Antiplatelets Flashcards
What are the 4 general steps to platelet activation ?
- Shape change , which incr surface area
- Degranulation to release ADP, 5HT, and more
- Secretion , releases TXA
- Glycoprotein 2b/3a activation
to crosslink platelets
Name the following Drug Targets:
1. P2Y12 inhibs
2. PAR-1 inhibitors
3. COX inhibitors
4. PDE inhibitors
- ADP
- Factor 2a
- COX1 and COX2
- PDE
Describe the USUAL pathway involving PAR-1
Tissue Factor + Factor 7 –> thrombin
which acts on PAR-1. this activates actin+myosin, and protein kinases to lead to platelet activation
PAR-1 is G___. Describe how cox inhibitors work on this pathway beginning with TXA, and thrombin.
Gq.
Thrombin –> PAR1 –> PI3K and PLC. TXA –> TP (Gq) –> PLC
PLC –> DAG + IP3 –> PKC from DAG and Ca2+ from IPE3 –> Actin&Myosin, protein kinases to activate platelets. Ca2+ from IPE3–> PLA2 –> AA –> TXA secretion . COX inhibitors work on the AA pathway to TXA
Explain the usual pathway involving P2Y12 inhibitors and PDE inhibitors
ADP –> P2Y-12 which is Gi –> PI3K
adenylyl cyclase –> cAMP –> blocks activation pathway (Usually, the P2Y12 R will inhib adenylyl cyclase)
P2Y12 inhibitors prohibit ADP binding to receptor which inhibs platelet activation and PDE inhibitors prevent PDE from blocking cAMP.
if cAMP is blocked by PDE (normally) this activates platelets . if PDE is blocked, cAMP can continue to inhib platelet activation
COX inhibitors :
COX1 on ____ –> _____ which does what to platelet formation?
COX2 on ___ –> _____ which does what to platelet formation?
Platelets, Thromboxane (TXA), activates
endothelia , prostacyclin (PGI) , inhibits
Name an IRREVERSIBLE COX Inhibitor (1)
- this drug is highly selective for ?
Platelets are unable to replace ___
Net effect ?
DECR?
INCR?
Aspirin
COX1 specifically (But can still block cox2)
COX 1
therapeutic platelet inhibition
risk of heart attacks and stroke
risk of bleeding
Reversible COX inhibitors such as?
Because they bind both cox 1 and cox 2, they can be termed____
COX recovers after what?
Net effect?
Incr risk of?
Does not prevent?
Can interfere with?
NSAIDS
Non-selective
drug is cleared (3-5 half lives)
Unreliable platelet inhibition
bleeding
heart attacks and strokes
aspirin therapy
- Name a selective COX-2 inhibitor
- Because there’s COX-2 mostly in endothelia and pain centers, what is the net effect of this drug?
- What can this drug lower the risk of?
- What can it increase the risk of?
- Celecoxib or celebrex
- Tx for pain and inflammation but LITTLE PLATELET inhibition
- stomach ulcers (bc only COX1 in stomach)
- THRombosis (aka clotting) because COX1 is in your platelets and you’re NOT inhibiting that
Half life of
1. Aspirin
2. Celecoxib
3. Ibuprofen
Reversible inhibs last ____?
Irreversible inhibs last ___?
- 3-6 hrs
- 12 hrs
- 2-4 hrs
as long as the drug (3-5 half lives)
as long as the platelet (7 days)
Co-admin of a reversible and irreversible cox inhibitor results in?
Interference with the IRREVERSIBLE inhibitor
P2Y12 Inhibitors IRREVERSIBLE
- Irreversible P2Y12 INHIBS known as ?
- Dosed?
- Dosed as ?
- Name 2 examples, what they’re activated by, onset, and DDI’s if any
- Thienopyridines
- every 24 hrs
- inactive prodrugs that require bioactivation
- Clopidogrel + Prasugrel
Clo : activated by CYP 2C19 (2 steps) , 2 hr onset, DDI w/omeprazole , genetic variability
Pra : Activated by CYP 3A4, 2B6 (1 step) , 30 mins onset
Reversible P2Y12 Inhibs
1. Name 2 , their dosage, half life and onset
- These are dosed more ____
- Don’t require?
- Ticagrelor
-dosed BID half life = 8 hrs
-30 min oonset - Cangrelor
-dosed IV infusion , half life 5 mins
-2 min onset - frequently
- bioactivation
PDE Inhibitors
1. Name 2
2. MOA?
3. Inhibits ___ and ___
- Dipyridamole , Cilostazol
- incr intracellular cAMP
- platelet activation , vasoconstriction
Misc Clinical Uses for :
1. Cilostazol?
2. Dipyridamole ?
3. Anagrelide?
- Intermittent claudication
- Secondary stroke prevention
- Treats thrombocytosis (Leukemia), not thrombosis
