BP4 Introduction and Anticoagulants L1 PDF

2024/09/17 Anticlotting agents: Intro and Anticoagulating Drugs L1 Dr Sarentha Chetty BPharm, MSc, PhD Objectives Pathophysiology of clots Classification anticlotting drugs Mechanism of action Therapeutic indications SEs and ADRs Drug Interactions ...

2024/09/17 Anticlotting agents: Intro and Anticoagulating Drugs L1 Dr Sarentha Chetty BPharm, MSc, PhD Objectives Pathophysiology of clots Classification anticlotting drugs Mechanism of action Therapeutic indications SEs and ADRs Drug Interactions  2024/09/17 Blood Clots Clot - important physiological process Prevent excessive bleeding Body naturally dissolves the clot once the injury is healed Clots - inside of vessels when there is no injury/clots do not dissolve naturally – DANGEROUS Clots can occur in veins or arteries Disorders in coagulation Hemostasis: finely tuned process of maintaining blood fluidity, repairing vascular injury, limiting blood loss whilst preventing tissue occlusion Platelet defects e.g. von Willebrand disease: Bleed from surfaces (gingiva, skin, heavy menses) on injury Defects in the clotting mechanism e.g. haemophilia: Bleed into deep tissues (joints, muscle, retroperitonium) – unpredictable Platelet rich thrombi (white thrombi) – high flow rate – arteries Venous clots (red thrombi) – more fibrin rich & trapped RBCs  2024/09/17 Disorders in coagulation Thrombus - unwanted clot in a blood vessel. Blood flow is sluggish accumulation of activated clotting factors Deep vein thrombosis (DVT) - major vein of leg/arms, pelvis or other large veins Part of a thrombus breaks off can travel to the heart or lungs -lodge and prevent adequate blood flow Pulmonary embolism (PE) -lungs How DVT Can Lead to Pulmonary Embolism: https://www.hematology.org/education/patients/blood-clots Atrial fibrillation (AF): Problems in atrial contraction  risk blood stasis Promotes the formation of a thrombus –could detach causes a MI or travel to the brain were it can cause cerebral embolism (stroke).  2024/09/17 The Clotting cascade Blood coagulation cascade Coagulation – transformation of soluble fibrinogen to insoluble fibrin Tissue factor (TF) main initiator binds to factor VIIa begins the cascade Antithrombin (AT) – endogenous anticoagulant Protein C and Protein S – attenuates the blood clotting cascade  2024/09/17 Anticlotting Drugs - Uses Treatment and prevention: oMyocardial infarction oIschaemic stroke in patients with AF oDVT Anticoagulant and thrombolytic drugs: Effective in treatment of venous and arterial thrombosis Antiplatelet drugs: Useful only for treatment of arterial disease.  2024/09/17 Anticoagulants Inhibit the formation of fibrin clots. Three major types: Heparin and related products Direct thrombin and factor X inhibitors Coumarin derivatives Heparin Large sulfated polysaccharide polymer Naturally occurring Molecules of varying size of between 5,000 – 20,000 Unfractionated Highly acidic IV or SC Risk of hematoma associated with IM  2024/09/17 Heparin - Mechanism and effects Unfractionated heparin (UFH) - indirect thrombin inhibitor. Binds to antithrombin III (ATIII) Heparin–ATIII complex irreversibly inactivates thrombin & several other factors, particularly factor Xa. Heparin acts on preformed blood components - immediate anticoagulation Anticoagulation effects monitored - activated partial thromboplastin time (aPTT) Low molecular Weight Fractions Heparin Dalteparin, enoxaparin, nadroparin: MW 2000 – 6000 Better bioavailability and longer durations of action than UFH Once or twice a day S/C Fondaparinux: Active pentasaccharide chemically related to LMW heparin Selective inhibitor of factor Xa with no effect on thrombin Administered S/C once daily.  2024/09/17 LMW Heparins Enoxaparin, dalteparin, and tinzaparin and fondaparinux binds ATIII. Also inhibits factor Xa LMW heparin–ATIII and fondaparinux–ATIII complexes -more selective action because no effect on thrombin. Heparin - Clinical use Rapid effect Common uses : DVT, pulmonary embolism, acute myocardial infarction. Combined with thrombolytics for revascularization Combined with glycoprotein IIb/IIIa inhibitors during angioplasty and placement of coronary stents. Does not cross the placental barrier – safe in pregnancy. LMW heparins & fondaparinux - similar clinical applications to heparin  2024/09/17 Heparin - Toxicity & Reversal Bleeding May result hemorrhagic stroke Antidote for UFH is Protamine sulphate Protamine partially reverses effects of LMW heparins, no effect on fondaparinux UFH causes moderate transient thrombocytopenia Heparin-induced thrombocytopenia (HIT) - Severe thrombocytopenia and thrombosis in those who produce an antibody that binds to a complex of heparin and platelet factor 4 LMW heparins and fondaparinux - less likely to cause HIT Prolonged use UFH - associated with osteoporosis Direct Thrombin Inhibitors Based on proteins made by Hirudo medicinalis Desirudin and bivalirudin are modified forms of hirudin Both are not yet available in SA. Argatroban (not available in SA) is a small molecule with a short half-life. Dabigatran is the only orally active direct thrombin inhibitor.  2024/09/17 Direct Thrombin Inhibitors – Clinical Uses MOA: Binds to the active site of thrombin and to thrombin substrates. The action of these drugs is monitored with the aPTT lab test Dabigatran: Prevention of stroke and systemic embolism in non-valvular AF Prophylaxis of venous thromboembolism (VTE) following hip or knee replacement surgery and Reduction of the risk of recurrent VTE Advantages of oral direct thrombin inhibitors Predictable pharmacokinetics - fixed dosing Predictable immediate anticoagulant response that makes routine monitoring or overlap with other anticoagulants unnecessary.  2024/09/17 Toxicity & Reversal Bleeding CI: Concomitant administration with heparins/warfarins/thrombolytic agents, GP IIb/IIIa inhibitors, clopidogrel, ticlopidine Drug Interactions Itraconazole, tacrolimus, ketoconazole - level of dabigatran by P- glycoprotein (MDR1) efflux transporter Idarucizumab (Praxbind®)is a humanized monoclonal antibody Fab fragment that binds to dabigatran and reverses the anticoagulant effect. Direct Oral Factor Xa inhibitors Rivaroxaban, apixaban (available in SA), and edoxaban (not available in SA) Rapid onset of action and shorter half-lives than warfarin. Fixed oral doses and do not require monitoring. Undergo cytochrome P450-dependent and cytochrome P450- independent elimination. MOA: Bind directly to and inhibit both free factor Xa and factor Xa bound in the clotting complex.  2024/09/17 Direct Oral Factor Xa inhibitors- Clinical use Rivaroxaban Prevention and treatment of VTE following hip or knee surgery Prevention of stroke in patients with AF, without valvular heart disease. Apixaban - Prevention of embolic stroke in patients with non-valvular AF Toxicity & Reversal Can cause bleeding. Reversal agent is andexanet alfa (AndexXa). This is a coagulation factor Xa [recombinant], inactivated-zhzo. Warfarin and Other Coumarin Anticoagulants Small, lipid-soluble molecules Oral Readily absorbed Highly bound to plasma proteins (>99%) Metabolised by cytochrome P450 enzymes  2024/09/17 Warfarin inhibits vitamin K epoxide reductase (VKOR) VCOR converts vitamin K epoxide Mechanism and effects to reduced Vitamin K Vitamin K dependent factors - thrombin and factors II, VII, IX, and X Clotting factors have half-lives of 8–60h. Anticoagulant effect - only after the elimination of the normal preformed factors (4-5 days). Mostbauer, Halyna & Nishkumay, Olga & Rokyta, Oksana & Vavryniuk, Valeriia. (2022). Warfarin resistance: possibilities to solve this problem. A case report. The Journal of international medical research. 50. 3000605221103959. 10.1177/03000605221103959.  2024/09/17 Warfarin – long half life (40hrs) Take up to 5 days for the prothrombin to return to normal after stopping warfarin Reversed with phytomendione (vitamin K), but requires the synthesis of new clotting factors, slow action (6–24 h) Rapid reversal – transfuse with fresh or frozen plasma that contains normal clotting factors. Monitored by the prothrombin time (PT) test Warfarin – Clinical Use Prevention and control of thromboembolism ↓thromboembolism - AF & prosthetic heart valves Toxicity Bleeding Contraindicated: Pregnancy - bone defects, hemorrhage in the developing fetus, CNS effects Recent stroke, intracerebral bleeding, aneurysms Narrow therapeutic window Monitor INR (International normalized Ratio)  2024/09/17 Warfarin – Drug Interactions Metabolized in the liver to inactive 7-hydroxywarfarin. Cytochrome P450-inducing drugs (carbamazepine, phenytoin, rifampin, barbiturates) warfarin’s clearance and ↓ the anticoagulant effect Cytochrome P450 inhibitors (amiodarone, SSRIs, cimetidine) ↓ warfarin’s clearance and  the anticoagulant effect. Genetic variability in cytochrome P450 2C9 and VKOR affect responses to warfarin: Over/under anticoagulation – dependent on metabolizing status (slow or ultra-rapid) Individualized warfarin therapy Task 1 Have a look in the current SAMF? 1. Identify the drugs that have drug-drug interactions with warfarin Group them into P450 inducers and inhibitors 2. Are there any other types of drug-drug interactions? 3. What common foods have interactions with warfarin? 4. What complementary medicines can enhance the effect of warfarin?  2024/09/17 Cautions & Adverse effects CAUTIONS:  risk of bleeding – chronic hepatic disease or severe renal disease Geriatrics -  risk of bleeding over 65 yr Paediatrics – more susceptible to anticoagulant effects – because of Vitamin K deficiency ADVERSE EFFECTS: Haemorrhage - due to warfarin toxicity Warfarin induced skin necrosis (Breasts, buttocks & thighs) Purple-toe syndrome: Rare – painful, purple lesions on the toes and sides of the feet Direct Oral Anticoagulants (DOACs) vs Warfarin DOACs (dabigatran, rivaroxaban) - similar antithrombotic efficacy Lower bleeding tendencies - compared to warfarin. No need for monitoring Fewer drug interactions in comparison to warfarin. Short half-life of the newer anticoagulants means that if the patient is non- compliant - could quickly lead to loss of anticoagulant effect and risk of thromboembolism. Convenient once or twice daily oral dosing Fewer documented drug and dietary interactions  2024/09/17 Drugs that affect Coagulation Michael J. Neal, Pharmacology at a Glance, References Medical Pharmacology at a Glance (Michael J. Neal) Chapter 34: Drugs Used in Coagulation Disorders, Katzung & Trevor's Pharmacology: Examination & Board Review, Basic and Clinical Pharmacology (Katzung), 12e, Accessed at: https://0-accessmedicine- mhmedical-com.innopac.wits.ac.za/Book.aspx?bookid=2465 SAMF