Gurusamy Lecture-2 Anticoagulants Sep 5 2024-1.pdf

Anticoagulant Drugs Anticoagulant Drugs Parenteral:  Oral: Indirect thrombin inhibitors Warfarin Unfractionated Heparin (UFH) Dabigatran etexilate Low molecular weight heparins Rivaroxaban...

Anticoagulant Drugs Anticoagulant Drugs Parenteral:  Oral: Indirect thrombin inhibitors Warfarin Unfractionated Heparin (UFH) Dabigatran etexilate Low molecular weight heparins Rivaroxaban Enoxaparin Dalteparin Apixaban Tinzaparin Edoxaban Fondaparinux Betrixaban Direct thrombin inhibitors Hirudin  Reversal agents for oral Bivalirudin anticoagulants: Desirudin Idarucizumab Argatroban Andexanet alfa Unfractionated Heparin Heparin Low Molecular Weight Heparin Glycosaminoglycans Made from UFH by enzymatic depolymerization Molecular weight 4-6 kDa Produced by mast cells and stored in security granules. Most medical grade heparin is purified from porcelain intestinal mucosa that is rich in mast cells. Molecular weight of chains varies from 3 to 30 kDa (ultra low molecular weight heparin) (mean 15 kDa; or ~45 monosaccharide chain length) A minimum of 18 sacred units is necessary to contain both antithrombin and thrombin binding domains Mechanism of action of heparin, LMWH, and fondaparinux A. Heparin (i) Binding to Antithrombin III (ATIII): Heparin binds to ATIII through a specific pentasaccharide sequence, which causes a conformational change in ATIII. This change accelerates ATIII’s ability to neutralize clotting factors, particularly Factor Xa and thrombin (ii) Inhibition of Factor Xa: Once heparin binds to ATIII, it increases the ability of ATIII to inhibit Factor Xa by up to 1000-fold. The combination of AT III with (iii) Inhibition of Thrombin: unfractionated heparin increases inhibition To inhibit thrombin (Factor IIa) effectively, heparin must of both factor Xa and thrombin. simultaneously bind to both ATIII and thrombin. This interaction only happens with longer heparin molecules (at least 18 saccharide units), like those found in unfractionated heparin. B. LMWH (mean MW ~4500–5000 Da). Predominantly inhibits Factor Xa. Because LMWH has shorter chains, it does not as effectively inhibit thrombin (too short to bridge antithrombin to thrombin). Combination with fondaparinux or LMW heparin more selectively increases inhibition of Xa. C. Fondaparinux, a synthetic pentasaccharide accelerates only factor Xa inhibition by antithrombin; the pentasaccharide is too short to bridge antithrombin to thrombin.  Parenteral Anticoagulants Heparin (Unfractionated heparin; UF) Indications: Initial Treatment of venous thromboembolism Not absorbed by the GI tract - (VTE) and pulmonary embolism. Given by continuous IV infusion, intermittent IV injection or deep SC Initial treatment for unstable angina and treatment injection. of acute myocardial infarction (MI) - during/after coronary angioplasty & stent IM not recommended. - hematomas replacement. will form!! Selected patients with disseminated intravascular Immediate onset of action via IV; SC coagulation. 30 mins - 2 hrs. Half life varies depending on dose: Drug of choice for anticoagulation during eg. 100, 400 or 800 U/kg of heparin pregnancy - does not cross the placenta - IV yields half-lives of 1, 2.5 and 5 discontinue at least 24 hours before delivery if hours, respectively. possible (bleeding issues) Half life is affected by pulmonary Prevention of recurring thromboembolism despite embolism, hepatic cirrhosis and end adequate oral anticoagulant therapy. Venous stage renal disease. thromboembolism in high-risk patients.  Heparin Side Effects: Bleeding episodes occur in 3% of patients (range: 1- 5%). Protamine sulfate is a heparin antagonist, positively charged and forms ionic complex with heparin. Dosing requires 1 mg of protamine for every 100 units of heparin. Protamine is isolated from salmon sperm so it can have anaphylactoid effects and has anticoagulant effects on its own. Only partially reverses LMWH effects Given routinely after certain types of surgery - cardiac  Heparin Side Effects: HIT - heparin induced thrombocytopenia HIT is serious can lead to loss of limbs and death. Seen in 3% of patients 5-10 d after initial therapy. heparin can also bind to platelet factor 4 (PF4), a protein that is released from activated platelets. The binding of heparin to PF4 forms a complex that can be recognized by the immune system as foreign, leading to the production of antibodies against the complex. These antibodies can activate platelets and lead to the formation of blood clots, which can cause the rare but potentially life-threatening side effect of heparin-induced thrombocytopenia. Heparin Side Effects: HIT may lead to life threatening thrombotic complications and/or amputations Thrombocytopenia occurs in 25% of patients. Platelet count C; 1075 C>A lead to reduced enzyme activity, leading to slower clearance of the drug 139 major drug interactions from the body.) 405 moderate drug interactions 70 minor drug interactions VKORC1 variants affect warfarin pharmacodynamics The most studied polymorphism is VKORC1 -1639G>A. Patients with the A variant have reduced expression of the VKORC1 enzyme, making them more sensitive to warfarin’s effects and requiring lower doses of the drug. https://www.drugs.com/drug- VKORC1 variants are more prevalent than those of CYP2C9, interactions/warfarin-index.html particularly in Asians, followed by European Americans and African Americans. The warfarin dose requirement is decreased in patients with these variants.  Warfarin cont’d… Monitoring Parameters In healthy people an INR of 1.1 or below is Warfarin has a narrow therapeutic index (the difference considered normal. between the effective dose and the toxic dose is small.) An INR range of 2.0 to 3.0 is generally an effective therapeutic range for people taking it is highly bound to plasma proteins thus it is highly warfarin for certain disorders. monitored. Treatment of toxicity Prothrombin Time- PT- measures the extrinsic Discontinue the drug if modest system anticoagulant activity without excessive bleeding occurs. INR < 5 International Normalized Ratio- INR was adopted in the 1990’s to monitor warfarin concentration. Administer large amounts of vitamin K (phytonatoide) if excessive The INR corrects for variations that would occur anticoagulant activity and bleeding with different thromboplastin reagents--between occurs. INR > 5 different hospitals, or when a single hospital gets a new lot of reagent. Serious bleeding requires vitamin K, PTpatient factor IX concentrates and fresh frozen INR = plasma to replace clotting factors. INR PTcontrol ≥ 20  Oral Anticoagulants Dabigatran (Pradaxa®) All ORAL direct acting anticoagulants are Dabigatran etexilate is rapidly converted to also known as (other names): dabigatran by plasma esterases (PRO-DRUG). Target specific oral anticoagulants (TSOAC) Direct Oral Anticoagulants (DOAC) Dabigatran competitively and reversibly blocks the Novel (New) Oral Anticoagulants (NOAC) active site of free and clot-bound thrombin; thereby inhibiting thrombin-mediated conversion of fibrinogen to fibrin, feedback activation of coagulation, and platelet activation. Do not bind to plasma proteins, and so produce a predictable therapeutic effect.  Dabigatran (Pradaxa®) Dabigatran, as of April 2014, has a revised Lowers rate of major bleeding, stroke medication guide to reflect the following FDA occurrence, & death; higher rate of dyspepsia approved indications: compared to warfarin. For the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in No need for routine anticoagulation patients who have been treated with a parenteral monitoring (due to more predictable anticoagulant for 5-10 days. anticoagulation response) To reduce the risk of recurrence of DVT and Fewer drug interactions. However: substrate PE in patients who have been previously treated. for P- glycoprotein (P-gp) (P-gp: an ATP- dependent efflux pump, which pumps many In 2015, also indicated for treatment of DVT and foreign substances including drugs out of cells) PE after hip replacement. Concomitant use with P-gp inducers (e.g., Approved in the USA (2010) to reduce the risk rifampin) reduces dabigatran - generally of stroke and systemic embolism in patients avoided. with nonvalvular atrial fibrillation: P-gp inhibitors ketoconazole, verapamil, Superior to warfarin in reduction of stroke and amiodarone, quinidine, and clarithromycin, no systemic embolism. dose adjustments.  Dabigatran (Pradaxa®) Contraindicated in significant renal FDA approved 2015- Idarucizumab impairment (Creatine Clearance (CrCl) < 30 (Praxbind) for use in patients taking mL/min). dabigatran during emergency situations in Dosage reduction is recommended in moderate which there is a need to reverse dabigatran's renal impairment (CrCl 30 to 50 mL/min). blood-thinning effects. Renally excreted by 80%. This is a major First reversal agent approved specifically problem in the elderly- a huge population for dabigatran. needing to take this type of medication. Binds to dabigatran to neutralize its effect. Dosing: 110mg orally twice per day. Labeling for Idarucizumab recommends that patients resume their anticoagulant treatment as soon as medically appropriate.  Dabigatran (Pradaxa®) Dabigatran disadvantages: Dabigatran cost: Approximately $6.75/day or $200/month. An excess of dyspepsia (Upper abdominal discomfort, such as burning sensation, bloating or gassiness, Warfarin cost: nausea, or feeling full too quickly after starting to eat) Approximately $2.5/day or $75/month + monthly INR Gastrointestinal bleeding monitoring cost. Dabigatran advantages over Warfarin: Myocardial infarction No INR monitoring. Not a narrow therapeutic index compared to warfarin The need of twice daily dosing - may Less toxicity profile. increase non-adherence to the treatment Less dietary & drug combination restriction compared to warfarin Safety and efficacy in patients with renal Less risk of bleeding and hepatic impairment Safety and efficacy in patients at high risk of bleeding  Oral Anticoagulant Rivaroxaban (Xarelto®) Not recommended in patients with Creatinine The first ORAL direct factor Xa inhibitor: peak clearance 95 Also approved for treating deep vein mL/min and that kidney function should be thrombosis (DVT) and pulmonary assessed prior to starting treatment. embolism (PE) in patients who have been treated with a parenteral anticoagulant for Patients with a creatinine clearance >95 5 to 10 days. mL/min have a greater risk of stroke compared with similar patients treated with warfarin, according to the FDA.  Oral Anticoagulant Betrixaban (Bevyxxa®) Minimal CYP-independent hydrolysis; P-gp Direct Oral once a day Factor Xa substrate. Inhibitor. Concomitant P-gp Inhibitors: Increased risk of First and only anticoagulant for hospital Caution: Half-life is 19 to 27 hours; bleeding events; reduce dose and extended duration (35-42 days) anticoagulant effect expected to persist for ≥72 prevention of venous thromboembolism hours. (VTE) in acutely ill medical patients. Used mainly in adult patients at risk of No specific antidote exists for betrixaban reversal. thromboembolic complications due to moderate or severe restricted mobility and Most common adverse reactions is bleeding (> 5 percent). - potentially fatal. other risk factors for VTE.  Oral Anticoagulant Betrixaban (Bevyxxa®) Thromboembolic events can occur with premature discontinuation if no alternative anticoagulation given. Avoid in patients with moderate-severe hepatic impairment. Patients with severe renal impairment (CrCl < 30 mL/min) may have an increased risk of bleeding events. Boxed Warning: Spinal/Epidural hematoma may occur in patients who are receiving neuraxial anesthesia or undergoing spinal puncture. Long-term or permanent paralysis may occur.