Chapter 34: Drugs Used in Coagulation Disorders

A. Classification

Anticoagulants inhibit the formation of fibrin clots. Three major types of anticoagulants are available: heparin and related products, which must be used parenterally; direct thrombin and factor X inhibitors, which are used parenterally or orally; and the orally active coumarin derivatives (eg, warfarin). Comparative properties of the heparins and warfarin are shown in Table 34–1.

B. Heparin

1. Chemistry

Heparin is a large sulfated polysaccharide polymer obtained from animal sources. Each batch contains molecules of varying size, with an average molecular weight of 15,000–20,000. Heparin is highly acidic and can be neutralized by basic molecules (eg, protamine). Heparin is given intravenously or subcutaneously to avoid the risk of hematoma associated with intramuscular injection.

Low-molecular-weight (LMW) fractions of heparin (eg, enoxaparin) have molecular weights of 2000–6000. LMW heparins have greater bioavailability and longer durations of action than unfractionated heparin; thus, doses can be given less frequently (eg, once or twice a day). They are given subcutaneously. Fondaparinux is a small synthetic drug that contains the biologically active pentasaccharide present in unfractionated and LMW heparins. It is administered subcutaneously once daily.

2. Mechanism and effects

Unfractionated heparin binds to endogenous antithrombin III (ATIII) via a key pentasaccharide sequence. The heparin–ATIII complex combines with and irreversibly inactivates thrombin and several other factors, particularly factor Xa (Figure 34–1). In the presence of heparin, ATIII proteolyzes thrombin and factor Xa approximately 1000-fold faster than in its absence. Because it acts on preformed blood components, heparin provides anticoagulation immediately after administration. The action of heparin is monitored with the activated partial thromboplastin time (aPTT) laboratory test.

LMW heparins and fondaparinux, like unfractionated heparin, bind ATIII. These complexes have the same inhibitory effect on factor Xa as the unfractionated heparin–ATIII complex. However, the short-chain heparin–ATIII and fondaparinux–ATIII complexes provide a more selective action because they fail to affect thrombin. The aPTT test does not reliably measure the anticoagulant effect of the LMW heparins and fondaparinux; this is a potential problem, especially in renal failure, in which their clearance may be decreased.

3. Clinical use

Because of its rapid effect, heparin is used when anticoagulation is needed immediately (eg, when starting therapy). Common uses include treatment of DVT, pulmonary embolism, and acute myocardial infarction. Heparin is used in combination with thrombolytics for revascularization and in combination with glycoprotein IIb/IIIa inhibitors during angioplasty and placement of coronary stents. Because it does not cross the placental barrier, heparin is the drug of choice when an anticoagulant must be used in pregnancy. LMW heparins and fondaparinux have similar clinical applications.

4. Toxicity

Increased bleeding is the most common adverse effect of heparin and related molecules; the bleeding may result in hemorrhagic stroke. Protamine can lessen the risk of serious bleeding that can result from excessive unfractionated heparin. Protamine only partially reverses the effects of LMW heparins and does not affect the action of fondaparinux. Unfractionated heparin causes moderate transient thrombocytopenia in many patients and severe thrombocytopenia and thrombosis (heparin-induced thrombocytopenia or HIT) in a small percentage of patients who produce an antibody that binds to a complex of heparin and platelet factor 4. LMW heparins and fondaparinux are less likely to cause this immune-mediated thrombocytopenia. Prolonged use of unfractionated heparin is associated with osteoporosis.

C. Direct Thrombin Inhibitors

1. Chemistry and pharmacokinetics

Direct thrombin inhibitors are based on proteins made by Hirudo medicinalis, the medicinal leech. Lepirudin is the recombinant form of the leech protein hirudin, while desirudin and bivalirudin are modified forms of hirudin. Argatroban is a small molecule with a short half-life. All 4 drugs are administered parenterally. Dabigatran is an orally active direct thrombin inhibitor.

2. Mechanism and effects

The protein analogs of lepirudin bind simultaneously to the active site of thrombin and to thrombin substrates. Argatroban binds solely to the thrombin-active site. Unlike the heparins, these drugs inhibit both soluble thrombin and the thrombin enmeshed within developing clots. Bivalirudin also inhibits platelet activation.

3. Clinical use

Direct thrombin inhibitors are used as alternatives to heparin primarily in patients with heparin-induced thrombocytopenia. Bivalirudin also is used in combination with aspirin during percutaneous coronary angioplasty. Like unfractionated heparin, the action of these drugs is monitored with the aPTT laboratory test. Advantages of oral direct thrombin inhibitors include predictable pharmacokinetics, which allows for fixed dosing, as well as a predictable immediate anticoagulant response that makes routine monitoring or overlap with other anticoagulants unnecessary. In addition, these agents do not interact with P450-interacting drugs. Dabigatran is approved for prevention of stroke and systemic embolism in nonvalvular atrial fibrillation.

4. Toxicity

Like other anticoagulants, the direct thrombin inhibitors can cause bleeding. No reversal agents exist. Prolonged infusion of lepirudin can induce antibodies that form a complex with lepirudin and prolong its action, and it can induce anaphylactic reactions. Lepirudin production was discontinued in 2012.

D. Direct Oral Factor Xa inhibitors

1. Chemistry and pharmacokinetics

Oral Xa inhibitors, including the small molecules rivaroxaban, apixaban, and edoxaban, have a rapid onset of action and shorter half-lives than warfarin. These drugs are given as fixed oral doses and do not require monitoring. They undergo cytochrome P450-dependent and cytochrome P450-independent elimination.

2. Mechanism and effects

These small molecules directly bind to and inhibit both free factor Xa and factor Xa bound in the clotting complex.

3. Clinical use

Rivaroxaban is approved for prevention and treatment of venous thromboembolism following hip or knee surgery and for prevention of stroke in patients with atrial fibrillation, without valvular heart disease. Apixaban is approved for prevention of embolic stroke in patients with nonvalvular atrial fibrillation.

4. Toxicity

Like other anticoagulants, the factor Xa inhibitors can cause bleeding. No reversal agents exist.

E. Warfarin and Other Coumarin Anticoagulants

1. Chemistry and pharmacokinetics

Warfarin and other coumarin anticoagulants are small, lipid-soluble molecules that are readily absorbed after oral administration. Warfarin is highly bound to plasma proteins (>99%), and its elimination depends on metabolism by cytochrome P450 enzymes.

2. Mechanism and effects

Warfarin and other coumarins interfere with the normal post-translational modification of clotting factors in the liver, a process that depends on an adequate supply of reduced vitamin K. The drugs inhibit vitamin K epoxide reductase (VKOR), which normally converts vitamin K epoxide to reduced vitamin K. The vitamin K-dependent factors include thrombin and factors VII, IX, and X (Figure 34–1). Because the clotting factors have half-lives of 8–60 h in the plasma, an anticoagulant effect is observed only after sufficient time has passed for elimination of the normal preformed factors. The action of warfarin can be reversed with vitamin K, but recovery requires the synthesis of new normal clotting factors and is, therefore, slow (6–24 h). More rapid reversal can be achieved by transfusion with fresh or frozen plasma that contains normal clotting factors. The effect of warfarin is monitored by the prothrombin time (PT) test.

3. Clinical use

Warfarin is used for chronic anticoagulation in all of the clinical situations described previously for heparin, except in pregnant women.

4. Toxicity

Bleeding is the most important adverse effect of warfarin. Early in therapy, a period of hypercoagulability with subsequent dermal vascular necrosis can occur. This is due to deficiency of protein C, an endogenous vitamin K-dependent anticoagulant with a short half-life. Warfarin can cause bone defects and hemorrhage in the developing fetus and, therefore, is contraindicated in pregnancy.

Because warfarin has a narrow therapeutic window, its involvement in drug interactions is of major concern. Cytochrome P450-inducing drugs (eg, carbamazepine, phenytoin, rifampin, barbiturates) increase warfarin’s clearance and reduce the anticoagulant effect of a given dose. Cytochrome P450 inhibitors (eg, amiodarone, selective serotonin reuptake inhibitors, cimetidine) reduce warfarin’s clearance and increase the anticoagulant effect of a given dose. Genetic variability in cytochrome P450 2C9 and VKOR affect responses to warfarin. Algorithms to determine initial warfarin dose based on cytochrome P450 2C9 and VKOR, age, body size, and concomitant medications are being tested.

Patients with chronic atrial fibrillation routinely receive warfarin to prevent the formation of blood clots in the poorly contracting atrium and to decrease the risk of embolism of such clots to the brain or other tissues (See Chapters 13 and 14). Such patients are also often treated with antiarrhythmic drugs. The primary goals of antiarrhythmic treatment are to slow the atrial rate and, most importantly, control the ventricular rate.

1. Which antiarrhythmic drugs are most appropriate for treating chronic atrial fibrillation?

2. Do any of these drugs have significant interactions with warfarin?

The Skill Keeper Answers appear at the end of the chapter.

A. Classification and Prototypes

The thrombolytic drugs used most commonly are either forms of the endogenous tissue plasminogen activator (t-PA; eg, alteplase, tenecteplase, and reteplase) or a protein synthesized by streptococci (streptokinase). All are given intravenously.

B. Mechanism of Action

Plasmin is an endogenous fibrinolytic enzyme that degrades clots by splitting fibrin into fragments (Figure 34–2). The thrombolytic enzymes catalyze the conversion of the inactive precursor, plasminogen, to plasmin.

1. Tissue plasminogen activator

t-PA is an enzyme that directly converts plasminogen to plasmin (Figure 34–2). It has little activity unless it is bound to fibrin, which, in theory, should make it selective for the plasminogen that has already bound to fibrin (ie, in a clot) and should result in less danger of widespread production of plasmin and spontaneous bleeding. In fact, t-PA’s selectivity appears to be quite limited. Alteplase is normal human plasminogen activator. Reteplase is a mutated form of human t-PA with similar effects but a slightly faster onset of action and longer duration of action. Tenecteplase is another mutated form of t-PA with a longer half-life.

2. Streptokinase

Streptokinase is obtained from bacterial cultures. Although not itself an enzyme, streptokinase forms a complex with endogenous plasminogen; the plasminogen in this complex undergoes a conformational change that allows it to rapidly convert free plasminogen into plasmin. Unlike the forms of t-PA, streptokinase does not show selectivity for fibrin-bound plasminogen.

C. Clinical Use

The major application of the thrombolytic agents is as an alternative to percutaneous coronary angioplasty in the emergency treatment of coronary artery thrombosis. Under ideal conditions (ie, treatment within 6 h), these agents can promptly recanalize the occluded coronary vessel. Very prompt use (ie, within 3 h of the first symptoms) of t-PA in patients with ischemic stroke is associated with a significantly better clinical outcome. Cerebral hemorrhage must be positively ruled out before such use. The thrombolytic agents are also used in cases of severe pulmonary embolism.

D. Toxicity

Bleeding is the most important hazard and has about the same frequency with all the thrombolytic drugs. Cerebral hemorrhage is the most serious manifestation. Streptokinase, a bacterial protein, can evoke the production of antibodies that cause it to lose its effectiveness or induce severe allergic reactions on subsequent therapy. Patients who have had streptococcal infections may have preformed antibodies to the drug. Because they are human proteins, the recombinant forms of t-PA are not subject to this problem. However, they are much more expensive than streptokinase and not much more effective.

Platelet aggregation contributes to the clotting process (Figure 34–3) and is especially important in clots that form in the arterial circulation. Platelets appear to play a central role in pathologic coronary and cerebral artery occlusion. Platelet aggregation is triggered by a variety of endogenous mediators that include the prostaglandin thromboxane, adenosine diphosphate (ADP), thrombin, and fibrin. Substances that increase intracellular cyclic adenosine monophosphate (cAMP; eg, the prostaglandin prostacyclin, adenosine) inhibit platelet aggregation.

A. Classification and Prototypes

Antiplatelet drugs include aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), glycoprotein IIb/IIIa receptor inhibitors (abciximab, tirofiban, and eptifibatide), antagonists of ADP receptors (clopidogrel, prasugrel, and ticlopidine), and inhibitors of phosphodiesterase 3 (dipyridamole and cilostazol).

B. Mechanism of Action

Aspirin and other NSAIDs inhibit thromboxane synthesis by blocking the enzyme cyclooxygenase (COX; Chapter 18). Thromboxane A₂ is a potent stimulator of platelet aggregation. Aspirin, an irreversible COX inhibitor, is particularly effective. Because platelets lack the machinery for synthesis of new protein, inhibition by aspirin persists for several days until new platelets are formed. Other NSAIDs, which cause a less persistent antiplatelet effect (hours), are not used as antiplatelet drugs and, in fact, can interfere with the antiplatelet effect of aspirin when used in combination with aspirin.

Abciximab is a monoclonal antibody that reversibly inhibits the binding of fibrin and other ligands to the platelet glycoprotein IIb/IIIa receptor, a cell surface protein involved in platelet cross-linking. Eptifibatide and tirofiban also reversibly block the glycoprotein IIb/IIIa receptor.

Clopidogrel, prasugrel, and the older drug ticlopidine are converted in the liver to active metabolites that irreversibly inhibit the platelet ADP receptor and thereby prevent ADP-mediated platelet aggregation. Ticagrelor is a newer drug that does not require activation and reversibly inhibits the platelet ADP receptor.

Dipyridamole and the newer cilostazol appear to have a dual mechanism of action. They prolong the platelet-inhibiting action of intracellular cAMP by inhibiting phosphodiesterase enzymes that degrade cyclic nucleotides, including cAMP, an inhibitor of platelet aggregation, and cyclic guanosine monophosphate (cGMP), a vasodilator (see Chapter 19). They also inhibit the uptake of adenosine by endothelial cells and erythrocytes and thereby increase the plasma concentration of adenosine. Adenosine acts through platelet adenosine A₂ receptors to increase platelet cAMP and inhibit aggregation.

C. Clinical Use

Aspirin is used to prevent further infarcts in persons who have had 1 or more myocardial infarcts and may also reduce the incidence of first infarcts. The drug is used extensively to prevent transient ischemic attacks (TIAs), ischemic stroke, and other thrombotic events.

The glycoprotein IIb/IIIa inhibitors prevent restenosis after coronary angioplasty and are used in acute coronary syndromes (eg, unstable angina and non-Q-wave acute myocardial infarction).

Clopidogrel and ticlopidine are effective in preventing TIAs and ischemic strokes, especially in patients who cannot tolerate aspirin. Clopidogrel is routinely used to prevent thrombosis in patients who have received a coronary artery stent.

Dipyridamole is approved as an adjunct to warfarin in the prevention of thrombosis in those with cardiac valve replacement and has been used in combination with aspirin for secondary prevention of ischemic stroke. Cilostazol is used to treat intermittent claudication, a manifestation of peripheral arterial disease.

D. Toxicity

Aspirin and other NSAIDs cause gastrointestinal and CNS effects (Chapter 36). All antiplatelet drugs significantly enhance the effects of other anticlotting agents. The major toxicities of the glycoprotein IIb/IIIa receptor-blocking drugs are bleeding and, with chronic use, thrombocytopenia. Ticlopidine is used rarely because it causes bleeding in up to 5% of patients, severe neutropenia in about 1%, and very rarely thrombotic thrombocytopenic purpura (TTP), a syndrome characterized by the disseminated formation of small thrombi, platelet consumption, and thrombocytopenia. Clopidogrel is less hematotoxic. The most common adverse effects of dipyridamole and cilostazol are headaches and palpitations. Cilostazol is contraindicated in patients with congestive heart failure because of evidence of reduced survival.

Inadequate blood clotting can result from vitamin K deficiency, genetically determined errors of clotting factor synthesis (eg, hemophilia), a variety of drug-induced conditions, and thrombocytopenia. Treatment involves administration of vitamin K, preformed clotting factors, or antiplasmin drugs. Thrombocytopenia can be treated by administration of platelets or oprelvekin, the recombinant form of the megakaryocyte growth factor interleukin-11 (see Chapter 33).

A. Vitamin K

Deficiency of vitamin K, a fat-soluble vitamin, is most common in older persons with abnormalities of fat absorption and in newborns, who are at risk of bleeding due to vitamin K deficiency. The deficiency is readily treated with oral or parenteral phytonadione (vitamin K₁). In the United States, all newborns receive an injection of phytonadione. Large doses of vitamin K₁ are used to reverse the anticoagulant effect of excess warfarin.

B. Clotting Factors and Desmopressin

The most important agents used to treat hemophilia are fresh plasma and purified human blood clotting factors, especially factor VIII (for hemophilia A) and factor IX (for hemophilia B), which are either purified from blood products or produced by recombinant DNA technology. These products are expensive and carry a risk of immunologic reactions and, in the case of factors purified from blood products, infection (although most known blood-borne pathogens are removed by chemical treatment of the plasma extracts.)

The vasopressin V₂ receptor agonist desmopressin acetate (see Chapter 37) increases the plasma concentration of von Willebrand factor and factor VIII. It is used to prepare patients with mild hemophilia A or von Willebrand disease for elective surgery.

C. Antiplasmin Agents

Antiplasmin agents are valuable for the prevention or management of acute bleeding episodes in patients with hemophilia and others with a high risk of bleeding disorders. Aminocaproic acid and tranexamic acid are orally active agents that inhibit fibrinolysis by inhibiting plasminogen activation (Figure 34–2). Adverse effects include thrombosis, hypotension, myopathy, and diarrhea.

Questions 1-3. A 55-year-old lawyer is brought to the emergency department 2 h after the onset of severe chest pain during a stressful meeting. He has a history of poorly controlled mild hypertension and elevated blood cholesterol but does not smoke. ECG changes (ST elevation) and cardiac enzymes confirm the diagnosis of myocardial infarction. The decision is made to attempt to open his occluded artery.

1. Which of the following drugs accelerates the conversion of plasminogen to plasmin?

   • (A) Aminocaproic acid

   • (B) Heparin

   • (C) Argatroban

   • (D) Reteplase

   • (E) Warfarin

2. If a fibrinolytic drug is used for treatment of this man’s acute myocardial infarction, which of the following adverse drug effects is most likely to occur?

   • (A) Acute renal failure

   • (B) Development of antiplatelet antibodies

   • (C) Encephalitis secondary to liver dysfunction

   • (D) Hemorrhagic stroke

   • (E) Neutropenia

3. If this patient undergoes a percutaneous coronary angiography procedure and placement of a stent in a coronary blood vessel, he will need to be on dual antiplatelet therapy. eg, aspirin and clopidogrel for at least a year. Which of the following most accurately describes the mechanism of action of clopidogrel?

   • (A) Clopidogrel directly binds to the platelet ADP receptors

   • (B) Clopidogrel irreversibly inhibits cyclooxygenase

   • (C) Clopidogrel facilitates the action of antithrombin III

   • (D) The active metabolite of clopidogrel binds to the platelet ADP receptors

   • (E) The active metabolite of clopidogrel binds to the platelet glycoprotein IIb/IIIa receptors

   

4. The above graph shows the plasma concentration of free warfarin as a function of time for a patient who was treated with 2 other agents, drugs B and C, on a daily basis at constant dosage starting at the times shown. Which of the following is the most likely explanation for the observed changes in warfarin concentration?

   • (A) Drug B displaces warfarin from plasma proteins; drug C displaces warfarin from tissue-binding sites

   • (B) Drug B inhibits hepatic metabolism of warfarin; drug C displaces drug B from tissue-binding sites

   • (C) Drug B stimulates hepatic metabolism of warfarin; drug C displaces warfarin from plasma protein

   • (D) Drug B increases renal clearance of warfarin; drug C inhibits hepatic metabolism of drug B

   Questions 5-7. A 58-year-old woman with chronic hypertension and diabetes mellitus was recently admitted to the hospital for congestive heart failure and new onset atrial fibrillation. She is now seeing you after discharge and, though feeling better, is still in atrial fibrillation. An echocardiogram shows an ejection fraction of 40%; there are no valvular abnormalities. An ECG reveals only atrial fibrillation. You calculate her risk using the CHADS(2) system and the score indicates that she requires anticoagulation rather than antiplatelet therapy.

5. You are discussing the risks and benefits of anticoagulation therapy with her, including the option of using direct thrombin inhibitors. Which of the following anticoagulants is a direct inhibitor of thrombin?

   • (A) Abciximab

   • (B) Dabigatran

   • (C) Rivaroxaban

   • (D) Warfarin

6. She tells you that her main reason for not wanting oral anticoagulation is that she does not want to come to clinic for frequent blood draws. You agree on an oral alternative and start her on apixaban. You counsel her extensively on the importance of taking the medication each day, as suddenly stopping can lead to

   • (A) Anaphylaxis

   • (B) Excess bleeding

   • (C) Increase in INR

   • (D) Stroke

   • (E) Thrombocytopenia

7. She is excited about not having to come in for blood tests but wonders if there is a test, just in case the doctors need to know. Which of the following tests would provide accurate information about the coagulation status of a patient taking apixaban?

   • (A) aPTT

   • (B) Factor X test

   • (C) INR

   • (D) PT test

   Questions 8 and 9. A 67-year-old woman presents with pain in her left thigh muscle. Duplex ultrasonography indicates the presence of deep vein thrombosis (DVT) in the affected limb.

8. The decision was made to treat this woman with enoxaparin. Relative to unfractionated heparin, enoxaparin

   • (A) Can be used without monitoring the patient’s aPTT

   • (B) Has a shorter duration of action

   • (C) Is less likely to have a teratogenic effect

   • (D) Is more likely to be given intravenously

   • (E) Is more likely to cause thrombosis and thrombocytopenia

9. During the next week, the patient was started on warfarin and her enoxaparin was discontinued. Two months later, she returned after a severe nosebleed. Laboratory analysis revealed an INR (international normalized ratio) of 7.0 (INR value in such a warfarin-treated patient should be 2.0–3.0). To prevent severe hemorrhage, the warfarin should be discontinued and this patient should be treated immediately with which of the following?

   • (A) Aminocaproic acid

   • (B) Desmopressin

   • (C) Factor VIII

   • (D) Protamine

   • (E) Vitamin K₁

10. A patient develops severe thrombocytopenia in response to treatment with unfractionated heparin and still requires parenteral anticoagulation. The patient is most likely to be treated with which of the following?

    • (A) Abciximab

    • (B) Bivalirudin

    • (C) Tirofiban

    • (D) Plasminogen

    • (E) Vitamin K₁

1. Reteplase is the only thrombolytic drug listed. Heparin and warfarin are anticoagulants. Argatroban is a direct inhibitor of thrombin, and aminocaproic acid is an inhibitor, not an activator, of the conversion of plasminogen to plasmin. The answer is D.

2. The most common serious adverse effect of the fibrinolytics is bleeding, especially in the cerebral circulation. The fibrinolytics do not usually have serious effects on the renal, hepatic, or hematologic systems. Unlike heparin, they do not induce antiplatelet antibodies. The answer is D.

3. Clopidogrel is a prodrug that is activated by CYP2C9 and CYP2C19. It irreversibly binds to the ADP receptor on the surface of platelets that serves as a key role in platelet aggregation. Aspirin and clopidogrel help prevent platelet-induced occlusion of coronary stents. The answer is D.

4. A drug that increases metabolism (clearance) of the anticoagulant lowers the steady-state plasma concentration (both free and bound forms), whereas one that displaces the anticoagulant increases the plasma level of the free form only until elimination of the drug has again lowered it to the steady-state level. The answer is C.

5. Abciximab is an antiplatelet agent that binds to and inhibits GPIIb/IIIa. Rivaroxaban is an oral factor X inhibitor and warfarin inhibits vitamin K epoxide reductase (VKOR). The answer is B.

6. Due to the shorter half-life of the oral factor X and thrombin inhibitors, the anticoagulant status of the patient changes rapidly. Sudden cessation of short-acting oral anticoagulants can lead to stroke. Excess bleeding is associated with taking any of the anticoagulants not with stopping them. An increase in INR reflects increased anticoagulation by warfarin. Thrombocytopenia is a risk associated with heparin. The answer is D.

7. INR (measured as PT test) reflects changes due to warfarin and to some extent the thrombin inhibitors. Factor X inhibition is not reliably measured by the aPTT (used for unfractionated heparin) or PT test. The answer is B.

8. Enoxaparin is an LMW heparin. LMW heparins have a longer half-life than standard heparin and a more consistent relationship between dose and therapeutic effect. Enoxaparin is given subcutaneously, not intravenously. It is less, not more, likely to cause thrombosis and thrombocytopenia. Neither LMW heparins nor standard heparin are teratogenic. The aPTT is not useful for monitoring the effects of LMW heparins. The answer is A.

9. The elevated INR indicates excessive anticoagulation with a high risk of hemorrhage. Warfarin should be discontinued and vitamin K₁ administered to accelerate formation of vitamin K-dependent factors. The answer is E.

10. Direct thrombin inhibitors such as bivalirudin and argatroban provide parenteral anticoagulation similar to that achieved with heparin, but the direct thrombin inhibitors do not induce formation of antiplatelet antibodies. The answer is B.

1. The β-adrenoceptor-blocking drugs (class II; eg, propranolol, acebutolol) and calcium channel-blocking drugs (class IV; eg, verapamil, diltiazem) are useful for atrial fibrillation because they slow atrioventricular (AV) nodal conduction and thereby help control ventricular rate (See Chapters 13 and 14). Though rarely used, digoxin can be effective by increasing the effective refractory period in AV nodal tissue and decreasing AV nodal conduction velocity. If symptoms persist in spite of effective rate control, ablation therapy or class I or class III antiarrhythmic drugs (eg, amiodarone, procainamide, sotalol) can be used in an attempt to provide rhythm control.

2. With warfarin, one is always concerned about pharmacodynamic and pharmacokinetic drug interactions. A metabolite of amiodarone inhibits the metabolism of warfarin and can increase the anticoagulant effect of warfarin. None of the other antiarrhythmic drugs mentioned appears to have significant interactions with warfarin.

When you complete this chapter, you should be able to:

• ❑ List the 3 major classes of anticlotting drugs and compare their usefulness in venous and arterial thromboses.

• ❑ Name 3 types of anticoagulants and describe their mechanisms of action.

• ❑ Explain why the onset of warfarin’s action is relatively slow.

• ❑ Compare the oral anticoagulants, standard heparin, and LMW heparins with respect to pharmacokinetics, mechanisms, and toxicity.

• ❑ Give several examples of warfarin’s role in pharmacokinetic and pharmacodynamic drug interactions.

• ❑ Diagram the role of activated platelets at the site of a damaged blood vessel wall and show where the 4 major classes of antiplatelet drugs act.

• ❑ Compare the pharmacokinetics, clinical uses, and toxicities of the major antiplatelet drugs.

• ❑ List 3 drugs used to treat disorders of excessive bleeding.