Antiplatelets Flashcards
What is is Antiplatelet agent?
Antiplatelet agents are used both prophylactically and acutely in the setting of ACS to inhibit platelet activation and/or aggregation
What are the 4 main classes of antiplatelet drugs and examples?
Cyclooxygenase (COX-1) Inhibitors
ASA is prototype and only one used
Phosphodiesterase (PDE) inhibitors
Dipyridamole is prototype
ADP receptor antagonists
Clopidogrel, prasugrel, ticagrelor
GPIIb/IIIa receptor inhibitors
Abciximab, eptifibatide, tirofiban
Mechanism of Action of aspirin
Mechanism of Action:
Irreversibly blocks cyclooxygenase (COX-1) activity by acetylating the enzyme
Prevents the conversion of arachidonic acid to TXA2 in platelets
TXA2 promotes platelet aggregation and vasoconstriction
Platelet-induced TXA2 synthesis is blocked for the life of the platelet (7-10 days)
COX-1 inhibition also prevents the formation of PGI2 in vascular endothelium
PGI2 promotes vasodilation and inhibits platelet aggregation
endothelium can regenerate COX-1 restoring PGI2 production within hours
Net result is that aspirin preferentially inhibits TXA2 rather than PGI2, favoring vasodilation and inhibition of platelet aggregation
Aspirin does not inhibit platelet adherence
Indications for Aspirin
Myocardial infarction (MI)
Prevention of MI
Thrombotic stroke or transient ischemic attacks (TIAs)
Alternative to warfarin to prevent thrombosis in certain populations of patients with atrial fibrillation
Intermittent claudication
Antipyretic, analgesic and anti-inflammatory
Chemoprevention of colon cancer
What is the recommended dose of Aspirin?
Dosing of aspirin:
Recommended dose varies depending on indication
Antiplatelet doses range from 81-325 mg/day
Usual dose for ACS, acute MI, etc is 325 mg given immediately upon symptoms
Prophylactic dose ranges from 81 - 325 mg daily
Higher doses may decrease effectiveness due to decreased ability to regenerate PGI2
What are the Adverse effects of aspirin in response to PG and TX inhibition and are dose-dependent?
Adverse effects of ASA (acetylsalicylic acid) occur in response to PG and TX inhibition and are dose-dependent:
GI effects (due to PGE2 inhibition)
abdominal pain
heartburn
nausea
GI ulceration and bleeding
Enteric coated products and buffered products may decrease GI symptoms
What are the Adverse effects of ASA occur in response to PG and TX inhibition and are dose-dependent?
Adverse effects of ASA occur in response to PG and TX inhibition and are dose-dependent:
Bleeding (due to inhibition of TXA2)
Renal dysfunction (due to inhibition of renal PGs)
progressive dysfunction with chronic use
Exacerbation of asthma (due to shifting of AA metabolism to lipoxygenase pathway)
increases LT formation which are known inflammatory mediators in asthma
What are other adverse affects of aspirin?
Other adverse effects:
Tinnitus, headache, dizziness, confusion, hearing loss and metabolic acidosis due to salicylate toxicity
Hypersensitivity reactions ranging from rash to angioedema to anaphylaxis
Reye syndrome
do not administer to children under the age of 16
Avoid during pregnancy (esp. during 3rd trimester)
prolonged labor, increased risk for antepartum and postpartum hemorrhage
What are some drug interactions of aspirin?
Drug interactions:
NSAIDs: increased risk for bleeding
Warfarin: increased risk for bleeding
Other anti-platelets: increased risk for bleeding
Plasma protein binding displacement interactions:
variable depending on specific medications taken concurrently
valproic acid
tolazamide
tolbutamide
What is the Mechanism of Action of Dipyridamole?
Mechanism of Action:
Inhibits cyclic nucleotide phosphodiesterase (PDE) which causes cAMP breakdown
Results in increased cAMP and inhibition of platelet aggregation
Increased cAMP also results in vasodilation
Blocks adenosine uptake into cells
A2 receptors stimulate platelet adenylate cyclase and inhibit platelet activation
What is the Clinical use of Dipyridamole?
Clinical use:
Adjunct to coumarin anticoagulants (warfarin) in patients with prosthetic heart valves who cannot take aspirin
What are the Drug interaction of Dipyridamole?
Drug interactions:
Increased risk for bleeding when given in combination with ASA and other antiplatelets or anticoagulants
How can Dipyridamole/ASA combination to established?
Aggrenox is combination of 25 mg aspirin and 200 mg dipyridamole in a sustained release formulation to be taken twice daily
Approved for use to reduce the risk of stroke in patients with TIAs or with history of thrombotic stroke
Adverse effects and drug interactions are a combination of those seen with ASA and dipyridamole individually
What are some examples of ADP Antagonists (Thienopyridines)?
Clopidogrel, Prasugrel, Ticagrelor
What is the mechanism of action of ADP Antagonists?
Inhibit platelet aggregation by inhibiting ADP-induced platelet fibrinogen binding (this links platelets together to form aggregates or “plugs”)
Clopidogrel and Prasugrel are irreversible inhibitors
Ticagrelor is reversible
Antiplatelet effect takes 24-48 hours to develop ; Loading dose employed
