Formoterol

Formoterol
Clinical data

Formoterol (top), (R,R)-(−)-formoterol (center) and (S,S)-(+)-formoterol (bottom)
Trade names	See below
AHFS/Drugs.com	Monograph
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Routes of administration	Inhalation (capsules for oral inhalation, DPI, MDI)
ATC code	R03AC13 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only ℞ (Prescription only)
Pharmacokinetic data
Protein binding	61–64%
Metabolism	Hepatic demethylation and glucuronidation (CYP2D6, CYP2C19, CYP2C9 and CYP2A6 involved)
Biological 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^Y
PubChem (CID)	3083544 CID 3034756
IUPHAR/BPS	3465
DrugBank	DB00983^Y
ChemSpider	2340731^Y
UNII	5ZZ84GCW8B^Y
KEGG	D07990^Y
ChEBI	CHEBI:408174^Y
ChEMBL	CHEMBL1363^Y
ECHA InfoCard	100.131.654
Chemical and physical data
Formula	C₁₉H₂₄N₂O₄
Molar mass	344.405 g/mol
3D model (Jmol)	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^Y Key:BPZSYCZIITTYBL-YJYMSZOUSA-N^Y
(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 Atock, Atimos/Atimos Modulite, Foradil/Foradile, Oxeze/Oxis, and Perforomist. It is also marketed in the combination formulations budesonide/formoterol and mometasone/formoterol.

Formoterol 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. 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.

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.

Drugs for obstructive airway diseases: asthma/COPD (R03)

Adrenergics, inhalants

Short-acting β₂ agonists	Bitolterol Carbuterol Fenoterol Isoetarine Pirbuterol Procaterol Reproterol Rimiterol Salbutamol (albuterol)^#/Levosalbutamol (levalbuterol) Terbutaline Tulobuterol

Long-acting β₂ agonists	Bambuterol Clenbuterol Formoterol/Arformoterol Salmeterol Salmefamol

Ultra-long-acting β₂ agonists	Abediterol Carmoterol Indacaterol Olodaterol Vilanterol

Other	Epinephrine^# Hexoprenaline Isoprenaline (isoproterenol) Orciprenaline (metaproterenol)

Glucocorticoids

Anticholinergics/
muscarinic antagonist

Mast cell stabilizers

Xanthines

Eicosanoid inhibition

Leukotriene antagonists	Montelukast Pranlukast Zafirlukast

Arachidonate 5-lipoxygenase inhibitors	Zileuton

Thromboxane receptor antagonists	Ramatroban Seratrodast

Non-xanthine PDE4 inhibitors	Ibudilast Roflumilast

Others/unknown

Combination products

^#WHO-EM
^‡Withdrawn from market
Clinical trials:
- ^†Phase III
- ^§Never to phase III

Adrenergic receptor modulators

α₁

Agonists 6-FNE Amidephrine Anisodine Buspirone Cirazoline Corbadrine Dexisometheptene Dipivefrine Dopamine Droxidopa (L-DOPS) Ephedrine Epinephrine Etilefrine Etilevodopa Ethylnorepinephrine Indanidine Isometheptene L-DOPA (levodopa) L-Phenylalanine L-Tyrosine Melevodopa Metaraminol Methoxamine Methyldopa Midodrine Naphazoline Norepinephrine Octopamine (drug) Oxymetazoline Phenylephrine Phenylpropanolamine Pseudoephedrine Synephrine Tetryzoline Tiamenidine XP21279 Xylometazoline

Antagonists Abanoquil Adimolol Ajmalicine Alfuzosin Amosulalol Anisodamine Arotinolol Atiprosin Atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, risperidone) Benoxathian Buflomedil Bunazosin Carvedilol Corynanthine Dapiprazole Domesticine Doxazosin Ergolines (e.g., ergotamine, dihydroergotamine, lisuride, terguride) Etoperidone Eugenodilol Fenspiride Hydroxyzine Indoramin Ketanserin L-765,314 Labetalol mCPP Mepiprazole Metazosin Monatepil Moxisylyte Naftopidil Nantenine Nefazodone Neldazosin Niaprazine Nicergoline Niguldipine Pardoprunox Pelanserin Phendioxan Phenoxybenzamine Phentolamine Piperoxan Prazosin Quinazosin Ritanserin Silodosin Spiperone Talipexole Tamsulosin Terazosin Tiodazosin Tolazoline Trazodone Tetracyclic antidepressants (e.g., amoxapine, maprotiline, mianserin) Tricyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin, imipramine, trimipramine) Trimazosin Typical antipsychotics (e.g., chlorpromazine, fluphenazine, loxapine, thioridazine) Urapidil WB-4101 Zolertine

α₂

Agonists (R)-3-Nitrobiphenyline 4-NEMD 6-FNE Amitraz Apraclonidine Brimonidine Cannabivarin Clonidine Corbadrine Detomidine Dexmedetomidine Dihydroergotamine Dipivefrine Dopamine Droxidopa (L-DOPS) Etilevodopa Ephedrine Ergotamine Epinephrine Etilefrine Ethylnorepinephrine Guanabenz Guanfacine Guanoxabenz L-DOPA (levodopa) L-Phenylalanine L-Tyrosine Lofexidine Medetomidine Melevodopa Methyldopa Mivazerol Naphazoline Norepinephrine Oxymetazoline Phenylpropanolamine Piperoxan Pseudoephedrine Rilmenidine Romifidine Talipexole Tetrahydrozoline Tiamenidine Tizanidine Tolonidine Urapidil XP21279 Xylazine Xylometazoline

Antagonists 1-PP Adimolol Aptazapine Atipamezole Atypical antipsychotics (e.g., asenapine, clozapine, lurasidone, paliperidone, quetiapine, risperidone, zotepine) Azapirones (e.g., buspirone, tandospirone) BRL-44408 Buflomedil Cirazoline Efaroxan Esmirtazapine Fenmetozole Fluparoxan Idazoxan mCPP Mianserin Mirtazapine NAN-190 Olanzapine Pardoprunox Phentolamine Phenoxybenzamine Piperoxan Piribedil Rauwolscine Rotigotine SB-269970 Setiptiline Spiroxatrine Sunepitron Tolazoline Typical antipsychotics (e.g., chlorpromazine, fluphenazine, loxapine, thioridazine) Yohimbine

Agonists Abediterol Alifedrine Amibegron Arbutamine Arformoterol Arotinolol BAAM Bambuterol Befunolol Bitolterol Broxaterol Buphenine Carbuterol Carmoterol Cimaterol Clenbuterol Corbadrine Denopamine Dipivefrine Dobutamine Dopamine Dopexamine Droxidopa (L-DOPS) Ephedrine Epinephrine Etafedrine Etilefrine Etilevodopa Ethylnorepinephrine Fenoterol Formoterol Hexoprenaline Higenamine Indacaterol Isoetarine Isoprenaline Isoxsuprine L-DOPA (levodopa) L-Phenylalanine L-Tyrosine Levosalbutamol Mabuterol Melevodopa Methoxyphenamine Methyldopa Mirabegron Norepinephrine Orciprenaline Oxyfedrine PF-610355 Phenylpropanolamine Pirbuterol Prenalterol Ractopamine Procaterol Pseudoephedrine Reproterol Rimiterol Ritodrine Salbutamol Salmeterol Solabegron Terbutaline Tretoquinol Tulobuterol Vilanterol Xamoterol XP21279 Zilpaterol Zinterol

Antagonists Acebutolol Adaprolol Adimolol Afurolol Alprenolol Alprenoxime Amosulalol Ancarolol Arnolol Arotinolol Atenolol Befunolol Betaxolol Bevantolol Bisoprolol Bopindolol Bornaprolol Brefonalol Bucindolol Bucumolol Bufetolol Bufuralol Bunitrolol Bunolol Bupranolol Butaxamine Butidrine Butofilolol Capsinolol Carazolol Carpindolol Carteolol Carvedilol Celiprolol Cetamolol Cicloprolol Cinamolol Cloranolol Cyanopindolol Dalbraminol Dexpropranolol Diacetolol Dichloroisoprenaline Dihydroalprenolol Dilevalol Diprafenone Draquinolol Ecastolol Epanolol Ericolol Ersentilide Esatenolol Esprolol Eugenodilol Exaprolol Falintolol Flestolol Flusoxolol Hydroxycarteolol Hydroxytertatolol ICI-118,551 Idropranolol Indenolol Indopanolol Iodocyanopindolol Iprocrolol Isoxaprolol Isamoltane Labetalol Landiolol Levobetaxolol Levobunolol Levomoprolol Medroxalol Mepindolol Metipranolol Metoprolol Moprolol Nadolol Nadoxolol Nebivolol Nifenalol Nipradilol Oxprenolol Pacrinolol Pafenolol Pamatolol Pargolol Penbutolol Pindolol Practolol Primidolol Procinolol Pronethalol Propafenone Propranolol Ridazolol Ronactolol Soquinolol Sotalol Spirendolol SR 59230A Sulfinalol Talinolol Tazolol Tertatolol Tienoxolol Tilisolol Timolol Tiprenolol Tolamolol Toliprolol Xibenolol Xipranolol

See also: Dopaminergics

Melatonergics

Serotonergics

Monoamine reuptake and release modulators

Monoamine metabolism modulators

Monoamine neurotoxins

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