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Bivalirudin
Systematic (IUPAC) name
d-Phenylalanyl-l-prolyl-l-arginyl
-l-prolylglycylglycylglycylglycyl-l-asparaginylglycyl
-l-alpha-aspartyl-l-phenylalanyl
-l-alpha-glutamyl-l-alpha-glutamyl-l-isoleucyl
-l-prolyl-l-alpha-glutamyl-l-isoleucyl
-l-prolyl-l-alpha-glutamyl-l-alpha-glutamyl
-l-tyrosyl-l-leucine
Identifiers
CAS number 128270-60-0
ATC code  ?
PubChem  ?
Chemical data
Formula C98H138N24O33 
Mol. mass 2180. IUPAC Nomenclature is a system of naming Chemical compounds and of describing the science of Chemistry in general CAS registry numbers are unique numerical identifiers for Chemical compounds Polymers biological sequences mixtures and Alloys They are also referred to The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs It is controlled by the WHO Collaborating Centre for Drug PubChem is a Database of chemical Molecules The system is maintained by the National Center for Biotechnology Information (NCBI a component A chemical formula is a way of expressing information about the Atoms that constitute a particular Chemical compound, and how the relationship between those atoms changes Carbon (kɑɹbən is a Chemical element with the symbol C and its Atomic number is 6 Hydrogen (ˈhaɪdrədʒən is the Chemical element with Atomic number 1 Nitrogen (ˈnaɪtɹəʤɪn is a Chemical element that has the symbol N and Atomic number 7 and Atomic weight 14 Oxygen (from the Greek roots ὀξύς (oxys (acid literally "sharp" from the taste of acids and -γενής (-genēs (producer literally begetteris the The molecular mass (abbreviated m of a substance, more commonly referred to as molecular weight and abbreviated as MW, is the Mass of one 3
Pharmacokinetic data
Bioavailability 100 % (i. In Pharmacology, bioavailability is used to describe the fraction of an administered Dose of unchanged drug that reaches the Systemic circulation, one of v. application only)
Metabolism degraded through proteinases
Half life ~25 minutes
Excretion  ?
Therapeutic considerations
Pregnancy cat.

B(US)
Legal status

Rx-only. Drug metabolism is the Metabolism of drugs, their Biochemical modification or degradation usually through specialized enzymatic systems The biological half-life of a substance is the time it takes for a substance (drug radioactive nuclide or other to lose half of its pharmacologic physiologic or radiologic activity Excretion is the process of eliminating waste products of Metabolism and other non-useful materials The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical if it is used as directed by the mother during The United States of America —commonly referred to as the The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction Not a controlled substance.

Routes i. In Pharmacology and Toxicology, a route v. -injection/infusion only

Bivalirudin (Angiomax) is a drug that belongs to the anticoagulant class and acts as a direct thrombin inhibitor. An anticoagulant is a substance that prevents coagulation; that is it stops Blood from clotting Direct thrombin inhibitors (DTIs are a class of Medication that act as Anticoagulants (delaying blood clotting) by directly inhibiting the Enzyme

Contents

Basic chemical and pharmacological properties

Chemically it constitutes a synthetic congener of the naturally occurring drug hirudin (found in the saliva of the medicinal leech Hirudo medicinalis). Hirudin is a naturally occurring Peptide in the Salivary glands of medicinal Leeches (such as Hirudo medicinalis) that has a blood Medicinal Leeches are any of several Species of leeches but most commonly Hirudo medicinalis, the European Medical Leech'.

Both bivalirudin and hirudin directly inhibit thrombin by specifically binding as well to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin. Thrombin is a serine protease that plays a central role in the thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate Factor XIII to Factor XIIIa, allowing fibrin to develop a covalently cross-linked framework which stabilizes the thrombus; thrombin also activates Factors V and VIII, promoting further thrombin generation, and activates platelets, stimulating aggregation and granule release. Fibrin (also called Factor Ia) is a Protein involved in the clotting of blood Fibrin (also called Factor Ia) is a Protein involved in the clotting of blood

The pharmacological difference between both drugs is that Hirudin is an irreversible inhibitor of thrombin while Bivalirudin is a reversible one. This leads to a relatively small rate of severe bleedings under Bivalirudin compared to standard therapy (see below under section comparative results).

When delivered by i. v. -infusion with a rate of 2. 5 mg/kg/hr, the mean steady-state-concentration is 12. 4 µg/ml. Bivalirudin exhibits linear pharmacokinetics following IV administration to patients undergoing percutaneous coronary intervention. 80% of the drug is proteolytically cleaved, and the remaining 20% is renally metabolized. The half-life of Bivalirudin is 25 minutes.

The clinical onset of action is almost immediate after i. v. -bolus. Bivalirudin prolongs a number of coagulation parameters due to its mode of action. These are the activated clotting time (ACT), the activated partial thromboplastin time (aPPT), the thrombin time (TT), and the prothrombin time (PT,protime). After termination of treatment the coagulation parameters return to normal within 1 to 2 hours indicating a short action of Bivalirudin resulting in a good controllability of therapy.

Existing Drug Forms

In Europe Bivalirudin is sold under the brand name Angiox, in other countries under Angiomax (year of obtained license = 2005 in most countries).

The drug is intended for parenteral (i. v. ) use only. One vial contains 250mg.

Bivalirudin was initially approved by FDA based on results from 2 studies and subsequently approved for an expanded indication based on 3 additional studies. Bivalirudin was licensed in the EU based on 2 studies (see below under section comparative results).

Indications

Bivalirudin is indicated to reduce the risk of acute ischemic complications, for example death due to myocardial infarction or need for urgent revascularization procedures, in patients with unstable angina pectoris undergoing percutaneous coronary intervention (PCI). Myocardial infarction ( MI or AMI for acute myocardial infarction) also known as a heart attack, occurs when the blood supply Percutaneous coronary intervention ( PCI) commonly known as coronary angioplasty or simply Angioplasty, is a therapeutic procedure to treat If indicated, the therapy may be continued for up to 4 hours after termination of PCI.

Contraindications and Precautions

Side Effects

The main risk is the occurrence of severe bleedings in 2. 4 % of patients in clinical studies.

Elderly patients experienced more bleeding episodes than younger patients. Cases of deaths due to severe bleeding attributable to bivalirudin were seen.

Cases of local (skin) or generalized, sometimes severe, anaphylactic allergic reactions (including shock) were observed. Anaphylaxis is an acute systemic (multi-system and severe Type I Hypersensitivity allergic reaction in humans and other Mammals Isolated cases of death from anaphylactic reactions were seen. Thrombocytopenia was only infrequently encountered. Thrombocytopenia (or -paenia, or thrombopenia in short is the presence of relatively few Platelets in Blood. Unspecific pains and anxiety were frequent but tolerable side-effects.

Possible Interactions

When used with other anticoagulants (heparin, thrombolytics, glycoprotein IIB/IIIA blockers, coumarins, or aspirin), bivalirudin may lead to increased bleeding tendency. Heparin, a highly-sulfated Glycosaminoglycan, is widely used as an injectable Anticoagulant and has the highest negative Charge density of any known Thrombolysis is the breakdown ( lysis) of blood clots by pharmacological means Coumarin is a Chemical compound ( Benzopyrone) a Toxin found in many Plants notably in high concentration in the Tonka bean, Aspirin, or acetylsalicylic acid (ASA (əˌsɛtɨlsælɨˌsɪlɨk ˈæsɨd is a Salicylate drug, often used as an Analgesic to relieve

Dosage Regimen

It is recommended to start therapy with an initial i. v. -loading dose (fast injection) of 0. 75 mg/kg followed by i. v. -infusion at a rate of 1. 75mg/kg per hour for the duration of PCI. Continuation of the infusion for up to 4 hours is optional at the discretion of the treating physician. After 4 hours, an additional IV infusion of bivalirudin may be initiated at a rate of 0. 2 mg/kg per hour for up to 20 hours. 2 hours after withdrawal of bivalirudin infusion, sheaths may be removed in most patients.

Comparative Results

In a large comparative 30-days study encompassing 6,010 patients (called REPLACE-2 study) Bivalirudin was compared with a standard therapy of either Abciximab or Eptifibatide plus initial Heparin bolus. Abciximab (previously known as c7E3 Fab) manufactured by Centocor and distributed by Eli Lilly under the trade name ReoPro, is a platelet aggregation Eptifibatide ( Integrilin, Millennium Pharmaceuticals, also co-promoted by Schering-Plough/Essex is an Antiplatelet drug that selectively blocks the Heparin, a highly-sulfated Glycosaminoglycan, is widely used as an injectable Anticoagulant and has the highest negative Charge density of any known The study had a randomized, double-blinded design. Regarding the primary endpoint (death, myocardial infarction, urgent revascularization procedures, severe bleedings) no statistically significant difference between Bivalirudin and standard therapy was noticed (9. 2 versus 10. 0 %). Regarding ischemic complications (death, myocardial infarction, and urgent revascularization procedures) there was also no statistically significant difference (7. 6 vs. 7. 1 %). But the risk for severe bleedings was 2. 4 % in the Bivalirudin group compared to 4. 1 % in the standard therapy-group; a significant difference. In an additional study comparing historical data of Heparin alone (EPISTENT, ESPRIT) with current Bivalirudin results, Bivalirudin gave superior results. Bivalirudin was licensed based on the results of both the REPLACE-2 study and the historical data.

Conclusions

Bivalirudin has the potential to become an important anticoagulant during PCI procedures because of the reduced likelihood of severe bleeding as compared with standard therapy. There is ready reversibility of its action after the end of PCI, together with a relatively low frequency of allergic reactions and thrombocytopenia compared with heparin. It is also unnecessary to give other anticoagulants concomitantly with bivalirudin.

References

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