Ch 52 Anticoagulant, antiplatelet, and thrombolytic drugs Flashcards
Hemostasis occurs in two stages:
formation of a platelet plug, followed by coagulation (i.e., production of fibrin, a protein that reinforces the platelet plug)
Platelet aggregation depends on activation of platelet
___.
glycoprotein (GP) IIb/IIIa receptors,
which bind fibrinogen to form cross-links between platelets.
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.
the contact activation pathway (aka intrinsic pathway) and the tissue factor pathway (aka extrinsic pathway)
Four factors in the coagulation pathways require an activated form of ___ for their synthesis.
vitamin K
__ serves to degrade the fibrin meshwork of clots.
Plasmin (the active form of plasminogen)
A thrombus is a __.
blood clot formed within a blood vessel or the atria of the heart
Arterial thrombi begin with formation of __.
a platelet plug,
which is then reinforced with fibrin.
Venous thrombi begin with formation of __.
fibrin,
which then enmeshes red blood cells and platelets.
Arterial thrombi are best prevented with ___ , whereas venous thrombi are best prevented with ___.
antiplatelet drugs (e.g., aspirin, clopidogrel)
anticoagulants (e.g., heparin, warfarin, dabigatran)
Heparin is a large __.
polymer (molecular weight range, 3000 to 30,000) that carries many negative charges.
Heparin suppresses __.
coagulation by helping antithrombin inactivate thrombin and factor Xa.
Heparin is administered ___.
IV or subQ.
Because of its large size and negative charges, heparin is unable to cross membranes, and hence cannot be administered PO.
Anticoagulant effects of heparin develop within minutes
of __.
IV administration
The major adverse effect of heparin is __.
bleeding
Severe heparin-induced bleeding can be treated with
__.
protamine sulfate, a drug that binds heparin and thereby
stops it from working
___ is a potentially fatal condition caused by development of antibodies against heparin–platelet protein complexes.
Heparin-induced thrombocytopenia
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.
thrombocytopenia or uncontrollable bleeding
Heparin therapy is monitored by measuring the ___.
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.
___ are produced by breaking molecules of unfractionated heparin into smaller pieces.
Low-molecular-weight (LMW) heparins
In contrast to unfractionated heparin, which inactivates
factor Xa and thrombin equally, ___ preferentially inactivate factor Xa.
LMW heparins
In contrast to unfractionated heparin, LMW heparins do
not bind nonspecifically to plasma proteins and tissues.
As a result, their bioavailability is __.
high, making their plasma levels predictable.
Because plasma levels of LMW heparins are predictable,
these drugs can be administered using a __.
fixed dosage, with no need for routine laboratory monitoring.
As a result, LMW heparins can be used at home.
___ is our oldest oral anticoagulant.
Warfarin
Warfarin prevents the activation of __.
vitamin K and thereby blocks the biosynthesis of vitamin K–dependent clotting factors.
Anticoagulant responses to warfarin develop ___.
slowly and persist for several days after warfarin is discontinued
Warfarin is used to prevent __.
venous thromboembolism (VTE) and to prevent stroke and systemic embolism in patients with atrial fibrillation
Warfarin therapy is monitored by measuring __.
prothrombin time (PT).
Results are expressed as an international normalized ratio (INR). An INR of 2 to 3 is the target for most patients.
___ is the major complication of warfarin therapy.
Bleeding
Genetic testing for variant genes that code for VKORC1 and CYP2C9 can identify people with increased sensitivity to __.
warfarin,
and who therefore may need a dosage reduction.
Moderate warfarin overdose is treated with ___.
vitamin K
Warfarin must not be used during __.
pregnancy.
The drug can cause fetal malformation, CNS defects, and optic atrophy.
Warfarin is subject to a large number of clinically significant ___.
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.
__ is an oral anticoagulant that works by direct
inhibition of thrombin.
Dabigatran
Dabigatran is an alternative to warfarin for chronic anticoagulation in patients with __.
atrial fibrillation
Compared with warfarin, dabigatran has five advantages:
rapid onset, fixed dosage, no need for coagulation testing, few drug-food interactions, and a lower risk of hemorrhagic stroke and other major bleeds.
Compared with warfarin, dabigatran has three disadvantages:
no antidote,
limited clinical experience,
and more GI disturbances (dyspepsia, ulceration, gastritis, etc.).
Rivaroxaban, edoxaban, and apixaban are __.
oral anticoagulants that work by direct inhibition of factor Xa.
Like dabigatran, (3) are safer than warfarin and easier to use.
rivaroxaban, edoxaban, and apixaban
___ suppress thrombus formation in arteries.
Aspirin and other antiplatelet drugs
Aspirin inhibits platelet aggregation by causing irreversible inhibition of __.
cyclooxygenase.
Since platelets are unable to synthesize new cyclooxygenase, inhibition persists for the life of the platelet (7 to 10 days)
In its role as an antiplatelet drug, aspirin is given for multiple purposes, including __.
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).
When used to suppress platelet aggregation, aspirin is
administered __.
in low doses—typically 80 to 325 mg/day.
Clopidogrel suppresses __.
platelet aggregation by causing irreversible blockade of P2Y12 ADP receptors on the platelet surface
___ is a prodrug that undergoes conversion to its
active form by hepatic CYP2C19.
Clopidogrel
Patients with an inherited deficiency in CYP2C19 may
have an unreliable response to __.
clopidogrel
The major adverse effect of clopidogrel is __.
bleeding
The __ inhibit the final common step in platelet aggregation, and hence are the most effective antiplatelet drugs available.
GP IIb/IIIa receptor blockers (e.g., abciximab)
(2) are used to dissolve existing thrombi (rather than prevent thrombi from forming).
Alteplase (tPA) and other thrombolytic drugs (aka fibrinolytic drugs)
Thrombolytic drugs work by converting plasminogen to
__.
plasmin, an enzyme that degrades the fibrin matrix of
thrombi.
Thrombolytic therapy is most effective when started __.
early (e.g., for acute MI, within 4 to 6 hours of symptom onset, and preferably sooner)
Thrombolytic drugs carry a significant risk of __.
bleeding.
Intracranial hemorrhage is the greatest concern.
