What is salmeterol. Salmeterol: A Comprehensive Guide to Its Uses, Mechanism, and Benefits in Asthma and COPD Treatment

25.05.202316.07.2023 by alexxlab

What are the indications for salmeterol. How does salmeterol work in treating asthma and COPD. What are the potential side effects of salmeterol. How is salmeterol administered effectively. Why is salmeterol often combined with inhaled corticosteroids.

Содержание

Understanding Salmeterol: A Powerful Long-Acting Beta-2 Agonist

Salmeterol is a highly selective, long-acting beta-2 adrenergic agonist that plays a crucial role in the management of respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD). As a medication that has revolutionized the treatment of these chronic respiratory diseases, salmeterol offers extended bronchodilation and improved symptom control for patients struggling with airflow obstruction.

This potent bronchodilator belongs to the class of medications known as beta-2 agonists, which work by relaxing the smooth muscles in the airways. What sets salmeterol apart from its counterparts? Its unique molecular structure allows for a prolonged duration of action, providing relief for up to 12 hours with a single dose. This extended effect makes salmeterol an invaluable tool in the long-term management of asthma and COPD.

The Primary Indications for Salmeterol Use

Salmeterol’s versatility in treating respiratory conditions is evident in its approved indications. For which conditions is salmeterol primarily prescribed?

Treatment of asthma (in combination with inhaled corticosteroids)
Maintenance of airflow obstruction in COPD
Prevention of exercise-induced bronchospasm (EIB)

In the context of asthma management, salmeterol is particularly beneficial for patients with severe persistent asthma that is not adequately controlled by short-acting beta-agonists and corticosteroids alone. It’s important to note that salmeterol should not be used as monotherapy for asthma due to increased mortality risk. Instead, it is prescribed in combination with inhaled corticosteroids, which has been shown to significantly reduce asthma-related deaths.

For COPD patients, salmeterol can be used as a standalone maintenance treatment, offering improved lung function and symptom relief. Clinical studies have demonstrated that salmeterol increases FEV1 (forced expiratory volume in one second) and the FEV1/FVC (forced vital capacity) ratio in both asthma and COPD patients, indicating improved airflow and lung function.

Mechanism of Action: How Salmeterol Works in the Body

To understand the effectiveness of salmeterol, it’s crucial to delve into its mechanism of action. How does salmeterol produce its bronchodilating effect?

Salmeterol acts as a beta-2 agonist, which means it binds to and activates beta-2 adrenergic receptors in the smooth muscles of the airways. This activation triggers a cascade of events within the cells:

Salmeterol binds to the beta-2 receptor, activating a G protein-linked second messenger system.
The activated G protein stimulates adenylyl cyclase, which converts ATP to cyclic AMP (cAMP).
Increased cAMP levels activate protein kinase A.
Protein kinase A inhibits myosin light chain kinase, which is present in smooth muscle.
This inhibition results in the relaxation of bronchiolar smooth muscle, leading to bronchodilation and increased airflow.

What makes salmeterol unique among beta-2 agonists? Its molecular structure includes an elongated lipophilic side-chain that allows for repeated activation of the beta-2 receptor. This side chain binds to an “exosite” adjacent to the receptor, enabling the active portion of the molecule to engage and disengage with the receptor continuously. This unique binding mechanism is responsible for salmeterol’s extended duration of action, lasting approximately 12 hours compared to the 4-6 hour duration of short-acting beta-agonists like salbutamol (albuterol).

Salmeterol’s Anti-Inflammatory Properties: A Secondary Benefit

While bronchodilation is the primary function of salmeterol, it also exhibits some anti-inflammatory properties, albeit to a lesser degree. How does salmeterol contribute to reducing airway inflammation?

In human lungs, salmeterol has been shown to inhibit the release of inflammatory mediators from mast cells, including:

Histamine
Leukotrienes
Prostaglandins

By suppressing these inflammatory mediators, salmeterol helps to decrease overall airway inflammation. This dual action of bronchodilation and mild anti-inflammatory effect contributes to its efficacy in managing chronic respiratory conditions.

Comparative Efficacy: Salmeterol vs. Short-Acting Beta-Agonists

When comparing salmeterol to its short-acting counterparts, such as salbutamol (albuterol), several key differences emerge. How does salmeterol’s efficacy stack up against short-acting beta-agonists?

Clinical studies have shown that salmeterol is approximately ten times more potent than albuterol. Additionally, it boasts a much higher beta-2/beta-1 selectivity ratio:

Salmeterol: 50,000 to 1 beta-2/beta-1 selectivity ratio
Albuterol: 650 to 1 beta-2/beta-1 selectivity ratio

This high selectivity for beta-2 receptors contributes to salmeterol’s efficacy and reduced potential for unwanted systemic effects mediated by beta-1 receptors.

Head-to-head studies comparing salmeterol and salbutamol have revealed clinically superior results for salmeterol in several key areas:

Sustained bronchodilation
Better prevention of asthma symptoms
Improved pulmonary function
Higher peak expiratory flow
Reduced need for supplemental bronchodilators
Decreased frequency of nocturnal awakenings
Lower occurrence and severity of daily asthma symptoms

These findings underscore the value of salmeterol in the long-term management of asthma and COPD, particularly for patients who require more than occasional use of short-acting bronchodilators.

Salmeterol in Combination Therapy: Enhancing Asthma and COPD Management

One of the most significant developments in the use of salmeterol has been its combination with inhaled corticosteroids (ICS) for the treatment of asthma and COPD. Why is this combination approach so effective?

The FDA approved fluticasone propionate/salmeterol (FP/SAL) as a fixed-dose combination therapy following the initial approval of salmeterol xinafoate in 1994. This combination therapy offers several advantages:

Sustained bronchodilation
Prevention of exacerbations
Improved lung function
Reduced need for rescue medications

The synergistic effect of combining a long-acting beta-2 agonist (salmeterol) with an inhaled corticosteroid (fluticasone) addresses both the bronchoconstrictive and inflammatory components of asthma and COPD. This dual approach has proven more effective than either medication used alone, leading to better symptom control and improved quality of life for patients.

Administration and Dosing Considerations for Salmeterol

Proper administration of salmeterol is crucial for achieving optimal therapeutic benefits. How should salmeterol be administered, and what dosing considerations should be kept in mind?

Salmeterol is typically administered via inhalation using a metered-dose inhaler (MDI) or a dry powder inhaler (DPI). The standard dosing regimen for adults and adolescents is:

Two inhalations (50 mcg per inhalation) twice daily, approximately 12 hours apart
Maximum daily dose: 200 mcg (four inhalations)

It’s important to note that salmeterol is intended for the long-term maintenance treatment of asthma and COPD and should not be used for acute symptom relief. Patients should be instructed to use a short-acting beta-agonist for immediate relief of acute symptoms.

When using salmeterol in combination with an inhaled corticosteroid, the medications may be administered separately or as a combination inhaler, depending on the specific product prescribed.

Key Points for Proper Administration:

Administer salmeterol at consistent times each day to maintain steady blood levels
Do not exceed the recommended dose
Rinse mouth with water after each use to reduce the risk of oral thrush
Do not use salmeterol more frequently or at higher doses than prescribed
Always keep a short-acting bronchodilator available for acute symptoms

Healthcare providers should ensure that patients understand the proper technique for using their inhaler device, as incorrect usage can significantly reduce the medication’s effectiveness.

Potential Side Effects and Safety Considerations of Salmeterol

While salmeterol is generally well-tolerated, it’s important for healthcare providers and patients to be aware of potential side effects and safety considerations. What are the most common side effects associated with salmeterol use?

Common side effects of salmeterol may include:

Headache
Throat irritation
Muscle cramps
Nervousness
Tremor
Palpitations
Nausea

Most of these side effects are mild and tend to diminish with continued use. However, patients should be advised to report any persistent or severe side effects to their healthcare provider.

Safety Considerations and Precautions:

Several important safety considerations should be kept in mind when prescribing or using salmeterol:

Increased risk of asthma-related death when used as monotherapy for asthma
Potential for paradoxical bronchospasm
Cardiovascular effects, including increased heart rate and blood pressure
Potential for hypokalemia (low potassium levels)
Interactions with other medications, particularly strong CYP3A4 inhibitors

Healthcare providers should carefully assess the benefits and risks of salmeterol for each individual patient, taking into account their medical history, current medications, and the severity of their respiratory condition.

The Role of Salmeterol in Personalized Asthma and COPD Management

As our understanding of respiratory diseases continues to evolve, the role of salmeterol in personalized treatment approaches becomes increasingly important. How can healthcare providers optimize the use of salmeterol in individual patient care?

Personalized management strategies involving salmeterol may include:

Assessing patient-specific factors such as asthma phenotype or COPD severity
Considering comorbidities that may influence treatment choices
Evaluating patient preferences and ability to adhere to treatment regimens
Monitoring response to therapy and adjusting treatment as needed
Incorporating salmeterol into comprehensive management plans that include education, environmental control, and regular follow-up

By tailoring the use of salmeterol to individual patient needs and characteristics, healthcare providers can maximize its benefits while minimizing potential risks.

Future Directions: Ongoing Research and Potential Innovations in Salmeterol Use

The field of respiratory medicine is constantly evolving, and research into salmeterol and related medications continues to advance. What are some of the current areas of investigation and potential future developments in salmeterol use?

Ongoing research and potential innovations include:

Development of novel delivery systems for improved lung deposition and reduced systemic exposure
Investigation of salmeterol in combination with newer anti-inflammatory agents
Exploration of personalized dosing strategies based on genetic markers or biomarkers
Studies on the long-term effects of salmeterol use in various patient populations
Research into potential applications of salmeterol in other respiratory conditions

As our understanding of respiratory diseases and pharmacology continues to grow, it’s likely that the role of salmeterol in clinical practice will continue to evolve, potentially offering even greater benefits to patients with asthma and COPD.

In conclusion, salmeterol represents a significant advancement in the treatment of chronic respiratory conditions, offering extended bronchodilation and improved symptom control for patients with asthma and COPD. Its unique mechanism of action, coupled with its proven efficacy and safety profile when used appropriately, makes it a valuable tool in the arsenal of respiratory medications. As research continues and treatment strategies become increasingly personalized, salmeterol is likely to remain an important component of comprehensive respiratory care for years to come.

Salmeterol – StatPearls – NCBI Bookshelf

Continuing Education Activity

Salmeterol is a medication used in the management and treatment of asthma and COPD. It is in the beta-2 adrenergic agonist class medications. This activity reviews the indications, mechanism of action, and contraindications for salmeterol as a valuable agent in treating asthma and COPD. This activity will highlight the mechanism of action, adverse event profile, and dosing pertinent for members of the interprofessional team in the treatment of patients with asthma and related conditions.

Objectives:

Identify the mechanism of action of salmeterol.
Describe the potential adverse effects associated with salmeterol.
Review the appropriate administration for salmeterol.
Summarize some interprofessional team strategies for improving care coordination and communication to advance proper asthma treatment and improve outcomes.

Access free multiple choice questions on this topic.

Indications

Salmeterol is a highly selective, long-acting beta-2 adrenergic agonist indicated in the treatment of asthma, maintenance of airflow obstruction in chronic obstructive pulmonary disease (COPD), and prevention of exercise-induced bronchospasm (EIB).[1][2][3][4] Salmeterol is used in combination with inhaled corticosteroids in the treatment of asthma.[5] It can be useful in both the maintenance of asthma and the prevention of asthma attacks. It is usually prescribed for severe persistent asthma not properly controlled using a short-acting beta-adrenergic agonist and a corticosteroid. Salmeterol is not indicated in patients with mild asthma who are well maintained on short-acting beta-agonists. Salmeterol monotherapy is a contraindication for treating asthma patients due to the increased risk of mortality. Salmeterol administration with concomitant inhaled corticosteroid (ICS) has significantly reduced asthma mortality.[6] Salmeterol can, however, be used as a monotherapy in the treatment of COPD, particularly as a maintenance treatment. [7] Salmeterol has been shown to increase FEV1 and the FEV1/FVC ratio in both asthma and COPD patients.[8]

Following the approval in 1994 of salmeterol xinafoate, the FDA approved fluticasone propionate/salmeterol (FP/SAL) as a fixed-dose combination therapy for the treatment of asthma and COPD. Fluticasone/salmeterol combination provides sustained bronchodilation, prevention of exacerbation, improved lung function, and reduced rescue medicine use.[9]

Salmeterol is ten times more potent than its chemical analog albuterol. Additionally, it has a much higher beta-2/beta-1 selectivity ratio than albuterol, with a ratio of 50,000 to 1 vs. 650 to 1.[10]

A head-to-head study comparing the use of salmeterol and salbutamol (albuterol) revealed clinically superior results of inhaled salmeterol, providing sustained bronchodilatation and better prevention of the symptoms of asthma than salbutamol. These results measured pulmonary function, peak expiratory flow, the need for a supplemental bronchodilator, frequency of nocturnal awakening, and the occurrence and severity of daily symptoms of asthma. [10]

Salmeterol is used for prophylaxis of mild to moderate asthma and COPD and should never be used to treat acute bronchospasm.

Mechanism of Action

Salmeterol belongs to the group of drugs called beta-2 agonists. Beta-2 agonists are G protein-linked second messengers. The Gs protein stimulates adenylyl cyclase, which converts ATP to cAMP. Subsequently, cAMP activates protein kinase A, inhibiting myosin light chain kinase (present in smooth muscle). This cascade results in the relaxation of bronchiolar smooth muscle, bronchodilation, and increased bronchiole airflow.[11][12][13]

In human lungs, salmeterol also inhibits mast cell mediators, including histamine, leukotrienes, and prostaglandins; this suppression leads to decreased inflammation. Bronchodilation remains the primary function of salmeterol; its anti-inflammatory properties are present to a much lesser degree.

Salmeterol’s molecular structure confers its characteristic, extended duration of action. Its elongated lipophilic side-chain facilitates repeated activation of the beta-2 receptor. The side chain binds to the so-called “exosite” adjacent to beta-2 adrenergic receptors. The active portion of the molecule is allowed to remain at the receptor site and continuously engage and disengage with the receptor.[14] Due to this unique molecular structure, a single inhaled dose of salmeterol lasts approximately 12 hours compared to salbutamol, which lasts 4 to 6 hours. Salmeterol given twice daily in the management of mild-to-moderate asthma has proven clinically superior to albuterol given either regularly or intermittently as needed.[10]

Metabolism

Salmeterol is metabolized predominantly through CYP3A4, an isoform of cytochrome P450. CYP3A4 is responsible for the aliphatic oxidation of the salmeterol base. Salmeterol is extensively metabolized by hydroxylation into alpha-hydroxy-salmeterol and subsequently eliminated through the feces and urine. Salmeterol is 57. 4% eliminated in the feces and 23% in the urine.[15][16]

At recommended doses, systemic concentrations of salmeterol are low or undetectable. Only at very high doses is blood concentrations increased.

At a very low therapeutic dose, it is unlikely to observe any clinically relevant interactions as a consequence of co-administration of other medications metabolized through CYP3A4.[16] Specific guidelines for dosage adjustment in renal or hepatic impairment are not currently available. However, caution is necessary for patients with severe liver dysfunction and subsequent clearance decrease. Additionally, the use of potent CYP34A inhibitors is not recommended because increased cardiovascular and systemic corticosteroid adverse effects may occur. These inhibitors include but are not limited to ritonavir, atazanavir, indinavir, nelfinavir, saquinavir, itraconazole, ketoconazole, nefazodone, clarithromycin, and telithromycin.[17]

Administration

Salmeterol comes in a variety of dosing forms and strengths. The most common form is a fixed-dose combination containing both fluticasone propionate and salmeterol. As salmeterol monotherapy is contraindicated in the treatment of asthma, clinicians often use fixed-dose combinations to ensure adherence to both drugs.[6][9]

Salmeterol is currently available as an oral inhalation powder and an oral inhalation aerosol. Inhalation powder is available in 3 doses of fluticasone (100 mcg, 250 mcg, 500 mcg) and a fixed dose (50 mcg) of salmeterol. An aerosol metered-dose inhaler (MDI) is also available in 3 doses of fluticasone (45 mcg, 115 mcg, 230 mcg) and a fixed-dose (21 mcg) of salmeterol. A hydrofluoralkane propellant delivers the metered-dose inhaler. In an active-controlled, 12-week trial, improvements in morning peak expiratory flow (PEF) observed with 500/50 mcg formulation was similar to improvements seen with the 230/21 formulation. Though the mechanism of delivery and dose vary, research showed efficacy to be similar across treatments. [18] Paradoxical bronchospasm has been reported in patients using metered-dose inhalers but not dry powder inhalers.[19]

For the treatment of asthma in patients aged 12 years and older, one inhalation of fluticasone/salmeterol 100/50, 250/50, 500/50 mcg inhalation powder is taken twice daily.[1] The starting dosage is determined based on asthma severity. Conversely, two inhalations of fluticasone/salmeterol 45/21, 115/21, 230/21 mcg inhalation aerosol are dosed twice daily. After inhalation, patients should understand the need to rinse their mouths with water, and without swallowing, spit out the contents to avoid oral candidiasis.[20]

For the treatment of asthma in children between the ages of 4 and 11, the standard recommendation is one inhalation of fluticasone/ salmeterol 100/50 mcg twice daily.[1] Safety and efficacy have not been established in children less than four years old

For maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, the recommendation is one inhalation 250/50 mcg twice daily, approximately 12 hours apart. [2]

For the prevention of exercise-induced bronchospasm (EIB), single-agent administration of salmeterol inhalation powder may be clinically indicated in patients without persistent asthma. In these cases, one inhalation of 50 mcg, taken 20 to 30 minutes before exercise, has been shown to protect against EIB. Generally, the desired bronchodilation effects last 9 hours in adults and 12 hours in patients 4 to 11 years old. In patients with persistent asthma, monotherapy is contraindicated.[3]

Adverse Effects

The most common adverse reactions of salmeterol (incidence ≥3%) in asthmatics include upper respiratory infection or inflammation, oral candidiasis, pharyngitis, bronchitis, dysphonia, headaches, cough, nausea, and vomiting. In patients with chronic obstructive pulmonary disease, the most common adverse effects include pneumonia, throat irritation, viral respiratory infections, oral candidiasis, dysphonia, headaches, and musculoskeletal pains.[21]

Immediate hypersensitivity reactions may occur. Patients may present with urticaria, rash, angioedema, bronchospasm, headache, tremor, or anaphylaxis.

More severe adverse effects associated with salmeterol overdose are characterized by excessive beta-adrenergic stimulation to the heart. Although salmeterol is a highly selective beta-2 agonist, it still exhibits some beta-1 effects and can cause cardiac effects.

These symptoms include angina, tachycardia, hypertension, hypotension, arrhythmia, palpitation, and fatigue. These undesirable pharmacologic effects are predominantly a result of reflex activation in response to peripheral vasodilation, hypoxemia, hypokalemia, and direct stimulation of cardiac beta-adrenoceptors.[22]

Paradoxical bronchospasm, laryngeal spasm, and throat swelling can occur. In COPD patients, long-acting beta-agonists (LABA) have been shown to increase the risk of cardiac failure.[23]

Contraindications

Hypersensitivity is a contraindication for salmeterol. It is contraindicated in patients with a known hypersensitivity to any ingredient in the preparation, including lactose and milk protein. [24]

Salmeterol is contraindicated in patients who have had adverse reactions to salmeterol in the past. It should not be used for status asthmaticus or other acute asthma episodes. Salmeterol should not be used in combination with other long-acting beta-agonists. Studies have shown an increased risk for death in asthma patients taking salmeterol vs. placebo; this risk was highest for African-American patients.[25]

There is an FDA black box warning for asthma patients due to the increased incidence of asthma-related deaths with this medication. Salmeterol should not be used as a monotherapy in asthma patients. Clinicians should only use it as an adjunct medication in patients who have failed other asthma therapies such as low to medium dose inhaled steroids or those with severe asthma necessitating two maintenance therapies.

While not strictly contraindications, salmeterol use requires caution in patients with an existing cardiovascular disorder, convulsive disorder, hepatic impairment, diabetes mellitus, hyperthyroidism/thyrotoxicosis, or who use other CYP3A inhibitors, as this may increase toxicity and prolong the patient’s QT interval. There is a (usually transient) risk of hypokalemia; therefore, salmeterol use merits caution in patients with hypokalemia.

Monitoring

Monitoring parameters for salmeterol include heart rate, blood pressure, pulmonary function, forced expiratory volume, peak expiratory flow, frequency of nocturnal awakenings, central nervous system stimulation, and occurrence and severity of asthma symptoms.[26]

If there is a concern for any of the conditions noted above in the contraindication section, it may be helpful to periodically monitor blood glucose, potassium, thyroid function, hepatic function, and/or the QT interval if the patient is concomitantly taking other CYP3A4 inhibitors.

Patients with hepatic impairment require close monitoring as decreased liver function may lead to salmeterol accumulation in the plasma.[17]

Toxicity

There are reports of sympathomimetic syndrome with hyperlactatemia and metabolic acidosis after the intentional inhalation of salmeterol in a suicide attempt. Patients who overdose commonly present with heart palpitation, chest pain, hypophosphatemia, hypokalemia, lactic acidosis, ST-segment depression, and sinus tachycardia. Patients may also present with angina, hypotension, hypertension, dizziness, nausea, fatigue, malaise, insomnia, and muscle cramps. Overdose with salmeterol can lead to prolongation of the QT interval resulting in ventricular arrhythmias.[22]

The standard treatment for symptomatic salmeterol overdose is supportive and should include intravenous fluids, careful potassium supplementation, a cardioselective beta-blocker, and cardiac monitoring.

Enhancing Healthcare Team Outcomes

As most patients with COPD and severe asthma will require lifetime treatment with long-acting beta-2 agonists, a patient-centered approach involving multi-disciplinary coordination is requisite. At the level of primary care, the employment of respiratory therapists has shown improvement in the quality of asthma care. Patient outcomes have improved with more specialized care, decreasing the necessity for rescue inhaler use and overall symptom reduction. Additionally, proper inhaler device technique and spirometry for diagnosis increased in facilities with a designated respiratory care specialist (RCS). Pharmacists assist in verifying medication dosing and reinforcing proper inhalation technique. Nurses can educate, monitor care, and assess therapeutic effectiveness. In geriatric populations, long-term care facilities ensure medication compliance and appropriate outpatient care. [27] An interprofessional team-based approach involving physicians, respiratory therapists, respiratory care specialists, specialty-trained nurses, pharmacists, and patients leads to improved symptom control, decreased acute exacerbations, and improved quality of life. [Level 5]

Review Questions

Access free multiple choice questions on this topic.
Comment on this article.

References

1.: D’Alonzo GE, Tolep KA. Salmeterol in the treatment of chronic asthma. Am Fam Physician. 1997 Aug;56(2):558-62. [PubMed: 9262535]
2.: Yawn BP, Raphiou I, Hurley JS, Dalal AA. The role of fluticasone propionate/salmeterol combination therapy in preventing exacerbations of COPD. Int J Chron Obstruct Pulmon Dis. 2010 Jun 03;5:165-78. [PMC free article: PMC2898089] [PubMed: 20631816]
3.: Bronsky EA, Pearlman DS, Pobiner BF, Scott C, Wang Y, Stahl E. Prevention of exercise-induced bronchospasm in pediatric asthma patients: A comparison of two salmeterol powder delivery devices. Pediatrics. 1999 Sep;104(3 Pt 1):501-6. [PubMed: 10469776]
4.: Green CP, Price JF. Prevention of exercise induced asthma by inhaled salmeterol xinafoate. Arch Dis Child. 1992 Aug;67(8):1014-7. [PMC free article: PMC1793593] [PubMed: 1355645]
5.: Popov TA, De Niet S, Vanderbist F. Budesonide/salmeterol in fixed-dose combination for the treatment of asthma. Expert Rev Respir Med. 2016 Feb;10(2):113-25. [PubMed: 26677916]
6.: Lommatzsch M, Lindner Y, Edner A, Bratke K, Kuepper M, Virchow JC. Adverse effects of salmeterol in asthma: a neuronal perspective. Thorax. 2009 Sep;64(9):763-9. [PMC free article: PMC2730557] [PubMed: 19237390]
7.: Santus P, Radovanovic D, Paggiaro P, Papi A, Sanduzzi A, Scichilone N, Braido F. Why use long acting bronchodilators in chronic obstructive lung diseases? An extensive review on formoterol and salmeterol. Eur J Intern Med. 2015 Jul;26(6):379-84. [PubMed: 26049917]
8.: Grove A, Lipworth BJ, Reid P, Smith RP, Ramage L, Ingram CG, Jenkins RJ, Winter JH, Dhillon DP. Effects of regular salmeterol on lung function and exercise capacity in patients with chronic obstructive airways disease. Thorax. 1996 Jul;51(7):689-93. [PMC free article: PMC472490] [PubMed: 8882074]
9.: Calzetta L, Ritondo BL, Matera MG, Cazzola M, Rogliani P. Evaluation of fluticasone propionate/salmeterol for the treatment of COPD: a systematic review. Expert Rev Respir Med. 2020 Jun;14(6):621-635. [PubMed: 32168461]
10.: Pearlman DS, Chervinsky P, LaForce C, Seltzer JM, Southern DL, Kemp JP, Dockhorn RJ, Grossman J, Liddle RF, Yancey SW. A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. N Engl J Med. 1992 Nov 12;327(20):1420-5. [PubMed: 1357554]
11.: Billington CK, Penn RB, Hall IP. β₂ Agonists. Handb Exp Pharmacol. 2017;237:23-40. [PMC free article: PMC5480238] [PubMed: 27878470]
12.: Barisione G, Baroffio M, Crimi E, Brusasco V. Beta-Adrenergic Agonists. Pharmaceuticals (Basel). 2010 Mar 30;3(4):1016-1044. [PMC free article: PMC4034018] [PubMed: 27713285]
13.: Song N, Fang Y, Sun X, Jiang Q, Song C, Chen M, Ding J, Lu M, Hu G. Salmeterol, agonist of β2-aderenergic receptor, prevents systemic inflammation via inhibiting NLRP3 inflammasome. Biochem Pharmacol. 2018 Apr;150:245-255. [PubMed: 29447945]
14.: Johnson M, Butchers PR, Coleman RA, Nials AT, Strong P, Sumner MJ, Vardey CJ, Whelan CJ. The pharmacology of salmeterol. Life Sci. 1993;52(26):2131-43. [PubMed: 8099695]
15.: Manchee GR, Eddershaw PJ, Ranshaw LE, Herriott D, Park GR, Bayliss MK, Tarbit MH. The aliphatic oxidation of salmeterol to alpha-hydroxysalmeterol in human liver microsomes is catalyzed by CYP3A. Drug Metab Dispos. 1996 May;24(5):555-9. [PubMed: 8723736]
16.: Cazzola M, Testi R, Matera MG. Clinical pharmacokinetics of salmeterol. Clin Pharmacokinet. 2002;41(1):19-30. [PubMed: 11825095]
17.: Teply R, Campbell J, Hilleman D. Current trends in the treatment of asthma: focus on the simultaneous administration of salmeterol/fluticasone. J Asthma Allergy. 2010 Mar 11;3:1-8. [PMC free article: PMC3047914] [PubMed: 21437034]
18.: Bronsky E, Bucholtz GA, Busse WW, Chervinsky P, Condemi J, Ghafouri MA, Hudson L, Lakshminarayan S, Lockey R, Reese ME. Comparison of inhaled albuterol powder and aerosol in asthma. J Allergy Clin Immunol. 1987 May;79(5):741-7. [PubMed: 3553277]
19.: Wilkinson JR, Roberts JA, Bradding P, Holgate ST, Howarth PH. Paradoxical bronchoconstriction in asthmatic patients after salmeterol by metered dose inhaler. BMJ. 1992 Oct 17;305(6859):931-2. [PMC free article: PMC1883565] [PubMed: 1360855]
20.: Godara N, Godara R, Khullar M. Impact of inhalation therapy on oral health. Lung India. 2011 Oct;28(4):272-5. [PMC free article: PMC3213714] [PubMed: 22084541]
21.: Spencer CM, Jarvis B. Salmeterol/fluticasone propionate combination. Drugs. 1999 Jun;57(6):933-40; discussion 941-3. [PubMed: 10400406]
22.: Manara A, Hantson P, Vanpee D, Thys F. Lactic acidosis following intentional overdose by inhalation of salmeterol and fluticasone. CJEM. 2012 Nov;14(6):378-81. [PubMed: 23131487]
23.: Wu J, Ye Y, Li C, Zhou W, Chang R. Correlation of Inhaled Long-Acting Bronchodilators With Adverse Cardiovascular Outcomes in Patients With Stable COPD: A Bayesian Network Meta-Analysis of Randomized Controlled Trials. J Cardiovasc Pharmacol. 2019 Sep;74(3):255-265. [PubMed: 31306366]
24.: Robles J, Motheral L. Hypersensitivity reaction after inhalation of a lactose-containing dry powder inhaler. J Pediatr Pharmacol Ther. 2014 Jul;19(3):206-11. [PMC free article: PMC4187530] [PubMed: 25309152]
25.: Rider NL, Craig TJ. A safety review of long-acting beta2-agonists in patients with asthma. J Am Osteopath Assoc. 2006 Sep;106(9):562-7. [PubMed: 17079526]
26.: Cazzola M, Imperatore F, Salzillo A, Di Perna F, Calderaro F, Imperatore A, Matera MG. Cardiac effects of formoterol and salmeterol in patients suffering from COPD with preexisting cardiac arrhythmias and hypoxemia. Chest. 1998 Aug;114(2):411-5. [PubMed: 9726723]
27.: Hart MK, Millard MW. Approaches to chronic disease management for asthma and chronic obstructive pulmonary disease: strategies through the continuum of care. Proc (Bayl Univ Med Cent). 2010 Jul;23(3):223-9. [PMC free article: PMC2900972] [PubMed: 20671816]

: Disclosure: Bryan Adams declares no relevant financial relationships with ineligible companies.
: Disclosure: Hoang Nguyen declares no relevant financial relationships with ineligible companies.