Session 12: Anticoagulants Flashcards
Give common thromboembolic diseases.
DVT and PE
TIA
Ischaemic stroke
MI
AF
Pharmacokinetics of unfractionated heparin
Fast onset of action with a half-life of 30 min at low dose.
Half-life is 2h at higher dose
With a mixed elimination as well as unpredictable.
How is unfractionated heparin administered?
Typically IV bolus and infusion
Can be given s.c. for prophylaxis however the bioavailability is much lower in that case.
Explain the mechanism of action of unfractionated heparin.
Binds to antithrombin (ATIII) and causes conformational change as well as increasing the activity of antithrombin.
It also catalyses inhibition of thrombin (IIa). This requires heparin to simultaneously bind to ATIII and IIa.
Xa inhibition only needs ATIII binding.
Give examples of low molecular weight heparins (LMWH)
Dalteparin (most commonly prescribed)
Enoxaparin (Acute coronary syndrome)
Administration of LMWH
Almost always s.c.
However enoxaparin is given i.v. in ACS
Pharmacokinetics of LMWH
Bioavailability of >90% with a longer half-life (>2h) and independent of the dose
Why is it important that the half-life of LMWH is independent of dose?
This means that it is more predictable when given.
How does the action differ between unfractionated heparin and LMWH?
It is not long enough to bind to endothelial cells, plasma proteins and macrophages.
It is also not long enough to inactivate thrombin IIa.
This means that it specifically inhibits Xa but enhance ATIII activity.
Explain why fondaparinux might be given instead?
It is a synthetic pentasaccharide that selectively inhibits Xa by binding to ATIII.
You give it s.c. and has a half-life of 18h.
It is a great choice for vegans as heparin is extracted from pork otherwise.
When is heparin used?
Prevention of venous thromboembolism
Perioperative prophylaxis
During pregnancy as it is too big to cross the placenta
DVT and PE (usually just initial treatment)
Acute coronoary syndrome
NSTEMI
ADRs of heparin
Bruising and bleeding
Intracranial, site of injection bleeding and epistaxis
Heparin induced thrombocytopenia
Hyperkalaemia (via inhibition of aldosterone secretion)
Osteoporosis
How is heparin monitored?
By aPTT when using therapeutic doses of UFH.
The dose is then titrated to the aPTT value.
LMWH is much more predictable and only needs little monitoring if any.
Antidote of heparin
Protamine sulphate
Explain action of protamine sulphate
Forms inactive complex with heparin and is given i.v.
It dissociates heparin from ATIII, irreversibly binding.
Effects of protamine sulphate on UFH, LMWH and fondaparinux.
Greater effect on UFH than on LMWH.
There is no affect at all on fondaparinux
Give an example of a vitamin K antagonist.
Warfarin
Explain the action of warfarin.
Inhibits activation of vitamin K dependant clotting factors.
Inhibition of the conversion of vitamin K to its active form. This is by competitive inhibition of VKOR (epoxide reductase).
Give examples of clotting factors that needs active vitamin K as a cofactor in order to become activated.
Clotting factors II, VII, IX and X via hepatic synthesis requires active vitamin K.
Why is there a delay in warfarin to become active?
Because the circulating active clotting factors will be present for severel days and must be cleared and replaced with inactive clotting factors.
This can take up to 72 hours.
Half-life of warfarin.
36h-48h
Uses of warfarin.
Venous thromboembolism
PE
DVT
Superficial vein thrombosis
A-fib
After bio-prosthetic and also some mechanical heart valve replacements.
Generally used in longer term anticoagulation whereas heparin is used short term.
Pharmacokinetics of warfarin.
Good GI absorption with over 95% bioavailability if taken orally.
CYP2C9 inactivates warfarin in the liver.
Warfarin has two enantiomers with different potency and different metabolism.
Warfarin and pregnancy.
Crosses the placent and is teratogenic in 1st trimester and haemorrhagic in 3rd.
What will affect the effect vitamin K has?
There is functional CYP2C9 polymorphism meaning that people will have different rates of inactivation. This needs monitoring.
VKOR can also have a variability leading to different degrees of ADRs or effect.
Also the patient needs to have a steady diet of vitamin K, otherwise warfarin might have ADRs.
ADRs of warfarin
Bleeding
Epistaxis
Sponatenous retroperitoneal bleeding
What is the antidote of warfarin?
Vitamin K1 or
Prothrombin complex concentrate i.v.
Usually this is taken in a combination.
Explain bridging therapy between LMWH and warfarin.
When warfarin is to be initiated or stopped (prior to surgery e.g.) heparin is used either first (if initiated therapy).
Or heparin is started (prior to surgery) in order to wear off the effects of warfarin.
LMWH can be stopped much quicker than warfarin and is therefore used prior to surgery.
Give examples of DDIs of warfarin.
Inhibition of hepatic metabolism (CYP2C9) such as amiodarone, clopidogrel, intoxicating doses of alcohol, quinolone and metronidazole. Leads to more effect of warfarin.
Cephalosporin antibiotics can kill gut flora and its bacteria and cause less production of vitamin K in that way. Leads to more effect of warfarin.
Displacement of warfarin from plasma albumin from e.g. NSAIDs.
Drugs that decreases GI absorption of vitamin K.
Acceleration of warfarin metabolism by barbiturates, phenytoin, rifampicin and St Johns Wort. (Likely to decrease INR i.e. less of an effect of warfarin and more needed to give.)
How is warfarin use monitored?
By keeping a stable diet and lifestyle/medications stable as well.
INR is also used.
Explain INR.
Factor VII is the most sensitive clotting factor to vitamin K deficiency so it is used in prothrombin time (PT)
This is then standardised against control plasma and international normalised ratio (INR).
This means clotting time against a standard.
A high INR means a longer time for blood to clot and increased risk of bleeding.
Give examples of direct acting oral anticoagulants (DOACs)
Apixaban
Edoxaban
Rivaroxaban
Dabigatran
Explain the action of apixaban, edoxaban, and rivaroxaban.
Inhibit both free Xa and Xa that is bound with ATIII.
They do not directly effect thrombin IIa.
Explain the action of dabigatran.
Selective direct competitive inhibition of thrombin (IIa). Both the circulating and thrombus bound IIa.
Pharmacokinetics of apixaban, edoxaban, rivaroxaban.
Hepatic metabolism and excreted partly by the kidneys with a half-life of around 10h.
Administration of DOACs.
Orally
Standard dosing and little to no direct monitoring required.
ADRs of DOACs.
Bleeding
Caution and dose adjustment especially
When are DOACs contraindicated?
Dabigatran is CId in low creatinine clerance and the other DOACs in very low <15 ml/min.
DDIs of DOACs
Plasma concentrations are reduced by carbamazepine, phenytoin and barbiturates.
The plasma concentration is increased by macrolides.
Why might DOACs be a better option than warfarin?
Less monitoring is needed.
There is a lower risk of intracranial risk.
Less DDI and ADRs in general.
You can eat what you want and don’t need to think of a vitamin K stable diet.
Most importantly there is little need to monitor so there is more adherence.
When would warfarin be more appropriate than a DOAC?
In renal failure with low creatinine clearance.
