Pharmacokinetics and pharmacodynamics of glycoprotein IIb-IIIa inhibitors

doi:10.1053/hj.1999.v138.a100459

American Heart Journal

Volume 138, Issue 4, Supplement, October 1999, Pages S263-S275

https://doi.org/10.1053/hj.1999.v138.a100459 Get rights and content

Abstract

Antagonists of the platelet receptor glycoprotein (GP) IIb-IIIa are a novel class of antithrombotic agents that provide more comprehensive platelet blockade than the combination of aspirin and heparin. Studies in patients scheduled for percutaneous coronary intervention and those with unstable angina or non–Q-wave myocardial infarction have shown that a combination of intravenous GP IIb-IIIa inhibitors with aspirin and heparin is associated with a reduction in death or myocardial infarction compared with therapy with aspirin and heparin alone. As with other antithrombotic agents, the principal safety issue with GP IIb-IIIa inhibitors is bleeding, because the potent antiplatelet effect of these drugs may adversely affect hemostasis. Increased risk of hemorrhage is of particular concern for patients who subsequently require emergency or urgent bypass surgery because the rate of bleeding complications in these patients is considerable even in the absence of prior GP IIb-IIIa therapy. Additionally, antagonists of GP IIb-IIIa may increase the risk of thrombocytopenia. The safety profiles of various GP IIb-IIIa inhibitors are largely a function of their pharmacokinetic and pharmacodynamic properties, most notably the reversibility of platelet inhibition and the rate of plasma clearance. Knowledge of the pharmacokinetic and pharmacodynamic properties of the GP IIb-IIIa inhibitors is critical for the appropriate utilization of this new class of drugs. (Am Heart J 1999;138:S263-S275.)

Section snippets

Template bleeding times

Profound platelet blockade with GP IIb-IIIa antagonists is likely to limit the formation of hemostatic plugs and thus increase the potential for hemorrhage. For a long time, it had been assumed that the risk of clinically significant bleeding events could be predicted on the basis of prolongation of the Ivy template bleeding time. Recent evidence, however, does not support this view. In a meta-analysis of 18 trials encompassing more than 3300 patients, a correlation between bleeding time and

Abciximab: Binding characteristics and specificity

Abciximab was the first GP IIb-IIIa inhibitor to be evaluated in large-scale clinical trials. The mechanism of the GP IIb-IIIa binding of abciximab is qualitatively different from that used by peptides containing the RGD sequence (see above) and small-molecule GP IIb-IIIa inhibitors, whose design was based on the RGD sequence. Whereas all these ligands attach to a single discrete pocket on the heterodimeric GP IIb-IIIa and their binding is therefore mutually exclusive, the interaction between

Conclusions

Pharmacokinetic and pharmacodynamic evaluations of various GP IIb-IIIa inhibitors have focused on the identification of dosing regimens that would provide significant clinical benefits while minimizing safety concerns. Studies detailing the pharmacokinetic properties of the various GP IIb-IIIa antagonists have been performed in a relatively healthy group of patients; however, it may be expected that clearance of these agents will be altered in critically ill patients.

Preclinical experiments

References (68)

AM Lincoff et al.
Standard versus low-dose weight-adjusted heparin in patients treated with the platelet glycoprotein IIb/IIIa receptor antibody fragment abciximab (c7E3 Fab) during percutaneous coronary revascularization
Am J Cardiol
(1997)
MM Bernardi et al.
Lack of usefulness of prolonged bleeding times in predicting hemorrhagic events in patients receiving the 7E3 glycoprotein IIb/IIIa platelet antibody
Am J Cardiol
(1993)
DN Bell et al.
Extracellular-free Ca++ accounts for the sex difference in the aggregation of human platelets in citrated platelet-rich plasma
Thromb Res
(1990)
K Fujimura et al.
Calcium cation regulation of glycoprotein IIb-IIIa complex formation in platelet plasma membranes
J Biol Chem
(1983)
DR Phillips et al.
The platelet membrane glycoprotein IIb-IIIa complex
Blood
(1988)
GA Marguerie et al.
Interaction of fibrinogen with its platelet receptor as part of a multistep reaction in ADP-induced platelet aggregation
J Biol Chem
(1980)
DD Hu et al.
An allosteric Ca2+ binding site on the β₃-integrins that regulates the dissociation rate for RGD ligands
J Biol Chem
(1996)
DD Hu et al.
Ca2+ suppresses cell adhesion to osteopontin by attenuating binding affinity for integrin α_vβ3
J Biol Chem
(1995)
SE D’Souza et al.
Ligand and cation binding are dual functions of a discrete segment of the integrin β₃ subunit: cation displacement is involved in ligand binding
Cell
(1994)
RA Harrington et al.
Immediate and reversible platelet inhibition after intravenous administration of a peptide glycoprotein IIb/IIIa inhibitor during percutaneous coronary intervention
Am J Cardiol
(1995)

T-K Vu et al.

Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation

Cell

(1991)

NS Kleiman et al.

Differential inhibition of platelet aggregation induced by adenosine diphosphate or a thrombin receptor-activating peptide in patients treated with bolus chimeric 7E3 Fab: implications for inhibition of the internal pool of GP IIb/IIIa receptors

J Am Coll Cardiol

(1995)

BS Coller et al.

Inhibition of dog platelet function by in vivo infusion of F(ab’)2 fragments of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor

Blood

(1985)

TH Mondoro et al.

Selective induction of a glycoprotein IIIa ligand-induced binding site by fibrinogen and von Willebrand factor

Blood

(1996)

BR Alevriadou et al.

Real-time analysis of shear-dependent thrombus formation and its blockade by inhibitors of von Willebrand factor binding to platelets

Blood

(1993)

JM Ross et al.

Platelet adhesion and aggregation on human type VI collagen surfaces under physiological flow conditions

Blood

(1995)

DC Cardinal et al.

The electronic aggregometer: a novel device for assessing platelet behavior in blood

J Pharmacol Methods

(1980)

JS Gammie et al.

Abciximab and excessive bleeding in patients undergoing emergency cardiac operations

Ann Thorac Surg

(1998)

CP Juergens et al.

Routine platelet transfusion in patients undergoing emergency coronary bypass surgery after receiving abciximab

Am J Cardiol

(1997)

RM Scarborough et al.

Barbourin: a GP IIb-IIIa-specific integrin antagonist from the venom of Sistrurus m barbouri

J Biol Chem

(1991)

RM Scarborough et al.

Characterization of the integrin specificities of disintegrins isolated from American pit viper venoms

J Biol Chem

(1993)

DR Phillips et al.

Clinical pharmacology of eptifibatide

Am J Cardiol

(1997)

EPIC Investigators

Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty

N Engl J Med

(1994)

EPILOG Investigators

Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization

N Engl J Med

(1997)

EPISTENT Investigators

Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade

Lancet

(1998)

ER Burns et al.

Bleeding time: a guide to its diagnostic and clinical utility

Arch Pathol Lab Med

(1989)

GVR Born et al.

The aggregation of blood platelets

J Physiol (Lond)

(1963)

D Collen et al.

Antithrombotic effects and bleeding time prolongation with synthetic platelet GP IIb/IIIa inhibitors in animal models of platelet-mediated thrombosis

Thromb Haemost

(1994)

DR Phillips et al.

Effect of Ca2+ on GP IIb-IIIa interactions with integrilin: enhanced GP IIb-IIIa binding and inhibition of platelet aggregation by reductions in the concentration of ionized calcium in plasma anticoagulated with citrate

Circulation

(1997)

SS Rebello et al.

In vivo efficacy of SM-20302, a GP IIb/IIIa receptor antagonist, correlates with ex vivo platelet inhibition in heparinized blood but not in citrated blood

Arterioscler Thromb Vasc Biol

(1998)

RF Storey et al.

Differential effects of glycoprotein IIb/IIIa antagonists on platelet microaggregate and macroaggregate formation and effect of anticoagulant on antagonist potency: implications for assay methodology and comparison of different antagonists

Circulation

(1998)

J Kuzniar et al.

Pharmacodynamics of ticlopidine: relation between dose and time of administration to platelet inhibition

Int J Clin Pharmacol Ther

(1996)

G DiMinno et al.

Functionally thrombasthenic state in normal platelets following the administration of ticlopidine

J Clin Invest

(1985)

Cited by (71)

Platelet physiology and pharmacology-relevant considerations for patient care
2021, Dual Antiplatelet Therapy for Coronary and Peripheral Arterial Disease
Platelets have an important role in the formation of hemostatic thrombi that develop at the site of vascular injury. However, pathologic activation of platelets can lead to obstructive thrombi resulting in clinical manifestations such as acute myocardial infarction, stroke, and acute limb ischemia. Therefore antiplatelet therapy has a key role in the treatment of cardiovascular disease manifestations. However, antiplatelet agents are associated with an increased risk of bleeding. Thus the ideal antiplatelet agent should have an optimal balance between safety and efficacy. Most recent studies have suggested that alternative regimens without aspirin (defined as “aspirin free”) to be associated with a better safety profile while preserving efficacy. This chapter provides an overview on platelet physiology and its implications for the development and use of antiplatelet therapies in patients with atherothrombotic disease manifestations.
The mechanisms of action of new antiplatelet agents. How do they work?
2014, Revista Espanola de Cardiologia Suplementos
El tratamiento convencional con ácido acetilsalicílico y clopidogrel (una tienopiridina) ha quedado superado por el uso de nuevos inhibidores del receptor P2Y₁₂ como prasugrel y ticagrelor. El prasugrel, al igual que toda tienopiridina, se administra oralmente e inhibe de manera irreversible el receptor, pero, pese a ser un profármaco, tiene un metabolismo más rápido y eficaz que el clopidogrel, lo que deriva en un mayor beneficio clínico. El ticagrelor (derivado nucleósido) proporciona un bloqueo reversible del receptor y no requiere bioactivación hepática, con lo que ofrece una rápida y potente inhibición plaquetaria. Además, el cangrelor y el elinogrel son dos compuestos en fase de desarrollo disponibles como formulaciones intravenosas que presentan un efecto directo, reversible y de mayor seguridad para los pacientes sometidos a cirugía coronaria. En los últimos años, de estos compuestos, y muy especialmente del ticagrelor, se han demostrado efectos beneficiosos más allá de la inhibición plaquetaria, los llamados efectos pleiotrópicos.
Conventional treatment with aspirin and the thienopyridine clopidogrel has been superseded by the introduction of novel P2Y₁₂ receptor blockers such as prasugrel and ticagrelor. Prasugrel, like all thienopyridines, is administered orally and is an irreversible inhibitor of the receptor. Despite being a prodrug, prasugrel is metabolized more rapidly and effectively than clopidogrel and consequently offers a greater clinical benefit. Ticagrelor is a nucleoside analog that reversibly blocks the receptor and does not require hepatic bioactivation, which makes it a rapid and potent platelet inhibitor. In addition, two other compounds under investigation –cangrelor and elinogrel– are available in intravenous formulations. They have a direct, reversible effect on the P2Y₁₂ receptor and appear to have a better safety profile in patients undergoing coronary surgery. In recent years, all these compounds, and in particular ticagrelor, have been shown to have other clinical benefits in addition to platelet inhibition – their so-called pleiotropic effects.
Basics of antithrombotic therapy for cardiovascular disease: Pharmacologic tlargets of platelet inhibitors and anticoagulants
2013, Interventional Cardiology Clinics
Citation Excerpt :
Overall, these findings do not support the use of upstream compared with selective downstream GP IIb/IIIa inhibition in patients with ACS undergoing PCI. Tirofiban is a nonpeptide, tyrosine-derived, highly selective inhibitor associated with a rapid onset, a short plasma half-life (about 2 hours) and a renal clearance ranging from 25% to 50%.52 The efficacy and safety of tirofiban in subjects with ACS-PCI have been investigated in several trials.65,66
Mechanisms of action of antiplatelet agents
2013, Revista Espanola de Cardiologia Suplementos
Las manifestaciones clínicas de la aterosclerosis, tales como los síndromes coronarios agudos, los eventos cerebrovasculares y la enfermedad arterial periférica, son las principales causas de morbimortalidad en el mundo. La activación y la agregación plaquetarias son, en última instancia, la causa de la progresión y las presentaciones clínicas de la enfermedad. Por ello, los antiagregantes plaquetarios son un pilar fundamental del tratamiento farmacológico de estos pacientes. Una amplia variedad de receptores de superficie tipo integrinas, familia rica en leucina, receptores acoplados a proteínas G y receptores de tirosincinasa, así como moléculas intraplaquetarias, desencadenan y regulan el proceso de activación/agregación plaquetaria. Todas estas moléculas son dianas potenciales de fármacos antiplaquetarios destinados a prevenir y tratar la trombosis arterial. A pesar del beneficio clínico obtenido con el ácido acetilsalicílico (inhibidor de la ciclooxigenasa), el clopidogrel (antagonista del receptor del ADP P2Y₁₂) y los antagonistas de la glucoproteína IIb/IIIa (abciximab, eptifibatida, tirofibán, lamifibán) al disminuir significativamente el riesgo de episodios aterotrombóticos, la morbimortalidad residual sigue elevada. Por ello los esfuerzos se centran en la búsqueda de nuevos tratamientos antiplaquetarios a fin de mejorar su efectividad y su seguridad. De hecho, nuevos fármacos están en fase de desarrollo y varios han llegado ya a uso clínico. Entre ellos están los nuevos inhibidores de los receptores P2Y₁₂ (prasugrel, ticagrelor, cangrelor y elinogrel), antagonistas del receptor PAR1 de la trombina (vorapaxar, atopaxar) y moléculas de señalización intraplaquetaria. Esta revisión profundiza en los mecanismos de acción del arsenal antiplaquetario actualmente en uso y las nuevas aproximaciones terapéuticas.
The clinical manifestations of atherosclerotic diseases such as acute coronary syndromes, cerebrovascular events and peripheral arterial disease are major causes of mortality and morbidity worldwide. Platelet activation and aggregation are ultimately responsible for the progression and clinical presentation of the disease and, therefore, antiplatelet agents have become one of the mainstays of pharmacological treatment of these patients. A wide variety of surface receptors such as integrin family receptors, receptors rich in Leucine, protein G linked transmembrane receptor, tyrosine kinase receptors as well as intraplatelet molecules, trigger and regulate platelet activation/aggregation. All these molecules are potential targets for antiplatelet drugs to prevent and treat arterial thrombosis. Despite the overall clinical benefit obtained with aspirin (cyclooxygenase inhibitor), clopidogrel (ADP receptor antagonist P2Y₁₂) and antagonists of the glycoprotein IIb/IIIa (abciximab, eptifibatide, tirofiban, lamifiban) to significantly reduce the risk of atherothrombotic events, residual morbidity and mortality remain high. Therefore efforts have focused on the search for new antiplatelet treatments to improve their effectiveness and safety. In fact, new drugs are in development and various drugs have already reached clinical use. Among them, new P2Y₁₂ receptor blockers (prasugrel, ticagrelor, cangrelor and elinogrel), antagonists of the PAR1 thrombin receptor (vorapaxar and atopaxar) as well as intraplatelet signaling molecules. This review explores the mechanisms of action of the currently used antiplatelet armamentarium as well as new therapeutic approaches.
Coronary stents: factors contributing to perioperative major adverse cardiovascular events
2010, British Journal of Anaesthesia
Citation Excerpt :
Tirofiban has a short half-life (2 h) and has been suggested to meet the ‘bridge therapy’ requirement.65–68 Four hours after tirofiban infusion is stopped, bleeding time returns to normal and platelet aggregation increases to 50% of normal function.67 69 The pharmacologic profile of cangrelor and ticagrelor (reversible, rapid onset, and short half-life) might also be attractive for perioperative use; these drugs are in various phases of pre-market testing.42 43
Patients with coronary stents undergoing non-cardiac surgery are at increased risk of major adverse cardiovascular events perioperatively. Impeccable patient care and communication between all members of the healthcare team will minimize this risk. The dominant risk factor for stent thrombosis and major adverse cardiovascular events is the interruption of dual antiplatelet therapy (e.g. aspirin and clopidogrel). If clopidogrel therapy has to be interrupted due to increased risk of bleeding, continuation of aspirin is strongly recommended to reduce the risk of stent thrombosis. The interval between percutaneous coronary interventions and operation is the next major risk factor for stent thrombosis. The incidence of major adverse cardiovascular events is inversely related to this interval, with the highest mortality rate occurring <30 days after stent implantation. Ideally, for patients with drug-eluting stents, elective surgery should be delayed for at least 1 yr and for patients with bare-metal stents, the recommended minimum period is 6 weeks. The use of a neuraxial anaesthetic technique must be carefully considered due to the risk of an epidural haematoma. Perioperative monitoring should focus on early recognition of myocardial ischaemia, infarction, or both. If stent thrombosis is present, rapid triage to an interventional catheterization laboratory is essential for restoration of coronary blood flow.
Perioperative Management of Patients With Drug-Eluting Stents
2010, JACC: Cardiovascular Interventions
Thrombosis of a drug-eluting stent (DES) is a catastrophic complication. The risk of stent thrombosis (ST) is increased in the perioperative setting and is strongly associated with the cessation of antiplatelet therapy. This article reviews the perioperative management of patients with DES with a clinical focus on the perioperative use of antiplatelet therapy. Cessation of dual antiplatelet therapy is the single most significant predictor of perioperative ST. Available data on perioperative management of patients with DES are limited, and recommendations are therefore limited. To avoid ST with DES, aspirin and thienopyridines should ideally be continued throughout surgery. In spite of the increased risk of bleeding, this strategy is acceptable in many types of invasive surgical procedures with no change in outcome. However, if the bleeding risk outweighs the risk of ST, other potential strategies include treatment with aspirin alone, “bridging therapy” with aspirin and a glycoprotein IIb/IIIa inhibitor and/or heparin, and “bridging therapy” without aspirin. Novel antiplatelet therapies are promising and potentially valuable in the perioperative management of patients with DES. Maintaining dual antiplatelet therapy is the mainstay of perioperative ST prevention. However, short-term discontinuation of thienopyridines might be associated with relatively low risk if aspirin therapy is maintained perioperatively.

View all citing articles on Scopus

^☆: From the Division of Cardiology, Baylor College of Medicine, and the Methodist Hospital.

View full text

Pharmacokinetics and pharmacodynamics of glycoprotein IIb-IIIa inhibitors☆

Abstract

Section snippets

Template bleeding times

Abciximab: Binding characteristics and specificity

Conclusions

Am J Cardiol

Am J Cardiol

Thromb Res

J Biol Chem

Blood

J Biol Chem

J Biol Chem

J Biol Chem

Cell

Am J Cardiol

Cell

J Am Coll Cardiol

Blood

Blood

Blood

Blood

J Pharmacol Methods

Ann Thorac Surg

Am J Cardiol

J Biol Chem

J Biol Chem

Am J Cardiol

Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty

N Engl J Med

Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization

N Engl J Med

Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade

Lancet

Bleeding time: a guide to its diagnostic and clinical utility

Arch Pathol Lab Med

The aggregation of blood platelets

J Physiol (Lond)

Antithrombotic effects and bleeding time prolongation with synthetic platelet GP IIb/IIIa inhibitors in animal models of platelet-mediated thrombosis

Thromb Haemost

Effect of Ca2+ on GP IIb-IIIa interactions with integrilin: enhanced GP IIb-IIIa binding and inhibition of platelet aggregation by reductions in the concentration of ionized calcium in plasma anticoagulated with citrate

Circulation

In vivo efficacy of SM-20302, a GP IIb/IIIa receptor antagonist, correlates with ex vivo platelet inhibition in heparinized blood but not in citrated blood

Arterioscler Thromb Vasc Biol

Differential effects of glycoprotein IIb/IIIa antagonists on platelet microaggregate and macroaggregate formation and effect of anticoagulant on antagonist potency: implications for assay methodology and comparison of different antagonists

Circulation

Pharmacodynamics of ticlopidine: relation between dose and time of administration to platelet inhibition

Int J Clin Pharmacol Ther

Functionally thrombasthenic state in normal platelets following the administration of ticlopidine

J Clin Invest