What is salmeterol. Salmeterol: A Comprehensive Guide to Its Uses, Mechanism, and Clinical Implications

21.05.202316.07.2023 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. How does salmeterol compare to other bronchodilators. What precautions should be taken when using salmeterol.

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. Its primary uses include the treatment of asthma, maintenance of airflow obstruction in chronic obstructive pulmonary disease (COPD), and prevention of exercise-induced bronchospasm (EIB). As a potent bronchodilator, salmeterol offers extended relief from airway constriction, making it an essential component in the long-term management of chronic respiratory disorders.

Key Features of Salmeterol

Highly selective for beta-2 receptors
Long-acting, with effects lasting up to 12 hours
Used in combination with inhaled corticosteroids for asthma management
Effective as monotherapy for COPD maintenance
Ten times more potent than albuterol

Is salmeterol suitable for all types of asthma. Salmeterol is primarily indicated for patients with severe persistent asthma that is not adequately controlled with short-acting beta-agonists and corticosteroids. It is not recommended for patients with mild asthma who respond well to short-acting bronchodilators.

The Mechanism of Action: How Salmeterol Works

Salmeterol’s effectiveness in treating respiratory conditions stems from its unique mechanism of action. As a beta-2 agonist, it operates through a complex cascade of cellular events that ultimately lead to bronchodilation and reduced airway inflammation.

The Beta-2 Agonist Pathway

Salmeterol binds to beta-2 adrenergic receptors on airway smooth muscle cells
This activates G protein-linked second messengers
Gs protein stimulates adenylyl cyclase
Adenylyl cyclase converts ATP to cAMP
cAMP activates protein kinase A
Protein kinase A inhibits myosin light chain kinase
This cascade results in smooth muscle relaxation and bronchodilation

How does salmeterol’s structure contribute to its long-acting effects. Salmeterol’s unique molecular structure includes an elongated lipophilic side-chain that allows it to bind repeatedly to the “exosite” adjacent to beta-2 receptors. This enables the active portion of the molecule to engage and disengage with the receptor continuously, resulting in a prolonged duration of action lasting approximately 12 hours.

Clinical Applications: Asthma and COPD Management

Salmeterol has proven to be a valuable asset in the treatment of both asthma and COPD. Its long-acting nature and potent bronchodilatory effects make it particularly useful in maintaining airway patency and preventing exacerbations.

Salmeterol in Asthma Treatment

In asthma management, salmeterol is typically used in combination with inhaled corticosteroids (ICS). This combination therapy has shown significant benefits in reducing asthma mortality and improving overall symptom control. Salmeterol helps to:

Provide sustained bronchodilation
Prevent asthma attacks
Improve lung function
Reduce the need for rescue medications

Why is salmeterol not recommended as monotherapy for asthma. Salmeterol monotherapy in asthma is contraindicated due to an increased risk of mortality. The use of salmeterol in combination with inhaled corticosteroids has been shown to significantly reduce this risk while providing superior asthma control.

Salmeterol in COPD Management

Unlike in asthma treatment, salmeterol can be used as monotherapy in COPD management. It is particularly effective as a maintenance treatment for COPD patients, offering several benefits:

Increased FEV1 and FEV1/FVC ratio
Improved airflow obstruction
Better quality of life for COPD patients
Reduced frequency of exacerbations

How does salmeterol compare to short-acting beta-agonists in COPD management. Salmeterol’s long-acting nature provides more consistent bronchodilation throughout the day, reducing the need for frequent dosing and potentially improving patient adherence to treatment regimens.

Salmeterol vs. Other Bronchodilators: A Comparative Analysis

When comparing salmeterol to other bronchodilators, particularly its chemical analog albuterol (salbutamol), several key differences emerge. These distinctions highlight the unique properties of salmeterol and its specific role in respiratory care.

Salmeterol vs. Albuterol

Potency: Salmeterol is ten times more potent than albuterol
Selectivity: Salmeterol has a much higher beta-2/beta-1 selectivity ratio (50,000:1 vs. 650:1)
Duration of action: Salmeterol lasts approximately 12 hours, compared to 4-6 hours for albuterol
Clinical efficacy: Head-to-head studies have shown salmeterol to be clinically superior in providing sustained bronchodilation and better symptom prevention

What makes salmeterol more suitable for long-term management of asthma and COPD. Salmeterol’s extended duration of action and higher potency make it ideal for maintenance therapy, reducing the frequency of dosing and providing more consistent symptom control throughout the day and night.

Pharmacokinetics and Metabolism of Salmeterol

Understanding the pharmacokinetics and metabolism of salmeterol is crucial for healthcare providers to optimize its use and minimize potential drug interactions. The unique properties of salmeterol contribute to its effectiveness and safety profile.

Metabolism Pathway

Salmeterol is primarily metabolized through the CYP3A4 isoform of cytochrome P450. This enzyme is responsible for the aliphatic oxidation of salmeterol’s side chain, which is the principal metabolic pathway. The metabolism of salmeterol has important implications for drug interactions and dosing considerations.

How does the metabolism of salmeterol affect its potential for drug interactions. The involvement of CYP3A4 in salmeterol metabolism means that drugs that inhibit or induce this enzyme may affect salmeterol’s plasma concentrations and efficacy. Healthcare providers should be aware of potential interactions with CYP3A4 inhibitors or inducers when prescribing salmeterol.

Pharmacokinetic Properties

Onset of action: Typically within 10-20 minutes after inhalation
Peak effect: Usually reached within 3-4 hours
Duration of action: Approximately 12 hours
Half-life: Estimated to be 5.5 hours

Why is the long duration of action of salmeterol clinically significant. The extended bronchodilatory effect of salmeterol allows for twice-daily dosing, which can improve patient adherence and provide more consistent symptom control compared to short-acting bronchodilators that require more frequent administration.

Adverse Effects and Safety Considerations

While salmeterol is generally well-tolerated, it is associated with certain adverse effects and safety considerations that healthcare providers and patients should be aware of. Understanding these potential risks is crucial for safe and effective use of the medication.

Common Side Effects

Tremor
Nervousness
Headache
Palpitations
Tachycardia
Throat irritation

Are the side effects of salmeterol dose-dependent. Many of the side effects associated with salmeterol are dose-dependent, with higher doses more likely to cause adverse reactions. This underscores the importance of using the lowest effective dose to maintain symptom control.

Serious Adverse Effects

While less common, salmeterol can potentially cause more serious adverse effects, particularly when used improperly or in high doses:

Paradoxical bronchospasm
Cardiovascular effects (e.g., arrhythmias)
Hypokalemia
Increased risk of asthma-related death when used as monotherapy

How can the risk of serious adverse effects be minimized. Proper patient education, adherence to prescribed dosing regimens, and regular monitoring by healthcare providers are essential in minimizing the risk of serious adverse effects. Additionally, using salmeterol in combination with inhaled corticosteroids for asthma management significantly reduces the risk of asthma-related mortality.

Optimizing Salmeterol Administration for Maximum Efficacy

Proper administration of salmeterol is crucial for achieving optimal therapeutic outcomes and minimizing adverse effects. Healthcare providers should educate patients on the correct use of salmeterol inhalers and emphasize the importance of adherence to prescribed regimens.

Key Points for Effective Administration

Dosing frequency: Typically twice daily, approximately 12 hours apart
Proper inhaler technique: Ensure patients understand how to use their specific inhaler device correctly
Timing of doses: Administer at consistent times each day for optimal effect
Avoid overuse: Emphasize that salmeterol is not for acute symptom relief
Combination therapy: When used for asthma, always administer with an inhaled corticosteroid

How can healthcare providers ensure patients are using salmeterol correctly. Regular follow-up appointments, inhaler technique checks, and patient education sessions can help ensure proper use of salmeterol. Providers should also monitor patients for signs of overuse or inadequate control of symptoms, adjusting treatment plans as necessary.

Special Considerations for Different Patient Groups

Certain patient populations may require special consideration when using salmeterol:

Elderly patients: May be more sensitive to beta-agonist effects
Patients with cardiovascular disease: Monitor closely for cardiac side effects
Pregnant women: Use only when benefits outweigh potential risks
Children: Dosing may need to be adjusted based on age and weight

What precautions should be taken when prescribing salmeterol to patients with a history of cardiovascular disease. Healthcare providers should carefully assess the risk-benefit ratio for these patients, consider starting with lower doses, and monitor closely for cardiovascular side effects such as palpitations or tachycardia.

The Future of Salmeterol in Respiratory Medicine

As research in respiratory medicine continues to advance, the role of salmeterol in treating asthma and COPD is likely to evolve. Current trends and ongoing studies suggest several potential developments in the use of salmeterol and related long-acting beta-agonists.

Emerging Trends and Research Directions

Novel combination therapies: Exploring new combinations of salmeterol with other classes of respiratory medications
Improved delivery systems: Developing more efficient inhaler devices for better drug deposition
Personalized medicine approaches: Tailoring salmeterol use based on individual patient characteristics and biomarkers
Long-term safety studies: Continuing to assess the long-term effects of salmeterol use, particularly in combination therapies
Expanding indications: Investigating potential uses of salmeterol in other respiratory conditions

How might advances in personalized medicine impact the use of salmeterol in the future. As our understanding of genetic and biological markers of respiratory disease improves, it may become possible to predict which patients are most likely to benefit from salmeterol therapy, allowing for more targeted and effective treatment strategies.

Challenges and Opportunities

While salmeterol has proven to be a valuable tool in respiratory medicine, there are still challenges to address and opportunities for improvement:

Overcoming potential resistance: Investigating mechanisms of reduced responsiveness to beta-agonists over time
Minimizing side effects: Developing formulations or delivery methods that reduce systemic absorption and associated adverse effects
Improving patient adherence: Creating easier-to-use devices or longer-acting formulations to enhance treatment compliance
Addressing global accessibility: Ensuring availability and affordability of salmeterol in diverse healthcare settings worldwide

What role might digital health technologies play in optimizing salmeterol therapy. The integration of smart inhalers, mobile health apps, and remote monitoring systems could potentially improve patient adherence, allow for real-time tracking of medication use and symptoms, and facilitate more personalized adjustments to treatment regimens.

As research continues and new technologies emerge, salmeterol is likely to remain a cornerstone of asthma and COPD management. Its proven efficacy, combined with ongoing advancements in respiratory medicine, positions salmeterol to continue playing a crucial role in improving the lives of patients with chronic respiratory conditions. Healthcare providers should stay informed about these developments to ensure they are providing the most up-to-date and effective care for their patients.

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.

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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]

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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.