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Clopidogrel

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This is an old revision of this page, as edited by Ellusion (talk | contribs) at 08:34, 6 March 2009 (Added that it is of the thienopyridine class.). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Clopidogrel
Clinical data
Pregnancy
category
  • AU: B1
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: WARNING[1]Rx-only
Pharmacokinetic data
Bioavailability>50%
Protein binding94–98%
MetabolismHepatic
Elimination half-life7–8 hours (inactive metabolite)
Excretion50% renal
46% biliary
Identifiers
  • (+)-(S)-methyl 2-(2-chlorophenyl)-
    2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate
CAS Number
PubChem CID
DrugBank
ChemSpider
CompTox Dashboard (EPA)
ECHA InfoCard100.127.841 Edit this at Wikidata
Chemical and physical data
FormulaC16H16ClNO2S
Molar mass321.82 g/mol g·mol−1
3D model (JSmol)
  • COC(=O)C(N1CCc2sccc2C1)c1ccccc1Cl

Clopidogrel is an oral antiplatelet agent (thienopyridine class) to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It is marketed by Bristol-Myers Squibb and Sanofi-Aventis under the trade name Plavix, by Sun Pharmaceuticals under the trade name Clopilet and by Ranbaxy Laboratories under the trade name Ceruvin. It works by blocking a receptor called P2Y12. Adverse effects include hemorrhage.

Pharmacology

Clopidogrel is a pro-drug whose action may be related to adenosine diphosphate (ADP) receptor on platelet cell membranes. The specific subtype of ADP receptor that clopidogrel binds is P2Y12 and is important in platelet aggregation and the cross-linking of platelets by fibrin.[2] The blockade of this receptor inhibits platelet aggregation by blocking activation of the glycoprotein IIb/IIIa pathway. The IIb/IIIa complex functions as a receptor mainly for fibrinogen and vitronectin but also for fibronectin and von Willebrand factor. Activation of this receptor complex is the "final common pathway" for platelet aggregation, and is important in platelet aggregation, the cross-linking of platelets by fibrin.

Platelet inhibition can be demonstrated two hours after a single dose of oral clopidogrel, but the onset of action is slow, so that a loading-dose of 300-600 mg is usually administered.

Clinical use

Indications

Clopidogrel is indicated for:[3]

  • Prevention of vascular ischaemic events in patients with symptomatic atherosclerosis
  • Acute coronary syndrome without ST-segment elevation (NSTEMI), along with aspirin
  • ST elevation MI (STEMI)

It is also used, along with aspirin, for the prevention of thrombosis after placement of intracoronary stent. [3]

International guidelines granted the highest grade of recommendation for NSTE-ACS, PCI and stent,[clarification needed] for Clopidogrel in addition to Aspirin. Consensus-based therapeutic guidelines recommend also the use of clopidogrel, instead of aspirin, in patients requiring antiplatelet therapy but with a history of gastric ulceration, as inhibition of the synthesis of prostaglandins by aspirin (acetylsalicylic acid) can exacerbate this condition. A recent study has shown that in patients with healed aspirin-induced ulcers, however, patients receiving aspirin plus the proton pump inhibitor esomeprazole had a lower incidence of recurrent ulcer bleeding than patients receiving clopidogrel. [4]

Dosage forms

Clopidogrel is marketed as clopidogrel bisulfate (clopidogrel hydrogen sulfate), most commonly under the trade names Plavix, as 75 mg oral tablets.

Pharmacokinetics and metabolism

The active metabolite of clopidogrel [5]

After repeated 75-mg oral doses of clopidogrel (base), plasma concentrations of the parent compound, which has no platelet inhibiting effect, are very low and are generally below the quantification limit (0.000258 mg/L) beyond 2 hours after dosing.

Clopidogrel is a pro-drug activated in the liver by cytochrome P450 enzymes, including CYP2C19. The active metabolite has an elimination half-life of about 8 hours and acts by forming a disulfide bridge with the platelet ADP receptor. Patients with a variant allele of CYP2C19 are 1.5 to 3.5 times more likely to die or have complications than patients with the high-functioning allele.[6][7][8]

Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% was excreted in the urine and approximately 46% in the feces in the 5 days after dosing.

Effect of Food: Administration of PLAVIX (clopidogrel bisulfate) with meals did not significantly modify the bioavailability of clopidogrel as assessed by the pharmacokinetics of the main circulating metabolite.

Absorption and Distribution: Clopidogrel is rapidly absorbed after oral administration of repeated doses of 75 mg clopidogrel (base), with peak plasma levels (appx. 3 mg/L) of the main circulating metabolite occurring approximately 1 hour after dosing. The pharmacokinetics of the main circulating metabolite are linear (plasma concentrations increased in proportion to dose) in the dose range of 50 to 150 mg of clopidogrel. Absorption is at least 50% based on urinary excretion of clopidogrel-related metabolites. Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is nonsaturable in vitro up to a concentration of 110 μg/mL.

Metabolism and Elimination: In vitro and in vivo, clopidogrel undergoes rapid hydrolysis into its carboxylic acid derivative. In plasma and urine, the glucuronide of the carboxylic acid derivative is also observed.

Adverse effects

Serious adverse drug reactions associated with clopidogrel therapy include:

Marketing and litigation

A box of Plavix

Plavix has been the 2nd top selling drug in the world over the past several years[10] and was still growing by over 20% in 2007. In 2005 it had sales of US$5.9 billion.[11]

Plavix is marketed worldwide in nearly 110 countries.

In 2006, generic clopidogrel was briefly marketed by Apotex, a Canadian generic pharmaceutical company before a court order halted further production until resolution of a patent infringement case brought by Bristol-Myers Squibb.[12] The court ruled that Bristol-Myers Squibb's patent was valid and has patent protection until November 2011.[13] In 2007, the production was halted to many retail pharmacies and will be changing back to Plavix.

Generic clopidogrel is also produced by several pharmaceutical companies in India at significantly lower retail prices, up to 1/30th of the price.

It is worth noting that there are many counterfeit packs in circulation, as with any popular medicine and caution should be exercised to ensure that the supply chain has been secure.

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ Savi, P (2006). "The active metabolite of Clopidogrel disrupts P2Y12 receptor oligomers and partitions them out of lipid rafts". Proceedings of the National Academy of Sciences of the USA. 103 (29): 11069–11074. doi:10.1073/pnas.0510446103. PMID 16835302. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  3. ^ a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  4. ^ Chan FK, Ching JY, Hung LC; et al. (2005). "Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding". N. Engl. J. Med. 352 (3): 238–44. doi:10.1056/NEJMoa042087. PMID 15659723. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  5. ^ J. M. Pereillo, M. Maftouh, A. Andrieu, M. F. Uzabiaga, O. Fedeli, P. Savi, M. Pascal, J. M. Herbert, J. P. Maffrand, C. Picard (2002). "Structure and stereochemistry of the active metabolite of clopidogrel" (PDF). Drug Metab. Dispos. 30 (11): 1288–1295. doi:10.1124/dmd.30.11.1288. PMID 12386137.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Mega, J. L. (2009). "Cytochrome P-450 Polymorphisms and Response to Clopidogrel". New Engl. J. Med. 360: 354–362. doi:10.1056/NEJMoa0809171. PMID 19106084.
  7. ^ Simon, T. (2009). "Genetic Determinants of Response to Clopidogrel and Cardiovascular Events". New Engl. J. Med. 360: 363–375. doi:10.1056/NEJMoa0808227. PMID 19106083.
  8. ^ Collet, J (2009). "Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study". Lancet. 373: 309. doi:10.1016/S0140-6736(08)61845-0.
  9. ^ Diener HC, Bogousslavsky J, Brass LM; et al. (2004). "Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial". Lancet. 364 (9431): 331–7. doi:10.1016/S0140-6736(04)16721-4. PMID 15276392. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  10. ^ "Top Ten Global Products - 2007" (PDF). IMS Health. 2008-02-26. Retrieved 2009-03-02.
  11. ^ "New products and markets fuel growth in 2005". IMS Health. Retrieved 2009-03-02.
  12. ^ "Preliminary Injunction Against Apotex Upheld on Appeal — Press Release". Retrieved 2007-09-05.
  13. ^ "U.S. judge upholds Bristol, Sanofi patent on Plavix". Retrieved 2007-09-05. {{cite web}}: Text "Reuters" ignored (help)
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