Antiplatelet agents Flashcards
Antiplatelet agents are used for prevention and treatment of:
thrombotic disease (CVA, MI)
How is ASA different from other NSAIDs?
Irreversibly bind and inhibits COX enzyme for life of the platelet (7-10days)
What is the MOA of COX inhibitors?
Inhibit the COX enzyme which inhibits TxA2 which usually causes platelet aggregation
(also inhibits prostacyclin, which has a natural antiplt effect, in endothelial cells. Endothelial cells are able to synthesize new COX enzymes)
COX inhibitors include:
NSAIDs, ASA
What is the MOA of ADP Receptor Inhibitors?
Irreversibly inactivates or antagonizes the platelet P2Y (ADP) receptors which inhibits platelet activation
ADP Receptors Inhibitors include:
Ticlodipine (Ticlid)
Clopidogrel (Plavix)
Prasurgurel (Effient)
Ticragrelor (Brillanta)
All prodrugs and irreversible except Ticragrelor
Can be used with ASA
Ticlodipine (Ticlid):
ADP Receptor Inhibitor
- Prodrug
- Maximal plt inhibition within 8-11days, or 4-7 days with ASA
- Loading dose often given
- AE: neutropenia, thrombocytopenia, TTP
- Monitor CBC frequently
- Less tolerable and slower onset than clopidogrel
Clopidogrel (Plavix)
ADP Receptor Inhibitor
-Prodrug
**Metabolized to its active form by CYP 2C19
(poor met by genetic predisposition=less effective; drugs like omeprazole can inhibit CYP2C19= can’t activate prodrug)
-Loading dose often given
-Less AE
-GI AE similar to ASA
**Omeprazole inhibits CYP induction, Rotonavir induces
Prasugrel (Effient)
ADP receptor inhibitor
- Prodrug
- More complete inhibition of P2Y(ADP) receptor; efficiently metabolized=higher concentration of active drug= increased risk of bleeding
Ticagrelor (Brilinta)
ADP Receptor Inhibitor
- Active form (not a prodrug) with active metabolites
- Reversible and noncompetitive inhibition of P2Y (ADP) receptors (recovery of plt function depends on serum concentration of drug and its active metabolites)
- Metabolized by CYP 3A4
What is the MOA of GPIIb/IIIa Antagonists?
Inhibit the GPIIb/IIIa receptors on platelets which link together to cause aggregation (final pathway/step)
What is the route of administration of GPIIb/IIIa antagonists?
IV
The most common AE of GPIIb/IIIa antagonists:
Bleeding
Abciximab: Class, AE
GPIIb/IIIa antagonist
Bleeding: Irreversible, fresh platelet infusion needed
Eptifibatide, tirofiban: Class, AE
GPIIb/IIIa antagonists
Bleeding: Reversible, drug greatly outnumbers receptors. Wait for drug clearance, do not immediately transfuse platelets = drug will attach to new platelets as well.
What is the MOA of Phosphodiesterase inhibitors?
Inhibit breakdown of cAMP which decreases platelet activation. These drugs are uses in combination with another antiplatelet therapy
Dipyridamole:
Phosphodiesterase inhibitor
Weak plt inhibitor
Vit K is required for normal hepatic synthesis of what coagulation factors and proteins?
Factors, II, VII, IX, X
Protein C and S (body’s natural anticoagulants- balance)
Vit K in its inactive form is activated or regenerated by what and how is this related to warfarin’s MOA?
Epoxide reductase
Warfarin inhibits the C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme complex
Warfarin can also be called a____ _______.
Vit K antagonist
Degree of depression of VKORCI is dependent on:
Dosage
Patient’s VKORC1 genotype: sensitive/resistant
What are the half life of the clotting factors and proteins that warfarin affects?
Factor II: 60hrs Factor VII: 4-6hrs Factor IX: 24hrs Factor X: 48hrs Protein C: 8hrs Protein S: 30hrs
What is warfarin’s onset, peak, and duration of a single dose?
Onset: 24 hours
Peak: 72-96 hours
Duration of single dose: 2-5 days
Roughly how many days should you wait to check a warfarin level after a dose has been changed?
4 days
Warfarin is a racemic mixture of R- and S-enantiomers; which is the more active and how is it metabolized?
The S-enantiomer has 2-5x anticoagulant activity
Metabolized by CYP 2C9
Pts with variant CYP 2C9 alleles have decreased warfarin clearance
(R enantiomer also met by CYP pathway)
Two main genetic important components related to warfarin?
VKORC1
CYP 2C9 allele
What percentage of warfarin is albumin/protein bound and why is this important?
99%, this means most of drug is bound and not active in circulation.
Many drugs can displace warfarin from albumin and move to systemic circulation.
**Ex- amiodarone, chloral hydrate, clopiodogrel, alcohol
How do broad spectrum abx affect warfarin?
Eliminate gut bacteria which decreases availability of vit K that is usually present in the GI tract, enhancing the effects of warfarin
Examples of vit K rich foods and how patients should be counseled about their intake:
Green, leafy vegetables, beef/pork liver, legumes.
Keep intake consistent
What is the most common AE of warfarin and how is it treated?
Bleeding
Hemorrhage: administer FFP (contains II, VII, IX, X)
Minor: vit K administration
How can warfarin cause skin necrosis?
Microvascular thrombosis secondary to inhibition of Protein C & S (body’s natural anticoagulants). Many of the Factors have longer half lives. Protein C is inhibited earlier which causes thrombosis prior to other Factors being depleted.
**Bridge w/heparin
Purple toe syndrome caused by warfarin is related to the breakage of ________ which travel to the feet.
Small cholesterol deposits
How does warfarin causes osteoporosis?
Reduced dietary intake of vit K (misconception)
Inhibition of vit K mediated bone formation/maintenance
Goal INRs are generally:
2-3 or 2.5-3.5
standardized PT
Why is warfarin frequently monitored (4)?
- Narrow TI
- Drug interactions
- Pharmacogenetics (CYP2C9 and VKORC1)
- Toxicity risks
Unfractionated heparin catalyzes inactivation of:
Less selective:
Thrombin (IIa)
Xa
How is unfractioned heparin monitored?
aPTT (activated partial thromboplastin time)
High levels= prolonged time to fibrin clot formation
LMWH includes which drugs and is more selective for inactivation of what?
Exoxaparin, dalteparin, tinzaprin
More selective for inactivation of Factor Xa>thrombin (3:1)
Why is monitoring of LMWH less necessary than heparin?
Larger TI
Could measure antifactor Xa activity
How is LMWH eliminated?
Renally
What is the difference between UF and LMWH in respect to half life and therefore administration?
UF has a shorter half life and therefore needs to be administered continuously
LMWH’s half life is longer and injections usually need to be given twice a day
What is HIT?
What are the 2 types?
Heparin induced Thrombocytopenia
Development of Ab to heparin bound platelets
More common with UF
Type 1:
Ab coated plts targeted for removal from circulation
50-75% reduction in plt count in 5days
Transient and reversible (stop heparin)
Type 2:
Also targets platelets for destruction
Ab also causes platelet activation and aggregation which would lead to fatal thrombosis
What is the antidote for heparin?
Protamine chemically antagonizes heparin
some effect on LMWH, none on fondaprinux
Factor Xa inhibitors include:
Fondaparinux- IV
Rivaroxaban (Xarelto), apixaban (Eliquis)- oral
Direct thrombin inhibitors (Lepirudin, hirudin, desirudin, bivalirudin, argatroban, dabigatran) are often used to treat:
HIT
Prevent further reduction of plt count while preventing thrombosis
Dabigatran (Pradaxa):
Oral direct thrombin inhibitor
Prodrug, active drug binds competitively to active site of thrombin
No frequent laboratory monitoring
? Significant bleeding, MI risk increased
MOA of thrombolytics:
Lysis of existing clot
Restore patency of obstructed tissue and prevent distal tissue necrosis
Thrombolytics works as _________ activators.
Plasmin
which degrades cross-linked fibrin polymers which are essential to the formation of a stable clot
Clinical indications for thrombolytic administration:
Acute MI
Acute ischemic stroke (NOT hemorrhagic)
Massive PE
Central line occlusion (local application)
AE of thromboyltics include:
Dissolution of pathologic thrombi or physiologically appropriate fibrin clots
=Bleeding/Hemorrhage
