Tirofiban

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Tirofiban
Tirofiban.svg
Tirofiban ball-and-stick.png
Systematic (IUPAC) name
(S)-2-(butylsulfonamino)-3-(4-[4-(piperidin-4-yl)butoxy]phenyl)propanoic acid
Clinical data
Trade names Aggrastat
AHFS/Drugs.com monograph
MedlinePlus a601210
Legal status
  • Prescription only
Routes Exclusively intravenous
Pharmacokinetic data
Bioavailability n/a (IV only)
Protein binding 65%
Half-life 2 hours
Identifiers
CAS number 144494-65-5 YesY
ATC code B01AC17
PubChem CID 60947
DrugBank DB00775
ChemSpider 54912 YesY
UNII GGX234SI5H YesY
KEGG D08607 YesY
ChEBI CHEBI:9605 YesY
ChEMBL CHEMBL916 YesY
Chemical data
Formula C22H36N2O5S 
Mol. mass 440.598 g/mol
 YesY (what is this?)  (verify)

Tirofiban (INN, trade name Aggrastat) is an antiplatelet drug. It belongs to a class of antiplatelet named glycoprotein IIb/IIIa inhibitors. Tirofiban is the first drug candidate whose origins can be traced to a pharmacophore-based virtual screening lead.[1][2]

Basic chemical and pharmacological information[edit]

Tirofiban is a synthetic, non-peptide inhibitor acting at glycoprotein (GP) IIb/IIIa receptors in human platelets. It therefore constitutes an anticoagulant, specifically an inhibitor of platelet aggregation.

The drug is marketed under the brand name AGGRASTAT in the US by Medicure Pharma and the rest of the world by Correvio International Sàrl <http://www.correvio.com>.

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

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 Coagulation parameters turn to normal 4 to 8 hours after the drug is withdrawn.

It is a modified version of an anticoagulant found in the venom of the saw-scaled viper Echis carinatus.[3]

Indications[edit]

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

Contraindications and precautions[edit]

Tirofiban is contraindicated in patients with:

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

Cautions[edit]

  • Aggrastat can cause serious bleeding. If bleeding cannot be controlled discontinue Aggrastat.
  • Thrombocytopenia: Discontinue Aggrastat and heparin.

Adverse Reactions[edit]

Bleeding is the most commonly reported adverse reaction.

Use in pregnancy[edit]

Tirofiban has been demonstrated to cross 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.

Pediatric use[edit]

Safety and effectiveness in children have not been established.

Other precautions and laboratory exams[edit]

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.

Side effects[edit]

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

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 bleedings have been reported rarely.

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

Cases of hypersenitivity including acute anaphylaxis have been seen.

Interactions[edit]

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.

Dosage regimen[edit]

New Dosing Regimen Approved by FDA in October, 2013.

High-Dose Bolus Regimen: Administer intravenously 25 mcg/kg over 3 minutes and then 0.15 mcg/kg/min for up to 18 hours. In patients with creatinine clearance ≤60 mL/min, give 25 mcg/kg over 3 minutes and then 0.075 mcg/kg/min.

Duration of therapy[edit]

Patients should be treated for up to 18 hours.

Summary of trial results[edit]

In the multicenter, randomized, parallel, double-blind PRISM-PLUS trial component endpoints and a composite endpoint were defined for periods of 7 days, 30 days, and 6 months, respectively.

For the 7 days period the following results were obtained:

  • Myocardial infarction and death: Risk reduction for tirofiban/heparin compared with heparin alone: 42.8%.
  • Myocardial infarction: Risk reduction for tirofiban/heparin compared with heparin alone: 46.6%.
  • Death : No significant difference.
  • Refractory ischemia: Risk reduction for tirofiban/heparin compared with heparin alone: 29.6%.
  • Composite endpoint: Risk reduction for tirofiban/heparin compared with heparin alone: 31.6%.

All results for the 7 days period were statistically highly significant. At 30 days and 6 months the benefits of tirofiban/heparin remained statistically significant, although the differences to the control group were shrinking.

References[edit]

  1. ^ 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.; Chang, C. T.-C.; Gould, R.J. (1992). "Non-Peptide Fibrinogen Receptor Antagonists. 1. Discovery and Design of Exosite Inhibitors". Journal of Medicinal Chemistry (American Chemical Society) 35 (24): 4640–4642. doi:10.1021/jm00102a020. PMID 1469694. 
  2. ^ Van Drie, John H. (2007). "Computer-aided drug design: the next 20 years". J. Comput Aided Mol Des (Springer) 21 (10–11): 591–601. doi:10.1007/s10822-007-9142-y. PMID 17989929. Retrieved 2008-06-23. 
  3. ^ "Saw-Scaled Vipers". University of Edinburgh. Retrieved 2008-06-23. 

External links[edit]