Chemistry:Felodipine

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Short description: Medication of the calcium channel blocker type
Felodipine
Felodipine structure.svg
Felodipine-from-xtal-1989-3D-balls.png
Clinical data
Trade namesPlendil
AHFS/Drugs.comMonograph
MedlinePlusa692016
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability15%
MetabolismHepatic
Onset of action2.5–5 hours
Elimination half-life25 hours[1]
ExcretionRenal
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC18H19Cl2NO4
Molar mass384.25 g·mol−1
3D model (JSmol)
  (verify)

Felodipine is a medication of the calcium channel blocker type that is used to treat high blood pressure.

It was patented in 1978, and approved for medical use in 1988.[2]

Medical uses

Felodipine is used to treat high blood pressure and stable angina.[1][3]

It should not be used for people who are pregnant, have acute heart failure, are having a heart attack, have an obstructed heart valve, or have obstructions that block bloodflow out of the heart.[1]

For people with liver failure the dose needs to be lowered, because felodipine is cleared by the liver.[1]

Adverse effects

The only very common side effect, occurring in more than 1/10 people, is pain and swelling in the arms and legs.[1]

Common side effects, occurring in between 1% and 10% of people, include flushing, headache, heart palpitations, dizziness and fatigue.[1]

Felodipine can exacerbate gingivitis.[1]

Interactions

Felodipine is metabolized by cytochrome P450 3A4, so substances that inhibit or activate CYP3A4 can strongly effect how much felodipine is present.[1]

CYP3A4 inhibitors, which increase the amount of felodipine available per dose, include cimetidine, erythromycin, itraconazole, ketoconazole, HIV protease inhibitors, and grapefruit juice.[1][4]

CYP3A4 activators, which decrease the amount of felodipine available per dose, include phenytoin, carbamazepine, rifampicin, barbiturates, efavirenz, nevirapine, and Saint John's wort.[1]

Mechanism of action

Felodipine is a calcium channel blocker.[1] Felodipine has additionally been found to act as an antagonist of the mineralocorticoid receptor, or as an antimineralocorticoid.[5]

Different calcium channels are present in vascular tissue and cardiac tissue; an in vitro study on human vascular and cardiac tissues comparing how selective various calcium channel blockers are for vascular compared to cardiac tissue found the following vascular/cardiac tissue ratios: mibefradil 41, felodipine 12; nifedipine 7, amlodipine 5, and verapamil 0.2.[6]:172

Chemistry

Felodipine is a member of the 1,4-dihydropyridine class of calcium channel blockers.[6]:20–21 It is a racemic mixture, and is insoluble in water but is soluble in dichloromethane and ethanol.[6]:25

History

The Swedish company Hässle, a division of Astra AB, discovered felodipine;[7] it filed a patent application in 1979 claiming felodipine as an antihypertensive drug.[8][9] Astra partnered this drug and others with Merck & Co. in the US under a 1982 agreement between the companies.[7] The drug was approved by the FDA in 1991 after a three and a half year review; the drug entered a very crowded market to included the other calcium channel blockers nifedipine, verapamil, nicardipine, and isradipine.[7] The FDA gave the drug a 1C rating, meaning that it found little difference between felodipine and the drugs already approved for the same use.[7]

In 1994 Astra AB and Merck changed their partnership to a joint venture called Astra Merck,[10] and in 1998 Astra (by that time, AstraZeneca) bought out Merck's rights in the joint venture.[11]

The first generics became available in Sweden in 2003[12] and in the US in 2004.[13]:155

In April 2016, AstraZeneca announced that they were selling the right to market felodipine in China to China Medical System Holdings for $310 million; AZ would continue to manufacture the drug.[14]

Society and culture

As of 2016, felodipine was marketed under many brand names worldwide: Auronal, Cardioplen, Catrazil, Dewei, Dilahex, Enfelo, Erding, Fedil, Fedisyn, Feldil, Felicipin, Felo, Felocard, Felocor, Feloday, Felodil, Felodin, Felodip, Felodipin, Felodipina, Felodipine, Felodipino, Felodistad, Felogard, Felohexal, Felop, Felopine, Felostad, Feloten, Felotens, Felpin, Flodicar, Flodil, Keliping, Keydipin, Lodistad, Modip, Munobal, Nirmadil, Parmid, Penedil, Perfudal, Phelop, Phenodical, Plendil, Plentopine, Polo, Presid, Preslow, Prevex, Renedil, Sistar, Splendil, Stapin, Topidil, Vascalpha, Versant, and XiaoDing.[15]

The combination of felodipine and candesartan was marketed as Atacand.[15]

The combination of felodipine and ramipril was marketed as Delmuno, Tazko, Triacor, Triapin, Triasyn, Tri-Plen, Unimax, and Unitens.[15]

The combination of felodipine and enalapril was marketed as Lexxel.[15]

The combination of felodipine and metoprolol was marketed as Logimat, Logimax, and Mobloc.[15]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 "Felopidine UK label". UK Electronic Medicines Compendium. 15 September 2015. https://www.medicines.org.uk/emc/medicine/191/SPC/Plendil+2.5mg,+Plendil+5mg+and+Plendil+10mg/. 
  2. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 465. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA465. 
  3. ↑ "Felodipine US label". FDA. October 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019834s025lbl.pdf. 
  4. ↑ "Medicinal importance of grapefruit juice and its interaction with various drugs". Nutrition Journal 6 (33): 33. October 2007. doi:10.1186/1475-2891-6-33. PMID 17971226. .
  5. ↑ "Is there a new dawn for selective mineralocorticoid receptor antagonism?". Current Opinion in Nephrology and Hypertension 23 (5): 456–461. September 2014. doi:10.1097/MNH.0000000000000051. PMID 24992570. 
  6. ↑ 6.0 6.1 6.2 "Cardiac Drugs: Antianginal, Vasodilators, Antiarrhythmic". Burger's medicinal chemistry and drug discovery. Volume 3: Cardiovascular Agents and Endocrines (6th ed.). Hoboken, N.J.: Wiley. 2003. ISBN 9780471270904. 
  7. ↑ 7.0 7.1 7.2 7.3 "Merck's Plendil (Felodipine) Approved with "1C" Rating". Pink Sheet. 5 August 1991. https://pink.pharmamedtechbi.com/PS019532/MERCKs-PLENDIL-FELODIPINE-APPROVED-WITH-1C-RATING. 
  8. ↑ Astrazeneca AB v. Mutual Pharmaceutical Co. (United States Court of Appeals for the Federal Circuit 2004). Text
  9. ↑ Berntsson P, Carlsson S, Gaarder J, Ljung B, "2,6-Dimethyl-4-2,3-Disubstituted Phenyl-1,4-Dihydro-Pyridine-3,5 Dicarboxylic Acid-3,5-Asymmetric Diesters having Hypotensive Properties, as well as Method for Treating Hypertensive Conditions and Pharmaceutical Preparations Containing Same", US patent 4,264,611, issued 28 April 1981, assigned to Aktiebolaget Hassle
  10. ↑ "Secret of Astra Merck". Philadelphia Business Journal (Philadelphia). 1997-07-28. http://www.bizjournals.com/philadelphia/stories/1997/07/28/story3.html. 
  11. ↑ "Astra, Merck restructure". CNNMoney. 1998-06-19. https://money.cnn.com/1998/06/19/deals/merck/. 
  12. ↑ "Sweden". Cost Containment and Efficiency in National Health Systems a Global Comparison.. Weinheim: Wiley-VCH. 2008. p. 218. ISBN 9783527622955. https://books.google.com/books?id=XdMez8MdN0sC&pg=PA218. 
  13. ↑ Approved Drug Products with Therapeutic Equivalence Evaluations (36th ed.). FDA. 2014. http://www.nber.org/fda/orange-book/pdf/UCM071436.pdf. 
  14. ↑ "AstraZeneca enters licensing agreement with China Medical System Holdings for hypertension medicine" (Press release). AstraZeneca. 29 February 2016. Retrieved 2016-11-07.
  15. ↑ 15.0 15.1 15.2 15.3 15.4 "International brand names: Felodipine". Drugs.com. https://www.drugs.com/international/felodipine.html. 



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