Anti-coagulant agents

Question 1

What role does Vitamin K have in coagulation?

Answer 1

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

Question 2

What does gamma- glutamyl carboxylase do?

Answer 2

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

Question 3

Why might someone be vitamin K deficient? What is the result?

Answer 3

causes: antibiotic overdose, alcoholic liver disease, malntrition
symptoms: bruising, haemorrhagic disease of newborn,

Question 4

How does Warfarin work to prevent coagulation?

Answer 4

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 -

Question 5

when is warfarin given?

Answer 5

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

Question 6

is warfarin a ‘blood thinner’?

Answer 6

God no. Doesn’t effect viscosity of blood - it simply prevents blood from clotting

Question 7

Does warfarin pass through ‘first pass metabolism’?

Answer 7

yes! It is metabolised by Cytochrome P450 in the liver -

Question 8

what lab measurement monitors the effects of warfarin?

Answer 8

The Pro-Thrombin time (PT) test

Question 9

what percent of the warfarin is bound to protein at any particular time?

Answer 9

99%

Question 10

what does ‘low therapeutic index’ mean?

Answer 10

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

Question 11

What drugs interact with warfarin? Any contraindications?

Answer 11

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

Question 12

What drug interactions decrease the anticoagulant effect of warfarin?

Answer 12

Rifampicin

Carbamazepine

Alcohol

Question 13

What drugs increase the anticoagulant effect of warfarin?

Answer 13

NSAIDS

amiodarone

foods which contain large amounts of Vitamin K - rich green vegetables

Question 14

What kind of molecule is heparin?

Answer 14

a proteoglycan

Question 15

how does heparin work?

Answer 15

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

Question 16

What is ‘low molecular weight heparin’?

Answer 16

–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)

Question 17

When would we use Heparin ?

Answer 17

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

Question 18

What two coagulation factors does heparin effect?

Answer 18

it effects factor Xa and Thrombin

Question 19

What test measures heparin levels?

Answer 19

aPTT test

Question 20

What are the adverse side effects of heparin?

Answer 20

• 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 -

Question 21

If we require urgent reversal of heparin what do we give?

Answer 21

protamine sulfate is administered by slow intravenous infusion

Question 22

What is HIT (heparin induced thrombocytopenia)?

Answer 22

•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)

Question 23

what are some advantages and disadvantages of using unfractionated heparin?

Answer 23

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

Question 24

What are the advantages and disadvantages of using low molecular weight heparin?

Answer 24

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

Question 25

What are NOACs and how do they work?

Answer 25

Dabigatran - direct thrombin inhibitor

Rivaroxaban - direct factor Xa inhibitor

Question 26

What are the advantages to using Dabigatran?

Answer 26

It allows predictable anticoagulation with no need for dose adjustments and routine coagulation monitoring

Question 27

What is the benefit to using Rivaroxaban?

Answer 27

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

Question 28

Overall what is the benifit to using NOACs/DOACs over warfarin?

Answer 28

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

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