Chemistry:Ezetimibe

From HandWiki
Short description: Medication used to treat high cholesterol
Ezetimibe
Ezetimibe.svg
Clinical data
Pronunciation/ɛˈzɛtɪmɪb, -maɪb/
Trade namesZetia, Ezetrol, others
AHFS/Drugs.comMonograph
MedlinePlusa603015
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classCholesterol absorption inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability35% to 65%
Protein binding>90%
MetabolismIntestinal wall, liver
Elimination half-life19 h to 30 h
ExcretionKidney 11%, fecal 78%
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC24H21F2NO3
Molar mass409.433 g·mol−1
3D model (JSmol)
Melting point164 to 166 °C (327 to 331 °F)
  (verify)

Ezetimibe is a medication used to treat high blood cholesterol and certain other lipid abnormalities.[2][3] Generally it is used together with dietary changes and a statin.[4] Alone, it is less preferred than a statin.[3] It is taken by mouth.[3] It is also available in the fixed combinations ezetimibe/simvastatin,[5] ezetimibe/atorvastatin,[6] ezetimibe/rosuvastatin,[3][7] and ezetimibe/bempedoic acid.[8]

The most commonly reported adverse events include upper respiratory tract infections, joint pain, diarrhea, and tiredness.[3] Serious side effects may include anaphylaxis, liver problems, depression, and muscle breakdown.[3][4] Use in pregnancy and breastfeeding is of unclear safety.[9] Ezetimibe works by decreasing cholesterol absorption in the intestines.[4]

Ezetimibe was approved for medical use in the United States in 2002.[3] It is available as a generic medication.[4] In 2020, it was the 100th most commonly prescribed medication in the United States, with more than 7 million prescriptions.[10][11]

Medical uses

A 2015 review found that adding ezetimibe to statin treatment of high blood cholesterol had no effect on overall mortality or cardiovascular mortality, although it significantly reduced the risk of myocardial infarction and stroke.[12] A 2015 trial found that adding ezetimibe to simvastatin had no effect on overall mortality but did lower the risk of heart attack or stroke in people with prior heart attack.[13][14] Several treatment guidelines recommend adding ezetimibe in select high risk persons in whom LDL goals cannot be achieved by maximally tolerated statin alone.[15][16][17][18][19]

Ezetimibe is indicated in the United States as an add-on to dietary measures to reduce levels of certain lipids in people with:[2]

  • Primary hyperlipidemia, alone or with a statin
  • Mixed hyperlipidemia, in combination with fenofibrate
  • Homozygous familial hypercholesterolemia, in combination with specific statins
  • Homozygous sitosterolemia

A 2018 review found that ezetimibe used as sole treatment slightly lowered plasma levels of lipoprotein(a), but the effect was not large enough to be important.[20]

Ezetimibe improves the non-alcoholic fatty liver disease activity score but the available evidence indicates it does not improve outcomes of hepatic steatosis.[21]

Contraindications

The two contraindications to taking ezetimibe are a previous allergic reaction to it, including symptoms of rash, angioedema, and anaphylaxis, and severe liver disease, especially when taken with a statin.[22]

Ezetimibe may have significant medication interactions with ciclosporin and with fibrates other than fenofibrate.[2]

Adverse effects

Common adverse drug reactions (≥1% of patients) associated with ezetimibe therapy include headache and/or diarrhea (steatorrhea). Infrequent adverse effects (0.1–1% of patients) include myalgia and/or raised liver function test (ALT/AST) results. Rarely (<0.1% of patients), hypersensitivity reactions (rash, angioedema) or myopathy may occur.[2] Cases of muscle problems (myalgia and rhabdomyolysis) have been reported and are included as warnings on the label for ezetimibe.[2]

Since NPC1L1 also regulates vitamin K uptake, the use of ezetimibe can lead to side effects in warfarin therapy.[23]

Overdose

The incidence of overdose with ezetimibe is rare; subsequently, few data exist on the effects of overdose. However, an acute overdose of ezetimibe is expected to produce an exaggeration of its usual effects, leading to loose stools, abdominal pain, and fatigue.[24]

Pharmacology

Mechanism of action

Ezetimibe inhibits the absorption of cholesterol from the small intestine and decreases the amount of cholesterol normally available to liver cells. The lower levels of cholesterol in the liver cells leads them to absorb more cholesterol from circulation and thus lowering the levels of circulating cholesterol. It blocks the critical mediator of cholesterol absorption, the Niemann-Pick C1-like 1 (NPC1L1) protein on the gastrointestinal tract epithelial cells, as well as in hepatocytes; it blocks aminopeptidase N and interrupts a caveolin 1–annexin A2 complex involved in trafficking cholesterol.[13]

Pharmacokinetics

Within 4–12 hours of the oral administration of a 10-mg dose to fasting adults, the attained mean ezetimibe peak plasma concentration (Cmax) was 3.4–5.5 ng/ml. Following oral administration, ezetimibe is absorbed and extensively conjugated to a phenolic glucuronide (active metabolite). Mean Cmax (45–71 ng/ml) of ezetimibe-glucuronide is attained within 1–2 hours. The concomitant administration of food (high-fat vs. nonfat meals) has no effect on the extent of absorption of ezetimibe. However, coadministration with a high-fat meal increases its Cmax by 38%. The absolute bioavailability cannot be determined, since ezetimibe is insoluble in aqueous media suitable for injection. Ezetimibe and its active metabolites are highly bound to human plasma proteins (90%).[2]

Ezetimibe is primarily metabolized in the liver and the small intestine via glucuronide conjugation with subsequent renal and biliary excretion.[25] Both the parent compound and its active metabolite are eliminated from plasma with a half-life around 22 hours, allowing for once-daily dosing. Ezetimibe lacks significant inhibitor or inducer effects on cytochrome P450 isoenzymes, which explains its limited number of drug interactions. No dose adjustment is needed in patients with chronic kidney disease or mild hepatic dysfunction (Child-Pugh score 5–6). Due to insufficient data, the manufacturer does not recommend ezetimibe for patients with moderate to severe hepatic impairment (Child-Pugh score 7–15). In patients with mild, moderate, or severe hepatic impairment, the mean AUC values for total ezetimibe are increased about 1.7-fold, 3-to-4-fold, and 5-to-6-fold, respectively, compared to healthy subjects.[2]

References

  1. ↑ 1.0 1.1 https://www.tga.gov.au/resources/auspar/auspar-ezetimibe
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 "Zetia- ezetimibe tablet". 26 January 2011. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=582e1593-1e6c-4ce8-8bae-134fbc3a66f0. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 "Ezetimibe Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/ezetimibe.html. 
  4. ↑ 4.0 4.1 4.2 4.3 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 196. ISBN 9780857113382. 
  5. ↑ "Vytorin- ezetimibe and simvastatin tablet". 1 June 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=89b860d2-de83-468e-b7e8-76aeec2edca2. 
  6. ↑ "Liptruzet (ezetimibe and atorvastatin) tablets for oral useInitial U.S. Approval: 2013". 30 September 2016. https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=257849. 
  7. ↑ "Roszet- rosuvastatin and ezetimibe tablet Roszet (- rosuvastatin and ezetimibe tablet". 15 September 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1653b3c4-2b2a-408b-918a-c687918c6265. 
  8. ↑ "Nexlizet- bempedoic acid and ezetimibe tablet, film coated". 24 September 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3fa2108c-0300-47b8-9d34-f762af7c93c6. 
  9. ↑ "Ezetimibe (Zetia) Use During Pregnancy". https://www.drugs.com/pregnancy/ezetimibe.html. 
  10. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  11. ↑ "Ezetimibe - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Ezetimibe. 
  12. ↑ "Safety and efficacy of ezetimibe: A meta-analysis". International Journal of Cardiology 201: 247–252. December 2015. doi:10.1016/j.ijcard.2015.08.103. PMID 26301648. 
  13. ↑ 13.0 13.1 "Ezetimibe therapy: mechanism of action and clinical update". Vascular Health and Risk Management 8: 415–427. 2012. doi:10.2147/VHRM.S33664. PMID 22910633. 
  14. ↑ "Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes". The New England Journal of Medicine 372 (25): 2387–2397. June 2015. doi:10.1056/NEJMoa1410489. PMID 26039521. 
  15. ↑ "Management of Blood Cholesterol". JAMA 321 (8): 800–801. February 2019. doi:10.1001/jama.2019.0015. PMID 30715135. 
  16. ↑ "ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS)". Atherosclerosis 217 (1): 3–46. July 2011. doi:10.1016/j.atherosclerosis.2011.06.011. PMID 21882396. 
  17. ↑ "Executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan -2012 version". Journal of Atherosclerosis and Thrombosis 20 (6): 517–523. 2013. doi:10.5551/jat.15792. PMID 23665881. 
  18. ↑ "Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease | Guidance and guidelines | NICE". http://www.nice.org.uk/Guidance/CG181++++. 
  19. ↑ "An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia--full report". Journal of Clinical Lipidology 8 (1): 29–60. 2014. doi:10.1016/j.jacl.2013.12.005. PMID 24528685. 
  20. ↑ "Effect of Ezetimibe Monotherapy on Plasma Lipoprotein(a) Concentrations in Patients with Primary Hypercholesterolemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials". Drugs 78 (4): 453–462. March 2018. doi:10.1007/s40265-018-0870-1. PMID 29396832. 
  21. ↑ "Ezetimibe decreased nonalcoholic fatty liver disease activity score but not hepatic steatosis". The Korean Journal of Internal Medicine 34 (2): 296–304. March 2019. doi:10.3904/kjim.2017.194. PMID 29551054. 
  22. ↑ "Ezetimibe". Medline Plus. U.S. National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services.. 27 October 2014. https://www.nlm.nih.gov/medlineplus/druginfo/meds/a603015.html. 
  23. ↑ "NPC1L1 is a key regulator of intestinal vitamin K absorption and a modulator of warfarin therapy". Science Translational Medicine 7 (275): 275ra23. February 2015. doi:10.1126/scitranslmed.3010329. PMID 25696002. 
  24. ↑ "Ezetimibe - National Library of Medicine HSDB Database". National Library of Medicine. https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+7737. 
  25. ↑ "Concurrent determination of ezetimibe and its phase-I and II metabolites by HPLC with UV detection: quantitative application to various in vitro metabolic stability studies and for qualitative estimation in bile". Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences 853 (1–2): 88–96. June 2007. doi:10.1016/j.jchromb.2007.02.053. PMID 17442643. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Ezetimibe&oldid=3423031"