Formoterol

Formoterol
	Formoterol (top),; (R,R)-(−)-formoterol (center) and; (S,S)-(+)-formoterol (bottom)
Clinical data
Trade names	See below
AHFS/Drugs.com	Monograph
Pregnancy; category	AU: B3; ;
Routes of; administration	Inhalation (capsules for oral inhalation, DPI, MDI)
ATC code	R03AC13 (WHO) ;
Legal status
Legal status	UK: POM (Prescription only); US: ℞-only; In general: ℞ (Prescription only);
Pharmacokinetic data
Protein binding	61–64%
Metabolism	Hepatic demethylation and glucuronidation (CYP2D6, CYP2C19, CYP2C9 and CYP2A6 involved)
Elimination half-life	10 hours
Excretion	Renal and fecal
Identifiers
	IUPAC name (RR,SS)-N-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl) propan-2-ylamino]ethyl] phenyl]formamide;
CAS Number	73573-87-2 ;
PubChem CID	3083544; 3034756;
IUPHAR/BPS	3465;
DrugBank	DB00983 ;
ChemSpider	2340731 ;
UNII	5ZZ84GCW8B;
KEGG	D07990 ;
ChEBI	CHEBI:408174 ;
ChEMBL	ChEMBL1363 ;
CompTox Dashboard (EPA)	DTXSID20860603 DTXSID1023077, DTXSID20860603 ;
ECHA InfoCard	100.131.654
Chemical and physical data
Formula	C19H24N2O4
Molar mass	344.405 g/mol g·mol−1
3D model (JSmol)	Interactive image;
Chirality	Racemic mixture
	SMILES O=CNc1cc(ccc1O)[C@@H](O)CN[C@H](C)Cc2ccc(OC)cc2;
	InChI InChI=1S/C19H24N2O4/c1-13(9-14-3-6-16(25-2)7-4-14)20-11-19(24)15-5-8-18(23)17(10-15)21-12-22/h3-8,10,12-13,19-20,23-24H,9,11H2,1-2H3,(H,21,22)/t13-,19+/m1/s1 ; Key:BPZSYCZIITTYBL-YJYMSZOUSA-N ;
	(verify)

Formoterol (INN) or eformoterol (former BAN) is a long-acting β₂ agonist (LABA) used in the management of asthma and COPD. It is marketed in three forms: a dry-powder inhaler, a metered-dose inhaler and an inhalation solution, under various trade names including Foradil/Foradile, Oxeze/Oxis and many others. It is also marketed in the combination formulations budesonide/formoterol and mometasone/formoterol.

Formoterol is a long-acting β₂ agonist that has an extended duration of action (up to 12 hours) compared to short-acting β₂ agonists such as salbutamol (albuterol), which are effective for 4–6 hours. LABAs such as formoterol are used as "symptom controllers" to supplement prophylactic corticosteroid therapy (e.g., fluticasone). A "reliever" short-acting β₂ agonist (e.g., salbutamol) is still required, since LABAs are not recommended for the treatment of acute asthma.

Mechanism of action

Inhaled formoterol works like other β₂ agonists, causing bronchodilation by relaxing the smooth muscle in the airway so as to treat the exacerbation of asthma. The long duration of formoterol action occurs because the formoterol molecules initially diffuse into the plasma membrane of the lung cells, and then are slowly released back outside, where they can come into contact with β₂ adrenergic receptors. Formoterol has been demonstrated to have a faster onset of action than salmeterol as a result of 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.

Safety

In November 2005, the US FDA released a health advisory alerting the public to findings that show the use of long-acting β₂ agonists could lead to a worsening of wheezing symptoms in some patients.^[1]

At the current time, available long-acting β₂ agonists include salmeterol, formoterol, bambuterol, and sustained-release oral salbutamol. Combinations of inhaled steroids and long-acting bronchodilators are becoming more widespread – combination preparations include fluticasone/salmeterol and budesonide/formoterol.

Additional potential uses

β₂ agonists in treatment of obesity

β₂ agonists increase energy utilization and fat metabolism, however, therapeutic use for obesity has been limited by the concomitant activation of β₁ receptors resulting in excessive increases in heart rate. A recent 2012 dose-finding study (in healthy men) demonstrated significantly increased resting energy expenditure, and fat oxidation at a dose of 160 μg of formoterol per day without significantly increased heart rate. Formoterol's specificity for the β₂ receptor (relative to β₁ receptors) may facilitate its use for this purpose. A combination of a highly selective β₂ agonist like formeterol with a low dose highly selective β₁ blocker may further improve the differential therapeutic ability to selectively agonize β₂ receptors for metabolic benefits in treating obesity without adverse β₁ agonist effects.^[2]

Stimulation of mitochondrial biogenesis

Formoterol may also help stimulate mitochondrial biogenesis. Mitochondrial dysfunction is related to many degenerative diseases — particularly neurodegenerative disorders.^[3]

Treatment for Down syndrome

Preliminary research offers hope that formoterol may be a useful treatment in Down syndrome. In a mouse model of the disease, the drug strengthened nerve connections in the hippocampus, a brain center used for spatial navigation, paying attention and forming new memories.^[4]

Trade names

Foradil/Foradile capsules for oral inhalation (Schering-Plough in the U.S., Novartis rest of world)
Oxeze/Oxis Turbuhaler DPI (AstraZeneca)
Atock (Astellas)
Atimos/Atimos Modulite MDI (Chiesi)
Perforomist inhalation solution (Mylan N.V.)

References

^ Center for Drug Evaluation and Research. "Advair Diskus, Advair HFA, Brovana, Foradil, Perforomist, Serevent Diskus, and Symbicort Information (Long Acting Beta Agonists)". Postmarket Drug Safety Information for Patients and Providers.
^ Lee, P; Day, RO; Greenfield, JR; Ho, KKY (May 29, 2012). "Formoterol, a highly β2-selective agonist, increases energy expenditure and fat utilisation in men". International Journal of Obesity. 37 (4): 593–597. doi:10.1038/ijo.2012.90. ISSN 1476-5497. PMID 22641064.
^ Wills, Lauren P; Trager, Richard E; Beeson, Gyda C; Lindsey, Christopher C; Peterson, Yuri K; Beeson, Craig C; Schnellmann, Rick G (April 6, 2012). "The β2-adrenoceptor agonist formoterol stimulates mitochondrial biogenesis". The Journal of Pharmacology and Experimental Therapeutics. 342 (1): 106–118. doi:10.1124/jpet.112.191528. ISSN 1521-0103. PMC 3383035. PMID 22490378.
^ Dang, Van; Medina, Brian; Das, Devsmita; Moghadam, Sarah; Martin, Kara J.; Lin, Bill; Naik, Priyanka; Patel, Devan; Nosheny, Rachel; Wesson Ashford, John; Salehi, Ahmad (February 2014). "Formoterol, a Long-Acting β₂ Adrenergic Agonist, Improves Cognitive Function and Promotes Dendritic Complexity in a Mouse Model of Down Syndrome". Biological Psychiatry. 75 (3): 179–188. doi:10.1016/j.biopsych.2013.05.024. ISSN 1873-2402. PMID 23827853. {{cite journal}}: |access-date= requires |url= (help)

[1] Center for Drug Evaluation and Research. "Advair Diskus, Advair HFA, Brovana, Foradil, Perforomist, Serevent Diskus, and Symbicort Information (Long Acting Beta Agonists)". Postmarket Drug Safety Information for Patients and Providers.

[2] Lee, P; Day, RO; Greenfield, JR; Ho, KKY (May 29, 2012). "Formoterol, a highly β2-selective agonist, increases energy expenditure and fat utilisation in men". International Journal of Obesity. 37 (4): 593–597. doi:10.1038/ijo.2012.90. ISSN 1476-5497. PMID 22641064.

[3] Wills, Lauren P; Trager, Richard E; Beeson, Gyda C; Lindsey, Christopher C; Peterson, Yuri K; Beeson, Craig C; Schnellmann, Rick G (April 6, 2012). "The β2-adrenoceptor agonist formoterol stimulates mitochondrial biogenesis". The Journal of Pharmacology and Experimental Therapeutics. 342 (1): 106–118. doi:10.1124/jpet.112.191528. ISSN 1521-0103. PMC 3383035. PMID 22490378.

[4] Dang, Van; Medina, Brian; Das, Devsmita; Moghadam, Sarah; Martin, Kara J.; Lin, Bill; Naik, Priyanka; Patel, Devan; Nosheny, Rachel; Wesson Ashford, John; Salehi, Ahmad (February 2014). "Formoterol, a Long-Acting β₂ Adrenergic Agonist, Improves Cognitive Function and Promotes Dendritic Complexity in a Mouse Model of Down Syndrome". Biological Psychiatry. 75 (3): 179–188. doi:10.1016/j.biopsych.2013.05.024. ISSN 1873-2402. PMID 23827853. {{cite journal}}: |access-date= requires |url= (help)

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