Fluticasone Propionate / Mometasone Furoate (Intranasal)

Mechanism

Pharmacological Class and Group

Second generation intranasal topical corticosteroids of extreme local potency and ultra-low systemic bioavailability.

Mechanism of Action

They act at the intranasal level by regulating the transcription of pro-inflammatory and anti-inflammatory proteins directly in the epithelium and lamina propria of the rhinosinusal mucosa:

Molecular Mechanism in the Rhinosinusal Mucosa

1. High Affinity Binding to the Glucocorticoid Receptor (GR-alpha): Mometasone furoate and fluticasone propionate/furoate have a much higher binding affinity to the GR-alpha receptor than hydrocortisone or dexamethasone.

2. Inhibition of Inflammatory Cell Recruitment: Suppresses the synthesis of chemotactic cytokines such as eotaxin and RANTES in the epithelial cells of the nasal fossa. This prevents the migration and degranulation of eosinophils, basophils and mast cells in the affected rhinosinusal mucosa.

3. Blockade of the IgE-Mediated Allergic Cascade (Late Phase): Inhibits the transcription of the mRNA for the interleukins IL-4, IL-5 and IL-13, responsible for maintaining plasma IgE synthesis, decreasing the infiltration of inflammatory cells in the late phase of the hypersensitivity reaction.

↓ Vascular permeability of the mucosa Rapid resolution of rhinorrhea, sneezing and nasal congestion

4. Reduction of Mucous Gland Hypertrophy: Progressively decreases mucus secretion by reducing the number and hyperactivity of goblet cells and submucosal mucous glands.

Pharmacokinetics

High Resolution Pharmacokinetics

• Systemic Bioavailability: Extremely low. For mometasone furoate it is <0.1%; for fluticasone propionate it is approximately < 1%. This is due to its negligible mucosal absorption and the fact that the swallowed fraction undergoes 99% complete hepatic first-pass metabolism by cytochrome CYP3A4.
• Distribution: Very high binding to plasma proteins (98-99%).
• Half-life (t_1/2): The plasma elimination half-life of the absorbed fraction is approximately 5 hours.

Indicators and dose

Clinical Indications and Off-Label Uses

• Allergic Rhinitis (Seasonal and Perennial): Prophylaxis and symptomatic treatment of watery rhinorrhea, sneezing, nasal itching and nasal congestion in adults and children over 2 years of age.
• Unilateral or Bilateral Nasosinusal Polyposis: Reduction in the size of nasal polyps of eosinophilic origin, decrease in associated nasal obstruction and progressive recovery of smell (hyposmia/anosmia).
• Uncomplicated Acute Rhinosinusitis: As an anti-inflammatory adjuvant in combination with saline washes and hydration to facilitate drainage of rhinosinusal mucus.
• Adenoid Hypertrophy in Pediatrics (off-label): Reduction of cavum lymphoid tissue in children with mild to moderate obstructive sleep apnea syndrome (OSAS).

Dosage and Clinical Adjustment

Intranasal Mometasone Furoate (50 µg per application):

• Adults and Adolescents (>12 years): 2 applications in each nostril once a day (total daily dose of 200 µg). After achieving control of symptoms, it is advisable to reduce to 1 application in each nostril once a day (100 µg/day).
• Children (2 to 11 years): 1 application in each nostril once a day (100 µg/day).

Intranasal Fluticasone Furoate (27.5 µg per application):

• Adults and Adolescents (>12 years): 2 applications in each nostril once a day (total daily dose of 110 µg).
• Children (2 to 11 years): 1 application in each nostril once a day (55 µg/day).

Adjustment in Renal or Hepatic Failure: No dosage adjustment is required due to low bioavailability and local clearance.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Hypersensitivity to the active ingredient or to the excipients of the nasal formulation.
• Active herpes simplex infection of nasal or ocular location.
• Recent postoperative episode of nasal surgery (septoplasty, turbinectomy or FESS): Corticosteroids significantly delay the healing of the epithelium and nasal grafts, and should be avoided until complete re-epithelialization (generally 2 weeks).

Relative Contraindications

• Active or latent respiratory tuberculosis without optimal treatment.
• Local nasal fungal infections (nasal candidiasis).
• History of severe recurrent epistaxis or active anterior septal perforation.

Adverse Effects (ADR) and Specific Toxicity

• Frequent (1%-10%): Mild transient epistaxis (in the form of streaks of blood in the nasal mucus), dryness of the nasal mucosa, formation of nasal crusts, tension headache, oropharyngeal irritation.
• Uncommon (0.1%-1%): Transient dysphonia, alteration of taste (dysgeusia) or smell (transient hyposmia due to irritation of the posterior olfactory epithelium).
• Rare (<0.1%): Perforation of the anterior nasal septum (usually associated with an incorrect application technique, where the spray is constantly directed against the anterior nasal septum, inducing progressive tissue ischemia and local chondral atrophy), increased intraocular pressure (mild glaucoma or cortical cataract in predisposed patients under chronic continuous use).

Drug Interactions of Clinical Relevance

• Potent inhibitors of the liver enzyme CYP3A4 (Ritonavir, Ketoconazole, Clarithromycin): They can block the hepatic clearance of the minimal swallowed fraction of fluticasone or mometasone, increasing their systemic plasma levels with the consequent risk of adrenal suppression or iatrogenic Cushing's syndrome.

Safety in Pregnancy and Breastfeeding

• Pregnancy: Compatible. They are considered the corticosteroids of choice in pregnancy for the control of chronic allergic rhinitis (especially budesonide and mometasone furoate) due to their insignificant maternal systemic plasma level.
• Breastfeeding: Compatible. They do not represent a risk of hormonal suppression or side effects in the infant due to their ultra-low bioavailability.

Clinical

Pearl of Technique: Nasal Spray Direction

To prevent the development of anterior septal perforation or recurrent epistaxis, the patient should apply the drug using the "cross hand rule": hold the bottle with the right hand to apply to the left nostril, and with the left hand to apply to the right nostril. The nasal applicator should be directed towards the external wall of the nostril (towards the eye or ear on the same side), avoiding directing the jet against the middle nasal septum.