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Therapeutics II > Antiplatelets > Flashcards

Antiplatelets Flashcards

1
Q

Drugs used in coagulation disorders

A

-antiplatelets
-anticoagulants
-thrombolytics
-coagulants

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2
Q

Normal homeostasis

A

-arrest of bleeding from damages blood vessel
1. vasospasm
2. platelet plug formation
3. fibrin clot formation
4. Fibrinolysis

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3
Q

Coagulation

A

-process to plug leaking blood vessel

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4
Q

Platelet plug formation

A

-platelet adherence and aggregation
-thanks to fibrin

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5
Q

Fibrin clot formation

A

-prothrombin
-thrombin
-fibrogen
-fibrin

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6
Q

Fibrinolysis

A

-plasminogen
-plasmin
-fibrin
-split products

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7
Q

Artherosclerotic plaque and thrombosis

A

-deadly duo
-coronary plaque rupture

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8
Q

Platelet Formation

A

-megakaryocytes
1. granules in cell
2. maturation w centrosomal microtubule array
3. pseudopod formation
4. microtubules slide to power proplatelet ELONGATION granules move toward ends (branching amplifies ends also)
5. Platelets realeased from mother cell until naked nucelus

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9
Q

Platelet structure

A

-organelles
-secretory granules
-NO NUCLEUS = cant make proteins/cant reproduce

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10
Q

Thrombus Formation

A

-platelet plug/white thrombitis
-3 step process
-initiated by contact with ECM
1.adhesion and shape change
2. Secretion Reaction
3. Aggregation

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11
Q

slide 7

A

:(

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12
Q
  1. Adhesion (platelet activation)
A

-mediated by:
-GO 1a binding collagen (detect wall)
-GP 1b binding vonW factor bridged to collagen (detect wall)
-shape change facilitates receptor binding

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13
Q

How do intact endothelial cells inhibit thrombogenesis

A

-secrete prostacylin (PGI2)
-barrier to ECM

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14
Q
  1. Platelet Secretion (release reaction)
A

-degranulation
-platelet granules release ADP, TXA2, 5-HT

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15
Q

Released from platelet granules

A

-ADP
-Thromboxane A2*
-Serotonin (5-HT)*
-activate and recruit other platelets
-induces change in GPIIb/IIIa receptors to bind fibrinogen
*vasoconstrictors (restrict blood flow)

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16
Q
  1. Platelet aggregation
A

-ADP, 5-HT, TXA2 = GPIIb/GPIIIa receptors bind fibrinogen (aka integrinaIIbB3)
-fibrinogen cross links platelets = hemostatic plug
-contract to form IRREVERSIBLY fused mass
-fibrin stabilizes and anchors aggreggated platelets
=surface for clot formation

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17
Q

Fibrinogen

A

-binds GPIIb/IIIa receptors
-cross-links platelets during aggregation

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18
Q

Fibrin

A

-stabilizes aggregated platelets

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19
Q

Antiplatelet drugs

A

-COX-1 inhibitors
-ADP receptor inhibitors
-GPIIb/IIIa BLOCKERS
-Phosphodiesterase-3 inhibitors
-Protease-Activate Receptor inhibitors

-all inhibitors

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20
Q

Cyclooxygenase-1 inhibitor

A

-aspirin
-ring w ketone and carboxyl

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21
Q

Asprin Function

A

-inhibits COX-1 by acetylation
-interferes w platelet aggregation
-prolongs bleeding
-prevents arterial thrombi formation
-inhibition of TXA2 synthesis in platelets is the key of anti-platelet activity of ASA

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22
Q

Aspirin MOA

A

-IRREVERSIBLE COX-1 inhibition by acetylation
-permanent loss of COX-1 activity
=dec TXA2
-PGI2 production inhibited in tissue by higher doses

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23
Q

Aspirin dose

A

-max dose 50-320mg/day
-PGI2 production inhibited at higher dose (we dont want that)

24
Q

Aspirin indications

A

-prophylaxis
-tx of arterial thromboembolic disorders
-prevent coronary thombosis in unstable angina
-adj to thrombolytic therapy
-reduce recurrence of thrombotic stroke

25
Q

Aspirin counseling

A

-prolongs bleeding time but no inc in PT time
-hemostasis returns to normal 36h after last dose
-risk of upper bleeding (age, NSAIDs, alcohol)

26
Q

Aspirin side effect

A

-upper GI bleeding
-inhibition of COX-1 mediated PGs needed for mucosa production
-risk inc w age, NSAIDs, alcohol

27
Q

Acute Aspirin overdose

A

-can be induced by doses above 150mg/kg
-doses > 500 mg/kg can be fatal
-sx: N/V/D/fever/coma

28
Q

COX-2 enxyme

A

-produces prostacyclin (PGI2) in endothelial cells
=vasodilation and inhibition of platelet aggregation
-does not prevent TXA2 tho (inc CV risk!)

-selectively targeting COX-2 blocks prostacyclin
=platelet aggregation
-but TXA2 not inhibited = CV risk

29
Q

ADP receptor inhibitors

A

-P2Y1
-P2T12
-activation by BOTH needed to activate platelet by ADP

30
Q

P2Y1

A

-ADP receptor
-Gq-PLC-IP3-Ca pathway

31
Q

P2Y12

A

-Gi and inhibition of adenylyl cyclase
-target of ADP inhibitors

32
Q

P2Y12 receptor MOA

A

-Gi = cAMP = phosphorylation of VASP by PKA = platelet activation
-want to inhibit this

-adenylyl cyclase inhibts aggregation

33
Q

ADP receptor inhibitor drugs

A

-P2Y12
-Ticlopidine*
-Clopidogrel*
-Prasugrel*
-Ticagrelor
-Cangrelor

-*prodrug

34
Q

Thienopyridine class of ADP receptor inhibitors

A

-Ticlopidine (Ticlid)
-Clopidogrel (Plavix)
-prodrugs
-IRREVERSIBLE block

35
Q

Ticlopidine and Clopidgrel

A

-Thienopyridine ADP inhibitors
-prodrugs
-oral
-IRREVERSIBLLY block ADP receptor on platelet
=block GPIIb/IIIa complex
-action lasts several days after last dose (bc irreversible)
-Ticlopidine may induce TTP

36
Q

Ticlopidine and Clopidgrel use

A

-acute coronary syndrome
-recent MI, stoke, PVD, coronary stent procedure

37
Q

Prasugrel (Effient)

A

-P2Y12 ADP on platelet surface inhibitor
-tx Acute Coronary Syndrome and Percutaneous coronary intervention (PCI)
-take orally
-prodrug
-IRREVERSIBLE binding
-activity lasts several days after last dose
-bleeding risk – not for elderly

38
Q

Prasugrel (Effient) prodrug

A

-activated by esterase and CYP 3A4/2B6
-PO
-IRREVERSIBLE P2Y12 binding
-high risk of bleeding (not recommended in elderly or before CABG)

39
Q

Ticagrelor (Brilinta)

A

-tx Acute coronary syndrome
-PCl-taken PO
-binds to allosteric site
-REVERSIBLE binding
-CYP3A4 substrate
-faster onset than clopidogrel (7-9h t1/2)
-risk of bleeding
=do NOT use immediately before CABG

40
Q

Cangrelor (Kangreal)

A

-P2Y12 ADP inhibitor
-adjunct to PCl – give IV
-REVERSIBLE
-fast onset
-short t1/2 (3-5min)
-activity terminated early which can be good in MI bc it works really quick then the antiplatelet effect is gone before surgery

41
Q

Activation of P2Y12 ADP receptor antagonists

A

-clopidogrel activated by CYP2C19
-prasugrel activated by esterases/CYP3A4/CYP2B6

=longer onset and t1/2 than the nonprodrugs

-closed S pentagon opens to SH

42
Q

Mech of PDE inhibitors

A

-enhance cAMP levels by inhibiting PDEIII that breaks it down
=maintain platelet activity
- i dont understand

43
Q

Phosphodiesterase-3 (PDE) inhibitors

A

-platelet aggregation inhibitor
-oppose P2Y12 action! (cAMP inhibition)
-inhibit adenosine uptake
-Dipyridamole
-Cilostazol

44
Q

PDE inhibitor drugs

A

-Dipyridamole (Persantine)
-Cilostazol (Pletal)

45
Q

Dipyridamole (persantine)

A

-PDE inhibitor
-combo w warfarin to prevent embolization in prosthetic heart valves
-combo w aspirin to prevent cerebrovascular ischemia

46
Q

Cilostazol (pletal)

A

-intermittent claudication (block aggregation in legs)
-PDE inhibitor

47
Q

Glycoprotein IIb/IIIa receptor inhibitors MOA

A

-inhibits fibrinogen cross-linking of platelets

48
Q

GPIIb/IIIa inhibitor drugs

A

-Abciximab (ReoPro)
-Eptifibitide (integrilin)
-Tirofiban (Aggrastat)

49
Q

Abciximab (reoPro)

A

-mAb (Fab fragment) againts GPIIb-IIIa
-inhibits platelet aggregation
-IV bolus then infusion
-long duration (=inc risk of bleeding)
-prevent thromboembolism in coronar angioplasty
-combo w t-PA for early tx of acute MI

50
Q

Epitifibitide (Integrilin)

A

-synthetic peptide
-reversibly and selectively blocks GPIIb-IIIa
-inhibits fibrinogen binding to dec platelet aggregation
-admin IV bolus then infusion (upto 72h)
-short duration of action (6-12h)
-prevent thromboembolism in unstable angina and angioplastic coronary procedures
-cyclic heptapeptide derived from rattlesnake venom

51
Q

Tirofiban (Aggrastat)

A

-nonpeptide TYROSINE ANALOG
-selective
-REVERSIBLY inhibits fibrinogen binding
-admin IV in dilute solution
->90% inhibition of aggregation after 30 min infusion
-2h t1/2
-combo w heparin to tx acute coronary syndrome
-some structural similarities to RGD

52
Q

Protease Activated Receptor inhibitor MOA

A

-slide 32-33
-thombin activates platelets
-proteolytic cleavaage of PAR-1 on platelet surface
-PARs are GPCRs coupled to release of Ca2+ from stores
-Vorapaxar

53
Q

Vorapaxar (Zontivity)

A

-reversible PAR-1 antagonist!
-PO qd
-prophylactic to prevent thrombosis in pt w previous MI or PAD
-combo w aspirin or clopidogrel!
-t1/2 of 3-4 days = antiplatelet effect for days after dc!
-CYP3A4 (avoid use w 3A4 inhibitors/inducers)
-do NOT use in history of stroke, TIAs, or intracranial hemorrhage

54
Q

summary

A

-slide 35

55
Q

Prostacyclin

A

-released in to plasma by endothelium
-binds platelet receptors = camp synthesis
-camp inhibits aggregation

56
Q

Thromboxane A2

A

-inhibited by aspirin

57
Q

RGD motif in glycoprotein IIb/IIIa inhibitors

A

-arginine, glysine, aspartic acid
-binds receptor
-eptifibatide, tirofiban,

Therapeutics II (45 decks)

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