IC6 Clopidogrel, Ticagrelor

Question 1

Clopidogrel is a prodrug involved in __ step bioactivation, involving what CYP enzymes?

Answer 1

2 steps

Activated via CYP3A4, 2B6, 1A2, 2C9, 2C19

Question 2

Which CYP enzymes play a role in DDI of Clopidogrel?

Answer 2

Clopidogrel is a:

CYP2C19 substrate
CYP3A4 substrate
PGP Substrate

Question 3

List some CYP2C19 inducers

Answer 3

Rifampicin
Ritonavir
St John Wort
Prednisone
CBZ
Efavirenz

Question 4

List some CYP2C19 inhibitors

Answer 4

Omeprazole (X) => switch to H2RA/Antacid/Pantoprazole
Fluconazole
Fluoxetine
Oral contraceptives

Question 5

Clopidogrel may also have interaction with CYP3A4 inhibitors such as:

Answer 5

Macrolides

Question 6

Clopidogrel PGx LoF alleles and GoF alleles

Implications

Answer 6

LoF: *2, *3

• increased risk of therapeutic failure
• higher risk of major adverse cardiovascular events following PCI

GoF: *17

• Not a/w increased potency
• Not a/w increased risk of bleeding

Question 7

How long should Clopidogrel be held in the event of cardiac surgery?

Answer 7

Minimum 5 days - approx. amount of time for platelet function recovery

Typically 24h-5d prior to cardiac surgery

Question 8

Should Clopidogrel be withheld in the event of non-cardiac surgery or lower GI bleed?

Answer 8

DAPT must be continued if <30d following bare metal stent placement, or <3 months following DES placement

Question 9

Ticagrelor is metabolized by?

Answer 9

CYP3A4 into active metabolite (40% of parent drug activity)

*IT IS NOT A PRODRUG

Question 10

Ticagrelor substrate/inhibitor status

Answer 10

Substrate of: CYP3A4, 2C19, 1A2, PGP

Inhibitor of: CYP3A4, PGP

Inducer of: 2C9

Question 11

What are some DDIs a/w Ticagrelor?

Answer 11

1. Digoxin

• Ticagrelor is a PGP inhibitor, and may increase serum levels of Digoxin

2. Simvastatin

• Ticagrelor is a CYP3A4/5 inhibitor, may increase serum levels of simvastatin (therefore simvastatin dose should not exceed 40mg)

3. CYP3A4 inhibitors: azoles, clarithromycin

• increase serum conc. of Ticagrelor

4. CYP3A4 inducers: CMZ, phenytoin, rifampicin, St John’s Wort, dexamethasone

• decrease serum conc. of Ticagrelor

5. Aspirin doses >100mg/day: decrease Ticagrelor effect and increase bleeding risk

Question 12

When to withhold Ticagrelor before surgery?

Answer 12

Typically 2-3 days

Ticagrelor is a reversible ADP P2Y12 inhibitor, recovery of platelet function twice as rapid as Clopidogrel

Question 13

Ticagrelor VS Clopidogrel

• potency
• bleeding risk

Answer 13

Ticagrelor more potent but has higher bleeding risk

Question 14

Side effects of Ticagrelor

Answer 14

1. Dyspnea
2. Bradycardia

*Both due to adenosine effect

Also:

• increases serum creatinine
• increases uric acid
• ventricular pauses lasting >=3s

Question 15

Ticagrelor is contraindicated in…

Answer 15

Severe hepatic impairment