Chapter 50 - Anticoagulant, Anti Platelet, Thrombolytic Drugs

CHAPTER 50

ANTICOAGULANT, ANTIPLATELET, & THOMBOLYTIC DRUGS

Drugs used to prevent formation of thrombi (intravascular blood clots) and to dissolve thrombi that have already formed. - act in several ways: some suppress coagulation some inhibit platelet aggregation some promote clot dissolution - interfere with normal hemostasis, carrying a significant risk of hemorrhage

I.

PHYSIOLOGY

AND

PATHOPHYSIOLOGY

OF

COAGULATION

A.

HEMOSTASIS - physiologic process by which bleeding is stopped - occurs in the formation of a platelet plug followed by reinforcement of the platelet plug with fibrin - set in motion by blood vessel injury 1.

Stage One: Formation of Platelet Plug - initiated when platelets come in contact with collagen on the exposed surface of a damaged blood vessel - response to contact with collagen, platelets adhere to the site of vessel injury - aggregated platelets constitute a plug that stops bleeding - plug is unstable and must be reinforced with fibrin if protection is to last 2.

B.

Stage Two: Coagulation - production of fibrin, a protein that reinforces the platelet plug - produced by way of two convergent pathways: • intrinsic system – all necessary clotting factors are present within the vascular system • extrinsic system – tissue thromboplastin, a factor from outside the vascular system, is required for operation

THOMBOSIS thrombus – blood clot formed within a blood vessel or within the heart

1. Arterial Thrombosis – formation begins with adhesion of platelets to the arterial wall - adhesion is stimulated by damage to the wall or rupture of an atherosclerotic plaque - following adhesion, platelets attract additional platelets to the evolving thrombus - with continued platelet aggregation, occlusion of the artery takes place - as blood flow comes to a stop, the coagulation cascade is initiated, causing the

original plug to undergo reinforcement with fibrin - consequence is localized tissue injury owing to lack of perfusion 2.

Venous Thrombosis – develops at sites where blood flow is slow - stagnation of blood initiates the coagulation cascade, resulting in the production of fibrin, which enmeshes red blood cells and platelets to form the thrombus - has a long tail that can break off to produce an embolus - emboli travel within the vascular system and become lodged at faraway sites, frequently the pulmonary arteries - occurs secondary to embolization at a site distant from the original thrombus

II.

OVERVIEW

OF

DRUGS USED

TO

TREAT THROMBOEMBOLIC DISORDERS

Major Categories:

anticoagulants – heparin, warfarin - drugs that disrupt the coagulation cascade, suppressing production of fibrin - most effective against venous thrombosis antiplatelet drugs – aspirin, tirofiban - drugs that inhibit platelet aggregation - most effective at preventing arterial thrombosis thrombolytic drugs – alteplase, streptokinase - drugs that promote lysis of fibrin, causing dissolution of thrombi - these drugs differ in their effects and applications

III.

PARENTERAL ANTICOAGULANTS I:

HEPARIN

AND

RELATED DRUGS

- greatly enhance the activity of antithrombin, a protein that inactivates two major clotting factors: thrombin and factor Xa - production of fibrin is reduced, suppressing clotting A.

HEPARIN (UNFRACTIONATED) - rapid acting anticoagulant administered only by injection - by promoting the inactivation of thrombin and factor Xa, ultimately suppresses formation of fibrin - especially useful for prohpylaxis of venous thrombosis - effects of heparin develop quickly (within minutes of IV administration) - preferred anticoagulant for use during pregnancy and in situation that require rapid onset of anticoagulant effects, including pulmonary embolism, evolving stroke, and massive deep vein

thrombosis (DVT) - used for patients undergoing open heart surgery and renal dialysis - low-dose therapy is used to prevent postoperative venous thrombosis - may also be useful for treating disseminated intravascular coagulation, a complex disorder in which fibrin clots form throughout the vascular system and in which bleeding tendencies may be present - used as an adjunct to thrombolytic therapy of acute myocardial infarction (MI) Adverse Effects:

hemorrhage = bleeding is the principal complication of

treatment - monitor closely for signs of blood loss - symptoms include reduced blood pressure, increased heart rate, bruises, petechiae, hematomas, red or black stools, cloudy or discolored urine, pelvic pain (suggesting ovarian hemorrhage) headache or faintness (suggesting cerebral hemorrhage) and lumbar pain (suggesting adrenal hemorrhage) - risk can be decreased by careful control of dosage so that not to exceed 2 times the control valve, careful screening of heparin candidates for risk factors, and avoiding antiplatelet drugs

heparin-induced thrombocytopenia – potentially fatal immune-mediated disorder characterized by reduced platelet counts and seemingly paradoxical increase in thrombotic events - underlying cause is development of antibodies against heparin platelet protein complexes - antibodies activate platelets and damage the vascular endothelium, promoting both thrombosis and a rapid loss of circulating platelets hypersensitivity reactions – because commercial heparin is extracted from animal tissues, these preparation may be contaminated with antigens that can promote allergy

- possible allergic responses include chills, fever, and urticaria others – local irritation and hematoma, vasospastic reactions, osteoporosis Contraindications: after surgery of the eye, brain,

should be avoided both during and immediately

or spinal cord lumbar puncture and regional anesthesia Lab Monitoring: objective of anticoagulant therapy is to reduce blood coagulability to a level that is low enough to prevent thromosis, but not so low as to promote spontaneous bleeding goal is difficult and requires careful control of dosage based on frequent tests of coagulation most commonly used test is the Activated Partial Thromboplastin Time (aPTT) - normal value is 40 seconds - at therapeutic levels, heparin increases aPTT by a factor of 1.5 – 2, making the aPTT 60 – 80 seconds - measurement of aPTT should be made frequently (every 4 – 6 hrs) during the initial phase of therapy and once daily after effective dosage is established B.

LOW MOLECULAR WEIGHT HEPARINS - enoxaparin (lovenox), dalteparin (fragmin), tinzaparin (innohep) - simply heparin preparations composed of molecules that are shorter than those found in unfractionated heparin - as effective as unfractionated heparin, can be given on a fixed-dose schedule and don’t require aPTT monitoring, can be used at home, and is far less expensive than unfractionated heparin - less likely to cause thrombocytopenia - now considered the first line therapy for prevention and treatment of established DVT, and DVT following hip or knee replacement surgery - administered SC Adverse Effects: bleeding is the major complication with treatment can cause immune-mediated thrombocytopenia

can cause severe neurologic injury, including permanent paralysis - risk of serious harm is increased by concurrent use of antiplatelet drugs (aspirin) or warfarin 1.

Enoxaparin (lovenox) - approved for prevention of DVT following hip and knee replacement surgery or abdominal surgery in patients considered at high risk of thromboembolic complications - approved for prevention of ischemic complications in patients with unstable angina or non-Q-wave MI - administration is by deep SC injection

IV.

ORAL ANTICOAGULANTS

- warfarin, anisindione - used to prevent thrombosis - have a delayed onset of action, which makes them inappropriate for emergency use - well suited for long term prophylaxis - carry a significant risk of hemorrhage, amplified by the many drug interactions A.

WARFARIN - coumadin - initially used to kill rats and remains one of the most widely used rodenticides - suppresses coagulation by acting as an antagonist of vitamin K - blocks the biosynthesis of vitamin K dependent factors - specific indications are: • prevention of venous thrombosis and associated pulmonary embolism • prevention of thromboembolism in patients with prosthetic heart valves • prevention of thrombosis during a-fib - also used to reduce the risk of recurrent transient ischemic attacks (TIAs) and recurrent MI - due to delayed onset of effects, not useful in emergencies Monitoring: evaluated by monitoring prothrombin time (PT) – coagulation test that is especially sensitive to alterations in vitamin K dependent fators

- average PT value is 12 seconds - warfarin treatment prolongs PT results are reported in terms of an international normalized ratio (INR) - determined by multiplying observed PT ratio by a correction factor specific to particular thromboplastin preparation employed for the test objective of treatment is to raise the INR to appropriate valve - INR of 2 – 3 is appropriate for most patients, although for some the target INR is 3 – 4.5 - if INR is below recommended range, warfarin dosage is increased - if INR is above recommended range, warfarin dosage is reduced - INR cannot be altered quickly - PT must be determined frequently during therapy - daily during the first 5 days - twice a week for the next 1 – 2 weeks - once a week for the next 1 – 2 months - every 2 – 4 weeks thereafter - blood should be drawn no sooner than 5 hours after an IV injections and no sooner than 24 hours after an SC injection Adverse Effects:

hemorrhage - bleeding is the major complication - can occur at any site - severe overdose can be treated with vitamin K - patients should be encouraged to carry identification

(Medic Alert bracelet) to inform emergency personnel of warfarin use - given detailed verbal and written instructions regarding signs of bleeding, dosage size and timing, and scheduling of PT tests - advises to record administration of each dose, rather than relying on memory fetal hemorrhage & teratogenesis during pregnancy – warfarin can cross the placenta and effect the developing fetus - fetal hemorrhage and death can occur - can cause gross malformation, central nervous system (CNS) defects and optic atrophy - FDA Risk Category X: risks to the developing fetus outweigh any possible

benefits of treatment - if pregnancy occurs, possibility of termination should be discussed - heparin, which does not cross the placenta, should be employed if necessary during lactation – warfarin should be advised against while breast feeding Warnings and Contraindications – not for patients with severe thrombocytopenia or uncontrollable bleeding, lumbar puncture, regional anesthesia, surgery of the eye, brain, or spinal cord, hemophilia, increased capillary permeability, dissecting aneurysm, GI ulcers, severe hypertension, and women anticipating abortion Vitamin K1 for Warfarin Overdose: vitamin K1 antagonizes warfain’s actions and can thereby reverse warfarin-induced inhibition of clotting factors synthesis - vitamin K may be given orally or IV - should be diluted and infused slowly before IV administration due to causing severe anaphylactoid reactions (flushing, hypotension, and cardiovascular collapse) - if vitamin K fails, levels of clotting factors can be raised quickly by infusing fresh whole blood, fresh-frozen plasma, or plasma concentrates of vitamin Kdependent clotting factors

V.

ANTIPLATELET DRUGS - agents that suppress platelet aggregation - indication is prevention of thrombosis in arteries

A.

ASPIRIN - suppresses platelet aggregation - proven applications: primary prevention of MI (prevention of a first MI) secondary prevention of MI (prevention of reinfarction in patients who have already had an MI) prevention of stroke in patients with a history of TIAs - although it lowers the risk of MI, it does not reduce the risk of death - cardiovascular risk is based on age, gender, cholesterol levels, blood pressure, and smoking status Adverse Effects: increases the risk of GI bleeding and hemorrhagic stroke

B.

ADENOSINE DIPHOSPHATE RECEPTOR ANTAGONISTS - clopidogrel (plavix) - cause irreversible blockade of ADP receptors on the platelet surface, preventing ADP stimulated aggregation - effects begin 2 hrs after initial dose and plateau after 3 – 7 days of use - platelet function and bleeding time return to baseline about 7 – 10 days after treatment is stopped - approved for secondary prevention of ischemic stroke, MI, and other vascular events in patients with atherosclerosis documented by recent MI, recent stroke, or established peripheral arterial disease - administered orally, with or without food - dosage does not have to be changed for elderly or those with renal dysfunction - can cause potentially fatal hematologic effects Adverse Effects: generally well tolerated abdominal pain, dyspepsia, diarrhea, rash and GI bleeding can cause TTP, usually during the first 2 wks of treatment C.

GLYCOPROTEIN LLB/LLA RECEPTOR ANTAGONISTS - sometimes called “super aspirins” - mot effective antiplatelet drugs - administered IV, usually in combination with aspirin and low-dose heparin - treatment is expensive 1.

Abciximab (reopro) - purified fragment of a monoclonal antibody - binds to platelets and prevents receptor from binding

fibrinogen - in conjunction with aspirin and heparin, approved for IV therapy of acute coronary syndromes (ACSs) and patients undergoing balloon or laser angioplasty (PCIs) - can accelerate revascularization in patients undergoing thrombolytic therapy for acute MI - effects persist for 24 – 48 hours after stopping infusion Adverse Effects: doubles the risk of bleeding may cause GI, urogenital, and retroperitoneal bleeds

does not increase the risk of fatal hemorrhage or hemorrhagic stroke 2.

Eptifibatide (integrilin) - small peptide that causes reversible and highly selective inhibition of GP IIb/IIIa receptors - approved for use in ACSs and patients undergoing PCIs - effects reverse by 4 hrs after stopping infusion - bleeding is primary adverse effect

3.

Tirofiban (aggrastat) - neither an antibody nor a peptide, modeled after a platelet inhibitor isolated from the venom of the sawscaled viper, a snake indigenous to Africa - used to reduce ischemic events associated with ACSs and PCi - platelet function returns to baseline within 4 hrs of stopping the infusion - bleeding is primary adverse effect

V.

THROMBOLYTIC DRUGS

- also known as fibrinolytics (and formally as clot busters) - given to remove thrombi that have already formed - all carry a risk of serious bleeding and should be administered only by clinicians skilled in their use - employed acutely and only for severe thrombotic disease A.

ALTEPLASE (TPA) - activase - also known as tissue plasminogen activator (tPA) - commercial preparations are identical to naturally occurring human tPA, an enzyme that promotes conversion of plasminogen to plasmin, an enzyme that digests the fibrin matrix of clots - low therapeutic doses produce selective activation of plasminogen that is bound to fibrin in thrombi - activation of plasminogen in the general circulation is minimized - bleeding tendencies are equivalent to those seen with other thrombolytic drugs - risk of intracranial bleeding is higher - does not cause allergic reactions or induce hypotension - short half-life (about 5 minutes) owing to rapid hepatic inactivation - indicated for acute MI, pulmonary embolism and treating ischemic stroke - expensive

- given by an “accelerated” or “front-loaded” schedule - for patients who weigh over 67 kg, total dose for treating acute MI is 100 mg - administration is divided into 3 phases: a 15 mg bolus followed by 50 mg infused over 30 minutes followed by 35 mg infused over 60 minutes B.

TENECTEPLASE (TNKASE) - variant of human tissue plasminogen activator (tPA, alteplase) - approved for treating patients undergoing acute MI - just as safe and effective as tPA, but much easier to use - - given by bolus injection - thrombolysis develops faster and emergency room personnel are spared the work of monitorin a prolonged infusion - has the potential to allow dosing before the patient reaches a hospital - dosage is based on body weight - no one is given more than 50 mg - cost is identical to tPA (activase)