Anticoagulant Drugs PDF

Anticoagulant Drugs Fadi Khasawneh, Ph.D. (361) 221-0755 [email protected] 1 1 Learning Objectives At the end of the lectures you should be able to:...

Anticoagulant Drugs Fadi Khasawneh, Ph.D. (361) 221-0755 [email protected] 1 1 Learning Objectives At the end of the lectures you should be able to: List the major drugs used as anticoagulants thrombolytics, and procoagulants. Explain the mechanisms of action of coagulants, anticoagulants, and thrombolytics, their major side effects, their clinical indications, how their activity is monitored, and their antidotes, if any. Recall drug interactions where these drugs are involved, and explain the mechanisms of interactions. 2 2 1  Anticoagulant Drugs  Prevent formation of fibrin  Major drugs I. Heparin (parenteral) IV II. Warfarin (oral) Heparin chargedmolecule 3 3 Heparin  First extracted from liver by a 2nd year medical student (John Hopkins) in 1916  Commercially extracted from bovine lung, and porcine intestinal mucosa (found in mast cells)  Not a single compound - family of sulfated glucosaminoglycans (mucoploysaccharides) Content and dose expressed in units not mass not giveninmg   Categorized into 1. unfractionated (standard) and 2. low molecular weight (obtained by gel filtration of standard heparin) fractionated  Administered IV/SC not PO (highly negatively charged not absorbed; degraded) or IM (cause hematomas)  Immediate effect 4 localized bleeding 4 won'tbeabsorbedoral sinceitscharged particle 2  Heparin Chemistry dont memorise structure - Used as sodium salt 5 5 Heparin: Mechanism of Action pinhibitsthrombin Antithrombin inhibits several activated coagulation factors (proteases) super antithrombin Heparin binds with antithrombin and accelerates its protease inhibition mgyitoaptpa.in Binding of heparin also induces a conformational change in antithrombin that makes the reactive site more accessible to the protease Prevents formation of fibrin  prevent coagulation  Monitor by measuring aPTT 6 6 3  Heparin: Mechanism of Action (2) Heparin binds with the positively 0 charged region of antithrombin and increases the rate of interaction with proteases  i inactivate proteases  reduce coagulation. L rounds Iiii it 7 7 Heparin: Mechanism Heparin binds with antithrombin III and undergocarboxymodification inactivates proteases: IIa,VIIa, IXa, Xa, XIa, XIIa 10,9 7,2 Factorsinhibited byHeparin 12 197 10.9.7.2 IIa Gla residues fibrinformation inhibits 8 8 4  Heparin Vs. Warfarin Advantage: Unlike warfarin, heparin does not cross the placenta, therefore not associated with fetal malformations  drug of choice for anticoagulation during pregnancy. doesnt cross placenta ORformfetalmalformations canuseduring pregnancy 9 9 Heparin – Side Effects - Minor side effects: alopecia hairloss lowplatelets morebleedingrisk a - Major side effects: hemorrhage, thrombocytopenia, allergy rxn - Thrombocytopenia = HIT type 1 (rare; reversible upon withdrawal) 91 99Athmbotis – 2-14 days after initiation of therapy plateletcountbecomesnormalonceheparinstopped – Thrombosis !!! (rare; type 2 HIT: caused by antibodies against heparin- cattakesYtitosis platelet factor 4  platelet activation  clot formation  death G upannbindsto a bodyrecognizesthisasforeign releases - Anaphylactic type (life-threatening) hypersensitivity (rare; antibodies thataitivateplatelet currently watched by the FDA) LMWH is less liable to produce thrombocytopenia Faionatedheparin forhemostasis feedplatelet 10 10 5  Heparin Reversal  Antidote for heparin hemorrhage: Protamine toHeparin protamine – Protein from salmon sperm with basic nature; given slow IV infusion topreventitsfunction – Complex with heparin to form inactive complex – Most active against unfractionated heparin, and partially reverses the anticoagulant effects of LMWH 11 11 Comparison of Heparins LMWH The effects of LMWH are more predictable because of its selectivity to Xa inhibition. Common LMWHs: Enoxaparin Dalteparin Tinzaparin 12 12 6  LMWH  LMWH = low molecular weight heparin – Fractionated heparin containing MW of less than 8000 daltons – Prevention and treatment of deep vein thrombosis (DVT) – Inhibit Xa more selectively – Do not prolong aPTT – Higher therapeutic index – Given SC – Predictable pharmacokinetics  dosing convenient – Common LMWHs:  Enoxaparin (Lovenox®) (available as generic drug as of 7/23/2010)  Dalteparin (Fragmin®)  Do not affect aPTT  Tinzaparin (Innohep®) 13 13 cannotmonitorwithaPTT LMWH – Warning longterm paralysis w some patients http://www.fda.gov 14 14 7  Fondaparinux (Arixtra®) A synthetic pentasacharide Eg.mnteinYe Selective inhibitor of factor Xa Not sensitive to protamine O O 15 O 15 O O Warfarin (Coumadin®)  Discovery: serendipity  Sweet clover substituted for corn in cattle feeds in 1920s spoiledclover bleeding  Spoiled clover feed produced hemorrhagic disease and killed cattle  Culprit?: bishydroxycoumarin (coumarins)  wARFarin Wisconsin Alumni Research Foundation  Used initially as rat poison  Now very common oral anticoagulant 16 16 8  (Synthetic) 17 17 Warfarin - Mechanism of Action Glamodificationof 10,9 7 2 0 clotting factors 98919g roup Thedescarbonyversion of it arenot Enzymeepoxidereductase functional Él reduced hasenough ensuresbody vitkforala modification 18 18 factors Warfarin EpoxideReductase clotting vitaminic reduced Glaresidues nonfunctional prothrombin n fibrinformation 9  Warfarin: Anticoagulant Mechanism  Warfarin may be called as antagonist of vitamin K  Coagulation factors II, VII, IX, and X, as well as the anticoagulant proteins C and S are synthesized mainly in the liver and are biologically inactive unless 9 to 13 of the amino-terminal glutamate residues are carboxylated to form the Ca2+-binding -carboxyglutamate (Gla) residues.  This reaction of the descarboxy precursor protein requires carbon dioxide, molecular oxygen, and reduced vitamin K, and is catalyzed by  -glutamyl carboxylase  Carboxylation is directly coupled to the oxidation of vitamin K to its corresponding epoxide. Reduced vitamin K must be regenerated from the epoxide for sustained carboxylation and synthesis of biologically competent proteins.  The enzymes that catalyzes this; vitamin K epoxide reductase and vitamin K reductase, are inhibited by therapeutic doses of warfarin  inhibition of synthesis of coagulation factors  anticoagulant effect 19 19 Warfarin Mechanism Warfarin inhibits the SYNTHESIS of zymogens: II, VII, IX, X II 20 20 10  Warfarin: Pharmacokinetics CFthatdisappearsfirst V11 7  Delayed effect; 18-24 hrs (Why?) Gift ftpggg asmodiingE  Warfarin is almost completely (99%) bound to plasma proteins, principally albumin. otherproteinbinding warfarin  Vd: small drugscandisplace warfarineffect  Half life: 36 h (metabolized by the liver) bleedingrisk  Monitor INR (2-4) - Has a narrow therapeutic index Warfarin is usually started at a dose of 5–10 mg. The dose is then titrated to achieve the desired target INR. 21 21 Warfarin Reversal  Monitor INR (every 2-4 weeks)  In emergency, reverse with Vitamin K (PO or IV). Plasma infusion is also used. warfarin removesCE reverse sogiveplasmato  Menadiol sod phosphate (synthetic analogue of Vit K) How high doses of Vit K reverses warfarin effect? Vitamin K, if present in high concentrations, also can be converted to the corresponding hydroquinone by a second reductase, DT- diaphorase. This enzyme is less sensitive to coumarin drugs. 22 22 Heparin reversed using protamine sulfate 11  Warfarin – Side Effects - Bleeding - Birth defects (crosses placenta, NOT given during pregnancy) Heparin In begiven - Infrequent ADR  alopecia and anorexia. Hairloss - Of the estimated 100,000 elderly patients in the U.S. who are hospitalized each year through emergency departments due to adverse drug events, about a third of these cases are due to warfarin. 23 23 Warfarin – Drug Interactions enhance effect warfarin K enhancewarfarin lesswarfarineffect warfarin more metabolism Warfarin interacts with several drugs. Hence care should be exercised while dispensing warfarin 24 24 12  Warfarin – Drug Interactions (2) Cotrimoxazole (most commonly prescribed for the treatment of urinary-tract infections) appears to increase the risk of hemorrhage in patients also taking warfarin Cotrimoxazole is known to inhibit CYP2C9, which is involved in warfarin metabolism--this is on top of other known effects of many antibiotics on gut flora less warfarinmetabolised warfarineffeit blegging Fischer HD, Juurlink DN, Mamdani MM, et al. Hemorrhage during warfarin therapy associated with cotrimoxazole and other urinary tract anti-infective agents: A population-based study. Arch Intern Med 2010; 170:617-621. 25 25 Warfarin Pharmacogenomics (1) Relatively new labeling to reflect pharmacogenomics of warfarin was approved by the FDA in 2007. 26 26 13  Warfarin Pharmacogenomics (2)  Warfarin inhibits vitamin K epoxide reductase complex (VKORC1)  S-Warfarin is metabolized principally by CYP2C9.  Reduced vitamin K metabolism is catalyzed by CYP4F2. Response towarfarin depends Jonshon et al., Pharmacological Reviews, 2013 on eachperson'sspecificgenetic makeup 27 27 Novel Oral Anticoagulant direct - Dabigatran Etexilate (Pradaxa®), which is a direct EYE competitive thrombin inhibitor. It’s the first oral anticoagulant approved in the U.S. in over 50 years (approved in October 20 2010). inhibitor -Is a prodrug of dabigatran (a polar compound). Dabigatran Etexilate Dabigatran polar 28 28 14  severe SE Dyspepsia mayneed to stop med Dabigatran Etexilate -ADRs: Bleeding; GI side effects including dyspepsia (most common ADR, and may mandate discontinuation of therapy); and gastritis-like symptoms (e.g., GERD) -DDI: A substrate for p-glycoprotein (a transporter found in the intestine), thus rifampin, St. John’s wort, are likely to reduce blood levels of dabigatran. Jana Dapigatron levels However, no dose adjustment is required with the P-glycoprotein inhibitors such as verapamil, amiodarone. nodoseadjustment needed Reversal agent: Idarucizumab (humanized monoclonal antibody fragment) 29 29 Rivaroxaban (Xarelto®) - An oral factor Xa inhibitor - Approved in September of 2011 30 30 15  Apixaban (Eliquis®) - An oral factor Xa inhibitor - Approved in December 2012 31 31 Edoxaban (Savaysa®) - An oral factor Xa inhibitor - Approved in January 2015 32 32 16  Factor Xa Inhibitor Reversal Andexxa (is a recombinant modified human factor Xa (FXa) Reverse effect of Factor Xa inhibitor by justgiving pt more FactorXa 33 33 Fy FYI 34 34 17  Any questions? The End 35 35 Clot Formation Link for a video that describes the process of hemostasis and clot formation http://www.mhhe.com/biosci/esp/2002_general/Esp/folder_structure/tr/m1/s7/trm1s7_3.htm 36 36 18