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 lysed and blood is made fluid by
fibrinolytic system
9. • Receptors on platelets:
– GpIa/IIa: receptors for collagen
– GpIb: receptor for vWF
– GpIIb/IIIa: receptor for fibrinogen
– P2Y1/P2Y12: purinergic receptors for ADP
– PAR1/PAR4: protease activated receptors for
thrombin (IIa)
10. • Platelets provide the initial hemostatic plug at
sites of vascular injury
• They also participate in pathological
thromboses that lead to myocardial
infarction, stroke, and peripheral vascular
thromboses
15. Aspirin
• Aspirin blocks production of TxA2by
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 atleast one 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
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 prostacyclin production
• 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 phosphodiesterases and Blockade
of uptake of adenosine
• cAMPpotentiates PGI2 and interferes with
aggregation
20. • Dipyridamole alone has little clinically
significant effect
• Inhibits embolization from prosthetic heart
valves when used in combination with
warfarin
• May potentiate the action of aspirin in
preventing strokes in patients with TIA,
• No additional benefit as combination with
aspirin in preventing MI
21. Ticlopidine
• Ticlopidine is a thienopyridineprodrug that
inhibits the P2Y12receptor
• Converted to the active thiol metabolite in
liver
• It is rapidly absorbed and highly bioavailable
• It permanently inhibits the P2Y12receptor and
has prolonged action
22.
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 agranulocytosis with 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 purpurahemolytic uremic syndrome (TTP-HUS) – rare
adverse effect
26. Therapeutic uses
•
•
•
•
•
Prevention of stroke and TIAs
Intermittent claudication
Unstable angina
Prevention of MI
Preventing restenosis and stent thrombosis
after PCI
27. Clopidogrel
• Similar to ticlopidine
• Theinopyridine pro drug with slow onset of
action (only 15% is activated by CYP3A4)
• Irreversible inhibitor of platelet P2Y12
• 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
clopidogrel is seen
• Genetic polymorphism in CYP2C19
• Patients with reduced function of CYP219*2
allele show less inhibition of platelets by
clopidogrel and 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 clopidogrel on ADPinduced platelet aggregation
• Atorvastatin, a competitive inhibitor of
CYP3A4, reduced the inhibitory effect of
clopidogrel on 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
33.
34. • Irrversible inhibitor of P2Y12 receptor
• Has prolonged effect after discontinuation
• Better than clopidogrel in reducing incidence
of non fatal MI
• The incidence of stent thrombosis also was
lower with prasugrel than with clopidogrel
35. • However, it has higher rates of fatal and lifethreatening bleeding
• Contraindicated in those with a history of
cerebrovasculardisease - high risk of bleeding
• Caution is required if prasugrel is used in
patients weighing <60 kg or in those with
renal impairment
36. • After a loading dose of 60 mg, prasugrel is given
once daily at a dose of 10 mg
• Patients >75 years of age or weighing <60 kg may
do better with a daily prasugrel dose of 5 mg
• It is reasonable alternative to clopidogrel in
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
• Abciximab is the Fab fragment of a humanized
monoclonal antibody directed against the
GpIIb/IIIa receptor
• Uses:
– percutaneous angioplasty 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/IIIa receptor
• 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
42. Tirofiban
• Similar to eptifibatide
• Value in antiplatelet therapy after acute
myocardial infarction is limited
• Used in conjunction with heparin
46. Ticagrelor
• Orally active reversible inhibitor of P2Y12
receptor
• Rapid onset and offset of action
• Twice daily dosage
• First new antiplatelet drug to demonstrate a
reduction in cardiovascular death compared
with clopidogrel in patients with acute
coronary syndromes
47. SCH530348, E5555
• SCH530348 an orally active inhibitor of PAR1, 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 stenting of lesions now are
feasible with low rates of restenosis and
thrombosis when effective platelet inhibition
is employed
51. References
• Goodman & Gilman's The Pharmacological Basis of
Therapeutics, 12th edition, Section III. Modulation of Cardiovascular
Function, Chapter 30. Blood Coagulation and
Anticoagulant, Fibrinolytic, and Antiplatelet Drugs
• Robbins and Cotran’s Pathologic basis of disease, 8th
edition, Section IV, Hemodynamic disorders, Thromboembolic
disease and shock. Hemostasis and thrombosis.
• Tripathi K D, essentials of medical pharmacology, 6th
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 AgentsCurrent 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.
• Epoprostenol has a very short half life of 3 mins so
it has to be used by iv infusion.
• It causes headache and flushing due to
vasodilation.
• iloprost is similar to epoprostenol but iloprost is
longer acting.
Editor's Notes
Normal hemostasis is the result of a set of well-regulated processes that accomplish two important functions: (1) They maintain blood in a fluid, clot-free state in normal vessels; and (2) They are poised to induce a rapid and localized hemostatic plug at a site of vascular injury.thrombosis; it can be considered an inappropriate activation of normal hemostatic processes
On activation platelets spread podia leading to dramatic increase in surface area
Platelets first adhere to macromolecules in the subendothelial regions of the injured blood vessel, where they become activated. Adherent platelets release substances that activate nearby platelets, thereby recruiting them to the site of injury. Activated platelets then aggregate to form the primary hemostatic plugPlatelet adhesion and aggregation. GPIa/IIa and GPIb are platelet receptors that bind to collagen and von Willebrand factor (vWF), causing platelets to adhere to the subendothelium of a damaged blood vessel. PAR1 and PAR4 are protease-activated receptors that respond to thrombin (IIa); P2Y1 and P2Y12 are receptors for ADP; when stimulated by agonists, these receptors activate the fibrinogen-binding protein GPIIb/IIIa and cyclooxygenase-1 (COX-1) to promote platelet aggregation and secretion. Thromboxane A2 (TxA2) is the major product of COX-1 involved in platelet activation. Prostaglandin I2(prostacyclin, PGI2), synthesized by endothelial cells, inhibits platelet activation.
Because platelets do not synthesize new proteins, the action of aspirin on platelet COX-1 is permanent, lasting for the life of the platelet (7-10 days)
The unique sensitivity of platelets to inhibition by such low doses of aspirin is related to their presystemic inhibition in the portal circulation before aspirin is deacetylated to salicylate on first pass through the liver (Pedersen and FitzGerald, 1984). In contrast to aspirin, salicylic acid has no acetylating capacity
Other NSAIDs that are reversible inhibitors of COX-1 have not been shown to have anti-thrombotic efficacy and in fact may even interfere with low-dose aspirin regimenssingle 325-mg dose of aspirin approximately doubles the mean bleeding time of normal persons for 4-7 days
converted to the active thiol metabolite by a hepatic CYP
Mechanism of action of the P2Y12 antagonists. P2Y1 and P2Y12 are G-coupled receptors, which utilize ADP as an agonist. P2Y1 is a Gq-coupled receptor, which initiates ADP-induced platelet aggregation through the stimulation of PLC and phosphatidylinositol-signaling pathway. P2Y12 is a Gi-coupled 7-transmembrane domain receptor, which mediates platelet activation by inhibiting an AC-mediated signaling pathway and decreasing the cAMP intracellular levels. It also inhibits PI3K and induces Akt kinase activation. The decrease in cAMP intracellular levels reduces the rate of phosphorylation of VASP, thus inducing activation of the GPIIb/IIIa receptor and platelet aggregation. AC: Adenyl cyclase;; PLC: Phospholipase C;; VASP: Vasodilator-stimulated phosphoprotein;; VASP-P: Vasodilator- stimulated phosphoprotein phosphorylation.
Loading doses of 500 mg sometimes are given to achieve a more rapid onset of actionThe plasma t1/2 after single doseis 8 hr, but after multiple dosesit is 8 days
(absolute neutrophil count <500/L) , seen in 2.4% of stroke patients given the drug during premarketing clinical trials
Ttp has high mortality
Becauseof its potential for serious adverse reactions, use of ticlopidine is restricted to supplementing aspirin or when aspirin is contraindicated.
Even patients with the reduced-function CYP2C19*3, *4, or *5 alleles may derive less benefit from clopidogrel than those with the full-function CYP2C19*1 allele
Metabolism of ADP P2Y12 antagonists. The thienopyridines clopidogrel and prasugrel are prodrugs, requiring hepatic metabolism to form their active metabolites, which irreversibly bind to P2Y12. After intestinal absorption, clopidogrel prodrug is metabolized into inactive metabolites by ubiquitous esterases. The remainder (15%) undergoes activation in the liver by the hepatic CYP450 enzymatic pathway. Clopidogrel activation requires a two-step oxidative process conversion, first to 2-oxo-clopidogrel and then to its active thiol metabolite. Both steps involve several hepatic CYP isoenzymes. PON-1 may also participate in the formation of clopidogrel's active thiol metabolite. Prasugrel is a prodrug that first undergoes a rapid de-esterification to an intermediate thiolactone, which is then converted in the liver to the active metabolite by CYP isoenzymes in a single CYP-dependent process. Clopidogrel and prasugrel are irreversible antagonists of the P2Y12 receptor. Ticagrelor is a direct-acting, reversible, noncompetitive antagonist of the P2Y12 receptor, which does not need metabolic activation. Cangrelor and elinogrel cause reversible inhibition of the P2Y12 receptor as well. Both drugs directly and competitively antagonize ADP binding to the P2Y12 receptor without the need for any metabolic activation. CYP: Cytochrome P450;; PON-1: Paraoxonase-1.
Thrombocytopenia with a platelet count <50,000 occurs in about 2% of patients and may be due to development of neo-epitopes induced by bound antibodyfree antibody concentrations fall rapidly after cessation of infusion
It also binds to the vitronectin receptor on platelets, vascular endothelial cells, and smooth muscle cells.
Recent trials comparing cangrelor with placebo during coronary interventions or comparing cangrelor with clopidogrel after such procedures revealed little or no advantages of cangrelo
