View source for Salmeterol

{{Short description|Chemical compound}}
{{Infobox drug
| Verifiedfields     = changed
| Watchedfields      = changed
| verifiedrevid      = 464386379
| drug_name          = 
| INN                = 
| type               = <!-- empty -->
| image              = Salmeterol.svg
| width              = 220
| alt                = 
| caption            = 
| chirality          = [[Racemic mixture]]

<!-- Clinical data -->| pronounce          = 
| tradename          = Serevent, Aeromax, Qitai, Seretide, others
| Drugs.com          = {{drugs.com|monograph|serevent}}
| MedlinePlus        = 
| licence_CA         = <!-- Health Canada may use generic or brand name (generic name preferred) -->
| licence_EU         = yes
| DailyMedID         = Salmeterol
| licence_US         = <!-- FDA may use generic or brand name (generic name preferred) -->
| pregnancy_AU       = B3
| pregnancy_AU_comment = 
| pregnancy_category = 
| dependency_liability = 
| addiction_liability = 
| routes_of_administration = Respiratory inhalation ([[Metered-dose inhaler]] (MDI), [[Dry-powder inhaler]] (DPI))
| class              = 
| ATCvet             = 
| ATC_prefix         = R03
| ATC_suffix         = AC12
| ATC_supplemental   = <!-- Legal status -->
| legal_AU           = S4
| 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   = 
| legal_DE           = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment   = 
| legal_NZ           = <!-- Class A, B, C -->
| legal_NZ_comment   = 
| legal_UK           = POM
| legal_UK_comment   = 
| legal_US           = Rx-only
| legal_US_comment   = <ref name="Serevent FDA label" />
| legal_EU           = 
| legal_EU_comment   = 
| legal_UN           = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment   = 
| legal_status       = Rx-only

<!-- Pharmacokinetic data -->| bioavailability    = 
| protein_bound      = 96%
| metabolism         = [[Liver]] ([[CYP3A4]])
| metabolites        = 
| onset              = 
| elimination_half-life = 5.5 hours
| duration_of_action = 
| excretion          = <!-- Identifiers -->
| CAS_number_Ref     = {{cascite|correct|??}}
| CAS_number         = 89365-50-4
| CAS_supplemental   = 
| PubChem            = 5152
| IUPHAR_ligand      = 559
| DrugBank_Ref       = {{drugbankcite|correct|drugbank}}
| DrugBank           = DB00938
| ChemSpiderID_Ref   = {{chemspidercite|correct|chemspider}}
| ChemSpiderID       = 7987886
| UNII_Ref           = {{fdacite|correct|FDA}}
| UNII               = 2I4BC502BT
| KEGG_Ref           = {{keggcite|changed|kegg}}
| KEGG               = D05792
| ChEBI_Ref          = {{ebicite|changed|EBI}}
| ChEBI              = 9011
| ChEMBL_Ref         = {{ebicite|changed|EBI}}
| ChEMBL             = 1263
| NIAID_ChemDB       = 
| PDB_ligand         = K5Y
| synonyms           = <!-- Chemical and physical data -->
| IUPAC_name         = (''RS'')-2-(hydroxymethyl)-4-<nowiki/>{1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl}phenol
| C                  = 25
| H                  = 37
| N                  = 1
| O                  = 4
| SMILES             = OCc1cc(ccc1O)[C@H](O)CNCCCCCCOCCCCc2ccccc2
| StdInChI_Ref       = {{stdinchicite|correct|chemspider}}
| StdInChI           = 1S/C25H37NO4/c27-20-23-18-22(13-14-24(23)28)25(29)19-26-15-7-1-2-8-16-30-17-9-6-12-21-10-4-3-5-11-21/h3-5,10-11,13-14,18,25-29H,1-2,6-9,12,15-17,19-20H2/t25-/m1/s1
| StdInChI_comment   = 
| StdInChIKey_Ref    = {{stdinchicite|correct|chemspider}}
| StdInChIKey        = GIIZNNXWQWCKIB-RUZDIDTESA-N
| density            = 
| density_notes      = 
| melting_point      = 
| melting_high       = 
| melting_notes      = 
| boiling_point      = 
| boiling_notes      = 
| solubility         = 
| sol_units          = 
| specific_rotation  = 
}}

<!-- Definition and medical uses -->
'''Salmeterol''' is a [[Long-acting beta-adrenoceptor agonist|long-acting β<sub>2</sub> adrenergic receptor agonist]] (LABA) used in the treatment and prevention of [[asthma]] symptoms and control of [[chronic obstructive pulmonary disease]] (COPD) symptoms.<ref name="GOLD">{{cite web|title=global initiative for chronic obstructive disease|url=http://www.goldcopd.org/uploads/users/files/GOLDReport_April112011.pdf|website=goldcopd.org|access-date=30 October 2014|url-status=dead|archive-url=https://web.archive.org/web/20150924022846/http://www.goldcopd.org/uploads/users/files/GOLDReport_April112011.pdf|archive-date=24 September 2015}}</ref> Symptoms of [[bronchospasm]] include [[Dyspnea|shortness of breath]], [[Wheeze|wheezing]], [[cough]]ing and chest tightness. It is also used to prevent breathing difficulties during exercise ([[exercise-induced bronchoconstriction]]).<ref name="NIH">{{cite web|title=National Asthma Education and Prevention Program|url=https://www.nlm.nih.gov/medlineplus/druginfo/meds/a695001.html#why|archive-url=https://web.archive.org/web/20090123183304/http://www.nlm.nih.gov/medlineplus/druginfo/meds/a695001.html#why|url-status=dead|archive-date=January 23, 2009|access-date=30 October 2014}}</ref>

<!-- Society and culture -->
It was patented in 1983 and came into medical use in 1990.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=543 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA543 |language=en}}</ref> It is marketed as Serevent in the US.<ref name=medicinet>{{cite web|title=Salmeterol inhalation index|url=http://www.medicinenet.com/salmeterol/page2.htm|access-date=30 October 2014}}</ref> It is available as a [[dry-powder inhaler]] (DPI) that releases a powdered form of the drug. It was previously available as a [[metered-dose inhaler]] (MDI) but was discontinued in the US in 2002.<ref name="GOLD"/><ref name=FDA>{{cite web|title=Benefit Risk Assessment of Salmeterol for the Treatment of Asthma in Adults and Children|url=https://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4398b1-04-gsk.pdf|website=fda.gov|url-status=dead|archive-url=https://web.archive.org/web/20180126141921/https://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4398b1-04-gsk.pdf|archive-date=26 January 2018}}</ref> It is available as an MDI in other countries as of 2020.<ref>{{cite web |title=Serevent Dosieraeros 25 mcg FCKW-frei |url=https://compendium.ch/product/1016555-serevent-dosieraeros-25-mcg-fckw-frei |website=compendium.ch |language=de |access-date=2020-03-25 |archive-date=2021-07-24 |archive-url=https://web.archive.org/web/20210724164452/https://compendium.ch/product/1016555-serevent-dosieraeros-25-mcg-fckw-frei |url-status=dead }}</ref>

== Mechanism of action ==
Inhaled salmeterol belongs to a group of drugs called [[Beta-2 Agonists|beta-2 agonists]]. These drugs stimulate [[Beta-2 adrenergic receptor|beta-2 receptors]] present in the bronchial musculature. This causes them to relax and prevent the onset and worsening of symptoms of asthma. They act on the enzyme [[Adenylyl cyclase|adenyl cyclase]] which increases the concentration of cAMP ([[Cyclic adenosine monophosphate]]). This cyclic AMP decreases the smooth muscle tone. This drug is 10,000-times more lipid soluble than the short acting beta-2 adrenoceptor agonist, [[albuterol]]. Unlike albuterol, salmeterol becomes dissolved in the lipid bilayer of the cell membrane, and its gradual dissociation from the cell membrane provides beta-2 adrenoceptors with a supply of agonist for an extended period of time.<ref>{{Cite book|title=XPharm : the comprehensive pharmacology reference|date=2008|publisher=Elsevier|others=Enna, S. J., Bylund, David B., Elsevier Science (Firm)|isbn=978-0-08-055232-3|location=Amsterdam|oclc=712018683}}</ref>

The primary noticeable difference of salmeterol from [[salbutamol]], and other short-acting [[Beta2-adrenergic agonist|β<sub>2</sub> adrenoreceptor agonist]]s (SABAs), is its duration of action. Salmeterol lasts approximately 12 hours in comparison with [[salbutamol]], which lasts about 4&ndash;6 hours.<ref name="GOLD" /><ref name="GINA" /> When used regularly every day as prescribed, inhaled salmeterol decreases the number and severity of asthma attacks. [[Formoterol]] has been demonstrated to have a faster onset of action than salmeterol as a result of a lower [[lipophilic]]ity, and has also been demonstrated to be more potent&mdash;a 12&nbsp;μg dose of formoterol has been demonstrated to be equivalent to a 50&nbsp;μg dose of salmeterol.<ref name="NIH" /><ref name="Partnership">{{cite web|url=http://www.partnershiphp.org/Members/HealthEd/Asthma%20pdf/LongTermControlMeds12-adult_043010.pdf|title=Recommended Medication for Asthma|website=www.partnershiphp.org|archive-url=https://web.archive.org/web/20141103064100/http://www.partnershiphp.org/Members/HealthEd/Asthma%20pdf/LongTermControlMeds12-adult_043010.pdf|archive-date=2014-11-03|url-status=dead}}</ref>

==Medical uses==

* Salmeterol is used in moderate-to-severe persistent asthma following previous treatment with a short-acting [[Beta2-adrenergic agonist|β<sub>2</sub> adrenoreceptor agonist]] (SABA) such as  [[Salbutamol|salbutamol (albuterol)]].
* LABAs should not be used as a monotherapy, instead, they should be used concurrently with an inhaled corticosteroid, such as [[beclometasone dipropionate]] or [[fluticasone propionate]] in the treatment of [[asthma]] to minimize serious reactions such as asthma-related deaths. Combination of inhaled corticosteroids and salmeterol (LABA) has synergistic action and reduces the frequency of asthma attacks and also makes it less severe.   
* In [[chronic obstructive pulmonary disease]] (COPD), LABAs may be used as monotherapy or in combination with corticosteroids. The Torch study demonstrated benefits in terms of quality of life and lung function of salmeterol alone or in combination with inhaled corticosteroids in patients with COPD<ref>{{cite journal | vauthors = Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J | display-authors = 6 | title = Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease | journal = The New England Journal of Medicine | volume = 356 | issue = 8 | pages = 775–89 | date = February 2007 | pmid = 17314337 | doi = 10.1056/NEJMoa063070 | doi-access = free }}</ref>
* In exercise-induced [[bronchospasm]] monotherapy may be indicated in patients without persistent asthma. LABAs should not be used to treat acute symptoms.<ref name="GOLD" /><ref name="GINA">{{cite web|title=Global initiative for asthma|url=http://www.ginasthma.org/local/uploads/files/GINA_Report_2014_Aug12.pdf|archive-url=https://web.archive.org/web/20140822195114/http://www.ginasthma.org/local/uploads/files/GINA_Report_2014_Aug12.pdf|url-status=dead|archive-date=22 August 2014|website=ginasthma.org|access-date=30 October 2014}}</ref><ref name="MHRA">{{cite web|title=Use of long-acting beta agonist in chronic obstructive pulmonary disease|url=http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON087967|website=mhra.gov.uk|access-date=30 October 2014|url-status=dead|archive-url=https://web.archive.org/web/20141103072145/http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON087967|archive-date=3 November 2014}}</ref>

===Pregnancy and lactation===
Salmeterol use during pregnancy must be decided based on the risks versus benefits to the mother. There are no well-controlled studies with salmeterol in pregnant women. Some animal studies showed developmental malformation when the mother was given several clinical doses orally. In rats, salmeterol xinafoate is excreted in the milk. However, since there is no data to show excretion of salmeterol in a mother's breast milk, a decision on whether to continue or discontinue therapy should be decided based on the important benefits it provides to the mother. Pregnant and lactating women should consult their doctors before using salmeterol.<ref name="Serevent FDA label">{{cite web | title=Serevent Diskus- salmeterol xinafoate powder, metered | website=DailyMed | date=13 January 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=12d9728e-6b5c-4aee-bfb0-745e542ed2e4#section-8.1 | access-date=6 September 2020}}</ref>

==Side effects==
Due to its vasodilation properties, the common side effects of salmeterol are

* [[dizziness]], 
* [[Sinusitis|sinus infection]], and
* [[Migraine|migraine headaches]].

Other side effects

* muscle tremors,
* hypokalemia due to direct effect on beta-2 receptors on skeletal muscle.

In most cases, salmeterol side effects are minor and either do not require treatment or can easily be treated. Certain side effects, however, should be reported to a healthcare provider immediately.

Some of these more serious side effects include

* very fast heart rate,
* [[Hypertension|high blood pressure]], and
* worsening [[Dyspnea|breathing problems]].<ref>{{cite web|title=Medtv|url=http://asthma.emedtv.com/salmeterol/side-effects-of-salmeterol.html|publisher=HealthSavy|access-date=8 March 2012|archive-date=22 September 2013|archive-url=https://web.archive.org/web/20130922091705/http://asthma.emedtv.com/salmeterol/side-effects-of-salmeterol.html|url-status=dead}}</ref>

==Structure-activity relationship==
Salmeterol has an [[aryl]] [[alkyl]] group with a chain length of 11 atoms from the amine. This bulkiness makes the compound more lipophilic and it also makes it selective to β<sub>2</sub> adrenergic receptors.<ref>{{cite web | first = Akul | last = Mehta | name-list-style = vanc | url = http://pharmaxchange.info/notes/medicinal_chemistry/adrenergics_cholinergics.html | title = Medicinal Chemistry of Adrenergics and Cholinergics | work =  PharmaXChange | archive-url = https://web.archive.org/web/20101104022742/http://pharmaxchange.info/notes/medicinal_chemistry/adrenergics_cholinergics.html | archive-date = 2010-11-04 }}</ref>

==History==
[[Image:AsthmaInhaler.jpg|thumb|Previously used metered-dose [[inhaler]] of Serevent-brand salmeterol]]
[[File:Salmeterol diskus.jpg|thumb|A typical dry-powder inhaler salmeterol "diskus"]]
Salmeterol, first marketed and manufactured by [[GlaxoSmithKline|Glaxo]] (now GlaxoSmithKline, GSK) in the 1980s, was released as Serevent in 1990.<ref name="FDA"/> The product is marketed by GSK under the Allen & Hanburys brand in the UK.{{cn|date=September 2020}}

In November 2005, the US [[Food and Drug Administration]] (FDA) released a health advisory, alerting the public to findings that show the use of long-acting β<sub>2</sub> agonists could lead to a worsening of symptoms, and in some cases death.<ref name=fda>{{cite web|url=https://www.fiercebiotech.com/biotech/advair-diskus-advair-hfa-brovana-foradil-serevent-diskus-and-symbicort-information |title=Advair Diskus, Advair HFA, Brovana, Foradil, Perforomist, Serevent Diskus, and Symbicort Information (Long Acting Beta Agonists) | work = Fierce Biotech | date = 6 March 2008 }}</ref>

While the use of inhaled LABAs are still recommended in asthma guidelines for the resulting improved symptom control,<ref name=SIGN>British Thoracic Society & Scottish Intercollegiate Guidelines Network (SIGN). ''British Guideline on the Management of Asthma''. Guideline No. 63. Edinburgh:SIGN; 2004. ([http://www.sign.ac.uk/guidelines/fulltext/63/index.html HTML] {{webarchive|url=https://web.archive.org/web/20060618093345/http://www.sign.ac.uk/guidelines/fulltext/63/index.html |date=2006-06-18 }}, [http://www.sign.ac.uk/pdf/sign63.pdf Full PDF] {{webarchive|url=https://web.archive.org/web/20060724153838/http://www.sign.ac.uk/pdf/sign63.pdf |date=2006-07-24 }}, [http://www.sign.ac.uk/pdf/qrg63.pdf Summary PDF] {{webarchive|url=https://web.archive.org/web/20060724154104/http://www.sign.ac.uk/pdf/qrg63.pdf |date=2006-07-24 }})</ref> further concerns have been raised. A large meta-analysis of pooled results from 19 trials with 33,826 participants, suggests that salmeterol may increase the small risks of asthma-related deaths, and this additional risk is not reduced with the additional use of inhaled steroids (e.g., as with the combination product [[fluticasone/salmeterol]]).<ref>{{cite journal | vauthors = Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE | title = Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths | journal = Annals of Internal Medicine | volume = 144 | issue = 12 | pages = 904–12 | date = June 2006 | pmid = 16754916 | doi = 10.7326/0003-4819-144-12-200606200-00126 | doi-access = free }}</ref>
This seems to occur because although LABAs relieve asthma symptoms, they also promote bronchial inflammation and sensitivity without warning.<ref>{{cite news | first = Krishna | last = Ramanujan | name-list-style = vanc | title=Common asthma inhalers cause up to 80 percent of asthma-related deaths, Cornell and Stanford researchers assert  | url=https://www.news.cornell.edu/stories/June06/AsthmaDeaths.kr.html | date=June 9, 2006 | publisher=ChronicalOnline - Cornell University}}</ref>

== Society and culture ==

=== Names ===
Combinations of inhaled steroids and these long-acting bronchodilators are becoming{{when|date=September 2020}} more widespread; the most common combination currently{{when|date=September 2020}} in use is [[fluticasone/salmeterol]] (brand names Seretide (UK) and Advair (US)). Another combination is [[budesonide/formoterol]] (brand name Symbicort).<ref>{{Cite web|title=Australian Medicines Handbook|url=https://amhonline.amh.net.au/auth|website=amhonline.amh.net.au|access-date=2020-05-07}}</ref>

{{Clear}}

== References ==
{{Reflist}}

== External links ==
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/salmeterol | archive-url = https://web.archive.org/web/20170123194747/https://druginfo.nlm.nih.gov/drugportal/name/Salmeterol | url-status = dead | archive-date = January 23, 2017 | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Salmeterol }}

{{Adrenergic agonists}}
{{Asthma_and_copd_rx}}
{{GlaxoSmithKline}}
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[[Category:Beta2-adrenergic agonists]]
[[Category:Drugs developed by GSK plc]]
[[Category:Phenylethanolamines]]
[[Category:Withdrawn drugs]]