Respiratory Pharmacology: Corticosteroids and Leukotriene Antagonists in Asthma

Introduction/Overview

Asthma remains a prevalent chronic respiratory disorder characterized by reversible airway obstruction and airway hyperresponsiveness. The therapeutic armamentarium for asthma includes inhaled corticosteroids (ICS) and leukotriene receptor antagonists (LTRAs), both of which target distinct inflammatory pathways. The clinical relevance of these agents is underscored by their role in reducing exacerbations, improving lung function, and enhancing quality of life for patients across all age groups. This chapter aims to provide a comprehensive understanding of the pharmacological principles governing corticosteroids and leukotriene antagonists, with particular emphasis on their application in asthma management.

• Understand the classification and chemical structure of inhaled corticosteroids and leukotriene antagonists.
• Describe the molecular mechanisms that underlie the anti-inflammatory effects of these agents.
• Summarize pharmacokinetic properties relevant to dosing and therapeutic monitoring.
• Identify approved indications, off‑label uses, and therapeutic sequencing.
• Recognize common adverse events, drug interactions, and special population considerations.

Classification

Inhaled Corticosteroids

Inhaled corticosteroids are classified based on their potency, lipophilicity, and metabolic stability. Major classes include:

1. Phenylpropionic acids – e.g., fluticasone propionate, budesonide.
2. Alkylated butyrates – e.g., beclomethasone dipropionate.
3. Acetonitrile derivatives – e.g., mometasone furoate.

Potency is generally determined by receptor affinity and intrinsic glucocorticoid activity, with fluticasone and mometasone being among the most potent agents.

Leukotriene Receptor Antagonists

LTRAs are divided into two pharmacological subclasses:

1. 5‑lipoxygenase inhibitors – e.g., zileuton, which blocks leukotriene synthesis.
2. 5‑lipoxygenase product receptor antagonists – e.g., montelukast and zafirlukast, which competitively inhibit cysteinyl leukotriene receptor type 1 (CysLT1).

Montelukast, due to its favorable oral bioavailability and safety profile, is the most widely used LTRA in asthma therapy.

Mechanism of Action

Inhaled Corticosteroids

Inhaled corticosteroids exert their anti‑inflammatory effects primarily through genomic modulation. Upon binding to cytosolic glucocorticoid receptors (GR), the steroid–receptor complex translocates to the nucleus, where it interacts with glucocorticoid response elements (GREs) to up‑regulate anti‑inflammatory genes (e.g., lipocortin‑1) and down‑regulate pro‑inflammatory mediators (e.g., interleukin‑4, interleukin‑5, and eosinophil chemokines). Additionally, the complex interferes with transcription factors such as nuclear factor‑kappa B (NF‑κB) and activator protein‑1 (AP‑1), thereby attenuating the production of cytokines, chemokines, and adhesion molecules. The rapid onset of action observed clinically is attributed to both the anti‑inflammatory cascade and the direct inhibition of phospholipase A₂, which reduces prostaglandin and leukotriene synthesis.

Leukotriene Receptor Antagonists

Montelukast and zafirlukast competitively bind to the CysLT1 receptor on airway smooth muscle cells, mucosal cells, and inflammatory leukocytes. This inhibition blocks the actions of cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄) that mediate bronchoconstriction, vascular permeability, mucus secretion, and eosinophil recruitment. Zileuton, conversely, inhibits 5‑lipoxygenase, the key enzyme in leukotriene biosynthesis, thereby decreasing the formation of all leukotrienes. The net effect is a reduction in airway inflammation and hyperresponsiveness.

Pharmacokinetics

Inhaled Corticosteroids

Absorption: Inhaled corticosteroids are deposited in the lungs, with a small fraction swallowed and absorbed via the gastrointestinal tract. The pulmonary absorption is rapid, but the systemic bioavailability is limited due to extensive first‑pass metabolism, particularly for lipophilic compounds such as fluticasone.

Distribution: The high lipophilicity of many inhaled steroids facilitates extensive tissue binding, especially within the airway mucosa, leading to prolonged local effects. Systemic distribution is modest, with plasma concentrations remaining low under therapeutic dosing.

Metabolism: Hepatic cytochrome P450 enzymes, notably CYP3A4 and CYP2C9, metabolize most inhaled corticosteroids. Enzymatic activity can be altered by concomitant medications, potentially affecting systemic exposure.

Excretion: Metabolites are primarily excreted renally, with a minor contribution from biliary excretion. The plasma half‑life of the parent compound is typically short (1–3 hours), but the anti‑inflammatory actions persist due to tissue retention.

Dosing considerations: Due to variable systemic absorption, dosing regimens are tailored to achieve adequate airway concentrations while minimizing systemic exposure. The typical maintenance dose for fluticasone propionate ranges from 100 to 500 µg twice daily, depending on disease severity.

Leukotriene Receptor Antagonists

Absorption: Oral absorption of montelukast is rapid, with peak plasma concentrations reached within 1–2 hours post‑dose. Bioavailability is approximately 60–70% after a single dose.

Distribution: Montelukast displays extensive distribution, with a large volume of distribution (~4000 L), indicating extensive tissue binding. Plasma protein binding is high (~95% bound to albumin and α‑1‑acid glycoprotein).

Metabolism: The drug undergoes hepatic metabolism primarily via glucuronidation mediated by UDP‑glucuronosyltransferase (UGT) enzymes. Cytochrome P450 interactions are minimal, reducing the risk of significant drug–drug interactions.

Excretion: Metabolites are eliminated renally, with a terminal elimination half‑life of approximately 2–3 hours. The dosing interval is typically once daily, accommodating the pharmacokinetic profile.

Therapeutic Uses/Clinical Applications

Inhaled Corticosteroids

ICS are the cornerstone of controller therapy for persistent asthma. They are indicated for patients with moderate to severe symptoms, frequent exacerbations, or reduced lung function. Commonly prescribed regimens include:

1. Low‑dose fluticasone propionate (100–200 µg twice daily).
2. Medium‑dose budesonide (400–800 µg twice daily).
3. High‑dose mometasone furoate (400–800 µg twice daily).

Off‑label uses include the management of chronic obstructive pulmonary disease (COPD) exacerbations and the prevention of airway hyperresponsiveness in patients with exercise‑induced bronchoconstriction.

Leukotriene Receptor Antagonists

Montelukast is approved for the maintenance treatment of asthma and for the prophylaxis of exercise‑induced bronchospasm. It is also indicated for the treatment of allergic rhinitis in patients with concurrent asthma. Off‑label applications encompass the management of aspirin‑induced asthma and seasonal allergic rhinitis.

Adverse Effects

Inhaled Corticosteroids

Common side effects, primarily localized, include oral thrush, dysphonia, and cough. Systemic adverse events are infrequent but may encompass growth suppression in children, adrenal suppression, and osteoporosis with high‑dose long‑term therapy. Rare but serious complications include increased risk of pneumonia and cataract formation. Black‑box warnings are absent for most inhaled steroids, although caution is advised when prescribing high‑dose regimens.

Leukotriene Receptor Antagonists

Common adverse events include headache, abdominal pain, and gastrointestinal discomfort. Rare but notable reactions are hepatotoxicity and hypersensitivity reactions, including angioedema. No black‑box warnings are issued; however, monitoring liver function tests may be considered in patients with pre‑existing hepatic disease.

Drug Interactions

Inhaled Corticosteroids

Strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) can increase systemic exposure to lipophilic inhaled steroids, potentially elevating the risk of adrenal suppression. Conversely, potent CYP3A4 inducers (e.g., rifampin, carbamazepine) may reduce systemic levels, potentially diminishing efficacy. Co‑administration with systemic steroids may lead to additive immunosuppressive effects.

Leukotriene Receptor Antagonists

Montelukast has minimal interaction with the cytochrome P450 system, yet caution is warranted when combined with medications that affect UGT enzymes or potent inhibitors of the CYP2C19 pathway. Zileuton, due to its 5‑lipoxygenase inhibition, may interact with anticoagulants, increasing bleeding risk.

Special Considerations

Pregnancy and Lactation

Inhaled corticosteroids are classified as category C. While localized therapy is generally considered safe, systemic absorption may pose risks; therefore, dose optimization and monitoring of maternal and fetal growth are recommended. Montelukast is also category C; however, its oral route and minimal systemic absorption may reduce fetal exposure. Lactation is generally considered safe with both classes, though monitoring for infant growth and adrenal function is prudent.

Pediatric Considerations

Growth suppression is a notable concern with long‑term high‑dose inhaled steroid therapy. Baseline growth velocity assessment and periodic monitoring are advised, with dose adjustments to the lowest effective level. LTRAs, particularly montelukast, exhibit a favorable safety profile in children, with minimal impact on growth parameters.

Geriatric Considerations

Older adults may exhibit increased sensitivity to systemic side effects of inhaled steroids, including osteoporosis and adrenal suppression. Dose titration should be conservative, and bone mineral density assessment may be warranted. LTRAs demonstrate a low risk of interaction and are generally well tolerated in the elderly population.

Renal and Hepatic Impairment

Inhaled corticosteroids are primarily metabolized hepatically; therefore, severe hepatic dysfunction may necessitate dose reduction or alternative therapy. Renal impairment has minimal influence on systemic exposure to inhaled steroids. Montelukast metabolism is largely hepatic; however, altered UGT function in hepatic disease may increase plasma concentrations, recommending dose adjustment. Zileuton requires caution in hepatic impairment, given its potential hepatotoxicity.

Summary/Key Points

• Inhaled corticosteroids remain the mainstay of controller therapy in asthma, providing potent anti‑inflammatory effects with a favorable safety profile when appropriately dosed.
• Leukotriene receptor antagonists offer an effective add‑on or alternative strategy, particularly for patients with aspirin‑induced asthma or exercise‑induced bronchospasm.
• Systemic absorption of inhaled steroids is limited but can be amplified by CYP3A4 inhibition; monitoring for growth, adrenal function, and osteoporosis is essential in children and adults.
• Montelukast presents a favorable safety and interaction profile, though vigilance for hepatotoxicity is advisable in patients with underlying liver disease.
• Special populations—including pregnant, lactating, pediatric, geriatric, and patients with renal or hepatic impairment—require individualized dosing strategies and regular monitoring to mitigate adverse outcomes.

References

1. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
2. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
3. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
4. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
5. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
6. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
7. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.