View source for Felodipine

{{short description|Medication of the calcium channel blocker type}}
{{cs1 config|name-list-style=vanc}}
{{Use dmy dates|date=February 2015}}
{{Drugbox
| Watchedfields = changed
| verifiedrevid = 461099283
| IUPAC_name = (''RS'')-3-ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
| image = Felodipine structure.svg
| image_class = skin-invert-image
| image2 = Felodipine-from-xtal-1989-3D-balls.png
| image_class2 = bg-transparent
<!--Clinical data-->
| tradename = Plendil
| Drugs.com = {{drugs.com|monograph|felodipine}}
| MedlinePlus = a692016
| pregnancy_US = C
| legal_status = Rx-only
| routes_of_administration = [[Mouth|Oral]]
<!--Pharmacokinetic data-->
| bioavailability = 15%
<!-- | pKa = 5.07 <ref>Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, Volume 115, 2013, pp. 887-890</ref> -->
| metabolism = [[Liver|Hepatic]]
| onset = 2.5–5 hours
| elimination_half-life = 25 hours<ref name=UKlabel2015>{{cite web|title=Felopidine UK label|url=https://www.medicines.org.uk/emc/medicine/191/SPC/Plendil+2.5mg,+Plendil+5mg+and+Plendil+10mg/|publisher=UK Electronic Medicines Compendium|date=15 September 2015|access-date=19 February 2015|archive-date=16 August 2019|archive-url=https://web.archive.org/web/20190816034416/https://www.medicines.org.uk/emc/medicine/191/SPC/Plendil%2B2.5mg,%2BPlendil%2B5mg%2Band%2BPlendil%2B10mg/|url-status=dead}}</ref>
| excretion = [[Kidney|Renal]]
<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 72509-76-3
| ATC_prefix = C08
| ATC_suffix = CA02
| PubChem = 3333
| IUPHAR_ligand = 4190
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01023
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3216
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = OL961R6O2C
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00319
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 585948
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1480
<!--Chemical data-->
| C=18 | H=19 | Cl=2 | N=1 | O=4
| smiles = O=C(OCC)\C1=C(\N/C(=C(/C(=O)OC)C1c2cccc(Cl)c2Cl)C)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = RZTAMFZIAATZDJ-UHFFFAOYSA-N
}}
<!-- Definition and medical uses -->
'''Felodipine''' is a medication of the [[calcium channel blocker]] type that is used to treat [[hypertension|high blood pressure]].

<!-- Society and culture -->
It was patented in 1978, and approved for medical use in 1988.<ref>{{cite book | vauthors = Fischer J, Ganellin CR |title= Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=465 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA465 |language=en}}</ref>

==Medical uses==
Felodipine is used to treat [[hypertension|high blood pressure]] and stable [[angina]].<ref name=UKlabel2015/><ref name=USlabel2012>{{cite web|title=Felodipine US label|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019834s025lbl.pdf|archive-url=https://web.archive.org/web/20161115141024/http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019834s025lbl.pdf|url-status=dead|archive-date=15 November 2016|publisher=FDA|date=October 2012}}</ref>

It should not be used for people who are pregnant, have [[decompensated heart failure|acute heart failure]], are having a [[heart attack]], have an [[Valvular heart disease|obstructed heart valve]], or have obstructions that block [[Pressure overload|bloodflow out of the heart]].<ref name=UKlabel2015/>

For people with [[liver failure]] the dose needs to be lowered, because felodipine is cleared by the liver.<ref name=UKlabel2015/>

==Adverse effects==
The only very common side effect, occurring in more than 1/10 people, is [[edema|pain and swelling]] in the arms and legs.<ref name=UKlabel2015/>

Common side effects, occurring in between 1% and 10% of people, include flushing, headache, [[heart palpitation]]s, dizziness and fatigue.<ref name=UKlabel2015/>

Felodipine can exacerbate [[gingivitis]].<ref name=UKlabel2015/>

== Interactions ==

Felodipine is metabolized by [[CYP3A4|cytochrome P450 3A4]], so substances that inhibit or activate CYP3A4 can strongly effect how much felodipine is present.<ref name=UKlabel2015/>

CYP3A4 inhibitors, which increase the amount of felodipine available per dose, include [[cimetidine]], [[erythromycin]], [[itraconazole]], [[ketoconazole]], [[Protease inhibitor (pharmacology)|HIV protease inhibitors]], and [[grapefruit juice]].<ref name=UKlabel2015/><ref>{{cite journal | vauthors = Kiani J, Imam SZ | title = Medicinal importance of grapefruit juice and its interaction with various drugs | journal = Nutrition Journal | volume = 6 | issue = 33 | article-number = 33 | date = October 2007 | pmid = 17971226 | pmc = 2147024 | doi = 10.1186/1475-2891-6-33 | doi-access = free }}.</ref>

CYP3A4 activators, which decrease the amount of felodipine available per dose, include [[phenytoin]], [[carbamazepine]], [[rifampicin]], [[barbiturates]], [[efavirenz]], [[nevirapine]], and [[Saint John's wort]].<ref name=UKlabel2015/>

==Mechanism of action==
Felodipine is a [[calcium channel blocker]].<ref name=UKlabel2015/> Felodipine has additionally been found to act as an [[receptor antagonist|antagonist]] of the [[mineralocorticoid receptor]], or as an [[antimineralocorticoid]].<ref name="Luther2014">{{cite journal | vauthors = Luther JM | title = Is there a new dawn for selective mineralocorticoid receptor antagonism? | journal = Current Opinion in Nephrology and Hypertension | volume = 23 | issue = 5 | pages = 456–461 | date = September 2014 | pmid = 24992570 | pmc = 4248353 | doi = 10.1097/MNH.0000000000000051 }}</ref>

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.<ref name=Burger/>{{rp|172}}

==Chemistry==
Felodipine is a member of the 1,4-[[dihydropyridine]] class of calcium channel blockers.<ref name=Burger>{{cite book| vauthors = Joshi GS, Burnett JC, Abraham DJ | veditors = Abraham DJ |title=Burger's medicinal chemistry and drug discovery. Volume 3: Cardiovascular Agents and Endocrines |date=2003 |publisher=Wiley |location=Hoboken, N.J. |isbn=9780471270904|edition=6th|chapter=Cardiac Drugs: Antianginal, Vasodilators, Antiarrhythmic}}</ref>{{rp|20–21}}  It is a racemic mixture, and is insoluble in water but is soluble in dichloromethane and ethanol.<ref name=Burger/>{{rp|25}}

==History==
The Swedish company Hässle, a division of [[Astra AB]], [[drug discovery|discovered]] felodipine;<ref name=PinkSheet1991/> it filed a patent application in 1979 claiming felodipine as an antihypertensive drug.<ref name=court>{{cite court |litigants=Astrazeneca AB v. Mutual Pharmaceutical Co. |vol= |reporter= |opinion= |pinpoint= |court=United States Court of Appeals for the Federal Circuit |date=2004 |url=http://www.finnegan.com/files/Publication/accd1584-eb7c-4960-802d-575bd78b6477/Presentation/PublicationAttachment/19322ddc-88ee-42cb-8063-61f950956040/04-1100%209-30-04.pdf |access-date=2016-11-10 |quote=}}</ref><ref name=Patent611>{{cite patent| country = US| number  = 4,264,611| status  = patent| title = 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| gdate = 28 April 1981| fdate = 19 June 1979-06-19 | inventor = Berntsson P, Carlsson S, Gaarder J, Ljung B | assign1 = Aktiebolaget Hassle| url   = https://patents.google.com/patent/US4264611A/en}}</ref>  Astra partnered this drug and others with [[Merck & Co.]] in the US under a 1982 agreement between the companies.<ref name=PinkSheet1991>{{cite news|title=Merck's Plendil (Felodipine) Approved with "1C" Rating|url=https://pink.pharmamedtechbi.com/PS019532/MERCKs-PLENDIL-FELODIPINE-APPROVED-WITH-1C-RATING|work=Pink Sheet|date=5 August 1991}}</ref>  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]].<ref name=PinkSheet1991/>  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.<ref name=PinkSheet1991/>

In 1994 Astra AB and Merck changed their partnership to a [[joint venture]] called Astra Merck,<ref name=biz>{{cite news | vauthors = George J |date=1997-07-28 |title=Secret of Astra Merck |url=http://www.bizjournals.com/philadelphia/stories/1997/07/28/story3.html |newspaper=Philadelphia Business Journal |location=Philadelphia |access-date=2016-11-07 }}</ref> and in 1998 Astra (by that time, [[AstraZeneca]])  bought out Merck's rights in the joint venture.<ref name=cnnmoney>{{cite news |author=<!--Staff writer(s); no by-line.--> |title=Astra, Merck restructure |url=https://money.cnn.com/1998/06/19/deals/merck/ |newspaper=CNNMoney |date=1998-06-19 |access-date=2016-11-07}}</ref>

The first generics became available in Sweden in 2003<ref>{{cite book| vauthors = Jönsson B | veditors = Rapoport J, Jacobs P, Jonsson E |title=Cost Containment and Efficiency in National Health Systems a Global Comparison.|date=2008|publisher=Wiley-VCH|location=Weinheim|isbn=9783527622955|page=218|chapter-url=https://books.google.com/books?id=XdMez8MdN0sC&pg=PA218|chapter=Sweden}}</ref> and in the US in 2004.<ref>{{cite book|title=Approved Drug Products with Therapeutic Equivalence Evaluations |date=2014 |publisher=FDA |edition=36th |url=http://www.nber.org/fda/orange-book/pdf/UCM071436.pdf}}</ref>{{rp|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.<ref name=AZrelease>{{cite press release |author=<!--Staff writer(s); no by-line.--> |title=AstraZeneca enters licensing agreement with China Medical System Holdings for hypertension medicine |url=https://www.astrazeneca.com/media-centre/press-releases/2016/AstraZeneca-enters-licensing-agreement-with-China-Medical-System-Holdings-for-hypertension-medicine-29022016.html |publisher=AstraZeneca |date=29 February 2016 |access-date=2016-11-07}}</ref>

==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.<ref name=brands2016>{{cite web|title=International brand names: Felodipine|url=https://www.drugs.com/international/felodipine.html|publisher=Drugs.com|access-date=15 November 2016}}</ref>

The combination of felodipine and [[candesartan]] was marketed as Atacand.<ref name=brands2016/>

The combination of felodipine and [[ramipril]] was marketed as Delmuno, Tazko, Triacor, Triapin, Triasyn, Tri-Plen, Unimax, and Unitens.<ref name=brands2016/>

The combination of felodipine and [[enalapril]] was marketed as Lexxel.<ref name=brands2016/>

The combination of felodipine and [[metoprolol]] was marketed as Logimat, Logimax, and Mobloc.<ref name=brands2016/>

== References ==
{{Reflist}}

{{Navboxes
| title = [[Pharmacodynamics]]
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| list1 = 
{{Ion channel modulators}}
{{Mineralocorticoid receptor modulators}}
{{Xenobiotic-sensing receptor modulators}}
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[[Category:Antimineralocorticoids]]
[[Category:Calcium channel blockers]]
[[Category:CYP2D6 inhibitors]]
[[Category:Dihydropyridines]]
[[Category:Drugs developed by AstraZeneca]]
[[Category:Carboxylate esters]]
[[Category:Chloroarenes]]