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GP IIb/IIIa InhibitorsGP IIb/IIIa Inhibitors

-Kiran sotang -Kiran sotang

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• GP IIb IIIa antagonist are a new class of potent platelet GP IIb IIIa antagonist are a new class of potent platelet aggregation inhibitor which act by blocking key receptor aggregation inhibitor which act by blocking key receptor involved in platelet aggregation .involved in platelet aggregation .

• The GP IIa IIIa inhibitor is an adhesive receptor for The GP IIa IIIa inhibitor is an adhesive receptor for fibrinogen and vWF fibrinogen and vWF through which agonist like through which agonist like collagen , collagen , thrombus TXA2 , ADPthrombus TXA2 , ADP, , etc , induce platelet aggregation . etc , induce platelet aggregation .

• Thus GP IIb IIIa antagonist block aggregation induced by all Thus GP IIb IIIa antagonist block aggregation induced by all platelet agonist. platelet agonist.

GP IIb/IIIa Inhibitors

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GP IIb/IIIa InhibitorsGP IIb/IIIa Inhibitors

  GGlycoprotein IIb/IIIa inhibitorslycoprotein IIb/IIIa inhibitors, also , also GpIIb/IIIa GpIIb/IIIa inhibitorsinhibitors, is a class of , is a class of antiplatelet agents..

Several GpIIb/IIIa inhibitors exist:Several GpIIb/IIIa inhibitors exist:

abciximab (ReoPro) (ReoPro)

eptifibatide (Integrilin) (Integrilin)

tirofiban (Aggrastat) (Aggrastat)

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UseUse

• Glycoprotein IIb/IIIa inhibitors are frequently used during Glycoprotein IIb/IIIa inhibitors are frequently used during percutaneous coronary intervention ( (angioplasty with or  with or without intracoronary stent placement).without intracoronary stent placement).

They work by preventing They work by preventing platelet aggregation and  aggregation and thrombus formation. They do so by inhibition of the  formation. They do so by inhibition of the GpIIb/IIIa receptor  receptor on the surface of theon the surface of theplatelets..

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They may also be used to treat acute coronary syndromes, without percutaneous coronary intervention, depending on TIMI risk.

They should be given intravenously. The oral form is associated with increased mortality and hence should not be given.

In integrin nomenclature glycoprotein IIb/IIIa is called αIIbβ3

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Atherosclerosis

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AbciximabAbciximab

It is fab fragment of a chimeric monoclonal antibody It is fab fragment of a chimeric monoclonal antibody against GP II b IIIa .against GP II b IIIa .

Given along with aspirin + heparin during PCI it is Given along with aspirin + heparin during PCI it is markely reduce the incidence of restenosis subsequent markely reduce the incidence of restenosis subsequent MI and dead . MI and dead .

After a bolus dose platelet aggregation remain inhibitor After a bolus dose platelet aggregation remain inhibitor for 12-24 hr , while the remaining antibody is cleared for 12-24 hr , while the remaining antibody is cleared from blood with a t ½ of 10 – 30 min. from blood with a t ½ of 10 – 30 min.

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Abciximab risk. Abciximab risk.

1 .The main risk is hemorrhage , incidence of which can be 1 .The main risk is hemorrhage , incidence of which can be reduced by carefully managing the concomitant heparin reduced by carefully managing the concomitant heparin therapy .therapy .

2 .Thrombocytopenia is another complication . 2 .Thrombocytopenia is another complication . 3 . Constipation , 3 . Constipation , 4 . ileus and 4 . ileus and 5 . arrhythmias can occur . 5 . arrhythmias can occur .

It is very expensive , but is being used in unstable angina and It is very expensive , but is being used in unstable angina and as adjuvant to coronary thrombolysis /PCI with stent as adjuvant to coronary thrombolysis /PCI with stent placement placement

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ADMIRALADMIRALAbciximab before Direct angioplasty and stenting Abciximab before Direct angioplasty and stenting

in Myocardial Infarction Regarding Acute and in Myocardial Infarction Regarding Acute and Long-term follow-upLong-term follow-up

EventEvent *Abciximab*Abciximab PlaceboPlacebo(n=150)(n=150) (n=150) (n=150) PP

Death, MI, urgent Death, MI, urgent TVR at 30 dTVR at 30 d 10.7%10.7% 20.0%20.0% 0.030.03

TIMI-3 initialTIMI-3 initial 21%21% 10%10%<0.01<0.01

24 h24 h 86%86% 78%78%<0.03<0.03

LVEFLVEF 24 h24 h 55%55% 51%51%

30 d30 d 63%63% 55%55%

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TirofibanTirofiban

• TirofibanTirofiban ( (INN, trade name , trade name AggrastatAggrastat) is an ) is an antiplatelet drug. .

• It belongs to a class of antiplatelet named It belongs to a class of antiplatelet named glycoprotein IIb/IIIa inhibitors..

• Tirofiban is the first drug candidate whose origins can be Tirofiban is the first drug candidate whose origins can be traced to a traced to a pharmacophore-based -based virtual screening lead

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The drug is marketed under the brand name AGGRASTAT in The drug is marketed under the brand name AGGRASTAT in the US by the US by Medicure Pharma and the rest of the world by and the rest of the world by Irokocardio International SARL, Geneva..

It is sold in It is sold in parenteral dosage forms intended and readily dosage forms intended and readily constituted for constituted for IV administration containing 5 mg or 12.5 mg, administration containing 5 mg or 12.5 mg, respectively.respectively.

Tirofiban has a rapid onset and short duration of action after Tirofiban has a rapid onset and short duration of action after proper IV administration. Coagulation parameters turn to proper IV administration. Coagulation parameters turn to normal 4 to 8 hours after the drug is withdrawn.normal 4 to 8 hours after the drug is withdrawn.

****It is a modified version of an anticoagulant found in the venom of the saw-It is a modified version of an anticoagulant found in the venom of the saw-scaled viper scaled viper Echis carinatus

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Dosage regimenDosage regimen

Tirofiban is initially given as rapid Tirofiban is initially given as rapid intravenous infusion at a rate of 0.4 µg/kg and minute for 30 minutes. at a rate of 0.4 µg/kg and minute for 30 minutes.

Upon completion of the initial infusion, the rate is decreased to Upon completion of the initial infusion, the rate is decreased to 0.1 µg/kg and minute delivered as continuous infusion.0.1 µg/kg and minute delivered as continuous infusion.

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Duration of therapyDuration of therapy

Patients who do not show any signs of recurrent Patients who do not show any signs of recurrent ischemic symptoms and do not undergo symptoms and do not undergo angiography and and angioplasty should be treated for at least 48 hours.should be treated for at least 48 hours.

Patients proceeding into angiography and angioplasty should Patients proceeding into angiography and angioplasty should continue throughout both procedures and for at least 12 hours, continue throughout both procedures and for at least 12 hours, and not more than 24 hours after angioplasty. and not more than 24 hours after angioplasty.

Once a patient is clinically stable and no further coronary Once a patient is clinically stable and no further coronary intervention is planned by the treating physician, the infusion intervention is planned by the treating physician, the infusion should be discontinuedshould be discontinued

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Contraindications and precautionsContraindications and precautions

* hypersensitivity * hypersensitivity * internal bleeding * internal bleeding * * intracranial hemorrhage or neoplasm, or neoplasm, * * arteriovenous malformation, or , or aneurysm * * thrombocytopenia * platelet disorder * platelet disorder * * hemorrhagic stroke* major * major surgical procedure * or severe physical * or severe physical trauma * * aortic dissection * * hypertension* acute * acute pericarditis* * cirrhosis or other clinically significant or other clinically significant liver disease

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Reference;^ Hartzman, G.D.; Egbertson, M.S.; Halczenko, W.; Laswell, W.L.; Hartzman, G.D.; Egbertson, M.S.; Halczenko, W.; Laswell, W.L.;

Duggan, M.E.; Smith, R.L.; Naylor, A.M.; Manno, P.D.; Lynch, R.J.; Zhang, G.; Duggan, M.E.; Smith, R.L.; Naylor, A.M.; Manno, P.D.; Lynch, R.J.; Zhang, G.; Chang, C. T.-C.; Gould, R.J. (1992). "Non-Peptide Fibrinogen Receptor Antagonists. 1. Chang, C. T.-C.; Gould, R.J. (1992). "Non-Peptide Fibrinogen Receptor Antagonists. 1. Discovery and Design of Exosite Inhibitors". Discovery and Design of Exosite Inhibitors". Journal of Medicinal Chemistry (American Chemical Society) 35 (24): 4640–4642. doi:10.1021/jm00102a020. (American Chemical Society) 35 (24): 4640–4642. doi:10.1021/jm00102a020. PMID 1469694.  ^ Van Drie, John H. (2007). "Computer-aided drug design: the next 20 PMID 1469694.  ^ Van Drie, John H. (2007). "Computer-aided drug design: the next 20 years". years". J. Comput Aided Mol DesJ. Comput Aided Mol Des (Springer) 21 (10–11): 591–601. doi:10.1007/s10822- (Springer) 21 (10–11): 591–601. doi:10.1007/s10822-007-9142-y. PMID 17989929. http://www.springerlink.com/content/e2180556p4722000/. 007-9142-y. PMID 17989929. http://www.springerlink.com/content/e2180556p4722000/. Retrieved 2008-06-23.  ^ "Saw-Scaled Vipers". University of Edinburgh. Retrieved 2008-06-23.  ^ "Saw-Scaled Vipers". University of Edinburgh. http://www.portfolio.mvm.ed.ac.uk/studentwebs/session2/group13/vipers.html. http://www.portfolio.mvm.ed.ac.uk/studentwebs/session2/group13/vipers.html. Retrieved 2008-06-23.Retrieved 2008-06-23.

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TIGER- PATIGER- PA

• Tirofiban Given in the Emergency Room Tirofiban Given in the Emergency Room Before Primary AngioplastyBefore Primary Angioplasty

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TIGER-PATIGER-PAPilotPilot

• GoalsGoals

– To test the safety and efficacy of tirofiban in To test the safety and efficacy of tirofiban in the setting of an acute MIthe setting of an acute MI

– To compare early adjunctive use of tirofiban To compare early adjunctive use of tirofiban before primary PCI with peri-PCI usebefore primary PCI with peri-PCI use

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TIGER-PATIGER-PAPilotPilot

• DosingDosing

– Tirofiban: 10 µg/kg over 3 minutes, Tirofiban: 10 µg/kg over 3 minutes, then 0.15 µg/kg/min x 24 hoursthen 0.15 µg/kg/min x 24 hours

– HeparinHeparin

• Early: 70 U/kg IV bolus, then 7.5 U/kg/hEarly: 70 U/kg IV bolus, then 7.5 U/kg/h

• Delayed: 100 U/kg IV bolus, then 10 U/kg/hDelayed: 100 U/kg IV bolus, then 10 U/kg/h

– All other medications including NTG, All other medications including NTG, -blockers at the investigator’s discretion-blockers at the investigator’s discretion

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30-day MACE include 1 patient in each group admitted for 30-day MACE include 1 patient in each group admitted for chest pain and 1 patient who had SAT and repeat PCI at chest pain and 1 patient who had SAT and repeat PCI at

6 days in the cath lab group with no deaths.6 days in the cath lab group with no deaths.

TIGER-PATIGER-PAPilotPilot

• ComplicationsComplications

ERER Cath LabCath Lab

Minor bleedingMinor bleeding 44 22

Major bleedingMajor bleeding 11 11

30 d MACE30 d MACE 11 22

INTERIMINTERIM

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TIGER-PATIGER-PA

• SummarySummary

– Pilot study to determine safety and efficacy of Pilot study to determine safety and efficacy of tirofiban given in the ER before primary PTCAtirofiban given in the ER before primary PTCA

– ****Tirofiban given early in the ER may lead to further Tirofiban given early in the ER may lead to further improvement in TIMI flow and frame count compared improvement in TIMI flow and frame count compared with tirofiban given in the cath labwith tirofiban given in the cath lab

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SummarySummary

• GP IIb/IIIa receptor inhibitors may be GP IIb/IIIa receptor inhibitors may be beneficial as an adjunct in acute MIbeneficial as an adjunct in acute MI

• Safe and well toleratedSafe and well tolerated

• Further large-scale trials are needed to Further large-scale trials are needed to better delineate a long-term benefitbetter delineate a long-term benefit

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Eptifibatide(Integrilin)Eptifibatide(Integrilin)

Eptifibatide is an antiplatelet drug of theEptifibatide is an antiplatelet drug of the gp IIb/IIIa inhibitor class. gp IIb/IIIa inhibitor class.

****Eptifibatide is a cyclic heptapeptide derived fromEptifibatide is a cyclic heptapeptide derived from a protein found in the venom of the southeastern pygmy a protein found in the venom of the southeastern pygmy rattlesnake (Sistrurus miliarius barbouri).rattlesnake (Sistrurus miliarius barbouri).

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IndicationsIndications Cardiac ischemic events Cardiac ischemic events myocardial infarctionmyocardial infarctionunstable angina unstable angina percutaneous coronary intervention (PCI).percutaneous coronary intervention (PCI).

The drug is always applied together with aspirin or clopidogrel and (low The drug is always applied together with aspirin or clopidogrel and (low molecular weight or unfractionated) heparin. molecular weight or unfractionated) heparin.

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Contraindications and precautionsContraindications and precautions

* Thrombocytopenia .* Thrombocytopenia .* Renal insufficiency .* Renal insufficiency .* Current bleeding tendencies * Current bleeding tendencies * Coagulation parameters such as ACT, aPTT, TT, and PT should * Coagulation parameters such as ACT, aPTT, TT, and PT should be followed closely during therapy and afterwards.be followed closely during therapy and afterwards.* Allergy * Allergy * Severe, uncontrolled hypertension.* Severe, uncontrolled hypertension.

* Pediatric patients : Eptifibatide is not indicated in patients below * Pediatric patients : Eptifibatide is not indicated in patients below 18 years of age, because no experience exists.18 years of age, because no experience exists.

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Dosage regimen Dosage regimen

The recommended adult dosage is an i.v. The recommended adult dosage is an i.v. - of 180 µg/kg over 1 to 2 minutes{ - of 180 µg/kg over 1 to 2 minutes{immediately after diagnosisimmediately after diagnosis},},

- 2 µg/kg per minute until either hospital discharge or - 2 µg/kg per minute until either hospital discharge or initiation of coronary artery bypass grafting, or for up to 72 initiation of coronary artery bypass grafting, or for up to 72 hours. hours.

At least 4 hours before discharge all local or systemic bleedings At least 4 hours before discharge all local or systemic bleedings should have been controlled and terminated. should have been controlled and terminated.

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REFERENCE;REFERENCE;

^ Gordon W. Gribble (15 December 2010). ^ Gordon W. Gribble (15 December 2010). Heterocyclic Scaffolds II: Indoles: Synthesis, Heterocyclic Scaffolds II: Indoles: Synthesis, Properties and ApplicationsProperties and Applications. Springer. pp. 11–. ISBN 9783642157325. . Springer. pp. 11–. ISBN 9783642157325. http://books.google.com/books?id=srxzzUskq4wC&pg=PA11. Retrieved 12 November http://books.google.com/books?id=srxzzUskq4wC&pg=PA11. Retrieved 12 November 2010. 2010. AHFS Database OnlineAHFS Database OnlineArzneimittel Datenbank (in German)Arzneimittel Datenbank (in German)http://www.pharmazeutische-zeitung.de/index.php?id=352&type=0 (in German)http://www.pharmazeutische-zeitung.de/index.php?id=352&type=0 (in German)http://www.chemsoc.org/chembytes/ezine/1999/berressem_apr99.htm (information on http://www.chemsoc.org/chembytes/ezine/1999/berressem_apr99.htm (information on the biological origin of eptifibatide)the biological origin of eptifibatide)

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