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598 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

namic instability, severe deep venous thrombosis such as the superior vena caval syndrome, and ascending thrombophle- bitis of the iliofemoral vein with severe lower extremity ede- ma. These drugs are also given intra-arterially, especially for peripheral vascular disease. Thrombolytic therapy in the management of acute myo-

cardial infarction requires careful patient selection, the use of

a specific thrombolytic agent, and the benefit of adjuvant

therapy. Streptokinase is administered by intravenous infu- sion of a loading dose of 250,000 units, followed by 100,000 units/h for 24–72 hours. Patients with antistreptococcal anti- bodies 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 injec-

tions of 10 units each, separated by 30 minutes. Tenecteplase is given as a single intravenous bolus of 0.5 mg/kg. Anistre- plase (where available) is given as a single intravenous injec- tion of 30 units over 3–5 minutes. A single course of fibrinolytic drugs is expensive: hundreds of dollars for strep- tokinase and thousands for urokinase and t-PA. Recombinant t-PA has also been approved for use in acute ischemic stroke within 3 hours of symptom onset. In patients without hemorrhagic infarct or other contraindications, this therapy has been demonstrated to provide better out- comes in several randomized clinical trials. The recom- mended dose is 0.9 mg/kg, not to exceed 90 mg, with 10% given as a bolus and the remainder during a 1 hour infu- sion. 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.

BASIC PHARMACOLOGY OF ANTIPLATELET AGENTS

Platelet function is regulated by three categories of substances. The first group consists of agents generated outside the platelet that interact with platelet membrane receptors, eg, catechol- amines, collagen, thrombin, and prostacyclin. The second cate- gory contains agents generated within the platelet that interact with membrane receptors, eg, ADP, prostaglandin D 2 , prosta- glandin E 2 , and serotonin. The third group comprises agents generated within the platelet that act within the platelet, eg, prostaglandin endoperoxides and thromboxane A 2 , the cyclic nucleotides cAMP and cGMP, and calcium ion. From this list of agents, several targets for platelet inhibitory drugs have been identified (Figure 34–1): inhibition of prostaglandin synthesis (aspirin), inhibition of ADP-induced platelet aggregation (clo- pidogrel, ticlopidine), and blockade of glycoprotein IIb/IIIa re- ceptors on platelets (abciximab, tirofiban, and eptifibatide). Dipyridamole and cilostazol are additional antiplatelet drugs.

ASPIRIN

The prostaglandin thromboxane A 2 is an arachidonate prod- uct that causes platelets to change shape, release their gran- ules, and aggregate (see Chapter 18). Drugs that antagonize this pathway interfere with platelet aggregation in vitro and prolong the bleeding time in vivo. Aspirin is the prototype of this class of drugs. As described in Chapter 18, aspirin inhibits the synthesis of thromboxane A 2 by irreversible acetylation of the enzyme cyclooxygenase. Other salicylates and nonsteroidal anti-inflam- matory drugs also inhibit cyclooxygenase but have a shorter duration of inhibitory action because they cannot acetylate cyclooxygenase; that is, their action is reversible. The FDA has approved the use of 325 mg/d for primary prophylaxis of myocardial infarction but urges caution in this

use of aspirin by the general population except when pre- scribed as an adjunct to risk factor management by smoking cessation and lowering of blood cholesterol and blood pres- sure. Meta-analysis of many published trials of aspirin and other antiplatelet agents confirms the value of this interven- tion in the secondary prevention of vascular events among patients with a history of vascular events.

CLOPIDOGREL & TICLOPIDINE

Clopidogrel and ticlopidine reduce platelet aggregation by in- hibiting the ADP pathway of platelets. These drugs are thienopy- ridine derivatives that achieve their antiplatelet effects by irreversibly blocking the ADP receptor on platelets. Unlike as- pirin, these drugs have no effect on prostaglandin metabolism. Randomized clinical trials with both drugs report efficacy in the prevention of vascular events among patients with tran- sient ischemic attacks, completed strokes, and unstable angina pectoris. Use of clopidogrel or ticlopidine to prevent throm- bosis is now considered standard practice in patients under- going placement of a coronary stent. Adverse effects of ticlopidine include nausea, dyspepsia, and diarrhea in up to 20% of patients, hemorrhage in 5%, and, most seriously, leukopenia in 1%. The leukopenia is detected by regular monitoring of the white blood cell count during the first 3 months of treatment. Development of thrombotic thrombocytopenic purpura has also been associated with the ingestion of ticlopidine. The dosage of ticlopidine is 250 mg twice daily. It is particularly useful in patients who cannot tol- erate aspirin. Doses of ticlopidine less than 500 mg/d may be efficacious with fewer adverse effects. Clopidogrel has fewer adverse effects than ticlopidine and is rarely associated with neutropenia. Thrombotic thrombocyto-

penic purpura associated with clopidogrel has been reported. Because of its superior side effect profile and dosing require- ments, clopidogrel is preferred over ticlopidine. The antithrom- botic effects of clopidogrel are dose-dependent; within 5 hours after an oral loading dose of 300 mg, 80% of platelet activity will be inhibited. The maintenance dose of clopidogrel is 75 mg/d, which achieves maximum platelet inhibition. The duration of the antiplatelet effect is 7–10 days.

Aspirin & Clopidogrel Resistance

The reported incidence of resistance to these drugs varies greatly, from less than 5% to 75%. In part this tremendous variation in incidence reflects the definition of resistance (recurrent thrombosis while on antiplatelet therapy vs in vitro testing), methods by which drug response is mea- sured, and patient compliance. Several methods for testing aspirin and clopidogrel resistance in vitro are now FDA- approved; however, their utility outside of clinical trials re- mains controversial.

BLOCKADE OF PLATELET GLYCOPROTEIN IIB/IIIA RECEPTORS

The glycoprotein IIb/IIIa inhibitors are used in patients with acute coronary syndromes. These drugs target the platelet IIb/ IIIa receptor complex (Figure 34–1). The IIb/IIIa complex functions as a receptor mainly for fibrinogen and vitronectin but also for fibronectin and von Willebrand factor. Activation of this receptor complex is the “final common pathway” for platelet aggregation. There are approximately 50,000 copies of this complex on the surface of each platelet. Persons lacking

CHAPTER 34 Drugs Used in Disorders of Coagulation

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this receptor have a bleeding disorder called Glanzmann’s thrombasthenia. Abciximab, a chimeric monoclonal antibody directed against the IIb/IIIa complex including the vitronectin recep- tor, was the first agent approved in this class of drugs. It has been approved for use in percutaneous coronary intervention and in acute coronary syndromes. Eptifibatide is an analog of the sequence at the extreme carboxyl terminal of the delta chain of fibrinogen, which mediates the binding of fibrinogen to the receptor. Tirofiban is a smaller molecule with similar properties. Eptifibatide and tirofiban inhibit ligand binding to the IIb/IIIa receptor by their occupancy of the receptor but do not block the vitronectin receptor. The three agents described above are administered parenter- ally. Oral formulations of IIb/IIIa antagonists are in various stages of development.

ADDITIONAL ANTIPLATELET- DIRECTED DRUGS

Dipyridamole is a vasodilator that inhibits platelet function by inhibiting adenosine uptake and cGMP phosphodiesterase activ- ity. Dipyridamole by itself has little or no beneficial effect. There- fore, therapeutic use of this agent is primarily in combination with aspirin to prevent cerebrovascular ischemia. It may also be used in combination with warfarin for primary prophylaxis of thromboemboli in patients with prosthetic heart valves. A com- bination of dipyridamole complexed with 25 mg of aspirin is now available for secondary prophylaxis of cerebrovascular disease. Cilostazol is a newer phosphodiesterase inhibitor that pro- motes vasodilation and inhibition of platelet aggregation. Cil- ostazol is used primarily to treat intermittent claudication.

CLINICAL PHARMACOLOGY OF DRUGS USED TO PREVENT CLOTTING

VENOUS THROMBOSIS

Risk Factors

A. Inherited Disorders

The inherited disorders characterized by a tendency to form thrombi (thrombophilia) derive from either quantitative or qualitative abnormalities of the natural anticoagulant system. Deficiencies (loss of function mutations) in the natural antico- agulants antithrombin, protein C, and protein S account for ap- proximately 15% of selected patients with juvenile or recurrent thrombosis and 5–10% of unselected cases of acute venous thrombosis. Additional causes of thrombophilia include gain of function mutations such as the factor V Leiden mutation and the prothrombin 20210 mutation, elevated clotting factor and cofactor levels, and hyperhomocysteinemia that together ac-

count for the greater number of hypercoagulable patients. Al- though the loss of function mutations is less common, they are associated with the greatest thrombosis risk. Some patients have multiple inherited risk factors or combinations of inherited and acquired risk factors as discussed below. These individuals are at higher risk for recurrent thrombotic events and are often considered candidates for lifelong therapy.

B. Acquired Disease

The increased risk of thromboembolism associated with atrial fibrillation and with the placement of mechanical heart valves has long been recognized. Similarly, prolonged bed rest, high- risk surgical procedures, and the presence of cancer are clearly associated with an increased incidence of deep venous throm- bosis and embolism. Antiphospholipid antibody syndrome is another important acquired risk factor. Drugs may function as