Anticoagulants Flashcards
Anticoagulant drugs prevent thrombus formation and growth.
List 3 natural inhibitors of the clotting cascade
- Antithrombin III (especially with regards to Heparin’s action)
- Protein C
- Protein S
Which ion is a cofactor for the clotting cascade?
What can be given with a blood transfusion to prevent clotting?
- Calcium
- EDTA (Chelates Ca, preventing it from being used to clot)
Most heparins are sourced from animals
Compare the Heparins: UFH and LMWH in terms of size
How do Heparins work?
Unfractionated Heparins;
- Large
Low Molecular Weight Heparins;
- Smaller
- Heparins work by enhancing Antithrombin III activity (in vivo AND in vitro)
In what form are Heparin preparations?
Prepared in Units (IU) per ml
List the targets of the following Heparins;
- UFH
- LMWH
- Fondaparinux (A synthetic LMWH)
UFH;
- Acts on Thombin IIa and Xa mainly (also on 12a, 11a, 9a)
LMWH;
- Acts on Xa
Fondaparinux;
- Acts on Xa
Describe the Pharmacodynamics of UFH
- Fast onset of action
- 30 mins half life at Low doses
- 2 hours half life at high doses
- This difference in half life results in mixed elimination so is unpredictable elimination kinetics
Describe the Administration of UFH
- Typically, IV Bolus followed by Infusion
- Can be given Subcutaneously for prophylaxis, but low bioavailability
Describe the mechanism of action of UFH
- Binds to ATIII causing conformational change and increased activity
- To catalyse Thrombin IIa inhibition, UFH must bind to ATIII AND IIa
- To catalyse Xa inhibition, UFH only need to bind to ATIII
What kind of drug are Dalteparin and Enoxaparin?
State their administration, half life and bioavailability
- LMWHs
- Almost always given SC (can be IV) as high bioavailability
- Half life of 2hrs plus
(Slower onset of action)
Why are LMWHs more predictable than UFHs?
LMWHs are smaller and don’t bind to Endothelial cells (partial elimination of UFH here)
How do LMWHs work?
Enhance ATIII activity to inhibit Xa
Not long enough to inactivate Thrombin IIa
Compare Fondaparinux with the natural LMWHs
Fondaparinux;
- Same mechanism of action and administration route
- Longer half life of 18 hours
List 4 indications for use of Heparins
- Venous thromboembolism prevention (before/ after operations as patients have been immobile)
- During pregnancy (do not cross placenta)
- Treating + secondary prevention of DVT and PE (prior to DOACs)
- Acute Coronary Syndrome/ ACS (NSTEMI), in the short term
List 4 ADRs of Heparins
- Bruising + bleeding (Intracranial, Site of injection, GI, Nose)
- Heparin Induced Thrombocytopenia, HIT (Autoimmune response, more common with UFH)
- Hyperkalaemia (Inhibition of Aldosterone secretion)
- Osteoporosis (Rare, long term use, higher risk with UFH, more common in pregnancy)
Describe Heparin Induce Thrombocytopenia (HIT)
- Antibodies to Heparin-Platelet factor IV complex
- Platelets depleted
- IN SOME, can lead to Thrombosis as more platelets activated by endothelial damage
List 2 contraindications of Heparins
- Clotting disorders
- Renal impairment (LMWH + Fondaparinux)
List DDIs of Heparins
- Other antithrombotics
- ACEi/ ARBs + Spirionalctone (Increased risk of Hyperkalaemia)
Which form of Heparin requires more monitoring?
Against what value is the dose titrated?
- UFH
- APTT (Intrinsic pathway: XII, XI, IX, VIII + Common)
Suggest a drug used for Heparin Reversal Therapy
How does it work?
- Protamine Sulphate (given IV)
- Irreversibly forms inactive complex with Heparin, dissociating it from ATIII
Compare the effects of Protamine Sulphate on;
- UFH
- LMWH
- Fondaparinux
Protamine Sulphate;
- Greater effect on UFH
- Weaker effect on LMWH
- No effect on Fondaparinux
Name a Vitamin-K Antagonist
How do these drugs work as anticoagulants?
- Warfarin
- Inhibit conversion of Vit-K to active form via Competitive Inhibition of VKOR
- Thus, inhibited activation of Vit-K dependent clotting factors (7,9,10,2)
How is Vitamin K involved in production of Factors II, VII, IX and X
Hepatic synthesis of the clotting factors requires Vit-K as a cofactor for activation
Why does Warfarin have a delayed onset of action?
How can we speed this up?
- Already circulating active clotting factors are present for days
- Active factors can be cleared and replaced with non-carboxylated forms
State the half life of Warfarin
36 to 48 hours (some variation)
Warfarin is generally used in the longer-term compared to Heparin, and due to its delayed onset of action so a Heparin cover is often needed for immediate anticoagulation.
List some indications for Warfarin use
- Venous thromboembolism
- DVT + PE (secondary prevention)
- Superficial Vein Thrombosis
- AFib with high risk of stroke
- Heart valve replacement
Describe the Pharmacokinetics of Warfarin
- Good GI absorption (95% Bioavailability)
- CYP 2C9 polymorphism= Significant variability
- [Plasma] doesn’t correlate with clinical effect
- Mixture of R and S enantiomers which have different Potency and Metabolisms
List 2 contraindications of Warfarin
- Hepatic Disease
Crosses Placenta so;
- Avoided in Trimester 1 (Teratogenic)
- Avoided in Trimester 3 (Haemorrhagic)
Suggest 3 things that affect the response to Warfarin
- CYP 2C9
- Vitamin K intake
- Alcohol
State the primary ADR of Warfarin
- Bleeding (Epistaxis, Spontaneous Retroperitoneal bleeding in some old people)
Describe Warfarin Reversal Therapy
- Vitamin K1 is most effective
- Addition of IV Prothrombin complex concentrate
(Warfarin replaced with Heparin for a short time before and after surgery)
List 5 groups of DDIs of Warfarin
- PPIs can increase effect of Warfarin
- Amiodarone, Clopidogrel and large doses of alcohol (inhibit hepatic metabolism)
- Cephalosporin ABs (Reduce Vit K by eliminating gut bacteria involved in production)
- NSAIDs + drugs that decrease Vit K GI absorption (increase INR)
- Barbiturates, Phenytoin, Rifampicin, St Johns Wort accelerate Warfarin metabolism (decrease INR)
Compare High and Low INR
High INR;
- More anti-coagulated (more risk of bleeding)
Low INR;
- Less anti-coagulated
Factor VII is the most sensitive to Vitamin K deficiency.
What is the clinical significance of this?
- Factor VIII is used in measuring Prothrombin Time
- This is referred to as the INR, used to measure clotting time
What kind of drugs are Apixaban, Edoxaban, Rivaroxaban and Dabigatran
Apixaban, Edoxaban, Rivaroxaban are Direct Xa DOACs
Dabigatran is a Direct IIa DOAC
Compare the Direct Xa and Direct IIa DOACs
Direct Xa;
- Inhibit Free Xa AND Xa Bound to ATIII
- Don’t directly affect Thrombin IIa
Direct IIa;
- Competitive Thrombin IIa inhibitor (both circulating and thrombus bound IIa)
List Anticoagulants that inhibit Xa
- LMWH
- Fondaparinux
- Apixaban, Edoxaban, Rivaroxaban
(Also UFH)
List Anticoagulants that inhibit IIa
- UFH
- Dabigatran
Describe the administration and monitoring of the DOACs
DOACs are often used in situations where Warfarin could be used
- Oral administration
- Little to no monitoring required
Suggest an ADR of DOACs
- Bleeding (Lower intracranial bleed risk than Warfarin)
- (Dose adjustments particular in those at risk of GI bleed)
List 3 contraindications of DOACs
- Dabigatran contraindicated in Creatine clearance <30ml/min
- Other DOACs are contraindicated in Creatine clearance <15ml/min
- Avoid use in Pregnancy and Breastfeeding (little information)
List DDIs of DOACs
Affected by CYP inducers/inhibitors (less frequent than Warfarin)
- [Plasma] reduced by Carbamazepine, Phenytoin, Barbiturates
- [Plasma] increased by Macrolides
Andexanet and Idarucizumab are what kind of drugs?
These are expensive
DOAC Reversal drugs
Of the DOACs, which are not used in lactose intolerant patients and why?
AApixaban and Rivaroxaban, as they contain lactose (otherwise they are 1st line DOACs as they don’t require bridging therapy)
