally occurring inhibitors in plasma prevent its effects. However, the absence of inhibitors for urokinase and the strepto-kinase-proactivator complex permits their use clinically. Plasmin formed inside a thrombus by these activators is pro-tected from plasma antiplasmins, which allows it to lyse the thrombus from within.Anistreplase (anisoylated plasminogen streptokinase activatorcomplex; APSAC) consists of a complex of purified human plas-minogen and bacterial streptokinase that has been acylated to protect the enzyme’s active site. When administered, the acyl group spontaneously hydrolyzes, freeing the activated streptoki-nase-proactivator complex. This product (now discontinued in the USA) allows for rapid intravenous injection, greater clot selectivity (ie, more activity on plasminogen associated with clots than on free plasminogen in the blood), and more thrombolytic activity.

Plasminogen can also be activated endogenously by tissueplasminogen activators (t-PAs). These activators preferentiallyactivate plasminogen that is bound to fibrin, which (in theory) confines fibrinolysis to the formed thrombus and avoids systemic activation. Human t-PA is manufactured as alteplase by means of recombinant DNA technology. Reteplase is another recombinant human t-PA from which several amino acid sequences have been deleted. Reteplase is less expensive to produce than t-PA. Because it lacks the major fibrin-binding domain, reteplase is less fibrin-specific than t-PA. Tenecteplase is a mutant form of t-PA that has a longer half-life, and it can be given as an intravenous bolus. Tenecteplase is slightly more fibrin-specific than t-PA.

Indications & Dosage

Administration of fibrinolytic drugs by the intravenous route is indicated in cases of pulmonary embolism with hemodynamicinstability, severe deep venous thrombosis such as the superiorvena caval syndrome, and ascending thrombophlebitis of the iliofemoral vein with severe lower extremity edema. These drugs are also given intra-arterially, especially for peripheral vascular disease.

Thrombolytic therapy in the management of acute myocar-dial infarction requires careful patient selection, the use of aspecific thrombolytic agent, and the benefit of adjuvant therapy. Streptokinase is administered by intravenous infusion of a load-ing dose of 250,000 units, followed by 100,000 units/h for 24–72 hours. Patients with antistreptococcal antibodies can develop fever, allergic reactions, and therapeutic resistance. Urokinase requires a loading dose of 300,000 units given over 10 minutes and a maintenance dose of 300,000 units/h for 12 hours. Alteplase (t-PA) is given by intravenous infusion of 60 mg over the first hour and then 40 mg at a rate of 20 mg/h. Reteplase is given as two intravenous bolus injections of 10 units each, sepa-rated by 30 minutes. Tenecteplase is given as a single intravenous bolus of 0.5 mg/kg. Anistreplase (where available) is given as a single intravenous injection of 30 units over 3–5 minutes. A sin-gle course of fibrinolytic drugs is expensive: hundreds of dollars for streptokinase and thousands for urokinase and t-PA.

Recombinant t-PA has also been approved for use in acute isch-emic stroke within 3 hours of symptom onset. In patients without hemorrhagic infarct or other contraindications, this therapy has been demonstrated to provide better outcomes in several random-ized clinical trials. The recommended dose is 0.9 mg/kg, not to exceed 90 mg, with 10% given as a bolus and the remainder during a 1 hour infusion. Streptokinase has been associated with increased bleeding risk in acute ischemic stroke when given at a dose of 1.5 million units, and its use is not recommended in this setting.