anti-plateletagents-140120220538-phpapp02.pdf

anti platelet drugs

1. Anti-platelet agents
Dr. J Pradeep

2. Contents
•Introduction
•Classification
•Individual drugs
•Newer anti-platelet agents
•Summary

3. Introduction
•Normal hemostasis
–Maintenance of blood in a fluid, clot-free state in
normal vessels; and
–Formation of hemostaticplug at a site of vascular
injury.
•Opposite : Thrombosis
–Thrombi are lysedand blood is made fluid by
fibrinolyticsystem

4. Coagulation
Fibrinolysis

5. •Both hemostasisand thrombosis are regulated
by three general components
–The vascular wall,
–Platelets, and
–The coagulation cascade

6. Platelets
Megacaryocytes
CFU-M
Myeloid precursors

7. •Platelet count:150000 -400000/mm3
•Lifespan: 7-10 days
•No nucleus
•Cannot synthesiseproteins
•Shape: biconcave discs, fully spread cells

9. •Receptors on platelets:
–GpIa/IIa: receptors for collagen
–GpIb: receptor for vWF
–GpIIb/IIIa: receptor for fibrinogen
–P2Y
1/P2Y
12: purinergicreceptors for ADP
–PAR1/PAR4: protease activated receptors for
thrombin (IIa)

10. •Platelets provide the initial hemostaticplug at
sites of vascular injury
•They also participate in pathological
thromboses that lead to myocardial
infarction, stroke, and peripheral vascular
thromboses

11. Platelet adhesion and aggregation

12. Classification
•TXA2 inhibitors –Aspirin (non selective COX
inhibitor)
•Phosphodiesteraseinhibitors –Dipyridamole
•Thienopyridinederivatives –
Ticlopidine, Clopidogrel, Prasugrel

13. •Glycoprotein (GP) IIb/IIIainhibitor –
Abciximab, Eptifibatide, Tirofiban
•Newer anti-platelet agents –
Cangrelor, Ticagrelor, SCH530348

15. Aspirin
•Aspirin blocks production of TxA
2by
acetylating a serine residue near the active
site of platelet cyclooxygenase-1 (COX-1)
•The action of aspirin on platelet COX-1 is
permanent
•Action lasts for the life of the platelet (7-10
days)

16. •Cumulative effect on repeated doses
•Should be stopped atleastone week prior to
any surgical procedure
•Complete inactivation of platelet COX-1 is
achieved with a daily aspirin dose of 75 mg
•Maximal effective doses is 50-320 mg/day

17. TXA
2
•50-320mg/day
•Pro -
aggregation
PGI
2
•Higher doses
•Anti -
aggregation

18. •Anti-thrombotic dose is much lower than
doses required for other actions
•Higher doses do not improve efficacy
•Potentially less efficacious because of
inhibition of prostacyclinproduction
•Higher doses also increase toxicity, especially
bleeding

19. Dipyridamole
•Interferes with platelet function by increasing
the cellular concentration of cyclic AMP
•This effect is mediated by inhibition of cyclic
nucleotide phosphodiesterasesand Blockade
of uptake of adenosine
•cAMPpotentiatesPGI
2and interferes with
aggregation

20. •Dipyridamole alone has little clinically
significant effect
•Inhibits embolizationfrom prosthetic heart
valves when used in combination with
warfarin
•May potentiatethe action of aspirin in
preventing strokes in patients with TIA,
•No additional benefit as combination with
aspirin in preventing MI

21. Ticlopidine
•Ticlopidineis a thienopyridineprodrugthat
inhibits the P2Y
12receptor
•Converted to the active thiolmetabolitein
liver
•It is rapidly absorbed and highly bioavailable
•It permanently inhibits the P2Y
12receptor and
has prolonged action

23. •Cumulative effect is seen
•Maximal inhibition of platelet aggregation is
not seen until 8-11 days after starting therapy
•The usual dose is 250 mg twice daily
•Like aspirin it has short half life and inhibition
of platelet aggregation lasts for few days after
stopping drug

24. Side effects
•Common: nausea, vomiting, diarrhoea
•Serious adverse effect: severe neutropenia
•Fatal agranulocytosiswith thrombocytopenia
has occurred within the first 3 months of
therapy

25. •Frequent blood counts and platelet counts are
advised in first few months of therapy
•Discontinue therapy if counts fall
•Thrombotic thrombocytopenic purpura-
hemolytic uremic syndrome (TTP-HUS) –rare
adverse effect

26. Therapeutic uses
•Prevention of stroke and TIAs
•Intermittent claudication
•Unstable angina
•Prevention of MI
•Preventing restenosisand stentthrombosis
after PCI

27. Clopidogrel
•Similar to ticlopidine
•Theinopyridinepro drug with slow onset of
action (only 15% is activated by CYP3A4)
•Irreversible inhibitor of platelet P2Y
12
•More potent and lesser side effects
•Usual dose is 75 mg/day with or without an
initial loading dose of 300 or 600 mg

28. •Secondary prevention of stroke : somewhat
better than aspirin
•Prevention of recurrent ischemia in patients
with unstable angina: better as combination
with aspirin
•Synergistic with aspirin since mechanism of
action is different

29. •Wide inter-individual variability in efficacy of
clopidogrelis seen
•Genetic polymorphism in CYP2C19
•Patients with reduced function of CYP219*2
allele show less inhibition of platelets by
clopidogreland have higher rate of
cardiovascular events

30. Uses
•To reduce the rate of stroke, myocardial
infarction, and death in
–Patients with recent myocardial infarction or
stroke
–Established peripheral arterial disease
–Acute coronary syndrome

31. Interactions
•Proton pump inhibitors, inhibitors of
CYP2C19, produce a small reduction in the
inhibitory effects of clopidogrelon ADP-
induced platelet aggregation
•Atorvastatin, a competitive inhibitor of
CYP3A4, reduced the inhibitory effect of
clopidogrelon ADP-induced platelet
aggregation

32. Prasugrel
•Thienopyridineprodrug
•Rapid onset of action
•Greater inhibition of ADP induced platelet
aggregation
•Almost completely absorbed from the gut
•Almost all of the drug is activated

34. •Irrversibleinhibitor of P2Y
12 receptor
•Has prolonged effect after discontinuation
•Better than clopidogrelin reducing incidence
of non fatal MI
•The incidence of stentthrombosis also was
lower with prasugrelthan with clopidogrel

35. •However,it has higher rates of fatal and life-
threatening bleeding
•Contraindicated in those with a history of
cerebrovasculardisease -high risk of bleeding
•Caution is required if prasugrelis used in
patients weighing <60 kg or in those with
renal impairment

36. •After a loading dose of 60 mg, prasugrelis given
once daily at a dose of 10 mg
•Patients >75 years of age or weighing <60 kg may
do better with a daily prasugreldose of 5 mg
•It is reasonable alternative to clopidogrelin
patients with the loss-of-function CYP2C19 allele
because there is no association with decreased
anti platelet action in prasugrel

37. Glycoprotein IIb/IIIa inhibitors
•Block final step in platelet aggregation
induced by any agonist
•Abciximab
•Eptifibatide
•Tirofiban

38. Abciximab
•Abciximabis the Fabfragment of a humanized
monoclonal antibody directed against the
GpIIb/IIIareceptor
•Uses:
–percutaneousangioplasty for coronary
thromboses
–prevent restenosis, recurrent myocardial
infarction, and death: used in combination with
aspirin and heparin

39. •T1/2: 30 min
•Duration of action: 18 –24 hrs
•Dose: 0.25-mg/kg bolus followed by 0.125
g/kg/min for 12 hours or longer, IV
•Adverse effects:
–Hemorrhage (1-10%)
–Thrombocytopenia (2%)
•Platelet transfusions can reverse the
aggregation defect
•Expensive

40. Eptifibatide
•Cyclic peptide inhibitor of the fibrinogen
binding site on GpIIb/IIIareceptor
•Dose: 180 g/kg IV bolus followed by 2
g/kg/min for up to 96 hours
•Short duration of action: 6-12 hrs
•Given with aspirin and heparin

41. •Use:
–Acute coronary syndrome
–Angioplasticcoronary interventions
•Adverse effects:
–Bleeding (10%)
–Thrombocytopenia (0.5-1%)

42. Tirofiban
•Similar to eptifibatide
•Value in antiplatelettherapy after acute
myocardial infarction is limited
•Used in conjunction with heparin

43. GpIIb/IIIainhibitors
FeaturesAbciximab EptifibatideTirofiban
DescriptionFabfragment of
humanized mouse
monoclonal antibody
Cyclical
heptapeptide
Nonpeptide
Specific for
GPIIb/IIIa
No Yes Yes
Plasma t
1/2 Short Long (2.5h) Long (2.0h)
Platelet-bound
t
1/2
Long (days) Short (sec) Short (sec)
Renal
clearance
No Yes Yes

44. Newer anti-platelet agents
•Cangrelor
•Ticagrelor
•SCH530348
•E5555

45. Cangrelor
•Adenosine analogue
•Reversible inhibitor of P2Y
12receptor
•T1/2: 3-6 min
•Duration of action: 60 min
•Administration: IV bolus followed by infusion
•Little or no advantage over other drugs

46. Ticagrelor
•Orally active reversible inhibitor of P2Y
12
receptor
•Rapid onset and offset of action
•Twice daily dosage
•First new antiplateletdrug to demonstrate a
reduction in cardiovascular death compared
with clopidogrelin patients with acute
coronary syndromes

47. SCH530348, E5555
•SCH530348 an orally active inhibitor of PAR-
1, is under investigation as an adjunct to
aspirin or aspirin plus clopidogrel.
•Two large phase III trials are under way.
•E5555 is an oral PAR-1 antagonist in early
developement

48. Summary
•Potent inhibitors of platelet function have been
developed in recent years
•These drugs act by discrete mechanisms; thus, in
combination, their effects are additive or even
synergistic
•Aspirin
has remained, for over 50 years, the cornerst
one of antiplatelet therapy owing to its prove
n clinical benefit and very good cost–
effectiveness profile.

49. •Their availability has led to a revolution in
cardiovascular medicine, whereby angioplasty
and vascular stentingof lesions now are
feasible with low rates of restenosisand
thrombosis when effective platelet inhibition
is employed

50. THANK YOU.

51. References
•Goodman & Gilman's The Pharmacological Basis of
Therapeutics, 12
th
edition,Section III. Modulation of Cardiovascular
Function, Chapter 30. Blood Coagulation and
Anticoagulant, Fibrinolytic, and AntiplateletDrugs
•Robbins and Cotran’sPathologic basis of disease, 8
th
edition, Section IV, Hemodynamic disorders, Thromboembolic
disease and shock. Hemostasisand thrombosis.
•TripathiK D, essentials of medical pharmacology, 6
th
edition, Section ten, Drugs affecting blood and blood formation.
Drugs affecting coagulation, bleeding and thrombosis.
•Kallirroi I Kalantzi, Maria E Tsoumani, ET. AL.
Pharmacodynamic Properties of Antiplatelet Agents-
Current Knowledge and Future Perspectives, Expert Rev Clin Ph
armacol. 2012;;5(3):319-­336

52. Dazoxiben
•It inhibits the enzyme thromboxane synthetase
so reduces the concentration of thromboxane A2
•Its antiplatelet action is not satisfactory, when
used alone.
•However may be useful when used with
aspirin.

53. PROSTACYCLINE ANALOGUES
•Ex are epoprostenol, iloprost
•These group of drugs block all pathway for platelet
activation.
•They also inhibits the expression of GPIIb/IIIa
receptor.
•Epoprostenolhas a very short half life of 3 minsso
it has to be used by iv infusion.
•It causes headache and flushing due to
vasodilation.
•iloprostis similar to epoprostenolbut iloprostis
longer acting.