Pharmacology of Antiplatelet Agents

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Pharmacology of Antiplatelet Agents

• DMED 514

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Platelets in the Circulation
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Platelet Plug Formation

• 3 Stages
• Adhesion platelets recognize von Willebrand
  Factor and bind to endothelium
• Activation newly bound platelets recruit other
  platelets to site of injury
• Aggregation soluble fibrinogen recognized by
  activated platelets platelets are crosslinked

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Normal Platelet Morphology
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Morphology Change and Aggregation
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Stages in Platelet Aggregation
Resting
Adhesion
Aggregation
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Platelet Activation
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Factor Release by Platelets
Stimuli
Platelets release
MMP-2
TXA2
ADP
GPIIb/IIIa, GPIb
AGGREGATION
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Proaggregatory substances

• 1. Collagen, adrenaline, thrombin
• 2. ADP, PGD2, PGE2.
• 3. cAMP TXA2

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Aggregation-Inhibitory Pathways
MMP-9
INHIBIT
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Antiaggregatory substances

• PGI2,
• PGI3,,
• TXA3,
• NO

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• Drugs Used to Prevent Platelet Aggregation

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ASA (Acetylsalicylic acid)

• Indications
• Stroke and MI prevention
• Low dose (50mg) once daily
• Adverse reactions Bleeding
• Contraindications Other NSAIDS
• Warfarin interactions

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Dipyridamole

• Blocks adenosine uptake into RBCs
• Prolongs adenosine in plasma.
• May block phosphodiesterase in platelet
• Used as a slow release preparation in conjunction
  with ASA

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Dipyridamole II

• Superior to ASA (or dipyridamole) alone
• Indications-
• Stroke prevention.
• (MI rates not affected)

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Ticlopidine

• Binds to low affinity type 2 ADP receptor
• Prevents activation of GPIIb/IIIa receptors
• No binding of fibrinogen or platelet aggregation.
• No effect on shape change or calcium influx.
• May interfere with von Willebrand factor binding
  to GP Ib receptors
• Prodrug metabolized to unknown active metabolites

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Ticlopidine

• Indications
• Stroke and transient ischemic attack
• coronary stents, unstable angina
• Adverse effects
• Bleeding
• Neutropenia (2.4 patients, 0.9 severe)
• Diarrhea

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Clopidogrel

• Pro-drug requiring metabolic conversion to active
  species (not identified)
• Irreversible binding to ADP receptors on
  platelets - platelet permanently inactivated.
• Better than ASA at protecting from stroke or M.I.
  (just!)

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Clopidogrel II

• Adverse effects
• Bleeding episodes (no evidence of neutropenia or
  thrombotic thrombocytopenia purpura)
• Contraindications
• Hypersensitivity
• Bleeding and ulcers
• Liver impairment

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EPA (Eicosapentaenoic acid) (??-3 fatty acid)
Two series of non-interchangeable essential fatty
acids. Arachidonic acid precursor of TXA2 and
PGI2 belongs to ?-6 series. Membrane
phospholipids accept members of either series
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EPA (Eicosapentaenoic acid) (??-3 fatty acid) II

• Use as a dietary supplement
• Up to 5 G per day.
• Do not use fish liver oils risk of Vitamin A
  overdose.
• Fish oils other than liver are acceptable

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GPIIb/IIIa Receptor Blockers

• Largely in development and unpronounceable (also
  expensive).
• Abciximab (antibody given iv) for unstable angina
  and percutaneous coronary intervention (e.g.
  baloon angioplasty) in cases resistant to
  conventional therapy.
• Eptifibatide (analogue of peptide sequence at
  terminal of delta chain of fibrinogen) used as
  for abciximab.
• Tirobifan (contains Arg-Gly-Asp sequence
  recognized by GPIIb/IIIa receptor) used as for
  other two

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Future Directions

• There are many pathways that converge on the
  event of platelet aggregation
• Not all have been investigated for therapeutic
  potential
• Among the most promising are the protease
  activated receptors (PARs)
• PARs are linked to pro-aggregatory pathways and
  activated by thrombin.

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(No Transcript)
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Protease Activated Receptors

• Thrombin is an extracellular protease.
• The protease activated receptors PAR1 and PAR4
  are cellular targets of thrombin signaling and
  members of the G-protein coupled receptor gene
  family.
• Both of these receptors are cleaved in their
  N-terminus by thrombin, unmasking a portion of
  the receptor sequence that acts itself as a
  tethered peptide ligand to activate the receptor.
  
• The tethered ligand that activates PAR1 is SFLLRN
  and the tethered ligand that activates PAR4 is
  GYPGQV.
• Would PAR antagonists work?

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Protease Activated Receptors
Hirudin-like binding domain
Cleavage site
PAR-1 ESKATNATLDPR SFLLRN PN
DKYEPFWEDEEKNES PAR-2 GTNRSSKGR
SLIGKV DG PAR-3 NDTNNLAKPTLPIK TFRGAP PNS
FEEEP FSALE PAR-4 LPAPR
GYPGQV CANDSDTLELPDSS
Tethered ligand
LOOP 2
NH2
EXTRACELLULAR
Cell membrane
INTRACELLULAR
COOH
Only PAR-1 and PAR-4 are expressed by human
platelets