Pharmacology of Drugs for Asthma

Introduction/Overview

Asthma is a chronic inflammatory disorder of the airways characterized by variable and recurring symptoms, bronchial hyperresponsiveness, and underlying inflammation. The pharmacological management of asthma aims to achieve and maintain control of symptoms, prevent exacerbations, and minimize adverse effects from medications. This chapter provides a systematic examination of the drugs used in the treatment of asthma, detailing their pharmacological properties, clinical applications, and therapeutic considerations. A thorough understanding of these agents is fundamental for rational prescribing and optimal patient care.

Clinical Relevance and Importance

Asthma represents a significant global health burden, affecting individuals across all age groups. Pharmacotherapy forms the cornerstone of asthma management, with treatment strategies evolving from a primary focus on bronchodilation to a greater emphasis on controlling the underlying inflammatory process. The stepwise approach to treatment, as outlined in major international guidelines, is directly predicated on the pharmacological profiles of the available drug classes. Mastery of this topic enables clinicians to tailor therapy to disease severity, improve patient outcomes, and reduce the morbidity and mortality associated with this condition.

Learning Objectives

• Classify the major drug categories used in asthma management and describe their primary therapeutic roles.
• Explain the molecular and cellular mechanisms of action for bronchodilators, anti-inflammatory agents, and biologic therapies.
• Analyze the pharmacokinetic properties of inhaled versus systemic formulations and their implications for dosing and toxicity.
• Evaluate the clinical applications, major adverse effects, and significant drug interactions for each drug class.
• Integrate pharmacological principles into the stepwise management plan for asthma, considering special patient populations.

Classification

Drugs for asthma are classified primarily according to their therapeutic function and mechanism of action. The two broadest categories are relievers, which provide rapid symptom relief, and controllers, which are used for long-term management of inflammation and prevention of symptoms. A more detailed pharmacological classification is presented below.

Drug Classes and Categories

• Bronchodilators (Relievers)
  • Short-Acting Beta₂-Adrenoceptor Agonists (SABAs): e.g., albuterol (salbutamol), levalbuterol.
  • Long-Acting Beta₂-Adrenoceptor Agonists (LABAs): e.g., salmeterol, formoterol, vilanterol.
  • Muscarinic Antagonists
    • Short-Acting Muscarinic Antagonists (SAMAs): e.g., ipratropium bromide.
    • Long-Acting Muscarinic Antagonists (LAMAs): e.g., tiotropium, umeclidinium.
  • Methylxanthines: e.g., theophylline, aminophylline.
• Anti-inflammatory Agents (Controllers)
  • Inhaled Corticosteroids (ICS): e.g., beclomethasone, budesonide, fluticasone, mometasone.
  • Systemic Corticosteroids: e.g., prednisone, prednisolone, methylprednisolone.
  • Leukotriene Modifiers
    • Leukotriene Receptor Antagonists (LTRAs): e.g., montelukast, zafirlukast.
    • 5-Lipoxygenase Inhibitor: zileuton.
  • Mast Cell Stabilizers: e.g., cromolyn sodium, nedocromil.
• Biologic Therapies (Targeted Controllers)
  • Anti-IgE Monoclonal Antibody: omalizumab.
  • Anti-IL-5/IL-5R Monoclonal Antibodies: mepolizumab, reslizumab, benralizumab.
  • Anti-IL-4Rα Monoclonal Antibody: dupilumab.
  • Anti-TSLP Monoclonal Antibody: tezepelumab.
• Combination Therapies
  • ICS/LABA Fixed-Dose Combinations: e.g., fluticasone/salmeterol, budesonide/formoterol.
  • ICS/LABA/LAMA Triple Therapy: e.g., fluticasone/vilanterol/umeclidinium.

Chemical Classification

While therapeutic classification is most clinically relevant, chemical distinctions exist within classes. Beta₂-agonists are phenylethylamine derivatives. Inhaled corticosteroids are synthetic halogenated glucocorticoids with structural modifications to enhance topical potency and reduce systemic bioavailability. Leukotriene modifiers include quinoline derivatives (montelukast) and indole derivatives (zafirlukast). Theophylline is a dimethylxanthine. Biologic agents are monoclonal antibodies or antibody fragments engineered to target specific proteins in the inflammatory cascade.

Mechanism of Action

The mechanisms of action for asthma drugs involve interrupting the pathophysiological processes of bronchoconstriction, airway inflammation, and hyperresponsiveness. These effects are mediated through diverse receptor systems and intracellular signaling pathways.

Beta₂-Adrenoceptor Agonists

These agents act as agonists at the beta₂-adrenergic receptors located on airway smooth muscle cells. Receptor activation stimulates the G_s protein, which subsequently activates adenylyl cyclase. This enzyme catalyzes the conversion of ATP to cyclic adenosine monophosphate (cAMP). Elevated intracellular cAMP levels activate protein kinase A (PKA), which phosphorylates multiple target proteins. The net effects include inhibition of myosin light chain kinase, leading to smooth muscle relaxation and bronchodilation, and stabilization of mast cells, reducing mediator release. LABAs differ from SABAs primarily in their lipophilicity, which allows them to anchor in the plasma membrane near the receptor, resulting in prolonged stimulation.

Muscarinic Antagonists

Parasympathetic tone, mediated by acetylcholine acting on M₃ muscarinic receptors, maintains a baseline level of bronchoconstriction. Muscarinic antagonists competitively block these receptors on airway smooth muscle and submucosal glands. Inhibition of M₃ receptors prevents G_q-mediated activation of phospholipase C, reducing the generation of inositol trisphosphate (IP₃) and diacylglycerol (DAG). This leads to decreased intracellular calcium and smooth muscle relaxation. Blockade of M₁ and M₃ receptors on glands also reduces mucus secretion. LAMAs exhibit kinetic selectivity, dissociating very slowly from the M₃ receptor, which confers their long duration of action.

Methylxanthines

The precise mechanism of theophylline is multifactorial and not fully elucidated. The primary proposed mechanism is non-selective inhibition of phosphodiesterase (PDE) enzymes, particularly PDE3 and PDE4. This inhibition increases intracellular levels of cAMP and cyclic guanosine monophosphate (cGMP) in smooth muscle and inflammatory cells, promoting bronchodilation and anti-inflammatory effects. An additional important mechanism is antagonism of adenosine receptors (A₁, A₂, and A₃), which may prevent adenosine-induced bronchoconstriction and mast cell degranulation. Histone deacetylase activation, leading to enhanced corticosteroid function, represents another potential anti-inflammatory pathway.

Inhaled Corticosteroids

ICS exert profound anti-inflammatory and immunomodulatory effects. Being lipophilic, they diffuse across cell membranes and bind to the glucocorticoid receptor (GR) in the cytoplasm. The activated receptor-ligand complex translocates to the nucleus, where it modulates gene transcription through two primary mechanisms. First, it binds as a homodimer to glucocorticoid response elements (GREs) in the promoter regions of target genes, upregulating the expression of anti-inflammatory proteins such as lipocortin-1, which inhibits phospholipase A₂. Second, and more significant for asthma, the complex inhibits the activity of pro-inflammatory transcription factors like nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) via protein-protein interactions. This transrepression leads to downregulation of genes encoding cytokines (IL-4, IL-5, IL-13, GM-CSF), chemokines, adhesion molecules, and inflammatory enzymes like inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). ICS also promote eosinophil apoptosis and reduce microvascular permeability.

Leukotriene Modifiers

This class targets the arachidonic acid cascade via the 5-lipoxygenase pathway. Cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄) are potent mediators that cause bronchoconstriction, increased vascular permeability, mucus secretion, and eosinophil recruitment. Leukotriene receptor antagonists (LTRAs) like montelukast competitively block the CysLT₁ receptor on target cells, preventing leukotriene-mediated effects. Zileuton inhibits 5-lipoxygenase, the enzyme responsible for converting arachidonic acid to leukotriene A₄ (LTA₄), thereby reducing the synthesis of all downstream leukotrienes.

Mast Cell Stabilizers

Cromolyn and nedocromil are thought to act by blocking chloride channels on mast cells and other inflammatory cells, such as sensory neurons and eosinophils. This inhibition prevents cellular activation and degranulation triggered by allergens and other stimuli, thereby reducing the release of preformed mediators like histamine and the synthesis of newly formed mediators like leukotrienes and prostaglandins.

Biologic Therapies

These monoclonal antibodies target specific components of the type 2 (T2) inflammatory pathway prevalent in many asthma phenotypes.

• Omalizumab is a humanized anti-IgE antibody that binds to circulating IgE at the Cε3 domain, preventing IgE from binding to its high-affinity receptor (FcεRI) on mast cells and basophils. This downregulates receptor expression and inhibits allergen-induced activation.
• Anti-IL-5/IL-5R agents (mepolizumab, reslizumab, benralizumab) target the IL-5 pathway, a key cytokine for eosinophil growth, differentiation, activation, and survival. Mepolizumab and reslizumab bind directly to IL-5, while benralizumab binds to the IL-5 receptor alpha chain on eosinophils and basophils, inducing antibody-dependent cell-mediated cytotoxicity (ADCC).
• Dupilumab binds to the shared IL-4 receptor alpha (IL-4Rα) subunit, blocking signaling from both IL-4 and IL-13. These cytokines are central to IgE production, mucus hypersecretion, airway remodeling, and eosinophil recruitment.
• Tezepelumab binds to thymic stromal lymphopoietin (TSLP), an epithelial cytokine that acts upstream in the inflammatory cascade, initiating multiple T2 inflammatory pathways.

Pharmacokinetics

The pharmacokinetic profiles of asthma drugs vary dramatically depending on the route of administration, which is primarily chosen to maximize therapeutic effects in the lungs while minimizing systemic exposure and toxicity.

Absorption

For inhaled medications, absorption is a dual process. The fraction deposited in the lungs exerts the local therapeutic effect and is subsequently absorbed into the systemic circulation. The fraction deposited in the oropharynx is swallowed and subject to gastrointestinal absorption. The systemic bioavailability of an inhaled drug is therefore the sum of the pulmonary and oral components. For ICS and LABAs, the oral bioavailability is typically very low due to extensive first-pass metabolism. SABAs like albuterol have higher oral bioavailability but are still primarily administered via inhalation for rapid effect. Systemic drugs like theophylline, leukotriene modifiers, and biologics are absorbed from subcutaneous, intramuscular, or oral routes. Oral theophylline absorption can be variable and formulation-dependent.

Distribution

Distribution characteristics are drug-specific. Beta₂-agonists and theophylline distribute widely throughout body water. The volume of distribution for theophylline is approximately 0.5 L/kg. Inhaled corticosteroids, due to their lipophilicity, are retained in lung tissue for prolonged periods, which contributes to their duration of action. Biologic agents, being large proteins, are largely confined to the plasma and extracellular fluid, with limited volumes of distribution. Omalizumab forms complexes with IgE, which are cleared slowly.

Metabolism

Hepatic metabolism is the primary route of elimination for most small-molecule asthma drugs. Beta₂-agonists undergo sulfate conjugation and glucuronidation. Theophylline is metabolized extensively in the liver by cytochrome P450 enzymes, primarily CYP1A2, with contributions from CYP2E1 and CYP3A4. Its metabolism follows capacity-limited (Michaelis-Menten) kinetics at therapeutic concentrations, making it susceptible to nonlinear changes in clearance. Inhaled corticosteroids are subject to extensive first-pass hepatic metabolism by CYP3A4 to inactive metabolites, which accounts for their low systemic activity when swallowed. Leukotriene modifiers are also metabolized by CYP450 enzymes: montelukast by CYP2C8 and CYP3A4, and zafirlukast by CYP2C9. Biologic therapies are not metabolized by hepatic enzymes but are degraded via proteolytic catabolism throughout the body.

Excretion

Renal excretion of unchanged drug is minor for most agents. Metabolites of beta₂-agonists, theophylline, and corticosteroids are excreted primarily in urine. Approximately 10% of theophylline is excreted unchanged in urine. Montelukast and its metabolites are excreted almost exclusively via bile into feces. Biologics are eliminated via intracellular catabolism, with resulting peptides and amino acids recycled, and the immune complexes formed (e.g., omalizumab-IgE) are cleared by the reticuloendothelial system.

Half-life and Dosing Considerations

The elimination half-life (t_1/2) dictates dosing frequency. SABAs have a short t_1/2 of 3-6 hours, necessitating use every 4-6 hours as needed. LABAs like salmeterol (t_1/2 ~5.5 hours) and formoterol (t_1/2 ~10 hours) are dosed twice daily, while ultra-LABAs like vilanterol (t_1/2 ~25 hours) permit once-daily dosing. LAMAs such as tiotropium have a long effective half-life due to slow receptor dissociation, allowing once-daily inhalation. Theophylline has a highly variable t_1/2 (4-12 hours in adults) influenced by age, disease, and concomitant medications, often requiring therapeutic drug monitoring to maintain a serum concentration of 5-15 mcg/mL. Inhaled corticosteroids have long effective lung retention times but short plasma t_1/2 due to rapid hepatic clearance, supporting once or twice-daily dosing. Biologics have prolonged terminal half-lives: omalizumab ~26 days, mepolizumab ~16-22 days, dupilumab ~2-3 weeks, supporting subcutaneous administration every 2-8 weeks.

Therapeutic Uses/Clinical Applications

The application of asthma pharmacotherapy follows a stepwise approach based on symptom frequency, severity, and the level of control achieved.

Approved Indications

• Short-Acting Beta₂-Agonists (SABAs): First-line therapy for acute relief of bronchospasm and prevention of exercise-induced bronchoconstriction (EIB). They are used on an as-needed basis across all treatment steps.
• Inhaled Corticosteroids (ICS): First-line controller therapy for persistent asthma. Initiated at Step 2 for adults and adolescents, and considered at Step 1 for children under 5 with recurrent wheezing. Used daily to suppress airway inflammation.
• Long-Acting Beta₂-Agonists (LABAs): Never used as monotherapy in asthma. They are always combined with an ICS (as ICS/LABA combination therapy) for patients with moderate to severe persistent asthma (Step 3-4) inadequately controlled on medium-dose ICS alone.
• Leukotriene Receptor Antagonists (LTRAs): Alternative first-line controller therapy (Step 2), particularly in patients with concomitant allergic rhinitis or aspirin-exacerbated respiratory disease (AERD). Also used as add-on therapy to ICS.
• Long-Acting Muscarinic Antagonists (LAMAs): Approved as add-on therapy for patients aged ≥6 years with a history of exacerbations despite treatment with ICS/LABA (Step 5).
• Theophylline: A less commonly used alternative or add-on controller therapy (Step 3-5) due to its narrow therapeutic index.
• Systemic Corticosteroids: Used for short-term “burst” therapy to gain control during a moderate or severe exacerbation, and as chronic maintenance therapy in the lowest possible dose for severe, refractory asthma.
• Biologic Therapies: Reserved for severe, uncontrolled asthma with specific phenotypic features (e.g., elevated eosinophils, IgE, or FeNO) despite high-dose ICS/LABA therapy (Step 5). Specific indications are tied to biomarkers: omalizumab for allergic asthma, anti-IL-5/IL-5R agents for eosinophilic asthma, dupilumab for eosinophilic or oral corticosteroid-dependent asthma, and tezepelumab for severe asthma irrespective of eosinophil count.

Off-Label Uses

Some agents have common off-label applications. Low-dose theophylline is sometimes used for its potential anti-inflammatory effects. Tiotropium, prior to its formal approval, was used off-label in severe asthma. Inhaled corticosteroids are frequently used in the management of other inflammatory airway conditions, such as eosinophilic bronchitis and some forms of chronic obstructive pulmonary disease (COPD).

Adverse Effects

The adverse effect profile is closely linked to the drug’s mechanism, dose, and route of administration.

Common Side Effects

• Beta₂-Agonists: Tremor, tachycardia, palpitations, headache, hypokalemia (due to stimulation of Na+/K+ ATPase), and muscle cramps. Tolerance (tachyphylaxis) to the systemic effects can develop.
• Inhaled Corticosteroids: Local effects include oropharyngeal candidiasis (thrush) and dysphonia (hoarseness). These can be minimized by using a spacer and rinsing the mouth after use.
• Muscarinic Antagonists: Dry mouth, bitter taste, urinary retention (particularly in predisposed individuals), and blurred vision if the drug comes into contact with the eyes.
• Leukotriene Modifiers: Generally well-tolerated. Headache, dyspepsia, and, rarely, neuropsychiatric events such as agitation, sleep disturbances, and depression have been reported, particularly with montelukast.
• Theophylline: Nausea, vomiting, diarrhea, headache, insomnia, and tachycardia occur at serum concentrations near the upper therapeutic range.
• Biologics: Injection site reactions (pain, erythema, swelling) are common. Omalizumab carries a small risk of anaphylaxis (≈0.1%). Anti-IL-5 agents may be associated with herpes zoster reactivation. Dupilumab can cause conjunctivitis and eosinophilic conditions.

Serious/Rare Adverse Reactions

• Beta₂-Agonists: Paradoxical bronchospasm (rare), hypokalemia-induced arrhythmias, and, with excessive use of SABAs, increased risk of severe exacerbations and mortality. This risk is mitigated by concomitant ICS use.
• Systemic Corticosteroids: With prolonged use: adrenal suppression, osteoporosis, hyperglycemia, hypertension, cataracts, glaucoma, myopathy, weight gain, and psychological disturbances.
• Inhaled Corticosteroids: At high doses, systemic absorption can lead to adrenal suppression, reduced bone mineral density, skin thinning, easy bruising, and increased risk of cataracts and glaucoma. Growth velocity may be slowed in children, though the effect on final adult height is considered minimal with recommended doses.
• Theophylline: Severe toxicity (at serum levels >20 mcg/mL) includes seizures (which can be refractory), cardiac arrhythmias (supraventricular and ventricular), and even death.
• Zileuton: Potentially fatal hepatotoxicity, necessitating regular liver function test monitoring.
• Zafirlukast: Rare cases of Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis), often associated with corticosteroid tapering.

Black Box Warnings

Several asthma medications carry black box warnings from regulatory agencies. Long-acting beta₂-agonists (LABAs) carry a warning that they increase the risk of asthma-related death when used without an inhaled corticosteroid. Consequently, they are contraindicated as monotherapy for asthma and must be used only in fixed-dose combination with an ICS. Theophylline has a warning regarding the potential for fatal overdose, emphasizing the need for careful dosing and monitoring. Omalizumab carries a warning for anaphylaxis, which can occur up to 24 hours after administration, requiring observation post-injection. Montelukast has a boxed warning for serious neuropsychiatric events, including suicidal ideation and behavior.

Drug Interactions

Significant drug interactions can alter the efficacy and toxicity of asthma medications.

Major Drug-Drug Interactions

• Theophylline: Its metabolism is highly susceptible to inhibition and induction. Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin, erythromycin) can markedly increase theophylline levels, risking toxicity. Inducers of CYP450 enzymes (e.g., phenobarbital, phenytoin, rifampin, smoking) can decrease levels, leading to therapeutic failure. Theophylline itself can interact with other drugs; it may increase the risk of digoxin toxicity and antagonize the effects of beta-blockers.
• Beta₂-Agonists: Concomitant use with other sympathomimetic agents can lead to additive cardiovascular effects (tachycardia, hypertension). Use with non-potassium-sparing diuretics may exacerbate hypokalemia. Beta-blockers (especially non-selective) can antagonize the bronchodilator effects and potentially cause severe bronchoconstriction.
• Inhaled/Systemic Corticosteroids: Strong CYP3A4 inducers (e.g., rifampin, carbamazepine, St. John’s wort) can increase the clearance of corticosteroids, reducing their efficacy. Concurrent use with NSAIDs may increase the risk of gastrointestinal ulceration.
• Leukotriene Modifiers: Zafirlukast inhibits CYP2C9 and can increase plasma concentrations of warfarin, requiring close INR monitoring. Montelukast levels are reduced by phenobarbital and rifampin.
• Biologics: Limited data exist on significant pharmacokinetic interactions. However, live vaccines are generally contraindicated due to theoretical risks during immunosuppressive therapy.

Contraindications

Absolute contraindications are specific to each drug. Beta₂-agonists are contraindicated in patients with tachyarrhythmias and should be used with extreme caution in those with ischemic heart disease. LABAs are contraindicated as monotherapy for asthma. Theophylline is contraindicated in patients with active peptic ulcer disease or seizure disorders not adequately controlled. Muscarinic antagonists are contraindicated in patients with narrow-angle glaucoma and urinary retention. A history of hypersensitivity to any component of a drug formulation is a universal contraindication.

Special Considerations

The use of asthma medications requires careful adjustment in specific patient populations due to altered pharmacokinetics, pharmacodynamics, or safety profiles.

Use in Pregnancy and Lactation

Uncontrolled asthma poses a greater risk to the fetus than most asthma medications. SABAs, ICS (particularly budesonide, which has the most safety data), and systemic corticosteroids (if necessary) are considered acceptable. LABAs and LTRAs may be used if clearly needed. Theophylline can be used with careful monitoring. Biologic agents have limited data; their use should be reserved for severe cases where benefit outweighs potential risk. Most asthma drugs are present in breast milk in low concentrations; however, the benefits of breastfeeding generally outweigh the risks, with SABAs and ICS being preferred.

Pediatric Considerations

Pharmacokinetic parameters differ in children. Theophylline clearance is higher in children than in adults but decreases in adolescents. Dosing must be carefully weight-adjusted. Growth monitoring is recommended for children on chronic ICS therapy, though the clinical significance of any effect is debated. Montelukast is available in chewable and granule formulations for young children. The use of SABAs and controller therapy follows age-specific guidelines, with delivery device selection (spacer with mask or mouthpiece) being critical for effective administration in young children.

Geriatric Considerations

Age-related declines in renal and hepatic function may reduce the clearance of theophylline, beta-agonists, and corticosteroids, necessitating dose adjustments. Increased prevalence of comorbid conditions such as cardiovascular disease, osteoporosis, glaucoma, and benign prostatic hyperplasia influences drug choice. Beta₂-agonists may exacerbate underlying coronary artery disease or arrhythmias. Anticholinergic agents may worsen glaucoma or urinary retention. The risk of corticosteroid-induced osteoporosis is higher in postmenopausal women.

Renal and Hepatic Impairment

Renal Impairment: Dose adjustment is rarely needed for inhaled medications. Theophylline clearance is not significantly altered until severe renal failure, but its active metabolites may accumulate. Dosage reduction may be required for systemically administered drugs excreted renally.

Hepatic Impairment: This has a major impact on drugs metabolized by the liver. Theophylline clearance is markedly reduced in liver disease (e.g., cirrhosis, acute hepatitis), often requiring a 50% or greater dose reduction and close monitoring. The metabolism of beta₂-agonists, leukotriene modifiers, and corticosteroids may also be impaired. Zileuton is contraindicated in active liver disease. Pharmacokinetic data for biologics in hepatic impairment are limited.

Summary/Key Points

• Asthma pharmacotherapy is divided into relievers (SABAs) for acute symptom relief and controllers (ICS, LABAs, LTRAs, biologics) for long-term management of inflammation.
• The mechanism of bronchodilation involves increasing cAMP (beta-agonists), blocking muscarinic receptors, or inhibiting phosphodiesterase (theophylline). Anti-inflammatory effects are achieved via glucocorticoid receptor-mediated gene regulation, leukotriene pathway inhibition, or targeted cytokine blockade with monoclonal antibodies.
• The inhaled route is preferred for bronchodilators and corticosteroids to maximize lung delivery and minimize systemic effects. Pharmacokinetics, especially metabolism by CYP450 enzymes, are critical for dosing drugs like theophylline.
• Treatment follows a stepwise approach: SABA as needed for all; add low-dose ICS at Step 2; add LABA (in combination with ICS) at Step 3; consider add-on therapies like LAMA or theophylline at higher steps; use biologics for severe, phenotype-specific asthma.
• Major safety concerns include the risk of asthma-related death with LABA monotherapy (mitigated by fixed-dose ICS/LABA combinations), the narrow therapeutic index of theophylline, systemic effects of corticosteroids, and rare but serious neuropsychiatric events with montelukast.
• Drug interactions are highly significant for theophylline (CYP1A2 inhibitors/inducers) and zafirlukast (increases warfarin effect).
• Special population management requires dose adjustment in hepatic impairment (especially for theophylline), caution with anticholinergics in the elderly, and assurance that maintaining asthma control is paramount during pregnancy.

Clinical Pearls

• Patient education on proper inhaler technique and adherence to controller therapy is as important as drug selection.
• Over-reliance on SABA (e.g., >1 canister per month) indicates poor asthma control and necessitates a step-up in controller therapy.
• For acute exacerbations, systemic corticosteroids are key, and inhaled SABAs are administered frequently, often with ipratropium bromide in severe cases.
• The choice of biologic agent should be guided by the patient’s specific inflammatory phenotype (e.g., eosinophil count, IgE level, clinical features).
• Regular review of therapy is essential to ensure the minimal effective dose is used once control is achieved, minimizing the risk of adverse effects.

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