Anticoagulant Antiplatelet and Thrombolytic Drugs Physiology and Pathophysiology

Anticoagulant, Antiplatelet, and Thrombolytic Drugs

Physiology and Pathophysiology of Coagulation Hemostasis Stage 1: formation of platelet plug • Platelet aggregation Ø Stage 2: coagulation • Intrinsic coagulation pathway • Extrinsic coagulation pathway Ø Keeping hemostasis under control Ø Physiologic removal of clots Ø Thrombosis Ø Ø Arterial thrombosis Venous thrombosis

Overview of Drugs for Thromboembolic Disorders Three major groups Ø Ø Ø Anticoagulants Antiplatelets Thrombolytics See Table 52 -1

Anticoagulants Reduce the formation of fibrin Two mechanisms of action Ø Ø Inhibit the synthesis of clotting factors Inhibit the activity of clotting factors

Heparin and Heparin Derivatives Heparin (unfractionated) Enhances antithrombin Sources • Lungs of cattle • Intestines of pigs Ø Rapid-acting anticoagulant Ø Administered by injection only • IV Ø Ø Continuous and intermittent • Deep sub. Q

Heparin (Unfractionated) Therapeutic uses Preferred anticoagulant during pregnancy and when rapid anticoagulation is required Ø Pulmonary embolism (PE) Ø Stroke evolving Ø Massive deep venous thrombosis (DVT) Ø Open heart surgery Ø Renal dialysis Ø Low-dose therapy postoperatively Ø Disseminated intravascular coagulation (DIC) Ø Adjunct to thrombolytic therapy Ø

Heparin (Unfractionated) Adverse effects Ø Ø Ø Contraindicated Ø Ø Ø Hemorrhage Heparin-induced thrombocytopenia Hypersensitivity reactions Thrombocytopenia Uncontrollable bleeding During and immediately after surgery of the eye, brain, or spinal cord Antidote for OD: protamine sulfate Activated partial thromboplastin time (a. PTT)

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 Ø Treatment of established DVT Ø Prevention of ischemic complications • Patients with unstable angina, non–Q-wave MI, Ø and STEMI

Low-Molecular-Weight Heparins Administered sub. Q 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 Ø Ø Ø Bleeding (but less than with unfractionated heparin) Immune-mediated thrombocytopenia Severe neurologic injury for patients undergoing spinal puncture or spinal epidural anesthesia

Other LMW Heparin Ø Ø Ø In the United States, three LMW heparins are available: Enoxaparin Dalteparin Tinzaparin

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 Ø Vitamin K antagonist Ø Blocks biosynthesis of factors VII, IX, and X and prothrombin Ø

Warfarin, an Oral Anticoagulant Therapeutic uses Ø Not useful in emergencies Ø 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

Warfarin, an Oral Anticoagulant Monitoring treatment Ø Prothrombin time (PT) Ø International normalized ratio (INR) Adverse effects Ø Hemorrhage (vitamin K for toxicity) Ø Fetal hemorrhage and teratogenesis from use during pregnancy Ø Use during lactation Ø Other adverse effects

Warfarin, an Oral Anticoagulant Drug interactions Ø Ø Ø Drugs that increase anticoagulant effects Drugs that promote bleeding Drugs that decrease anticoagulant effects Heparin Aspirin Acetaminophen

Warfarin, an Oral Anticoagulant Warfarin overdose Ø Vitamin K Dietary vitamin K Contrasts between warfarin and heparin

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

Direct Thrombin Inhibitors Hiruden Analog: Bivalirudin (Angiomax) Ø 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 Ø Adverse effects • Bleeding • Back pain • Nausea, headache Ø

Other Direct Thrombin Inhibitors Lepirudin (Refludan) Argatroban (formerly known as Acova) Desirudin (Ipravask) Dabigatran (Pradaxa)

Selective Factor Xa Inhibitors Produce selective inhibition of factor Xa Fondaparinux Ø Ø Activation of antithrombin Injection Rivaroxaban Ø Ø Binds directly with factor Xa to cause inactivation Oral

Fondaparinux (Arixtra) Synthetic anticoagulant Selective inhibition Therapeutic uses Ø Ø Ø Prevention of DVT following surgery Treatment of acute PE (in conjunction with warfarin) Treatment of acute DVT (in conjunction with warfarin) Adverse effects Ø Ø Bleeding Avoid in patients weighing less than 50 kg Thrombocytopenia Spinal or epidural hematoma

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

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

Antiplatelet Drugs Aspirin (ASA) Ø Ø Ticlopidine (Ticlid) Ø Ø Inhibition of cyclooxygenase Adverse effect • Increases risk for GI bleeding Inhibits ADP-mediated aggregation Adverse effects • Hematologic effects Clopidogrel (Plavix) Ø ADP receptor antagonist

Aspirin (ASA) Therapeutic uses Ø Ø Ø Ø Ischemic stroke Transient ischemic attack (TIA) Chronic stable angina Unstable angina Coronary stenting Acute MI Previous MI Primary prevention of MI

Aspirin (ASA) Adverse effects Ø Bleeding Ø GI bleeding and hemorrhagic stroke Ø Enteric-coated tablets may not reduce the risk for GI bleeding

Clopidogrel (Plavix) Therapeutic uses Ø Ø 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

Antiplatelet Drugs Glycoprotein (GP) IIb/IIIa receptor antagonists Ø Ø Ø Most effective antiplatelet drugs “Super aspirins” Reversible blockade of platelet GP IIb/IIIa receptors

Other Antiplatelet Drugs Dipyridamole Dipyrindamole + aspirin Aggrenox Cilostazol

Thrombolytic Drugs Streptokinase (Streptase); Alteplase (t. Pa) Major adverse effect – bleeding (minor oozing to life-threatening amount) Ø 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

Minimizing the Risk of Bleeding Minimizing physical manipulation of the patient Avoiding sub. Q and IM injections Minimizing invasive procedures Minimizing concurrent use of anticoagulants (eg, heparin, warfarin, dabigatran) Minimizing concurrent use of antiplatelet drugs (eg, aspirin, clopidogrel)

Streptokinase (Streptase) Binds to plasminogen to form active complex Therapeutic uses Ø Ø Ø 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) Ø Antibody production Ø Hypotension Ø Fever Ø

Alteplase (t. Pa) Converts plasminogen to plasmin Given in accelerated schedule Therapeutic uses Ø Ø Ø Myocardial infarction Ischemic stroke Massive pulmonary emboli

Alteplase (t. Pa) Adverse effects Ø Bleeding • Risk for intracranial bleeding higher than with streptokinase Ø Fever Advantages Ø Ø Does not cause allergic reactions Does not induce hypotension

Other Thrombolytic Drugs Tenecteplase Reteplase