CPT24 - Anticoagulants

Question 1

4 general features of heparin

Production
Mechanism
Reversal/Antidote
Usage x3

Answer 1

1.) Production - mast cells and vascular endothelium
- extracted from pig intestinal mucosa and cattle lung

2.) Mechanism - enhances antithrombin III activity
- binds to ATIII –> confromational change –> ↑activity
- inhibits coagulation in vitro and in vivo

3.) Reversal/Antidote - protamine sulphate
- forms inactive complex w/ heparin
- irreversibly dissociates heparin from ATIII
- has greater effect w/ UFH, no effect on fondaparinux

4.) Usage
- prevention/management of VTE: DVT and PE
- ACS: short term in an STEMI or NSTEMI
- perioperative prophylaxis

Question 2

5 pharmacokinetic features of UFH vs LMWH

Administration
Dose Response
Bioavailability
Metabolism/Elimination
Half-Life

Answer 2

1.) Administration - parenteral because large negatively charged molecules have poor GI absorption
- UFH is IV or SC (prophylaxis), LMWH is only SC

2.) Dose Response
- UFH is non-linear because it can bind long enough to endothelial cells, plasma proteins and macrophages
- LMWH is predictable as it doesn’t bind long enough

3.) Bioavailability - when given SC
- UFH is variable whilst LMWH is predictable (90%)

4.) Metabolism/Elimination
- metabolised mainly by the liver
- LMWH is eliminated slowly by the kidneys
- UFH has mixed elimination making it unpredictable

5.) Half-Life - roughly 2 hours, LMWH can be longer
- UFH can be 30 mins if a low dose is given
- shorter t1/2 means you can have finer control

Question 3

3 features of unfractionated heparin (UFH)

Mechanism
Monitoring
Usage

Answer 3

1.) Mechanism - ↓factor Xa and ↓thrombin (II)
- accelerates interaction of ATIII w/ factor Xa
- can simultaneously bind to ATIII and thrombin to catalyse the inhibition of thrombin

2.) Monitoring - activated partial thromboplastin time (aPTT)
- measures blood clotting of the intrinsic pathway

3.) Usage - when LMWH is contrainidcated

Question 4

5 features of low molecular weight heparins (LMWH)

Examples x3
Mechanism
Fondaparinux
Usage
Contraindications

Answer 4

1.) Drug Names - dalteparin, enoxaparin, fondaparinux

2.) Mechanism - ↓factor Xa
- accelerates interaction of ATIII w/ factor Xa
- cannot bind to ATIII and thrombin simultaneously

3) Fondaparinux - synthetic with longer half-life (18h)
- no animal products and doesn’t cause HIT

4.) Usage - most of the time (the go-to)

5.) Contraindications
- severe renal impairment

Question 5

4 side effects/adverse reactions to heparins

Bleeding
Heparin Induced Thrombocytopenia (HIT) x4
Hyperkalaemia
Osteoporosis

Answer 5

1.) Bleeding - site of injection, GI, epistaxis, intracranial
- higher risk in hepatic and renal impairment, elderly

2.) Heparin-Induced Thrombocytopenia (HIT)
- more common with unfractionated heparin
- autoimmune response 2-14 days after initiation
- antibodies to platelet factor 4 –> ↓ in platelets
- can lead to thrombosis as more platelets are activated by the damaged endothelium
- switch to a direct thrombin inhibitor e.g. IV argatroban instead (NOT A DOAC)

3.) Hyperkalaemia - inhibition of aldosterone secretion

4.) Osteoporosis - rare long term use
- higher risk w/ UFH and ↑prevalence in pregnancy

Question 6

6 features of vitamin K antagonists (warfarin)

Mechanism
Briding Therapy
Monitoring
Usage x4
Contraindication
Side Effect

Answer 6

1.) Mechanism - inhibits activation of vitamin K dependant clotting factors (II, VII, IX, X)
- competitive inhibition of VK epoxide reductase
- ↓conversion of vitamin K epoxide into vitamin K

2.) Bridging Therapy - with heparin
- when initiating or temporarily stopping warfarin
- stop giving LMWH when INR is between 2-3

4.) Usage
- VTE: DVT, PE, superficial vein thrombosis
- long term anticoagulation
- AF with high risk of stroke (during cardioversion)
- heart valve replacement

5.) Contraindication
- pregnancy: teratogenic in T1 and haemorrhagic in T3

6.) Side Effect - bleeding
- epistaxis and spontaneous retroperitoneal bleeding
- antidote: vitamin K1, prothrombin complex conc

Question 7

4 pharmacokinetic features of warfarin

Structure
Administration
Onset of Action
Metabolism

Answer 7

1.) Structure - racemic mixtures of 2 enantiomers (R, S)
- both have different potency and metabolism

2.) Administration - oral
- good GI absorption w/ 95%+ bioavailability

3.) Onset of Action - delayed, takes several days
- the circulating active clotting factors must be cleared and replaced with noncarboxylated (inactive) forms

4.) Metabolism - liver via CYP2C9
- polymorphisms contribute to individual variability
- response affected by CYP2C9 and vitamin K intake

Question 8

4 DDIs of warfarin and their effect on INR

Acceleration of Hepatic Metabolism x4
Inhibition of Hepatic Metabolism x5
Displacement from Albumin x2
Reduce Vitamin K x1

Answer 8

1.) Drugs Reducing Efficacy of Warfarin - ↓INR
- CYP inducers which accelerate hepatic metabolism:
rifampicin, phenytoin, barbituates, St John’s Wort, some antiretrovirals
- drugs which reduce vitamin K: cephalosporins antibiotics can eliminate gut bacteria
- smoking, chronic alcohol intake

2.) Drugs Potentiating the Action of Warfarin - ↑INR
- CYP inhibitors which inhibit hepatic metabolism: ciprofloxacin, macrolides, metronidazole, imidazoles, omeprazole, cimetidine, clopidogrel, allopurinol, amiodarone, sodium valproate, sertraline, fluoxetine, isoniazid
- liver disease: reduced synthesis of clotting factors
- acute intoxicating dose of alcohol
- drugs which displace warfarin from albumin: NSAIDs
- drugs reducing GI absorption (of vit K)

Question 9

6 features of direct acting oral anticoagulants (DOACs)

Examples x4
Mechanism
Pharmacokinetics x3
Dabigatran
Contraindications x2
Side Effects

Answer 9

1.) Examples - apixaban, edoxaban, rivaroxaban
- dabigatran

2.) Mechanism - inhibits factor Xa
- inhibits both free ones and ones bound with ATIII

3.) Pharmacokinetics
- hepatic metabolism and partly excreted by kidneys
- half-life is roughly 10 hours

4.) Dabigatran - competitive thrombin (IIa) inhibitor
- inhibits both circulating and thrombus IIa
- half-life is slightly shorter (roughly 9 hrs)
- can be reversed with idarucizumab

5.) Contraindications
- low creatinine clearance (renal failure) eGFR <15
- pregnancy: not enough information

6.) Side Effects - bleeding (not as bad as warfarin)
- less frequent interactions than warfarin
- affected by CYP inhibitors and inducers

Question 10

4 advantages of DOACs over warfarin

Answer 10

1.) Less risk of intracranial bleeding

2.) Fewer drug-drug interaction

3.) No bridging therapy required

4.) Greater compliance - standard dosing and no monitoring required

Question 11

Warfarin Monitoring

International Normalised Ratio (INR)
High INR +/- Bleeding
Perioperative Warfarin

Answer 11

1.) International Normalised Ratio (INR) - patient’s PT/standardised PT time
- target INR is generally 2.5 (2-3 range) for majority of conditions
- target INR increases to 3.5 for patients with recurrent DVT/PEs and already currently on anticoagulation

2.) High INR +/- Bleeding - stop warfarin, target INR <35
- major bleeding: IV vitamin K1 5mg + IV dried prothrombin complex
- minor bleeding: IV vitamin K1 1-3mg (phytomenadione)
- no bleeding w/ INR >8: PO vitamin K1
- no bleeding w/ INR 5-8: withhold 1 or 2 doses of warfarin

3.) Perioperative Warfarin
- warfarin sodium should usually be stopped 5 days before elective surgery
- PO vitamin K1 given the day before surgery if the INR is ≥1.5
- can resume normal dose of warfarin on the evening of surgery or the next day
- bridging therapy w/ LMWH in those considered ‘high risk’ of thromboembolism
- emergency surgery: IV vitamin K1 +/- IV PCC (if surgery cant be delayed by 6-12hrs)