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Flashcards in lecture 7 Deck (74):
1

aggregated platelets

form the initial hemostatic plug at sites of vascular injury & are key played in thrombus formation

2

antiplatelet agents- ADP receptor blockers aka

thienopyridines

3

ADP is a

-potent initiator of plt aggregation.
- effects are mediated via P2Y12 & P2Y1

4

what must be stimulated to result in plt activation?

BOTH P2Y12 and P2Y1
- inhibition of either receptor is sufficient to block plt activation

5

thienopyridine (ADP receptor block) drugs

prasugrel (effient)
clopidogrel (plavix)

6

thienopyridines

- prodrugs
- bind covalently to P2Y12-> permanent blockage
- short half lives, but long lasting effects

7

life of a platelet

5-7 days

8

therapeutic use of thienopyridines

- initiated during ACS, particularly with angioplasty & stenting
- continued for secondary prevention of both MI & atheroembolic stroke

9

main adverse effects of thienopyridines

- increased risk of bleeding
- thrombotic thrombocytopenic purpura (TTP)

10

metabolic activation of thienopyridines

- enzymatic formation of the active metabolite PRECEDES covalent binding (S-S) to the P2Y12 receptor on plts
1. metabolism is required for activity (inhibition of plts)
2. inhibition is IRREVERSIBLE
3. nature of metabolizing enzyme is key for efficacy

11

what enzyme activates clopidogrel

CYP2C19

12

what enzyme activates prasugrel?

CYP3A4

13

what is the REVERSIBLE ADP receptor antagonist?

ticagrelor
(non-theopyridine)

14

MOA of ticagrelor

- NOT a prodrug- more consistent
- REVERSIBLE blockage of P2Y12 receptor-> recovery of plt function after stopping the drug is more rapid.
- less risk of bleeding!
- BID

15

what enzymemetabolizes ticagrelor?

CYP3A4
- also inhibits it

16

adverse effects of ticagrelor

bleeding
dyspnea
bradyarrhythmias
increased serum uric acid & Cr
- Prego C

17

thrombin receptor (protease-activated receptor 1: PAR1) antagonist

vorapaxar (Zontivity)

18

vorapaxar (zontivity) MOA

binds PAR1, thrombin can still chop it, but it won't be activated

19

thrombin causes

plt activation & aggregation through PAR1 & PAR4 receptors

20

thrombin is considered

the most potent endogenous activator of plts

21

PAR1 is

the high-affinity receptor
- responds more sensitively & rapidly to thrombin

22

what is the first FDA approved thrombin receptor antagonist which prevents actions of thrombin on plts (mediated via PAR1)?

vorapaxar

23

what enzyme metabolizes vorapaxar?

CYP3A4

24

vorapaxar caution

not recommended to use with CYP3A4 inhibitors & inducers

25

main indications for vorapaxar

coronary artery diease (MI) and peripheral arterial disease (PAD)

26

main adverse effects of vorapaxar

increased risk of bleeding

27

contraindications to vorapaxar

- history of stroke, TIA or intracranial hemorrhage
- active pathologic bleeding or underlying bleeding risk

28

antiplatelet agents aka

glycoprotein IIb/IIIa inhibitors

29

GP2b3a is a

platelet surface protein
- a receptor for fibrinogen & von Willebrand factor

30

upon activation, GP2b3a

anchors plts to each other via fibrinogen & to the surface of the injured vasculature via von WIllebrand factor

31

thrombin, TX-A2, ADP, collagen, NE, & other factors result in the activation of

GP2b3a-> plt aggregation

32

all GP2b3a inhibitors inhibit

the interaction of GP2b3a with fibrinogen & von willebrand factor-> impair plt AGGREGATION

33

GP2b3a agents

abciximab (reopro)
eptifibatide (integrilin)
tirofiban (aggrastat)

34

abciximab (Reopro)

- monoclonal antibody
- blcoks the receptors from activation

35

therapeutic use of abciximab

- in combo w/ precutaneous angioplasty for coronary thromboses
- in combo with aspirin & heparin to prevent restenosis & recurrent MI

36

main adverse effects of abciximab

- bleeding
- thrombocytapenia

37

eptifibatide (integrilin)

a cyclic peptide inhibitor of GP2b3a

38

tirofiban (Aggrastat)

a non-peptide inhibitor of GP2b3a
- inhibit ACTIVATED plts; shorter half-life

39

therapeutic use of eptifibatide & tirofiban

- UA, ACS, MI
- angioplastic coronary interventions

40

main ADE of eptifibatide & tirofiban

- bleeding
- thrombocytapenia

41

what converts plasminogen to plasmin

tissue plasminogen activator (tPA)

42

activation of plasmin leads to

enhanced fibrinolysis

43

fibrinolytic aka

thrombolytic agents

44

fibrinolytic (thrombolytic) agents

alteplase (activase)
reteplase (retavase)
tenecteplase (TNKase)

45

alteplase (activase)

- tPA produced by recombinant DNA technology

46

reteplase (retavase) & tenecteplase (TNKase)

-recombinant mutant variants of tPA
- longer T1/2 than alteplase

47

therapeutic use of fibrinolytic agents

acute MI & thromboembolic stroke

48

main adverse effect of fibrinolytic agents

- hemorrhage
- lysis of fibrin in physiological thrombi at sites of vascular injury
- systemic lytic state in the result of systemic formation of plasmin

49

contraindications for fibrinolytics is the same as

for GP2b3aI

50

main adverse effects of statins

myopathy
hepatoxicity

51

beneficial effects of statins

- lowering LDL, improve endothelial function (pleiotropic effects)

52

efficiency of statins in reducing

fatal & non-fatal CHD events, stroke & total mortality documented in multiple trials

53

main ADE of ACEI

dry cough, hypotension, angioedema

54

ACEI MOA

block angI to angII

55

pure antianginal agents

ranolazine (ranexa)

56

ranolazine (ranexa)

- used for the treatment of chronic angina
- usually in combo with amlodipine, BB or nitrates

57

MOA of ranolazine (ranexa)

- not well understood
- antianginal & anti-ischemic effects are NOT bc of reduction in BP, HR, or myocardial workload
- maybe: inhibition of FA oxidation-> ATP from glu-> improved O2 consumption or inhibition of late Na currents-> dec Ca overload during ischemic attack

58

pharmacokinetic properties of ranolazine

- primarily metabolized by CYP3A4 (caution w/ diliazem & verapamil)
- is a substrate of P-GP (PGP inhibitors-cyclosporine, incr its circulating conc.)

59

main ADE of ranolazine

dizziness
HA
constipation
nausea
- prolonged QT interval if overdosed ot combined w/ other drugs affecting it

60

precautions in using ranolazine

- in pts w/ pre-existing QT prolongation
- history of torsade de pointes
- pts w/ hepatic or renal impairment & filaure

61

contraindications to rnolazine

- concomitant use with potent inhibitors or inducers of CYP3A4
- hepatic cirrhosis

62

stroke

disease affecting blood vessels that supply the brain

63

two main types of stroke

hemorrhagic & ischemic

64

hemorrhagic stroke

damage of a vessel & bleeding
- higher death rate

65

ischemic stroke

blockage of a blood vessel by clot or some mass
- 87% of all cases

66

wandering clot

- embolus
- formed awy from the brain, blocks the blood flow
- usually from heart in the result of Afib

67

therapeutic goals of ischemic & thromboembolic stroke

- reduce ongoing neurological injury
- decrease mortality & long-term disability
- prevent complications secondary to immobility & dysfunction
- prevent stroke recurrence

68

non- pharmacologic ischemic stroke treatment

- carotid endarterectomy
-carotid stenting

69

pharmacologic agents used in ischemic acute stroke

- fibrinolytics: help restore perfusion in affected areas; caution- some pts may have CI; must follow strict protocol
- antiplt (ASA): reduces aggregative activity of plts; caution- incr bleeding with fibrinolytics

70

pharmacologic agents used in secondary prevention of ischemic stroke

- antiplt agents: primary used for atheroembolic stroke where plts are a major component of the thrombus
- anticoagulants: primarily used for cardio/thromboembolic stroke where clotting factors primarily constitute a thrombus which travels to the brain

71

pharmacologic agents used in ischemic stroke to lower BP

- ACEI: beneficial independent of accompanying HTN; reduce risk of stroke recurrance by 28-43%; not used in the first 7 days of acute stroke (to avoid dec cerebral blood flow)
- ARBs: alt to ACEI; cross BBB-may have more beneficial effects?

72

statin use in ischemic stroke

- reduce risk of stroke by 30% in CAD pts & pts with elevated plasma lipids
- use in ALL ischemic stroke pts

73

what do you use in all ischemic stroke pts?

STATINS!!!

74

beneficial effects of statins in ischemic stroke are attributed to

- lipid lowering effects (ischemic stroke is an equivalent of CAD)- high levels of LDL is a risk factor for ischemic stroke
- pleiotropic effects