Anti-coagulant agents Flashcards
What role does Vitamin K have in coagulation?
all coagulation factors are synthesized in the liver, but vitamin K is an essential catalyst for the gamma-glutamyl carboxylase which modifies factors 2,7,9,10
What does gamma- glutamyl carboxylase do?
it is a hepatic enzyme that adds a gamma-carboxyl group to clusters of glutamic acid residues- mainly this is for modification of coagulation factors 2,7,9,10
Vitamin K is an essential catalyst for this reaction
Why might someone be vitamin K deficient? What is the result?
causes: antibiotic overdose, alcoholic liver disease, malntrition
symptoms: bruising, haemorrhagic disease of newborn,
How does Warfarin work to prevent coagulation?
Warfarin is a Vitamin K anatagonist - coumarin compound
It inhibits correct synthesis of factors 2,7,9,10 - rendering them useless but it requires 24-48 hours to work b/c it needs time to deplete endogenous stores of these clotting factors -
when is warfarin given?
Warfarin is prescribed to people with an increased tendency for venous thrombosis - or as a secondary prophylaxis in individuals that have previously formed a blood clot
is warfarin a ‘blood thinner’?
God no. Doesn’t effect viscosity of blood - it simply prevents blood from clotting
Does warfarin pass through ‘first pass metabolism’?
yes! It is metabolised by Cytochrome P450 in the liver -
what lab measurement monitors the effects of warfarin?
The Pro-Thrombin time (PT) test
what percent of the warfarin is bound to protein at any particular time?
99%
what does ‘low therapeutic index’ mean?
Low therapeutic index is calculated as the lethal dose in 50% of the population divided by the effective dose in 50% of the population - the closer this number is to 1, the more dangerous the drug potentially is -
Warfarin has a very low therapeutic index, therefore it must be monitored carefully
What drugs interact with warfarin? Any contraindications?
Warfarin is metabolised hepatically - so things that are also metabolised hepatically like antibiotics, alcohol, antipsychotic drugs or antiplatelet agents can counteract it
- anything that is plasma protein bound can displace warfarin - i.e- aspirin
- teratogenic - do not use in pregnancy
What drug interactions decrease the anticoagulant effect of warfarin?
Rifampicin
Carbamazepine
Alcohol
What drugs increase the anticoagulant effect of warfarin?
NSAIDS
amiodarone
foods which contain large amounts of Vitamin K - rich green vegetables
What kind of molecule is heparin?
a proteoglycan
how does heparin work?
it enhances the ability of AntiThrombin 3 to inhibit the action of Thrombin or Factor Xa
- it binds to antithrombin and induces a conformational change that makes antithrombin 3 more efficient inactivator of coagulation factors
What is ‘low molecular weight heparin’?
–heparin that has been fractionated to sequester the fraction of molecules with low molecular weight. Compared to the unfractionated heparin which is a mix of different length polysaccharides
- its pharmacodynamics are more predictable
- Its half life is increased (5-4 hours)
- The minimal ATIII-binding region of heparin contains 5 saccharide units (HS pentasaccharide)
When would we use Heparin ?
as a treatment for DVT or PE- it also prevents a venous thromboembolism (VTE) following orthopedic surgery
used in MI events and coronary syndrome
Used in pregnant women at increased risk of thrombosis - note that warfarin is teratogenic, but heparin is not
What two coagulation factors does heparin effect?
it effects factor Xa and Thrombin
What test measures heparin levels?
aPTT test
What are the adverse side effects of heparin?
- haemorrhage
- osteoporosis- bone density screening is necessary for people recieving long-term therapy with a LMW heparin
- hypersensitivity
- heparin-induced platelet aggregation and thrombocytopenia
- HIT = heparin induced thrombocytopenia -
If we require urgent reversal of heparin what do we give?
protamine sulfate is administered by slow intravenous infusion
What is HIT (heparin induced thrombocytopenia)?
•caused by an immunological reaction that causes platelet activation within the blood vessels, thereby using up coagulation factors.
–Formation of platelet clots can lead to thrombosis, while the loss of coagulation factors and platelets may result in bleeding.
- HIT can (rarely) occur shortly after heparin is given, but also when a person has been on heparin for a long while.
- Frequency of HIT is “up to 5 percent of patients exposed, regardless of the dose, schedule, or route of administration.”
- Patients being treated with heparin need to be carefully monitored for HIT (by assessing platelet count) and for anti-coagulant effect (aPTT)
what are some advantages and disadvantages of using unfractionated heparin?
Advantage
- rapid onset of action/clearance
- ability to measure effects using aPTT test
- lack of renal metabolism = use in renal failure patients
- easy to reverse effects with protamine sulfate
- intravenous or sucutaneous route of administration
Disadvantages
- narrow therapeutic index
- highly variable dose response relationship - requires frequent lab monitoring
- no oral route
- potential risk of HIT
What are the advantages and disadvantages of using low molecular weight heparin?
Advantages
- greater bioavailability than unfractionated heparin
- subcutaenous or IV route
- longer duration of anti-coag effect
- easier to predict dose-response relationship
- no need for monitoring in the lab
- lower risk of HIT
- lower incidence of osteoporosis
- good for pregnancy
Disadvantages
- slightly delayed onset of action
- longer duration of action -less ability to stop rapidly
- less easily inactivated with protamine sulfate
- prolonged half life in patients with renal failure
What are NOACs and how do they work?
Dabigatran - direct thrombin inhibitor
Rivaroxaban - direct factor Xa inhibitor
What are the advantages to using Dabigatran?
It allows predictable anticoagulation with no need for dose adjustments and routine coagulation monitoring
What is the benefit to using Rivaroxaban?
it was the first orally available anticoag. drug since warfarin - it is well absorbed from the gut and maximum inhibition of factor Xa occurs four hours after a dose
it doesn’t require frequent blood tests for INR monitoring
Overall what is the benifit to using NOACs/DOACs over warfarin?
Advantages over warfarin
- allow predictable anticoagulation with no need for dose adjustments and routine coagulation monitoring
- lack significant drug interactions
- are excreted in the kidney
**however no antedote yet*
