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Clinical Pharmacology > Anticoagulants > Flashcards

Anticoagulants Flashcards

1
Q

Describe the coagulation cascade

A
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2
Q

What is the difference in the intrinsic pathway and extrinsic pathways of the coagulation cascade

A

Intrinsic pathway: activated by exposed collagen

Extrinsic pathway: activated by tissue factor (subendothelial)

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3
Q

What is the deficiency in Haemophillia A?

A

Factor VIII

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4
Q

What is the definiciency in Heamophillia B?

A

Factor IX

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5
Q

What element is an important co-factor for blood coagulation?

A

Ca2+

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6
Q

Where are heparins produced naturally in the body?

A

Produced naturally in mast cells and vascular endothelium

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7
Q

What are the 2 different sizes of heparin?

A

Unfractionated heparin (5-30 kDa)

Low molecular weight heparins (1-5 kDa)

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8
Q

Which factor of the coagulation cascade does heparin target?

A

Low molecular weight heparin: Targets factor Xa only

Unfractionated: Target Xa and 2a (thrombin)

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9
Q

How is unfractionated heparin usually administered?

A

Typically i.v. bolus and infusion

Can be given subcut for prophylaxis - has much lower bioavailability

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10
Q

Explain the mechanism of action of unfractionated heparin

A
  • Unfractionated heparin binds to antithrombin (ATIII) → conformational change which increases antithrombin activity
  • Once bound to heparnin, antitrhombin III binds to both thrombin (IIa) and factor Xa
  • Inhibits factor Xa → anticoagulation activity
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11
Q

Name 2 low molecular weight heparins

A

Dalteparin

Enoxaparin

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12
Q

Explain how low molecular weight heparins work

A
  • LMWH binds to antithrombin (IIIa)
  • Accelerates the interaction of antithrombin with Factor Xa → anticoagulant activity
  • Does not inactivate thrombin (IIa) as not long long enough
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13
Q

What is fondaparinux?

A

A synthetic polysaccharide that selectively inhibits factor Xa by binding to AT III

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14
Q

How is low molecular weight heparin administered?

A

Almost always subcut

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15
Q

Why do you get a more predictable response with low molecular weight heparin vs unfractionated heparin?

A

Low molecular weight does not bind to endothelial cells, plasma proteins or macrophages

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16
Q

How is unfractionated heparin monitored?

A

Monitored with activated partial thromboplastin time (aPTT)

(LMWH does not need monitoring due to more predictable response)

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17
Q

In what patients is unfractionated heparin more preferable than LMWH?

A

Patients with severe renal impairment

18
Q

For what conditions is heparin indicated?

A
  • Prevention of venous thromboembolism
  • During pregnancy - do not cross the placenta
  • DVT and PE
  • Acute Coronary Syndromes
    • short term to reduce recurrence
19
Q

What are some of the adverse side effects related to heparins?

A
  • Brusing and bleeding
  • GI disturbance
  • Epistaxis
  • Hepatic and renal impairment
  • Elderly/ those with carcinoma at higher risk
  • Heparin induced thrombocytopenia
  • Hyperkalaemia- inhibition of aldosterone secretion
  • Osteoporosis (rare long term use)
20
Q

What is heparin induced thrombocytopenia?

A
  • An autoimmune response to heparin, 2-14 days after initiation
  • Antibodies develop to heparin platelet factor 4 complex
  • Causes an initial depletion of platelets
  • Paradoxically can lead to to thrombosis as more platelets are activated by damage to endothelium
21
Q

What is the antidote to heparin?

A

Protamine sulphate

22
Q

How does protamine sulphate work?

A
  • Forms an inactive complex with heparin
  • Given I.V
  • Dissociates heparin from antithrombin III
  • Greater effect on unfractionated heparin than LMWH
23
Q

Name a Vitamin K antagonist

A

Warfarin

24
Q

Explain how Warfarin works

A
  • Warfarin inhibits vitamin K epoxide reductase (VKOR) as a competitive inhibitor
  • VKOR is needed to activate vitamin K
  • Active vitamin K is needed to activate clotting factors
25
Q

Which factors need vitamin K as a co-factor?

A

Factors II, VII, IX and X

(produced in the liver as inactive products)

26
Q

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

A
  • There will be circulating active factors present for several days
  • Must be cleared and replaced with noncarboxylated forms (inactive clotting factors)
27
Q

What is warfarin indicated for?

A
  • Venous thromboembolsim
    • PE
    • DVT and secondary prevention
    • superficial vein thrombosis
  • Atrial fibrillation with high risk of stroke
  • Heart valve replacement (bio prosthetics)
  • Generally used longer term than heparin
  • If coagulation needed immediately, need to statrt with heparin
28
Q

How is warfarin most commonly administered?

A

Orally

Good GI absorption, 95%+ bioavailability

29
Q

What is warfarin composed of?

A

A racemic mixture of two enantiomers

R and S: each have different potency and metabolised differently

30
Q

Can wafarin be given in pregnancy?

A

No

Need to be avoided

1st trimester: teratogenic

3rd trimester: haemorrhagic

31
Q

What affects the response to warfarin?

A
  • Genetic polymorphisms of CYP2C9
  • Vitamin K intake (found in veg)
32
Q

What are some of the adverse drug reactions of warfarin?

A
  • Mainly bleeding
  • Epistaxis and spontaneous retroperitoneal bleeding
33
Q

What is the most effective antidote to warfarin?

A

Vitamin K1

competes with warfarin for vitamin K epoxide reductase

34
Q

What are some of the drug-drug interactions with warfarin?

A
  • Inhibition of hepatic metabolism by CYP2C9
    • Amiodarone, clopidogrel, intoxicating dose of alcohol, quinolone, metronidazole
  • Cephalosporin antbiotics- reduce vitamin K by eliminating gut bacteria involved in production
  • Displacement of warfarin from plasma albumin e.g. NSAIDs
  • Barbiturate, phenytoin , rifampicin and St John’s Wort accelerate warfarn metabolism
35
Q

What is the target INR for wafarin?

A

INR 2.5

If at greater risk: INR 3.0-3.5

36
Q

Name 3 direct acting oral anticoagulants (DOAC)

A
  • Apixaban
  • Edoxaban
  • Rivaroxaban
37
Q

How do direct Xa DOACs work?

A
  • Inhibit both free Xa and Xa bound with ATIII
  • Does not directly affect thrombin (IIa)
38
Q

Name a direct IIa DOAC

A

Dabigatran

39
Q

How do direct IIa DOACs work?

A
  • A direct competitive inhibitor of thrombin - both circulating and thrombus bound
40
Q

What are some of the side effects of DOACs?

A
  • Bleeding
  • Use with caution in groups at risk of GI bleed
  • Dabigatran contraindicated in low creatinine clearance (<15 mL/min)
  • Avoid in pregnancy- not enough evidence

Clinical Pharmacology (25 decks)

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