Thrombolytic agents myocardial infarction

In situations where inappropriate clot formation results in the blockage of a blood vessel, the tissue damage that ensues depends, to a point, upon how long the clot blocks blood flow. Rapid removal of the clot can often minimize the severity of tissue damage. Thus, several thrombolytic (clot-degrading) agents have found medical application (Table 12.5). The market for an effective thrombolytic agent is substantial. In the USA alone, it is estimated that 1.5 million people suffer acute myocardial infarction each year, and there are another 0.5 million suffer strokes. 

Alteplase has proven effective in the early treatment of patients with acute myocardial infarction (i.e. those treated within 12 h after the first symptoms occur). Significantly increased rates of patient survival (as measured 1 day and 30 days after the initial event) are noted when tPA is administered in favour of streptokinase, a standard therapy (see later). tPA has thus established itself as a first-line option in the management of acute myocardial infarction. A therapeutic dose of 90-100 mg (often administered by infusion over 90 min) results in a steady-state alteplase concentration of 3-4 mg l 1 during that period. However, the product is cleared rapidly by the liver, displaying a serum half-life of approximately 3 min. As is the case for most thrombolytic agents, the most significant risk associated with tPA administration is the possible induction of severe haemorrhage. 

Collen, D. (1998). Staphylokinase a potent, uniquely fibrin-selective thrombolytic agent. Nature Med. 4(3), 279-284. Collins, R. et al. (1997). Drug therapy—aspirin, heparin and fibrinolytic therapy in suspected acute myocardial infarction. N. Engl. J. Med. 336(12), 847-860. 

Arterial thrombi (white thrombi) are formed initially from both platelets and fibrin in medium-sized arteries on the basis of atherosclerosis. These thrombi can lead to symptoms of, among others, myocardial ischemia and myocardial infarction. The treatment is primarily aimed at prevention of thrombus formation with platelet aggregation inhibitors. For the treatment of myocardial infarction thrombolytic agents are used and for secondary prevention both oral anticoagulants and anti-platelet drugs are employed. 

Plasminogen, an inactive precursor, is activated to plasmin which as a protease is able to break down fibrin clots. The thrombolytic agents in use promote the conversion of plasminogen to plasmin at the site of a thrombus. Indications include post-myocardial infarction treatment. The thrombolytic must be administered within 6 hours for an optimal effect. Other indications are treatment of acute pulmonary thromboembolism, deep-vein thrombosis, acute arterial thrombosis and thromboembolism, as well as in the clearance of arteriovenous catheters and can-nulae. Agents are streptokinase, anistreplase, urokinase, alteplase, reteplase and tenecteplase. 

E. Therapeutic response Activase, and other thrombolytic agents, used in a timely manner during an evolving myocardial infarction, decrease mortality and improve left ventricular function. Resolution of chest pain, resolution of baseline EKG changes, reduced total creatine phospho-kinase (CPK) release, and preserved left ventricular function are evidence of cardiac reperfusion. Activase, administered within the first 3 hours of ischemic stroke onset, has been shown to improve recovery. 

E Role in therapy Thrombolytic agents currently licensed for the treatment of AMI in the United States include streptokinase, tissue plasminogen activator, anistreplase, reteplase, and tenecteplase. TNKase and alteplase have similar clinical efficacy for thrombolysis after myocardial infarction (i.e., similar mortality and intracranial hemorrhage rates). However, advantages of TNKase include ease and rapidity of administration, longer half-life, greater fibrin specificity, and lower noncerebral bleeding rates. Reteplase shares some characteristics of tenecteplase (e.g., similar half-life, rapid onset, and ease of administration). 

Figure 4.6 PET pictures of the heart of a patient with acute myocardial infarction treated with a thrombolytic agent. Top row shows scans after administration of water containing lsO to trace blood flow. Bottom row shows tomograms obtained after administration of acetate containing nC to trace the heart s metabolism, that is, its rate of oxygen use. The defects tire clearly visible on day 1, both in the impaired blood flow (top left) and the impaired metabolic use of oxygen (bottom left). Recovery of blood circulation has taken place on day 2 and is maintained. (Figure also appears in color figure section.)...

All patients with acute myocardial infarction should be considered for intravenous thrombolytic therapy with streptokinase, tissue plasminogen activator (TPA), or anistreplase because these agents are effective in both preserving cardiac function and reducing mortality. 

Patients with acute myocardial infarction are best treated with emergency revascularization with either coronary angioplasty and a stent or a thrombolytic agent. Even with revascularization, acute failure may develop in such patients. Many of the signs and symptoms of acute and chronic failure... 

Thrombolytic therapy in the management of acute myocardial infarction requires careful patient selection, the use of a specific thrombolytic agent, and the benefit of adjuvant therapy. Considerable controversy surrounds the question of greater safety or efficacy of t-PA compared with the other thrombolytic agents (see Thrombolytic Drugs for Acute Myocardial Infarction). 

These agents have been tested in various conditions where platelet activation plays a major role, in particular in patients undergoing percutaneous coronary intervention (PCI), patients admitted with ACS, and patients receiving thrombolytic therapy for acute myocardial infarction (Ml) (Fig. 2). 

The cost of fibrinolytic agents is considerable streptokinase costs about US 100, and rt-PA and its mutants about US 2000, However, these agents have different early (90 minutes) recanalization rates over 50% for front-loaded tissue rt-PA versus only 30% to 35% for streptokinase. Since early patency is correlated with early survival (12), the initial cost of the thrombolytic drug alone is not important. Patients who present early with a large myocardial infarction benefit more from a drug with a high early patency rate than patients presenting late with a small myocardial infarction. 

Platelet aggregation inhibitors decrease the formation or the action of chemical signals that promote platelet aggregation. These agents have proven beneficial in the prevention and treatment of occlusive cardiovascular diseases, the maintenance of vascular grafts and arterial patency, and as adjuncts to thrombolytic therapy in myocardial infarction. 

Administration For myocardial infarction, intracoronary delivery of the drugs is the most reliable in terms of achieving recanalization. However, cardiac catheterization may not be possible in the 2 to 6 hour therapeutic window, beyond which significant myocardial salvage becomes less likely. Thus thrombolytic agents are usually administered intravenously, since this route is rapid, inexpensive, and does not have the risks of catheterization. 

The combination of thrombolytic agents with an anticoagulant and/or aspirin has been said to be life-threatening. An excess of major bleeding episodes with combined subcutaneous heparin and streptokinase or alteplase treatments (1.0% with heparin versus 0.5% without heparin) has been reported in the International Study Group Trial (103) in patients with suspected acute myocardial infarction. 

Monoclonal antibodies to GPlIb/IIIa receptors are effective inhibitors of platelet function. Animal studies suggest that they may reduce both the dose, and the delay in onset of thrombolytic effect with streptokinase and similar agents when they are used in treating the sequelae of myocardial infarction. Early trials in humans suggest that these agents will be valuable for some specialist applications. 

Mauri F, Maggioni AP, Franzosi MG et al. A simple electrocardiographic predictor of the outcome of patients with acute myocardial infarction treated with a thrombolytic agent. A Gruppo Italiano per lo Studio della Soprawivenza nell lnfarto Miocardico (GISSI-2)-derived analysis. J Am Coll Cardiol 1994 24 600. 

Boden WE, van Gilst WH, Scheldewaert RG, et al. Diltiazem in acute myocardial infarction treated with thrombolytic agents A randomised, placebo-controlled trial. Incomplete Infarction Trial of European Research Collaborators Evaluating Prognosis post-Thrombolysis (INTERCEPT). Lancet 2000 355 1751-1756. 

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