Continuing Education Activity

Albuterol, also known as salbutamol, is approved by the U.S. Food and Drug Association (FDA) for treating and preventing acute or severe bronchospasm in patients with reversible obstructive airway disease, including exercise-induced bronchospasm. Albuterol is a commonly prescribed bronchodilator used for managing diverse respiratory conditions, including asthma and exercise-induced bronchospasm. This activity covers the appropriate indications, administration, contraindications, adverse drug reactions, and precautions associated with albuterol to ensure its safe and proper utilization. This activity also aims to equip healthcare professionals with a comprehensive understanding of albuterol therapy in obstructive airway diseases, allowing for efficient and effective drug use in clinical settings.

Objectives:

• Identify appropriate indications for albuterol therapy, recognizing its role in treating acute or severe bronchospasm and preventing exercise-induced bronchospasm in patients with reversible obstructive airway disease.

• Implement proper administration techniques for different albuterol delivery systems, including aerosol metered-dose inhalers, nebulizers, and tablets, considering factors such as patient age, severity of symptoms, and comorbidities.

• Screen patients for contraindications and potential risks associated with albuterol, especially those with cardiovascular diseases or hypersensitivity reactions.

• Collaborate with other healthcare professionals, including physicians, immunologists, pharmacists, and nurses, to ensure a comprehensive, interprofessional approach to albuterol therapy.

Indications

FDA-Approved Indications

Albuterol, also known as salbutamol, is approved by the U.S. Food and Drug Association (FDA) for treating and preventing acute or severe bronchospasm in patients with reversible obstructive airway disease, including exercise-induced bronchospasm.[1][2][3] In the absence of albuterol's bronchodilatory effects, individuals may face the risk of catastrophic asphyxiation. This makes the drug highly desirable to be readily available for individuals experiencing recurrent obstructive airway symptoms, such as asthma.

Off-Label Uses

Albuterol is used off-label as an adjuvant treatment for hyperkalemia.[4][5] Notably, albuterol is not recommended as monotherapy due to its potentially weakened potassium-lowering effect in patients with end-stage renal disease. Instead, it should be considered only after successfully attempting treatment with intravenous calcium to stabilize cardiac tissue. The rhythm of the cardiac tissue is highly dependent on potassium concentrations. Subsequently, the administration of insulin and glucose is advised to facilitate the intracellular transport of potassium.[6] 

Currie et al conducted a study on the treatment preferences of Canadian pediatric emergency department physicians for wheezing preschool patients. Most physicians opted for albuterol treatment both in the emergency department and upon discharge. The additional use of oral glucocorticoids ranged from 12% to 81%. Factors influencing this treatment choice included age, a history of atopy, and the type of wheezing, particularly continuous wheezing. Currie et al discovered that physicians expressed willingness to enroll their patients in a randomized clinical trial to obtain guidance on when to incorporate oral glucocorticoids as part of the treatment.[7]

The Global Initiative for Asthma (GINA) guidelines now advise against the use of short-acting beta-agonists (SABA) alone, without inhaled corticosteroids (ICS), for the treatment of asthma in adults, adolescents, and children aged 5 or older. This change is attributed to the heightened risk of severe asthma exacerbations, potentially necessitating emergency department visits and hospitalization, which can contribute to asthma-related fatalities. Incorporating ICS with SABA or long-acting beta-agonists (LABA) substantially reduces these risks. Albuterol is utilized in the bronchodilator responsiveness test. In contrast to pre-test levels, measurements are obtained 10 to 15 minutes after administering 200 to 400 mcg of albuterol. In adults, a positive response is defined as an increase in Forced Expiratory Volume in 1 second (FEV1) of >12% and >200 mL (preferably, >15% and >400 mL). A greater than 12% increase in predicted FEV1 indicates a positive responsiveness in children. To enhance reliability, it is recommended to withhold SABA for ≥4 hours before the test.[8]

The 2023 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend initiating short-acting inhaled β2-agonists (SABA), such as albuterol, either alone or in combination with short-acting anticholinergics (SAMA), as the primary bronchodilators for the immediate treatment of chronic obstructive pulmonary disease (COPD) exacerbations.[9]

Mechanism of Action

Albuterol acts on β2-adrenergic receptors, inducing bronchial smooth muscle relaxation and inhibiting immediate hypersensitivity mediator release, particularly from mast cells. Although albuterol also affects β1-adrenergic receptors, the impact is minimal, exerting little effect on the heart rate.[10][11] In a particular study utilizing immuno-liposomes to deliver albuterol to oxytocin receptors, albuterol demonstrated the ability to alleviate uterine contractions.[12] Notably, albuterol is not approved for use as a tocolytic.

Pharmacokinetics

Absorption: Albuterol directly affects the bronchial smooth muscle upon inhalation without initially entering the bloodstream. Trace amounts appear in the blood approximately 2 to 3 hours after inhalation. Notably, albuterol levels in the body remain low when taken at recommended inhalation doses. In a study involving 12 healthy participants, a higher albuterol dosage (1080 mcg of albuterol base) led to peak concentrations of around 3 ng/mL when delivered through propellant HFA-134a. The time taken to reach these peak concentrations (Tmax) was noticeably longer with albuterol HFA (Tmax = 0.42 hours) compared to the CFC-propelled albuterol inhaler (Tmax = 0.17 hours).

Distribution: The volume of distribution of albuterol is 156 ± 38 L.

Metabolism: Albuterol undergoes hepatic metabolism, transforming into albuterol 4'-O-sulfate—a compound lacking β-adrenergic effects. Salbutamol experiences minimal metabolic transformation within the lung. Furthermore, salbutamol may undergo metabolic pathways such as oxidative deamination and conjugation with glucuronide. Therefore, administrating albuterol directly to the respiratory tract is the appropriate approach to bypass first-pass metabolism.[13]

Elimination: Within 24 hours, approximately 70% of an albuterol dose is eliminated through urinary excretion, whereas 80% to 100% of albuterol and its metabolites are excreted within 72 hours after exposure. In humans, up to 10% of an albuterol dose is excreted in the feces. The half-life for oral inhalation formulation ranges from 3.8 to approximately 5 hours. The immediate-release oral formulation of albuterol has a half-life of 5 to 6 hours, whereas the extended-release oral formulation has a half-life of 9.3 hours.

Administration

Available Dosage Forms and Strengths

Albuterol is available in various dosage forms and strengths. An aerosol metered-dose inhaler delivers 90 mcg (base)/actuation, equivalent to 108 mcg of albuterol sulfate. A powder, metered-dose inhaler form provides the same values as the aerosol, metered-dose inhaler. Albuterol is also offered in 2 mg and 4 mg tablets. Extended-release tablets are available in 4 mg and 6 mg strengths. Albuterol is available in various nebulized solutions, including 0.083%, 0.5%, 0.63 mg/3mL, and 1.25 mg/3mL. Furthermore, an oral syrup is available in a concentration of 2 mg/5 mL.[14] 

Adult Dosage

Several forms of albuterol are administered to patients for the treatment of bronchospasm. A nebulized solution of 2.5 mg administered 2 to 3 times a day, as needed, quickly relieves symptoms. In addition, a nebulized solution, with a dosing range of 1.25 to 5 mg administered every 4 to 8 hours, as required, is also effective for quickly relieving symptoms. The recommendation for the powder metered-dose and aerosol metered-dose inhaler is to administer 1 or 2 puffs of 90 mcg every 4 to 6 hours, depending on the patient's need. Notably, the dosage should not exceed 12 puffs within 24 hours. A recommended dosage for tablet and syrup formulations is 2 to 4 mg every 6 to 8 hours, with caution not to exceed 32 mg in a day. The extended-release tablets are taken in either 4 or 8 mg doses every 12 hours with a maximum limit of 32 mg daily, depending on the patient's need.[15] Rescue inhalers, also called reliever inhalers, are used to relieve asthma symptoms quickly. This category includes SABAs such as albuterol.

To address acute or severe bronchospasm, it is recommended to utilize a nebulizer solution with a concentration of 2.5 to 5 mg every 20 minutes for 3 cycles. Subsequently, repeat nebulizer treatments of 2.5 to 10 mg are advised every 1 to 4 hours as needed. Alternatively, if using a metered-dose inhaler, the standard practice involves 4 to 8 puffs of 90 mcg every 20 minutes for up to 4 hours, followed by 4 to 8 puffs every 1 to 4 hours as needed.

The recommendation for treating exercise-induced bronchospasm is to use an aerosol or powder metered-dose inhaler before exercise. Taking 2 puffs of 90 mcg (total 180 mcg) 15 to 20 minutes before exercise may help prevent symptoms.

Pediatric Dosage

The dosing recommendation for children aged 4 and older is 90 to 180 mcg (1 to 2 puffs) administered every 4 to 6 hours, and it should not exceed 12 puffs within 24 hours.[2]

The recommended nebulizer solution dosage for children aged 2 or younger is 0.2 to 0.6 mg/kg/d, divided into either a 4- or 6-hour cycle based on weight. For children aged 2 or older, a nebulizer solution dosing of 2.5 mg/0.5 mL is administered every 6 to 8 hours, with a maximum of 10 mg administered in 24 hours.

Albuterol tablets with extended-release formulation are contraindicated in patients aged 6 or younger. The recommendation of albuterol dosage for pediatric patients aged 6 to 12 is 4 mg administered every 12 hours and should not exceed 24 mg in 24 hours. The recommended albuterol dosage for adolescent patients can be increased to 8 mg every 12 hours and not to exceed 32 mg in 24 hours.

The syrup formulation of albuterol has not been studied in children aged 2 or younger. The recommended albuterol dosage for patients aged 2 to 6 is 0.1 mg/kg every 8 hours, which can be increased to 0.2 mg/kg every 8 hours as needed. For children aged 6 to 14, taking 2 mg of the medication every 6 to 8 hours is recommended. The recommended dosage for pediatric patients aged 14 and older is 2 to 4 mg every 6 to 8 hours, with a daily maximum of 32 mg.

The dosing of albuterol tablets in pediatric patients 6 or younger is 0.2 to 0.3 mg/kg/d, divided into 3 treatments administered every 8 hours throughout the day. Healthcare providers advise not to exceed the dosage of 12 mg/d. Pediatric patients aged 6 to 12 can take 2 mg of albuterol every 6 to 8 hours, with a maximum daily dosage of 24 mg. For pediatric patients aged 12 or older, 2 to 4 mg is administered every 6 to 8 hours, with a maximum daily dosage of 32 mg.[16]

Specific Patient Populations

Hepatic impairment: The manufacturer's labeling for albuterol does not provide any specific recommendations for dosage adjustments in cases of hepatic impairment.

Renal impairment: The manufacturer's labeling for albuterol does not provide any specific recommendations for dosage adjustments in cases of renal impairment. Clinicians should exercise caution when prescribing high doses of albuterol to individuals with renal impairment, as renal clearance is reduced.

Pregnancy considerations: According to the manufacturer's labeling, there is a lack of sufficient and well-controlled studies on the effects of albuterol in pregnant women. The use of albuterol during pregnancy should only be considered after a careful risk-benefit evaluation. Reports of congenital anomalies, including cleft palate and limb defects, have been noted in children born to patients receiving albuterol treatment. Notably, some mothers used multiple medications during their pregnancies. Regarding labor and delivery, caution is advised due to the potential interference of beta-agonists with uterine contractility. The use of albuterol sulfate inhalation aerosol for relieving bronchospasm during labor should be limited to situations where the benefits outweigh the risks.

According to GINA guidelines, the patterns of asthma control during pregnancy are variable, with one-third worsening, improving, or remaining stable. Exacerbations, particularly in the second trimester, can result in adverse outcomes for both the mother (pre-eclampsia) and the baby (preterm delivery, low birth weight, and increased perinatal mortality). Well-controlled asthma poses minimal pregnancy risk. Notably, it is crucial to treat asthma as the benefits of medication generally outweigh the potential risks. Acute exacerbations should be managed aggressively with SABA, oxygen, and early systemic corticosteroids. The usual controller medications should be continued during labor, and relievers should be used if needed. Although rare, labor-induced hyperventilation may cause bronchoconstriction, which can be managed with SABA, such as albuterol. Neonatal hypoglycemia, especially in preterm infants, may result from high beta-agonists, such as albuterol, in the last 48 hours before delivery. Monitoring neonatal blood glucose, especially if the infant is preterm, is advised for the first 24 hours.

Breastfeeding considerations: Although no specific studies on albuterol's use through oral or inhaler routes during lactation exist, insights from the analogous drug terbutaline indicate minimal excretion into breast milk. The consensus from multiple reviews and expert opinions supports the acceptability of inhaled bronchodilators during breastfeeding, given their low bioavailability and limited presence in maternal serum following administration.[17]

Pediatrics patients: The safety and efficacy of albuterol MDI have not been established in pediatric patients aged 4 and younger. Age is a crucial factor in determining the treatment approach for pediatric patients.

According to the GINA guidelines, inhaled albuterol (salbutamol) is the standard bronchodilator for acute asthma management. In cases of mild-to-moderate exacerbations, the repetitive administration of SABA (4 to 10 puffs every 20 minutes within the initial hour) has been demonstrated to be effective for promptly reversing airflow limitation (Evidence A). After the first hour, the requisite SABA dosage ranges from 4 to 10 puffs every 3 to 4 hours, potentially escalating to 6 to 10 puffs every 1 to 2 hours or more frequently. Additional SABA administration is unnecessary if the initial treatment results in a favorable response (eg, peak expiratory flow >60% to 80% of predicted or personal best for 3 to 4 hours).[18]

Teper et al conducted a double-blinded randomized study involving 50 children with asthma. The participants, comprising 29 boys and 21 girls, had a mean age of 12 ± 3 years. All children demonstrated mild-to-moderate asthma with a predicted FEV1 of 40% to 79%. The bronchodilation effects of nebulized albuterol in normal saline and 3% hypertonic saline solutions were compared. The assessment took place 30 minutes post-administration for both forms. The study revealed that the bronchodilating effects, as measured by FEV1, were 41.2% and 17.3% for 3% hypertonic saline and normal saline solutions, respectively. Moreover, the maximum mid-expiratory flow was 130% and 69.8% for 3% hypertonic saline and normal saline solutions, respectively. Based on their findings, Teper et al concluded that the 3% hypertonic saline formulation of albuterol resulted in a more pronounced bronchodilator effect.[19]

Older patients: Caution should be exercised when using albuterol in older patients, particularly those with cardiovascular comorbidities. 

Adverse Effects

The primary adverse effects of albuterol therapy are tremors and nervousness, and although they can occur at any age, they are predominantly observed in children aged 2 to 6. Tremors result from the activation of β2-receptors found on motor nerve terminals, leading to an increase in intracellular cAMP. These adverse effects occur in approximately 1 in every 5 patients. Additional adverse effects include insomnia and nausea, which occur in approximately 1 in every 10 patients. Less common adverse effects may include fever, bronchospasm, vomiting, headache, dizziness, cough, allergic reactions, otitis media, epistaxis, increased appetite, urinary tract infections, dry mouth, gas, hyperhidrosis, pain, dyspepsia, hyperactivity, chills, lymphadenopathy, ocular pruritus, sweating, conjunctivitis, and dysphonia. Albuterol also has been shown to increase blood pressure levels and may cause hypokalemia. Although rare, occurrences of increased blood glucose concentrations, prolonged QTc interval, and ST-segment depression have been reported.[20][21]

Drug-Drug Interactions

Tricyclic antidepressants (TCA) or monoamine oxidase inhibitors (MAOIs): Special attention is warranted when administering albuterol sulfate inhalation aerosol to individuals undergoing treatment with MAOIs or TCAs or within 2 weeks of discontinuing such agents. This is due to the potential for an amplified impact of albuterol on the cardiovascular system in these cases.

Beta-blockers: Beta-blockers neutralize the pulmonary effects of beta-agonists, such as albuterol sulfate inhalation aerosol, and may also trigger severe bronchospasm in individuals with asthma. As a result, caution is recommended when contemplating nonselective beta-blocker therapy (eg, propranolol) for asthma patients. However, cardioselective beta-blockers may be considered in specific scenarios, such as post-myocardial infarction.[16]

Diuretics: Combining non-potassium–sparing diuretics, such as thiazide or loop diuretics, with beta-agonists, especially in doses higher than recommended, may worsen electrocardiographic (ECG) changes and hypokalemia. Although the clinical relevance of these effects remains uncertain, caution is advised when co-administering beta-agonists with non-potassium-sparing diuretics.[22]

Digoxin: Investigations following single-dose intravenous and oral administration of albuterol to normal volunteers receiving digoxin for 10 days have revealed average reductions of 16% and 22% in serum digoxin levels, respectively. Thus, it is advisable to carefully monitor serum digoxin levels for patients concurrently using digoxin and albuterol.[23]

Contraindications

Hypersensitivity is a contraindication for albuterol. In cases of hypersensitivity to milk protein, it is advisable to avoid albuterol formulations that contain lactose as an excipient.[24][25]

Warnings and Precautions

Cardiovascular effects: Albuterol sulfate inhalation aerosol, such as other β-adrenergic agonists, may induce clinically relevant cardiovascular responses, including changes in pulse rate, blood pressure levels, and symptomatic presentations. Although infrequent at recommended dosages, if encountered, discontinuation of the drug may be warranted. Furthermore, beta-agonists have been associated with ECG changes, including T wave flattening, QTc interval prolongation, and ST segment depression. The clinical implications of these ECG findings remain uncertain. Hence, prudence is advised, particularly in patients with underlying cardiovascular disorders.

Asthma deterioration: Asthma may deteriorate acutely over hours or chronically over days. An increased requirement for albuterol may signify a destabilization of asthma, necessitating a re-evaluation of the patient and treatment regimen. Special consideration should be given to potentially incorporating anti-inflammatory agents, such as corticosteroids.

Use of anti-inflammatory agents: Relying solely on β-adrenergic agonist bronchodilators may be insufficient and detrimental to patient outcomes. Therefore, early consideration of ICS is essential.

Paradoxical bronchospasm: Inhaling albuterol sulfate may lead to paradoxical bronchospasm, occasionally of severe consequence. If this occurs, it is crucial to immediately discontinue albuterol sulfate inhalation aerosol and initiate alternative therapeutic modalities. This phenomenon is notably linked to the benzalkonium chloride preservative in albuterol nebulizers.[26]

Hypersensitivity reactions: Although infrequent, immediate hypersensitivity reactions may occur following the administration of albuterol and can present with urticaria, angioedema, bronchospasm, or anaphylaxis.[27]

Monitoring

Monitoring parameters for albuterol include blood pressure, heart rate, forced expiratory volume, peak flow, central nervous system stimulation, serum potassium, serum glucose, and asthma symptoms. Due to the potential for paradoxical bronchospasm, patients should be advised to discontinue use and seek medical attention if symptoms worsen with use. If additional doses become necessary over time, the clinician may need to reassess the patient's current treatment regimen, as the patient's condition may have deteriorated.[28]

Toxicity

Signs and Symptoms of Overdose

An albuterol dose of 1 mg/kg is potentially toxic for children 6 or younger. Similar to other β2-adrenergic receptor agonists, albuterol has been shown to cause an increase in liver aminotransferase concentrations on rare occasions. This specific toxicity reaction is more common in other β2-adrenergic receptor agonists, such as terbutaline, which is administered in much greater quantities, such as in the context of abating uterine contractions. Although overdose from inhaled albuterol is rare, recognizing the signs of albuterol toxicity is clinically significant.

Management of Overdose

Diagnosis relies on a comprehensive evaluation, combining clinical assessments and laboratory findings. Essential indicators include tremors, hypokalemia, hyperglycemia, and cardiac arrhythmias. Acute albuterol toxicity can result in lactic acidosis. β2-adrenergic stimulation increases cAMP-mediated gluconeogenesis and lipolysis, leading to elevated plasma glucose levels. Consequently, there is an increased conversion to pyruvate and lactate. In instances of albuterol toxicity, hyperventilation typically stems from a compensatory response to metabolic acidosis rather than an indication of worsening respiratory distress requiring an increased albuterol requirement. The management of albuterol-induced hypokalemia should be approached cautiously, as the underlying mechanism involves a transcellular shift rather than a total body potassium deficit. Treatment primarily involves supportive measures, including discontinuing the offending agent and managing arrhythmias according to ACLS protocol.[29]

Enhancing Healthcare Team Outcomes

All healthcare professionals, including physicians, physician assistants, and nurse practitioners who prescribe inhalers, should educate patients on the proper usage of medications. Using a face mask is crucial for children aged 4 or younger. Caution is necessary when treating patients with cardiovascular diseases, such as heart disease, as supratherapeutic albuterol may exacerbate heart failure with reduced ejection fraction. Close monitoring is essential for patients with diabetes mellitus, hyperthyroidism, hypokalemia, or glaucoma.[30] 

Clinicians initiate albuterol therapy for specific medical conditions or indications. Nurses and pharmacists play a critical role in patient care. Nurses educate patients on medicine usage, monitor their progress and compliance, and ensure their well-being. On the other hand, pharmacists demonstrate the proper use of inhalers, spacers, and nebulizers. Both nurses and pharmacists communicate openly with the clinician to address any concerns.

An observational study examined patients with severe asthma, emphasizing specialist care provided by allergists, immunologists, and pulmonologists. The study revealed that only 38.2% of the 54,332 commercially insured individuals meeting severe asthma criteria received care from these specialists over 2 years. Factors associated with specialist visits included higher asthma exacerbation frequency, younger age, and a greater allergy or respiratory comorbidities burden. Following specialist care, there was a noticeable reduction in asthma exacerbations and rescue inhaler use. This highlights the potential benefits of increased specialist involvement in managing severe asthma, particularly among those with complex comorbidities.[31] An interprofessional healthcare team approach, characterized by open communication among physicians/advanced practice practitioners, immunologists, pharmacists, and nurses, can enhance patient outcomes associated with albuterol therapy while minimizing adverse effects.