Anti-coagulant drugs Flashcards
1
Q
Warfarin
A
- Vitamin K antagonist
- therefore Prevents γ-carboxylation of factors II, VII, IX, X
- Prolongs the extrinsic pathway (tested by measuring 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
2
Q
Describe the metabolism of warfarin
A
3
Q
Describe the Pharmaco-dynamics of warfarin
A
- reduces the half-life of Factor VII, IX, X and II
- Warfarin can take > 3 days to reach therapeutic levels
- also inhibits the natural anti-coagulants: Protein C and S
- these have a shorter half-life so become prothrombotic before combing anticoagulant because the natural sources (protein C and S) are initially depleted
4
Q
How should warfarin be prescribed?
A
- usually loaded with low molecular weight heparin (LMWH) cover
- typically: 10mg, 5mg
- a fall in Protein C and S occurs within hours, can result in a temporary procoagulant state
- hence, LMWH is usually continued until the INR is > 2.0 for 2 consecutive days
5
Q
thrombomodulin is a endothelial cell surface receptor
What are Protein C and S? describe their action.
A
- they are inhibitors of coagulation factor V and VIII
- bothe are vitamin K dependent proteins
- Protein C is activated by a thrombin-Thrombomodulin complex
- activated protein C is able to destroy factor Va and VIIIa
- therefore further thrombin cannot be generated: creating a negative feedback loop
- Protein S promotes the action of protein C
- activated protein C is inactivated by serpins( serum protease inactivators) e.g antithrombin
6
Q
What other drugs/chemicals does warfarin interact with?
A
- beware of interactions with other drugs due to cytochrome P450 in the liver
- enzyme inhibitors potentiate warfarin: may want to reduce the dosage
- carbamazepine, azathioprine, allopurinol
- erythromycin, ciprofloxacin, metronidazole, fluconazole
- Enzyme inducers inhibit warfarin: may want to increase the dosage
- rifampicin, amiodarone, citalopram, phenytoin
- Interactions with alcohol: may have a high IRN and are at risk of bleeds
7
Q
What are some side effects of warfarin?
A
- teratogenic: must use LMW heparin in pregnancy
- significant haemorrhage risk: leads to intracranial bleeds p to 15 a year, increased risk in elderly with a higher INR target
- minor bleeding: 20% per ann.
- skin necrosis
- alopecia: hair loss
8
Q
Explain how warfarin can be reversed
A
- Give vitamin K 2-10mg iv/po depending on INR level
- 6-12 hours to take into effect so give other treatments first (octaplex)
- The 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), plasma-derived product
- Fresh frozen plasma (FFP) can also be used
9
Q
Heparin
A
- 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
10
Q
first binds to antithrombin
Describe the action of Heparin
A
11
Q
How/ when is unfractionated heparin used?
A
- Not often used due to inconvenience, unless in renal failure
- Given i.v. with 5000U bolus and ~1000U/hour infusion
- Monitored by APTT with a 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 (HIT)
12
Q
When/ How is Low molecular weight heparin used
A
- 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
13
Q
What are Novel oral anticoagulants?
A
- alternative to warfarin
- orally available, no monitoring required, has a good safety profile
- Dabigatran: direct thrombin (IIa) inhibitor
- Rivaroxaban: direct factor Xa inhibitor
- trials show that it is as good as warfarin and LMW heparin but the anticoagulation action is irreversible
14
Q
It is a novel anticoagulant drug class
Explain how Dabigatran is used.
A
- used as a direct inhibitor to factor IIa (thrombin)
Indications (usage)
- used as a VTE (venous thromboembolism) prophylaxis
- treatment for DVTs and PEs
- stroke prevention in atrial fibrillation
- Dosing is 110mg bd or 150mg bd
- must be a creatine clearance of > 30ml/min
- Argatroban: direct thrombin inhibitor given iv: safe in renal failure
15
Q
Explain how Rivaroxaban is used
A
- 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 (morning and evening), slightly better plasma levels with this drug
16
Q
Describe the action of antiplatelet drugs
A
