Med Phys Pharm L27 Anticoagulant Pharmacology (student) (1), Fall 2024 PDF

Lecture #27: Anticoagulant Pharmacology Brian Skinner, PharmD, BCPS Associate Professor of Internal Medicine Marian University – College of Osteopathic Medicine BMS 551 Med Phys Pharm Schedule Office...

Lecture #27: Anticoagulant Pharmacology Brian Skinner, PharmD, BCPS Associate Professor of Internal Medicine Marian University – College of Osteopathic Medicine BMS 551 Med Phys Pharm Schedule Office Hours Fall 2024  Objectives 1. Define hemostasis, it’s clinical manifestations, and general therapeutic strategies for treatment 2. Recall the three components of Virchow’s Triad, and recognize examples of each component 3. Diagram the clotting cascade and correlate how anticoagulants disrupt the cascade 4. Describe the roles of Antithrombin III, Protein C, and Protein S in the clotting cascade 5. Relate how changes in aPTT, PT, and INR are reflected in the clotting cascade, and how they are utilized for therapeutic drug monitoring 6. Identify the mechanism of action, dosage form, adverse events, and contraindications of anticoagulants and thrombolytics discussed in this lecture 7. Recall the drug of choice for treatment and prophylaxis of blood clots in pregnant patients 8. Identify the antidotes associated with warfarin, heparin products, factor Xa inhibitors, and directed thrombin inhibitors and how they work 9. Predict the impact of Antithrombin III deficiency on pharmacotherapeutic selection 10. Given a simplified patient case, recommend the most appropriate pharmacotherapeutic strategy Unless otherwise noted, figures in today’s lecture are from: Principles of Pharmacology 3e Baca, Golan (Ch. 22), Lippincott Illustrated Reviews: Pharmacology 6e Yellepeddi (Ch. 22)  Drug List Drug Name Mechanism of How Supplied? Adverse Effects/ Therapeutic Reversal Agent(s) Action (Oral vs injectable) Contraindications Indications (including safety in pregnancy) Heparin Enoxaparin Apixaban Rivaroxaban Fondaparinux Argatroban NONE Bivalirudin Dabigatran Warfarin Alteplase NONE My advice: Pay attention to drug names and spelling **hints are above**!!!!! Hemostasis and Thrombosis Hemostasis – the stopping of blood flow Thrombosis – the most common abnormality of hemostasis Platelet-rich clots (White thrombus) Myocardial Infarction (MI) Focus of L28 Transient Ischemic Attacks (TIAs) Peripheral Arterial Clots Fibrin-rich clots (Red thrombus) Cardioembolic strokes from atrial fibrillation Focus of L27 Deep Vein Thrombosis (DVT) Pulmonary Embolism (PE)  Virchow’s Triad Immobility Venous obstruction (obesity, Circulatory Stasis pregnancy, tumor) Varicose Veins Atrial fibrillation Surgery Malignancy Cellulitis Pregnancy THROMBUS Atherosclerosis Estrogen therapy FORMATION Venepuncture Inherited thrombophilia Trauma Hypercoagulability Endothelial Injury  Clotting Cascade: Simplified XII XI VII III Intrinsic Pathway IX Extrinsic Pathway (aPTT) (PT) VIII ________________ Start of the common pathway X Common Pathway _______________ V Extrinsic Pathway II Common Pathway _______________ (aPTT & PT) Intrinsic Pathway I ________________ Fibrin Clot  Clotting Cascade: Simplified XII XI VII III Intrinsic Pathway IX Extrinsic Pathway (aPTT) (PT) VIII X Antithrombin III V II Common Pathway (aPTT & PT) Protein C & S I Fibrin Clot  Understanding Bleeding Times Activated Partial Prothrombin Time Thromboplastin Time (aPTT) (PT) Pathways measured Intrinsic and Common Extrinsic and Common Normal Values 30-40 seconds 11-13.5 seconds Pharmacological Uses Unfractionated Heparin Efficacy Warfarin Efficacy (via PT/INR*) *INR is calculated by taking the patients PT and dividing by a standard PT. A normal INR is equal to 1  Comprehension Check #1 A 53 year old male is brought to the ER after a motor vehicle accident. Coagulation studies are sent off to the lab, and a blood transfusion is initiated. The following are results from the lab: Test Patient Result Reference Range aPTT 58 seconds 30-40 seconds PT 20.4 seconds 11-13.5 seconds Assuming a single factor deficiency exists, which of the following factors is most likely affected in this patient? A. Factor II B. Factor VII C. Factor XII  Anticoagulants Used therapeutically and prophylactically AKA can both treat and prevent thrombotic disease Four main classes Vitamin K Antagonists Heparin and heparin-derived products Factor Xa inhibitors Direct Thrombin (Factor IIa) Inhibitors Goal of Therapy Prevent clot formation Prevent clot from getting bigger and allow body to natural breakdown clot over 3-6 months (treatment) Vitamin K Antagonists: Warfarin  Vitamin K Antagonists: Warfarin Mechanism of Action: Inhibition of vitamin K-dependent clotting factors (II, VII, IX, & X along with Protein C & S) Inhibition of vitamin k epoxide reductase complex 1 (VKORC1) Mnemonic: Calculation Skills: 2 + 7 = 9, not 10 Reduces clotting factor production by 10-40% due to lack of γ-carboxyglutamyl side chains Therapeutic Use: Treatment and prevention of DVT, PE, and cardioembolic stroke from atrial fibrillation and/or prosthetic heart valves  Simplified Clotting Cascade: Warfarin XII XI VII III Intrinsic Pathway IX Extrinsic Pathway (aPTT) (PT) VIII X V II Common Pathway (aPTT & PT) Protein C & S I Fibrin Clot  Full Clotting Cascade: Warfarin Name Function Half Life Protein C Anticoagulant 8 hours Protein S Anticoagulant 30 hours Factor VII Procoagulant 7 hours Factor IX Procoagulant 24 hours Factor X Procoagulant 36 hours Factor II Procoagulant 50 hours Patients are initially HYPERcoagulable when starting warfarin therapy https://teachmephysiology.com/immune-system/haematology/coagulation/  Vitamin K Antagonists: Warfarin Pharmacokinetics: Slow onset compared to all other anticoagulants May take 3-5 days to fully deplete clotting factors When starting therapy, patients are put on a heparin or enoxaparin bridge for 3-5 days Metabolism: CYP2c9 (Major); CYP2C19, CYP3A4, CYP 1A2 (Minor) AKA: TONS OF DRUG INTERACTIONS  Vitamin K Antagonists: Warfarin Reversal Agent: Non-life-threatening bleeds: Vitamin K1 (phytonadione) Life-threatening bleeds: Vitamin K1 PLUS either4-Factor Prothrombin Concentrate Complex (4F-PCC) or fresh frozen plasma (FFP) 4F-PCC FFP Blood Type Matching No Yes Thaw Time N/A 30-45min Clotting factors II, VII, IX, X I, VII, X Volume > II Onset 20-30 minutes 3-5 hours Half-life 1.5-2 hours 4.5-7 hours Epidural Placement 6-12 hours after last dose 12-24 hours after last dose Place in Therapy 3rd Trimester 1st and 2nd Trimester  Fondaparinux Synthetically derived pentasaccharide sequence found in heparin products Injectable formulation only (subcutaneous) What do you think it’s mechanism is? Will it interact with antithrombin III? Will it inactivate Xa, thrombin, or both? Contraindicated in end stage renal disease  “Indirect” Factor Xa Inhibitors: Fondaparinux Mechanism of Action: Inhibition of factor Xa via antithrombin III binding Indications: Treatment and prevention of DVT and PE Side effects: Bleeding, but NO risk for HIT Substantial renal elimination, therefore contraindicated in patients with severe renal impairment Reversal Agent: There is no available agent approved for fondaparinux reversal “Direct” Factor Xa Inhibitors: Rivaroxaban and Apixaban Mechanism of Action: Inhibition of factor Xa independent of antithrombin III activity Binds directly to Factor Xa How Supplied: Oral tablets Indications: Treatment and prevention of DVT, PE, and cardioembolic stroke from atrial fibrillation Side effects: Bleeding (risk is greater with rivaroxaban) Rivaroxaban only – increased risk of treatment failure when taken on an empty stomach therefore must be taken with a meal Rivaroxaban only – contraindicated in patients with severe renal disease  “Direct” Factor Xa Inhibitors: Rivaroxaban and Apixaban Reversal agent: Andexanet alfa Dosing is based on the dose of the factor Xa inhibitor administered and the timing of the last dose Mechanism of Reversal Andexanet alfa is a truncated, inactive Lexi-Comp® form of human factor Xa Serine 149 replaced with alanine Removal of membrane-binding domain (γ-carboxyglutamic acid) Binds to and sequesters factor Xa Favresse et al. Expert Opinion BiologTher. 2019;19(5)387-97 inhibitors  Direct Thrombin Inhibitors: Dabigatran etixalate Mechanism of Action: Prodrug converted in the blood, liver, and gut to dabigatran via nonspecific esterases Dabigatran inhibits thrombin (factor IIa) independent of antithrombin III activity Binds directly to thrombin How Supplied: Oral tablets Indications: Treatment and prevention of DVT, PE, and cardioembolic stroke from atrial fibrillation Side effects: Bleeding (much greater bleeding risk than rivaroxaban and apixaban) Contraindicated in patients with renal dysfunction  Direct Thrombin Inhibitors: Dabigatran etixalate Reversal agent: Idarucizumab Mechanism of Reversal Idarucizumab is a humanized https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.115.019628 monoclonal antibody fragment (Fab) that binds to specifically to dabigatran 350x’s more potent than thrombin at binding to dabigatran Binds to and sequesters dabigatran in minutes https://www.stroke-manual.com/praxbind-idarucizumab/ What do we do if we need an intravenous agent but the patient has a history of HIT?  Direct Thrombin Inhibitors: Bivalirudin and Argatroban Mechanism of Action: inhibits thrombin (factor IIa) independent of antithrombin III activity Originally derived from leech saliva (hirudin) How Supplied: IV infusions (only used on inpatients) Indications: Bivalirudin – alternative to heparin in patients undergoing percutaneous coronary intervention (PCI) at risk of HIT or with a history of HIT Argatroban – alternative to heparin in patients with DVT/PE at risk of HIT or for the treatment of HIT Side effects: Bleeding Reversal agent: No available reversal What do we do if we need to quickly eliminate a clot that has already formed? Remember: The anticoagulants only stabilize the clot and prevent it from getting bigger so our body can naturally eliminate it over ~3 months  Thrombolytic Pathway (simplified) Goal – Acutely eliminate a clot that has already formed II I Fibrin Clot tissue plasminogen activator (t-PA) Plasminogen Plasmin Fibrin Degradation Products (FDP)  Thrombolytics – Alteplase Treatment goal – Acutely eliminate a clot that has already formed Reserved for high-risk patients Therapeutic Uses: Acute ischemic stroke, high-risk PE, STEMI Low-dose also used for catheter clearance ONLY Available as an IV formulation Mechanism of action: Initiation of fibrinolysis by binding to fibrin and converting plasminogen to plasmin Adverse Effects: INCREDIBLY HIGH RISK OF BLEEDING – GREATER THAN ANYTHING WE HAVE TALKED ABOUT TODAY Thrombolytics – Alteplase (FYI ONLY) https://www.ebmedicine.net/topics.php?paction=dLoadPP&topic_id=678&referrer=External  Comprehension Check #2 Jane Doe is an 87 year old female with chronic kidney disease on dialysis. She was newly diagnosed with atrial fibrillation and has been determined to be a candidate for anticoagulation. She is very nervous about being placed on an anticoagulant and is terrified of the thought of sticking herself with a needle everyday, though she is fine with getting her blood drawn if necessary. Which of the following is BEST to begin in this patient? A. Dabigatran B. Enoxaparin C. Fondaparinux D. Rivaroxaban E. Warfarin Questions?  Lecture #26: Anticoagulant Pharmacology Brian Skinner, PharmD, BCPS Assistant Professor of Internal Medicine Marian University – College of Osteopathic Medicine BMS 551 Med Phys Pharm Schedule Office Hours Fall 2023  Comprehension Check #1 A 53 year old male is brought to the ER after a motor vehicle accident. Coagulation studies are sent off to the lab, and a blood transfusion is initiated. The following are results from the lab: Test Patient Result Reference Range aPTT 58 seconds 30-40 seconds PT 20.4 seconds 11-13.5 seconds Assuming a single factor deficiency exists, which of the following factors is most likely affected in this patient? A. Factor II B. Factor VII C. Factor XII  Comprehension Check #2 Jane Doe is an 87 year old female with chronic kidney disease on dialysis. She was newly diagnosed with atrial fibrillation and has been determined to be a candidate for anticoagulation. She is very nervous about being placed on an anticoagulant and is terrified of the thought of sticking herself with a needle everyday, though she is fine with getting her blood drawn if necessary. Which of the following is BEST to begin in this patient? A. Dabigatran B. Enoxaparin C. Fondaparinux D. Rivaroxaban E. Warfarin  Lecture #27: Anticoagulant Pharmacology Brian Skinner, PharmD, BCPS Associate Professor of Internal Medicine Marian University – College of Osteopathic Medicine BMS 551 Med Phys Pharm Schedule Office Hours Fall 2024