11 - Anticoagulants Flashcards

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1
Q

What two things are needed to control bleeding?

A

Haemostatic platelet plug and fibrin mesh

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2
Q

How do anticoagulant drugs work and what are some examples?

A

They prevent thrombus formation and the thrombus growing

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3
Q

What is the mechanism of action of heparin and where is it produced naturally in the body?

A

Enhances Antithrombin III activity via unique pentasaccharide sequence

Deactivates thrombin, Factor Xa, IIa, IXa

Usually made in mast cells and vascular endothelium

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4
Q

What are the two different types of heparin and how are they administered?

A

Given parenterally (sub cut/IV) as poor GI absorption

- Low molecular weight heparin (only subcut - enzymatically made from UFH)

- Unfractionated heparin (IV for continuous or subcut)

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5
Q

Apart from inactivating thrombin, what other clotting factors does heparin inhibit?

A
  • Deactivates thrombin, Factor Xa, IIa, IXa, (probably VIIa, XIa, XIIa)
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6
Q

What are the differences between UFH and LMWH in terms of their action on thrombin and ATIII?

A
  • LMWH only deactivates Xa
  • UFH deactivates Xa and Thrombin
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7
Q

Compare and contrast UFH and LMWH based on the following factors:

  • Dose-response
  • Bio-availability
  • Action
  • Administration
  • Initiation
A

LMWH used more!!! less monitoring needed

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8
Q

What are some of the characteristics of unfractionated heparin?

A

- Fast onset

  • Short half life so need IV bolus

- Unpredictable

  • SC if prophylaxis
  • Needs to bind ATIII and IIa to inhibit thrombin but only need ATIII binding with Xa inhibition
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9
Q

Which heparin needs monitoring and why?

A

Unfractionated with APTT test as affecting intrinsic pathway

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10
Q

What are some of the characteristics of low molecular weight heparin?

A

- More predictable as higher bioavailability and does not bind to endothelial cells, plasma proteins and macrophages as not long enough

  • Longer half life
  • Given subcut
  • Only inhibits Xa
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11
Q

What are some examples of LMWH’s?

A
  • Dalteparin
  • Enoxaparin
  • Fondaparinux (synthetic so cheaper and good for veggies)
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12
Q

What are some indications for heparin use?

A

- Prevention of venous thromboembolism before surgery or for immobile patients (LMWH)

- DVT/PE give LMWH before warfarin to achieve loading dose

- Acute coronary syndromes use LMWH

- Pregnancy instead if warfarin as too large to cross placenta but monitor carefully

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13
Q

What are some adverse drug reactions to heparin?

A

- Bruising/bleeding intracranially, at site of injection, GI, epistaxis and if old, renally/hepatically impaired or carcinoma, at great risk of bleeding

- Heparin induced thrombocytopenia (more common in UFH)

- Hyperkalaemia due to inhibition of aldosterone sedcretion as acts on mineralcorticoid receptors

- Osteoporosis with long term use and in pregnancy, more common in UFH

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14
Q

What is heparin induced thrombocytopenia?

A

Autoimmune response up to 2 weeks after initiation of heparin

  • Antibodies to heparin platelet factor 4 so depletion of platelets
  • Paradoxically lead to more thrombosis as more platelets activated by damaged endothelium
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15
Q

How are the effects of heparin reversed? (e.g if administered too much so bleeding risk or allergy risk)

A

Protamine Sulphate

  • Forms inactive irreversible complex with heparin causing it to disocciate from ATIII. Cationic peptide that binds to heparin forming inactive ion pair
  • Given IV
  • Greater effect with UFH, no effect on fonaparinux
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16
Q

What is the mechanism of action of warfarin?

A

Vitamin K antagonist: stops conversion of vit K to active reduced form by competitively inhibiting reduction of Vitamin K by VKOR

Prevents hepatic synthesis of active clotting factors 2, 7, 9, 10 as they need vit K as a co factor

17
Q

Why is there a delay in onset of action of warfarin?

A
  • Circulating active clotting factors are present for a few days, must be cleared and replaced with inactive clotting factors
  • Given once a day, half life of 36 to 48 hours
  • Heparin cover for first few days
18
Q

When is warfarin used?

A
  • Same setting as heparin but long term, e.g PE, venous thromboembolisms, DVT secondary prevention
  • AF with high risk of stroke or before cardioversion
  • Heart valve replacement with bio prosthetic valve and some mechanical
19
Q

What are the pharmacokinetics of warfarin?

A

- Good GI absorption (95%) so taken orally

  • Metabolised by CYP2C9 which is highly polymorphic
  • Plasma concentration does not correlate with clinical effect
  • Response affected by CYP2C9 and Vit K intake

- Heavily protein bound so may be displaced by drugs like NSAIDs

20
Q

Why should warfarin not be given in pregnancy or before surgery?

A
  • Crosses placenta and highly tetarogenic in first trimester and haemorraghic in third trimester
  • Stopped 3 days before surgery as long half life and given heparin. Prevent risk of bleeding. Bridging therapy is LMWH
21
Q

What are some adverse drug reactions of warfarin?

A
  • Bleeding (epistaxis and retroperitoneal common)
  • Tetarogenic
22
Q

What is the antidote for warfarin?

A

- Parenteral Vitamin K1: acts slowly as need to synthesis new clotting factors

- Prothrombin complex concentrate

  • Stop warfarin

- Fresh frozen plasma can immediately increase clotting factors

23
Q

What are some drug interactions with warfarin?

A
  • Anything that affects CYP2C9 can increase anticoagulant affect of warfarin

- Inhibitors of CYP2C9 (increase INR): amiodarone, clopidogrel, alcohol binge, quinolones, metronidazole

- Inducers of CYP2C9 (decrease INR): barbiturates, phenytoin, rifampicin, St John’s Wort

- Drugs reducing Vit K enhancing effect of warfarin: cephalosporins

- Displacement of warfarin from albumin: NSAIDS

24
Q

How do we monitor warfarin use and what are the target values for monitoring?

A
  • Need healthy diet and lifestyle
  • Factor 7 most sensitive to Vit K deficiency so used this, use PT time (INR)
  • INR 2.5 for DVT, PE, AF
  • INR 3-3.5 for recurrent DVT

- Usually 2-3

25
Q

What are DOACs and what is their mechanism of action?

A

Direct Oral Anticoagulants

Inhibit Xa and Xa bound to ATIII (Selective Xa inhibitors): apixaban, edoxaban, rivaroxaban

IIa (thrombin) competitive inhibitor (Direct Thrombin Inhibitors): dabigatran

26
Q

How are DOACs administered and when are they used?

A
  • Orally
  • Little monitoring needed but could be bad if patient is non-complier
  • Used for the same things as warfarin
27
Q

What are some ADRs associated with DOACs?

A
  • Cannot use in renal failure as renally excreted (especially dabigatran)
  • Bleeding risk but lower intracranial bleeding risk than warfarin
  • Avoid in pregnancy and breastfeeding
28
Q

What are the antidotes for DOACs?

A

Andexanet

Idarucizumab (Dabigatran)

29
Q

What are some DDIs with DOACs?

A
  • Less interactions than warfarin but:

- [plasma] reduced by carbamazepine, phenytoin and barbiturates

- [plasma] increased by macrolides

30
Q

How do we treat pneumonia?

A
  • May give doxycycline for better compliance and if allergic to penicillins
  • Co-amoxiclav if CURB65>3
31
Q

If someone had a renal issue and needed a heparin for PE, which one would you give?

A

Unfractionated heparin as LMWH cannot be used in renal impairment

32
Q

How do you transfer a patient from warfarin to a DOAC?

A