Lect 7- CAD & Thromboembolic Stroke Pt 2 Flashcards
what are some factors that stimulate plt activation and aggregation?
thrombin, ADP, collagen, thromboxane A2
these can all therefore serve as drug targets to inhibit plt activation and aggregation
ADP in plt aggregation
ADP= potent initiator of plt aggregation
effects mediated via purinergic receptors P2Y12 and P2Y1
BOTH P2Y12 and P2Y1 receptors must be stimulated to result in plt activation (so inhibiting either is sufficient to block plt activation)
ADP receptor blockers
AKA “thienopyridines”
prasugrel (Effient); clopidogrel (Plavix)
PRODRUGS= activated by P450’s
MOA of ADP receptor blockers
metabolites bind COVALENTLY to P2Y12 resulting in permanent blockade (IRREVERSIBLE INHIBITION)
Relatively short t1/2 but have long-lasting effect
therapeutic use of ADP receptor blockers
initiated during ACS, particularly w/ angioplasty and stenting
continued for secondary prevention of both MI and atheroembolic stroke
main adverse effects of ADP receptor blockers
**increased risk of bleeding
thrombotic thrombocytopenic purpura (TTP) (rare)
which CYP activates clopidogrel?
CYP2C19
which CYP activates prasugrel?
CYP3A4
Ticagrelor (Brilinta) MOA
REVERSIBLE ADP receptor antagonist (non-thienopyridiine) so a little less potent than clopidogrel and prasugrel
reversible blockade of P2Y12 receptor → recovery of plt function after stopping the drug is more rapid → less risk of major bleeding!
**NOT A PRODRUG
which CYP metabolizes Ticagrelor?
Metablized by CYP3A4 to inactivate it
inhibits CYP3A4 and P-GP to some extent- drug interactions!
what is a disadvantage of Ticagrelor?
taken BID
adverse effects of Ticagrelor
bleeding (but less risk of bleeding than clopidogrel or prasugrel
Thrombin effects on plt activation and aggregation
Causes plt activation and aggregation through PAR1 and PAR4 receptors
MOST POTENT endogenous activator of plts (thrombin is a protease)
PAR1= high affinity receptor (responds more sensitively/ rapidly to thrombin)
vorapaxar (Zontivity) MOA
thrombin receptor (PAR1) antagonist
Binds to the receptor and blocks actions of thrombin
PAR1= protease-activated receptor 1
• Held the ligand as part of their sequence on the extracellular domain
○ Thrombin cleaves part of the receptor so that part left over can fold down and activate the receptor
§ Why they are called protease activated receptors
○ With vorapaxar, the receptor can still be cleaved by proteases but it cannot be activated since drug is blocking the fold-down part
which CYP metabolizes vorapaxar?
CYP3A4
special facts about vorapaxar
Long half life (3-4 days) so takes 21 days of QD dosing to reach Css
main indications for vorapaxar
MI and PAD
C/I for vorapaxar
history of stroke, TIA, intracranial hemorrhage, active bleeding
how glycoprotein works in plt aggregation
GP iib/iiia is a plt surface protein
receptor for fibrinogen and von Willebrand factor
upon activation, GP iib/iiia ANCHORS PLTS to each other via fibrinogen and to the surface of the injured vasculature via vW factor (vW factor important in forming mesh so plts can adhere)
what activates the GP IIb/IIIa?
thrombin, TX-A2, ADP, collagen, norepinephrine, etc
All have their own receptors but all have the ultimate result of activation of GP IIb/IIIa then after that you have aggregation of plts
This blockade of GP is a very powerful mechanism b/c then it doesn’t matter which factor you have around it will still inhibit the last step
Glycoprotein IIb/IIIa inhibitors
abciximab (Reopro)= monoclonal antibody
eptifibatide (Integrelin; tirofiban (Aggrastat)= require ACTIVATED plts/ GP IIb/IIIa to bind and inhibit
Glycoprotein IIb/IIIa inhibitors MOA
inhibit interaction of GP IIb/IIIa with fibrinogen and vW factor to impair plt aggregation!
abciximab (Reopro)
monoclonal antibody
blocks the receptor from activation
therapeutic use of abciximab (Reopro)
- in conjugation w/ percutaneous angioplasty for coronary thromboses
- in combo w/ aspirin & heparin to prevent restenosis and recurrent MI
main adverse effects of GP IIb/IIIa inhibitors
MAJOR= bleeding (can be very severe so you have to be very careful with these)
thrombocytopenia
therapeutic use of eptifibatide and tirofiban
- unstable angina, ACS, MI
2. angioplastic coronary interventions
C/I’s for GP IIb/IIIa inhibitors
LOOK AT SLIDE
fibrinolytic (thrombolytic) agents
Deals with a thrombus that are already in place
alteplase (Activase)= tPA prod by recombinant DNA technology
reteplase (Retavase) and tenecteplase (TNKase)
therapeutic use of fibrinolytic agents
acute MI & thromboembolic stroke
main adverse effect of fibrinolytic agents
HEMORRHAGE
lysis of fibrin at “physiological thrombi” at sites of vascular injury results in systemic lytic state
If we cut ourselves, we can bleed to death
C/I for fibrinolytic agents
same as the ones for GP IIb/IIIa inhibitors
fibrinolytic agents MOA
tPA= tissue plasminogen activator; converts plasminogen to plasmin which then enhances degradation of fibrin
Drugs are recombinant tPA
pure antianginal agents
ranolazine (Ranexa)
used for treatment of chronic angina
usually in combo with amlodipine, beta-blockers, or nitrates
MOA of Ranexa
not well understood
effects are NOT b/c of reduction of HR or myocardial workload
speculated mechanisms: inhibition of FA oxidation or inhibition of late Na+ currents
which CYP metabolizes ranolazine?
CYP3A4
is also a substrate for P-GP inhibitors
main adverse effects of ranolazine
constipation, headache, dizziness, nausea
prolongation of QT interval if overdosed or combined with drugs affecting its metabolism or elimination
stroke definition
disease affecting blood vessels that supply blood to the brain
2 main types of stroke
- hemorrhagic= damage of a vessel & bleeding (higher death rates)
- ischemic (87% of all cases)= blockage of a blood vessel by clot of some mass
“wandering clot” or embolus causing a stroke
formed away from the brain and blocks blood flow to the brain
usually comes from the heart in the result of atrial fibrillation
therapeutic goals of ischemic and thromboembolic stroke
- reduce ongoing neurologic injury
- decrease mortality and long-term disability
- prevent complications secondary to immobility & dysfunction
- prevent stroke recurrence
pharmacological agents used in acute stroke
- fibrinolytic agents (tPA analogs)= help to restore perfusion in affected areas (CAUTION: some pts may be ineligible; see C/Is)
- antiplatelet agents (aspirin)= reduces aggregative activity of platelets (CAUTION: increase bleeding risk w/ fibrinolytic agents
pharmacological agents used in secondary prevention of ischemic stroke
- antiplatelet agents= primarily used for atheroembolic stroke where plts are a major component of the thrombus
- anticoagulants= primarily used for cardio/thromboembolic stroke where clotting factors are major component of thrombus
when are antiplatlet agents used as secondary prevention of ischemic stroke?
arterial plaque rupture
when are anticoagulants used as secondary prevention of ischemic stroke?
stasis of blood as a result of arrhythmia or valvular disease
blood pressure lowering agents used in ischemic stroke
Have neuroprotective effects on their own too
- ACE-I & diuretics (thiazides)
- ARBs
ACE-I and thiazides in ischemic stroke
beneficial INDEPENDENT of accompanying HTN
reduce risk of stroke
NOT used in the 1st 7 days of the acute stroke period (to avoid less cerebral blood flow from decrease in BP)
ARBs in ischemic stroke
alternative to ACE-I if intolerant to ACE-I
ARBs that cross BBB may have more beneficial effects
statins in ischemic stroke
reduce risk of stroke by 30% in pts w/ CAD and high plasma lipids
use should be considered in ALL ischemic stroke pts
effects are due to both lipid lowering effects and pleiotropic effects
