Ch 52 Anticoagulant, antiplatelet, and thrombolytic drugs

Question 1

Hemostasis occurs in two stages:

Answer 1

formation of a platelet plug, followed by coagulation (i.e., production of fibrin, a protein that reinforces the platelet plug)

Question 2

Platelet aggregation depends on activation of platelet

___.

Answer 2

glycoprotein (GP) IIb/IIIa receptors,

which bind fibrinogen to form cross-links between platelets.

Question 3

Fibrin is produced by two pathways—(2)—that converge at clotting factor Xa, which catalyzes formation of thrombin, which in turn catalyzes formation of fibrin.

Answer 3

the contact activation pathway (aka intrinsic pathway) and the tissue factor pathway (aka extrinsic pathway)

Question 4

Four factors in the coagulation pathways require an activated form of ___ for their synthesis.

Answer 4

vitamin K

Question 5

__ serves to degrade the fibrin meshwork of clots.

Answer 5

Plasmin (the active form of plasminogen)

Question 6

A thrombus is a __.

Answer 6

blood clot formed within a blood vessel or the atria of the heart

Question 7

Arterial thrombi begin with formation of __.

Answer 7

a platelet plug,

which is then reinforced with fibrin.

Question 8

Venous thrombi begin with formation of __.

Answer 8

fibrin,

which then enmeshes red blood cells and platelets.

Question 9

Arterial thrombi are best prevented with ___ , whereas venous thrombi are best prevented with ___.

Answer 9

antiplatelet drugs (e.g., aspirin, clopidogrel)

anticoagulants (e.g., heparin, warfarin, dabigatran)

Question 10

Heparin is a large __.

Answer 10

polymer (molecular weight range, 3000 to 30,000) that carries many negative charges.

Question 11

Heparin suppresses __.

Answer 11

coagulation by helping antithrombin inactivate thrombin and factor Xa.

Question 12

Heparin is administered ___.

Answer 12

IV or subQ.

Because of its large size and negative charges, heparin is unable to cross membranes, and hence cannot be administered PO.

Question 13

Anticoagulant effects of heparin develop within minutes

of __.

Answer 13

IV administration

Question 14

The major adverse effect of heparin is __.

Answer 14

bleeding

Question 15

Severe heparin-induced bleeding can be treated with

__.

Answer 15

protamine sulfate, a drug that binds heparin and thereby

stops it from working

Question 16

___ is a potentially fatal condition caused by development of antibodies against heparin–platelet protein complexes.

Answer 16

Heparin-induced thrombocytopenia

Question 17

Heparin is contraindicated for patients with ___, and must be used with extreme caution in all patients for whom there is a high likelihood of bleeding.

Answer 17

thrombocytopenia or uncontrollable bleeding

Question 18

Heparin therapy is monitored by measuring the ___.

Answer 18

activated partial thromboplastin time (aPTT) or anti-Xa heparin assay.

The target aPTT is 60 to 80 seconds (i.e., 1.5 to 2 times
the normal value of 40 seconds).
The target anti-Xa level is 0.3 to 0.7 IU/mL.

Question 19

___ are produced by breaking molecules of unfractionated heparin into smaller pieces.

Answer 19

Low-molecular-weight (LMW) heparins

Question 20

In contrast to unfractionated heparin, which inactivates

factor Xa and thrombin equally, ___ preferentially inactivate factor Xa.

Answer 20

LMW heparins

Question 21

In contrast to unfractionated heparin, LMW heparins do
not bind nonspecifically to plasma proteins and tissues.
As a result, their bioavailability is __.

Answer 21

high, making their plasma levels predictable.

Question 22

Because plasma levels of LMW heparins are predictable,

these drugs can be administered using a __.

Answer 22

fixed dosage, with no need for routine laboratory monitoring.

As a result, LMW heparins can be used at home.

Question 23

___ is our oldest oral anticoagulant.

Answer 23

Warfarin

Question 24

Warfarin prevents the activation of __.

Answer 24

vitamin K and thereby blocks the biosynthesis of vitamin K–dependent clotting factors.

Question 25

Anticoagulant responses to warfarin develop ___.

Answer 25

slowly and persist for several days after warfarin is discontinued

Question 26

Warfarin is used to prevent __.

Answer 26

venous thromboembolism (VTE) and to prevent stroke and systemic embolism in patients with atrial fibrillation

Question 27

Warfarin therapy is monitored by measuring __.

Answer 27

prothrombin time (PT).

Results are expressed as an international normalized ratio (INR). An INR of 2 to 3 is the target for most patients.

Question 28

___ is the major complication of warfarin therapy.

Answer 28

Bleeding

Question 29

Genetic testing for variant genes that code for VKORC1 and CYP2C9 can identify people with increased sensitivity to __.

Answer 29

warfarin,

and who therefore may need a dosage reduction.

Question 30

Moderate warfarin overdose is treated with ___.

Answer 30

vitamin K

Question 31

Warfarin must not be used during __.

Answer 31

pregnancy.

The drug can cause fetal malformation, CNS defects, and optic atrophy.

Question 32

Warfarin is subject to a large number of clinically significant ___.

Answer 32

drug interactions.

Drugs can increase anticoagulant effects by displacing warfarin from plasma albumin, by inhibiting hepatic enzymes that degrade warfarin, and by decreasing synthesis of clotting factors.

Drugs can decrease anticoagulant effects by inducing hepatic drug-metabolizing enzymes, increasing synthesis of clotting factors, and inhibiting warfarin absorption.

Drugs that promote bleeding, such as heparin and aspirin, will obviously increase the risk of bleeding in patients taking warfarin.

Instruct patients to avoid all drugs—prescription and nonprescription—that have not been specifically approved by the prescriber.

Question 33

__ is an oral anticoagulant that works by direct

inhibition of thrombin.

Answer 33

Dabigatran

Question 34

Dabigatran is an alternative to warfarin for chronic anticoagulation in patients with __.

Answer 34

atrial fibrillation

Question 35

Compared with warfarin, dabigatran has five advantages:

Answer 35

rapid onset, 
fixed dosage, 
no need for coagulation testing, 
few drug-food interactions, 
and a lower risk of hemorrhagic stroke and other major bleeds.

Question 36

Compared with warfarin, dabigatran has three disadvantages:

Answer 36

no antidote,
limited clinical experience,
and more GI disturbances (dyspepsia, ulceration, gastritis, etc.).

Question 37

Rivaroxaban, edoxaban, and apixaban are __.

Answer 37

oral anticoagulants that work by direct inhibition of factor Xa.

Question 38

Like dabigatran, (3) are safer than warfarin and easier to use.

Answer 38

rivaroxaban, edoxaban, and apixaban

Question 39

___ suppress thrombus formation in arteries.

Answer 39

Aspirin and other antiplatelet drugs

Question 40

Aspirin inhibits platelet aggregation by causing irreversible inhibition of __.

Answer 40

cyclooxygenase.

Since platelets are unable to synthesize new cyclooxygenase, inhibition persists for the life of the platelet (7 to 10 days)

Question 41

In its role as an antiplatelet drug, aspirin is given for multiple purposes, including __.

Answer 41

primary prevention of myocardial infarction (MI), acute management of MI, and reduction of cardiovascular events in patients with unstable angina, chronic stable angina, ischemic stroke, or a history of transient ischemic attacks (TIAs).

Question 42

When used to suppress platelet aggregation, aspirin is

administered __.

Answer 42

in low doses—typically 80 to 325 mg/day.

Question 43

Clopidogrel suppresses __.

Answer 43

platelet aggregation by causing irreversible blockade of P2Y12 ADP receptors on the platelet surface

Question 44

___ is a prodrug that undergoes conversion to its

active form by hepatic CYP2C19.

Answer 44

Clopidogrel

Question 45

Patients with an inherited deficiency in CYP2C19 may

have an unreliable response to __.

Answer 45

clopidogrel

Question 46

The major adverse effect of clopidogrel is __.

Answer 46

bleeding

Question 47

The __ inhibit the final common step in platelet aggregation, and hence are the most effective antiplatelet drugs available.

Answer 47

GP IIb/IIIa receptor blockers (e.g., abciximab)

Question 48

(2) are used to dissolve existing thrombi (rather than prevent thrombi from forming).

Answer 48

Alteplase (tPA) and other thrombolytic drugs (aka fibrinolytic drugs)

Question 49

Thrombolytic drugs work by converting plasminogen to

__.

Answer 49

plasmin, an enzyme that degrades the fibrin matrix of

thrombi.

Question 50

Thrombolytic therapy is most effective when started __.

Answer 50

early (e.g., for acute MI, within 4 to 6 hours of symptom onset, and preferably sooner)

Question 51

Thrombolytic drugs carry a significant risk of __.

Answer 51

bleeding.

Intracranial hemorrhage is the greatest concern.