Session 12: Anticoagulants

Question 1

Give common thromboembolic diseases.

Answer 1

DVT and PE

TIA

Ischaemic stroke

MI

AF

Question 2

Pharmacokinetics of unfractionated heparin

Answer 2

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.

Question 3

How is unfractionated heparin administered?

Answer 3

Typically IV bolus and infusion

Can be given s.c. for prophylaxis however the bioavailability is much lower in that case.

Question 4

Explain the mechanism of action of unfractionated heparin.

Answer 4

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.

Question 5

Give examples of low molecular weight heparins (LMWH)

Answer 5

Dalteparin (most commonly prescribed)

Enoxaparin (Acute coronary syndrome)

Question 6

Administration of LMWH

Answer 6

Almost always s.c.

However enoxaparin is given i.v. in ACS

Question 7

Pharmacokinetics of LMWH

Answer 7

Bioavailability of >90% with a longer half-life (>2h) and independent of the dose

Question 8

Why is it important that the half-life of LMWH is independent of dose?

Answer 8

This means that it is more predictable when given.

Question 9

How does the action differ between unfractionated heparin and LMWH?

Answer 9

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.

Question 10

Explain why fondaparinux might be given instead?

Answer 10

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.

Question 11

Answer 11

Question 12

When is heparin used?

Answer 12

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

Question 13

ADRs of heparin

Answer 13

Bruising and bleeding

Intracranial, site of injection bleeding and epistaxis

Heparin induced thrombocytopenia

Hyperkalaemia (via inhibition of aldosterone secretion)

Osteoporosis

Question 14

How is heparin monitored?

Answer 14

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.

Question 15

Antidote of heparin

Answer 15

Protamine sulphate

Question 16

Explain action of protamine sulphate

Answer 16

Forms inactive complex with heparin and is given i.v.

It dissociates heparin from ATIII, irreversibly binding.

Question 17

Effects of protamine sulphate on UFH, LMWH and fondaparinux.

Answer 17

Greater effect on UFH than on LMWH.

There is no affect at all on fondaparinux

Question 18

Give an example of a vitamin K antagonist.

Answer 18

Warfarin

Question 19

Explain the action of warfarin.

Answer 19

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).

Question 20

Give examples of clotting factors that needs active vitamin K as a cofactor in order to become activated.

Answer 20

Clotting factors II, VII, IX and X via hepatic synthesis requires active vitamin K.

Question 21

Why is there a delay in warfarin to become active?

Answer 21

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.

Question 22

Half-life of warfarin.

Answer 22

36h-48h

Question 23

Uses of warfarin.

Answer 23

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.

Question 24

Pharmacokinetics of warfarin.

Answer 24

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.

Question 25

Warfarin and pregnancy.

Answer 25

Crosses the placent and is teratogenic in 1st trimester and haemorrhagic in 3rd.

Question 26

What will affect the effect vitamin K has?

Answer 26

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.

Question 27

ADRs of warfarin

Answer 27

Bleeding

Epistaxis

Sponatenous retroperitoneal bleeding

Question 28

What is the antidote of warfarin?

Answer 28

Vitamin K1 or

Prothrombin complex concentrate i.v.

Usually this is taken in a combination.

Question 29

Explain bridging therapy between LMWH and warfarin.

Answer 29

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.

Question 30

Give examples of DDIs of warfarin.

Answer 30

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.)

Question 31

How is warfarin use monitored?

Answer 31

By keeping a stable diet and lifestyle/medications stable as well.

INR is also used.

Question 32

Explain INR.

Answer 32

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.

Question 33

Give examples of direct acting oral anticoagulants (DOACs)

Answer 33

Apixaban

Edoxaban

Rivaroxaban

Dabigatran

Question 34

Explain the action of apixaban, edoxaban, and rivaroxaban.

Answer 34

Inhibit both free Xa and Xa that is bound with ATIII.

They do not directly effect thrombin IIa.

Question 35

Explain the action of dabigatran.

Answer 35

Selective direct competitive inhibition of thrombin (IIa). Both the circulating and thrombus bound IIa.

Question 36

Pharmacokinetics of apixaban, edoxaban, rivaroxaban.

Answer 36

Hepatic metabolism and excreted partly by the kidneys with a half-life of around 10h.

Question 37

Administration of DOACs.

Answer 37

Orally

Standard dosing and little to no direct monitoring required.

Question 38

ADRs of DOACs.

Answer 38

Bleeding

Caution and dose adjustment especially

Question 39

When are DOACs contraindicated?

Answer 39

Dabigatran is CId in low creatinine clerance and the other DOACs in very low <15 ml/min.

Question 40

DDIs of DOACs

Answer 40

Plasma concentrations are reduced by carbamazepine, phenytoin and barbiturates.

The plasma concentration is increased by macrolides.

Question 41

Why might DOACs be a better option than warfarin?

Answer 41

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.

Question 42

When would warfarin be more appropriate than a DOAC?

Answer 42

In renal failure with low creatinine clearance.