Salmeterol

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Salmeterol
Structure of Salmeterol.png
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. C
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 YesY
ATC code R03AC12
PubChem CID 5152
IUPHAR ligand 559
DrugBank DB00938
ChemSpider 7987886 YesY
UNII 2I4BC502BT YesY
KEGG D05792 N
ChEBI CHEBI:9011 N
ChEMBL CHEMBL1263 N
Chemical data
Formula C25H37NO4 
Mol. mass 415.57
 N (what is this?)  (verify)

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][dead link] It is still available as a MDI in the UK as of 2013.[2]

Structure activity relationship[edit]

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 beta2-adrenergic receptor selective.[3]

Indications[edit]

It is a long-acting beta2-adrenoceptor agonists (LABAs), usually prescribed only for severe persistent asthma following previous treatment with a short-acting beta2-adrenoceptor agonists (SABAs) such as salbutamol (albuterol) and is prescribed concurrently with a corticosteroid, such as beclometasone dipropionate or fluticasone propionate. The primary noticeable difference of salmeterol from salbutamol is that the former's duration of action lasts approximately 12 hours in comparison with the latter's 4–6 hours.

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 in 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 beta2 adrenoceptors, with the long carbon chain forming an anchor in the membrane. Interestingly, salmeterol binding to the beta2-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[edit]

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

Side effects[edit]

Due to its vasodilation properties, 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.[4]

History and concerns[edit]

A typical inhaler of Serevent brand salmeterol

Salmeterol, first marketed and manufactured by Glaxo in the 1980s, 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 beta2-agonists could lead to a worsening of symptoms, and in some cases death.[5]

While the use of inhaled LABAs are still recommended in asthma guidelines for the resulting improved symptom control,[6] 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).[7] This seems to occur because although LABAs relieve asthma symptoms, they also promote bronchial inflammation and sensitivity without warning.[8]

Synthesis[edit]

Salmeterol can be prepared starting from phenethyl alcohol.[9]

Salmeterol pictorial.png

Footnotes[edit]

  1. ^ Serevent MDI discontinued
  2. ^ Serevent MDI available in BNF (subscription only)
  3. ^ Medicinal Chemistry of Adrenergics and Cholinergics
  4. ^ "Medtv". HealthSavy. Retrieved 8 March 2012. 
  5. ^ Advair Diskus, Advair HFA, Brovana, Foradil, Perforomist, Serevent Diskus, and Symbicort Information (Long Acting Beta Agonists)
  6. ^ 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)
  7. ^ 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. 
  8. ^ 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. 
  9. ^ Skidmore, I. F.; Lunts, L. H. C.; Finch, H.; Naylor, A.; German Offen., 1984, 3414752; Chem. Abstr., 1986, 102, 95383.