10. Anticoagulants

Question 1

Which drugs would you recommend to treat a DVT or PE? An MI?

no contra-indications

Answer 1

DVT/PE: warfarin (with heparin cover whilst warfarin loading is achieved)

MI: aspirin (+/- heparin)

Question 2

Which drug would you recommend to treat/prevent DVT/PE in pregnant women? Why?

Answer 2

Heparin (with caution) - is not teratogenic whereas warfarin is

Question 3

Explain the MOA of warfarin.

Answer 3

Inhibits production of vitK-dependent clotting factors (II, VII, IX and X) by competitive inhibition of vitK epoxide reductase (which recycles vitK).

Question 4

Does warfarin require monitoring?

Answer 4

Yes, INR monitoring required (indicator of extrinsic pathway) as has slow action onset (T1/2 48hrs) and variable effect

Question 5

When is warfarin use indicated? What INR should be achieved?

Answer 5

1. Treatment and prophylaxis of venous thrombi: DVT and PE (INR: 2-3)
2. Prophylaxis in AF (INR: 2-3), mechanical prosthetic valves, inherited thrombophilias (INR: 2.5-4.5)

Question 6

Name an important ADR of warfarin? How can risk be reduced?

Answer 6

Increased risk of haemorrhage: intracranial, GI loss, epistaxis, injection site.

So INR should not be higher than 4-5 as risk of intracranial bleed severely increased.

Question 7

How is warfarin administered? And initiated?

Answer 7

• Oral administration (good GI absorption)

- Initiation: loading dose (with heparin cover) then schedule dosing according to INR

Question 8

How is warfarin metabolised? What are the consequent cautions/contra-indications?

Answer 8

Hepatic metabolism with CYP450s so cautions/contra-indications include:

1. liver disease
2. drugs inhibiting CYP450s (increase warfarin effect): amiodarone, quinolones, metronidazole, alcohol

(if taking CYP450 inducer drugs - anti-epileptics, rifampicin, St Johns Wort - may need to increase dose)

Question 9

How can warfarin therapy be reversed if INR increases too much/bleeding occurs?

Answer 9

• INR <8 (no/minor bleeding): stop warfarin, restart with INR <5
• INR >8 (no/minor bleeding): stop warfarin, restart when INR <5 and give 0.5-2.5mg oral vitK if other bleeding risk factors
• major bleeding: stop warfarin, give PT complex concentrate or FFP and give 5mg oral/IV vitK

Question 10

What are the 2 types of heparin? What is their MOA?

Answer 10

1. Unfractionated heparin
   i. binds to anti-thrombin III (increases its activity) and thrombin… inactivates thrombin
   ii. binds to anti-thrombin … stimulates FXa inactivation
2. LMWH
   i. binds to ATIII… stimulates FXa inactivation

Question 11

How are UH and LMWH administered?

Answer 11

Poor GI absorption so:

• UH: IV (loading bolus then IVI)
• LMWH: SC, long T1/2 so less frequent dosing (once/twice daily)

Question 12

Does heparin use require monitoring?

Answer 12

1. UH:
   
   • has variable bioavailability (binds macrophages, endothelial cells, plasma proteins)… less predictable dose response and variable action
   • requires APTT monitoring
2. LMWH:
   
   • high bioavailability >90%… predictable dose response
   • no monitoring required

Question 13

What are the indications for heparin therapy?

Answer 13

1. treatment for DVT and PE, prophylaxis in AF - cover P whilst warfarin loading achieved (LMWH unless fine control required)
2. Treatment for ACSs (MI and UA) - reduces recurrence/extension
3. Prophylaxis in peri-operative (inc. Ps on wafarin stopped for surgery) or immobile Ps - low dose LMWH

Question 14

Name 4 possible ADRs of heparin.

Answer 14

1. Haemorrhage: intracranial, GI loss, epistaxis
2. Thrombocytopenia (rare): autoimmune reaction as heparin is immunogenic. Results in platelet depletion and bleeding.
3. Osteoporosis (if long term use)
4. Hyperkalaemia: hepatin-induced aldosterone suppression

Question 15

How can heparin therapy be reversed if required?

Answer 15

Protamine sulphate - irreversibly binds hepatin and neutralises its negative sulphate charge… dissociates from AT III

Question 16

Name 2 examples of novel anti-coagulation drugs and describe their MOA.

Answer 16

1. Factor Xa inhibitors (e.g. rivaroxaban, apixaban)
   - bind anti-thrombin III… inactivate Xa (no effect on thrombin)
2. Thrombin inhibitors (e.g. hirudin)
   - selectively inactivate thrombin (no effect on Xa)

Question 17

Describe the MOA of aspirin.

Answer 17

irreversibly inhibits COX1 in platelets… inhibits thromboxane A2 production (+PGs)… prevents platelet aggregation by decrease expression of GPIIb-IIIa

Question 18

Name 2 indications for aspirin.

Answer 18

1. Treatment of ACSs: UA and MIs

2. Prophylaxis following coronary bypass surgery

Question 19

Name 3 possible ADRs of aspirin.

Answer 19

1. Haemorrhage
2. GI irritation/ulceration (peptic ulcers = contra-indication)
3. Bronchospasms (asthma = caution)

Question 20

Name a drug that can be used as an adjunct to aspirin or in cases of aspirin intolerance. What is its MOA?

Answer 20

Clopidogrel: irreversible inhibitor of P2Y12 ADP R (important in platelet actiavation and fibrin cross-linking)

Question 21

Name 2 anti-platelet drugs other than aspirin and clopidogrel. What is their MOA?

Answer 21

1. Glycoprotein IIb/IIIa inhibitors
   - inhibit GPIIb and IIIa Rs… decreases platelet cross-linking by fibrin (normally binds these Rs)
2. Dipyrimadole
   - inhibits phosphodiesterase… inhibits cAMP breakdown… prevents platelet aggregation