Anticoagulants Flashcards
What is the mechanism of action of Warfarin?
- Inhibits production of Vitamin K dependant clotting factors (2, 7, 9, 10)
- Stop conversion of Vitamin K to active reduced form so extrinsic pathway is affected
Describe the onset and offset of Warfarin?
- Onset is days due to turnover of clotting factors (slow half-life) so heparin is used to cover initially
- Offset is slow as time is required to synthesise new clotting factors
What are the uses of Warfarin?
- DVT
- PE
- Atrial fibrillation
- Mechanical prosthetic valves (high risk)
- Patients with recurrent thromboses on warfarin
- Thrombosis associated with inherited thrombophilia conditions
What are the factors that should be taken into account when starting warfarin?
- Indication
- PMH
- Medications
- Age, Mobility (blood tests and clinics), Falls risk score
- Review blood tests (LFTs, Plt, INR)
- Consider Loading Dose and Heparin cover
- Prescribe (when to start)
What are the side effects of Warfarin?
Bleeding/Bruising
- Intracranial
- Epistaxis
- Injection
- GI loss
How are the effects of Warfarin reversed?
- Parenteral vitamin K which is slow
- Fresh frozen plasma which is fast
Describe the pharmacokinetics of Warfarin?
- Good GI absorption so give orally. Preferred choice for long term anticoagulation
- Dose dependent reduction in Vitamin K dependent factors
- Heavily protein bound so caution with drugs that displace it
How is warfarin metabolised?
- Hepatic metabolism
- Caution with liver disease
- Caution if used with drugs that affect p450 system
What factors need to be taken into account if administering warfarin to pregnant individual?
-Crosses the placenta so do not give during 1st trimester (tetratogenic) and do not give in the 3rd trimester (brain haem)
How is warfarin monitored?
Extrinsic pathway factors
- Prothrombin time: Citrated plasma clotting time after adding calcium and thromboplastins
- I.N.R = International Normalised Ratio (monitoring)
What are the benefits to INR?
- Allows a standard value between labs
- Corrected from different lab thromboplastins reagents
Which drugs act to increase effects of warfarin?
- Inhibition of hepatic metabolism: Amiodarone, Quinolone, Metronidazole, Cimetidine, Ingesting alcohol
- Inhibit platelet function: Aspirin
- Reduce vitamin K from gut bacteria: Cephalosporin Antibiotics
Which drugs act to inhibit the effects of Warfarin?
Induction of hepatic enzymes increasing metabolism of warfarin
- Antiepileptic
- Rifampicin
- St John’s Wort
What are some features of heparin?
- Glycosaminoglycan
- One of 5 different groups on each glucose, some with sulphate. Produced by mast cells
What are the types of heparin?
- Unfractionated heparin
- Low molecular weight heparins
What is the mechanism of action of heparin?
- Both activate anti-thrombin 3 (AT3) via unique pentasaccharide sequence
- Deactivates Factor Xa, 2a, 9a
What is the effect of unfractionated heparin and LMWH on thrombin?
- Unfractionated heparin binds to antithrombin 3 (AT3) and thrombin to inactivate thrombin
- Low molecular weight heparins bind to antithrombin 3 via pentasaccharide but not to thrombin to poorly inactivate thrombin
What is the effect of unfractionated heparin and LMWH on Factor Xa?
- Unfractionated heparin binds to antithrombin 3 via pentasaccharide which is sufficient in activate factor Xa
- LMWH heparin bind to antithrombin 3 via pentasaccharide which is sufficient to inactivate factor 10a
How is heparin used as preventative?
- Perioperative: LMWH low dose
- Immobility: CCF, frail, or Unwell patient
- Used to cover for risk of thrombosis around times of operation in those normally on warfarin but who have stopped it for surgery, as quick offset time allows its cessation if bleeding
How is heparin used in treatment?
- DVT/PE and AF. Administered prior to warfarin-quick onset to cover patient whilst warfarin loading is achieved. LMWH often used unless fine control required
- Acute Coronary Syndromes. Reduces recurrence/extension of coronary artery thrombosis. In order to prevent MI, Unstable angina
- Pregnancy. Can be used cautiously in pregnancy in place of warfarin
What are the side effects of Heparin?
Bruising/bleeding sites
- Intracranial
- Injection sites
- Gastrointestinal loss
- Epitaxis
- Thrombocytopenia
- Osteoporosis
How does Thrombocytopenia occur as a result of Heparin?
- Autoimmune phenomenon (usually 1-2 weeks of Rx)
- May bleed or get serious thrombosis
- Heparin and PF4 on platelet surface are immunogenic - immune complexes activate more platelet, release more PF4, forms more IgG and complexes, leads to depletion platelets, thrombosis
- Platelet <100 (or a 50% reduction)
- Lab assay for these antibodies
- Stop heparin, add hirudin
What is pharmacokinetics of heparin?
- Must be given parenterally as poor GI absorption
- Rapid onset and offset of action
What are the pharmacokinetic of Unfractionated heparin?
- Dose-response: Non-Linearity
- Bioavailability: Variable due to unpredictable bind to cells and proteins
- Variable action so monitor with APTT test
- Administration by IV
- Initiated by bolus then IV
What are the pharmacokinetics of low molecular weight heparin?
- Dose response: Predictable
- Bio-availability: Predictable due to less binding to macrophages and endothelium
- Action: No monitoring so little effect on APTT
- Administration: Subcutaneous
- Initiation: OD/BD
How is the therapy of heparin reversed?
Protamine Sulphate
Stop Heparin if actively bleeding and start Protamine Sulphate which:
- Dissociates heparin from antithrombin 3
- Irreversible binding to heparin
- Allergy/Anaphylaxis
Monitor APTT if unfractionated
What is the mechanism of action of Selective Factor 10a inhibitors?
-Binds to antithrombin 3 (AT3) via pentasacharide (sufficient to inactive Xa)
What is the mechanism of action of Selective Factor 2a inhibitors?
-Selectively inactivates thrombin
What is the mechanism of action of Aspirin?
- COX-1 inhibition irreversibly
- Cox-2 inhibition
- Covalent acetylation of serine
What is the mechanism of action of Dipyridamole?
Phosphodiesterase Inhibitors so less breakdown of cAMP so less platelet aggregation
What are the uses of Dipyridamole?
- Postive inotrope and vasoilatory
- Secondary prevention of stroke
What is the mechanism of action of Clopidogrel?
ADP antagonists so inhibition of ADP dependant aggregation
- Block P2Y12 subtype of ADP receptor.
- P2Y12 normally decreases cAMP via Gi which causes increased aggregation of platelets
What are the uses of Clopidogrel?
- Acute coronary Syndrome
- Angioplasty
Used with aspirin
- More serious bleeds but same rate of life threatening
- Not for long term use if possible
What is the mechanism of action of Glycoprotein 2b/3a inhibitors?
-Block the pathway which involves fibrinogen binding to these receptors which cause platelet aggregation
What are the 3 classes of Glycoprotein 2b/3a inhibitors?
- Mab
- Abciximab
- Peptides
What are the uses of Glycoprotein 2b/3a inhibitors?
- High risk acute coronary syndrome
- Post percutaneous coronary intervention (angioplasty). It increases bleeding complication but decreases acute thrombosis and re-stenosis
What are examples of fibrinolytics?
- Alteplase
- Reteplase
