Clopidogrel , sold as a brand name Plavix among others, is an antiplatelet drug used to reduce the risk of heart disease and stroke in those at high risk. It is also used in conjunction with aspirin in a heart attack and follows the placement of a coronary artery stent (dual antiplatelet therapy). It was taken by mouth. The onset of the effect is about 2 hours and lasts for 5 days.
Common side effects include headache, nausea, easy bruising, itching, and heartburn. More severe side effects include thrombotic thrombocytopenic hemorrhage and thrombocytopenic purpura. Although there is no evidence of harm from use during pregnancy, such use has not been well studied. Clopidogrel is in the antiplatelet class of thienopyridine. It works by inhibiting receptors called P2Y 12 on platelets.
Clopidogrel was first written in 1982 and approved for medical use in 1998. Clopidogrel is listed on the World Organization's Essential Medicines List, the most effective and safe medication needed in the health system. Wholesale costs in developing countries are around 0.77 to 31.59 USD per month. In the United States, one month maintenance fee is less than 25 USD.
Video Clopidogrel
Medical use
Clopidogrel is used to prevent heart attacks and strokes in people at high risk for this incident, including those with a history of myocardial infarction and other forms of acute coronary syndrome, stroke, and those with peripheral arterial disease.
Treatment with clopidogrel or related drugs is recommended by the American Heart Association and the American College of Cardiology for people who:
- Present for treatment with myocardial infarction with ST-elevation included
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- The loading dose given before percutaneous coronary intervention (PCI), followed by one year of treatment for those receiving a vascular stent
- The loading dose given before fibrinolytic therapy is continued for at least 14 days
- Present for the treatment of non-ST myocardial infarction or unstable angina
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- Includes loading dose and maintenance therapy on those receiving PCI and can not tolerate aspirin therapy
- Maintenance therapy for up to 12 months in those with moderate to high risk for which noninvasive treatment strategies are selected
In those with stable ischemic heart disease, treatment with clopidogrel is described as a "sensible" option for monotherapy in those who can not tolerate aspirin, such as treatment with clopidogrel in combination with aspirin at a certain level. patient risk. - Thrombotic thrombocytopenic purpura (incidence: four per million treated patients)
- Bleeding - an annual haemorrhage may be increased by simultaneous administration of aspirin.
- Big bleed: clopidogrel 3.7%, placebo 2.7%
- Life-threatening haemorrhage: clopidogrel 2.2%, placebo 1.8%
- Hemorrhagic stroke: 0.1% clopidogrel, placebo 0.1%
- Gastrointestinal hemorrhage: clopidogrel 2.0%, aspirin 2.7%
- Intracranial hemorrhage: 0.4% clopidogrel, aspirin 0.5%
It is also used, along with acetylsalicylic acid (ASA, aspirin), for the prevention of thrombosis after the installation of a coronary stent or as an alternative antiplatelet agent for people who are intolerant of aspirin.
Clopidogrel benefits mainly in those who smoke (25% benefit), with only a few (8%) benefits for those who do not smoke.
Consensus-based therapy guidelines also recommend the use of clopidogrel rather than ASA for antiplatelet therapy in people with a history of gastric ulceration, because inhibition of prostaglandin synthesis by ASA may aggravate this condition. In people with ASA-induced ulcers, however, those receiving ASA plus esomeprazole proton pump inhibitors have a lower incidence of recurrent ulcer hemorrhage than those receiving clopidogrel. However, prophylaxis with a proton pump inhibitor along with clopidogrel after acute coronary syndromes may improve adverse cardiac outcomes, possibly because of CYP2C19 inhibition, which is necessary for the conversion of clopidogrel to its active form. The European Medicines Agency has issued a public statement about possible interactions between clopidogrel and proton pump inhibitors. However, some cardiologists have raised concerns that this warning-based study has many limitations and is uncertain whether the interaction between clopidogrel and proton pump inhibitors is real.
Maps Clopidogrel
Adverse effects
The serious harmful drug reactions associated with clopidogrel therapy include:
In the CURE test, people with acute coronary syndromes without ST elevation were treated with aspirin plus clopidogrel or placebo and followed for up to one year. The following major bleeding levels are seen:
The CAPRIE trial compared clopidogrel monotherapy to aspirin monotherapy for 1.6 years in people who recently had a stroke or heart attack. In this experiment, the following bleeding rates were observed.
In CAPRIE, itching is the only side effect seen more frequently with clopidogrel than aspirin. In CURE, there was no difference in the rate of non-hemorrhagic side effects.
Rashes and itching are rare in the study (between 0.1 and 1% of people); serious hypersensitivity reactions are rare.
Interactions
Clopidogrel generally has low potential to interact with other pharmaceutical drugs. Combinations with other drugs that affect blood clotting, such as aspirin, heparin and thrombolytics, show no relevant interactions. Naproxen increases the likelihood of gastrointestinal bleeding, as is the case with other nonsteroidal anti-inflammatory drugs. When clopidogrel inhibits the CYP2C9 liver enzyme in the cellular model, it has been suggested that it may increase blood plasma levels of drugs metabolized by these enzymes, such as phenytoin and tolbutamide. Clinical studies show that this mechanism is not relevant for practical purposes.
In November 2009, the FDA announced that clopidogrel should be used with caution in people using proton pump inhibitors omeprazole or esomeprazole, but pantoprazole appears to be safe. Newer antiplatelet agents prasugrel have minimal interaction with (es) omeprazole, then it may be a better antiplatelet agent (if no other contraindications are present) in people who are in proton pump inhibitors.
Pharmacology
Action mechanism
Clopidogrel is a prodrug, which is enabled in two steps, first by CYP2C19, CYP1A2 and CYP2B6, then by CYP2C19, CYP2C9, CYP2B6 and CYP3A. The active metabolite then in particular and irreversibly inhibits the subepace ADP receptor P2Y 12 , which is important in platelet activation and ultimately cross-linking by fibrin protein. Inhibition of platelets can be demonstrated two hours after a single dose of oral clopidogrel, but the onset of action is slow, so a good dose of 600 or 300 mg is given when a rapid effect is required.
Pharmacokinetics and metabolism
After recurrent oral doses of 75 mg clopidogrel (base), plasma concentrations of the parent compound, which have no platelet-inhibitory effect, are very low and, in general, are below the quantification limit (0.258 Ã,Âμg/l) over two hours after dosing.
Clopidogrel is activated in the liver by the P450 cytochrome enzyme, including CYP2C19. Because of the opening of the thiophene ring, the chemical structure of the active metabolite has three stereochemically relevant sites, making a total of eight possible isomers. This is: a stereocentre on C4 (attached to the thiol -SH group), double bonds on C3 - C16, and the original stereocentre in C7. Only one of the eight structures is an active antiplatelet drug. It has the following configuration: Z configuration on double bond C3 - C16, original configuration S in C7, and, although stereocentre in C4 can not be directly determined, because the thiol group is too reactive, working with active metabolites of the associated drug prasugrel showed R -configuration of C4 groups is very important for P2Y 12 and platelet-inhibitory activity.
The active metabolite has a elimination half-life of about 0.5 to 1.0 hours, and acts by forming a disulfide bridge with a platelet ADP receptor. Patients with CYP2C19 variant alleles were 1.5 to 3.5 times more likely to die or have complications than patients with high-functioning alleles.
After oral dosage of 14 C-label clopidogrel in humans, about 50% were excreted in urine and 46% in the feces within five days after dosing.
- Food effect: Feeding clopidogrel of bisulfate with food does not significantly alter the bioavailability of clopidogrel as assessed by the main metabolite pharmacokinetics in circulation. Absorption and distribution: Clopidogrel is rapidly absorbed after recurrent oral dosing of 75-milligram (base) clopidogrel, with peak plasma levels (approximately 3 mg/l) of the major circulating metabolite occurring approximately one hour after dosing. The pharmacokinetics of circulating principal metabolites is linear (plasma concentrations increase proportional to dose) within the 50 to 150 mg clopidogrel dose range. Absorption of at least 50% based on excretion of clabidogrel-related metabolite urine.
Clopidogrel and main metabolites in circulation bind reversibly in vitro to human plasma proteins (98% and 94% respectively). Unsaturated bond in vitro to a concentration of 110? G/ml.
- Metabolism and elimination: In vitro and in vivo , clopidogrel undergoes rapid hydrolysis into carboxylic acid derivatives. In plasma and urine, glucuronide from carboxylic acid derivatives is also observed.
In March 2010, the US FDA added a box warning to Plavix who warned that the drug could be less effective in people who can not metabolize the drug to convert it into its active form.
Pharmacogenetic
CYP2C19 is an important enzyme that metabolizes drugs that catalyze the biotransformation of many clinically useful drugs, including antidepressants, barbiturates, proton pump inhibitors, and antimalarial and antitumor drugs. Clopidogrel is one of the drugs that is metabolized by this enzyme.
Several recent landmark studies have proven the importance of the 2C19 genotype in the treatment of clopidogrel. In March 2010, the FDA posted a black box warning to Plavix to keep patients and healthcare providers aware that poor CYP2C19-metabolism, representing up to 14% of patients, is at a high risk of treatment failure and available testing. Patients with variants in the cytochrome P-450 2C19 (CYP2C19) had lower levels of clopidogrel active metabolites, less platelet inhibition, and 3.58 times greater risk for severe cardiovascular events such as death, heart attack, and stroke; the greatest risk to CYP2C19 is poor metabolism.
Marketing and litigation
Plavix is ​​marketed worldwide in nearly 110 countries, with sales of US $ 6.6 billion in 2009. It was the second best-selling drug in the world for several years in 2007 and still growing more than 20% in 2007. US sales were US $ 3.8 billion in 2008.
Before the expiration of his patent, clopidogrel is the second best-selling drug in the world. In 2010, it grossed global sales of more than US $ 9 billion.
In 2006, the generic clopidogrel was briefly marketed by Apotex, a Canadian generic pharmaceutical company before a court order to stop further production until the settlement of a patent infringement case filed by Bristol-Myers Squibb. The Court ruled that the Bristol-Myers Squibb patent is legal and provides protection until November 2011. The FDA extends the patent protection of clopidogrel for six months, providing exclusivity that will expire on May 17, 2012. FDA approves the generic version of Plavix on May 17, 2012.
The generic clopidogrel is marketed by many companies worldwide with many brand names, including combination drugs with acetylsalicylic acid (aspirin).
Research
Use in cat
Clopidogrel has also been shown to be effective in reducing platelet aggregation in cats, so its use in the prevention of cat aortic thromboembolism has been recommended.
References
External links
- Bristol-Myers Squibb Bristol-Myers Squibb/Sanofi official site
- Plavix provisioning Bristol-Myers Squibb/Sanofi
- Plavix, Aspirin and Stents: Forum Patient: Angioplasty.Org
- Drug promise ends migraine suffering
- US. National Medical Library: Drug Information Portal - Clopidogrel
Source of the article : Wikipedia
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