Fluticasone, Budesonide, Beclomethasone and Ciclesonide

Mechanism

Genomic and non-genomic mechanism of action

ICS passively cross the membrane of immune and epithelial cells to bind to the cytoplasmic glucocorticoid receptor (GR-α). The GR-α-steroid complex dimerizes and actively translocates to the cell nucleus, exerting two main mechanisms:

1. Transrepression (Inhibition of inflammation): The dimer physically interacts with activated proinflammatory transcription factors, such as nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1). This prevents the transcription of target genes that encode cytokines (IL-1, IL-4, IL-5, IL-13, TNF-α), chemokines (eotaxin), proinflammatory enzymes (COX-2, iNOS) and vascular adhesion molecules.
2. Transactivation (Anti-inflammation activation): The dimer binds to specific DNA sequences called glucocorticoid response elements (GREs), promoting the transcription of anti-inflammatory proteins such as lipocortin-1 (annexin-1), which inhibits phospholipase A2, the IL-1 decoy receptor, and the inhibitor of NF-κB (IκB).
3. Synergistic effect on β₂ receptors: Corticosteroids increase the transcription and expression of the β₂-adrenergic receptor in bronchial smooth muscle and prevent its desensitization due to chronic use of LABA.

Ciclesonide: The Pulmonary Prodrug

Ciclesonide is administered as an inactive prodrug. When inhaled, it is selectively hydrolyzed by endogenous carboxylesterases located in the lung parenchyma cells to release its biologically active metabolite, des-ciclesonide. Since conversion occurs almost exclusively in the lung, the levels of active drug in the oral cavity and oropharynx are negligible, which minimizes the incidence of oral candidiasis and dysphonia.

Pharmacokinetics

Pharmacokinetics and tissue selectivity

Indicators and dose

Dosage and Clinical Adjustment

Dosage varies widely depending on asthma symptomatic control (GINA classification of low, medium and high doses):

• Fluticasone propionate (Low dose): 100 - 250 µg per day; High dose: > 500 µg per day (divided into 2 doses).
• Fluticasone furoate (Low dose): 92 µg once daily; High dose: 184 µg once a day.
• Budesonide (Low dose): 200 - 400 µg per day; High dose: > 800 µg per day.

Adjustment in Liver Failure: Patients with advanced liver cirrhosis (Child-Pugh B/C) have decreased systemic clearance for corticosteroids that suffer from residual enteral absorption. The use of fluticasone furoate or propionate should be preferred over beclomethasone due to its greater first-pass hepatic clearance (>99%).

Security

Adverse effects (ADRs)

• Local (Preventable): Oropharyngeal candidiasis (due to local immunosuppression that facilitates colonization by *Candida albicans*) and dysphonia (due to bilateral myopathy of the lingeal tensor muscles of the vocal cords). *Mandatory prevention:* Thorough mouthwash with water and subsequent gargling and expulsion of the liquid after each inhalation.
• Systemic (Chronic use at high doses): Mild suppression of the hypothalamic-pituitary-adrenal (HPA) axis, transient reduction in growth velocity in pediatric patients (usually self-limited to the first year of treatment, with no impact on final adult height), osteoporosis, skin thinning and bruising, increased risk of pneumonia in patients with COPD (mainly described for fluticasone propionate in clinical studies such as the TORCH trial).