Novel Anticoagulant Drugs by: Dr. M. Kamandi Fellowship of hematology and Oncology
A-Novel Oral Anticoagulants A drug that is: safe and effective has predictable pharmacology has few drug drug and drug dietary interactions does not require laboratory monitoring has the potential to revolutionize the chronic management of patients with atrial fibrillation, prosthetic heart valves, and recurrent venous thrombosis as well as facilitate better compliance with out-of-hospital thromboprophylaxis regimens.
1-Dabigatran etexilate potent univalent DTI bioavailability is 6% to 7% uptake is reduced by proton pump inhibitors and delayed with food Peak dabigatran serum levels occur 2 hours after an oral dose primarily eliminated by renal clearance
1-Dabigatran... has a half-life of 14 to 17 hours contraindicated in patients with a clearance <15 ml/minute Strong p-glycoprotein inhibitors (e.g., quinidine, ketoconazole) and inducers (e.g., rifampin) affect serum levels laboratory monitoring is unnecessary a normal aptt, thrombin time, or ecarin clotting time :little drug activity INR is insensitive to the presence of dabigatran
1-Dabigatran... the primary adverse effect of dabigatran is an increase in bleeding risk. increased risk of dyspepsia In cases of overdose:rapid administration of charcoal/ hemodialysis can remove 60% of plasma drug levels there is no known reversal agent life-threatening bleeding: administration of recombinant factor VIIa or activated prothrombin complex concentrates
1-Dabigatran... dabigatran etexilate is currently approved in the United States for the prevention of stroke and systemic embolism in patients with atrial fibrillation dabigatran was clearly superior for those patients on warfarin who have a time in TTR of less than 57.1% whereas benefit was less certain in those with a TTR of >72.6%
2-Dabigatran Dosing form: Cap Pradaxa. 75mg, 110mg, 150mg Nonvalvular atrial fibrillation(to prevent stroke and embolism): 150mg/BID Post-operative thrombophylaxis:110mg given 1-4h after completion of surgery OR 22omg if therapy is not initiated on the day of surgerymaintenance 220mg Qd duration of therapy :10 days
2-Oral Factor Xa Inhibitors Rivaroxaban and Apixaban are approved for use in the European Union, Canada, or the United States.
Rivaroxaban... Rivaroxaban is a reversible small molecule direct factor Xa inhibitor oral bioavailability of 60% to 80% peak levels achieved 2 to 3 hours after an oral dose has an elimination half-life of 7 to 11 hours Potent combined P-gp and CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, indinavir,conivaptan) and inducers (e.g., carbamezapine, phenytoin, rifampin) should be avoided in patients on Rivaroxaban
Rivaroxaban approved for: prevention of VTE in patients undergoing elective joint replacement surgery prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation treatment of VTE
Rivaroxaban... Dosing Form: Tablet 10mg, 15mg, 20mg DVT, PTE: 15mg PO/BID for 3 weeks then 20mg/QD Nonvalvular AF(prevent stroke and systemic embolism): 20 mg/qd Post-operative thrombophylaxis: intiation 6-10h postoperatively- 10mg/QD
Apixaban Apixaban is a reversible, small molecule, direct factor Xa inhibitor has an oral bioavailability of >45,% achieves peak levels 3 hours after an oral dose has an elimination half-life of 8 to 14 hours potent inhibitors of CYP3A4 and inducers should be avoided Apixaban is currently approved for the treatment of non-valvular atrial fibrillation.
Apixaban Dosing form: Tablet 2.5mg, 5 mg Non-valvular atrial fibrillation(prevention of stroke and systemic embolism): 5mg/BD(if body weight<60kg or Crt>1.5 : 2.5 mg/bd) Post-operative thrombophylaxis:2.5 mg/bd beginning 12-24h postoperatively DVT,PTE: 2.5 mg/bd
2-Oral Factor Xa Inhibitors Because of the predictability in dose-response, laboratory monitoring of the oral factor-xa inhibitors is unnecessary a normal aptt and a normal INR suggest little anticoagulant presence the primary adverse effect:an increase in bleeding risk. not anticipated to be dialyzable no known reversal agent life-threatening bleeding:activated prothrombin complex concentrates may be effective
B-Parenteral Anticoagulant Drugs Heparin Low molecular- weight heparins Heparinoids Pentasaccharides Parenteral Direct Thrombin Inhibitors
Enoxaparin sodium Dalteparin sodium Tinzaparin sodium Low-molecular-weight Heparins
Dermatan sulfate Danaparoid sodium Heparinoids
fondaparinux Idraparinux ldrabiotaparinux pentasaccharides
Fondaparinux an FDA-approved synthetic pentasaccharide selective indirect (AT-mediated) inhibitor of factor Xa Administered subcutaneously. half-life of 17 hours Does not require therapeutic monitoring. Elimination is prolonged: renal impairment, >75 years or weighing <50 kg. used in treatment of HIT approved for the prevention and treatment of VTE
Fondaparinux. Dosing form: Injection 2.5mg/0.5ml 5 mg/0.4ml 7.5mg/0.6ml 10mg/0.8ml DVT prophylaxis:2.5mg/qd subq in adults>50kg DVT/PTE: 5mg/QD in <50kg 7.5mg/Qd in 50-100kg 10mg/QD in >100kg (start with warfarin on the first or second treatment day & continue until INR>2 for at least 24h(usually 5-7 days) ACS: UA/NSTEMI: 2.5 mg /QD SubQ STEMI: 2.5mg I.V., subsequent doses:2.5mg/qd SubQ
Hirudins Argatroban Bivalirudin Parenteral Direct Thrombin Inhibitors
Argatroban FDA approved for prophylaxis & treatment of thrombosis in HIT. a rapid and reversible DTI does not cross-react with heparin metabolized by liver with biliary excretion half-life ~ 40 minutes does not require dose adjustment in renal insufficiency Dose reduction is required in significant hepatic disease
Argatroban. dosed based on patient weight starting intravenous infusion rate is 2 mcg/kg/minute target aptt of 1.5 to 3.0 times the baseline value also be monitored by ACT and the ecarin clotting time. PT is prolongation makes determination of an accurate INR during conversion to oral warfarin therapy a challenge. Provide adequate anticoagulation with minimal bleeding risk success in HIT patients undergoing PCI
Argatroban. Dosing Forms: infusion premixed in NS:125 mg infusion premixed in water :50mg(50ml) injection 100mg/ml(2.5ml) Prophylaxis of thrombosis(hit): 2mcg/kg/min maintenance: measure PTT after 2h, adjust dose until PTT is 1.5-3 times the initial baseline, not exceeding 100 seconds dose should not exceed 10mcg/kg/min
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