Lecture 6: Anticoagulant drugs

Question 1

What are some anti-platelet drugs?

Answer 1

• Aspirin
• Clopidogrel
• Ticagrelor

Question 2

What are some anti-coagulants?

Answer 2

• Warfarin
• Heparin
• Dabigatran
• Rivaroxaban

Question 3

What are anti-coagulant indications?

Answer 3

Arterial disease (anti-platelets + anti-coagulants
i.e CAD, Cerebrovascular disease, peripheral vascular dsiease

Thromboembolic disease (anti-coagulants)
- Atrial fibrillation
- Venous thrombo-embolism (DVT, PE)
- Prosthetic cardiac valves

Question 4

How are the anti-coags and anti-platelets adminsitered?

Answer 4

Parenteral: Heparin

Oral: Warfarin, dabigatran, rivoraxaban

Question 5

What is unfractionated heparin used for?

Answer 5

• Acute coronary syndromes
• Thromboembolism (propholaxis and treatment) (DVT, PE)
• Temporary heparin replacement
• Extracorpereal units i.e dialysis.

Question 6

How does heparin function?

Answer 6

Binds and increases the activity of antithrombin 3.

Inactivating:
- Thrombin 2a and factor 10a
- also IXa, XIa, XIIa

Requires APTT monitoring blood test.

Question 7

What are the pharmacokinetics of unfractionated heparin?

Think T1/2, Bioavail etc

Answer 7

• Parentally, no GI absorb
• T1/2 60 mins
• Variable bioavailability
• Needs APTT monitoring

Question 8

Whats the therapeutic APTT range of UH?

Answer 8

Normal adults: 25-37s

Therapeutic: 50-80s

Question 9

What are the main points when it comes to unfractionated heparin?

Answer 9

Unfractionated heparin therapy
- Difficult
- Complicated
- Time consuming
- Blood tests
- Variable APTT control

Question 10

What are the side effects of UH?

Answer 10

• Bruising and bleeding sites
• Thrombocytopenia
• Osteoporosis (long term)

Question 11

How do you reverse UH therapy?

Answer 11

• Stop heparin
• Give protamine to reverse immediately.

Question 12

What is good about LMWH and how does it differ?

Answer 12

• Binds anti-thrombin 3 specifically.
• Impacts factor Xa specifically.
• Doesnt impact thrombin 2a
• No monitoring required

Question 13

What are the advantages of LMWH?

Answer 13

• Better absorbed, higher bioavailability.
• Does not bind to proteins etc
• SC injection
• Lower risk of thrombocytopeania and bleeding.

Question 14

Whats the downside to LMWH?

Answer 14

• Cant be monitored by APTT
• Not fully reversible by protamine
• Care in renal failure. Dose reduction.

Question 15

Whats the action of warfarin?

Answer 15

Vit K antagonists - Prevents formation of vit k dependent clotting factors; 10,9,7,2 and substance P+S

Question 16

What is warfarin used for?

Answer 16

• Treatment of venous or arterial thrombosis
• Prevention of venous or arterial thromboembolism
  -> Mechanical heart valves (only licensed anti-coagulant for this)
• Atrial fibrillation

Question 17

How long are patients on warfarin following mechanical heart valve or VTE?

Answer 17

Mechanical heart valve - Life long

VTE (DVT/PE)
- Difficult
- Balance between bleeding vs VTE recurrence

Question 18

Write some notes on warfarin metabolism:

Answer 18

• Orally
• 99% bound to plasma proteins
• Completely absorbed (Crosses placenta so C/I in pregnancy)
• Metabolised in liver
• Huge variance in individual dosing requirements

Question 19

How do you monitor warfarin?

Answer 19

INR : Patients PT / mean normal PT

Question 20

How does INR change for different indications?

Answer 20

Treating: venous thrombosis, PE, atrial fibrillation. INR ~ 2-3.

Treating mechanical prosthesis, recurrent thromboses, anti-phospholipid syndrome. INR 2.5-4.5

Question 21

What are the potential unwanted side effects of warfarin?

Answer 21

Haemorrhage

Tetarogenic if pregnant

Question 22

What are the relevant contraindications to warfarin therapy?

Answer 22

• Pregnancy
• Situations where the risk fo hemorrhage is greater than the potential clinical benefits of therapy i.e uncontrolled alcohol/drugs, falls risk

Question 23

What are the drug interactions of warfarin?

Answer 23

Effects on anticoagulation

Majority increase anticoagulant effect i.e inc. INR (Cyto P450 inhibitors)

Some decrease effect (Dec. INR)

Cyto P450 inducers

Interactions with warfarin are highly significant

Question 24

What drugs potentiate warfarin by inhibiting P450?

Answer 24

• Chronic alcohol
• Analgesics i.e paracetamol, NSAIDS
• Antacids i.e omeprazole

Question 25

What drugs inhibit warfarin by inducing P450?

Answer 25

• Acute alcoholic binge
• Barbituates

Question 26

Whats the practical advice when initiating warfarin?

Answer 26

• Dosing: Loading then maintenance based on INR (day 4-5 before therapeutic)
• LMWH cover whilst commencing warfarin.

Question 27

How do you manage a patient on warfarin who has had their INR increase too much?

Answer 27

Depending on severity of bleeding:

• Vit K (slow onset, long acting)
• IV prothrombinex (contains factors)

Less life threatening cases:
- Withold warfarin and recheck INR daily, lower dosage

Question 28

What are the problems of warfarin?

Answer 28

• Narrow therapeutic window
• Lifetime risk fo haemorrhage
• Drug interactions
• Regular INR

Question 29

Where do dabigatran and rivaroxaban act?

Answer 29

Dabigatran: 2a inhibitor

Rivaroxaban: 10a inhibitor

Question 30

What is dabigatran?

Answer 30

Competitive, reversible inhibitor of thrombin (v predictable in action)

Question 31

What is dabigatran used for?

Answer 31

• Atrial fibrillation
• VTE

NOT used for mechanical heart valves

Question 32

How can you reverse dabigatran?

Answer 32

IV monoclonal AB ; Idarucizumab

Binds dibigatran:Thrombin complex and sperates them

Question 33

How does rivaroxaban work?

Answer 33

Selective direct inhibitor of 10a

Renally excreted, cant be used in those with very low GFR

Dont use for heart valves.

Use for Afib/DVT/PE