Bronchodilators

Mechanism of Action

The mechanism of action of bronchodilators involves targeting the beta-2 receptors, a G-protein–coupled receptor found in the lung airways. Activation of these receptors causes relaxation of the airway smooth muscle, resulting in improved airflow for a limited duration. However, prolonged and consistent use of beta-2 agonists can lead to receptor downregulation, reducing drug efficacy and necessitating higher doses to achieve the same bronchodilatory effect.

Bronchodilators are primarily metabolized in the gastrointestinal tract by cytochrome P450 enzymes. Approximately 80% to 100% of the drug is excreted in the urine, whereas less than 20% is eliminated in feces. Short-acting bronchodilators typically have a half-life of 3 to 6 hours, whereas long-acting bronchodilators have a half-life ranging from 18 to 24 hours.[16][17]

Anticholinergic drugs target receptors of the parasympathetic nervous system in the airways and inhibit their activity. As the parasympathetic nervous system is responsible for increased bronchial secretions and airway constriction, reversing these effects should provide bronchodilation and reduced secretions. The anticholinergic drugs predominantly target the M3 receptor.[18] 

Revefenacin is considered an innovative inhaled muscarinic antagonist due to its classification within a novel chemical category of inhaled muscarinic antagonists, differentiating it from established agents such as glycopyrrolate, tiotropium bromide, and umeclidinium bromide. In contrast to the existing LAMAs, which are categorized as quaternary ammonium compounds, revefenacin is classified as a tertiary amine. This structural distinction may facilitate enhanced selectivity for pulmonary tissues while potentially minimizing systemic adverse effects.[19]

Pharmacokinetics

Absorption: Inhaled bronchodilators such as albuterol, formoterol, salmeterol, ipratropium, and tiotropium are formulated to provide localized pulmonary action with minimal systemic absorption. Albuterol is quickly absorbed through the bronchial mucosa, producing an onset of action within minutes. Formoterol, which is moderately hydrophilic, also has a rapid onset of action, whereas salmeterol's lipophilic side chain results in a slower onset due to membrane binding. Both ipratropium and tiotropium are quaternary ammonium compounds with poor systemic absorption, which contributes to their safety profile.

Distribution: The distribution of formoterol and salmeterol is influenced by their lipophilicity. Salmeterol, in particular, exhibits high membrane affinity and prolonged receptor occupancy. Both agents selectively target bronchial smooth muscle, with minimal distribution to extrapulmonary tissues. Ipratropium has limited systemic distribution due to its hydrophilic nature and inability to cross the blood–brain barrier. Tiotropium demonstrates sustained pulmonary receptor occupancy, supporting its 24-hour bronchodilatory effect with minimal central nervous system involvement.

Metabolism: Albuterol is primarily metabolized through phase II sulfation by sulfotransferase enzymes (eg, SULT1A3), producing inactive sulfate conjugates. Salmeterol and indacaterol undergo extensive hepatic metabolism via CYP3A4. Ipratropium is minimally metabolized and largely excreted unchanged, whereas tiotropium undergoes slow hepatic biotransformation and nonenzymatic hydrolysis.

Excretion: Albuterol and ipratropium are primarily excreted unchanged in the urine. Formoterol is eliminated via both renal and fecal pathways, whereas salmeterol and indacaterol are predominantly excreted in the feces via biliary routes. Tiotropium is mainly excreted renally, and its prolonged terminal half-life supports once-daily dosing.

Administration

Available Dosage Forms and Strengths

Inhaled bronchodilators are available in various delivery forms, including metered-dose inhalers (MDIs), dry powder inhalers (DPIs), soft mist inhalers (eg, Respimat), nebulizer solutions, and capsules for oral inhalation. SABAs, such as albuterol and levalbuterol, are typically administered via MDI or nebulization, delivering 90 µg to 108 µg per actuation or 2.5 mg per nebulized dose every 4 to 6 hours as needed. LABAs, including formoterol, salmeterol, arformoterol, olodaterol, and indacaterol, are generally administered once or twice daily, depending on the formulation, with strengths ranging from 12 µg to 50 µg per inhalation.

Muscarinic antagonists are similarly categorized into short-acting (eg, ipratropium) and long-acting agents (eg, tiotropium, glycopyrrolate, aclidinium, and umeclidinium), with dosing frequencies ranging from 4 times daily (QID) to once daily. Combination inhalers incorporate agents from both classes, such as formoterol/glycopyrrolate or umeclidinium/vilanterol, and are typically administered once or twice daily according to product-specific labeling.

The administration of bronchodilators is primarily achieved through inhalation devices, which deliver the medication directly to the bronchioles in the lungs. These devices vary in shape and size, but the critical factor is to maximize the amount of drug that reaches the bronchioles. Despite optimal technique, the systemic bioavailability of inhaled bronchodilators remains low. The best way to achieve maximum bioavailability is for the patient to exhale fully, position the inhaler in the mouth, and take a full inhalation. After the patient has inhaled completely, a 10-second pause in breathing is recommended to allow the medicine to dissipate into the lung space. This should be followed by a slow exhalation to resume normal breathing.[20]

Failure to follow proper inhalation techniques can prevent patients from receiving the full therapeutic benefit of inhaled medications. Short-acting bronchodilators typically produce effects within seconds to minutes and provide clinical relief for approximately 4 hours. These medications are often referred to as emergency or rescue inhalers due to their immediate impact on bronchodilation. In contrast, long-acting bronchodilators have a slower onset of action and are not suitable for use in emergency settings.[21]

Dosage

Short-acting beta-2 agonists: Albuterol is typically dosed at 90 µg per actuation using an MDI, administered as two inhalations every 4 to 6 hours as needed, or 2.5 mg through nebulization, up to 4 times daily. Levalbuterol is administered at 45 µg per actuation (MDI) or via nebulizer at doses of 0.31 mg, 0.63 mg, or 1.25 mg every 6 to 8 hours, depending on the severity of the condition. Levalbuterol may show fewer systemic adverse effects due to its selective R-isomer composition.

Long-acting beta-2 agonists: LABAs are used in combination with ICS for maintenance therapy in asthma and COPD. Salmeterol is administered at 50 µg via a DPI twice daily. Formoterol is available in 12 µg doses via a DPI or 20 µg doses via a nebulizer, administered twice daily. Arformoterol, the R-enantiomer of formoterol, is administered at a dose of 15 µg via nebulizer twice daily. Indacaterol (75–150 µg DPI), olodaterol (5 µg via a soft mist inhaler), and vilanterol (25 µg DPI, only in combination products) are administered once daily for the treatment of COPD.

Short-acting muscarinic antagonists: SAMAs are primarily used in the treatment of COPD and combination products for asthma. Ipratropium is administered as 17 µg per actuation via MDI, typically two inhalations four times daily (maximum 12 inhalations per day), or 500 µg via nebulizer every 6 to 8 hours. It may be combined with SABAs for additive bronchodilation, especially in acute exacerbations.

Long-acting muscarinic antagonists: These medications are indicated for long-term bronchodilation in COPD and, in some cases, asthma. Tiotropium is available as an 18 µg capsule for DPI, administered once daily, or 2.5 µg per actuation via a soft mist inhaler, with two inhalations administered once daily (total of 5 µg). Other LAMAs include glycopyrrolate (15.6–25 µg DPI twice daily or 25 µg via nebulizer), aclidinium (400 µg DPI twice daily), and umeclidinium (62.5 µg DPI once daily), with specific delivery based on device type and formulation. The dosage of all medications depends on individualized dosing, institutional guidelines, clinical status, and the patient's age.

Specific Patient Populations

Hepatic impairment: Bronchodilators are generally well tolerated in hepatic dysfunction. However, LABAs such as formoterol, arformoterol, indacaterol, and vilanterol are metabolized in the liver via cytochrome P450 3A4 (CYP3A4) and should be used with caution in severe hepatic impairment. SAMA and LAMA, such as ipratropium and tiotropium, have minimal hepatic metabolism.

Renal impairment: LAMAs such as tiotropium, glycopyrrolate, and aclidinium are primarily renally excreted. In chronic kidney disease stage 3 or worse (estimated glomerular filtration rate <60 mL/min/1.73 m²), they may accumulate and increase anticholinergic adverse effects such as urinary retention and xerostomia. The American Geriatrics Society (AGS) Beers Criteria 2023 recommends caution with anticholinergic agents in patients with renal impairment. SABAs and LABAs do not require renal dose adjustment; however, levalbuterol may be better tolerated due to its selective enantiomeric profile.

Pregnancy considerations: According to the American College of Obstetricians and Gynecologists, albuterol is the preferred bronchodilator for symptom relief during pregnancy. If controller therapy is necessary, an ICS plus LABA combination therapy (eg, fluticasone/salmeterol) is acceptable when ICS alone is insufficient to control symptoms. Salmeterol and formoterol have more extensive safety data. Tiotropium and ipratropium have shown no teratogenic effects in animal models; however, human data are limited. The priority is to maintain adequate maternal oxygenation, which outweighs the potential risks of the drug.[22] 

Breastfeeding considerations: Most inhaled bronchodilators, including albuterol, levalbuterol, salmeterol, formoterol, ipratropium, tiotropium, and revefenacin, have minimal systemic absorption and are considered compatible with breastfeeding. However, risk-benefit evaluation is required. During extended use, watch for signs of decreased lactation.[23][24][25][26] 

Pediatric patients: According to the National Heart, Lung, and Blood Institute (NHLBI), SABAs are the first-line treatment for rescue therapy in all pediatric age groups. LABAs must not be used alone in asthma; they must be combined with an ICS. According to the 2020 NHLBI guidelines, a combination of ICS/LABA in a fixed-dose inhaler is preferred to ensure adherence. Tiotropium is approved by the US Food and Drug Administration (FDA) as an add-on maintenance therapy in children 6 years or older with severe asthma. Ipratropium can be used in emergency settings in combination with albuterol for the treatment of moderate-to-severe exacerbations.[27][11] 

Older patients: Inhaled beta-2 agonists may cause tachycardia, tremors, and hypokalemia, especially in frail or cardiovascularly compromised older adults. The AGS Beers Criteria (2023 update) caution against systemic beta-2 agonists, although inhaled forms are acceptable with monitoring. LAMAs are effective for COPD but may worsen benign prostatic hyperplasia, glaucoma, or cognitive impairment due to anticholinergic effects. Use the lowest effective dose and reassess cognitive and urinary function periodically to ensure optimal outcomes.[28]

Adverse Effects

The adverse effects of bronchodilators are due to sympathetic system activation. The most frequent and common adverse effects include trembling, nervousness, sudden, noticeable heart palpitations, and muscle cramps. More severe effects include sudden constriction of the bronchial airways, paradoxical bronchospasm, hypokalemia, and in rare cases, myocardial infarction. A patient should talk to their primary care physician if they have any comorbidities.[29] For anticholinergics, adverse effects include dry mouth, urinary retention, tachycardia, constipation, and gastrointestinal upset. Caution is always necessary when administering an anticholinergic agent to older patients due to the possibility of acute delirium.[17]

Drug-Drug Interactions

Beta-2 agonists: Beta-2 agonists can have antagonistic effects when used with nonselective beta-blockers, such as propranolol, potentially leading to bronchospasm and reduced bronchodilation. If beta-blocker use is essential, cardioselective beta-1 blockers, such as atenolol, may be used cautiously.

Co-administration with monoamine oxidase inhibitors (eg, phenelzine) or tricyclic antidepressants (eg, amitriptyline) can potentiate the risk of cardiovascular adverse effects, such as tachycardia and hypertension; a minimum 14-day washout period is recommended before initiating a beta-agonist. Concomitant use with loop or thiazide diuretics may lead to additive hypokalemia, especially in patients prone to electrolyte disturbances; potassium levels should be monitored closely.

Beta-2 agonists may also reduce serum digoxin levels, potentially decreasing its therapeutic efficacy; serum digoxin concentrations should be monitored if clinically warranted. LABAs can have elevated plasma concentrations and an increased risk of QT prolongation or cardiac arrhythmias when co-administered with potent cytochrome CYP3A4 inhibitors, such as ketoconazole or ritonavir. Such combinations should be avoided. When used concurrently with other drugs that prolong the QT interval (eg, macrolide antibiotics, antipsychotics), there is an additive risk of ventricular arrhythmias; electrocardiogram (ECG) monitoring may be warranted.

Muscarinic antagonists: SAMAs may cause additive anticholinergic adverse effects, such as dry mouth, blurred vision, and urinary retention, when used in combination with other anticholinergic agents, including first-generation antihistamines or tricyclic antidepressants. Ipratropium, when combined with oral solid potassium chloride formulations, may increase the risk of gastrointestinal ulceration or strictures due to reduced gastrointestinal motility; a liquid potassium formulation is preferred in such cases. Additionally, concurrent use with clozapine may exacerbate anticholinergic toxicity and lead to paralytic ileus or severe constipation, especially in vulnerable patients. LAMAs exhibit additive systemic anticholinergic effects when co-administered with other anticholinergic medications such as oxybutynin or benztropine, especially in older adults; this combination should be used with caution. LAMAs may worsen urinary retention when used with agents that impair bladder emptying (eg, opioids, alpha-adrenergic agonists); patients should be assessed for urologic symptoms.

Contraindications

If a patient has a known hypersensitivity to the drug, then physicians should not prescribe it. These hypersensitivities may involve severe allergic reactions that can cause hemodynamic instability or loss of a patent airway. Use caution when treating patients with ischemic heart disease, arrhythmias, or hypokalemia, as bronchodilators have demonstrated worsening of the effects of these conditions.[1] Exercising caution with this class of medication is also essential during labor and delivery, as well as when treating geriatric patients. In very high doses, caution is also necessary for patients with renal impairment.[30]

Box Warnings

Asthma-related death with long-acting beta-2 agonists monotherapy: LABAs like salmeterol increase the risk of asthma-related death when used as monotherapy without ICS. This risk has been observed clinically when LABAs are used without the anti-inflammatory protection provided by ICS, leading to severe exacerbations and fatal outcomes. However, when LABAs are used in fixed-dose combination with ICS, the risk of serious asthma-related events such as hospitalization, intubation, or death does not appear to increase compared to ICS alone.

Use of any LABA alone in the treatment of asthma is contraindicated. LABAs should only be used as add-on therapy for patients who are already on ICS but remain symptomatic. They should not be initiated in patients whose asthma is adequately controlled with low- or medium-dose of ICS alone. Inappropriate monotherapy with LABAs can mask underlying inflammation, delay appropriate treatment, and increase the risk of life-threatening events. In pediatric and adolescent patients, LABA monotherapy has been associated with an increased risk of asthma-related hospitalizations. For these patients, when LABA use is indicated, a fixed-dose combination of ICS and LABA should generally be used to promote adherence and reduce risk.

If separate inhalers are necessary, clinicians must ensure that both ICS and LABA are taken consistently. If compliance cannot be reliably ensured, a combination inhaler is preferred to mitigate the risks associated with LABA monotherapy. 

The boxed warning for LABA-containing asthma medications was first introduced due to early concerns about increased asthma-related deaths, intubations, and hospitalizations, particularly when LABAs were used without ICSs. To address these concerns, the FDA mandated large-scale, randomized, double-blinded trials comparing fixed-dose ICS–LABA combinations with ICS monotherapy.

The trials consistently met their predefined safety objectives, showing no significant increase in the risk of asthma-related deaths, intubations, or hospitalizations when ICS–LABA combinations were used compared to ICS alone. Combination therapy significantly reduced asthma exacerbations requiring systemic corticosteroids. Based on this robust and consistent evidence, the FDA removed the boxed warning in December 2017 for ICS–LABA combination products, affirming their safety and therapeutic benefit when used appropriately in asthma management.

While some uncertainties remain, particularly in patients with life-threatening asthma or regarding pediatric trial margins, the overall benefit-risk profile strongly supports continued use of LABAs only in combination with ICS, and never as monotherapy.[31]

Monitoring

Clinicians should advise patients on how to take the medication with the correct dosage. Serious adverse effects of bronchodilators include paradoxical bronchospasm, hypersensitivity reactions, hypertension, hypotension, cardiac arrest, hypokalemia, and hyperglycemia. Anticholinergics have been associated with dry mouth, constipation, urinary retention, and delirium. If a patient experiences any of these symptoms or general discomfort after taking this medicine, they should seek emergency medical attention promptly. In particular, chronic use of SABAs can lead to downregulation of beta-2 receptors. Continuous stimulation causes receptor desensitization and internalization, reducing the number of active receptors on airway smooth muscle. This results in a reduced bronchodilator response, requiring higher doses to achieve the same effect. Over time, this may contribute to decreased symptom control and increased adverse effects.[29]

Monitor asthma severity control by the Asthma Control Test.[32] The 6-minute walk test can be a useful predictor of functional capacity.[33] Serial spirometry and peak expiratory flow monitoring are also essential assessment tools. Fractional Exhaled Nitric Oxide is a marker of eosinophilic airway inflammation, which can help determine the response to steroids.[34]

Toxicity

Signs and Symptoms of Overdose

Overdose of inhaled beta-2 agonists (both SABA and LABA)—including albuterol, levalbuterol, salmeterol, and formoterol—is characterized by symptoms of excessive beta-2-adrenergic stimulation. These may include tachycardia, palpitations, chest pain, anxiety, tremor, headache, dizziness, hypokalemia, QTc prolongation, arrhythmias, lactic acidosis, and, rarely, seizures. Overdose of muscarinic antagonists (SAMAs/LAMAs) such as ipratropium, tiotropium, and glycopyrrolate may present with anticholinergic effects, including dry mouth, blurred vision, urinary retention, constipation, tachycardia, and, in older adults, possible confusion or hallucinations at high doses. In emergency settings, a physician can assess the patient’s vital signs and perform blood tests to identify any electrolyte abnormalities.[35]

Management of Overdose

First, immediately discontinue the offending agent and provide supportive therapy, including continuous ECG monitoring and vital sign assessment. Most patients can be managed with observation and supportive care. Patients should be started on intravenous fluids as necessary. For beta-2-agonist overdose, check and correct serum potassium levels as needed. If severe tachyarrhythmia occurs, consider judicious use of cardioselective beta-blockers. Intubation may be necessary in severe cases to protect and control the airway. For seizures, benzodiazepines may be necessary. For anticholinergic overdose, provide symptomatic treatment—such as hydration, treatment of urinary retention or constipation—and consider physostigmine in cases of severe toxicity.[36]

Enhancing Healthcare Team Outcomes

Bronchodilators are prescribed by nurse practitioners, physician assistants, family medicine physicians, internists, emergency department clinicians, and other healthcare providers. Advanced practice providers and primary care physicians often initiate therapy based on the clinical presentation, ensuring appropriate use. Pulmonologists specialize in optimizing long-term treatment for patients with moderate-to-severe airway diseases. Critical care physicians manage acute exacerbations, administering and titrating bronchodilators in emergencies, including overdose scenarios. Nurses play a vital role in patient education, inhaler technique, and monitoring for adverse effects. Pharmacists ensure safe prescribing by checking for drug interactions and counseling on adherence. Anyone prescribing bronchodilators must educate patients about potential adverse effects, which can include anticholinergic symptoms as well as cardiac symptoms and emphasize the importance of seeking medical attention if these symptoms arise. Overall, bronchodilators are safe when prescribed and administered correctly, and they can significantly enhance the quality of life for asthma patients. An interprofessional team approach and effective communication among physicians, advanced practice providers, pharmacists, and nurses are crucial to reducing potential adverse effects and improving patient outcomes related to bronchodilator therapy in obstructive lung disease.