Clopidogrel

Last updated

Clopidogrel
Clopidogrel skeletal formula.svg
Clopidogrel molecule ball from xtal.png
Clinical data
Pronunciation /kləˈpɪdəɡrɛl,kloʊ-/ [1]
Trade names Plavix, Iscover, others [2]
AHFS/Drugs.com Monograph
MedlinePlus a601040
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability >50%
Protein binding 94–98%
Metabolism Liver
Onset of action 2 hours [9]
Elimination half-life 7–8 hours (inactive metabolite)
Duration of action 5 days [9]
Excretion 50% Kidney
46% bile duct
Identifiers
  • (+)-(S)-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.127.841 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C16H16ClNO2S
Molar mass 321.82 g·mol−1
3D model (JSmol)
  • COC(=O)[C@H](c1ccccc1Cl)N2CCc3c(ccs3)C2
  • InChI=1S/C16H16ClNO2S/c1-20-16(19)15(12-4-2-3-5-13(12)17)18-8-6-14-11(10-18)7-9-21-14/h2-5,7,9,15H,6,8,10H2,1H3/t15-/m0/s1 Yes check.svgY
  • Key:GKTWGGQPFAXNFI-HNNXBMFYSA-N Yes check.svgY
   (verify)

Clopidogrel, sold under the brand name Plavix among others, is an antiplatelet medication used to reduce the risk of heart disease and stroke in those at high risk. [9] It is also used together with aspirin in heart attacks and following the placement of a coronary artery stent (dual antiplatelet therapy). [9] It is taken by mouth. [9] Its effect starts about two hours after intake and lasts for five days. [9]

Contents

Common side effects include headache, nausea, easy bruising, itching, and heartburn. [9] More severe side effects include bleeding and thrombotic thrombocytopenic purpura. [9] While there is no evidence of harm from use during pregnancy, such use has not been well studied. [3] Clopidogrel is in the thienopyridine-class of antiplatelets. [9] It works by irreversibly inhibiting a receptor called P2Y12 on platelets. [9]

Clopidogrel was patented in 1982, and approved for medical use in 1997. [6] [10] It is on the World Health Organization's List of Essential Medicines. [11] In 2021, it was the 37th most commonly prescribed medication in the United States, with more than 16 million prescriptions. [12] [13] It is available as a generic medication. [9]

Medical uses

Clopidogrel is used to prevent heart attack and stroke in people who are at high risk of these events, including those with a history of myocardial infarction and other forms of acute coronary syndrome, stroke, and those with peripheral artery disease.

Treatment with clopidogrel or a related drug is recommended by the American Heart Association and the American College of Cardiology for people who:

  • Including a loading dose and maintenance therapy in those receiving PCI and unable to tolerate aspirin therapy
  • Maintenance therapy for up to 12 months in those at medium to high risk for which a noninvasive treatment strategy is chosen

It is also used, along with acetylsalicylic acid (ASA, aspirin), for the prevention of thrombosis after placement of a coronary stent [17] or as an alternative antiplatelet drug for people intolerant to aspirin. [18] It is available as a fixed-dose combination with aspirin. [19]

A meta-analysis found clopidogrel's benefit as an antiplatelet drug in reducing cardiovascular death, myocardial infarction, and stroke to be 25% benefit in smokers, with little (8%) benefit in non-smokers. [20]

Consensus-based therapeutic guidelines also recommend the use of clopidogrel rather than aspirin (ASA) for antiplatelet therapy in people with a history of gastric ulceration, as inhibition of the synthesis of prostaglandins by ASA can exacerbate this condition. In people with healed ASA-induced ulcers, however, those receiving ASA plus the proton-pump inhibitor (PPI) esomeprazole had a lower incidence of recurrent ulcer bleeding than those receiving clopidogrel. [21] However, prophylaxis with proton-pump inhibitors along with clopidogrel following acute coronary syndrome may increase adverse cardiac outcomes, possibly due to inhibition of CYP2C19, which is required for the conversion of clopidogrel to its active form. [22] [23] [24] The European Medicines Agency has issued a public statement on a possible interaction between clopidogrel and proton-pump inhibitors. [25] However, several cardiologists have voiced concern that the studies on which these warnings are based have many limitations and that it is not certain whether an interaction between clopidogrel and proton-pump inhibitors is real. [26]

Adverse effects

Serious adverse drug reactions associated with clopidogrel therapy include:

In the CURE trial, people with acute coronary syndrome without ST elevation were treated with aspirin plus either clopidogrel or placebo and followed for up to one year. The following rates of major bleed were seen: [6]

The CAPRIE trial compared clopidogrel monotherapy to aspirin monotherapy for 1.6 years in people who had recently experienced a stroke or heart attack. In this trial the following rates of bleeding were observed. [6]

In CAPRIE, itching was the only adverse effect seen more frequently with clopidogrel than aspirin. In CURE, there was no difference in the rate of non-bleeding adverse events. [6]

Rashes and itching were uncommon in studies (between 0.1 and 1% of people); serious hypersensitivity reactions are rare. [29]

Interactions

Clopidogrel generally has a low potential to interact with other pharmaceutical drugs. Combination with other drugs that affect blood clotting, such as aspirin, heparins and thrombolytics, showed no relevant interactions. Naproxen did increase the likelihood of occult gastrointestinal bleeding, as might be the case with other nonsteroidal anti-inflammatory drugs. As clopidogrel is metabolized by the liver enzyme CYP2C19, in cellular models it has been theorized that it might increase blood plasma levels of other drugs that are metabolized by this enzyme, such as phenytoin and tolbutamide. Clinical studies showed that this mechanism is irrelevant for practical purposes. [29]

In November 2009, the US Food and Drug Administration (FDA) announced that clopidogrel should be used with caution in people using the proton-pump inhibitors omeprazole or esomeprazole, [30] [31] [32] but pantoprazole appears to be safe. [33] The newer antiplatelet agent prasugrel has minimal interaction with (es)omeprazole, hence might be a better antiplatelet agent (if no other contraindications are present) in people who are on these proton-pump inhibitors. [34]

Pharmacology

Clopidogrel is a prodrug which is metabolized by the liver into its active form. The active form specifically and irreversibly inhibits the P2Y12 subtype of ADP receptor, which is important in activation of platelets and eventual cross-linking by the protein fibrin. [35]

Pharmacokinetics and metabolism

Clopidogrel (top left) being activated: The first step is an oxidation mediated (mainly) by the enzyme CYP2C19, unlike the activation of the related drug prasugrel. The two structures at the bottom are tautomers of each other; and the final step is a hydrolysis. The active metabolite (top right) has Z configuration at the double bond C3-C16 and possibly R configuration at the newly asymmetric C4. Clopidogrel activation.svg
Clopidogrel (top left) being activated: The first step is an oxidation mediated (mainly) by the enzyme CYP2C19, unlike the activation of the related drug prasugrel. The two structures at the bottom are tautomers of each other; and the final step is a hydrolysis. The active metabolite (top right) has Z configuration at the double bond C3–C16 and possibly R configuration at the newly asymmetric C4.

After repeated oral doses of 75 mg of clopidogrel (base), plasma concentrations of the parent compound, which has no platelet-inhibiting effect, are very low and, in general, are below the quantification limit (0.258 μg/L) beyond two hours after dosing.[ medical citation needed ]

Clopidogrel is a prodrug, which is activated in two steps, first by the enzymes CYP2C19, CYP1A2 and CYP2B6, then by CYP2C19, CYP2C9, CYP2B6 and CYP3A. [35] Due to opening of the thiophene ring, the chemical structure of the active metabolite has three sites that are stereochemically relevant, making a total of eight possible isomers. These are: a stereocentre at C4 (attached to the —SH thiol group), a double bond at C3—C16, and the original stereocentre at C7. Only one of the eight structures is an active antiplatelet drug. This has the following configuration: Z configuration at the C3—C16 double bond, the original S configuration at C7, [36] and, although the stereocentre at C4 cannot be directly determined, as the thiol group is too reactive, work with the active metabolite of the related drug prasugrel suggests the R-configuration of the C4 group is critical for P2Y12 and platelet-inhibitory activity.[ medical citation needed ]

The active metabolite has an elimination half-life of about 0.5 to 1.0 h, 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. [37] [38] [39]

Following an oral dose of 14C-labeled clopidogrel in humans, about 50% was excreted in the urine and 46% in the feces in the five days after dosing. [9]

Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is not saturable in vitro up to a concentration of 110 μg/mL.

In 2010, the US Food and Drug Administration (FDA) added a boxed warning, later updated, to Plavix, alerting that the drug can be less effective in people unable to metabolize the drug to convert it to its active form. [40]

Pharmacogenetics

CYP2C19 is an important drug-metabolizing enzyme that catalyzes the biotransformation of many clinically useful drugs, including antidepressants, barbiturates, proton-pump inhibitors, and antimalarial and antitumor drugs. Clopidogrel is one of the drugs metabolized by this enzyme. [9]

The US Food and Drug Administration (FDA) added a boxed warning on clopidogrel in 2010 about CYP2C19-poor metabolizers. [40] People with variants in cytochrome P-450 2C19 (CYP2C19) have lower levels of the active metabolite of clopidogrel, less inhibition of platelets, and a 3.58-times greater risk for major adverse cardiovascular events such as death, heart attack, and stroke; the risk was greatest in CYP2C19 poor metabolizers. [6] [41]

A published review showed that some mutations of CYP2C19, CYP3A4, CYP2C9, CYP2B6, and CYP1A2 genes could affect the clinical efficacy and safety of clopidogrel treatment. For instance, patients carrying the mutations CYP2C19*2, CYP2C19*3, CYP2C9*2, CYP2C9*3, and CYP2B6*5 alleles may not respond to clopidogrel due to poor platelet inhibition efficacy revealed among them. [42]

Mechanism of action

The active metabolite of clopidogrel specifically and irreversibly inhibits the P2Y12 subtype of ADP receptor, which is important in activation of platelets and eventual cross-linking by the protein fibrin. [35] Platelet inhibition can be demonstrated two hours after a single dose of oral clopidogrel, but the onset of action is slow, so a loading dose of either 600 or 300 mg is administered when a rapid effect is needed. [43] [ full citation needed ]

Society and culture

Economics

A box of Plavix Plavix 2007-04-19.jpg
A box of Plavix

Plavix is marketed worldwide in nearly 110 countries, with sales of US$6.6 billion in 2009. [44] It was the second-top-selling drug in the world in 2007 [45] and was still growing by over 20% in 2007. US sales were US$3.8 billion in 2008. [46]

Before the expiry of its patent, clopidogrel was the second best-selling drug in the world. In 2010, it grossed over US$9 billion in global sales. [47]

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. [48] The court ruled that Bristol-Myers Squibb's patent was valid and provided protection until November 2011. [49] The FDA extended the patent protection of clopidogrel by six months, giving exclusivity that would expire in May 2012. [50] The FDA approved generic versions of clopidogrel in May 2012. [51]

Names

Generic clopidogrel is marketed by many companies worldwide under many brand names. [2]

List of brand names

As of March 2017, brands included Aclop, Actaclo, Agregex, Agrelan, Agrelax, Agreless, Agrelex, Agreplat, Anclog, Angiclod, Anplat, Antiagrex, Antiban, Antigrel, Antiplaq, Antiplar, Aplate, Apolets, Areplex, Artepid, Asogrel, Atelit, Atelit, Ateplax, Atervix, Atheros, Athorel, Atrombin, Attera, Bidogrel, Bigrel, Borgavix, Carder, Cardogrel, Carpigrel, Ceraenade, Ceruvin, Cidorix, Clatex, Clavix, Clentel, Clentel, Clidorel, Clodel, Clodelib, Clodian, Clodil, Cloflow, Clofre, Clogan, Clogin, Clognil, Clogrel, Clogrelhexal, Clolyse, Clont, Clood, Clopacin, Clopcare, Clopeno, Clopex Agrel, Clopez, Clopi, Clopid, Clopida, Clopidep, Clopidexcel, Clopidix, Clopidogrel, Clopidogrelum, Clopidomed, Clopidorex, Clopidosyn, Clopidoteg, Clopidowel, Clopidra, Clopidrax, Clopidrol, Clopigal, Clopigamma, Clopigrel, Clopilet, Clopimed, Clopimef, Clopimet, Clopinovo, Clopione, Clopiright, Clopirite, Clopirod, Clopisan, Clopistad, Clopistad, Clopitab, Clopithan, Clopitro, ClopiVale, Clopivas, Clopivaz, Clopivid, Clopivin, Clopix, Cloplat, Clopra, Cloprez, Cloprez, Clopval, Clorel, Cloriocard, Cloroden, Clotix, Clotiz, Clotrombix, Clova, Clovas, Clovax, Clovelen, Clovex, Clovexil, Clovix, Clovvix, Copalex, Copegrel, Copidrel, Copil, Cordiax, Cordix, Corplet, Cotol, CPG, Cugrel, Curovix, Dapixol, Darxa, Dasogrel-S, Dclot, Defrozyp, Degregan, Deplat, Deplatt, Diclop, Diloxol, Dilutix, Diporel, Doglix, Dogrel, Dogrel, Dopivix, Dorel, Dorell, Duopidogrel, DuoPlavin, Eago, Egitromb, Espelio, Eurogrel, Expansia, Farcet, Flucogrel, Fluxx, Freeclo, Globel, Glopenel, Grelet, Greligen, Grelix, Grepid, Grepid, Grindokline, Heart-Free, Hemaflow, Hyvix, Idiavix, Insigrel, Iscover, Iskimil, Kafidogran, Kaldera, Kardogrel, Karum, Kerberan, Keriten, Klepisal, Klogrel, Klopide, Klopidex, Klopidogrel, Klopik, Klopis, Kogrel, Krossiler, Larvin, Lodigrel, Lodovax, Lofradyk, Lopigalel, Lopirel, Lyvelsa, Maboclop, Medigrel, Miflexin, Mistro, Mogrel, Monel, Monogrel, Moytor, Myogrel, Nabratin, Nadenel, Nefazan, Niaclop, Nivenol, Noclog, Nofardom, Nogreg, Nogrel, Noklot, Norplat, Novigrel, Oddoral, Odrel, Olfovel, Opirel, Optigrel, Panagrel, Pedovex, Pegorel, Piax, Piclokare, Pidgrel, Pidogrel, Pidogul, Pidovix, Pigrel, Pingel, Placta, Pladel, Pladex, Pladogrel, Plagerine, Plagrel, Plagril, Plagrin, Plahasan, Plamed, Planor, PlaquEx, Plasiver, Plataca, Platarex, Platec, Platel, Platelex, Platexan, Platil, Platless, Platogrix, Platrel, Plavedamol, Plavicard, Plavictonal, Plavidosa, Plavigrel, Plavihex, Plavitor, Plavix, Plavocorin, Plavogrel, Plavos, Pleyar, Plogrel, Plvix, Pravidel, Pregrel, Provic, Psygrel, Q.O.L, Ravalgen, Replet, Respekt, Revlis, Ridlor, Roclas, Rozak, Sanvix, Sarix, Sarovex, Satoxi, Shinclop, Sigmagrel, Simclovix, Sintiplex, Stazex, Stroka, Stromix, Sudroc, Synetra, Talcom, Tansix, Tessyron, Thinrin, Throimper, Thrombifree, Thrombo, Timiflo, Tingreks, Torpido, Triosal, Trogran, Troken, Trombex, Trombix, Tuxedon, Unigrel, Unplaque, Vaclo, Vasocor, Vatoud, Venicil, Vidogrel, Vivelon, Vixam, Xydrel, Zakogrel, Zillt, Zopya, Zylagren, Zyllt, and Zystol. [2]

As of 2017, it was marketed as a combination drug with acetylsalicylic acid (aspirin) under the brand names Anclog Plus, Antiban-ASP, Asclop, Asogrel-A, Aspin-Plus, Cargrel-A, Clas, Clasprin, Clavixin Duo, Clodrel Forte, Clodrel Plus, Clofre AS, Clognil Plus, Clontas, Clopid-AS, Clopid-AS, Clopida A, Clopil-A, Clopirad-A, Clopirin, Clopitab-A, Clorel-A, Clouds, Combiplat, Coplavix, Coplavix, Cugrel-A, Dorel Plus, DuoCover, DuoCover, DuoPlavin, DuoPlavin, Ecosprin Plus, Grelet-A, Lopirel Plus, Myogrel-AP, Noclog Plus, Noklot Plus, Norplat-S, Odrel Plus, Pidogul A, Pladex-A, Plagerine-A, Plagrin Plus, Plavix Plus, Replet Plus, Stromix-A, and Thrombosprin. [2]

Veterinary uses

Clopidogrel for use in cats Clopidogrel 1.jpg
Clopidogrel for use in cats

Clopidogrel has been shown to be effective at decreasing platelet aggregation in cats, so its use in prevention of feline aortic thromboembolism has been advocated. [52]

Related Research Articles

<span class="mw-page-title-main">Aspirin</span> Medication

Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat include Kawasaki disease, pericarditis, and rheumatic fever.

An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effective in the arterial circulation where classical Vitamin K antagonist anticoagulants have minimal effect.

<span class="mw-page-title-main">Omeprazole</span> Medication to treat gastroesophageal reflux disease and other conditions

Omeprazole, sold under the brand names Prilosec and Losec, among others, is a medication used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger–Ellison syndrome. It is also used to prevent upper gastrointestinal bleeding in people who are at high risk. Omeprazole is a proton-pump inhibitor (PPI) and its effectiveness is similar to that of other PPIs. It can be taken by mouth or by injection into a vein. It is also available in the fixed-dose combination medication omeprazole/sodium bicarbonate as Zegerid and as Konvomep.

<span class="mw-page-title-main">Thromboxane</span> Group of lipids

Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring.

<span class="mw-page-title-main">Ticlopidine</span> Chemical compound

Ticlopidine, sold under the brand name Ticlid, is a medication used to reduce the risk of thrombotic strokes. It is an antiplatelet drug in the thienopyridine family which is an adenosine diphosphate (ADP) receptor inhibitor. Research initially showed that it was useful for preventing strokes and coronary stent occlusions. However, because of its rare but serious side effects of neutropenia and thrombotic microangiopathy it was primarily used in patients in whom aspirin was not tolerated, or in whom dual antiplatelet therapy was desirable. With the advent of newer and safer antiplatelet drugs such as clopidogrel and ticagrelor, its use remained limited.

<span class="mw-page-title-main">Dipyridamole</span> Anticoagulant drug

Dipyridamole is a nucleoside transport inhibitor and a PDE3 inhibitor medication that inhibits blood clot formation when given chronically and causes blood vessel dilation when given at high doses over a short time.

<span class="mw-page-title-main">Prasugrel</span> Medication used to prevent formation of blood clots

Prasugrel, sold under the brand name Effient in the US, Australia and India, and Efient in the EU) is a medication used to prevent formation of blood clots. It is a platelet inhibitor and an irreversible antagonist of P2Y12 ADP receptors and is of the thienopyridine drug class. It was developed by Daiichi Sankyo Co. and produced by Ube and marketed in the United States in cooperation with Eli Lilly and Company.

<span class="mw-page-title-main">Cilostazol</span> Chemical compound

Cilostazol, sold under the brand name Pletal among others, is a medication used to help the symptoms of intermittent claudication in peripheral vascular disease. If no improvement is seen after 3 months, stopping the medication is reasonable. It may also be used to prevent stroke. It is taken by mouth.

<span class="mw-page-title-main">Eptifibatide</span> Antiplatelet drug

Eptifibatide, is an antiplatelet drug of the glycoprotein IIb/IIIa inhibitor class. Eptifibatide is a cyclic heptapeptide derived from a disintegrin protein found in the venom of the southeastern pygmy rattlesnake. It belongs to the class of the arginin-glycin-aspartat-mimetics and reversibly binds to platelets. Eptifibatide has a short half-life. The drug is the third inhibitor of GPIIb/IIIa that has found broad acceptance after the specific antibody abciximab and the non-peptide tirofiban entered the global market.

<span class="mw-page-title-main">CYP2C19</span> Mammalian protein found in humans

Cytochrome P450 2C19 is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some proton pump inhibitors and antiepileptic drugs. In humans, it is the CYP2C19 gene that encodes the CYP2C19 protein. CYP2C19 is a liver enzyme that acts on at least 10% of drugs in current clinical use, most notably the antiplatelet treatment clopidogrel (Plavix), drugs that treat pain associated with ulcers, such as omeprazole, antiseizure drugs such as mephenytoin, the antimalarial proguanil, and the anxiolytic diazepam.

P2Y<sub>12</sub> Protein-coding gene in the species Homo sapiens

P2Y12 is a chemoreceptor for adenosine diphosphate (ADP) that belongs to the Gi class of a group of G protein-coupled (GPCR) purinergic receptors. This P2Y receptor family has several receptor subtypes with different pharmacological selectivity, which overlaps in some cases, for various adenosine and uridine nucleotides. The P2Y12 receptor is involved in platelet aggregation and is thus a biological target for the treatment of thromboembolisms and other clotting disorders. Two transcript variants encoding the same isoform have been identified for this gene.

<span class="mw-page-title-main">Bivalirudin</span> Anticoagulant drug

Bivalirudin, sold under the brand names Angiomax and Angiox, among others, is a specific and reversible direct thrombin inhibitor (DTI). Chemically, it is a synthetic congener of the naturally occurring drug hirudin, found in the saliva of the medicinal leech Hirudo medicinalis. It is manufactured by The Medicines Company.

<span class="mw-page-title-main">Triflusal</span> Antiplatelet drug

Triflusal is a platelet aggregation inhibitor that was discovered and developed in the Uriach Laboratories, and commercialised in Spain since 1981. Currently, it is available in 25 countries in Europe, Asia, Africa and America. It is a derivative of acetylsalicylic acid in which a hydrogen atom on the benzene ring has been replaced by a trifluoromethyl group. Trade names include Disgren, Grendis, Aflen and Triflux.

<span class="mw-page-title-main">Vorapaxar</span> Chemical compound

Vorapaxar is a thrombin receptor antagonist based on the natural product himbacine, discovered by Schering-Plough and developed by Merck & Co.

<span class="mw-page-title-main">Ticagrelor</span> Coronary medication

Ticagrelor, sold under the brand name Brilinta among others, is a medication used for the prevention of stroke, heart attack and other events in people with acute coronary syndrome, meaning problems with blood supply in the coronary arteries. It acts as a platelet aggregation inhibitor by antagonising the P2Y12 receptor. The drug is produced by AstraZeneca.

<span class="mw-page-title-main">Thienopyridine</span> Class of chemical compounds

Thienopyridines are a class of selective, irreversible ADP receptor/P2Y12 inhibitors used for their anti-platelet activity. They have a significant role in the management of cardiovascular disease.

<span class="mw-page-title-main">Cangrelor</span> Chemical compound

Cangrelor, sold under the brand name Kengreal among others, is a P2Y12 inhibitor FDA approved as of June 2015 as an antiplatelet drug for intravenous application. Some P2Y12 inhibitors are used clinically as effective inhibitors of adenosine diphosphate-mediated platelet activation and aggregation. Unlike clopidogrel (Plavix), which is a prodrug, cangrelor is an active drug not requiring metabolic conversion.

Adenosine diphosphate (ADP) receptor inhibitors are a drug class of antiplatelet agents, used in the treatment of acute coronary syndrome (ACS) or in preventive treatment for patients who are in risk of thromboembolism, myocardial infarction or a stroke. These drugs antagonize the P2Y12 platelet receptors and therefore prevent the binding of ADP to the P2Y12 receptor. This leads to a decrease in aggregation of platelets, prohibiting thrombus formation. The P2Y12 receptor is a surface bound protein found on blood platelets. They belong to G protein-coupled purinergic receptors (GPCR) and are chemoreceptors for ADP.

<span class="mw-page-title-main">Management of acute coronary syndrome</span>

Management of acute coronary syndrome is targeted against the effects of reduced blood flow to the affected area of the heart muscle, usually because of a blood clot in one of the coronary arteries, the vessels that supply oxygenated blood to the myocardium. This is achieved with urgent hospitalization and medical therapy, including drugs that relieve chest pain and reduce the size of the infarct, and drugs that inhibit clot formation; for a subset of patients invasive measures are also employed. Basic principles of management are the same for all types of acute coronary syndrome. However, some important aspects of treatment depend on the presence or absence of elevation of the ST segment on the electrocardiogram, which classifies cases upon presentation to either ST segment elevation myocardial infarction (STEMI) or non-ST elevation acute coronary syndrome (NST-ACS); the latter includes unstable angina and non-ST elevation myocardial infarction (NSTEMI). Treatment is generally more aggressive for STEMI patients, and reperfusion therapy is more often reserved for them. Long-term therapy is necessary for prevention of recurrent events and complications.

<span class="mw-page-title-main">Darexaban</span> Chemical compound

Darexaban (YM150) is a direct inhibitor of factor Xa created by Astellas Pharma. It is an experimental drug that acts as an anticoagulant and antithrombotic to prevent venous thromboembolism after a major orthopaedic surgery, stroke in patients with atrial fibrillation and possibly ischemic events in acute coronary syndrome. It is used in form of the maleate. The development of darexaban was discontinued in September 2011.

References

  1. ↑ "Clopidogrel". Lexico Dictionaries. Archived from the original on 25 October 2019. Retrieved 26 October 2019.
  2. 1 2 3 4 "Clopidogrel International brand names". Drugs.com. Archived from the original on 1 April 2017. Retrieved 1 April 2017.
  3. 1 2 "Clopidogrel (Plavix) Use During Pregnancy". Drugs.com. Archived from the original on 21 December 2016. Retrieved 14 December 2016.
  4. ↑ "Plavix Summary of Product Characteristics (SmPC)". (emc). 23 January 2023. Retrieved 15 January 2024.
  5. ↑ "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 October 2023.
  6. 1 2 3 4 5 6 7 "Plavix- clopidogrel bisulfate tablet, film coated". DailyMed. Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. 17 May 2019. Archived from the original on 4 August 2020. Retrieved 26 December 2019.
  7. ↑ "Plavix- clopidogrel tablet, film coated". DailyMed. 22 September 2022. Retrieved 15 January 2024.
  8. ↑ "Plavix EPAR". European Medicines Agency (EMA). 14 July 1998. Retrieved 15 January 2024.
  9. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Clopidogrel Bisulfate". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  10. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 453. ISBN   9783527607495. Archived from the original on 20 December 2016.
  11. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
  12. ↑ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  13. ↑ "Clopidogrel - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  14. ↑ O'Gara PT, Kushner FG, Ascheim DD, Casey DE, Chung MK, de Lemos JA, et al. (January 2013). "2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines". J. Am. Coll. Cardiol. 61 (4): e78–140. doi: 10.1016/j.jacc.2012.11.019 . PMID   23256914.
  15. ↑ Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE, et al. (August 2012). "2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/Non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines". Circulation. 126 (7): 875–910. doi: 10.1161/CIR.0b013e318256f1e0 . PMID   22800849.
  16. ↑ Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, et al. (December 2012). "2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons". Circulation. 126 (25): 3097–137. doi: 10.1161/CIR.0b013e3182776f83 . PMID   23166210.
  17. ↑ Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN   0-9757919-2-3
  18. ↑ Michael D Randall; Karen E Neil (2004). Disease management. 2nd ed. London: Pharmaceutical Press. 159.
  19. ↑ "DuoPlavin EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 4 September 2020. Retrieved 21 August 2020.
  20. ↑ Gagne JJ, Bykov K, Choudhry NK, Toomey TJ, Connolly JG, Avorn J (17 September 2013). "Effect of smoking on comparative efficacy of antiplatelet agents: systematic review, meta-analysis, and indirect comparison". BMJ (Clinical Research Ed.). 347: f5307. doi: 10.1136/bmj.f5307 . PMC   3775704 . PMID   24046285.
  21. ↑ Chan FK, Ching JY, Hung LC, Wong VW, Leung VK, Kung NN, 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.
  22. ↑ Mistry SD, Trivedi HR, Parmar DM, Dalvi PS, Jiyo C (2011). "Impact of proton pump inhibitors on efficacy of clopidogrel: Review of evidence". Indian Journal of Pharmacology . 43 (2): 183–6. doi: 10.4103/0253-7613.77360 . PMC   3081459 . PMID   21572655.
  23. ↑ Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, et al. (2009). "Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome". Journal of the American Medical Association . 301 (9): 937–44. doi: 10.1001/jama.2009.261 . PMID   19258584.
  24. ↑ Stockl KM, Le L, Zakharyan A, Harada AS, Solow BK, Addiego JE, et al. (April 2010). "Risk of rehospitalization for patients using clopidogrel with a proton pump inhibitor" (PDF). Arch Intern Med. 170 (8): 704–10. doi: 10.1001/archinternmed.2010.34 . ISSN   1538-3679. PMID   20421557. Archived from the original on 4 March 2016.
  25. ↑ Wathion N. "Public statement on possible interaction between clopidogrel and proton pump inhibitors" (PDF). Archived (PDF) from the original on 6 February 2011. Retrieved 31 March 2011.
  26. ↑ Hughes S. "EMEA issues warning on possible clopidogrel-PPI interaction, but is there really a problem?". Archived from the original on 22 May 2013. Retrieved 31 March 2011.
  27. ↑ Zakarija A, Bandarenko N, Pandey DK, Auerbach A, Raisch DW, Kim B, et al. (2004). "Clopidogrel-Associated TTP An Update of Pharmacovigilance Efforts Conducted by Independent Researchers, Pharmaceutical Suppliers, and the Food and Drug Administration". Stroke. 35 (2): 533–8. doi: 10.1161/01.STR.0000109253.66918.5E . PMID   14707231.
  28. ↑ Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, 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". The Lancet . 364 (9431): 331–7. doi:10.1016/S0140-6736(04)16721-4. PMID   15276392. S2CID   9874277.
  29. 1 2 Jasek, W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 6526–7. ISBN   978-3-85200-181-4.
  30. ↑ DeNoon DJ (23 February 2016). "FDA Warns Plavix Patients of Drug Interactions". WebMD. Archived from the original on 23 February 2016. Retrieved 23 November 2009.
  31. ↑ "Public Health Advisory: Updated Safety Information about a drug interaction between Clopidogrel Bisulfate (marketed as Plavix) and Omeprazole (marketed as Prilosec and Prilosec OTC)". Food and Drug Administration (FDA). 17 November 2009. Archived from the original on 29 December 2009. Retrieved 13 March 2010.
  32. ↑ Farhat N, Haddad N, Crispo J, Birkett N, McNair D, Momoli F, et al. (February 2019). "Trends in concomitant clopidogrel and proton pump inhibitor treatment among ACS inpatients, 2000-2016". Eur. J. Clin. Pharmacol. 75 (2): 227–235. doi:10.1007/s00228-018-2564-8. PMID   30324301. S2CID   53085923.
  33. ↑ Wedemeyer RS, Blume H (2014). "Pharmacokinetic Drug Interaction Profiles of Proton Pump Inhibitors: An Update". Drug Safety. 37 (4): 201–11. doi:10.1007/s40264-014-0144-0. PMC   3975086 . PMID   24550106.
  34. ↑ John J, Koshy SK (2012). "Current Oral Antiplatelets: Focus Update on Prasugrel". The Journal of the American Board of Family Medicine. 25 (3): 343–349. doi: 10.3122/jabfm.2012.03.100270 . PMID   22570398.
  35. 1 2 3 Cattaneo M (March 2012). "Response variability to clopidogrel: is tailored treatment, based on laboratory testing, the right solution?". Journal of Thrombosis and Haemostasis. 10 (3): 327–36. doi: 10.1111/j.1538-7836.2011.04602.x . PMID   22221409. S2CID   34477003.
  36. 1 2 Pereillo JM, Maftouh M, Andrieu A, Uzabiaga MF, Fedeli O, Savi P, et al. (2002). "Structure and stereochemistry of the active metabolite of clopidogrel". Drug Metab. Dispos. 30 (11): 1288–95. doi:10.1124/dmd.30.11.1288. PMID   12386137. S2CID   2493588.
  37. ↑ Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, et al. (January 2009). "Cytochrome p-450 polymorphisms and response to clopidogrel". The New England Journal of Medicine . 360 (4): 354–62. doi: 10.1056/NEJMoa0809171 . PMID   19106084.
  38. ↑ Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, et al. (January 2009). "Genetic Determinants of Response to Clopidogrel and Cardiovascular Events". The New England Journal of Medicine . 360 (4): 363–75. doi: 10.1056/NEJMoa0808227 . PMID   19106083.
  39. ↑ Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, et al. (January 2009). "Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study". The Lancet . 373 (9660): 309–17. doi:10.1016/S0140-6736(08)61845-0. PMID   19108880. S2CID   22405890.
  40. 1 2 "Safety announcement: Reduced effectiveness of Plavix in patients who are poor metabolizers". U.S. Food and Drug Administration. 3 August 2017. Archived from the original on 15 March 2010.
  41. ↑ "FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug". U.S. Food and Drug Administration (FDA). 28 June 2019. Archived from the original on 18 June 2019. Retrieved 30 January 2022.
  42. ↑ Alkattan A, Alsalameen E (June 2021). "Polymorphisms of genes related to phase-I metabolic enzymes affecting the clinical efficacy and safety of clopidogrel treatment". Expert Opinion on Drug Metabolism & Toxicology. 17 (6): 685–95. doi:10.1080/17425255.2021.1925249. PMID   33931001. S2CID   233470717.
  43. ↑ Clopidogrel Multum Consumer Information
  44. ↑ "New products and markets fuel growth in 2005". IMS Health. Archived from the original on 3 June 2008. Retrieved 2 March 2009.
  45. ↑ "Top Ten Global Products – 2007" (PDF). IMS Health. 26 February 2008. Archived (PDF) from the original on 25 February 2011. Retrieved 2 March 2009.
  46. ↑ "Details for Plavix". Archived from the original on 14 August 2014.[ verification needed ]
  47. ↑ Topol EJ, Schork NJ (January 2011). "Catapulting clopidogrel pharmacogenomics forward". Nature Medicine. 17 (1): 40–41. doi:10.1038/nm0111-40. PMID   21217678. S2CID   32083067.
  48. ↑ "Preliminary Injunction Against Apotex Upheld on Appeal" (Press release). Bristol-Myers Squibb. 8 December 2006. Archived from the original on 14 April 2014. Retrieved 14 March 2010.
  49. ↑ "U.S. judge upholds Bristol, Sanofi patent on Plavix". Reuters. 19 June 2007. Archived from the original on 20 May 2011. Retrieved 5 September 2007.
  50. ↑ "FDA Gives Plavix a 6 Month Extension-Patent Now Expires on 17 May 2012". 26 January 2011. Archived from the original on 12 October 2011. Retrieved 12 January 2012.
  51. ↑ "FDA approves generic versions of blood thinner Plavix" (Press release). U.S. Food and Drug Administration (FDA). 17 May 2012. Archived from the original on 11 March 2016.
  52. ↑ Hogan DF, Andrews DA, Green HW, Talbott KK, Ward MP, Calloway BM (2004). "Antiplatelet effects and pharmacodynamics of clopidogrel in cats". J Am Vet Med Assoc. 225 (9): 1406–1411. doi: 10.2460/javma.2004.225.1406 . PMID   15552317.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.