Platelet%20Aggregation%20Inhibitors

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Platelet Aggregation Inhibitors

• Professor. Dr.
• MAHMOUD KHATTAB,

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The components of a platelet
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Platelets and the Mechanisms of Arterial
Thrombosis

• Platelet adhesion and aggregation occur at the
  site of plaque rupture at luminal exposed
  subendothelium
• ADHESION occurs in response to collagen or vWf
  followed by a cascade of further platelets
  recruitment
• Activated platelets exert pro-coagulant effects
  and the soluble coagulation cascade is activated
• Fibrin strands and erythrocytes predominate
  within the lumen of the vessel and downstream in
  the body and tail of the thrombus

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Platelet Aggregation

• Activated platelets undergo three consecutive
  processes (a) shape change, (b) secretion of
  platelet granular contents (ADP, fibrinogen
  5-HT) and finally (c) platelet aggregation
• The final common pathway in platelet aggregation
  is cross-linking of the activated GP IIb/IIIa
  receptor (integrin aIIbß3) with circulating
  adhesive arginine-glycine-asparagine (R-G-D)
  sequence macromolecules, predominantly fibrinogen
  and von Willebrand factor
• There is 50,000-80,000 GP IIb/IIIa receptors on
  the surface of each platelet

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Platelet Aggregation

• GP IIb/IIIa receptors undergo inside-out
  (low-high affinity) signalling in order to bind
  to vWf/fibrinogen
• Main stimuli for full platelet aggregation
  include
• Collagen, ADP, thromboxane A2 (TXA2), thrombin
• All except for collagen act through G-protein
  coupled receptors activating two transductions
• Phospholipase C
• Phospholipase A2
• Stored ADP de novo synthesized TXA2 act as
  positive feedback mediators

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The stimulatory pathway for platelet secretion

• TXA2 is produced from AA via 3-steps enzymatic
  process PLA2-COX-1/TXA2 synthase
• ADP activates Gi-coupled P2Y12 receptors
• TXA2 thrombin activate Gq-PLC-coupled TXA2
  thrombin receptors respectively
• Ultimately, GP IIb/IIIa receptors undergo
  inside-out signalling bringing platelet
  aggregation

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Platelet Activation

• Activation of membrane-bound G proteins catalyzes
  the intracellular signaling system, predominantly
  inositol biphosphate (IP3) and diacyl glycerol
  (DAG)
• IP3 causes the release of intracellular calcium
  from the SR dense granules, phosphorylation of
  the myosin light chain, and allows the platelet
  contractile apparatus to perform platelet shape
  changes
• DAG activates PKC and in turn the activation of
  the surface integrin glycoprotein (GP) IIb/IIIa
  receptor occurs
• Activated receptor undergoes a conformational
  change and binds to the arginine-glycine-asparagin
  e (R-G-D) sequence on circulating macromolecules
  mainly fibrinogen vWf, and is responsible for
  cross-linking platelets together
• TXA2 provides amplification of the aggregation
  response a significant vasoconstrictor effect

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Increased platelet activity implicated in post-MI
reocclusion and ischemia

• Several lines of evidence implicate increased
  platelet activity in reocclusion and recurrent
  ischemia following acute MI
• A, Autopsy data indicate that patients who died
  after acute MI are several times more likely to
  have a platelet-rich thrombus occluding the
  coronary infarct-related coronary artery if they
  had received thrombolytic therapy than if they
  had been treated without it
• B, The production of thromboxane B2 (TXB2), the
  stable metabolite of TXA2, is markedly increased,
  indicating that platelet activation is stimulated
  in the early minutes after thrombolytic therapy
  is given (The administration of oral aspirin is
  able to block this reaction)
• C, Platelet aggregability following thrombolysis
  with either streptokinase or tissue-type
  plasminogen activator is increased, as measured
  by responses to either thrombin or ADP added to
  platelet-rich plasma

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ASPIRIN IN ACUTE ISCHEMIC SYNDROMES

• Low dose of aspirin inhibit TXA2 production by
  inhibiting irreversibly COX-1 acetylation (at
  serine-530)
• After oral intake, platelets are exposed to
  relatively high concentration of ASA in the
  portal circulation
• Antiplatelet activity is achieved at low dose of
  ASA than that required for analgesia or
  endothelial PGI2 production?

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Aspirin Antiplatelet Efficacy1- Dose

• Inhibition of 90 to 95 of TXA2 levels is needed
  to abolish in vitro platelet aggregation
• Given over a period of days, this level of
  inhibition can be achieved with doses as low as
  20 mg
• In volunteer subjects, a dose of 80 mg can
  inhibit aggregation as soon as 15 minutes after
  ingestion in the unstable patient, however, in
  whom absorption is more likely to be a problem
  and in whom circulating platelets are more likely
  to be activated
• Most authorities recommend initial therapy with a
  dose of 160 mg (one half-tablet) to 325 mg (one
  adult tablet)
• The aspirin should be crushed/chewed to
  facilitate absorption
• The frequency of gastrointestinal complications
  appears to be dose-dependent
• Aspirin prolongs bleeding time, risk of hemorrhage

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Aspirin Antiplatelet Efficacy

• A, Efficacy of aspirin in patients with unstable
  angina
• Studies have demonstrated reductions in morbid
  ischemic events in patients with unstable angina
  following the ingestion of aspirin using varying
  doses of aspirin and varying periods between the
  onset of symptoms and treatment with aspirin
• B. Efficacy of aspirin in patients following
  acute MI
• Analysis of 10 trials of antiplatelet agents
  (mainly aspirin) for secondary prophylaxis of
  vascular events following acute MI, the
  Antiplatelet Trialists Collaboration reported
  striking reductions in nonfatal MI and nonfatal
  stroke in patients treated chronically with
  antiplatelet therapy (n18,441) as well as a
  highly significant reduction in cardiovascular
  mortality
• Similar reductions were seen for patients
  receiving antiplatelet therapy following stroke.
  There were no differences in effect between
  varying doses of aspirin

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II- Glycoprotein IIb/IIIa Receptor Antagonists1-
Glycoprotein IIb/IIIa murine-derived 7E3 Fab
monoclonal antibody (Abciximab)

• Abciximab is composed of 7E3 Fab fragments a
  murine-derived (m) monoclonal antibody directed
  against glycoprotein GPIIb/IIIa.
• Mechanism The m7E3 Fab binds selectively to the
  glycoprotein GPIIb/IIIa receptors inhibiting
  platelets binding to fibrinogen and von
  Willebrand factor, and consequently inhibiting
  platelet aggregation
• Clinical Efficacy In acute MI patients, when the
  m7E3 Fab antibody was administered 3, 6, or 15
  hours after beginning treatment with rt-PA, the
  incidence of recurrent ischemia was lower than
  expected

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II- Glycoprotein IIb/IIIa Receptor Antagonists1-
Glycoprotein IIb/IIIa murine-derived 7E3 Fab
monoclonal antibody (Abciximab)

• Administration and therapeutic use Abciximab is
  administered intravenously as an adjuvant to
  angioplasty surgery for the prevention of
  ischemic complications of angioplasty
• Heparin or aspirin is given with abciximab
• Blockade of glycoprotein IIb/IIIa receptors
  following a bolus injection of c7E3 Fab (0.25
  mg/kg)
• Although the plasma half-life of this monoclonal
  antibody is only several minutes, a potent
  biologic effect can be measured 2 hours after the
  injection
• In patients undergoing elective angioplasty, at
  this point, more than 80 of receptors are bound
  by the antibody (and therefore unable to
  participate in aggregation). At 6 hours, between
  60 and 70 of receptors are bound, and at 24
  hours, 50 are bound
• In patients undergoing thrombolysis for acute MI,
  the return toward baseline occurs more rapidly. A
  continuous infusion leads to sustained blockade
  of the receptor

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II- Glycoprotein IIb/IIIa Receptor Antagonists
2- Synthetic arginine-glycine-aspartic acid
(R-G-D) sequence mimetics

• Eptifibatide (peptidergic) and tirofiban
  (non-peptiic) are synthetic mimetics of the R-G-D
  sequence of fibrinogen
• Hence, they block the binding of fibrinogen to
  glycoprotein GPIIb/IIIa receptors
• They are given intravenously for the reduction of
  thrombotic complications during coronary
  angioplasty
• Clinical trials showed reductions in incidence of
  death and non-fatal MI in response to the use of
  both agents

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III- Thromboxane Antagonists

• Ridogrel is a combined thromboxane synthase
  inhibitor and thromboxane A2 (TXA2) receptor
  antagonist, orally active
• It has no effect on the vascular production of
  prostacyclin but cyclic endoperoxides (PGH2) may
  increase
• In the Ridogrel Aspirin Perfusion Trial (RAPT),
  patients received either ridogrel or aspirin
  (initially given IV then orally) IV
  streptokinase for acute MI
• In both groups of patients inhibition of TXA2 was
  markedly inhibited, but recurrent ischemic events
  (angina, reinfarction, and ischemic stroke) were
  observed less frequently among the
  ridogrel-treated patients

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IV- Platelet ADP Receptor Antagonists
(Thienopyridines) Ticlopidine Clopidogrel

• They inhibit irreversibly ADP binding to
  receptors
• Prevent ADP-mediated activation of the
  glycoprotein GPIIb/IIIa ultimately inhibiting
  platelet aggregation
• No effect on PGs synthesis
• In the small percentage of patients who are truly
  aspirin-intolerant, ticlopidine should be
  considered as an alternative form of therapy

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Ticlopidine ClopidogrelAdverse Effects

• Ticlopidine is associated with more side effects
  than Clopidogrel
• Nausea, dyspepsia, diarrhea (20 of patients)
• Hemorrahge (5)
• Leukopenia in 1 of patients (most serious),
  check WBC in the first 3 months of treatment
• Ticlopidine, but not, clopidogrel can lead to
  fatal neutopenia
• Thrombotic thrombocytopenic purpura may occur
  with both agents

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Other Antiplatelet Agents

• Dipyridamole, inhibits phosphodiesterase activity
  and inhibit adenosine uptake
• It is weak antiplatelet vasodilator
• If used, should be combined with aspirin
• Cliostazol is another PD inhibitor used for
  intermittent claudication

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Antiplatelet Drugs
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Overview of Antiplatelets