Inhaled corticosteroids

1. Introduction

• Inhaled corticosteroids are synthetic glucocorticoids formulated for delivery directly to the airways via inhalation.

• They are the cornerstone of anti-inflammatory therapy in asthma and are used in chronic obstructive pulmonary disease (COPD) for selected patients.

• Developed to maximize local pulmonary anti-inflammatory effects while minimizing systemic side effects compared to oral corticosteroids.

---

2. Mechanism of Action

• Bind to intracellular glucocorticoid receptors in airway epithelial cells and immune cells.

• The corticosteroid–receptor complex translocates to the nucleus, binding to glucocorticoid response elements (GREs) in DNA.

• Upregulates anti-inflammatory protein transcription (e.g., lipocortin-1, which inhibits phospholipase A2).

• Downregulates pro-inflammatory genes (e.g., cytokines, chemokines, adhesion molecules).

• Reduces inflammatory cell infiltration (eosinophils, T lymphocytes, mast cells) in the airway mucosa.

• Decreases airway hyperresponsiveness and edema over time.

---

3. Commonly Used Agents (Generic → Brand examples)

• Beclometasone dipropionate – Qvar, Clenil.

• Budesonide – Pulmicort, Symbicort (with formoterol).

• Ciclesonide – Alvesco.

• Fluticasone propionate – Flixotide.

• Fluticasone furoate – Arnuity Ellipta, Relvar Ellipta (with vilanterol).

• Mometasone furoate – Asmanex, Dulera (with formoterol).

---

4. Formulations and Delivery Devices

• Metered-Dose Inhaler (MDI) – delivers a fixed aerosolized dose with each actuation; may require a spacer for optimal delivery.

• Dry Powder Inhaler (DPI) – breath-actuated powder delivery.

• Nebulized Suspension – for patients unable to coordinate inhaler use (young children, severe exacerbations).

---

5. Pharmacokinetics

• Absorption:

  • Pulmonary absorption of inhaled fraction; some swallowed portion undergoes first-pass hepatic metabolism.

• Distribution: high local airway concentrations; minimal systemic exposure if technique is correct.

• Metabolism: predominantly hepatic via CYP3A4.

• Elimination: excreted via urine and feces as metabolites.

---

6. Therapeutic Indications

• Asthma – long-term control in persistent asthma (all severities).

• COPD – in patients with frequent exacerbations despite optimal bronchodilator therapy, particularly with high eosinophil counts.

• Other – occasionally used in eosinophilic bronchitis, allergic bronchopulmonary aspergillosis (ABPA), and post-lung transplant airway inflammation.

---

7. Dosing Principles

• Use the lowest effective dose to maintain control.

• Step-up therapy if symptoms not controlled; step-down once stable.

• For asthma, usually administered twice daily (some agents allow once daily).

• Consistency in inhaler technique is essential for efficacy.

---

8. Contraindications and Cautions

• Absolute: hypersensitivity to the active drug or excipients.

• Relative cautions:

  • Untreated respiratory infections (e.g., tuberculosis, fungal infections).

  • Severe liver impairment (due to metabolism).

  • Immunosuppression risk.

---

9. Adverse Effects

Local

• Oropharyngeal candidiasis (thrush) – reduced by rinsing mouth after use.

• Dysphonia (hoarseness) from vocal cord myopathy.

• Cough and throat irritation.

Systemic (with high doses or prolonged use)

• Adrenal suppression.

• Decreased bone mineral density.

• Glaucoma, cataracts.

• Growth suppression in children (usually small and reversible).

• Increased risk of pneumonia in COPD patients.

---

10. Drug Interactions

• Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) – can increase systemic corticosteroid exposure → risk of Cushing’s syndrome/adrenal suppression.

• Co-administration with other immunosuppressants may increase infection risk.

---

11. Monitoring

• Asthma/COPD control: symptom scores, exacerbation frequency, peak flow.

• Growth in pediatric patients.

• Signs of adrenal suppression with high doses.

• Intraocular pressure and eye exams in long-term use.

---

12. Advantages

• Direct delivery to target tissue → high efficacy with low systemic risk.

• Significant improvement in symptoms, lung function, and quality of life in asthma.

• Prevents exacerbations and hospitalizations.

---

13. Limitations

• No immediate bronchodilation – not for acute relief (requires combination with short-acting β₂-agonist for rescue).

• Effect builds over days to weeks.

• Poor adherence due to lack of rapid symptom relief.

---

14. Clinical Pearls

• Technique training is critical – incorrect use drastically reduces drug delivery.

• Spacers improve lung deposition and reduce oropharyngeal side effects with MDIs.

• In COPD, ICS are not first-line; used in combination with long-acting bronchodilators in selected patients.

• Lowest dose principle reduces long-term adverse effects.