Lecture 6 Pharmacology of anticoagulants, antithrombotics, and thrombolytics Flashcards
Describe the classification of antagulants based on their mechanism of action.
Anticoagulants are classified into recombinant Anti-thrombin III,
Vitamin K antagonists (e.g., warfarin),
Antithrombin III potentiators (heparins), and
DOACs (Direct-oral anticoagulants) like Direct thrombin inhibitors and Active Factor X inhibitors.
How do anticoagulants like warfarin work at a molecular level?
Warfarin inhibits the Vitamin K-dependent synthesis of coagulation factors (Factor II, VII, IX, X) by blocking the reduction of oxidized vitamin K by vitamin K epoxide reductase, preventing posttranslational carboxylation of coagulation factors.
Define the indications for using anticoagulants in medical practice.
Anticoagulants are used to reduce the risk of stroke, systemic embolisation in atrial fibrillation, prevent DVT and PE in patients undergoing joint replacement, and treat/prevent recurrence of DVT and PE.
How is the clinical use of warfarin affected by its delayed onset of action?
Warfarin has a delayed onset, requiring time to deplete circulating clotting factors. Maximal effect is seen 3-5 days post-initiation. Patients at acute thromboembolic risk may need bridging therapy with LMWH.
Describe the monitoring and reversal methods for warfarin therapy.
Warfarin therapy is monitored using INR to ensure patients are within the therapeutic range. Vitamin K can reverse its effects in case of bleeding. INR levels need frequent monitoring to prevent bleeding or clotting risks.
What are the drawbacks associated with the clinical use of warfarin?
Warfarin drawbacks include slow onset, need for regular INR monitoring, frequent dose adjustments, inter-patient genetic variations affecting response, low time in therapeutic range, drug interactions, and contraindications in pregnancy.
Describe the mechanism of action heparins inentiating the effects of Antithrombin III. How do unfractionated hein and low molecular heparins differ in terms of molecular weight and anticoagulant effects?
Heparins bind to and activate Antithrombin III, enhancing its inhibitory effects on coagulation enzymes. Unfractionated heparin has a wide molecular weight range (2000-30000) and inactivates both thrombin and Factor X, while LMWHs have a narrower range (2000-9000) predominantly inactivating Factor X with more predictable effects.
What are the clinical considerations for using Antithrombin III potentiators like heparins in medical practice? How are these agents administered and what are the reversal agents available for them?
Heparins are used in treating PE, DVT, ACS, prophylaxis in medical and surgical patients. They are administered parenterally, with UFH given intravenously and LMWHs subcutaneously. Reversal agents include protamine for UFH and LMWHs, while recombinant clotting factors are used for fondaparinux.
Define the mechanism of action of Dabigatran etexilate (Pradaxa) as a direct thrombin inhibitor. How does it differ from heparin-type drugs in inhibiting thrombin?
Dabigatran etexilate is converted to active dabigatran, a potent and reversible thrombin inhibitor. It binds competitively to thrombin’s active site, inhibiting both free and fibrin-bound thrombin, unlike heparin-type drugs that only inhibit free thrombin.
How does Dabigatran etexilate (Pradaxa) prevent blood coagulation? What are the adverse effects associated with its use, and what reversal agent is available for it?
Dabigatran inhibits thrombin, preventing the conversion of fibrinogen to fibrin in the final step of coagulation. Adverse effects include increased bleeding risk and gastrointestinal complaints. Idarucizamab is a reversal agent that binds to dabigatran.
Describe the differences in administration and anticoagulant effects between unfractionated heparin, low molecular weight heparins, and fondaparinux. What are the clinical uses of these agents in medical practice?
Unfractionated heparin is given via continuous IV infusion, LMWHs are administered SC once or twice daily, and fondaparinux is given SC once daily. They differ in their selectivity for Factor X and thrombin. These agents are used in treating PE, DVT, ACS, and as prophylaxis in various patient populations.
How do heparins like unfractionated heparin and LMWHs interact with Antithrombin III to exert their anticoagulant effects? What are the differences in their molecular weights and clinical applications?
Heparins bind to and activate Antithrombin III, enhancing its inhibitory effects on coagulation enzymes. Unfractionated heparin has a wider molecular weight range (2000-30000) and inactivates both thrombin and Factor X, while LMWHs have a narrower range (2000-9000) predominantly inactivating Factor X with more predictable effects.
Describe the mechanism of action Direct Oral Anticoagulants (DOACs) in inhibiting blood clot formation.
DOACs, such as apixaban and rivaroxaban, bind to the active site of Factor Xa, inhibiting the formation of the prothrombinase complex. This prevents the conversion of prothrombin to thrombin, ultimately reducing blood clot formation.
How do Direct Oral Anticoagulants (DOACs) differ from warfarin in terms of clinical considerations and why are they preferred?
DOACs offer fixed dosing, less food and drug interactions, and are not affected by vitamin K. They have increasing evidence for better efficacy and lower bleed risk than warfarin, especially in renal impairment, making them a preferred choice.
Define the clinical considerations for choosing and dosing Direct Oral Anticoagulants (DOACs) according to the NI Formulary.
The NI Formulary recommends apixaban as the 1st line choice of DOAC, with edoxaban, dabigatran, and rivaroxaban as 2nd line options. Patient factors like adherence, renal function, and concomitant interactions influence the choice.
