BL 02-27-14 11am-Noon Pharmacology of Anticoagulation Therapy - Leslie Flashcards
Classes of antithrombotic drugs:
- Heparin and oral anticoagulants (prevent clots)
- Fibrinolytic agents (clot busters)
- Anti-platelet agents (prevent clots)
Heparin and oral anticoagulants
- interfere w/ coagulation cascade
- prevent formation of thrombin, which converts fibrinogen to fibrin
Fibrinolytic agents
- promote lysis of clots by increasing formation of plasmin, a serine protease that degrades fibrin
Anti-platelet agents
- inhibit formation of platelet products or block
platelet adhesion, thus preventing platelet aggregation and clot formation
Antithrombotic drugs affect & caution
- Antithrombotic drugs disrupt hemostasis.
- Therefore, fine balance btwn efficacy *& toxicity
- Pts on anti-coagulant therapy must be carefully monitored to avoid hemorrhage.
Heparin - type of drug, source
= an anticoagulant
- occurs naturally in granules of mast cells
- extracted from porcine intestine or bovine lung for therapeutic use
-
Heparin - 3 types
Unfractionated Heparin
Low molecular weight heparins (LMWH)
Unfractionated Heparin
= Proteoglycan containing covalently-linked sulfated
polysaccharide chains of varying length
- Mean MW of 12,000 daltons
- Has the highest negative charge density of any known macromolecule –> poor pharmacokinetcs & bioavailability
Low molecular weight heparins (LMWH)
- lovenox, enoxaparin, dalteparin, nadroparin
- Produced by chemical or enzymatic depolymerization of heparin to 1/3 the size of heparin (~4500 Daltons)
Fondaparinux (Arixtra)
- Synthetic pentasaccharide corresponding to the minimal sequence in heparin for binding antithrombin
Heparins are used for treatment and prevention of:
- Venous thrombosis & pulmonary embolism (rapid onset of action )
- – Used w/ oral anticoagulants & fibrinolytic drugs (heparin as initiation therapy, then switch to warfarin, etc.) - Unstable angina or acute MI
- During & after coronary angioplasty or stent placement.
- During surgery requiring cardiopulmonary bypass.
- Kidney dialysis
Toxicity of heparins
- Bleeding
- Heparin-induced thrombocytopenia syndrome (HIT)
- Allergic events
Bleeding w/heparin
- Anticoagulant effect of heparin disappears w/in hours of discontinuation of drug
- If life-threatening hemorrhage occurs, effect of heparin (and LMWH) can be reversed w/ protamine sulfate (+charged compound that neutralizes heparin)
Heparin-induced thrombocytopenia syndrome (HIT)
- Platelet count decreases (>50%) in 3-5% of patients 5-10 days after heparin
- Caused by development of Abs to platelet factor 4/heparin complexes
- These Abs bind to & activate platelets resulting in a prothrombotic state (venous thromboembolism, arterial thrombosis, MI, stroke)
- Thrombocytopenia is less common with LMWH
Treatment of HIT (heparin-induced thrombocytopenia syndrome)
Direct thrombin inhibitors:
- Argatroban (Novastan) - small molecule inhibitor
- Lepirudin (Refludan) - Recombinant form of hirudin, the anticoagulant from leeches
Allergic events w/ heparin
- Due to contaminant oversulfated chondroitin sulfate (rarely if ever found in nature).
- Activation of contact system (production of bradykinin & complement activation).
- Development of improved screening methods
Warfarin (coumadin)
- the most commonly used oral anti-coagulant
Source/structure of Warfarin
= a derivative of dicumarol, which was discovered as a component in spoiled sweet clover responsible for a hemorrhagic disease in cattle
- Warfarin (Wisconsin Alumni Research Foundation) initially was made (1948) for rodent control
= a vitamin K analogue
Action of Warfarin
= inhibits enzymes that use vitamin K as a
cofactor (acts as VitK cofactor)
- Several coagulation proteins (II, VII, IX & X) undergo vitamin K-dependent gamma carboxylation of N-terminal glutamates
- Vitamin K undergoes oxidation/reduction during the rxn
- Recycling of vitamin K to reduced form by reductases is inhibited by warfarin
- –> depletion of vitamin K
- Coagulation proteins lacking gamma carboxylation cannot bind calcium and are non-functional.
Pharmacokinetics of warfarin
- rapidly absorbed (90 min)
- good bioavailability
- long half-life (36-48 hr).
Full antithrombotic effect of warfarin not achieved until existing coagulation factors in circulation are removed (requires 2-3 days), then they can be replaced by the inactivated factors
—> takes time (3-5 days til action)
Warfarin is used to prevent:
- Venous thromboembolism (in combo w/ heparin, which acts more rapidly)
- Systemic embolism in patients w/ prosthetic heart valves or atrial fibrillation
- Stroke, recurrent infarction, or death in pts w/ acute MI
Adverse effects of Warfarin
Hemorrhage
- Drug is stopped & vitamin K is administered (takes 24-48 hr for reversal since coagulation factors have to be resynthesized)
- Can transfuse plasma to replace coagulation factors
Teratogenic
- Cannot be used during pregnancy since it crosses the placenta & is teratogenic
Drug and food interactions with Warfarin: Increasing Warfarin affect
- Drugs that inhibit platelet function (aspirin).
- Drugs that decrease vitamin K synthesis by intestinal microbes (antibiotics).
- Drugs that displace warfarin from plasma proteins, effectively increasing [active free drug] (clofibrate, phenytoin)
- Drugs that reduce metabolism & elimination of warfarin in liver (cimetidine, amiodorone, phenylbutazone).
Drug and food interactions with Warfarin: Decreasing Warfarin affect
- Drugs that increase the metabolism by inducing metabolic enzymes in the liver (barbiturates, rifampin).
- Drugs that decrease warfarin absorption from the GI tract (cholestyramine).
New oral anticoagulants - Direct thrombin or Factor Xa inhibitors - Advantages
- Rapid onset of action
- Absence of food interactions
- Do not require monitoring (though this is being rethought)
New oral anticoagulants - Direct thrombin or Factor Xa inhibitors - Disadvantages
- Contraindicated w/ kidney disease
- Greater GI bleeding than w/ warfarin
- Short half-life (2 per day –> compliance issues)
- Cost (20X>warfarin)
- No antidote available to reverse effects
Dabigatran etexilate (Pradaxa)
- new oral anticoagulant
- direct thrombin inhibitor
- FDA approved 2010 in atrial fibrillation
- Oral prodrug converted to dabigatran, a potent, direct inhibitor of thrombin.-
- Lower rates of stroke & systemic embolism than with warfarin
- Less intracranial hemorrhage (but increased MI)
- Should not be used in pts w/ prosthetic heart valves (inferior to warfarin)
Apixaban (Eliquis)
- new oral anticoagulant
- Factor Xa inhibitor
- FDA approved 2012 for atrial fibrillation
Rivaroxaban (Xarelto)
- new oral anticoagulant
- Synthetic anti-coagulants that directly inhibit Factor Xa
- FDA approved 2011, 2012 for atrial fibrillation, VTE
- Superior to warfarin in preventing strokes & emboli for treatment of atrial fibrillation
Fibrinolytic Agents - action
Convert plasminogen to plasmin, a protease that degrades fibrin clots
Tissue plasminogen activator (t-PA) (Alteplase)
- a fibrinolytic agent
- Serine protease produced by recombinant DNA technology
- Newer modified forms can be given as bolus injections & have prolonged half-life (retoplase, lanoteplase, tenecteplase)
- The t-PA type fibrinolytic drugs bind fibrin, which increases cleavage of plasminogen to plasmin.
Urokinase (u-PA) (Abbokinase)
- a fibrinolytic agent
- Enzyme obtained from renal cells in culture that
converts plasminogen to plasmin - Does not bind fibrin
Streptokinase (Streplase)
- a fibrinolytic agent
- Non-enzymatic protein obtained from β-hemolytic
streptococci (less expensive than t-PA) - Forms complex w/ plasminogen, which becomes activate and converts to plasmin
Fibrinolytic agents are used for treatment of…
- Acute MI (AMI) - Used in combo w/ aspirin, ASAP after MI (or else not effective)
- Ischemic stroke - Effective if given w/in 3 hr after
- DVT - Used in conjunction w/ heparin / warfarin treatmen
- PE
Adverse effects of Fibrinolytic agent
- Hemorrhage from lysis “physiologic thrombi” at sites of vascular injury
- Induces systemic lytic state due to increased formation of plasmin which destroys other coagulation factors (V,VIII).
- Allergic rxn & formation of Abs to streptokinase
Antiplatelet Drugs - use
- Platelets provide initial hemostatic plug at sites of vascular injury & contribute to pathological thrombi
- Antiplatelet drugs treat acute coronary syndrome (angina, MI) characterized by atherosclerotic plaque rupture & platelet-mediated thrombosis
Three classes of anti-platelet drugs
- inhibit formation of platelet products (aspirin)
- prevent activation/aggregation (ADP receptor antagonists)
- block adhesion proteins (glycoprotein
IIb/IIIa inhibitors)
Aspirin (acetylsalicylic acid)
- anti-platelet drug
- Irreversibly inactivates COX, preventing thromboxane A2 formation by platelets
- Since platelets cannot synthesize new proteins (i.e. COX) the effect is permanent, lasting the life of the platelet (7-10 days)
- used in combination w/ thrombolytic therapy after AMI & thrombotic stroke
- Used for prevention of AMI & stroke in high-risk pts with atherosclerosis
ADP receptor antagonists
- Thienopyridines (clopidogrel (Plavix), ticlopidine (Ticlid), prasugrel
- Ticagrelor (approved 2010)
Thienopyridines - examples
= ADP receptor antagonists Examples: - clopidogrel (Plavix) - ticlopidine (Ticlid) - prasugrel.
Thienopyridines - action
= Oral antiplatelet agents that bind to ADP receptor (P2Y12) on platelets
- block platelet activation by ADP, which inhibits secretion of alpha granules & blocks expression of adhesion proteins GPIIb/IIIa
- binds irreversibly to platelets —> effect lasts for platelet life span (7-10 days)
Thienopyridines - pharmacokinetics
- rapidly absorbed
- BUT have slow onset of action (max effect in 5-7
days) b/c prodrugs (metabolized in liver to active
intermediate –> variable patient responses)
Thienopyridines - uses
- Prevention of cardiac events in pts w/ atherosclerosis & unstable angina in combo w/ aspirin
- Pts w/ aspirin intolerance
- Clopidogrel has fewer adverse effects but Prasugrel is most potent (shown in clinical trails to be better than clopidogrel in preventing death & MI (increased risk of bleeding & cancer))
Ticagrelor - action
- Oral ATP analogue that binds reversibly to ADP receptor P2Y12
Ticagrelor - use/pharmacokinetics
- More rapid action than thienopyridines since it does not require metabolic activation
- Greater platelet inhibition than clopidogrel.
- in treatment of acute coronary syndrome, ticagrelor reduced rate of death w/out an increase in overall major bleeding (compared to clopidogrel)
Glycoprotein IIb/IIIa (GPIIb/IIIa; αIIbβ3)
= an adhesion protein (integrin) on the surface of platelets that is a receptor for fibrinogen
Glycoprotein IIb/IIIa (GPIIb/IIIa; αIIbβ3) inhibitors - action
= block receptor for fibrinogen (Glycoprotein IIb/IIIa) on surface of platelets —> prevent platelet aggregation
Glycoprotein IIb/IIIa (GPIIb/IIIa; αIIbβ3) inhibitors - examples
Abciximab (Reopro)
Eptifibatide (Integrilin)
Abciximab (Reopro)
= Monoclonal antibody fragment against glycoprotein receptor, GPIIb/IIIa
- used following coronary angioplasty & for unstable angina
- Prevents restenosis, recurrent AMI & death when used w/ aspirin & heparin
- Also used in combo w/ thrombolytic drugs for AMI.
- Given IV, inpatient use only
Eptifibatide (Integrilin)
Cyclic peptide inhibitor of binding site on GPIIb/IIIa that is used for unstable angina & during angioplasty
Tirofiban (Aggrastat)
Small molecule inhibitor used for treatment of unstable angina & MI
Adverse effects of Glycoprotein IIb/IIIa inhibitors
- bleeding & thrombocytopenia
- can be reversed by platelet infusions
