Anticoagulant, Antiplatelet, and Fibrinolytic Drugs

Anticoagulant, Antiplatelet, and Fibrinolytic Drugs

Blood Coagulation

Normal Hemostasis

When a small blood vessel is injured, hemorrhage is prevented by vasospasm, the formation of a platelet plug and a fibrin clot (Fig. 16-1). After the vessel is repaired, the clot is removed via the process of fibrinolysis.

Vasospasm reduces bleeding and blood flow and thereby facilitates platelet aggregation and blood coagulation. Exposure of the blood to extravascular collagen causes adherence of platelets to the injured vessel wall and initiates the sequential activation (cascade) of numerous coagulation factors (blood clotting factors), most of which are serine proteases. In this cascade, the inactive factors are converted to active enzymes by the previous coagulation factor or stimulus. The factors and their synonyms are listed in Table 16-1, and the coagulation pathways are illustrated in Figure 16-2. The intrinsic pathway may be activated by surface contact with a foreign body or extravascular tissue, whereas the extrinsic pathway is activated by a complex tissue factor called thromboplastin. The pathways converge with the activation of factor X, which is the major rate-limiting step in the coagulation cascade. The activation of factor X leads to the formation of thrombin, and thrombin, in turn, catalyzes the conversion of fibrinogen to fibrin. Thrombin is also a powerful stimulant of platelet aggregation. The fibrin meshwork traps erythrocytes and platelets to complete the formation of a hemostatic thrombus (clot).

Pathologic Thrombus Formation

The processes leading to thrombosis and embolism are complex and not completely understood.

Atherosclerosis and other abnormalities affecting the vascular endothelium can serve as stimuli for platelet aggregation and blood coagulation in arteries. Venous pooling, sluggish blood flow, and inflammation of veins may permit inappropriate platelet adhesion and coagulation in vessels. Platelet aggregation appears to have a larger role in the formation of arterial thrombi (white thrombi), whereas coagulation predominates in the formation of venous thrombi (red thrombi). Platelet aggregation followed by coagulation, however, occurs both in arteries and in veins, and the processes differ only in the degree of contribution by platelets or coagulation to the thrombus.

An arterial or venous thrombus can become dislodged from the vessel wall and form an embolus that travels through the circulation and eventually occludes a smaller vessel in the lungs or brain, thereby causing pulmonary embolism or a cerebrovascular occlusion (stroke), respectively.

Anticoagulant Drugs

Anticoagulants are drugs that impede blood coagulation and prevent the occurrence or expansion of a thrombus. The anticoagulants are classified according to their mechanism of action and include vitamin K antagonists, drugs that potentiate antithrombin III, and drugs that directly inhibit thrombin or active factor X. Table 16-2 compares the properties of various anticoagulant drugs.


Chemistry and Mechanisms

Coumarin compounds such as warfarin were originally identified as the substances in spoiled clover hay that caused hemorrhagic disease in cattle. These compounds were subsequently developed as anticoagulants and rodenticides.

Warfarin and other coumarin derivatives are structurally related to vitamin K. These drugs inhibit the synthesis of coagulation factors II (prothrombin), VII, IX, and X, whose carboxylation is dependent on a reduced form of vitamin K. As shown in Figure 16-3, warfarin blocks the reduction of oxidized vitamin K and thereby prevents the posttranslational (following protein synthesis) carboxylation of these four factors. Warfarin also inhibits the synthesis of proteins C and S, which are endogenous anticoagulants that inactivate factors V and VIII and promote fibrinolysis. It is possible that the inhibition of proteins C and S contributes to a transient procoagulant effect when warfarin is first administered.

Pharmacokinetic and Pharmacologic Effects

Warfarin is well absorbed from the gut and extensively metabolized before being excreted in the urine. Unlike heparin and related anticoagulants, warfarin crosses the placenta and can cause fetal hemorrhage.

Warfarin has a delayed onset of action owing to the time required to deplete the pool of circulating clotting factors after synthesis of new factors is inhibited. The half-life of circulating vitamin K–dependent clotting factors ranges from 6 hours (factor VII) to 50 hours (factor II). Therefore the maximal effect of warfarin is not observed until 3 to 5 days after therapy is started. Patients with acute thromboembolic disorders can be initially treated with a low-molecular-weight heparin (LMWH) plus warfarin, and the LMWH is then withdrawn after warfarin becomes effective. A period of several days is also required for coagulation factor levels to return to normal after warfarin has been discontinued. The recovery of clotting factors can be accelerated by administration of phytonadione (vitamin K1), as described later.

Adverse Effects and Interactions

The most common adverse effect of warfarin is bleeding (Table 16-3), which can range in severity from mild nosebleed to life-threatening hemorrhage. Patients should be instructed to report any signs of bleeding, including hematuria and bleeding into the skin (ecchymoses).

TABLE 16-3

Adverse Effects and Drug Interactions of Anticoagulant, Antiplatelet, and Fibrinolytic Drugs

Warfarin Birth defects and bleeding Serum levels altered by drugs that induce or inhibit cytochrome P450, by drugs that inhibit gut absorption, and by drugs that directly increase or decrease the anticoagulant effect.
Rivaroxaban Bleeding Serum levels increased by cytochrome P450 3A4 inhibitors and by drugs that inhibit P-glycoprotein (Pgp) drug transport.
Dalteparin, enoxaparin Bleeding and thrombocytopenia Risk of bleeding increased by salicylates.
Heparin Bleeding, hyperkalemia, and thrombocytopenia Same as dalteparin.
Hirudin and related drugs Bleeding Same as dalteparin.
Antiplatelet Drugs    
Abciximab Bleeding, bradycardia, hypotension, and thrombocytopenia Unknown.
Aspirin Gastrointestinal irritation and bleeding, hypersensitivity reactions, and tinnitus Increases hypoglycemic effect of sulfonylureas. Increases risk of gastrointestinal bleeding and ulceration associated with methotrexate, valproate, and other drugs. Inhibits uricosuric effect of probenecid.
Dipyridamole Gastrointestinal distress, headache, mild and transient dizziness, and rash Decreases metabolism of adenosine. Increases risk of bradycardia associated with β-adrenergic receptor antagonists.
Clopidogrel Bleeding, diarrhea, gastrointestinal pain, increased cholesterol and triglyceride levels, nausea, and neutropenia Increases levels of drugs metabolized by liver microsomal enzymes.
Fibrinolytic Drugs    
Streptokinase* Bleeding, hypersensitivity reactions, and reperfusion arrhythmias Increases risk of bleeding associated with anticoagulant and antiplatelet drugs.

*Also alteplase, urokinase, anistreplase, reteplase, and tenecteplase.

Warfarin is contraindicated in pregnancy because of its potential to cause fetal hemorrhage and various structural malformations referred to as the fetal warfarin syndrome. These malformations are partly a result of antagonism of vitamin K–dependent maturation of bone proteins during a process in which these proteins are carboxylated in the same manner as the nascent clotting factors. Warfarin and other vitamin K antagonists block this process and can cause bone deformities and various birth defects that are listed in Table 4-6.

Warfarin interacts with many drugs that either induce or inhibit cytochrome P450 (CYP) enzymes, but a few of its interactions result from antagonism or potentiation of its anticoagulant effect. The most serious interactions are with drugs that increase the anticoagulant effect and place the patient at risk of hemorrhage. Because the number of drugs that interact with warfarin is large, patients who are taking this drug should be instructed to consult a health care provider before starting or discontinuing any other medication.

High doses of salicylates and some third-generation cephalosporins directly reduce prothrombin levels and thereby increase the anticoagulant effect of warfarin. In contrast, treatment with rifampin or barbiturates induces CYP enzymes that metabolize warfarin and decreases its anticoagulant effect. Cholestyramine inhibits the absorption of warfarin from the gut. Amiodarone, cimetidine, erythromycin, fluconazole, gemfibrozil, isoniazid, metronidazole, sulfinpyrazone, and other drugs inhibit the metabolism of warfarin and increase the risk of bleeding. The prothrombin time (PT) should be monitored when adding or discontinuing drugs that interact with warfarin.

Phytonadione (vitamin K1) directly antagonizes the effect of warfarin on clotting factor synthesis and is used to treat hemorrhage caused by anticoagulant activity.


Warfarin has been primarily used in the long-term treatment of patients who have a thromboembolic disorder such as deep vein thrombosis (DVT) and patients who have atrial fibrillation or an artificial heart valve (Table 16-4). It has also been used with a heparin-type anticoagulant for the treatment of MI. The goals of warfarin therapy are to prevent thrombus formation or expansion and to prevent embolization and other potentially fatal consequences of thrombosis.

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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Anticoagulant, Antiplatelet, and Fibrinolytic Drugs

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