Felodipine

Felodipine
Names
Trade namesPlendil
IUPAC name
  • (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]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
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
    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)
    SMILES
    • O=C(OCC)\C1=C(\N/C(=C(/C(=O)OC)C1c2cccc(Cl)c2Cl)C)C
    InChI
    • 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

    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.[4] It is a calcium channel blocker of the dihydropyridine type.[1]

    Felodipine was patented in 1978 and approved for medical use in 1988.[5] 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.[6] It is also available in combination with ramipril.[2]

    Medical uses

    Felodipine is used to treat high blood pressure and stable angina.[3][7]

    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][8]

    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.[9]

    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.[10]: 172 

    Chemistry

    Felodipine is a member of the 1,4-dihydropyridine class of calcium channel blockers.[10]: 20–21  It is a racemic mixture, and is insoluble in water but is soluble in dichloromethane and ethanol.[10]: 25 

    History

    The Swedish company Hässle, a division of Astra AB, discovered felodipine;[11] it filed a patent application in 1979 claiming felodipine as an antihypertensive drug.[12][13] Astra partnered this drug and others with Merck & Co. in the US under a 1982 agreement between the companies.[11] 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.[11] 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.[11]

    In 1994 Astra AB and Merck changed their partnership to a joint venture called Astra Merck,[14] and in 1998 Astra (by that time, AstraZeneca) bought out Merck's rights in the joint venture.[15]

    The first generics became available in Sweden in 2003[16] and in the US in 2004.[17]: 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.[18]

    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.[19]

    The combination of felodipine and candesartan was marketed as Atacand.[19]

    The combination of felodipine and ramipril was marketed as Delmuno, Tazko, Triacor, Triapin, Triasyn, Tri-Plen, Unimax, and Unitens.[19]

    The combination of felodipine and enalapril was marketed as Lexxel.[19]

    The combination of felodipine and metoprolol was marketed as Logimat, Logimax, and Mobloc.[19]

    References

    1. 1 2 3 4 5 6 7 8 9 "Felodipine Monograph for Professionals". Drugs.com. Archived from the original on 15 August 2020. Retrieved 10 December 2021.
    2. 1 2 3 4 5 6 7 8 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 174. ISBN 978-0857114105.
    3. 1 2 3 4 5 6 7 8 9 10 11 "Felopidine UK label". UK Electronic Medicines Compendium. 15 September 2015. Archived from the original on 16 August 2019. Retrieved 9 March 2021.
    4. ↑ "Felodipine (Plendil) Use During Pregnancy". Drugs.com. Archived from the original on 29 November 2020. Retrieved 10 December 2021.
    5. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 465. ISBN 9783527607495. Archived from the original on 27 August 2021. Retrieved 9 March 2021.
    6. ↑ "Felodipine ER Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 10 December 2021.
    7. ↑ "Felodipine US label" (PDF). FDA. October 2012. Archived (PDF) from the original on 31 March 2021. Retrieved 9 March 2021.
    8. ↑ 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..
    9. ↑ 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.
    10. 1 2 3 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.
    11. 1 2 3 4 "Merck's Plendil (Felodipine) Approved with "1C" Rating". Pink Sheet. 5 August 1991. Archived from the original on 15 November 2016. Retrieved 9 March 2021.
    12. ↑ Astrazeneca AB v. Mutual Pharmaceutical Co. (United States Court of Appeals for the Federal Circuit 2004).Text
    13. ↑ 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 
    14. ↑ George J (28 July 1997). "Secret of Astra Merck". Philadelphia Business Journal. Philadelphia. Archived from the original on 10 November 2016. Retrieved 7 November 2016.
    15. ↑ "Astra, Merck restructure". CNNMoney. 19 June 1998. Archived from the original on 16 August 2019. Retrieved 7 November 2016.
    16. ↑ 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. Archived from the original on 21 March 2017. Retrieved 9 March 2021.
    17. ↑ Approved Drug Products with Therapeutic Equivalence Evaluations (PDF) (36th ed.). FDA. 2014. Archived (PDF) from the original on 15 November 2016. Retrieved 9 March 2021.
    18. ↑ "AstraZeneca enters licensing agreement with China Medical System Holdings for hypertension medicine" (Press release). AstraZeneca. 29 February 2016. Archived from the original on 3 March 2021. Retrieved 7 November 2016.
    19. 1 2 3 4 5 "International brand names: Felodipine". Drugs.com. Archived from the original on 15 November 2016. Retrieved 15 November 2016.
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