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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 thesuperior 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 forperipheral vascular disease.

Thrombolytic therapy in the management of acute myo-

cardial infarction requires careful patient selection, the use ofa specific thrombolytic agent, and the benefit of adjuvanttherapy. Streptokinase is administered by intravenous infu-sion of a loading dose of 250,000 units, followed by 100,000units/h for 2472 hours. Patients with antistreptococcal anti-bodies can develop fever, allergic reactions, and therapeuticresistance. Urokinase requires a loading dose of 300,000 unitsgiven over 10 minutes and a maintenance dose of 300,000units/h for 12 hours. Alteplase (t-PA) is given by intravenousinfusion of 60 mg over the first hour and then 40 mg at a rateof 20 mg/h. Reteplase is given as two intravenous bolus injec-

tions of 10 units each, separated by 30 minutes. Tenecteplaseis 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 35 minutes. A single course offibrinolytic 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 acuteischemic stroke within 3 hours of symptom onset. In patientswithout 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 increasedbleeding risk in acute ischemic stroke when given at a doseof 1.5 million units, and its use is not recommended in thissetting.

BASIC PHARMACOLOGY OF ANTIPLATELET AGENTS

Platelet function is regulated by three categories of substances.The first group consists of agents generated outside the plateletthat interact with platelet membrane receptors, eg, catechol-amines, collagen, thrombin, and prostacyclin. The second cate-gory contains agents generated within the platelet that interactwith membrane receptors, eg, ADP, prostaglandin D2, prosta-glandin E2, and serotonin. The third group comprises agentsgenerated within the platelet that act within the platelet, eg,

prostaglandin endoperoxides and thromboxane A2, the cyclicnucleotides cAMP and cGMP, and calcium ion. From this list ofagents, several targets for platelet inhibitory drugs have beenidentified (Figure 341): 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 A2 is an arachidonate prod-uct that causes platelets to change shape, release their gran-ules, and aggregate (see Chapter 18). Drugs that antagonizethis pathway interfere with platelet aggregation in vitro andprolong the bleeding time in vivo. Aspirin is the prototype ofthis class of drugs.

As described in Chapter 18, aspirin inhibits the synthesis ofthromboxane A2 by irreversible acetylation of the enzymecyclooxygenase. Other salicylates and nonsteroidal anti-inflam-matory drugs also inhibit cyclooxygenase but have a shorterduration of inhibitory action because they cannot acetylatecyclooxygenase; 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 smokingcessation and lowering of blood cholesterol and blood pres-sure. Meta-analysis of many published trials of aspirin andother antiplatelet agents confirms the value of this interven-tion in the secondary prevention of vascular events amongpatients 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 byirreversibly 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 inthe prevention of vascular events among patients with tran-sient ischemic attacks, completed strokes, and unstable anginapectoris. 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 detectedby regular monitoring of the white blood cell count during thefirst 3 months of treatment. Development of thromboticthrombocytopenic purpura has also been associated with theingestion of ticlopidine. The dosage of ticlopidine is 250 mgtwice daily. It is particularly useful in patients who cannot tol-erate aspirin. Doses of ticlopidine less than 500 mg/d may beefficacious with fewer adverse effects.

Clopidogrel has fewer adverse effects than ticlopidine and is

rarely associated with neutropenia. Thrombotic thrombocyto-

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CHAPTER 34 Drugs Used in Disorders of Coagulation 599

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 hoursafter an oral loading dose of 300 mg, 80% of platelet activity willbe inhibited. The maintenance dose of clopidogrel is 75 mg/d,

which achieves maximum platelet inhibition. The duration ofthe antiplatelet effect is 710 days.

Aspirin & Clopidogrel Resistance

The reported incidence of resistance to these drugs variesgreatly, from less than 5% to 75%. In part this tremendousvariation in incidence reflects the definition of resistance(recurrent thrombosis while on antiplatelet therapy vs invitro testing), methods by which drug response is mea-sured, and patient compliance. Several methods for testingaspirin 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 withacute coronary syndromes. These drugs target the platelet IIb/IIIa receptor complex (Figure 341). The IIb/IIIa complexfunctions as a receptor mainly for fibrinogen and vitronectinbut also for fibronectin and von Willebrand factor. Activationof this receptor complex is the final common pathway forplatelet aggregation. There are approximately 50,000 copies ofthis complex on the surface of each platelet. Persons lacking

this receptor have a bleeding disorder called Glanzmannsthrombasthenia.

Abciximab, a chimeric monoclonal antibody directedagainst the IIb/IIIa complex including the vitronectin recep-tor, was the first agent approved in this class of drugs. It hasbeen approved for use in percutaneous coronary intervention

and in acute coronary syndromes. Eptifibatide is an analog ofthe sequence at the extreme carboxyl terminal of the deltachain of fibrinogen, which mediates the binding of fibrinogento the receptor. Tirofiban is a smaller molecule with similarproperties. Eptifibatide and tirofiban inhibit ligand binding tothe IIb/IIIa receptor by their occupancy of the receptor but donot block the vitronectin receptor.

The three agents described above are administered parenter-ally. Oral formulations of IIb/IIIa antagonists are in variousstages of development.

ADDITIONAL ANTIPLATELET-

DIRECTED DRUGS

Dipyridamole is a vasodilator that inhibits platelet function byinhibiting 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 combinationwith aspirin to prevent cerebrovascular ischemia. It may also beused in combination with warfarin for primary prophylaxis ofthromboemboli in patients with prosthetic heart valves. A com-bination of dipyridamole complexed with 25 mg of aspirin is nowavailable 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 FactorsA. Inherited Disorders

The inherited disorders characterized by a tendency to formthrombi (thrombophilia) derive from either quantitative orqualitative 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 recurrentthrombosis and 510% of unselected cases of acute venousthrombosis. Additional causes of thrombophilia include gain offunction mutations such as the factor V Leiden mutation andthe 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 areassociated with the greatest thrombosis risk. Some patients have

multiple inherited risk factors or combinations of inherited andacquired risk factors as discussed below. These individuals areat higher risk for recurrent thrombotic events and are oftenconsidered candidates for lifelong therapy.

B. Acquired Disease

The increased risk of thromboembolism associated with atrialfibrillation and with the placement of mechanical heart valveshas long been recognized. Similarly, prolonged bed rest, high-risk surgical procedures, and the presence of cancer are clearlyassociated with an increased incidence of deep venous throm-bosis and embolism. Antiphospholipid antibody syndrome is

another important acquired risk factor. Drugs may function as