Salmeterol

Usage

• Salmeterol is prescribed for the long-term maintenance treatment of asthma and chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. It helps prevent asthma attacks and shortness of breath but does not relieve sudden asthma attacks. For that, a fast-acting inhaler is necessary. It is also used to prevent exercise-induced bronchospasm.
• Pharmacological Classification: Long-acting beta2-adrenergic agonist (LABA) bronchodilator.
• Mechanism of Action: Salmeterol relaxes the muscles in the airways, which widens the airways and makes breathing easier.

Alternate Names

• Salmeterol xinafoate (the chemical name)
• Brand Names: Serevent Diskus, Serevent Evohaler, Serevent Accuhaler (and in combination with fluticasone: Advair, AirDuo, Wixela Inhub).

How It Works

• Pharmacodynamics: Salmeterol acts as a selective, long-acting beta2-adrenergic agonist. Binding to beta2-adrenergic receptors in the lungs leads to smooth muscle relaxation and bronchodilation. This effect reduces airway resistance and improves airflow.
• Pharmacokinetics:
  • Absorption: Salmeterol is administered via inhalation, where it is absorbed into the lungs. Systemic absorption is low, minimizing systemic side effects.
  • Metabolism: Hepatic metabolism via CYP3A4 enzymes to inactive metabolites.
  • Elimination: Primarily eliminated through feces, with a small portion excreted in urine.
• Mode of Action: Salmeterol binds to beta2-adrenergic receptors on the surface of airway smooth muscle cells. This binding activates intracellular signaling pathways, leading to a decrease in intracellular calcium levels and relaxation of the smooth muscle, ultimately causing bronchodilation.
• Receptor Binding: Selectively binds to beta2-adrenergic receptors.
• Elimination Pathways: Primarily hepatic metabolism via CYP3A4, followed by fecal excretion. A small percentage is excreted unchanged in the urine.

Dosage

Standard Dosage

Adults:

• Asthma and COPD: One inhalation (50 mcg) twice daily, approximately 12 hours apart. In more severe cases, the dose can be increased to two inhalations (100 mcg) twice daily. The maximum recommended dose is 100 mcg twice a day.
• Exercise-Induced Bronchospasm (EIB): One inhalation (50 mcg) 30 minutes before exercise.

Children:

• 4 years and older: One inhalation (50 mcg) twice daily, 12 hours apart.
• Under 4 years: Safety and efficacy not established. Not recommended.

Special Cases:

• Elderly Patients: No dose adjustment is typically needed.
• Patients with Renal Impairment: No dose adjustment is typically needed.
• Patients with Hepatic Dysfunction: Use with caution as salmeterol is metabolized in the liver. Dosage adjustments may be necessary.
• Patients with Comorbid Conditions: Use with caution in patients with cardiovascular disease, diabetes, hyperthyroidism, or seizure disorders.

Clinical Use Cases

Salmeterol is not indicated for:

• Intubation
• Surgical Procedures
• Mechanical Ventilation
• Intensive Care Unit (ICU) Use
• Emergency Situations (e.g., status asthmaticus, cardiac arrest)

Dosage Adjustments

• Consider reducing the dosage in patients experiencing adverse effects or those with hepatic impairment.
• Drug interactions, particularly with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir), may necessitate dosage adjustments. Close monitoring of patients on concomitant CYP3A4 inhibitors is warranted.

Side Effects

Common Side Effects:

• Headache
• Flu-like symptoms
• Throat irritation
• Cough
• Runny or stuffy nose
• Muscle or joint pain

Rare but Serious Side Effects:

• Worsening of asthma symptoms (paradoxical bronchospasm)
• Allergic reactions (hives, swelling of face, lips, tongue, or throat, difficulty breathing)
• Cardiovascular effects (chest pain, fast or irregular heartbeat, palpitations)
• Tremors, nervousness
• Hyperglycemia
• Hypokalemia

Long-Term Effects:

• Potential for reduced bone mineral density with long-term inhaled corticosteroid use (especially important in children). Note: This pertains to inhaled corticosteroids often used in combination with salmeterol, not to salmeterol itself. Salmeterol should always be used with an ICS in asthma.
• Increased risk of cataracts and glaucoma with long-term inhaled corticosteroid use. Note: This pertains to inhaled corticosteroids often used in combination with salmeterol, not to salmeterol itself.

Adverse Drug Reactions (ADR):

• Paradoxical bronchospasm, angioedema, and cardiac arrhythmias require immediate medical attention.

Contraindications

• Hypersensitivity to salmeterol or any of its components.
• Primary treatment of acute asthma exacerbations or status asthmaticus.
• Severe milk protein allergy (for formulations containing milk proteins).
• Should not be used as monotherapy for asthma; must be used concomitantly with an inhaled corticosteroid.

Drug Interactions

• CYP3A4 Inhibitors: Concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, erythromycin) can significantly increase salmeterol plasma levels, increasing the risk of adverse effects, especially QTc prolongation.
• Beta-blockers: Can reduce the bronchodilatory effects of salmeterol and may induce bronchospasm in susceptible individuals.
• Diuretics: May increase the risk of hypokalemia, especially with non-potassium-sparing diuretics.
• MAOIs and TCAs: May potentiate the cardiovascular effects of salmeterol.
• Other LABAs: Concurrent use with other long-acting beta2-agonists is not recommended, as it can increase the risk of adverse effects.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C (US FDA). Use only if the potential benefit outweighs the potential risk to the fetus. No adequate and well-controlled studies in pregnant women.
• Fetal Risks: Animal studies have shown some developmental toxicity at high doses. Possible risk of preterm birth, low birth weight, and small for gestational age in women with poorly controlled asthma.
• Breastfeeding: It is unknown if salmeterol is excreted in human milk. Consider the benefits of breastfeeding alongside the mother’s clinical need for the drug and any potential adverse effects on the breastfed child. Limited data suggests that inhaled bronchodilators are generally compatible with breastfeeding due to minimal levels in breastmilk. However, inform patient that minimal amounts of the drug may be present in breast milk and to monitor for possible effects in the infant.

Drug Profile Summary

• Mechanism of Action: Long-acting beta2-adrenergic agonist, bronchodilator.
• Side Effects: Headache, flu-like symptoms, throat irritation, cough, palpitations, paradoxical bronchospasm.
• Contraindications: Hypersensitivity, acute asthma exacerbations, severe milk protein allergy.
• Drug Interactions: CYP3A4 inhibitors, beta-blockers, diuretics, MAOIs, TCAs, other LABAs.
• Pregnancy & Breastfeeding: Category C; use with caution. Minimal amounts may pass into breast milk.
• Dosage: 50 mcg twice daily via inhalation. Up to 100 mcg twice daily in severe cases. 50 mcg 30 min before exercise for EIB.
• Monitoring Parameters: Pulmonary function, blood pressure, heart rate, blood glucose, potassium levels.

Popular Combinations

• Fluticasone/Salmeterol: Combines an inhaled corticosteroid (ICS) with a LABA. This combination is used for long-term asthma control and reduces the risk of exacerbations.

Precautions

• General Precautions: Assess for pre-existing conditions such as cardiovascular disease, diabetes, hyperthyroidism, or seizure disorders.
• Specific Populations:
  • Pregnant Women: Assess risks and benefits carefully. Use the lowest effective dose if necessary.
  • Breastfeeding Mothers: Advise regarding potential minimal exposure in breast milk and to monitor infant.
  • Children & Elderly: Follow recommended age-specific dosing guidelines.
• Lifestyle Considerations: Smoking cessation counseling is essential for patients with asthma or COPD. Alcohol may exacerbate certain side effects. Driving impairment is unlikely.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Salmeterol?

A: For adults and children over 4 years of age, the usual dose is 50 mcg twice daily, approximately 12 hours apart. For EIB, 50 mcg 30 minutes prior to exercise.

Q2: How does Salmeterol differ from short-acting beta-agonists (SABAs) like albuterol?

A: Salmeterol is a LABA, providing long-term bronchodilation (up to 12 hours), whereas SABAs like albuterol provide rapid, short-term relief (4-6 hours). Salmeterol is for maintenance therapy and prevention of symptoms, not for acute symptom relief.

Q3: Can Salmeterol be used alone to treat asthma?

A: No. Salmeterol should never be used as monotherapy for asthma. It must always be used in conjunction with an inhaled corticosteroid.

Q4: What are the most serious side effects of Salmeterol?

A: Serious side effects include worsening of asthma symptoms (paradoxical bronchospasm), allergic reactions (angioedema, urticaria), and cardiac arrhythmias. These warrant immediate discontinuation and medical attention.

Q5: What should patients be advised regarding the concomitant use of Salmeterol and CYP3A4 inhibitors?

A: Patients should be cautioned about the potential for increased salmeterol levels and adverse effects when co-administered with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir). Close monitoring is essential, and dosage adjustments may be necessary.

Q6: Can Salmeterol be used during pregnancy?

A: Salmeterol is a Pregnancy Category C drug. Its use during pregnancy should be considered only if the potential benefit to the mother outweighs the potential risk to the fetus. Close monitoring of maternal asthma control and fetal well-being is critical.

Q7: What are the key drug interactions to be aware of with Salmeterol?

A: Key drug interactions include CYP3A4 inhibitors, beta-blockers, non-potassium-sparing diuretics, MAOIs, TCAs, and other LABAs. These interactions can lead to reduced efficacy or increased risk of adverse events.

Q8: What should be done if a patient experiences paradoxical bronchospasm after using Salmeterol?

A: Salmeterol should be discontinued immediately, and alternative bronchodilator therapy should be considered. Paradoxical bronchospasm is a serious adverse reaction that can worsen breathing difficulties.

Q9: Is Salmeterol safe to use in patients with renal impairment?

A: Yes, no dose adjustments are typically needed in patients with renal impairment as Salmeterol is minimally renally cleared.

Q10: What is the duration of action for salmeterol?

A: Salmeterol typically provides bronchodilation lasting up to 12 hours.