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PDAT5 CV > 18 - Pharmacology Antiplatelet Drugs > Flashcards

18 - Pharmacology Antiplatelet Drugs Flashcards

1
Q

P2Y12 Inhibitors

Ticagrelor Metabolism

T = Two = 2x Day Dosing

A

NOT PRODRUGS = Already ACTIVE

GREATEST INHIBITION
of Platelet Aggrgation
&
REACHES 50% the FASTEST

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2
Q

P2Y12 Inhibitors

All Drugs

A

Clopidogrel

Prasugrel = Effient

Ticagrelor = Brilinta

Ticlopidine = Ticlid
MYELOSUPRESSION

Cangrelor
IV ONLY

Thienopyridine

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3
Q

P2Y12 Inhibitors

Clopidogrel Metabolism

A

Clopidogrel = PRODRUG

CYP2c19 & CYP1A2 & CYP3A4 –> 85% INACTIVE metabolites

SECOND CYP2c19 PROCESS
VVV
PLATELET EFFECT

ASIANS are commonly INTERMEDIATE METABOLIZERS
of CYP2c19
↓Antiplatelet activity –> need HIGHER dose?

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4
Q

PDE-Inhibitors

Drugs & MoA

A

Dipyridamole** & **Cilostazol

  • *P2y1 / P2y12 receptor binding = G-protein –AC:**
  • *cAMP + cGMP** -> ↓ platelet activation
  • *PDE is what BREAKS DOWN**
  • *cAMP / cGMP -> AMP/GMP**
  • *PDE Inhibition** –> ↑ cAMP/cGMP to inhibit platelet activation
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5
Q

Platelet Receptors & Their Functions

Which Receptors?

PLATELET ADHESION

A
  • *Collagen Receptor**
  • *GPV1** & FcRy-chain

GP1B / IX / V / vW

Platelet Adhesion:
Bind to collagen & vWF

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6
Q

Which Antiplatelet Drug has this ADR?

TPP = Thrombotic Thrombocytopenia Purpura

A

CLOPIDOGREL
P2Y12 Inhibitor

TPP

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7
Q

ASPIRIN

  • *Low Dose MoA**
  • *50-325 mg/day**
A

COX-1 ONLY
Arachidonic acid –/–> Prostaglandin G2
acetylates serine residue near active site of COX-1

↓Thromoxane = ↓TxA2
irreversible inhibition for LIFESPAN of PLATELET (5-9days)

vvvv

↓ Vasoconstriction
↓ PLATELET ACTIVATION** & ↓**AGGREGATION

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8
Q

GP IIb/IIIa Inhibitors

EPTIFIBATIDE
Integrilin

Structure
Half Life / Duration of Effect
Clearance?

A
  • *Cyclical KGD-containing heptapeptide**
  • *EP**tifabatide = hEPtapaptide

1.5-2 hours / 2-4 hour Duration

RENAL CLEARANCE

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9
Q

P2Y12 Inhibitors

Clopidogrel

Onset / Duration / Drug Interactions

A

2-6 Hour Onset
requires PRODRUG activation by :
CYP = 2C19 / 1A2 / 3A4

3-10 Day Effect
due to
Irreversible binding

DI w/
CYP2C19 Inhibitors

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10
Q

ASPIRIN

  • *HIGH DOSE MoA**
  • *>325 mg/day**
A

COX-2 INHIBITION

↓Prostglandins = ↓PGD2 ↓PGE2 ↓PGF2

vvvv

↓ INFLAMMATION
↑ Platelet ACTIVATION

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11
Q

GP IIb/IIIa Inhibitors

ABCIXIMAB
Reopro

Structure
Half Life / Duration of Effect
Clearance?

A

Fab fragment of humanized mouse:
MONOCLONAL ANTIBODY

10-30 min / ~2 DAYS
LONG duration of effect
half life is insignificant because drug is STUCK to target

non-renal clearance

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12
Q

P2Y12 Inhibitors

Prasugrel

Onset / Duration / Drug Interactions

A

0.5-2 Hour Onset
esterase hydrolysis –> active drug

7-10 Day Effect
due to
Irreversible binding

no drug interactions

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13
Q

Vasculoprotective Effects of ASPIRIN

A

Aspirin 75mg/day
= COMPLETE Inactivation of COX-1

Vasculoprotective Effects:

Prevent LEUKOCYTE rolling

Prevent MACROPHAGE-induced ENDOTHEILIAL DYSFUNCTION

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14
Q

Which Antiplatelet Drug has this ADR?

Thrombocytopenia

A

GP IIB/IIA Inhibitors
MOST problematic

ABCIXIMAB >> eptifibatide=tirofiban

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15
Q

Platelet Receptors & Their Functions

Which Receptors?

PLATELET ACTIVATION:
↑GP IIb/IIIa expression

A
  • *PAR-1_ & _PAR4**
  • *Thrombin Receptors**
  • *Catecholamines**
  • *+ A2 agonist +**
  • *- B1 agonist -**

ADP: P2Y1** + **P2Y12

Serotonin

TXA2: TPa-R / TPb-R

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16
Q

Platelet Receptors & Their Functions

Which Receptors?

PLATELET AGGREGATION

Platelets bind to one another

A

GP1a + GPIIb

FIBRONOGEN RECEPTOR

17
Q

P2Y12 Inhibitors

Cangrelor
Metabolism**&**Onset/Duration

A

NOT PRODRUGS = Already ACTIVE

IV Only

2 MIN ONSET OF ACTION
Lasting
1-2 Hours = Reversible Binding

18
Q
  • *GP IIb/IIIa Inhibitors**
  • *Abciximab / Eptifibatide / Tirofibin**

Mechanism of Action

A

inhibit:
PLATELET AGGREGATION
TARGET IS:
Binding ligands contain RGD = Arg-Gly-Asp Sequence
50-100k receptorsoneach platelet

Blocking 60-80% –> significant platelet aggregation

Blocking >80% –> ↑thrombin formation & ↑bleeding time

19
Q

Which Antiplatelet Drug has this ADR?

MYELOSUPPRESSION

A

TICLOPIDINE
P2Y12 Inhibitor

MYELOSUPPRESSION

20
Q

Aspirin Resistance

Mechanisms?

A
  • *~25% are NONresponsive** to
  • *antiplatelet effects of aspirin**

↑dose does NOT affect responsiveness

Mechanisms:
COX-1 Structure Changes / Inability to Block active site

NSAID Drug Interactions

21
Q

P2Y12 Inhibitors

Prasugel Metabolism

A

Hydrolysis by:
ESTERASE–>ACTIVE FORM

some enzymatic activation
BUT
that’s already the ACTIVE form –> no effect

CYP3a4/5
CYP2B6 / CYP2c19 / CYP2c9

22
Q

Which Antiplatelet Drug has this ADR?

Dypsnea - Lung SOB

Bradycardia & Ventricular Pauses

A

TICAGRELOR
P2Y12 Inhibitor - BID Dosing

Dyspnea / Bradycardia / Ventricular Pauses

23
Q

P2Y12 Inhibitors

Ticagrelor

Onset / Duration / Drug Interactions

A

T = Two = 2 Day Dosing

0.5-2 Hour Onset

3-5 day Duration = REVERSIBLE BINDING

drug interactions:
Strong CYP3A4 Inhibitors & Inducers

PDAT5 CV (30 decks)

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