Page 633 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 34 Drugs Used in Disorders of Coagulation 619

Thrombolytic Drugs For Acute Myocardial Infarction

The paradigm shift in 1980 on the causation of acute myo- of a stent, thrombolytic therapy is still very important where
cardial infarction to acute coronary occlusion by a thrombus PCI is not readily available.
created the rationale for thrombolytic therapy of this com- The proper selection of patients for thrombolytic therapy
mon lethal disease. At that time—and for the first time— is critical. The diagnosis of acute myocardial infarction is made
intravenous thrombolytic therapy for acute myocardial clinically and is confirmed by electrocardiography. Patients with
infarction in the European Cooperative Study Group trial ST-segment elevation and bundle branch block on electrocardi-
was found to reduce mortality. Later studies, with thousands ography have the best outcomes. All trials to date show the great-
of patients in each trial, provided enough statistical power est benefit for thrombolytic therapy when it is given early, within
for the 20% reduction in mortality to be considered statisti- 6 hours after symptomatic onset of acute myocardial infarction.
cally significant. Although the standard of care in areas with Thrombolytic drugs reduce the mortality of acute myocardial
adequate facilities and experience in percutaneous coronary infarction. The early and appropriate use of any thrombolytic drug
intervention (PCI) now favors catheterization and placement probably transcends possible advantages of a particular drug.

effects. However, the absence of inhibitors for urokinase and the Tenecteplase is given as a single intravenous bolus ranging from
streptokinase-proactivator complex permits their use clinically. 30 to 50 mg depending on body weight. Recombinant t-PA has
Plasmin formed inside a thrombus by these activators is protected also been approved for use in acute ischemic stroke within 3 hours
from plasma antiplasmins; this allows it to lyse the thrombus from of symptom onset. In patients without hemorrhagic infarct or
within. other contraindications, this therapy has been demonstrated to
Plasminogen can also be activated endogenously by tissue provide better outcomes in several randomized clinical trials. The
plasminogen activators (t-PAs). These activators preferentially recommended dose is 0.9 mg/kg, not to exceed 90 mg, with 10%
activate plasminogen that is bound to fibrin, which (in theory) given as a bolus and the remainder during a 1-hour infusion.
confines fibrinolysis to the formed thrombus and avoids sys- Streptokinase has been associated with increased bleeding risk in
temic activation. Recombinant human t-PA is manufactured acute ischemic stroke when given at a dose of 1.5 million units,
as alteplase. Reteplase is another recombinant human t-PA and its use is not recommended in this setting.
from which several amino acid sequences have been deleted.
Tenecteplase is a mutant form of t-PA that has a longer half-
life, and it can be given as an intravenous bolus. Reteplase and ■ BASIC PHARMACOLOGY OF
tenecteplase are as effective as alteplase and have simpler dosing ANTIPLATELET AGENTS
schemes because of their longer half-lives.
Platelet function is regulated by three categories of substances. The
Indications & Dosage first group consists of agents generated outside the platelet that
interact with platelet membrane receptors, eg, catecholamines,
Administration of fibrinolytic drugs by the intravenous route is collagen, thrombin, and prostacyclin. The second category con-
indicated in cases of pulmonary embolism with hemodynamic tains agents generated within the platelet that interact with mem-
instability, severe deep venous thrombosis such as the superior brane receptors, eg, ADP, prostaglandin D , prostaglandin E ,
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vena caval syndrome, and ascending thrombophlebitis of the and serotonin. A third group comprises agents generated within
iliofemoral vein with severe lower extremity edema. These drugs are the platelet that act within the platelet, eg, prostaglandin endo-
also given intra-arterially, especially for peripheral vascular disease. , the cyclic nucleotides cAMP and
Thrombolytic therapy in the management of acute myocardial peroxides and thromboxane A 2
cGMP, and calcium ion. From this list of agents, several targets
infarction requires careful patient selection, the use of a specific for platelet inhibitory drugs have been identified (Figure 34–1):
thrombolytic agent, and the benefit of adjuvant therapy. Strepto- inhibition of prostaglandin synthesis (aspirin), inhibition of ADP-
kinase is administered by intravenous infusion of a loading dose induced platelet aggregation (clopidogrel, prasugrel, ticlopidine),
of 250,000 units, followed by 100,000 units/h for 24–72 hours. and blockade of glycoprotein IIb/IIIa (GP IIb/IIIa) receptors on
Patients with antistreptococcal antibodies can develop fever, platelets (abciximab, tirofiban, and eptifibatide). Dipyridamole
allergic reactions, and therapeutic resistance. Urokinase requires and cilostazol are additional antiplatelet drugs.
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 as a 15-mg bolus followed by 0.75 mg/kg (up to ASPIRIN
50 mg) over 30 minutes and then 0.5 mg/kg (up to 35 mg) over
60 minutes. Reteplase is given as two 10-unit bolus injections, The prostaglandin thromboxane A is an arachidonate product
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the second administered 30 minutes after the first injection. that causes platelets to change shape, release their granules, and