Pharmacology of Fluticasone

Introduction/Overview

Fluticasone represents a cornerstone synthetic glucocorticoid medication extensively utilized in the management of chronic inflammatory respiratory and dermatological conditions. As a potent anti-inflammatory agent, its development marked a significant advancement in topical and inhaled corticosteroid therapy, primarily due to its favorable pharmacokinetic profile which enhances therapeutic index. The clinical relevance of fluticasone is substantial, forming a first-line maintenance therapy in persistent asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis, thereby reducing morbidity and improving quality of life for millions of patients globally. Its importance is further underscored by its availability in various formulations—including propionate and furoate esters—tailored for specific routes of administration such as inhalation, intranasal application, and topical use.

Learning Objectives

Upon completion of this chapter, the reader should be able to:

• Describe the chemical classification of fluticasone and its relationship to glucocorticoid receptor binding affinity.
• Explain the molecular mechanism of action, detailing genomic and non-genomic pathways mediating its anti-inflammatory and immunosuppressive effects.
• Analyze the pharmacokinetic properties of fluticasone, including absorption, distribution, metabolism, and excretion, and relate these to dosing regimens and systemic side effect profiles.
• Identify the approved clinical indications for fluticasone formulations and recognize common off-label applications.
• Evaluate the spectrum of adverse effects, potential drug interactions, and special population considerations to inform safe and effective clinical prescribing.

Classification

Fluticasone is definitively classified within the broad therapeutic category of corticosteroids. More specifically, it is a synthetic trifluorinated glucocorticoid receptor agonist. The distinction from mineralocorticoids is critical, as fluticasone possesses negligible mineralocorticoid activity, which minimizes electrolyte disturbance risks such as sodium retention and hypokalemia.

Chemical and Pharmacological Classification

Chemically, fluticasone is a 17α-carbothioate ester derivative of androstane, featuring a fluoromethyl thioester group at the 17α-position and a fluorine atom at the 6α- and 9α-positions. The two primary esters used clinically are fluticasone propionate and fluticasone furoate. Fluticasone propionate is used in inhaled, intranasal, and topical formulations. Fluticasone furoate, characterized by a furoate ester group, is typically utilized in intranasal sprays and certain combination inhalers, often cited for its prolonged receptor binding affinity. Pharmacologically, these agents are classified as potent, selective glucocorticoid receptor agonists with high topical potency and low systemic bioavailability, which categorizes them as “soft” drugs designed for local effect.

Mechanism of Action

The therapeutic efficacy of fluticasone is mediated through its action as a ligand for the intracellular glucocorticoid receptor (GR), a member of the nuclear receptor superfamily. The ensuing pharmacodynamic effects are predominantly anti-inflammatory and immunosuppressive, achieved through complex genomic and non-genomic pathways.

Receptor Interaction and Genomic Pathways

Fluticasone, being highly lipophilic, passively diffuses across the cell membrane and binds with high affinity to the cytosolic glucocorticoid receptor. In its inactive state, the GR is complexed with heat shock proteins (HSPs) such as HSP90 and immunophilins. Ligand binding induces a conformational change, causing dissociation of the chaperone proteins. The activated glucocorticoid-receptor complex then translocates to the nucleus.

Within the nucleus, the mechanism proceeds via two primary genomic pathways: transactivation and transrepression. Transactivation involves the homodimerization of ligand-bound GR complexes and their binding to specific DNA sequences known as glucocorticoid response elements (GREs) in the promoter regions of target genes. This binding typically upregulates the transcription of anti-inflammatory proteins, including:

• Lipocortin-1 (Annexin-1): inhibits phospholipase A₂, reducing arachidonic acid release and subsequent synthesis of pro-inflammatory eicosanoids (prostaglandins, leukotrienes).
• IκB-α: the inhibitor of nuclear factor kappa-B (NF-κB), sequestering NF-κB in the cytoplasm and preventing its pro-inflammatory transcriptional activity.
• Interleukin-10 (IL-10): an anti-inflammatory cytokine.

Transrepression is considered the more critical pathway for the anti-inflammatory effects. The ligand-bound GR monomer interacts directly with pro-inflammatory transcription factors such as NF-κB and Activator Protein-1 (AP-1), preventing them from binding to their respective response elements on DNA. This interaction suppresses the transcription of genes encoding numerous inflammatory mediators, including cytokines (e.g., IL-1, IL-2, IL-4, IL-5, IL-6, IL-13, TNF-α), chemokines, adhesion molecules (e.g., ICAM-1), and inducible enzymes like cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS).

Non-Genomic and Cellular Mechanisms

Rapid effects of fluticasone, occurring within minutes, are attributed to non-genomic mechanisms. These may involve:

• Membrane-bound GR interactions leading to secondary messenger modulation.
• Inhibition of phospholipase C and subsequent reduction in inositol triphosphate (IP₃) and diacylglycerol (DAG), affecting calcium mobilization and protein kinase C activation.
• Direct effects on mitochondrial membranes, influencing apoptosis of inflammatory cells like eosinophils and T-lymphocytes.

At the cellular level, fluticasone induces a reduction in the number and activity of key inflammatory cells in target tissues. In the airways, this includes decreased eosinophils, mast cells, T-helper 2 lymphocytes, and dendritic cells. It also inhibits microvascular leakage and mucus hypersecretion, while potentially enhancing the responsiveness of β₂-adrenergic receptors in bronchial smooth muscle.

Pharmacokinetics

The pharmacokinetic profile of fluticasone is characterized by low systemic bioavailability following administration by intended routes, extensive tissue distribution, rapid and extensive metabolism, and primarily fecal excretion. These properties are central to its localized therapeutic action and relatively favorable systemic safety profile when used at recommended doses.

Absorption

Absorption is highly dependent on the route of administration and the specific ester formulation.

• Inhalation (Oral/Respiratory): For inhaled fluticasone propionate via metered-dose or dry powder inhalers, the majority of the dose (approximately 80-90%) is deposited in the oropharynx and swallowed. The fraction that reaches the lungs (typically 10-20% of the metered dose) is absorbed systemically from the alveolar space. The oral bioavailability of the swallowed portion is negligible (<1%) due to extensive first-pass metabolism in the liver. Consequently, the systemic bioavailability of inhaled fluticasone is largely equivalent to the lung-absorbed fraction.
• Intranasal: Systemic absorption from nasal mucosa is minimal, with bioavailability estimated at <2%. Most of the dose is either locally active or swallowed, with the swallowed portion undergoing extensive first-pass metabolism.
• Topical (Cutaneous): Percutaneous absorption is generally low but can be increased by factors such as application to inflamed skin, use on large body surface areas, use under occlusive dressings, or application to thin-skinned areas. Even with these factors, systemic absorption from topical use is typically low.
• Oral Administration: Orally administered fluticasone has very low bioavailability (<1%) due to near-complete pre-systemic extraction by cytochrome P450 3A4 (CYP3A4) in the gut wall and liver.

Distribution

Following systemic absorption, fluticasone is widely distributed into tissues. Its high lipophilicity contributes to a large volume of distribution, estimated to be approximately 4.2 L/kg for fluticasone propionate. The drug is extensively bound to plasma proteins, primarily albumin, with a binding percentage exceeding 90%. This high protein binding limits the amount of free, pharmacologically active drug in circulation and may contribute to its low systemic activity. Distribution into the central nervous system is likely minimal.

Metabolism

Fluticasone undergoes rapid and extensive hepatic metabolism, which is the primary determinant of its low systemic exposure. The metabolism is mediated almost exclusively by the cytochrome P450 enzyme CYP3A4. The primary metabolic pathway involves hydrolysis of the 17α-carbothioate ester to form the inactive 17β-carboxylic acid metabolite. Further oxidative metabolism may occur. Fluticasone furoate is also metabolized by CYP3A4 via hydrolysis of the furoate ester. No active circulating metabolites have been identified; all are considered pharmacologically inert. This characteristic makes fluticasone a “soft drug,” designed to be active locally and rapidly inactivated systemically.

Excretion

Elimination occurs predominantly via the fecal route. Following intravenous administration, approximately 75-100% of the dose is recovered in feces as parent drug and metabolites, with less than 5% excreted in urine. The terminal elimination half-life (t_1/2) of fluticasone propionate after intravenous administration is approximately 7-8 hours. However, the effective half-life relevant to clinical effect is governed by the rate of absorption from the site of administration (e.g., lung, nasal mucosa) and is often longer. For instance, the context-sensitive half-life from lung tissue may contribute to a once- or twice-daily dosing regimen. Total systemic clearance is high, primarily reflecting hepatic metabolic capacity.

Pharmacokinetic Parameters and Dosing Considerations

The relationship between dose and systemic exposure (AUC, C_max) is generally linear within the therapeutic range for inhaled and intranasal routes. However, saturation of first-pass metabolism may theoretically occur at very high doses, leading to a disproportionate increase in systemic bioavailability. Dosing considerations must account for the route-specific delivery and the patient’s ability to use the delivery device correctly, as improper technique drastically reduces lung deposition and efficacy. For all routes, the therapeutic strategy is to maximize local concentration at the target tissue while minimizing systemic absorption and subsequent adverse effects.

Therapeutic Uses/Clinical Applications

Fluticasone is employed across a spectrum of inflammatory conditions, with its application defined by the formulation and route of administration. Its use is typically as a maintenance controller therapy rather than for acute symptom relief.

Approved Indications

1. Asthma: Fluticasone propionate inhalers are indicated for the prophylactic management of persistent asthma in adults and children (typically aged 4 years and above, depending on formulation). It reduces airway inflammation, decreases airway hyperresponsiveness, and improves lung function (FEV₁), leading to fewer exacerbations and reduced use of rescue bronchodilators. It is available as a monotherapy inhaler and in fixed-dose combination inhalers with long-acting beta-agonists (LABAs) like salmeterol (e.g., Advair/Seretide) or vilanterol (e.g., Breo Ellipta with fluticasone furoate).

2. Allergic Rhinitis: Fluticasone propionate and furoate nasal sprays are first-line treatments for moderate-to-severe seasonal and perennial allergic rhinitis. They effectively reduce nasal congestion, rhinorrhea, sneezing, and nasal itching.

3. Chronic Obstructive Pulmonary Disease (COPD): In patients with severe COPD (FEV₁ < 50% predicted) and a history of frequent exacerbations, inhaled fluticasone propionate in combination with a LABA is indicated to reduce the frequency of exacerbations. Its role is more limited than in asthma due to a different inflammatory pathology and a higher risk of side effects like pneumonia in this population.

4. Atopic Dermatitis and Other Inflammatory Dermatoses: Topical fluticasone propionate cream or ointment is used for the relief of inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses, including atopic dermatitis, psoriasis, and contact dermatitis. It is classified as a medium- to high-potency topical corticosteroid depending on concentration and vehicle.

5. Eosinophilic Esophagitis: Off-label, viscous topical fluticasone (swallowed from a metered-dose inhaler mixed with a carrier) is a common treatment to reduce esophageal eosinophilia and symptoms.

Off-Label Uses

Common off-label applications include the treatment of croup in children (nebulized), prevention of nasal polyposis recurrence post-surgery, and management of some forms of interstitial lung disease characterized by inflammation. Its use in eosinophilic esophagitis, as mentioned, is widespread but formally off-label in many jurisdictions.

Adverse Effects

The adverse effect profile of fluticasone is dichotomized into local effects, resulting from direct contact of the medication with application sites, and systemic effects, which occur due to absorption into the circulation. The risk of systemic effects is generally low with standard doses but increases with higher doses, prolonged use, and factors enhancing systemic absorption.

Common Local Adverse Effects

Inhaled Formulations:

• Oropharyngeal candidiasis (thrush).
• Dysphonia (hoarseness).
• Pharyngeal irritation and cough (sometimes due to the propellant or powder).

Intranasal Formulations:

• Epistaxis (nosebleeds).
• Nasal dryness, burning, or irritation.
• Headache.
• Rarely, nasal septal perforation (with improper directed spray).

Topical Formulations:

• Skin atrophy, telangiectasia, striae (especially with prolonged use or under occlusion).
• Burning, itching, or dryness at the application site.
• Contact dermatitis (rare).

Serious and Systemic Adverse Reactions

While uncommon at recommended doses, systemic absorption can lead to effects typical of systemic corticosteroid therapy. The risk is dose-dependent.

• Adrenal Suppression: Potentially the most serious systemic effect. Chronic high-dose inhaled or topical therapy can suppress the hypothalamic-pituitary-adrenal (HPA) axis, leading to reduced cortisol secretion. This may result in adrenal insufficiency, particularly during periods of physiological stress (e.g., surgery, infection, trauma). Symptoms can include fatigue, weakness, nausea, hypotension, and hypoglycemia.
• Ophthalmic Effects: Increased intraocular pressure, glaucoma, and posterior subcapsular cataracts have been associated with long-term, high-dose inhaled corticosteroid use.
• Effects on Bone Metabolism: Long-term use may contribute to reduced bone mineral density (osteoporosis) and increased fracture risk, potentially due to effects on calcium absorption and osteoblast/osteoclast activity.
• Growth Retardation in Children: A reduction in growth velocity may be observed in children receiving chronic inhaled corticosteroid therapy. This effect appears to be dose-related and may not correlate with final adult height, but monitoring of growth is essential.
• Metabolic Effects: Hyperglycemia, weight gain, and fluid retention can occur with significant systemic exposure.
• Psychiatric Effects: Anxiety, depression, irritability, and, very rarely, psychotic reactions have been reported.
• Increased Risk of Infections: There is an increased risk of lower respiratory tract infections, including pneumonia, in patients with COPD treated with inhaled corticosteroids. Local immunosuppression may also predispose to oropharyngeal candidiasis.

No specific black box warnings exist for fluticasone monotherapy. However, combination products containing a LABA carry a black box warning regarding an increased risk of asthma-related death, emphasizing that LABAs should never be used as monotherapy for asthma but only in combination with an asthma controller medication like fluticasone.

Drug Interactions

Significant drug interactions with fluticasone primarily involve agents that alter its metabolism via CYP3A4, potentially leading to increased systemic exposure and toxicity.

Major Drug-Drug Interactions

Potent CYP3A4 Inhibitors: Concomitant use with strong inhibitors of CYP3A4 significantly increases fluticasone plasma concentrations by reducing its first-pass and systemic metabolism. This elevates the risk of systemic corticosteroid adverse effects, including Cushing’s syndrome and adrenal suppression. Key inhibitors include:

• Antifungals: ketoconazole, itraconazole, posaconazole, voriconazole.
• Antivirals: ritonavir, cobicistat, indinavir, nelfinavir (protease inhibitors).
• Others: clarithromycin, nefazodone, grapefruit juice (in large quantities).

Concomitant use is generally not recommended, or the dose of fluticasone should be significantly reduced with close monitoring. For instance, co-administration with ritonavir is contraindicated for most fluticasone formulations due to profound increases in fluticasone levels.

Other Corticosteroids: Concurrent use of other systemic, inhaled, or potent topical corticosteroids results in additive systemic effects and increased risk of HPA axis suppression.

Vaccines: The use of live attenuated vaccines (e.g., MMR, varicella, nasal influenza) is generally contraindicated in patients on immunosuppressive doses of corticosteroids due to the risk of vaccine-induced disease. The threshold for this risk is typically defined as a systemic corticosteroid equivalent of ≥20 mg of prednisone daily for ≥2 weeks. Most patients on standard-dose inhaled fluticasone do not reach this level of immunosuppression, but assessment is required on a case-by-case basis.

Contraindications

Fluticasone is contraindicated in patients with a history of hypersensitivity to fluticasone or any component of its formulation. Primary treatment of status asthmaticus or other acute episodes requiring intensive measures is a contraindication, as inhaled corticosteroids are not bronchodilators. As noted, co-administration with potent CYP3A4 inhibitors like ritonavir is contraindicated for most routes due to the high risk of severe systemic corticosteroid toxicity.

Special Considerations

The use of fluticasone requires careful evaluation in specific patient populations where pharmacokinetics, pharmacodynamics, or risk-benefit ratios may be altered.

Pregnancy and Lactation

Pregnancy (Category C per prior FDA classification): Animal reproduction studies have shown evidence of fetal harm (teratogenicity, embryocidal effects) at doses producing systemic exposure. There are no adequate and well-controlled studies in pregnant women. Inhaled corticosteroids, including fluticasone, are generally considered the preferred treatment for controlling asthma during pregnancy, as uncontrolled asthma poses a greater risk to the fetus (hypoxia) than the medication itself. The lowest effective dose should be used.

Lactation: It is unknown whether fluticasone is excreted in human milk. However, given its low oral bioavailability, the amount ingested by a nursing infant is likely to be negligible and not clinically significant. The benefits of breastfeeding generally outweigh the theoretical risk. Caution is advised, and monitoring the infant for signs of corticosteroid effects is prudent if the mother is on high-dose therapy.

Pediatric and Geriatric Considerations

Pediatrics: Safety and efficacy for inhaled fluticasone propionate have been established in children as young as 4 years for asthma and 2 years for allergic rhinitis (specific formulations). Monitoring of growth velocity is mandatory. Linear growth may be reduced; however, the effect on final adult height remains uncertain and must be balanced against the risks of uncontrolled respiratory disease. The use of spacer devices with metered-dose inhalers is strongly recommended to improve lung deposition and reduce oropharyngeal side effects.

Geriatrics: No major differences in safety or efficacy are reported in elderly patients. However, increased sensitivity to some systemic effects, such as osteoporosis, hypertension, or hyperglycemia, may be present due to age-related comorbidities or polypharmacy. Renal or hepatic impairment does not typically necessitate dose adjustment for inhaled forms due to local action and extensive metabolism, but vigilance for systemic effects is warranted.

Hepatic and Renal Impairment

Hepatic Impairment: Fluticasone is extensively metabolized by the liver. In patients with severe hepatic impairment (e.g., Child-Pugh Class C), the clearance of systemically absorbed drug may be reduced, leading to increased plasma levels and a higher risk of systemic adverse effects. Dose reduction and careful monitoring for corticosteroid side effects may be necessary, particularly with higher inhaled doses or topical use on large areas.

Renal Impairment: Formal pharmacokinetic studies in renal impairment are lacking. However, as renal excretion is a minor elimination pathway (<5%), no dose adjustment is anticipated for inhaled or intranasal formulations. Caution should be exercised in severe renal impairment due to the potential for fluid retention and hypertension from systemic exposure.

Summary/Key Points

Fluticasone is a potent, synthetic trifluorinated glucocorticoid with high receptor affinity and a pharmacokinetic profile optimized for local therapeutic action.

Clinical Pearls

• Fluticasone’s therapeutic action is mediated via genomic (transactivation/transrepression) and non-genomic pathways following binding to the intracellular glucocorticoid receptor, leading to broad anti-inflammatory and immunosuppressive effects.
• Systemic bioavailability is very low for inhaled, intranasal, and topical routes due to extensive first-pass metabolism by hepatic CYP3A4, classifying it as a “soft drug.” This underpins its favorable safety profile at standard doses.
• It is a first-line maintenance therapy for persistent asthma, allergic rhinitis, and certain dermatoses. In COPD, its use is reserved for severe cases with frequent exacerbations.
• The most common adverse effects are local (oropharyngeal candidiasis, dysphonia, nasal irritation). Systemic effects (adrenal suppression, osteoporosis, growth retardation) are dose-dependent and more likely with high-dose or prolonged use.
• Concomitant use with potent CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) is a major interaction that can lead to toxic systemic corticosteroid levels and is often contraindicated.
• Special attention is required in pediatric populations for growth monitoring, in all patients for proper inhaler technique to ensure efficacy, and during periods of physiological stress to assess for adrenal insufficiency.

The effective and safe use of fluticasone hinges on employing the lowest dose that achieves disease control, utilizing proper administration technique to maximize local delivery, and maintaining vigilance for signs of both local intolerance and systemic absorption.

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