Anticoagulant drugs Flashcards
Which genetic predispositions increase the risk of blood clots?
Anti-thrombin deficiency
Protein C deficiency
Protein f deficiency
Factor Leiden thrombophilia
What are the different classes of anticoagulants?
Warfarin - teratogenic
Heparin - unfractionated and LMWH
DOACs - e.g., dabigatran, rivaroxaban
Other non anticoagulant classes that have anticoagulant effects are:
Anti-platelet drugs
Anti-fibrinolytics
What is the action of warfarin?
Vitamin K antagonists
Prevents γ-carboxylation of factors II, VII, IX, X (a.k.a., vitamin K dependent factors)
This prolongs the extrinsic pathway (PT time)
How is warfarin monitored?
International normalised ratio (INR)
Based on the ratio between the PTs of the test and control samples
Most accurately measured in the venous blood samples
When being treated on warfarin what is the target INR for DVT/PE and AF?
2.5
When being treated on warfarin what is the target INR for recurrent VTE or metal heart valves?
3.5
What is the metabolism of warfarin?
Hepatic via CYP2C9
What are the half lives of the different clotting factors?
VII = 6 hours
IX = 24 hours
X = 40 hours
II = 60 hours
In light of the different half lives of the clotting factors, how long can it take warfarin to reach therapeutic levels?
> 3 days
What drug should be given whilst you wait for warfarin to reach therapeutic levels?
LMWH
Typical loading regime is 10 mg, 10mg, 5mg
LMWH is usually continued until INR is > 2.0 for 2 consecutive days
What other natural anti-coagulants does warfarin inhibit?
Protein C
Protein S
How does warfarin initially cause a temporary pro-coagulant state?
Fall in protein C and S which occurs in within hours can cause a temporary pro-coagulant state
Which drugs can potentiate the effect of warfarin?
Enzyme inhibitors
Fluconazole
Azathioprine
Allopurinol
Erythromycin (a macrolide)
Ciprofloxacin (a fluoroquinolone)
Amiodarone
Which drugs can inhibit the effect of warfarin?
Enzyme inducers e.g.,
Rifampicin
Citalopram
Phenytoin
Carbamazepine
Which other substance can warfarin interact with?
Alcohol
What other conditions can potentiate the effect of warfarin?
Liver disease due to decreased synthesis of vitamin K factors
Decreased absorption of vitamin K e.g., malabsorption, Abx therapy, laxatives
What are the important side effects of warfarin?
Teratogenic
Significant haemorrhage risk - intracranial bleeds up to 1% per year, increased risk in elderly and those with higher INR target
Minor bleeding up to 20% per year
Skin necrosis
Alopecia
How can you reverse warfarin?
Life-threatening bleed = prothrombin complex (Octaplex) which contains factors II, VII, IX, X - dosed according to patient’s INR and weight
Vitamin K 2-10 mg IV/PO depending on INR level
FFP can also be used
What is a heparin?
Mucopolysaccharide that potentiates anti-thrombin
Can the effects of heparins be reversed?
No
Irreversibly inactivates factors IIa (thrombin) and Xa
How is heparin given?
Parenterally (e.g., SC)
What are the two types/formulations of heparin?
Unfractionated (given via IV)
LMWH (given SC)
Can heparins be used in pregnancy?
Yes
LMWH more commonly used
TRUE or FALSE
Unfractionated heparin can be given in renal failure
TRUE
Why is unfractionated heparin not often used?
Due to its inconvenience
How is unfractionated heparin administered?
IV with 5000U bolus and ~ 1000U/hour infusion
What is a rare but important side effected of unfractionated heparin?
Thrombocytopenia and VTE which results in Heparin-induced thrombocytopenia (HIT)
How is unfractionated heparin monitored?
APTT
Target range of 1.5-2.5 x normal
How can unfractionated heparin be partially reversed?
With protamine sulphate (not really effective)
How is LMWH given and prescribed?
SC
Prescribed according to patient’s weight
Is LMWH usually monitored?
No (but can use the anti-Xa assay)
What creatinine clearance must patients have to use LMWH?
> 30 ml/min
Hence it CANNOT be given to people with renal impairment
Give examples of LMWH formulations
Tinzaparin (Innohep) 175U/kg (OD)
Enoxaparin (Clexane) 1.5mg/kg (OD)
Dalteparin (Fragmin)
What dose of the different LMWH are used for thromboprophylaxis in hospital in-patients?
3,500 or 4,500U for Tinzaparin
20 or 40mg Enoxaparin
What is the basis of INR?
PT
Tube contains citrate, which allows the cellular portion to be separated from the plasma (which contains the clotting factors)
Name other parenteral anticoagulants
Hirudin
-Snake venom derived
-Argatroban - direct thrombin inhibitor
-Used in place of heparin in patients with HIT
Heparinoids
-Danaparoid – heparin-like compound
Fondaparinux
-Arixtra – potentiates anti-thrombin, inhibits factor Xa
What are DOACs?
Oral anticoagulants
Developed as an alternative to warfarin
Require no monitoring and have a good safety profile
What are the 2 classes of DOACs?
Direct thrombin (IIa) inhibitor e.g., dabigatran
Direct factor Xa inhibitor e.g., rivaroxaban, apixaban
According to trials how do DOACs compare to warfarin?
Non-inferiority of DOACs to warfarin and LMW heparin for VTE and AF (but not cardiac valves)
How does Rivaroxaban work? Is it reversible?
Direct factor Xa inhibitor
It is NOT reversible
What are the indications for Rivaroxaban?
VTE prophylaxis
Tx of DVTs and PEs
Stroke prevention in AF
What is the dosing for Rivaroxaban?
15mg BD for 3 weeks
THEN
20mg OD or 15mg OD if CrCl is 15-50ml/min
What is an alternative drug and how is it dosed?
Apixaban
Dosed BD
Less affected by renal function (safe > 15 ml/min)
What is dabigatran?
Direct IIa (thrombin) inhibitor
What are indications for Dabigatran?
VTE prophylaxis
Tx of DVTs and PEs
Stroke prevention in AF
What is the dosing for Dabigatran?
Treatment dose is 150mg bd
Prophylactic dose is 110mg bd
Confirm creatinine clearance > 30ml/min
What drug is used to reverse Dabigatran?
Praxbind (Idarucizumab)
What are the different types of anti-platelet drugs?
Aspirin = cyclo-oxygenase (COX) inhibitor
Clopidogrel = ADP receptor blocker
Dipyridamole = inhibits phosphodiesterase
Prostacyclin = stimulate adenylate cyclase
Glycoprotein IIb/IIIa inhibitors:
Abciximab – monoclonal antibody
Eptifibatide – snake venom derivative
Tirofiban – blocks platelet aggregation
What are fibrinolytic agents? How do they work?
Thrombolytic agents
Lyse fresh thrombi (arterial)
Convert plasminogen into plasmin
What are examples of fibrinolytic agents?
Alteplase = Tissue Plasminogen Activator (tPA)
Streptokinase
How are fibrinolytic agents administered and when?
Systemically
Acute MI
Recent thrombotic stroke
Major PE
Iliofemoral thrombosis
When should you aim to use standardised dosage regimens?
Within 6 hours
What are the contraindications to thrombolysis?
Recent intracranial haemorrhage (ICH)
Structural cerebral vascular lesion.
Intracranial neoplasm.
Ischemic stroke within three months.
Possible aortic dissection.
Active bleeding or bleeding diathesis (excluding menses)
Significant head injury or facial trauma within 3 months
What is the starting dose when warfarin Tx is initiated?
Typical induction dose = 10mg daily for 2 days
Low starting dose - 5mg - for frail/elderly/people with low body weight
Subsequent doses depend on prothrombin time i.e., INR
What is the maintenance dose of warfarin?
3-9mg taken at the same time each day
Which anticoagulant should be given if you want an immediate effect but also want to give warfarin e.g., in PE or DVT?
Start them on heparin or LMWH - bridging treatment and warfarin
What is the duration of Tx for DVT/PE with warfarin?
At least:
6 weeks - distal DVT (calf vein thrombosis)
3 months - proximal DVT or PE where there are known temporary risk factors and a low risk of recurrence.
6 months - proximal DVT due to an unknown cause
Long-term - recurrent DVTs or PEs
What is the duration of Tx for AF with warfarin?
Usually long-term
If pt undergoing cardioversion - ensure target INR (i.e., 2.5) is met at least 3 weeks before cardioversion and 4 weeks after
What is the duration of Tx with warfarin for patients with prosthetic valves?
Long-term
When on warfarin, how frequently should the INR be measured?
Daily or on alternate days until target INR achieved
Then twice weekly for 1-2 weeks
Then weekly measurements until at least 2 INR measurements are within the therapeutic range
Thereafter, depending on the stability of the INR, at longer intervals
Once a stable warfarin dose that controls the INR has been established, changes in dose are seldom required.
What are the 1st steps you should take if the INR is not within therapeutic ranges when a person is on warfarin?
Ask patient about:
- adherence to warfarin Tx
- use of other medications inc. OTC, vitamins, herbal or homeopathic remedies
- use of alcohol or illicit drugs
- food and drink intake (e.g., veggies, cranberry juice)
- their general health - any episodes of illness, nausea, vomiting, diarrhoea, weight loss
What should you do if the INR > 8 with minor bleeding?
Stop warfarin
Give phytomenadione (Vit K) by slow IV injection
Dose of pytomenadione can be repeated after 24 hours if INR is still high
Restart warfarin once INR < 5
What should you do if the INR is > 8 with no bleeding?
Stop warfarin
Give phytomenadione (Vit K) orally using the IV preparation
Dose of pytomenadione can be repeated after 24 hours if INR is still high
Restart warfarin once INR < 5
What should you do if the INR 5-8 with minor bleeding?
Stop warfarin
Give phytomenadione (Vit K) by slow IV injection
Restart warfarin once INR < 5
What should you do if the INR 5-8 with no bleeding?
Withhold 1-2 doses of warfarin
Reduce subsequent maintenance dose
What should you do if a patient on warfarin has major bleeding?
Stop warfarin
Give:
Phytomenadione (Vit K)
Octaplex (prothrombin complex concentrate with factors II, VII, IX, and X)
FFP if Octaplex is unavailable
What advice should be given to patients about warfarin check-ups?
Important to have their INR check regularly at intervals agreed with the patient
They should always take their anticoagulant Tx booklet (Yellow book) when they go to clinic to have their INR checked
What does the Yellow book contain?
Advice for people of anticoagulants
An alert card (which a patient should carry at all times)
A section for recording INR readings
What should you advice patients about how to take warfarin?
Take at the same time each day
They should not miss doses or take additional doses without advice from a HCP
They should inform anticoagulant clinic staff if they have taken too much warfarin or missed any doses
Never take a double dose if they have missed a dose and should continue with the prescribed regimen
What advice should be given to patients on warfarin around diet, additional meds etc?
Seek med advice before making any major changes to diet (e.g., eating more vit K rich food like spinach, kale, broccoli which can affect anticoagulation control)
Limit alcohol intake to 1-2 drinks max per day - avoid binge drinking
Inform the anticoagulant clinic or other HCPs about changes to their lifestyle e.g., if they start, stop or change the dose of other medications
In which situations should patients on warfarin seek urgent medical attention?
Spontaneous bleeding that does not stop or recurs (inc. postmenopausal bleeding, nosebleeds, prolonged bleed from a clot)
Sudden severe back pain - could indicate spontaneous retroperitoneal bleeding
Difficulties breathing, increased breathing rate or chest pain - could be Sx of PE
What other advice should patients on warfarin be given?
Seek medical attention if they experience other adverse effects
They may have to stop warfarin before surgery or dental procedures
They should expect to bleed more easily and take extra care when brushing their teeth or using a razor - they should consider using a soft toothbrush or an electric razor
What other advice should women of child-bearing age on warfarin be given?
Use effective contraception as warfarin is a known teratogen
If she become pregnant she’ll need to stop taking warfarin and use a LMWH instead
What is self-testing and self-management of warfarin?
Self-testing is where a person tests their own international normalized ratio (INR) but contacts a healthcare professional for dose adjustment.
Self-management is where the person tests their own INR and also adjusts the dose of warfarin themselves (based on an individualized algorithm).
Sources
https://cks.nice.org.uk/topics/anticoagulation-oral/management/warfarin/
https://cks.nice.org.uk/topics/anticoagulation-oral/background-information/mode-of-action/
