Anticoagulants Flashcards
Describe the coagulation cascade
What is the difference in the intrinsic pathway and extrinsic pathways of the coagulation cascade
Intrinsic pathway: activated by exposed collagen
Extrinsic pathway: activated by tissue factor (subendothelial)
What is the deficiency in Haemophillia A?
Factor VIII
What is the definiciency in Heamophillia B?
Factor IX
What element is an important co-factor for blood coagulation?
Ca2+
Where are heparins produced naturally in the body?
Produced naturally in mast cells and vascular endothelium
What are the 2 different sizes of heparin?
Unfractionated heparin (5-30 kDa)
Low molecular weight heparins (1-5 kDa)
Which factor of the coagulation cascade does heparin target?
Low molecular weight heparin: Targets factor Xa only
Unfractionated: Target Xa and 2a (thrombin)
How is unfractionated heparin usually administered?
Typically i.v. bolus and infusion
Can be given subcut for prophylaxis - has much lower bioavailability
Explain the mechanism of action of unfractionated heparin
- Unfractionated heparin binds to antithrombin (ATIII) → conformational change which increases antithrombin activity
- Once bound to heparnin, antitrhombin III binds to both thrombin (IIa) and factor Xa
- Inhibits factor Xa → anticoagulation activity
Name 2 low molecular weight heparins
Dalteparin
Enoxaparin
Explain how low molecular weight heparins work
- LMWH binds to antithrombin (IIIa)
- Accelerates the interaction of antithrombin with Factor Xa → anticoagulant activity
- Does not inactivate thrombin (IIa) as not long long enough
What is fondaparinux?
A synthetic polysaccharide that selectively inhibits factor Xa by binding to AT III
How is low molecular weight heparin administered?
Almost always subcut
Why do you get a more predictable response with low molecular weight heparin vs unfractionated heparin?
Low molecular weight does not bind to endothelial cells, plasma proteins or macrophages
How is unfractionated heparin monitored?
Monitored with activated partial thromboplastin time (aPTT)
(LMWH does not need monitoring due to more predictable response)
In what patients is unfractionated heparin more preferable than LMWH?
Patients with severe renal impairment
For what conditions is heparin indicated?
- Prevention of venous thromboembolism
- During pregnancy - do not cross the placenta
- DVT and PE
- Acute Coronary Syndromes
- short term to reduce recurrence
What are some of the adverse side effects related to heparins?
- Brusing and bleeding
- GI disturbance
- Epistaxis
- Hepatic and renal impairment
- Elderly/ those with carcinoma at higher risk
- Heparin induced thrombocytopenia
- Hyperkalaemia- inhibition of aldosterone secretion
- Osteoporosis (rare long term use)
What is heparin induced thrombocytopenia?
- An autoimmune response to heparin, 2-14 days after initiation
- Antibodies develop to heparin platelet factor 4 complex
- Causes an initial depletion of platelets
- Paradoxically can lead to to thrombosis as more platelets are activated by damage to endothelium
What is the antidote to heparin?
Protamine sulphate
How does protamine sulphate work?
- Forms an inactive complex with heparin
- Given I.V
- Dissociates heparin from antithrombin III
- Greater effect on unfractionated heparin than LMWH
Name a Vitamin K antagonist
Warfarin
Explain how Warfarin works
- Warfarin inhibits vitamin K epoxide reductase (VKOR) as a competitive inhibitor
- VKOR is needed to activate vitamin K
- Active vitamin K is needed to activate clotting factors
Which factors need vitamin K as a co-factor?
Factors II, VII, IX and X
(produced in the liver as inactive products)
Why is there a delay in the onset of action of warfarin?
- There will be circulating active factors present for several days
- Must be cleared and replaced with noncarboxylated forms (inactive clotting factors)
What is warfarin indicated for?
- Venous thromboembolsim
- PE
- DVT and secondary prevention
- superficial vein thrombosis
- Atrial fibrillation with high risk of stroke
- Heart valve replacement (bio prosthetics)
- Generally used longer term than heparin
- If coagulation needed immediately, need to statrt with heparin
How is warfarin most commonly administered?
Orally
Good GI absorption, 95%+ bioavailability
What is warfarin composed of?
A racemic mixture of two enantiomers
R and S: each have different potency and metabolised differently
Can wafarin be given in pregnancy?
No
Need to be avoided
1st trimester: teratogenic
3rd trimester: haemorrhagic
What affects the response to warfarin?
- Genetic polymorphisms of CYP2C9
- Vitamin K intake (found in veg)
What are some of the adverse drug reactions of warfarin?
- Mainly bleeding
- Epistaxis and spontaneous retroperitoneal bleeding
What is the most effective antidote to warfarin?
Vitamin K1
competes with warfarin for vitamin K epoxide reductase
What are some of the drug-drug interactions with warfarin?
- Inhibition of hepatic metabolism by CYP2C9
- Amiodarone, clopidogrel, intoxicating dose of alcohol, quinolone, metronidazole
- Cephalosporin antbiotics- reduce vitamin K by eliminating gut bacteria involved in production
- Displacement of warfarin from plasma albumin e.g. NSAIDs
- Barbiturate, phenytoin , rifampicin and St John’s Wort accelerate warfarn metabolism
What is the target INR for wafarin?
INR 2.5
If at greater risk: INR 3.0-3.5
Name 3 direct acting oral anticoagulants (DOAC)
- Apixaban
- Edoxaban
- Rivaroxaban
How do direct Xa DOACs work?
- Inhibit both free Xa and Xa bound with ATIII
- Does not directly affect thrombin (IIa)
Name a direct IIa DOAC
Dabigatran
How do direct IIa DOACs work?
- A direct competitive inhibitor of thrombin - both circulating and thrombus bound
What are some of the side effects of DOACs?
- Bleeding
- Use with caution in groups at risk of GI bleed
- Dabigatran contraindicated in low creatinine clearance (<15 mL/min)
- Avoid in pregnancy- not enough evidence
