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Tirofiban
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| Systematic (IUPAC) name | |
| (2S)-2-(butylsulfonylamino)-3-[4-[4-(4-piperidyl)butoxy]phenyl propanoic acid |
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| Identifiers | |
| CAS number | |
| ATC code | B01 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C22H36N2O5S |
| Mol. mass | 440.598 g/mol |
| Pharmacokinetic data | |
| Bioavailability | n/a (IV only) |
| Protein binding | 65% |
| Metabolism | ? |
| Half life | 2 hours |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
? |
| Legal status |
℞ Prescription only |
| Routes | Exclusively intravenous |
Tirofiban (INN, trade name Aggrastat) is an antiplatelet drug. It belongs to a class of anticoagulants 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]
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Basic chemical and pharmacological information
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 in many countries under the brand name Aggrastat by either Merck Sharp & Dohme or Medicure Pharma.
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 Coagulation parameters turn to normal 4 to 8 hours after the drug is withdrawn.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
Tirofiban in combination with heparin and aspirin is indicated in the management of patients with unstable angina or non-Q-wave myocardial infarction, including patients who may subsequently undergo percutaneous transluminal coronary angioplasty (PTCA), to decrease the rate of refractory ischemic conditions, new myocardial infarction and death.
Contraindications and precautions
Tirofiban is containdicated in patients with:
- known hypersensitivity to any component of the product
- active (internal) bleeding or a history of abnormal bleeding tendencies
- a history of intracranial hemorrhage or neoplasm, arteriovenous malformation, or aneurysm
- patients who developed thrombocytopenia following prior exposure to tirofiban
- known coagulopathy, platelet disorder or history of thrombocytopenia
- stroke within 30 days prior to hospitalization or any history of hemorrhagic stroke
- major surgical procedure or severe physical trauma within the previous month
- history, symptoms or findings suggestive of aortic dissection
- severe uncontrolled hypertension
- acute pericarditis
- cirrhosis or other clinically significant liver disease
- angina caused by obvious provoking factors (arrhythmia, severe anemia, hyperthyroidism or hypotension)
Cautions
Tirofiban should be used with caution in the following clinical situations:
- recent (<1 year) bleeding, including a history of gastrointestinal bleeding, or genitouritary bleeding of clinical significance (e.g. macrohematuria)
- platelet count < 150,000/µl
- history of cerebrovascular disease in the past year
- hemorrhagic retinopathy
- chronic hemodialysis
Use in pregnancy
Tirofiban has been demonstrated to cross the placenta in pregnant rats and rabbits. Although the doses employeed 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
Safety and effectiveness in children have not been established.
Other precautions and laboratory exams
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 assiociated to 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
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 man.
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
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 regime
Tirofiban is initially given as rapid intravenous infusion at a rate of 0.4 µg/kg and minute for 30 minutes. Upon completion of the initial infusion, the rate is decreased to 0.1 µg/kg and minute delivered as continuous infusion.
Duration of therapy
Patients who do not show any signs of recurrent ischemic symptoms and do not undergo angiography and angioplasty should be treated for at least 48 hours.
Patients proceeding into angiography and angioplasty should continue throughout both procedures and for at least 12 hours, and not more than 24 hours after angioplasty. Once a patient is clinically stable and no further coronary intervention is planned by the treating physician, the infusion should be discontinued.
Summary of trial results
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
- ^ 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 35: 4640-4642. American Chemical Society. Retrieved on 2008-06-23.
- ^ Van Drie, John H. (2007). "Computer-aided drug design: the next 20 years". J. Comput Aided Mol Des 21: 591-601. Springer. Retrieved on 2008-06-23.
- ^ Saw-Scaled Vipers. University of Edinburgh. Retrieved on 2008-06-23.
External links
- Tirofiban - Stanford University.
- Aggrastat - Food and Drug Administration (FDA) information.
- Product monograph for Aggrastat - Merck Frosst Canada.
Wikipedia content modification information:
- This page was last modified on 23 June 2008, at 18:43.
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