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Felodipine

Felodipine
Clinical data
Trade namesPlendil
AHFS/Drugs.comMonograph
MedlinePlusa692016
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
  • (RS)-3-ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.149.305 Edit this at Wikidata
Chemical and physical data
FormulaC18H19Cl2NO4
Molar mass384.25 g·mol−1
3D model (JSmol)
  • O=C(OCC)\C1=C(\N/C(=C(/C(=O)OC)C1c2cccc(Cl)c2Cl)C)C
  • InChI=1S/C18H19Cl2NO4/c1-5-25-18(23)14-10(3)21-9(2)13(17(22)24-4)15(14)11-7-6-8-12(19)16(11)20/h6-8,15,21H,5H2,1-4H3 checkY
  • Key:RZTAMFZIAATZDJ-UHFFFAOYSA-N checkY
  (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. ^ a b c d e f g h i j k "Felopidine UK label". UK Electronic Medicines Compendium. 15 September 2015. Archived from the original on 16 August 2019. Retrieved 19 February 2015.
  2. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 465. ISBN 9783527607495.
  3. ^ "Felodipine US label" (PDF). FDA. October 2012.
  4. ^ Kiani J, Imam SZ (October 2007). "Medicinal importance of grapefruit juice and its interaction with various drugs". Nutrition Journal. 6 (33): 33. doi:10.1186/1475-2891-6-33. PMC 2147024. PMID 17971226..
  5. ^ Luther JM (September 2014). "Is there a new dawn for selective mineralocorticoid receptor antagonism?". Current Opinion in Nephrology and Hypertension. 23 (5): 456–461. doi:10.1097/MNH.0000000000000051. PMC 4248353. PMID 24992570.
  6. ^ a b c Joshi GS, Burnett JC, Abraham DJ (2003). "Cardiac Drugs: Antianginal, Vasodilators, Antiarrhythmic". In Abraham DJ (ed.). Burger's medicinal chemistry and drug discovery. Volume 3: Cardiovascular Agents and Endocrines (6th ed.). Hoboken, N.J.: Wiley. ISBN 9780471270904.
  7. ^ a b c d "Merck's Plendil (Felodipine) Approved with "1C" Rating". Pink Sheet. 5 August 1991.
  8. ^ Astrazeneca AB v. Mutual Pharmaceutical Co. (United States Court of Appeals for the Federal Circuit 2004), Text.
  9. ^ US patent 4,264,611, 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", issued 28 April 1981, assigned to Aktiebolaget Hassle 
  10. ^ George J (28 July 1997). "Secret of Astra Merck". Philadelphia Business Journal. Philadelphia. Retrieved 7 November 2016.
  11. ^ "Astra, Merck restructure". CNNMoney. 19 June 1998. Retrieved 7 November 2016.
  12. ^ Jönsson B (2008). "Sweden". In Rapoport J, Jacobs P, Jonsson E (eds.). Cost Containment and Efficiency in National Health Systems a Global Comparison. Weinheim: Wiley-VCH. p. 218. ISBN 9783527622955.
  13. ^ Approved Drug Products with Therapeutic Equivalence Evaluations (PDF) (36th ed.). FDA. 2014.
  14. ^ "AstraZeneca enters licensing agreement with China Medical System Holdings for hypertension medicine" (Press release). AstraZeneca. 29 February 2016. Retrieved 7 November 2016.
  15. ^ a b c d e "International brand names: Felodipine". Drugs.com. Retrieved 15 November 2016.
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