Anti-coagulant drugs Flashcards
Anti-coagulant drugs
Warfarin
Heparin
Unfractionated heparin
Low molecular weight heparin
Newer agents
Dabigatran – oral direct thrombin (factor IIa) inhibitor
Rivaroxaban – oral direct factor Xa inhibitor
Anti-platelet drugs
Anti-fibrinolytics
Warfarin
Vitamin K antagonist
Prevents γ-carboxylation of factors II, VII, IX, X
Prolongs the extrinsic pathway (prothrombin time)
Monitored by the international normalised ratio (INR)
Target INR usually 2.5 for DVT/PE and AF
Target 3.5 for recurrent VTE or metal heart valves
Pharmaco-dynamics of warfarin
Clotting factor Half-life VII 6 hours IX 24 hours X 40 hours II 60 hours
Warfarin can take > 3 days to achieve therapeutic levels
Warfarin also inhibits the natural anti-coagulants:
Protein C
Protein S
Prescribing warfarin
Patient usually loaded with LMW heparin cover
Typical loading regime is 10mg, 10mg, 5mg
Beware - patients have different levels of sensitivity to warfarin
Fall in protein C and S occurs within hours and can result in a temporary pro-coagulant state
Therefore, LMW heparin is usually continued until the INR is >2.0 for 2 consecutive days
Target INR: 2.5 (2.0–3.0)
treatment of DVT, pulmonary embolism, atrial fibrillation,
recurrent DVT off warfarin;
symptomatic inherited thrombophilia, cardiomyopathy, mural thrombus, cardioversion
Target INR:
3.0 (2.5–3.5)
Recurrent DVT while on warfarin, mechanical prosthetic heart valves, antiphospholipid syndrome (some cases)
Warfarin interactions
Due to cytochrome P450
Enzyme inhibitors potentiate warfarin:
carbamazepine, azathioprine, allopurinol
erythromycin, ciprofloxacin, metronidazole, fluconazole
Enzyme inducers inhibit warfarin:
rifampicin, amiodarone, citalopram, phenytoin
Beware 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
Give vitamin K 2-10mg iv/po depending on INR level
Patient can become refractory to re-loading with warfarin
If life-threatening bleed, give activated prothrombin complex (Octaplex) containing factors II, VII, IX and X (25-50 units per kg)
Fresh frozen plasma (FFP) can also be used
Heparin
Mucopolysaccharide that potentiates anti-thrombin
Irreversibly inactivates factors IIa (thrombin) and Xa
Administered parenterally
Two formulations of heparin:
Unfractionated heparin given by i.v. infusion
Low molecular weight heparin given as s.c. injections
Safe in pregnancy
Unfractionated heparin
Not often used due to inconvenience
Given i.v. with 5000U bolus and ~1000U/hour infusion
Monitored by APTT with target range of 1.5-2.5 x normal
Safe in renal failure
Can be partially reversed with protamine sulphate
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)
Patient must have creatinine clearance of over 30ml/minute
LMW heparin formulations include:
Tinzaparin (Innohep) 175U/kg
Enoxaparin (Clexane) 1.5mg/kg
Dalteparin (Fragmin)
Used for thromboprophylaxis for hospital in-patients:
3,500U or 4,500U Tinzaparin
20 or 40mg Enoxaparin
Other parenteral anticoagulants
Hirudin
Heparinoids
Fondaparinux
Hirudin
Lepirudin, snake venom derived
Direct thrombin inhibitor
Used in place of heparin in HIT
Heparinoids
Danaparoid – heparin-like compound
Fondaparinux
Arixtra – potentiates anti-thrombin, inhibits factor Xa
Novel oral anti-coagulants
Developed as an alternative to warfarin
Orally available, no monitoring, good safety profile
Two classes of drugs:
Dabigatran – direct thrombin (IIa) inhibitor
Rivaroxaban – direct factor Xa inhibitor
Trials show non-inferiority to warfarin and LMW heparin (but the anti-coagulant action is irreversible)
Dabigatran
Dabigatran is a direct thrombin inhibitor
Indications:
VTE prophylaxis
Used for treatment of DVTs and PEs
Stroke prevention in atrial fibrillation
Dosing is 110mg bd or 150mg bd
Confirm creatinine clearance > 30ml/min
Argatroban – direct thrombin inhibitor given i.v.
safe in renal failure
Rivaroxaban
Rivaroxaban is a direct factor Xa inhibitor
Indications:
VTE prophylaxis
Used for treatment of DVTs and PEs
Stroke prevention in atrial fibrillation
Dosing is 15mg bd for 3 weeks, then 20mg od
or 15mg od if CrCl is 15-50ml/min
Apixaban is alternative drug dosed bd
Types of anti-platelet drugs
Aspirin – cyclo-oxygenase inhibitor
Clopidogrel – ADP receptor blocker
Dipyridamole – inhibits phosphodiesterase
Prostacyclin – stimulates adenylate cyclase
Glycoprotein IIb/IIIa inhibitors:
Abciximab – monoclonal antibody
Eptifibatide – snake venom derivative
Tirofiban – blocks platelet aggregation
Fibrinolytic agents
Thrombolytic agents used to lyse fresh thrombi (arterial) by converting plasminogen to plasmin
Tissue Plasminogen Activator (tPA, Alteplase) and Streptokinase
Administered systemically in acute MI, recent thrombotic stroke, major PE or iliofemoral thrombosis
Standardized dosage regimens aim to use within 6 hours
Beware of contra-indications to thrombolysis
