Felodipine Explained

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.[1]

Medical uses

Felodipine is used to treat high blood pressure and stable angina.[2]

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.

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

Adverse effects

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

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

Felodipine can exacerbate gingivitis.

Interactions

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

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

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

Mechanism of action

Felodipine is a calcium channel blocker. Felodipine has additionally been found to act as an antagonist of the mineralocorticoid receptor, or as an antimineralocorticoid.[4]

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.

Chemistry

Felodipine is a member of the 1,4-dihydropyridine class of calcium channel blockers.[5] It is a racemic mixture, and is insoluble in water but is soluble in dichloromethane and ethanol.[5]

History

The Swedish company Hässle, a division of Astra AB, discovered felodipine; it filed a patent application in 1979 claiming felodipine as an antihypertensive drug.[6] [7] Astra partnered this drug and others with Merck & Co. in the US under a 1982 agreement between the companies.[8] 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.[8] 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.[8]

In 1994 Astra AB and Merck changed their partnership to a joint venture called Astra Merck,[9] and in 1998 Astra (by that time, AstraZeneca) bought out Merck's rights in the joint venture.[10]

The first generics became available in Sweden in 2003[11] and in the US in 2004.[12]

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.[13]

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.[14]

The combination of felodipine and candesartan was marketed as Atacand.[14]

The combination of felodipine and ramipril was marketed as Delmuno, Tazko, Triacor, Triapin, Triasyn, Tri-Plen, Unimax, and Unitens.[14]

The combination of felodipine and enalapril was marketed as Lexxel.[14]

The combination of felodipine and metoprolol was marketed as Logimat, Logimax, and Mobloc.[14]

Notes and References

  1. Book: Fischer J, Ganellin CR . Analogue-based Drug Discovery . 2006 . John Wiley & Sons . 9783527607495 . 465 . en.
  2. Web site: Felodipine US label. FDA. October 2012.
  3. Kiani J, Imam SZ . Medicinal importance of grapefruit juice and its interaction with various drugs . Nutrition Journal . 6 . 33 . 33 . October 2007 . 17971226 . 2147024 . 10.1186/1475-2891-6-33 . free . .
  4. Luther JM . Is there a new dawn for selective mineralocorticoid receptor antagonism? . Current Opinion in Nephrology and Hypertension . 23 . 5 . 456–461 . September 2014 . 24992570 . 4248353 . 10.1097/MNH.0000000000000051 .
  5. Book: Joshi GS, Burnett JC, Abraham DJ . Abraham DJ . Burger's medicinal chemistry and drug discovery. Volume 3: Cardiovascular Agents and Endocrines . 2003 . Wiley . Hoboken, N.J. . 9780471270904. 6th. Cardiac Drugs: Antianginal, Vasodilators, Antiarrhythmic.
  6. Astrazeneca AB v. Mutual Pharmaceutical Co. . United States Court of Appeals for the Federal Circuit . 2004 . http://www.finnegan.com/files/Publication/accd1584-eb7c-4960-802d-575bd78b6477/Presentation/PublicationAttachment/19322ddc-88ee-42cb-8063-61f950956040/04-1100%209-30-04.pdf . 2016-11-10 .
  7. US. 4,264,611. patent. 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. 28 April 1981. 19 June 1979-06-19 . Berntsson P, Carlsson S, Gaarder J, Ljung B . Aktiebolaget Hassle.
  8. News: Merck's Plendil (Felodipine) Approved with "1C" Rating. Pink Sheet. 5 August 1991.
  9. News: George J . 1997-07-28 . Secret of Astra Merck . Philadelphia Business Journal . Philadelphia . 2016-11-07 .
  10. News: . Astra, Merck restructure . CNNMoney . 1998-06-19 . 2016-11-07.
  11. Book: Jönsson B . Rapoport J, Jacobs P, Jonsson E . Cost Containment and Efficiency in National Health Systems a Global Comparison.. 2008. Wiley-VCH. Weinheim. 9783527622955. 218. https://books.google.com/books?id=XdMez8MdN0sC&pg=PA218. Sweden.
  12. Book: Approved Drug Products with Therapeutic Equivalence Evaluations . 2014 . FDA . 36th .
  13. . AstraZeneca enters licensing agreement with China Medical System Holdings for hypertension medicine . AstraZeneca . 29 February 2016 . 2016-11-07.
  14. Web site: International brand names: Felodipine. Drugs.com. 15 November 2016.