Lect 7- CAD & Thromboembolic Stroke Pt 2 Flashcards by Amy Johnson

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

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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)

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ADP receptor blockers

AKA “thienopyridines”
prasugrel (Effient); clopidogrel (Plavix)
PRODRUGS= activated by P450’s

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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

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therapeutic use of ADP receptor blockers

initiated during ACS, particularly w/ angioplasty and stenting
continued for secondary prevention of both MI and atheroembolic stroke

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main adverse effects of ADP receptor blockers

**increased risk of bleeding

thrombotic thrombocytopenic purpura (TTP) (rare)

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which CYP activates clopidogrel?

CYP2C19

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which CYP activates prasugrel?

CYP3A4

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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

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which CYP metabolizes Ticagrelor?

Metablized by CYP3A4 to inactivate it

inhibits CYP3A4 and P-GP to some extent- drug interactions!

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what is a disadvantage of Ticagrelor?

taken BID

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adverse effects of Ticagrelor

bleeding (but less risk of bleeding than clopidogrel or prasugrel

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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)

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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

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which CYP metabolizes vorapaxar?

CYP3A4

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special facts about vorapaxar

Long half life (3-4 days) so takes 21 days of QD dosing to reach Css

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main indications for vorapaxar

MI and PAD

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C/I for vorapaxar

history of stroke, TIA, intracranial hemorrhage, active bleeding

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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)

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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

1. 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

1. hemorrhagic= damage of a vessel & bleeding (higher death rates) 2. 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

1. fibrinolytic agents (tPA analogs)= help to restore perfusion in affected areas (CAUTION: some pts may be ineligible; see C/Is) 2. antiplatelet agents (aspirin)= reduces aggregative activity of platelets (CAUTION: increase bleeding risk w/ fibrinolytic agents

pharmacological agents used in secondary prevention of ischemic stroke

1. antiplatelet agents= primarily used for atheroembolic stroke where plts are a major component of the thrombus 2. 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