Anti-coagulant drugs Flashcards
Warfarin
- Vitamin K antagonist
- Prevents gamma-carboxylation of factors II, VII, IX, X
- Prolongs the extrinsic pathway (prothrombin time)
- Monitored by the international normalised ratio (INR)
Warfarin - target INR
Usually 2.5 for DVT/PE, AF, recurrent DVT off warfarin, symptomatic inherited thrombophilia, cardiomyopathy, mural thrombus, cardioversion
Target 3.5 for recurrent VTE or metal heart valves, recurrent DVT while on warfarin, mechanical prosthetic heart valves, antiphospholipid syndrome (some cases)
How long does it take for warfarin to achieve therapeutic levels
- Warfarin can take > 3 days to achieve therapeutic levels
Warfarin mechanism of action
- Inhibits vitamin K-dependent synthesis of biologically active forms of clotting factors II, VII, IX and X
What else does warfarin inhibit
- Warfarin also inhibits the natural anti-coagulants protein C and protein S
What is warfarin usually loaded with and why
- Patient usually loaded with LMW heparin cover
- Typical loading regime is 10mg, 10mg, 5mg
- Fall in protein C and S occurs within hrs and can result in temporary pro-coagulant state so LMW heparin is usually continued until the INR is > 2 for 2 consecutive days
Warfarin interactions
- Beware interactions with other drugs due to cytochrome P450
- Enzyme inhibitors potentiate warfarin - carbamazepine, azathioprine, allopurinol, erythromycin, ciprofloxacin, metronidazole, fluconazole
- Enzyme inducers inhibit warfarin - rifampicin, amiodarone, citalopram, phenytoin
- Between interaction with alcohol
Warfarin side-effects
- Teratogenic - therefore use LMW heparin in pregnancy
- Significant haemorrhage risk intra-cranial bleeds up to 1% per year, increased risk in elderly and with higher INR target
- Minor bleeding up to 20% per year
- Skin necrosis
- Alopecia
Reversing warfarin
- If life-threatening bleed, give activated prothrombin complex (octaplex) containing factors II, VII, IX and X (25-50 units per kg)
- Give vitamin K 2-10 mg iv/po depending on INR level (patient can become refractory to re-loading with warfarin)
- Fresh frozen plasma (FFP) can also be used
Heparin
- Mucopolysaccharide that potentiates anti-thrombin
- Irreversibly inactivates factors IIa (thrombin) and Xa
- Administered parenterally
- Safe in pregnancy
Formulations of heparin
- Unfractionated heparin given by i.v. infusion
- Low molecular weight heparin given as s.c. injections
Unfractionated heparin
- Not often used due to inconvenience
- Given i.v with 5000u and - 1000u/hour infusion
Safe in renal failure
How is unfractionated heparin monitored
- Monitored by APTT with target range of 1.5-2.5 x normal
What can unfractionated heparin be reversed with
- Can be partially reversed with protamine sulphate
What is a rare complication of heparin usage
- Thrombocytopenia and VTE is a rare complication resulting in heparin-induced thrombocytopenia ( or HIT )
Low molecular weight heparin
- Very convenient due to once daily s.c. injections
- Prescribed according to patient’s weight
- Not usually monitored(but can use the anti-Xa assay)
Required creatinine clearance for LMW heparin usage
- Patient must have creatinine clearance of over 30ml/min
LMW heparin formulations
- Tinzaparin (innohep)
- Enoxaparin (clexane)
- Dalteparin (fragmin)
Other parenteral anticoagulants
- Hirudin
Snake venom derived
Argatroban (direct thrombin inhibitor)
Used in place of heparin in patients with HIT - Heparinoids
Danaparoid - heparin-like compound - Fondaparinux
Arixra - potentiates anti-thrombin, inhibits factor Xa
Direct oral anti-coagulants (DOACs)
- Developed as an alternative to warfarin
- Orally available, no monitoring, good safety profile
- Trials show non-inferiority of DOACs to warfarin and LMW heparin for VTE and AF (but not cardiac valves)
Classes of DOACs
- Direct thrombin (IIa) inhibitor, eg dabigatran
- Direct factor Xa inhibitor
