Oral Anticoagulants Lecture Notes PDF

Oral Anticoagulants Cyrielle Billon, Ph.D [email protected] IP: Cardiology (PHAR5121) 11/01/2024  Learning objectives 1. Explain the mechanism of action of warfarin 2. Know the factors that affect individual’s response to warfarin 3. Discuss the adverse effects of warfarin...

Oral Anticoagulants Cyrielle Billon, Ph.D [email protected] IP: Cardiology (PHAR5121) 11/01/2024  Learning objectives 1. Explain the mechanism of action of warfarin 2. Know the factors that affect individual’s response to warfarin 3. Discuss the adverse effects of warfarin 4. Know the treatment of warfarin toxicity and explain the rationale behind it 5. Understand warfarin interactions (drug-drug, drug-food) 6. Explain mechanism of action of DOACs 7. Discuss reversal agents for DOACs 8. Compare and contrast newer oral therapies and warfarin 2 Footer  Anticoagulants Parenteral anticoagulants (used both in arterial and venous thrombosis): – Indirect thrombin inhibitors: Heparin – Direct thrombin inhibitors: Lepirudin (obsolete) Bivalirudin Argatroban Oral anticoagulants (used mainly in venous thrombosis): – Warfarin – Direct thrombin (dabigatran) or factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban), also known as direct oral anticoagulants (DOACs) 3 Footer  Coagulation cascade: 4 Footer https://www.chegg.com/learn/biology/anatomy-physiology-in-biology/prothrombin-and-blood-clotting Activation of clotting factors Inactive clotting factors: N-terminal γ- carboxyglutamic acid (Gla) Binds Ca2+ γ-carboxyglutamic acid (Gla) Synthesis by g-glutamyl enzyme Dependent of vitamin K 5 Footer From Rang and Dale’s Pharmacology Activation of inactive clotting factors and vitamin K cycle And anti-coagulant And anti-coagulant protein C and S protein C and S Carboxy-glutamic Acid => Increase Ca2+ binding for activation Vitamin K Oxide Reductase 6 Footer From VALERY L. CHU; HELENE C. MALTZ  Oral anticoagulants: Warfarin Synthetic congener of dicumarole, a substance identified as a hemorrhagic agent that caused disease in cattle fed spoiled sweet clover Originally used as rodenticide 7 Footer Warfarin: Mechanisms of Action Hepatocytes - Vitamin K antagonist - Inhibition of VKORC1 - No recycling of Vitamin K - No g-carboxylation of newly synthesized clotting factors 8 Footer  Warfarin: clinical use Prevention and treatment of venous thrombosis SLOW onset of action (no effect on fully carboxylated coagulation factors). Long half-life of coagulation factors => full effect is not achieved for several days. Therapy is monitored – INR (international normalized ratio) =(patient PT/the mean of PT for the lab)ISI – Target INR is 2-3 for most indications 9 Footer  Drug and other interactions Absorption can be reduced by binding to cholestyramine Warfarin: racemic mixture of R (less potent) and S (more potent) enantiomers. S-warfarin is metabolized by CYP2C9 R-warfarin is metabolized predominantly by CYP1A2 and CYP3A4. Some drugs stereoselectively inhibit the metabolism of warfarin. Excessive vitamin K intake might cause “resistance” to warfarin Patients must be educated to report addition and discontinuation of any medication 10 Footer Major CYP isoforms involved in Warfarin’s metabolism CYP2C9: Role in activation of Warfarin (S isoform). Prone to polymorphism VKORC1: prone to polymorphism too 11 Footer Pharmacotherapy(28):9, pp. 1084-1097, 2008  Examples of drug interactions From Katzung: Basic and Clinical Pharmacology 12 Footer  Question: Which Cyp is involved in S-Warfarin metabolism? A. Cyp1A1 B. Cyp1A2 C. Cyp2C9 D. Cyp 3A4 13 Footer  Question: Which Cyp is involved in S-Warfarin metabolism? A. Cyp1A1 B. Cyp1A2 C. Cyp2C9 D. Cyp 3A4 14 Footer  Warfarin pharmacogenetics: Polymorphisms in metabolizing enzymes (CYP2C9) More than 30 variants CYP2C9 variants affect warfarin pharmacokinetics. - Reduced – CYP2C9*2: missense mutation 430C>T, causes Arg144Cys enzymatic activity – CYP2C9*3 missense mutation 1075A>C, causes Ile359Leu - Dose reduction 15 Footer  Warfarin pharmacogenetics: Genetic polymorphisms in VKORC1 Promoter region of VKORC1 – -1639G>A, also known as 3673. Other intronic polymorphisms: – 497T→G or 5808 Haplotype Group A – 1173C→T or 6484 – 1542G→C or 6853 – 2255C→T or 7566 VKORC1 variants affect warfarin pharmacodynamics. The non-A/A and A/A forms have decreased requirements for warfarin compared to non-A/non-A. 16 Footer  Effect of CYP2C9 genotypes and VKORC1 haplotypes on Warfarin dosing Genotype/ Frequency (%) Dose Haplotype reduction Caucasians African Asians compared with Americans wild type (%) CYP2C9 *1/*1 70 90 95 - *1/*2 17 2 0 22 *1/*3 9 3 4 34 *2/*2 2 0 0 43 *2/*3 1 0 0 53 *3/*3 0 0 1 76 VKORC1 Non-A/non-A 37 82 7 - Non-A/A 45 12 30 26 17 Footer A/A 18 6 63 50  Genetic determinants of response to warfarin during initial anticoagulation 18 Footer Schwarz U et al. NEJM, 358(10): pp. 999–1008, 2008  Dosing considerations Clinical factors including age, race, body weight, sex, concomitant medications, diet and comorbidities Genetic factors (CYP2C9 and VKORC1 genotypes) Onset of action is delayed based on half life of vitamin K-dependent coagulation factors and anticoagulant proteins 19 Footer  Warfarin: toxicity Bleeding – INR above therapeutic range: discontinue warfarin, or adjust dose – INR>10 with no evidence of bleeding: give vitamin K – Warfarin-associated major bleeding: four-factor concentrate (containing factors II, VII, IX, and X) + vitamin K Causes birth defects (contraindicated in pregnancy) Skin necrosis – Occurs rarely (3 to 10 days after treatment is initiated). – Probably a consequence of a temporary imbalance between anticoagulant protein C and coagulation factors (protein C has shorter half-life than vitamin K-dependent coagulation factors) 20 Footer  Warfarin: summary 21 Footer  Direct oral anticoagulants (DOACs) Recently introduced Direct thrombin inhibitor – Dabigatran Factor Xa inhibitors – Rivaroxaban – Apixaban – Edoxaban 22 Footer  Direct oral anticoagulants (DOACs): Mechanism of action 23 Footer Modified from: Heike Schwarb and Dimitrios A. Tsakiris  DOACs Immediate onset of action Direct inhibition clotting factors (Xa and IIa) already in plasma No monitoring required Less drug interactions in comparison with Warfarin All DOACs are p-glycoprotein substrates (transport for drug efflux) 24 Footer  Example : Dabigatran - Inhibitor of thrombin (factor IIa) - Pro-drug metabolize to active form in liver - Antidote: - Idarucizumab, proprietary name: Praxbind - Antibody fragment - Approved in 2015 25 Footer  Example : Rivaroxaban and apixaban - Reversible inhibitors of active Factor X (Xa) - High affinity for Factor Xa - Bind both free and clot bound factor Xa - Reminder: Factor Xa activates Thrombin - Decreases thrombin formation - Bot drugs are CYP3A4 substrates - Antidote: - Andexanet alfa: FDA-approved agent 26 Footer Example : Factor Xa inhibitor - Factor Xa: crossroads between the intrinsic and extrinsic pathways S419: Catalytic site for Factor Xa (conversion prothrombin to thrombin). GLA: the ɤ-carboxyglutamic, responsible for factor Xa binding to platelet membranes. Platelet membrane 27 Footer Modified form Shah and Rattu  Example : Factor Xa inhibitor antidote Andexanet Alpha - Approved in 2018 - Modified recombinant protein derived from human coagulation factor Xa - S419A: Mutation Catalytic site (block conversion prothrombin to thrombin). - Lack GLA domain - Sequesters with high specificity factor Xa inhibitor - 28 Footer Modified form Shah and Rattu Ciraparantag Investigational reversal agent (antidote), also known as PER977 and aripazine Cationic molecule, Non-covalent hydrogen bonds, as well as charge-charge interactions with its anticoagulant targets Predicted to interact with DOACs, heparins and dabigatran Some studies are questioning its ability to directly interact with certain anticoagulants and propose role for activation of factor IXa 29 Footer  Question: What drug is an imitation of factor Xa that reverses the anticoagulant action of Xa? A. Rivaroxaban B. Apixaban C. Dabigatran D. Andexanet Alpha 30 Footer  Question: What drug is an imitation of factor Xa that reverses the anticoagulant action of Xa? A. Rivaroxaban B. Apixaban C. Dabigatran D. Andexanet Alpha 31 Footer  Existing and emerging anticoagulant drugs 32 Footer Wolberg, A. S. et al. (2015) Venous thrombosis Nat. Rev. Dis. Primers  Learning objectives 1. Explain the mechanism of action of warfarin 2. Know the factors that affect individual’s response to warfarin 3. Discuss the adverse effects of warfarin 4. Know the treatment of warfarin toxicity and explain the rationale behind it 5. Understand warfarin interactions (drug-drug, drug-food) 6. Explain mechanism of action of DOACs 7. Discuss reversal agents for DOACs 8. Compare and contrast newer oral therapies and warfarin 33 Footer