L3 Anti-coagulant drugs Flashcards
When are anti-coagulants used and when are they used with anti-platelets
Ac: Thrombo-embolic disease - eg. AF, DVT, PE, Prosthetic heart valve
Ac + Ap: Arterial thrombus: Coronary artery, Cerebrovascular, Peripheral vascular Disease
What are uses of unfractionated Heparin vs LMW Heparin
LMWH is most commonly used.
Both:
- Acute Coronary syndromes,
- initial treatment Thromboembolism,
UH only: dialysis machines
LMWH only: prophylaxis, cancer’s DVT
UH is Temporary warfarin replacement whereas LMWH is Warfarin replacement for pregnancy, post-op.
What is the structure of Unfractionated Heparin and consequences of that
What is the administration
UH are linear mucopolysaccarides:
- heterogenous chain length = pharmacokinetics is variable/ effectiveness.
- It has rapid onset and offset of action within an hour.
- Negatively charged: no GI absorption so
Parenteral admin but requires APTT monitoring, to check if its hitting target 50-80s.
Needs platelet monitoring every 2 days
= Time consuming, difficult, blood tests
What are the adverse effects of unfractionated Heparin and how can they be reversed
- Bleeding/brusing site. eg. Epistaxis, intracranial, GI loss
- Osteoporosis (if prolonged treatment)
- Hep induced Thrombocytopenia: stimulation of autoantibodies against platelets. which may lead to bleeding or serious thrombosis
Reversal=
Stop Heparin if little bleeding,
If actively bleeding, then
- Give protamine sulphate (dissociates heparin from anti-thrombin irreversibly
What are the mechanism of action of UH vs LMW Heparin
UH: It binds to and increases activity of anti-thrombin 3 which inactivates thrombin, 10a, + 9a, 11a, and 12a
LMWH: Has a unique sequence to bind to Anti-thrombin 3 but doesn’t not inactivate Thrombin 2a, affects 10a specifically.
What is the structure of LMW Heparin and consequences of that
What is the administration
Smaller chains generated by depolymerisation of UH.
- more predictable pharmacokinetics, still -ly charged.
Admin via parenteral
- Weight based dosing without requiring monitoring.
What are the side effects/cons of using LMW Heparin (with reference to
UH)
- It has less thrombocytopenia, osteoporosis
- It cannot be monitored by APTT
- Bleeding is not fully reversed by protamine
- Renal excretion so there is dose reduction/care with eGFR <30.
What is the speed of onset for Warfarin and why.
What it is used to treat and for how long.
Warfarin has a slow onset of action (3-4 days) because you have to wait for the degradation of remaining clotting factors that were already made before warfarin use
- Long term treatment of venous/arterial thrombosis. LV thrombus (if risk factors 3-6 mo, if no risk factors 6-12/lifelong)
- Mechanical heart valves, atrial fibrillation (lifelong)
What is the route of administration for Warfarin, what are risks associated with absorption and metabolism
(acutely alcohol inhibits, longterm it induces)
Once daily, oral.
- Rapidly, Completely absorbed: crosses the placenta so not allowed in pregnancy
- Metabolised in the liver CYP450 which increases risk of drug interactions -
If enzyme if induced
- eg. OCP, Rifampicin, carbemazepine, barbituates
thrombotic.
If inhibited
-eg. antibiotics, anticonvulsants, antacids: over anti-coagulated
How is dosing of warfarin monitored, how often is this and why
INR: Patients Prothrombin time (s)/ Mean normal PT in seconds
Not taking warfarin - INR: 1.
Therapeutic 2-3. higher if heart valves, thrombophilia.
Dose to get therapeutic level varies due to differences in
- liver function, vit K intake, reduced absorption due to Diar/Vom
Initially INR done daily, then 2-3 times weekly for the first few weeks.
Adverse effects of warfarin and who is at risk
Haemorrhage: GI, intracranial - greater risk in elderly with comorbidities which are generally the same population we want to treat with higher doses. Also those with uncontrolled alcohol/dementia who can’t
Also Teratogenic: leading to bone and CNS problems in 1st trim, last 4 weeks intracerebral haemorrhage
- Narrow therapeutic window
- Drug interactions
- Regular monitoring (INR) outpatient blood test
How to manage bleeding on warfarin
If slow: Vit K via IV - onset will be slow
If immediate : clotting factor replacement Prothrombinex IV
Dabigatran: mechanism, disease, metabolism, excretion, cautions and antidote
-Given in capsules with tartaric acid to improve absorption but can give indigestion.
- Oral prodrug reversibly inhibits thrombin (2a)
- used for AF and VTE. Can’t be used for metal heart valves.
- Metabolised in liver or gut esterases, so not cyp450 dependent
- renally excreted so don’t use for GFR <30.
- No monitoring with INRS.
- Idarucizumab which pulls the thrombin /dabigatran complex apart
Rivaroxaban:
mechanism, disease, metabolism, excretion, cautions and antidote
- Selective direct inhibitor of 10a.
- Used in DVT, PE, AF but not metal heart valves
- Orally active/ no monitoring
- Renally excreted can use it down to GFR <15
- Can be started immediately for DVT, PE instead of dabigatran needing some enoxaparin first
