Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Nifedipine: Difference between pages

{{Short description|Calcium channel blocker medication}}

{{Redirect|Camont|the unincorporated community in West Virginia|Gaymont, West Virginia}}

{{Use dmy dates|date=October 2022}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

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| imageL = Nifedipine.svg

| imageR = Nifedipine-from-xtal-3D-balls.png

| image2 = Nifedipine_substance_photo.jpg

| =

| altR =

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<!--Clinical data-->

| tradename = Procardia

| DailyMedID = Nifedipine

|

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web|title=Nifedipine Pregnancy and Breastfeeding Warnings|url=https://www.drugs.com/pregnancy/nifedipine.html|access-date=25 December 2015|url-status=live|archive-url=https://web.archive.org/web/20151221122156/http://www.drugs.com/pregnancy/nifedipine.html|archive-date=21 December 2015}}</ref>

| pregnancy_category=

| routes_of_administration = [[Oral administration|By mouth]], [[Topical administration|topical]]

| class = [[Calcium channel blocker]] ([[dihydropyridine]])<ref name=AHFS2015/>

| ATC_prefix = C08

| ATC_suffix = CA05

| ATC_supplemental =

<!-- -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = Rx-only

| legal_CA_comment = <ref>{{cite web | title=Product monograph brand safety updates | website=Health Canada | date=February 2024 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/label-safety-assessment-update/product-monograph-brand-safety-updates.html | access-date=24 March 2024}}</ref>

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| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->

| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment =

| legal_EU =

| legal_EU_comment =

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->

| metabolism = Gastrointestinal,

| excretion = : >50%, : 5-15%

<!--Identifiers-->

| IUPHAR_ligand = 2514

| ChEBI_Ref = {{ebicite||EBI}}

<!--Chemical data-->

| IUPAC_name = 3,5-dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

| C=17 | H=18 | N=2 | O=6

<!-- Definition and medical uses -->

'''Nifedipine''', sold under the brand name '''Procardia''' among others, is a [[calcium channel blocker]] medication used to manage [[angina]], [[hypertension|high blood pressure]], [[Raynaud's phenomenon]], and [[premature labor]].<ref name=AHFS2015>{{cite web|title=Nifedipine|url=https://www.drugs.com/monograph/nifedipine.html|publisher=The American Society of Health-System Pharmacists|access-date=17 September 2019|url-status=live|archive-url=https://web.archive.org/web/20180808043257/https://www.drugs.com/monograph/nifedipine.html|archive-date=8 August 2018}}</ref> It is one of the treatments of choice for [[Prinzmetal angina]].<ref name=AHFS2015/> It may be used to treat severe [[high blood pressure in pregnancy]].<ref name=AHFS2015/> Its use in preterm labor may allow more time for [[corticosteroid|steroids]] to improve the baby's lung function and provide time for transfer of the mother to a well qualified medical facility before delivery.<ref name=AHFS2015/> It is a calcium channel blocker of the [[Dihydropyridine calcium channel blockers|dihydropyridine]] type.<ref name=AHFS2015/> Nifedipine is taken by mouth and comes in fast- and slow-release formulations.<ref name=AHFS2015/>

<!-- Side effects and mechanism -->

Common side effects include [[lightheadedness]], [[headache]], feeling tired, leg swelling, cough, and shortness of breath.<ref name=AHFS2015/> Serious side effects may include [[hypotension|low blood pressure]] and [[heart failure]].<ref name=AHFS2015/> Nifedipine is considered safe in pregnancy and breastfeeding.<ref name="NICHHD 2023">{{cite journal | journal = Drugs and Lactation Database | location = Bethesda (MD) | publisher = National Institute of Child Health and Human Development | title = Nifedipine | date = 15 August 2023 | pmid = 30000106 | url = https://www.ncbi.nlm.nih.gov/books/NBK501047/ |access-date=14 October 2023 }}</ref>

<!-- History, society and culture -->

Nifedipine was patented in 1967, and approved for use in the United States in 1981.<ref name=AHFS2015/><ref>{{cite book | vauthors = Sliskovic DR | veditors = Li JJ, Corey EJ |editor-link1=Jie Jack Li |editor-link2=E.J. Corey |year=2013 |orig-date= |chapter= Cardiovascular Drugs | title= Drug Discovery: Practices, Processes, and Perspectives |isbn=9781118354469 | chapter-url= https://books.google.com/books?id=mIyxO5cLEAcC&pg=PA172 |url-status= live |location= Hoboken, NJ |publisher= John Wiley & Sons |pages= 141–204 |archive-url= https://web.archive.org/web/20170901032155/https://books.google.ca/books?id=mIyxO5cLEAcC&pg=PA172 |archive-date= 1 September 2017 |access-date= 20 January 2022 |quote= nifedipine...1,4-dihydropyrine originally approved in 1981. |quote-page=172 |mode= }}</ref><ref>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=464 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA464 |language=en}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> It is available as a [[Generic drug|generic medication]].<ref name=AHFS2015/> In 2021, it was the 128th most commonly prescribed medication in the United States, with more than 4{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Nifedipine - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Nifedipine | access-date = 14 January 2024}}</ref>

==Medical uses==

===High blood pressure===

The approved uses are for the long-term treatment of [[hypertension]] and [[angina pectoris]]. In hypertension, recent clinical guidelines generally favour [[diuretic]]s and [[ACE inhibitor]]s, although calcium channel antagonists, along with [[Thiazide|thiazide diuretics]], are still favoured as primary treatment for patients over 55 and black patients.<ref>{{cite book | title = Hypertension: management of hypertension in adults in primary care. Clinical guideline CG34 | publisher = [[National Institute for Health and Clinical Excellence]] (NICE) | date = June 2006 | url = http://www.nice.org.uk/CG034 | archive-url = https://web.archive.org/web/20070617040043/http://www.nice.org.uk/CG034 | archive-date=17 June 2007 | isbn = 1-86016-285-1}}</ref>

Nifedipine given as [[sublingual administration]] has previously been used in [[Hypertensive emergency|hypertensive emergencies]]. It was once frequently prescribed on an as-needed basis to patients taking [[Monoamine oxidase inhibitor|MAOIs]] for real or perceived hypertensive crises.<ref>{{cite web|url = http://www.dr-bob.org/tips/split/Nifed-MAOI-hypertension.html | vauthors = Gelenberg AJ |title = Nifedipine for MAOI Hypertension? Reversing a Previous Recommendation|date = March 1997|access-date = 22 January 2015| work = Biological Therapies in Psychiatry | via = Dr. Bob's Psychopharmacology Tips |url-status = dead|archive-url = https://web.archive.org/web/20150910023142/http://www.dr-bob.org/tips/split/Nifed-MAOI-hypertension.html|archive-date = 10 September 2015}}</ref> This was found to be dangerous, and has been abandoned. Sublingual administration of nifedipine promotes a hypotensive effect via peripheral vasodilation. It can cause an uncontrollable decrease in blood pressure, [[Tachycardia|reflex tachycardia]], and a ''steal phenomenon'' in certain vascular beds. There have been multiple reports in the medical literature of serious adverse effects with sublingual nifedipine, including [[Brain ischemia|cerebral ischemia/infarction]], [[myocardial infarction]], complete [[heart block]], and death. As a result of this, in 1985 the [[Food and Drug Administration|FDA]] reviewed all data regarding the safety and effectiveness of sublingual nifedipine for the management of hypertensive emergencies, and concluded that the practice should be abandoned because it was neither safe nor effective.<ref name="pmid8861992">{{cite journal | vauthors = Grossman E, Messerli FH, Grodzicki T, Kowey P | title = Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies? | journal = JAMA | volume = 276 | issue = 16 | pages = 1328–1331 | year = 1996 | pmid = 8861992 | doi = 10.1001/jama.1996.03540160050032 }}</ref><ref name="pmid12974970">{{cite journal | vauthors = Varon J, Marik PE | title = Clinical review: the management of hypertensive crises | journal = Critical Care | volume = 7 | issue = 5 | pages = 374–384 | date = October 2003 | pmid = 12974970 | pmc = 270718 | doi = 10.1186/cc2351 | doi-access = free }}</ref> An exception to the avoidance of this practice is in the use of nifedipine for the treatment of hypertension associated with [[autonomic dysreflexia]] in [[spinal cord injury]].<ref>{{cite web| vauthors = Campagnolo DI |title=Autonomic Dysreflexia in Spinal Cord Injury|url=http://emedicine.medscape.com/article/322809-medication|publisher=eMedicine|access-date=14 July 2011}}</ref>

===Early labor===

Nifedipine has been used frequently as a [[tocolytic]] (agent that delays premature labor). A [[Cochrane review]] has concluded that it has benefits over placebo or no treatment for prolongation of pregnancy. It also has benefits over [[beta-agonists]] and may also have some benefits over [[atosiban]] and [[magnesium sulfate]], although [[atosiban]] results in fewer maternal adverse effects. No difference was found in the rate of deaths among babies around the time of birth, while data on longer-term outcomes is lacking.<ref>{{cite journal | vauthors = Flenady V, Wojcieszek AM, Papatsonis DN, Stock OM, Murray L, Jardine LA, Carbonne B | title = Calcium channel blockers for inhibiting preterm labour and birth | journal = The Cochrane Database of Systematic Reviews | volume = 2014 | issue = 6 | pages = CD002255 | date = June 2014 | pmid = 24901312 | pmc = 7144737 | doi = 10.1002/14651858.CD002255.pub2 }}</ref>

===Other===

[[Raynaud's phenomenon]] is often treated with nifedipine. A 2005 meta-analysis showed modest benefits (33% decrease in attack severity, 2.8-5 reduction in absolute number of attacks per week); it does conclude that most included studies used low doses of nifedipine.<ref>{{cite journal | vauthors = Thompson AE, Pope JE | title = Calcium channel blockers for primary Raynaud's phenomenon: a meta-analysis | journal = Rheumatology | volume = 44 | issue = 2 | pages = 145–150 | date = February 2005 | pmid = 15546967 | doi = 10.1093/rheumatology/keh390 | doi-access = free }}</ref>

[[Topical]] nifedipine has been shown to be as effective as topical nitrates for [[anal fissure]]s.<ref name="pmid12794583">{{cite journal | vauthors = Ezri T, Susmallian S | title = Topical nifedipine vs. topical glyceryl trinitrate for treatment of chronic anal fissure | journal = Diseases of the Colon and Rectum | volume = 46 | issue = 6 | pages = 805–808 | date = June 2003 | pmid = 12794583 | doi = 10.1007/s10350-004-6660-8 | s2cid = 24717470 }}</ref>

Nifedipine is also used in high-altitude medicine to treat [[high altitude pulmonary edema]].<ref name="eMedicine">{{cite web| url= http://www.emedicine.com/med/topic1956.htm| title= Pulmonary Edema, High-Altitude| vauthors = Ali MO, Qazi S | date= 19 September 2007| publisher= eMedicine| access-date= 25 November 2007| url-status= live| archive-url= https://web.archive.org/web/20071116141543/http://www.emedicine.com/med/topic1956.htm| archive-date= 16 November 2007}}</ref>

Nifedipine is one of the main choices for the treatment of [[Prinzmetal angina]] due to its vasodilating effects on the coronary arteries.<ref name=AHFS2015/>

Other uses include painful spasms of the [[esophagus]] such as from [[cancer]] or [[tetanus]].{{medcn|date=January 2020}} It is also used for the small subset of people with [[pulmonary hypertension]].{{medcn|date=January 2020}}

Finally, nifedipine can be used in the treatment of renal calculi, which are commonly referred to as [[kidney stones]]. Studies have indicated that it helps to relieve renal colic. However, alpha blockers (such as [[tamsulosin]]) have been described as being significantly better.<ref>{{cite journal | vauthors = Bos D, Kapoor A | title = Update on medical expulsive therapy for distal ureteral stones: Beyond alpha-blockers | journal = Canadian Urological Association Journal | volume = 8 | issue = 11–12 | pages = 442–445 | date = November 2014 | pmid = 25553160 | pmc = 4277526 | doi = 10.5489/cuaj.2472 | doi-access = free }}</ref>

==Side effects==

Nifedipine rapidly lowers blood pressure, and patients are commonly warned they may feel dizzy or faint after taking the first few doses. [[Tachycardia]] (fast heart rate) may occur as a reaction. These problems are much less frequent in the sustained-release preparations of nifedipine.{{medcn|date=January 2020}}

Extended release formulations of nifedipine should be taken on an empty stomach, and patients are warned not to consume anything containing [[grapefruit]] or grapefruit juice, as they raise blood nifedipine levels. There are several possible mechanisms, including the inhibition of [[CYP3A4]]-mediated metabolism.<ref>{{cite journal | vauthors = Odou P, Ferrari N, Barthélémy C, Brique S, Lhermitte M, Vincent A, Libersa C, Robert H | title = Grapefruit juice-nifedipine interaction: possible involvement of several mechanisms | journal = Journal of Clinical Pharmacy and Therapeutics | volume = 30 | issue = 2 | pages = 153–158 | date = April 2005 | pmid = 15811168 | doi = 10.1111/j.1365-2710.2004.00618.x | s2cid = 30463290 | doi-access = free }}</ref>

As calcium channel blocker, nifedipine has a risk of causing [[gingival hyperplasia]].<ref>{{cite web|title=Nifedipine|url=https://bnf.nice.org.uk/drug/nifedipine.html|access-date=1 April 2021|website=NICE}}</ref>

==Overdose==

A number of persons have developed toxicity due to acute overdosage with nifedipine, either accidentally or intentionally, and via either oral or [[parenteral administration]]. The adverse effects include lethargy, bradycardia, marked hypotension and [[unconsciousness|loss of consciousness]]. The drug may be quantified in blood or plasma to confirm a diagnosis of poisoning, or to assist in a medicolegal investigation following death. Analytical methods usually involve gas or liquid [[chromatography]] and specimen concentrations are usually in the 100-1000 μg/L range.<ref>Nifediac package insert, TEVA Pharmaceuticals, Sellersville, Pennsylvania, August 2009.</ref><ref>{{cite book | vauthors = Baselt RC |title=Disposition of Toxic Drugs and Chemicals in Man |publisher=Biomedical Publications |location=Foster City, CA |year=2008 |pages=1108–1110|isbn=978-0-9626523-7-0}}</ref>

==Mechanism of action==

Nifedipine is a [[calcium channel blocker]]. Although nifedipine and other [[dihydropyridines]] are commonly regarded as specific to the [[L-type calcium channel]], they also possess nonspecific activity towards other [[voltage-dependent calcium channels]].<ref>{{cite journal | vauthors = Curtis TM, Scholfield CN | title = Nifedipine blocks Ca2+ store refilling through a pathway not involving L-type Ca2+ channels in rabbit arteriolar smooth muscle | journal = The Journal of Physiology | volume = 532 | issue = Pt 3 | pages = 609–623 | date = May 2001 | pmid = 11313433 | pmc = 2278590 | doi = 10.1111/j.1469-7793.2001.0609e.x }}</ref><ref>{{cite journal | vauthors = McDonald TF, Pelzer S, Trautwein W, Pelzer DJ | title = Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells | journal = Physiological Reviews | volume = 74 | issue = 2 | pages = 365–507 | date = April 1994 | pmid = 8171118 | doi = 10.1152/physrev.1994.74.2.365 }}</ref>

Nifedipine 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>

==History==

Nifedipine (initially BAY a1040, then Adalat) was developed by the German pharmaceutical company [[Bayer]], with most initial studies being performed in the early 1970s.<ref>{{cite journal | vauthors = Vater W, Kroneberg G, Hoffmeister F, Saller H, Meng K, Oberdorf A, Puls W, Schlossmann K, Stoepel K | title = [Pharmacology of 4-(2'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (Nifedipine, BAY a 1040)] | language = de | journal = Arzneimittel-Forschung | volume = 22 | issue = 1 | pages = 1–14 | date = January 1972 | pmid = 4622472 }}</ref>

In 1980, [[Ahmed Hegazy (pharmacist)|Ahmed Hegazy]] and Klaus-Dieter Rämsch submitted their invention on [[extended release]] formulation that became known as ''Adalat retard''.<ref>{{cite patent | country = EP | number = 0047899B2 | inventor = Hegasy A, Rämsch KD | assign = Bayer AG | gdate = 28 February 1996| title = Solid pharmaceutical compositions containing nifedipine, and process for their preparation | url = https://patents.google.com/patent/EP0047899B2/en}}</ref> Marketed as ''Adalat CC'' in US, a 1995 US lawsuit found that Pfizer's Procardia XL was also based on Bayer's Adalat European and US patents.<ref>{{cite web|title=Pfizer Found Guilty In Adalat CC Case | date = 4 September 1994 | location = London | work = [[The Pharma Letter]]|url=https://www.thepharmaletter.com/article/pfizer-found-guilty-in-adalat-cc-case|access-date=29 January 2022 | archive-url=https://web.archive.org/web/20240625064851/https://www.thepharmaletter.com/pfizer-found-guilty-in-adalat-cc-case | archive-date=June 25, 2024 | url-status=live}}</ref><ref>{{cite patent | country = US | number = US5264446A | inventor = Hegasy A, Ramsch KD | assign = Bayer AG | gdate = November 23, 1993| title = Solid medicament formulations containing nifedipine, and processes for their preparation | url = https://patents.google.com/patent/US5264446A/en}}</ref>

The use of nifedipine and related calcium channel antagonists was much reduced in response to 1995 trials that mortality was increased in patients with [[coronary artery disease]] who took nifedipine.<ref>{{cite journal |vauthors=Furberg CD, Psaty BM, Meyer JV |date=September 1995 |title=Nifedipine. Dose-related increase in mortality in patients with coronary heart disease |journal=Circulation |volume=92 |issue=5 |pages=1326–1331 |doi=10.1161/01.cir.92.5.1326 |pmid=7648682 |s2cid=32044931}}</ref> This study was a meta-analysis, and demonstrated harm mainly in short-acting forms of nifedipine (that could cause large fluctuations in blood pressure) and at high doses of 80&nbsp;mg a day and more.<ref>{{cite journal |vauthors=Opie LH, Messerli FH |date=September 1995 |title=Nifedipine and mortality. Grave defects in the dossier |journal=Circulation |volume=92 |issue=5 |pages=1068–1073 |doi=10.1161/01.cir.92.5.1068 |pmid=7648646}}</ref>

== Society and culture ==

=== Brand names ===

In India, nifedipine is manufactured by JB Chemicals, and comes in brands Nicardia Retard (Nifedipine 10&nbsp;mg, 20&nbsp;mg tablets) and Nicardia XL 30/60, which are Nifedipine Extended Release tablets.<ref>{{cite web | url=https://medicaldialogues.in/partner/jbcpl/nicardia-xl-nifedipine | title=Nicardia XL | publisher=Medical Dialogues | access-date=24 February 2021}}</ref>

In Switzerland, nifedipine is sold only as a generic version of extended release formulation, under the names Nifedipin Mepha and Nifedipin Spirig.<ref>{{cite web | url=https://compendium.ch/search?q=Nifedipin&type=ProductActiveSubstanceGroup | title=Compendium | access-date=10 February 2023}}</ref>

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