E1: Antiplatelets

Question 1

Aspirin (ASA)
Indication
Pharmacology (low dose vs high dose)
ADR
DI

Answer 1

Indication: prophylaxis/treatment of myocardial infarction/stroke/angioplasty (81mg to 325mg) (DR)

Pharmacology (low dose vs high dose):
1. non-selective COX-1 > COX -2 inhibition of PG and thromboxane synthesis
A. ↓ inflammation: ↓ vasoactive and chemotactic prostaglandins available to bind to receptors in target tissues
B. analgesia: ↓ PG’s and TxA’s that activate sensory afferent pain fibers
2. low-dose ASA blockade: COX-1 > COX-2
A. platelets: irreversible acetylation of COX -1 which ↓ thromboxane A2 (TXA2) formation from arachidonic acid which ↓ platelet aggregation
1) because the platelet is anuclear, it can’t synthesize more COX-1 during its 10-day lifespan
ASA dose required for antiplatelet effect? 81mg
platelet inactivating dose < pain relief dose < anti inflammatory

ADR: bleeding, GI erosin/ulceration
DI: NSAIDS ↓ ASA anti-platelet effect; combo can ↑ risk of MI; take ASA prior to NSAID
- ASA irreversible acetylation of COX-1 in platelet
- NSAID’s reversible competitive blockade of COX-1
- NSAID’s prevent ASA binding and then dissociate making
COX-1 available

Question 2

Dipyridamole-Persantine
General info:
Pharmacology:

Answer 2

General info:
-little to no benefit by itself
-given in combo w/ASA
-↓thrombus potential in patients undergoing cardiac procedures

Pharmacology: phosphodiesterase inhibitor (PDE 3 inhibitor)
A. ↑ cAMP by inhibiting cyclic adenosine nucleotide dependent phosphodiesterase (cAMP-PDE), ↓ platelet activating factors release which ↓ platelet adhesion, ↓ GP IIb/IIIa activation, and ↓ aggregation
B. peripheral vasodilation

Question 3

Clopidogrel
Prodrug or not?
Pharmacology (irreversible or reversible binding)
DI
Special consideration: Clopidogrel resistance, why?
Clinical consideration:

Answer 3

Prodrug (2 step conversion)
Pharmacology: IRREVERSIBLE binding
-P2Y12 receptor antagonist: active metabolites inhibit binding of ADP to its receptor on platelets thereby preventing ADP-mediated activation of GP IIb/IIIa and thus ↓ platelet aggregation

DI: Omeprazole (2C19 inhibitor)

Clopidogrel resistance: variable ↓ therapeutic response due to pharmacogenomics (*2 and *3 combinations)

Clinical consideration: preferred post-fibrinolysis

Question 4

Prasugrel
More or less potent than clopidogrel?
Prodrug or not?
Pharmacology
Clinical consideration:

Answer 4

More potent than clopidogrel
Prodrug (1 step conversion)
Pharmacology: * P2Y12 receptor antagonist: active metabolites inhibit binding of ADP to its receptor on platelets thereby preventing ADP-mediated activation of GP IIb/IIIa and thus ↓ platelet aggregation
* IRREVERSIBLE
Clinical consideration: CI history of stroke or TIA

Question 5

Ticagrelor
More or less potent that Clopidogrel?
Prodrug or not?
Pharmacology
Clinical consideration:
ADR:

Answer 5

More potent, quickest onset (30min)
NOT PRODRUG

Pharmacology:
* P2Y12 receptor antagonist: modifies the ADP receptor to affect binding of ADP on platelets thereby preventing ADP-mediated activation of GP IIb/IIIa and thus ↓ platelet aggregation
* REVERSIBLE, does not directly bind to ADP binding site on receptor

Clinical consideration: Maintenance doses of ASA exceeding 100mg ↓ the effectiveness of ticagrelor and should be avoided when used w/ticagrelor

ADR:
-Bradyarrythmia
-dyspnea
-hyperuricemia

Question 6

Cangrelor
Prodrug or not?
Pharmacology
Clinical consideration
How to initiate oral P2Y12

Answer 6

Not prodrug
Pharmacology: reversibly binds to ADP binding site

Clinical consideration:
PCI adjunct in patients not treated w/oral P2Y12 or GP IIb/IIIa inhibitor
Ticagrelor can be admin during infusion (no prodrug)
Clopidogrel or Prasugrel admin AFTER infusion

Question 7

eptifibatide-Integrilin
Class
Pharmacology
SAR
Clinical considerations

Answer 7

Class: GP IIb/IIIa
Pharmacology:
1. binds to glycoprotein IIb/IIIa receptor of platelet
A. major platelet surface receptor involved in platelet aggregation
2. blocks fibrinogen from binding to GPIIb/IIIa receptors
- platelets can not aggregate
3. inhibition of final common pathway of platelet aggregation regardless of initiating stimulus

SAR: GPRA chimeric Mab directed against the IIb/IIIa receptors (Synthetic derivatives use lysine-glycine-aspartic acid (KGD) sequence which binds to the IIb/IIIa receptor)
-normal fibrinogen sequences is RGD

Clinical considerations: Requires renal dose adjustments

Question 8

Abciximab (Reopro)
Class:

Answer 8

Class: GP IIb/IIIa

Question 9

Tirofiban (Aggrastat)
Class:

Answer 9

Class: GP IIb/IIIa

Question 10

When may glycoprotein IIb/IIIa inhibitors be considered in select patients (3)

Answer 10

1. Large thrombus burden
2. Inadequate P2Y12 loading
3. “bail-out” if in-stent thrombosis needed