S10) Anti-Coagulant and Anti-Platelet Therapy

Question 1

What is warfarin’s mechanism of action?

Answer 1

Warfarin inhibits the production of Vitamin K dependent clotting factors by stopping the conversion of Vit K to active reduced form

Question 2

Warfarin is the preferred drug choice for long term anti-coagulation.

How is warfarin administered?

Answer 2

Orally – due to good GI absorption

Question 3

Briefly, describe the pharmacokinetics of warfarin

Answer 3

• Slow onset of action (needs Heparin initially)
• Slow offset (t_1/2 48 hrs)
• Heavily protein bound

Question 4

How is warfarin metabolised and what is the clinical significance of this?

Answer 4

Mixed function Oxidase cytochrome p450 system:

• Caution with liver disease
• Caution if used with drugs that affect p450 system

Question 5

Warfarin crosses the placenta.

What is the clinical signicance of this?

Answer 5

• Do not give in 1st Trimester → Teratogenic
• Do not give in 3rd Trimester → Brain Haem

Question 6

How can one monitor the effects of warfarin?

Answer 6

• Extrinsic Pathway Factors
• Prothrombin Time
• INR (International Normalised Ratio)

Question 7

Provide some examples of drugs which potentiate the actions of warfarin

Answer 7

• Amiodarone, quinolone, metronidazole – inhibit hepatic metabolism
• Aspirin – inhibit platelet function
• Cephalosporin antibiotics – reduce Vitamin K from gut bacteria

Question 8

Provide some examples of drugs which inhibit the actions of warfarin

Answer 8

Inducing hepatic enzymes, thus increasing metabolism of warfarin:

• Anti-epileptics (except Na⁺ valproate)
• Rifampicin
• St Johns Wort

Question 9

What are the usual indications for warfarin?

Answer 9

• DVT (3-6 months)
• PE (6 Months)
• Atrial fibrillation (Until risk > benefit)

Question 10

What are the adverse drug reactions of warfarin?

Answer 10

• Teratogenic
• Bleeding/bruising (intracranial, epistaxis, injection, GI loss)

Question 11

In seven steps, describe the clinical approach one takes before prescribing warfarin

Answer 11

⇒ Indication

⇒ PMH e.g PUD, SAH, bleeding disorder

⇒ Medications (interactions)

⇒ Age, Mobility (blood tests and clinics)

⇒ Review blood tests (LFTs, Plt, INR),

⇒ Consider loading dose and heparin cover

⇒ Prescribe

Question 12

How does one manage a patient on warfarin with increasing INR levels of 3.0 < INR < 6.0 (no bleeding)?

Answer 12

• Reduce warfarin dose and stop
• Restart warfarin when INR < 5.0

Question 13

How does one manage a patient on warfarin with increasing INR levels of 6.0 < INR < 8.0 (no bleeding / minor bleeding)?

Answer 13

• Stop warfarin
• Restart warfarin when INR < 5.0

Question 14

How does one manage a patient on warfarin with increasing INR levels of INR > 8.0 (no bleeding / minor bleeding)?

Answer 14

• Stop warfarin
• Restart warfarin when INR < 5.0
• If other risk factors for bleeding, give patient oral Vitamin K

Question 15

How does one manage a patient on warfarin who experiences major bleeding?

Answer 15

• Stop warfarin
• Give prothrombin complex
• Give oral Vitamin K

Question 16

Describe the mechanism of action of heparin

Answer 16

• Activate Anti-Thrombin III (ATIII) via unique pentasaccharide sequence
• Deactivates thrombin, Factor Xa, IIa, IXa, (probably VIIa, XIa, XIIa)

Question 17

Identify and describe the two different types of heparin molecules

Answer 17

• Unfractionated Heparin (intravenous for continuous or subcutaneous for prophylaxis) 20 kDa
• Low molecular weight Heparins (subcutaneous) 3-4 kDa

Question 18

Compare and contrast the varying effects of LMW heparin and Unfractionated heparin on Factor Xa and thrombin

Answer 18

Question 19

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

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

Answer 19

Question 20

How is heparin administered?

Answer 20

Parenterally – due to poor GI absorption

Question 21

Briefly, describe the pharmacokinetics of heparin

Answer 21

• Rapid onset of action (heparin cover)
• Rapid offset of action

Question 22

Describe the uses of heparin

Answer 22

• Prevention of thrombo-embolism during operation in those normally on warfarin (stopped for surgery)
• Heparin cover for DVT/PE and AF
• Pregnancy in place of warfarin
• Reduces recurrence/extension of acute coronary syndromes

Question 23

Identify some adverse drug reactions of heparin

Answer 23

• Bruising/bleeding sites (intracranial, GI loss, epistaxis, injection sites)
• Osteoporosis
• Thrombocytopenia

Question 24

Describe the reversal therapy for heparin (what is used, how?)

Answer 24

Protamine sulphate:

• Dissociates heparin from anti-thrombin III
• Irreversible binding to heparin
• Used for major bleeding, allergy / anaphylaxis

Question 25

Identify some anti-platelet drugs and their mechanism of action

Answer 25

• Aspirin – COX-1 inhibition
• Dipyridamole – Phosphodiesterase Inhibitors
• Clopidogrel – Inhibit ADP dependent aggregation
• Glycoprotein IIb / IIIa Inhibitors – decreases platelet crosslinking by fibrinogen