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.

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]