книга / 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

Anticoagulants 1

Learning Objectives

Compare the use and toxicities of heparin and warfarin

OVERVIEW

Blood coagulates by transformation of soluble fibrinogen into insoluble fibrin. Circulating proteins interact in a “cascade,” where clotting factors undergo limited proteolysis to become active serine proteases. Anticoagulants are drugs that decrease the formation of fibrin clots. Oral anticoagulants (e.g., warfarin) inhibit the hepatic synthesis of clotting factors II, VII, IX, and X. Heparin inhibits the activity of several activated clotting factors (especially factors IIa and Xa) via its activation of antithrombin III. The endogenous anticoagulants, protein C and protein S, cause proteolysis of factors Va and VIIIa.

Plasminogen Plasmin

(activated by streptokinase and alteplase)

Figure VII-1-1. Actions of Blood Drugs

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Chapter 1 λ Anticoagulants

Warfarin

λDrug interactions:

–Acidic molecule: oral absorption ↓ by cholestyramine

–Extensive (but weak) plasma protein binding: displacement by other drugs may increase free fraction →↑ PT (e.g., ASA, sulfonamides, phenytoins)

–Slow hepatic metabolism via P450:

ºInducers (barbiturates, carbamezepine, rifampin) →↓ PT

ºInhibitors (cimetidine, macrolides, azole antifungals) →↑ PT

λProtein C deficiency:

Thrombomodulin (transmembrane protein)

+

Thrombin

Figure VII-1-2. Activation and Role of Protein C

–Transient protein C deficiency can be induced when initiating treatment with warfarin because factors VII and protein C have the shortest half-lives of the coagulation factors (Table VII-1-2).

Table VII-1-2. Coagulation Factor Half-Lives

–Consequently, the extrinsic pathway and protein C system are inactivated, whereas the intrinsic system remains active for a few days. Hypercoagulability occurs (Figure VII-1-2), which may result in dermal vascular thrombosis and skin necrosis.

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Section VII λ Drugs Used in Blood Disorders

Direct Activated Clotting Factor Inhibitors

Direct thrombin inhibitors

λDirectly inhibit thrombin and do not require antithrombin III

λDrugs

–Argatroban

ºDoes not interact with heparin-induced antibodies

ºUsed in HIT

–Dabigatran

ºOral anticoagulant that does not require monitoring of PT or INR

ºUsed in atrial fibrillation as an alternative to warfarin

–Bivalirudin

ºUsed with aspirin in unstable angina when undergoing percutaneous transluminal coronary angioplasty (PTCA)

Direct Factor Xa Inhibitors: Rivaroxaban and Other “-xabans”

λFactor Xa inhibitor, does not require monitoring of PT or INR

λUsed to prevent DVTs after knee/hip surgery; prevention of stroke and systemic embolism in non-valvular atrial fibrillation

Chapter Summary

λTable VII-1-1 summarizes the properties of heparin and warfarin (a coumarin).

λLow-molecular-weight heparin derivatives (e.g., enoxaparin) and danaparoid, a heparan with heparin-like properties, have potential advantages over heparin itself.

λThe drug interactions of warfarin are given.

λThe activation and role of protein C in the clotting cascade are illustrated in

FigureVII-1-2.Transient protein C deficiency can be induced by treatment with warfarin, which promotes hypercoagulation through the action of the intrinsic pathway.

λDirect thrombin inhibitors and direct Factor Xa inhibitors do not require antithrombin III or therapeutic monitoring of PT or INR

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Thrombolytics 2

Learning Objectives

Describe the clinical features of commonly used fibrinolytic agents

Also called fibrinolytics, these agents lyse thrombi by catalyzing the formation of the endogenous fibrinolytic plasmin (a serine protease) from its precursor, plasminogen.

λThrombolytics include tissue plasminogen activator (tPA, recombinant) and streptokinase (bacterial). They are used intravenously for shortterm emergency management of coronary thromboses in myocardial infarction (MI), deep venous thrombosis, pulmonary embolism, and ischemic stroke (tPA).

λDrugs:

–Streptokinase

ºActs on both bound and free plasminogen (not clot specific), depleting circulating plasminogen and factors V and VIII

ºIs antigenic (foreign protein derived from β-hemolytic strepto-

cocci); may cause a problem if recent past use or infection—strep antibodies may ↓ activity

–Alteplase (tPA)

ºClot specific, acting mainly on fibrin-bound plasminogen, the natural activator, so no allergy problems

Activation

Figure VII-2-1. Actions of Streptokinase and Alteplase

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Section VII λ Drugs Used in Blood Disorders

λClinical features:

–Overriding factor in effectiveness is early administration, e.g., >60% decrease in mortality post-MI if used within 3 hours

–ASA, beta blockers, and nitrates further ↓ mortality, and adenosine ↓ infarct size

–Complications include bleeding, possible intracerebral hemorrhage

–Streptokinase may cause hypersensitivity reactions and hypotension

–Antifibrinolysins (aminocaproic and tranexamic acids)—possible antidotes in excessive bleeding

Chapter Summary

λThrombolytics (also referred to as fibrinolytics) are of clinical value in the early treatment of fibrin-clot–induced ischemia (e.g., >60% decrease in post-MI mortality if used within 3 hours).

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Section VII λ Drugs Used in Blood Disorders

λClopidogrel, prasugrel, ticagrelor, and ticlopidine

–Block ADP receptors on platelets → ↓ activation

–Alternatives to ASA in TIAs, post-MI, and unstable angina

–Aspirin + ADP receptor blockers are used in patients with non-ST elevation ACS

–Hemorrhage, leukopenia, and thrombocytopenic purpura

λAbciximab, eptifibatide, and tirofiban

–Antagonists that bind to glycoprotein IIb/IIIa receptors → ↓ aggregation by preventing the cross-linking reaction

–Used mainly in acute coronary syndromes and postangioplasty

Chapter Summary

λPlatelets adhere to sites of vascular injury, where they are activated by various factors to express a glycoprotein to which fibrinogen binds, resulting in platelet aggregation and formation of a platelet plug. Antiplatelet drugs inhibit this process, thus reducing the chances of thrombi formation. The major drugs are aspirin, ticlopidine, clopidogrel, abciximab, eptifibatide, and tirofiban.

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Anticoagulants

λHeparin

λWarfarin

λArgatroban

λBivalirudin

λDabigatran

λRivaroxaban

Thrombolytics

λAlteplase (tPA)

λStreptokinase

Antiplatelet

λAspirin

λTiclopidine

λClopidogrel

λAbciximab

λPrasugrel

λTicagrelor

Review Questions

1.Which of the following compounds is most likely to block ADP receptors and prevent platelet aggregation?

A.Clopidogrel

B.Aspirin

C.Prostacyclin

D.Abciximab

E.Montelukast

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Section VII λ Drugs Used in Blood Disorders

2.A woman who has a mechanical heart valve and who is taking warfarin informs you that she hopes to get pregnant in the near future. What advice should she receive regarding her antithrombotic medication during the anticipated pregnancy?

A.Warfarin should be continued until the third trimester.

B.Warfarin should be replaced with aspirin at analgesic doses.

C.All medications that affect the blood should be discontinued.

D.Warfarin should be replaced with heparin.

E.Warfarin should be discontinued, and supplementary vitamin K taken throughout the pregnancy.

3.The primary advantage of enoxaparin over heparin is that it

A.is unlikely to cause bleeding

B.more effectively Inhibits the synthesis of clotting factors

C.has a more rapid onset

D.does not case thrombocytopenia

E.has a longer half-life

4.Which of the following statements regarding warfarin is true?

A.It is a prodrug converted to its active metabolite spontaneously in the blood.

B.It has low lipophilicity and does not cross the placental barrier.

C.It causes a depletion in protein C before it decreases prothrombin.

D.It inhibits release of vitamin K–dependent clotting factors from hepatocytes.

E.It is inactivated by protamine.

5.Which of the following statements is true regarding the parenteral administration of alteplase?

A.It increases the formation of plasminogen.

B.It is less effective than streptokinase when given after a myocardial infarction.

C.It causes a high incidence of thrombocytopenia.

D.It may cause bleeding reversible by aminocaproic acid.

E.It activates free plasminogen.

6.Following a myocardial infarction, a patient is stabilized on warfarin, the dose being adjusted to give a prothrombin time of 22 seconds. Which of the following statements regarding potential drug interactions in this patient is accurate?

A.Cholestyramine will increase prothrombin time.

B.Cimetidine is likely to decrease prothrombin time.

C.Antibacterial sulfonamides may enhance the effects of warfarin.

D.Vitamin K would restore prothrombin time to normal within 30 minutes.

E.If this patient takes half an aspirin tablet daily, the dose of warfarin will need to be increased.

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