What is salmeterol. Salmeterol: A Comprehensive Overview of the Long-Acting Beta-2 Adrenergic Agonist for Asthma and COPD Treatment

19.05.202316.07.2023 by alexxlab

What is salmeterol? How does it work? What are its potential adverse effects and appropriate administration? Discover the answers to these questions and more in this in-depth article.

Содержание

Introduction to Salmeterol

Salmeterol is a highly selective, long-acting beta-2 adrenergic agonist medication used in the treatment and management of asthma and chronic obstructive pulmonary disease (COPD). It belongs to a class of drugs known as beta-2 agonists, which play a crucial role in relaxing and dilating the bronchiolar smooth muscle, leading to improved airflow and respiratory function.

Mechanism of Action

Salmeterol’s mechanism of action involves the activation of G protein-linked second messengers. When salmeterol binds to beta-2 adrenergic receptors, it stimulates the Gs protein, which in turn activates adenylyl cyclase. This conversion of ATP to cAMP leads to the activation of protein kinase A, which ultimately results in the relaxation of bronchiolar smooth muscle, resulting in bronchodilation and increased airflow.

In addition to its bronchodilatory effects, salmeterol also exhibits anti-inflammatory properties, although to a lesser degree. It inhibits the release of various mast cell mediators, such as histamine, leukotrienes, and prostaglandins, contributing to the reduction of inflammation in the airways.

The unique molecular structure of salmeterol, with its elongated lipophilic side-chain, allows for repeated activation of the beta-2 receptor, leading to a prolonged duration of action compared to shorter-acting beta-2 agonists like salbutamol (albuterol).

Indications and Usage

Salmeterol is indicated for the treatment and maintenance of asthma and COPD. It is particularly useful in the management of severe persistent asthma, where it is typically prescribed in combination with inhaled corticosteroids to provide sustained bronchodilation, prevent exacerbations, and improve lung function.

Salmeterol is not recommended for the treatment of mild asthma that is well-controlled with short-acting beta-agonists. Additionally, salmeterol monotherapy for the treatment of asthma is contraindicated due to the increased risk of mortality.

In the context of COPD, salmeterol can be used as a monotherapy for maintenance treatment, as it has been shown to improve FEV1 and the FEV1/FVC ratio.

Adverse Effects and Precautions

Like other beta-2 agonists, salmeterol can cause adverse effects such as tremor, headache, and cardiovascular effects, including tachycardia and palpitations. Patients with underlying cardiovascular conditions may be at a higher risk of these side effects.

Salmeterol should not be used to treat acute bronchospasm, as it is intended for prophylaxis and maintenance therapy. In such cases, a short-acting beta-2 agonist should be utilized.

Salmeterol may interact with certain medications, such as cytochrome P450 3A4 inhibitors, which can lead to increased salmeterol exposure and the potential for adverse effects. Healthcare providers should be aware of these interactions when prescribing salmeterol.

Dosing and Administration

Salmeterol is typically administered via inhalation, with the recommended dose for the treatment of asthma being 50 mcg twice daily. For COPD, the recommended dose is also 50 mcg twice daily.

It is essential to emphasize to patients the importance of using salmeterol regularly as prescribed, rather than only when needed, to maintain its effectiveness and prevent asthma or COPD exacerbations.

Interprofessional Collaboration in Asthma and COPD Management

Effective management of asthma and COPD requires a collaborative effort between various healthcare professionals, including physicians, nurses, pharmacists, and respiratory therapists. This interprofessional approach helps to ensure proper medication selection, dosing, administration, and patient education, ultimately leading to improved patient outcomes.

Pharmacists, for instance, can play a crucial role in reviewing medication regimens, identifying potential drug interactions, and providing patient counseling on the appropriate use of salmeterol and other respiratory medications.

Nurses and respiratory therapists can contribute by educating patients on proper inhaler technique, monitoring adherence, and reinforcing the importance of regular medication use.

Conclusion

Salmeterol is a valuable long-acting beta-2 adrenergic agonist used in the management of asthma and COPD. Its unique mechanism of action, involving sustained bronchodilation and anti-inflammatory effects, makes it an important tool in the treatment of these respiratory conditions. By understanding the indications, administration, and potential adverse effects of salmeterol, healthcare professionals can effectively incorporate it into their patients’ treatment plans, ultimately improving respiratory function and overall quality of life.

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

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