Αλέξανδρος Δ. Τσελέπης, MD, PhDΚαθηγητής Βιοχηµείας - Κλινικής Χηµείας

ΠΑΝΕΠΙΣΤΗΜΙΟ ΙΩΑΝΝΙΝΩΝΕΡΕΥΝΗΤΙΚΟ ΚΕΝΤΡΟΑΘΗΡΟΘΡΟΜΒΩΣΗΣ

Μηχανισµοί δράσης αντιαιµοπεταλιακών φαρµάκων

Hemostasis: Vasoconstriction and Plug Formation

Hemostasis: Coagulation and Clot Stabilization

Triggers of arterial and venous thrombosis

Nigel  Mackman,  Nature  (2008)  451:914-­‐918

ArteryVein

Platelet Aggregation

0.5 µΜ ADP

1.0 µΜ ADP

2.5 µΜ ADP

5.0 µΜ ADP

10 µΜ ADP

Διαπερατότητα,

%

1 min

Χρόνος, min

Mc Neely W, Goa KL. Triflusal. Drugs 1998 Jun; 55(6):823-33

SALICYLIC ACIDSALICYLIC ACID

COOHCOOH

OHOH

ACETYLSALICYLIC ACIDACETYLSALICYLIC ACID

OCOCHOCOCH33

COOHCOOH

INACTIVEACTIVE

Aspirin as α cornerstone therapy for CVD

COX-1 Inhibition With Aspirin

Schroeder WS, et al. J Thr Thrombol. 2006; 22:139-150 Patrono C, et al. Nature. 2007; 4:42-50

SALICYLIC ACIDSALICYLIC ACID

COOHCOOH

OHOH

HTBHTB

COOHCOOH

OHOH

CFCF33

ACETYLSALICYLIC ACIDACETYLSALICYLIC ACID

OCOCHOCOCH33

COOHCOOH

TRIFLUSALTRIFLUSAL

OCOCHOCOCH33

COOHCOOH

CFCF33

Triflusal

Mc Neely W, Goa KL. Triflusal. Drugs 1998 Jun; 55(6):823-33

ACTIVEACTIVE

INACTIVEACTIVE

Mode of Action

VascularCyclooxygenase cAMP-

Phosphodiesterase

PlateletCyclooxygenase

Arachidonicacid PGI2 ATP cAMP

Adenylatecyclase

5'-AMPArachidonic

acid

Inhibition ofTxA2

Synthesis

PLATELET AGGREGATION INHIBITION

TRIFLUSAL

DIPYRIDAMOLE

CILOSTAZOL

TRIFLUSAL

ASPIRIN

Ca++ Block

Phospholipase A2 activation

Ca-dependentplatelet reaction

ASPIRIN

Cilostazol, Dipyridamol

Η σηµασία του αιµοπεταλιακού υποδοχέα P2Y12 στην ενεργοποίηση των αιµοπεταλίων και οι σηµαντικότεροι αναστολείς του

The P2Y12 receptor and platelet activation

• Adenosine diphosphate (ADP) is secreted by activated platelets (Davi 2007; Meadows 2007)

• ADP binding to the P2Y12 receptor is important for sustaining platelet activation and aggregation (Dorsam 2004; Davi 2007)– G-protein-coupled receptor on

platelet surface [Dorsam 2004]– Potentiates further ADP

secretion– Recruits additional platelets– Facilitates platelet adhesion

Davi GD, et al. N Engl J Med. 2007;357:2482-2494; Meadows TA, et al. Circ Res. 2007;100:1261-1275; Dorsam RT, et al. J Clin Invest. 2004;113:340-345.

White HD, et al. Am Heart J 2011;161:450-61

Σηµατοδοτικές πορείες που ενεργοποιούνται διαµέσου των κύριων αιµοπεταλιακών υποδοχέων

Pathways Activated Following

Stimulation of P2Y12 by ADP

Kleiman NS, et al. JACC. 2008; 51: 1412-1414

VASP: Vasodilator-Stimulated Phosphoprotein

Ticlopidine(1st generation)

N

SCl

N

SCl

Prasugrel(CS-747, LY640315)

S

N

F

O

OCH3

O

Clopidogrel(2nd generation)

OCH3

N

SCl

N

SCl

O

Θειενοπυριδίνες Μη αντιστρεπτοί αναστολείς του Υποδοχέα του ADP P2Y12

Mechanism of action of thienopyridines

Irreversible, covalent binding to P2Y12 receptor

Hydrolysis by esterases

Active drug

Inactive metabolites elimination by urine/

feces Platelets require replacement for return to activity

Variable proportion of prodrug metabolized to active drug by

cytochrome P450

ADP

Meadows TA, et al. Circ Res. 2007;100(9):1261-1275; Beitelshees A, et al. Arterioscler Thromb Vasc Biol. 2006;26:1681-1683; Wiviott S, et al. Circulation. 2010; 122: 394-403; Cattaneo M. Eur Heart J. 2008;10(Suppl I):I33-I3; Ibanez B, et al. Eur Heart J. 2006:8:G.3

Κλοπιδογρέλη

Μέγιστη ανασταλτική δράση

75 mg 24 h

300 mg

600 mg ή900 mg

6 h

2 h

P2Y12 ADP receptor inhibition by clopidogrel

SSΚλοπιδογρέλη  (προφάρμακο)

Κλοπιδογρέλη  (ενεργός  μεταβολίτης)

Μη  αντιστρεπτή  (ομοιοπολική)  σύνδεση  της    κλοπιδογρέλης  στον  υποδοχέα  P2Y12

Clopidogrel–Drug Interactions

Sibbing D, et al. J Am Coll Cardiol 2009;53:849–56

Kaplan-Meier analysis for the cumulative incidence of stent Thrombosis and for the composite of death or stent thrombosis

Association between the CYP2C19*2 Reduced-Function Allele and the Primary Efficacy Outcome or Stent

Thrombosis in Subjects Receiving Clopidogrel

Mega JL, et al. N Engl J Med 2009;360:354-62

Active Metabolite FormationPrasugrelClopidogrel

Gut CYPs (3A, 2C9, 2C19)

Prodrug

IntermediateMetabolite

Liver CYPs(2C19, 1A2, 2B6)

Activemetabolite

Liver CYPs: (3A, 2B6, 2C19, 2C9)

EsterasesInactive Acid Metabolite(85% of parent)

hCE1(mainly liver) Esterases

hCE2 (mainly gut)

Prodrug

Activemetabolite

IntermediateMetabolite

Farid NA et al. Drug Metab Dispos 2007;35:1096-1104 Rehmel JLF et al. Drug Metab Dispos 2006;34:600-607 Williams ET et al. Drug Metab Dispos 2008;36:1227-1232

Kurihara A et al. Drug Metab Rev 2005;37(S2):99 Tang M et.al. J Pharmacol Exp Ther 2006;319:1467-1476

hCE1

Liver CYPs: (3A, 2B6, 2C9, 2C19)

Active Metabolite Plasma Concentrations After the Loading Dose

Time (hours)0 1 2 3 4

Act

ive

Met

abol

ite C

once

ntra

tion

(

ng/m

L; m

ean

± SD

)

0

200

400

600

800

Prasugrel 60 mg LD

Clopidogrel 600 mg LD

Clopidogrel 300 mg LD

SD=Standard deviation; LD=Loading dose Winters K, et al. Eur Heart J. 2007;28:218

Inhibition of Platelet Aggregation After Loading Dose in Patients With Elective PCI

Hours

IPA

% (2

0 µM

AD

P) Prasugrel 60 mg

***p<0.0001 Prasugrel vs. Clopidogrel

Clopidogrel 600 mg

*********

***

0.5 4 8 12 16 20 24

0

20

40

60

80

100

62

IPA=inhibition of platelet aggregation; PCI=Percutaneous coronary intervention Wiviott SD et al. Circulation 2007;116(25):2923-2932

Loading Dose Phase VASP Platelet Reactivity Index

PRI=platelet reactivity index; VASP=vasodilator-stimulated phosphoprotein

Hours

Prasugrel 60 mg

Clopidogrel 600 mg

******

***

VASP

PR

I (%

)

***p<0.0001 Prasugrel vs. Clopidogrel

4 862 12 16 20 240

20

40

60

80

100

0

Αντιστρεπτοί Αναστολείς του Υποδοχέα του ADP P2Y12

Ticagrelor (AZD 6140)

Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP)

Ticagrelor P2Y12 receptor binding

• Ticagrelor is highly selective for the P2Y12 receptor, compared with its effect at other P2 receptors (van Giezen 2008)

• Unlike thienopyridines ticagrelor does not interfere with ADP binding (van Giezen

2008)

• Ticagrelor prevents ADP- mediated P2Y12 receptor activation (van Giezen 2008)

• Upon discontinuation, ticagrelor has a predictable and reliable offset reflecting the gradual fall in plasma concentration (Husted 2006; Gurbel 2009; van Giezen 2008)

• Platelet activity returns as ticagrelor is eliminated (van Giezen 2008)

van Giezen JJJ. Eur Heart J. 2008;10 (Suppl D):D23-D29; Husted S, et al. Eur Heart J. 2006;27:1038-1047; Gurbel PA, et al. Circulation. 2009;120:2577-2585.

Husted S, et al. Cardiov Therap 27 (2009) 259–274

Ticagrelor proposed metabolic route

Sillιn H, et al. J. Chromatogr. B 878 (2010) 2299-2306

ARC133913XX.

Ticagrelor

AR-C124910XX

Gurbel PA, et al. Circulation 2010;121;1188-1199

The RESPOND StudyInhibition of platelet aggregation to ADP in clopidogrel-nonresponsive patients

Gurbel PA, et al. Circulation 2010;121;1188-1199

The RESPOND StudyInhibition of platelet aggregation in response to ADP

in clopidogrel-responsive patients

Before and after crossover Patients maintained on constant therapy

GPIIb/IIIa inhibitors

Αιμοπεταλιακοί

υποδοχείς της

θρομβίνηςProtease-activated receptor (PAR)1(“υψηλής συγγένειας”

υποδοχέας)

PAR4 (“χαμηλής

συγγένειας”

υποδοχέας)

Η θροµβίνη µετατρέπει το Ινωδογόνο σε ινώδες και ενεργοποιεί τα αιµοπετάλια

Θρόµβος

Πρωτεολυτική

ενεργοποίηση του PAR1

Landis, R.C., et al. Ann Thorac Surg 2001;72:2169-75

Σχάση με τη δράση

της θρομβίνης

Ενεργο

ποίηση

G

= Προσδέτης (SFLLRN)

(Coughlin, S.R., et al. J Throm Hemost 2005;3:1800-14)

Angiolillo DJ, et al. Eur Heart J 2009

PAR-1 antagonists

SCH 530348

Becker RC, et al. Lancet 2009; 373: 919–28

PAR-1 antagonists