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Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Chapter 52
Anticoagulant, Antiplatelet, and Thrombolytic Drugs
2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Physiology and Pathophysiology of Coagulation
Hemostasis Stage 1: formation of platelet plug
• Platelet aggregation Stage 2: coagulation
• Intrinsic coagulation pathway• Extrinsic coagulation pathway
Keeping hemostasis under control Physiologic removal of clots
Thrombosis Arterial thrombosis Venous thrombosis
3Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Overview of Drugs for Thromboembolic Disorders
Three major groups Anticoagulants Antiplatelets Thrombolytics
See Table 52-1
4Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Anticoagulants
Reduce the formation of fibrin Two mechanisms of action
Inhibit the synthesis of clotting factors Inhibit the activity of clotting factors
5Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Heparin and Heparin Derivatives
Heparin (unfractionated) Enhances antithrombin Sources
• Lungs of cattle • Intestines of pigs
Rapid-acting anticoagulant Administered by injection only
• IV Continuous and intermittent
• Deep subQ
6Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Heparin (Unfractionated)
Therapeutic uses Preferred anticoagulant during pregnancy and
when rapid anticoagulation is required Pulmonary embolism (PE) Stroke evolving Massive deep venous thrombosis (DVT) Open heart surgery Renal dialysis Low-dose therapy postoperatively Disseminated intravascular coagulation (DIC) Adjunct to thrombolytic therapy
7Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Heparin (Unfractionated)
Adverse effects Hemorrhage Heparin-induced thrombocytopenia Hypersensitivity reactions
Contraindicated Thrombocytopenia Uncontrollable bleeding During and immediately after surgery of the eye, brain, or
spinal cord Antidote for OD: protamine sulfate Activated partial thromboplastin time (aPTT)
8Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Low-Molecular-Weight Heparins
Heparin preparations composed of molecules that are shorter than those found in unfractionated heparin
Therapeutic uses Prevention of DVT following surgery
• Including replacement of hip, knee Treatment of established DVT Prevention of ischemic complications
• Patients with unstable angina, non–Q-wave MI, and STEMI
9Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Low-Molecular-Weight Heparins
Administered subQ Dosage based on body weight Antidote for toxicity: protamine sulfate Costs more than unfractionated heparin Does not require monitoring; can be given at home Adverse effects and interactions
Bleeding (but less than with unfractionated heparin) Immune-mediated thrombocytopenia Severe neurologic injury for patients undergoing spinal
puncture or spinal epidural anesthesia
10Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Other LMW Heparin
In the United States, three LMW heparins are available:
Enoxaparin Dalteparin Tinzaparin
11Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Warfarin, an Oral Anticoagulant
Originally discovered while cattle were observed ingesting spoiled clover silage
Used as rat poison Failed suicide attempt with large dose
brought renewed clinical interest Clinical use
Oral anticoagulant with delayed onset Vitamin K antagonist Blocks biosynthesis of factors VII, IX, and X and
prothrombin
12Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Warfarin, an Oral Anticoagulant
Therapeutic uses Not useful in emergencies Long-term prophylaxis of thrombosis
• Prevention of venous thrombosis and associated pulmonary embolism
• Prevention of thromboembolism (in patients with prosthetic heart valves)
• Prevention of thrombosis during atrial fibrillation
13Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Warfarin, an Oral Anticoagulant
Monitoring treatment Prothrombin time (PT) International normalized ratio (INR)
Adverse effects Hemorrhage (vitamin K for toxicity) Fetal hemorrhage and teratogenesis from
use during pregnancy Use during lactation Other adverse effects
14Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Warfarin, an Oral Anticoagulant
Drug interactions Drugs that increase anticoagulant effects Drugs that promote bleeding Drugs that decrease anticoagulant effects Heparin Aspirin Acetaminophen
15Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Warfarin, an Oral Anticoagulant
Warfarin overdose Vitamin K
Dietary vitamin K Contrasts between warfarin and heparin
16Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Direct Thrombin Inhibitors
Direct inhibition of thrombin (unlike heparin, which enhances the activity of antithrombin)
Dabigatran Etexilate Approved in 2010 Oral prodrug undergoes conversion to
dabigatran Advantages of dabigatran: doesn’t require
monitoring of anticoagulation, little risk of adverse interactions, same dose can be used for all patients regardless of age or weight
17Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Direct Thrombin Inhibitors
Hiruden Analog: Bivalirudin (Angiomax) Prevents clot formation (combined with aspirin) in patients
with unstable angina who are undergoing coronary angioplasty
Mechanism of action• Facilitates the actions of antithrombin• Prevents conversion of fibrinogen to fibrin• Prevents activation of factor XIII
Adverse effects• Bleeding• Back pain• Nausea, headache
18Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Other Direct Thrombin Inhibitors
Lepirudin (Refludan) Argatroban (formerly known as Acova) Desirudin (Ipravask) Dabigatran (Pradaxa)
19Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Selective Factor Xa Inhibitors
Produce selective inhibition of factor Xa Fondaparinux
Activation of antithrombin Injection
Rivaroxaban Binds directly with factor Xa to cause inactivation Oral
20Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Fondaparinux (Arixtra)
Synthetic anticoagulant Selective inhibition Therapeutic uses
Prevention of DVT following surgery Treatment of acute PE (in conjunction with warfarin) Treatment of acute DVT (in conjunction with warfarin)
Adverse effects Bleeding Avoid in patients weighing less than 50 kg Thrombocytopenia Spinal or epidural hematoma
21Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Rivaroxaban (Xarelto)
Oral anticoagulant approved in 2011 Does not require laboratory monitoring Patients who received rivaroxaban were
found to be much less likely to experience DVT, VTE, PE, or death
22Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Antithrombin (AT)
Endogenous compound that suppresses coagulation, primarily by inhibiting thrombin and factor Xa
Used to prevent thrombosis in patients with inherited AT deficiency
Two preparations, marketed as Atryn and Thrombate III
23Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Antiplatelet Drugs
Aspirin (ASA) Inhibition of cyclooxygenase Adverse effect
• Increases risk for GI bleeding Ticlopidine (Ticlid)
Inhibits ADP-mediated aggregation Adverse effects
• Hematologic effects Clopidogrel (Plavix)
ADP receptor antagonist
24Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Aspirin (ASA)
Therapeutic uses Ischemic stroke Transient ischemic attack (TIA) Chronic stable angina Unstable angina Coronary stenting Acute MI Previous MI Primary prevention of MI
25Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Aspirin (ASA)
Adverse effects Bleeding GI bleeding and hemorrhagic stroke Enteric-coated tablets may not reduce the
risk for GI bleeding
26Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Clopidogrel (Plavix)
Therapeutic uses Prevents blockage of coronary artery stents Reduces thrombotic events in patients with acute
coronary syndromes• MI, ischemic stroke, and vascular death
Similar adverse effects to those of aspirin Use with caution in combination with other
drugs that promote bleeding
27Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Antiplatelet Drugs
Glycoprotein (GP) IIb/IIIa receptor antagonists Most effective antiplatelet drugs “Super aspirins” Reversible blockade of platelet GP IIb/IIIa
receptors
28Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Other Antiplatelet Drugs
Dipyridamole Dipyrindamole + aspirin Aggrenox Cilostazol
29Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Thrombolytic Drugs
Streptokinase (Streptase); Alteplase (tPa) Major adverse effect – bleeding (minor oozing
to life-threatening amount) Likely sites of bleeding
• Recent wounds, needle puncture sites, invasive procedure sites
Anticoagulants increase the risk for hemorrhage
Blood replacement may need to be considered
30Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Minimizing the Risk of Bleeding
Minimizing physical manipulation of the patient
Avoiding subQ and IM injections Minimizing invasive procedures Minimizing concurrent use of anticoagulants
(eg, heparin, warfarin, dabigatran) Minimizing concurrent use of antiplatelet
drugs (eg, aspirin, clopidogrel)
31Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Streptokinase (Streptase)
Binds to plasminogen to form active complex Therapeutic uses
Acute coronary thrombosis (acute MI) Deep venous thrombosis (DVT) Massive pulmonary emboli
Adverse effects Bleeding – excessive fibrinolysis can be reversed with IV
aminocaproic acid (Amicar) Antibody production Hypotension Fever
32Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Alteplase (tPa)
Converts plasminogen to plasmin Given in accelerated schedule Therapeutic uses
Myocardial infarction Ischemic stroke Massive pulmonary emboli
33Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Alteplase (tPa)
Adverse effects Bleeding
• Risk for intracranial bleeding higher than with streptokinase
Fever Advantages
Does not cause allergic reactions Does not induce hypotension
34Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Other Thrombolytic Drugs
Tenecteplase Reteplase