Felodipine

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Felodipine
Felodipine structure.svg
Felodipine-from-xtal-1989-3D-balls.png
Names
Trade namesPlendil
  • (RS)-3-ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
Clinical data
Drug classCalcium channel blocker[1]
Main usesHigh blood pressure, angina[1][2]
Side effectsSwelling, headache, flushing[1]
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
use
By mouth
Onset of action2.5–5 hours
Typical dose2.5 to 10 mg OD[2]
External links
AHFS/Drugs.comMonograph
US NLMFelodipine
MedlinePlusa692016
Legal
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetics
Bioavailability15%
MetabolismLiver
Elimination half-life25 hours[3]
ExcretionKidney
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, sold under the brand name Plendil among others, is a medication is used to treat high blood pressure and heart related chest pain (angina).[1][2] It is one of several first line options.[1] It is taken by mouth.[1]

Common side effects include swelling, headache, and flushing.[1] Other side effects may include syncope and low blood pressure.[1] There are concerns regarding negative effects if used during pregnancy.[5] It is a calcium channel blocker of the dihydropyridine type.[1]

Felodipine was patented in 1978 and approved for medical use in 1988.[6] It is available as a generic medication.[2] In the United Kingdom 4 weeks of 5 mg per day costs about £4 as of 2021.[2] This amount is about 11 USD in the United States.[7] It is also available in combination with ramipril.[2]

Medical uses

Felodipine is used to treat high blood pressure and stable angina.[3][8]

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.[3]

For people with liver failure the dose needs to be lowered, because felodipine is cleared by the liver.[3]

Dosage

It is generally started at 5 mg per day and may be increased to 10 mg per day if needed.[2] In the elderly 2.5 mg per day may be used.[2]

Side effects

Gum enlargement due to felodipine

The only very common side effect, occurring in more than 1/10 people, is pain and swelling in the arms and legs.[3]

Common side effects, occurring in between 1% and 10% of people, include flushing, headache, heart palpitations, dizziness and fatigue.[3]

Felodipine can exacerbate gingivitis.[3]

Interactions

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

CYP3A4 inhibitors, which increase the amount of felodipine available per dose, include cimetidine, erythromycin, itraconazole, ketoconazole, HIV protease inhibitors, and grapefruit juice.[3][9]

CYP3A4 activators, which decrease the amount of felodipine available per dose, include phenytoin, carbamazepine, rifampicin, barbiturates, efavirenz, nevirapine, and Saint John's wort.[3]

Mechanism of action

Felodipine is a calcium channel blocker.[3] Felodipine has additionally been found to act as an antagonist of the mineralocorticoid receptor, or as an antimineralocorticoid.[10]

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.[11]: 172 

Chemistry

Felodipine is a member of the 1,4-dihydropyridine class of calcium channel blockers.[11]: 20–21  It is a racemic mixture, and is insoluble in water but is soluble in dichloromethane and ethanol.[11]: 25 

History

The Swedish company Hässle, a division of Astra AB, discovered felodipine;[12] it filed a patent application in 1979 claiming felodipine as an antihypertensive drug.[13][14] Astra partnered this drug and others with Merck & Co. in the US under a 1982 agreement between the companies.[12] The drug was approved by the FDA in 1991 after a three and a half year review; the drug entered a very crowded market the included the other calcium channel blockers nifedipine, verapamil, nicardipine, and isradipine.[12] 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.[12]

In 1994 Astra AB and Merck changed their partnership to a joint venture called Astra Merck,[15] and in 1998 Astra (by that time, AstraZeneca) bought out Merck's rights in the joint venture.[16]

The first generics became available in Sweden in 2003[17] and in the US in 2004.[18]: 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.[19]

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.[20]

The combination of felodipine and candesartan was marketed as Atacand.[20]

The combination of felodipine and ramipril was marketed as Delmuno, Tazko, Triacor, Triapin, Triasyn, Tri-Plen, Unimax, and Unitens.[20]

The combination of felodipine and enalapril was marketed as Lexxel.[20]

The combination of felodipine and metoprolol was marketed as Logimat, Logimax, and Mobloc.[20]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "Felodipine Monograph for Professionals". Drugs.com. Retrieved 10 December 2021.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 174. ISBN 978-0857114105.
  3. 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 "Felopidine UK label". UK Electronic Medicines Compendium. 15 September 2015.
  4. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, Volume 115, 2013, pp. 887-890
  5. "Felodipine (Plendil) Use During Pregnancy". Drugs.com. Retrieved 10 December 2021.
  6. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 465. ISBN 9783527607495.
  7. "Felodipine ER Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 10 December 2021.
  8. "Felodipine US label" (PDF). FDA. October 2012.
  9. 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..
  10. Luther JM (September 2014). "Is there a new dawn for selective mineralocorticoid receptor antagonism?". Current Opinion in Nephrology and Hypertension. 23 (5): 456–61. doi:10.1097/MNH.0000000000000051. PMC 4248353. PMID 24992570.
  11. 11.0 11.1 11.2 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.
  12. 12.0 12.1 12.2 12.3 "Merck's Plendil (Felodipine) Approved with "1C" Rating". Pink Sheet. 5 August 1991.
  13. Astrazeneca AB v. Mutual Pharmaceutical Co. (United States Court of Appeals for the Federal Circuit 2004).Text
  14. US patent 4,264,611, Berntsson, Peder; Carlsson, Stig & Gaarder, Jan et al., "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 
  15. George J (28 July 1997). "Secret of Astra Merck". Philadelphia Business Journal. Philadelphia. Retrieved 7 November 2016.
  16. "Astra, Merck restructure". CNNMoney. 19 June 1998. Retrieved 7 November 2016.
  17. 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.
  18. Approved Drug Products with Therapeutic Equivalence Evaluations (PDF) (36th ed.). FDA. 2014.
  19. "AstraZeneca enters licensing agreement with China Medical System Holdings for hypertension medicine" (Press release). AstraZeneca. 29 February 2016. Retrieved 7 November 2016.
  20. 20.0 20.1 20.2 20.3 20.4 "International brand names: Felodipine". Drugs.com. Retrieved 15 November 2016.

External links

Identifiers: