Tirofiban

Tirofiban

Names
Trade names	Aggrastat, others
Clinical data
Pregnancy category	AU: B1
Routes of use	Intravenous
Onset of action	Rapid
Duration of action	Up to 8 hrs
External links
AHFS/Drugs.com	Monograph
MedlinePlus	a601210
Legal
License data	US DailyMed: Tirofiban
Legal status	US: ℞-only In general: ℞ (Prescription only)
Pharmacokinetics
Protein binding	65%
Elimination half-life	2 hours
Chemical and physical data
Formula	C22H36N2O5S
Molar mass	440.60 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=S(=O)(N[C@H](C(=O)O)Cc2ccc(OCCCCC1CCNCC1)cc2)CCCC
InChI InChI=1S/C22H36N2O5S/c1-2-3-16-30(27,28)24-21(22(25)26)17-19-7-9-20(10-8-19)29-15-5-4-6-18-11-13-23-14-12-18/h7-10,18,21,23-24H,2-6,11-17H2,1H3,(H,25,26)/t21-/m0/s1 Y Key:COKMIXFXJJXBQG-NRFANRHFSA-N Y

Tirofiban, sold under the brand name Aggrastat, is an antiplatelet medication used to treat unstable angina or non-ST-segment-elevation MI (NSTEMI). It is used together with other medications. It is given by injection into a vein. Effects begin rapidly and last up to 8 hours.

Common side effects include bleeding, slow heart rate, swelling, and dizziness. Other side effects may include anaphylaxis and low platelets. It belongs to the glycoprotein IIb/IIIa inhibitors class of medications and works by temporarily preventing platelets for clumping together.

Tirofiban was approved for medical use in the United States in 1998. It is available as generic medication. In the United Kingdom a vial of 12.5 mg costs the NHS about 150£. This amount in the United States costs about 260 USD as of 2021.

Medical uses

Tirofiban is indicated to reduce the rate of thrombotic cardiovascular events (combined endpoint of death, myocardial infarction, or refractory ischemia/repeat cardiac procedure) in people with non-ST elevation acute coronary syndrome (NSTE-ACS).

Contraindications

Tirofiban is contraindicated in:

• Known hypersensitivity to any component of tirofiban.
• History of thrombocytopenia with prior exposure to tirofiban.
• Active internal bleeding, or history of bleeding diathesis, major surgical procedure or severe physical trauma within the previous month.

Side effects

The following side effects were noted under treatment with tirofiban and heparin (and aspirin, if tolerated). Other drugs were used as necessary.

Bleeding is the most commonly reported adverse reaction.

The major adverse effect is bleeding on local sites of clinical intervention and systemically (regarding parts of the body or the whole body system). Major bleeding has occurred in 1.4% of patients and minor bleeding in 10.5%. Transfusions were required to terminate bleeding and to improve bleeding-related anemia in 4.0% of all patients. Geriatric patients have experienced more bleeding episodes than younger, women more than men.

Thrombocytopenia was more often seen in the tirofiban + heparin group (1.5%) than in the heparin control group (0.8%). This adverse effect was usually readily reversible within days.

Positive fecal and urine hemoglobin tests have also been reported.

Post-marketing events have been the occurrence of intracranial bleeding, retroperitoneal bleeding, pulmonary hemorrhage and spinal-epidural hematoma. Fatal bleeding have been reported rarely.

Sometimes, thrombocytopenia was associated with chills, low-grade fever or bleeding complications (see above).

Cases of hypersensitivity including anaphylaxis have occurred.

The activated partial thromboplastin time (aPTT) is the most reliable coagulation parameter and should be obtained regularly during treatment, particular if a bleeding episode occurs that may be associated with tirofiban therapy. Other important hematological parameters are platelet count, clotting time, hematocrit and hemoglobin. Proper technique regarding artery site access for sheath placement and removal of sheath should be followed. Arterial sheaths should be removed when the patient's activated clotting time is < 180 sec. or 2 to 6 hours following withdrawal of heparin.

Pregnancy

Tirofiban crosses the placenta in pregnant rats and rabbits. Although the doses employed in these studies were a multiple of those used in human beings no adverse effects on the offspring in both animals have been seen. However, there are no adequate and well controlled studies in pregnant women. Therefore, tirofiban should be used during pregnancy only if clearly indicated.

Nursing mothers: It is not known whether tirofiban is excreted in human milk. However, significant levels of tirofiban are excreted in rat milk. Therefore, nursing should be discontinued during the period of drug administration and the milk discarded. Nursing may resume 24 hours after cessation of treatment with tirofiban.

Interactions

The concomitant application of warfarin or other oral anticoagulants may increase the risk of serious bleeding events. The decision whether maintenance therapy with these drugs should be discontinued during tirofiban treatment has to be made by the responsible clinician.

Pharmacology

Mechanism of action of antiplatelet drug

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

Chemistry

Tirofiban is a synthetic, non-peptide inhibitor of the interaction of fibrinogen with the integrin glycoprotein (GP) IIb/IIIa on human platelets. The Merck chemistry team of George Hartman, Melissa Egbertson and Wasyl Halczenko developed tirofiban from a lead compound discovered in focused screening of small molecule replacements of the key arginine-glycine-aspartic acid (Arg-Gly-Asp) subunit of fibrinogen. Computation of the distance between the charged Arg and Asp sites in fibrinogen provided guidance leading to directed screening success. Tirofiban constitutes an antithrombotic, specifically an inhibitor of platelet aggregation.

Tirofiban is a modified version of a molecule found in the venom of the saw-scaled viper Echis carinatus.

History

The drug is marketed under the brand name Aggrastat in the US by Medicure Pharma, in China by Eddingpharm, and in the rest of the world by Correvio International Sàrl.

According to the US Orange Book, it was first approved in the US on 20 April 2000. Patent numbers 5733919; 5965581 and 5972967 all expired in October 2016. Patent 5978698 expired in October 2017. Patent 6136794 expired in January 2019. Patent 6770660 expires in June 2023.

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

Further reading

• Hartman GD, Egbertson MS, Halczenko W, Laswell WL, Duggan ME, Smith RL, Naylor AM, Manno PD, Lynch RJ, Zhang G (November 1992). "Non-peptide fibrinogen receptor antagonists. 1. Discovery and design of exosite inhibitors". Journal of Medicinal Chemistry. 35 (24): 4640–2. doi:10.1021/jm00102a020. PMID 1469694.

External links

External sites:	US NLM: Tirofiban
Identifiers:	ATC code: B01AC17 (WHO) CAS Number: 144494-65-5 Y PubChem CID: 60947 IUPHAR/BPS: 6586 DrugBank: DB00775 Y ChemSpider: 54912 Y UNII: GGX234SI5H KEGG: D08607 Y ChEBI: CHEBI:9605 ChEMBL: ChEMBL916 Y