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antiplatelet

antiplatelet agents

aspirin

  • see aspirin (acetylsalicylic acid) (acetylsalicylic acid)
  • It inhibits platelets by irreversibly covalently acetylating the active site of cyclooxygenase which is the enzyme that produces the cyclic endoperoxide precursor of thromboxane A2.
  • Since platelets do not synthesise new proteins, this action is permanent, lasting the life of the platelet (7-10days).
  • Repeated doses produce a cumulative effect on platelet function.
  • Complete inactivation is achieved when 160mg is taken daily.
  • 300mg is given to be chewed in a single dose as early as possible in pts with AMI.
  • Higher doses do not improve efficacy but increase bleeding & produce aspirin's other actions.

irreversible adenosine diphosphate P2Y12 receptor antagonists

clopidogrel

  • a thienopyridine derivative structurally related to ticlodipine
  • prevents ADP-mediated activation of GP IIb/IIIa complex and thus prevents platelet aggregation.

ridogrel:

  • Combined thromboxane A2 synthase inhibitor & endoperoxide blocker;

prasugrel:

  • same class as clopidogrel, introduced in Australia in 2009 as Effient
  • fewer non-fatal MI's but more serious bleeds than clopidogrel
  • adult dose:
    • usual dose: 60 mg loading dose, then 10 mg once daily maintenance.
    • weight < 60 kg: 60 mg loading dose, then 5 mg once daily maintenance.
    • elderly >= 75 yrs: 60 mg loading dose, then consider 5 mg once daily maintenance.
    • endstage renal disease, Asian patients, galactose intolerance: monitor closely

reversible adenosine diphosphate P2Y12 inhibitor

ticagrelor

  • marketed in Australia in 2011 as Brilinta 90mg tablets
  • give with aspirin 75-150 mg/day.
  • adult dose:
    • 180 mg loading dose, then 90 mg twice daily;
    • switching from clopidogrel: give 90 mg 24 hrs after last clopidogrel dose

GP IIb/IIIa receptor antagonists:

  • GP IIb/IIIa blockers refer to drugs that block the integrin receptor alphaIIIbbeta3 which normally binds to glycoprotein GP IIb/IIIa, thereby inhibiting platelet aggregation without compromising platelet adhesion to the subendothelial matrix, thereby reducing risk of bleeding whilst still providing anti-platelet activity.

ticlopidine:

  • A thienopyridine that inhibits platelet function by inducing a thrombasthenia-like state.
  • It interacts with platelet glycoprotein IIb/IIIa in an unknown way to inhibit the binding of fibrinogen to activated platelets. It thus inhibits platelet aggregation & clot retraction & prolongs bleeding time.

Abciximab:

  • 1st agent used in humans acting specifically on the platelet GP IIb/IIIa receptor
  • monoclonal Fab fragments (IV use only)
  • EPIC trial: compared with placebo, 41% reduction in composite endpoint of AMI, death, urgent revascularisation at 30 days in high risk pts undergoing PTCA
    • ⇒ approved by FDA for Rx of pts undergoing high-risk PTCA
  • subsequent trials: EPILOG, CAPTURE

IV non-Fab agents:

  • research drugs only but all have shown a class effect in reducing mortality in PTCA & acute coronary syndromes, with a 0.1-0.5% risk of developing severe thrombocytopenia < 20,000/uL.
  • integrilin (a peptide)
  • tirofiban
  • lamifiban

oral agents:

  • sibrafiban

older agents

dipyridamole (Persantin):

  • 1st used in IHD as known to have a potent coronary vasodilator effect without increasing oxygen consumption. It was later shown to also exert a direct effect on cell metabolism as it protects sarcomeres from hypoxic damage & has a beneficial effect on ATP synthesis, & delays the deamination of adenosine.
  • It interferes with platelets by increasing cellular c-AMP via inhibition of cyclic nucleotide phosphodiesterase &/or by blockade of uptake of adenosine, which acts at A2 receptors & stimulates adenylyl cyclase.
  • But its prime action that seems to be beneficial in IHD is its reduction in platelet aggregation & hence antithrombotic activity.
  • By itself, it has little anti-thrombotic activity but when used with:
    • warfarin it inhibits emboli from prosthetic heart valves this remains its only current recommended use.
    • aspirin (acetylsalicylic acid) it reduces thrombosis in pts with thrombotic diseases BUT the Antiplatelet Trialists Collaboration in 1988 showed that it was not of any additional benefit cf aspirin alone.
antiplatelet.txt · Last modified: 2014/12/16 16:23 (external edit)