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Salmeterol is a long-acting beta2-adrenergic receptor agonist drug that is prescribed for the treatment of asthma and chronic obstructive pulmonary disease(COPD). It is available as a dry powder inhaler that releases a powdered form of the drug. Before 2008, it was also available as a metered-dose inhaler (MDI).^[1]

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 β receptor selective.^[2]

Indications

It is a long-acting beta-adrenoceptor agonist (LABA), usually prescribed only for severe persistent asthma following previous treatment with a short-acting beta agonist such as salbutamol and is prescribed concurrently with a corticosteroid, such as beclomethasone. The primary noticeable difference of salmeterol to salbutamol is that the duration of action lasts approximately 12 hours in comparison with 4–6 hours of salbutamol.

When used regularly every day as prescribed, inhaled salmeterol decreases the number and severity of asthma attacks. However, like all LABA medications, it is not for use for relieving an asthma attack that has already started.

Inhaled salmeterol works like other beta 2-agonists, causing bronchodilation by relaxing the smooth muscle in the airway so as to treat the exacerbation of asthma. The long duration of action occurs by the molecules initially diffusing into the plasma membrane of the lung cells, and then slowly being released back outside the cell where they can come into contact with the beta-2 adrenoceptors, with the long carbon chain forming an anchor in the membrane. Interestingly, salmeterol binding to the beta-adrenoceptor does not induce desensitisation or internalisation of receptors which may also contribute to its long therapeutic duration of action. Formoterol has been demonstrated to have a faster onset of action than salmeterol as a result of a lower lipophilicity, and has also been demonstrated to be more potent—a 12 µg dose of formoterol has been demonstrated to be equivalent to a 50 µg dose of salmeterol.

Formulations

Currently available long-acting beta₂-adrenoceptor agonists include salmeterol, formoterol, bambuterol, and sustained-release oral salbutamol. Combinations of inhaled steroids and long-acting bronchodilators are becoming more widespread; the most common combination currently in use is fluticasone/salmeterol (Advair in the United States, Seretide in the UK).

Side effects

Among the common side effects of salmeterol are dizziness, sinus infection, and migraine headaches. In most cases, salmeterol side effects are minor and either don't 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 a very fast heart rate, high blood pressure, and worsening breathing problems.^[3]

History and concerns

A typical inhaler, of Serevent (salmeterol) (no longer on market)

Salmeterol, marketed and manufactured by GlaxoSmithKline, in the 1980s and was released as Serevent in 1990.^{[citation needed]} The product is marketed by GSK under the Allen & Hanburys brand in the UK.

In November 2005, the US Food and Drug Administration released a health advisory, alerting the public to findings that show the use of long-acting β₂-agonists could lead to a worsening of symptoms, and in some cases death.^[4]

While the use of inhaled LABAs are still recommended in asthma guidelines for the resulting improved symptom control,^[5] further concerns have been raised, by a large meta-analysis of the pooled results from 19 trials with 33,826 participants, that salmeterol may increase the small risks of asthma deaths, and this additional risk is not reduced with the additional use of inhaled steroids (e.g., as with the combination product Fluticasone/salmeterol).^[6] This seems to occur because although LABAs relieve asthma symptoms, they also promote bronchial inflammation and sensitivity without warning.^[7]

Synthesis

Salmeterol can be prepared starting from phenethyl alcohol.^[8]

Footnotes

^ Serevent MDI discontinued
^ Medicinal Chemistry of Adrenergics and Cholinergics
^ "Medtv". HealthSavy. http://asthma.emedtv.com/salmeterol/side-effects-of-salmeterol.html. Retrieved 8 March 2012.
^ Advair Diskus, Advair HFA, Brovana, Foradil, Perforomist, Serevent Diskus, and Symbicort Information (Long Acting Beta Agonists)
^ British Thoracic Society & Scottish Intercollegiate Guidelines Network (SIGN). British Guideline on the Management of Asthma. Guideline No. 63. Edinburgh:SIGN; 2004. (HTML, Full PDF, Summary PDF)
^ Salpeter S, Buckley N, Ormiston T, Salpeter E (2006). "Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths". Ann Intern Med 144 (12): 904–12. PMID 16754916.
^ Krishna Ramanujan (June 9 2006). "Common asthma inhalers cause up to 80 percent of asthma-related deaths, Cornell and Stanford researchers assert". ChronicalOnline - Cornell University. http://www.news.cornell.edu/stories/June06/AsthmaDeaths.kr.html.
^ Skidmore, I. F.; Lunts, L. H. C.; Finch, H.; Naylor, A.; German Offen., 1984, 3414752; Chem. Abstr., 1986, 102, 95383.

UpToDate Contents

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1. 喘息におけるβ刺激剤：長期使用に関する議論 beta agonists in asthma controversy regarding chronic use
2. 安定した慢性閉塞性肺疾患（COPD）のマネージメント management of stable chronic obstructive pulmonary disease
3. 思春期および成人における間欠型喘息および軽症持続型喘息の治療 treatment of intermittent and mild persistent asthma in adolescents and adults
4. 喘息のマネージメントの概要 an overview of asthma management
5. 12歳未満の小児における慢性喘息：コントローラ剤 chronic asthma in children younger than 12 years controller medications

English Journal

Resorcinol-, catechol- and saligenin-based bronchodilating β2-agonists as inhibitors of human cholinesterase activity.

Bosak A1, Knežević A2, Gazić Smilović I2, Šinko G1, Kovarik Z1.
Journal of enzyme inhibition and medicinal chemistry.J Enzyme Inhib Med Chem.2017 Dec;32(1):789-797. doi: 10.1080/14756366.2017.1326109.
PMID 28573890

Which inhaled corticosteroid and long-acting β-agonist combination is better in patients with moderate-to-severe asthma, a dry powder inhaler or a pressurized metered-dose inhaler?

Muraki M1, Gose K1, Hanada S1, Sawaguchi H1, Tohda Y2.
Drug delivery.Drug Deliv.2017 Nov;24(1):1395-1400. doi: 10.1080/10717544.2017.1378937.
PMID 28929816

Particle interactions of fluticasone propionate and salmeterol xinafoate detected with single particle aerosol mass spectrometry (SPAMS).

Jetzer MW1, Morrical BD2, Fergenson DP3, Imanidis G4.
International journal of pharmaceutics.Int J Pharm.2017 Oct 30;532(1):218-228. doi: 10.1016/j.ijpharm.2017.08.113. Epub 2017 Aug 31.
PMID 28864391

Japanese Journal

COPDにおけるsalmeterol/fluticasone配合剤追加効果および効果予測因子に関する検討

呼吸器内科 = Respiratory medicine 28(5), 413-422, 2015-11
NAID 40020665219

サルメテロール/フルチカゾンプロピオン酸エステル配合剤を導入した小児気管支喘息患者の特徴と有用性

日本小児アレルギー学会誌 29(1), 123-131, 2015
NAID 130005074492

気管支喘息におけるブデソニド/ホルモテロール配合剤とフルチカゾン/サルメテロール配合剤のアドヒアランスの検討

アレルギー・免疫 21(11), 1742-1750, 2014-11
NAID 40020240020

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リンク元	「サルメテロール」
拡張検索	「salmeterol xinafoate」

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Salmeterol
Systematic (IUPAC) name
	(RS)-2-(hydroxymethyl)-4-{1-hydroxy-2-[6-(4-phenylbutoxy) hexylamino]ethyl}phenol
Clinical data
Trade names	Serevent
AHFS/Drugs.com	monograph
Pregnancy cat.	?
Legal status	Prescription Only (S4) (AU) POM (UK) ℞-only (US)
Routes	Inhalation
Pharmacokinetic data
Protein binding	96%
Metabolism	hepatic CYP3A4
Half-life	5.5 h
Identifiers
CAS number	89365-50-4
ATC code	R03AC12
PubChem	CID 5152
IUPHAR ligand	559
DrugBank	DB00938
ChemSpider	7987886
UNII	2I4BC502BT
KEGG	D05792
ChEMBL	CHEMBL1263
Chemical data
Formula	C25H37NO4
Mol. mass	415.57
	SMILES OCc1cc(ccc1O)[C@H](O)CNCCCCCCOCCCCc2ccccc2;
	InChI InChI=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 ; Key:GIIZNNXWQWCKIB-RUZDIDTESA-N ;
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