Anti-coagulant & Thrombolytic agents Flashcards
Unfractionated Heparin - Mechanism
Acts in plasma by binding and accelerating the activity of ATIII; Heparin-ATIII complex inhibits action of activated factors IIa, IXa, Xa, XIa, XIIa, XIIIa
Low molecular weight heparin - Mechanism
Binds to ATIII, increasing its ability to inactivate factor Xa; does not directly inactivate thrombin
Benefits of LMWH > UFH
Equal efficacy with less tendency for bleeding and less risk of thrombocytopenia
No effect on aPTT - monitoring not routinely required
Fondaprainux - Mechanism
Pentasaccharide activator of ATIII - inactivates factor Xa only
Heparin - Pharmacokinetics
Administered IV or SC with loading dose for immediate effect; continuous infusion preferred
UFH has a more rapid onset than LMWH
UFH is cleared by RE system whereas LMWH is cleared by renal elimination
Benefits of UFH > LMWH
More rapid onset - minutes if IV w/ LD
Effects can be more rapidly and completely reversed by protamine sulfate; may be safer for patients with renal impairment
Uses of Heparin
Prophylaxis / treatment of VTE and PE
Prevention of cerebral thrombosis in evolving stroke
Low dose prophylaxis of post-op thromboembolism
Heparin - Adverse Reactions
Hemorrhage (10%)
Thrombocytopenia - severe, via immune-mediated reaction; antibody-platelet-heparin complex activates platelets and leads to thromboembolism
Osteoporosis - in patients taking heparin > 6 mos
Treatment of Heparin overdose
Presents as nosebleeds, hematuria, or tarry stools +/- bruising
Treatment: Protamine - complexes with and neutralizes heparin within 5 min; given slowly IV
Incomplete reversal of LMWH overdose
Warfarin - Mechanism
Inhibits Vitamin K epoxide reductase, which is responsible for reducing Vitamin K, a necessary co-factor for the post-translational modification of factors II, VII, IX, X, Protein C, and Protein S
Onset of effect delayed to allow turnover of existing clotting factors; increased PTT in 8-12 hours with steady state reached in 3-5 days
Warfarin - Pharmacokinetics
Essentially 100% oral absorption
Hepatic metabolism to inactive metabolites; genetic polymorphisms and DDIs affect plasma concentration
Warfarin - Uses
Atrial fibrillation - prevention of thromboembolism
Prophylaxis / treatment of VTE
Warfarin - Advantages & Disadvantages
Advantages: Once-daily oral dosing, reversal of effect with Vitamin K
Disadvantages: INR monitoring required, many DDIs
Warfarin - Adverse Reactions
Hemorrhage
Necrosis of fatty soft tissue
GI upset
Osteoporosis
*Contraindicated in pregnancy
Warfarin - Overdose Management
INR > therapeutic but < 4.5 - reduce or skip dose
Dabigatran - Mechanism
Directly inhibits Thrombin (free and clot-bound); also inhibits thrombin-induced platelet aggregation
Dabigatran - Pharmacokinetics
Twice daily oral - administered as pro-drug, hepatic metabolism to active form
Renal excretion
Dabigatran, Rivaroxaban, and Apixaban - Uses
Reducing risk of stroke and embolism in patients with atrial fibrillation
Dabigatran - Adverse Reactions
Bleeding
GI complaints
Dabigatran - Benefits & Disadvantages
Benefits: More rapid onset than warfarin, does not require frequent monitoring/dosing adjustments, fewer DDIs (not a CYP substrate)
Disadvantages: No antidote for rapid reversal of effect, shorter acting
Rivaroxaban and Apixaban - Mechanism
Directly inhibits Factor Xa in the plasma
Rivaroxaban and Apixaban - Pharmacokinetics
Oral absorption - twice daily dosing Hepatic metabolism (CYP450 substrate) Renal excretion
Rivaroxaban and Apixaban - Uses
Prevention of stroke & embolism in atrial fibrillation
Prevention of VTE and PE
Streptokinase - Mechanism
Converts plasminogen to plasmin; not specific for fibrin-bound plasminogen
Streptokinase - Uses
Thrombolytic; used for emergency treatment of:
Coronary artery thrombosis
DVT
Multiple PEs
Streptokinase - Adverse Reactions
Hemorrhage due to lysis of physiologic thrombi at sites of vascular injury; intracranial hemorrhage is most serious
Antibody formation - fever, hypersensitivity reaction, therapeutic failure
tPA - Mechanism
Human tPA from recombinant DNA; selectively activates fibrin-bound plasminogen (“clot selective”)
tPA - Uses
Emergency treatment of:
Coronary artery thrombosis
DVT
PEs
Anticoagulant Monitoring Lab Tests
UFH - aPTT
LMWH - N/A, action is predictable when dosed on a magn/kg basis
Warfarin - INR (from PT)
Warfarin - DDIs that increase effect
CYP450 inhibitors - Amiodarone, Cimetidine, Fluconazole, Metronidazole
Antibiotics
Warfarin - DDIs that decrease effect
CYP450 inducers - Barbituates, Phenytoin, Rifampin, St. John’s Wort
Vitamin K
