Rhinocort - Pharmacology

- What is the mechanism of action of Rhinocort® in allergic rhinitis?
  Intranasal corticosteroids, such as budesonide, the active ingredient in Rhinocort®, have a profound anti-inflammatory action, which can block both early- and late-phase allergic responses. This anti-inflammatory action can be studied at different functional levels in the nose and nasal mucosa. Several facets of the inflammatory response are affected by treatment with intranasal corticosteroids (reviewed by Nelson 1999). Intranasal corticosteroids reduce the number of eosinophils by inhibiting their recruitment and promoting apoptosis, and may also reduce levels of eosinophil-derived inflammatory mediators, such as the eosinophil cationic protein. Basophils and mast cells are also involved in late-phase allergic reaction, and increasing numbers of mast cells are associated with the less intense, more prolonged allergen exposure seen in allergic rhinitis. Intranasal corticosteroids can inhibit both the influx and activation of basophils, in addition to preventing an increase in mast cell numbers and reducing the levels of histamine. Other important inflammatory mechanisms affected by intranasal corticosteroids include plasma exudation, adhesion molecule expression, nasal hyper-responsiveness and the release of various chemokines and pro-inflammatory cytokines from epithelial cells.
  Figure 1. Anti-inflammatory effects of once-daily Rhinocort® Aqua™ and placebo in 478 patients with perennial allergic rhinitis over a 6-week period (Meltzer 1998)
  
  Many studies have demonstrated that Rhinocort® has a potent anti-inflammatory action with prolonged binding to mucosal tissue (Brattsand 2002). One such study has shown that Rhinocort® reduces cytologic markers of allergic inflammation compared with placebo (Figure 1; Meltzer 1998), and another recent study by Mastruzzo and colleagues (2003) suggested that treatment with Rhinocort® promotes epithelial restitution of nasal mucosa, in a similar way to that seen with inhaled budesonide in the lower airways of asthma patients (Laitinen et al 1992).
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- How fast is the onset of action of Rhinocort®?
  If possible, intranasal steroids should be given before the nasal mucosa is exposed to allergens. However, it is not always possible for patients to foresee allergen exposure. A study by Andersson et al (1988) demonstrated that pre-treatment with intranasal budesonide 200 µg twice daily 48 h before allergen challenge can effectively moderate the immediate inflammatory response, measured by combined symptom scores. However, the other treatment regimens in this study (budesonide treatment 12 or 2 h before or 2 h after allergen challenge) did not produce similar, significant effects. However, Rhinocort® was more effective than placebo when given 48, 12 or 2 h before the allergen challenge in reducing nasal hyper-reactivity, an indicator of continued mucosal inflammation. Notably, a significant (p<0.05) benefit was observed with Rhinocort® when given 2 h after allergen challenge (Figure 2), underscoring that Rhinocort® induces clinically relevant effects very rapidly after application.
  Figure 2. Time course of Rhinocort® 400 µg/day on nasal hyper-reactivity following allergen challenge (Andersson et al 1988)
  
  The rapid onset of effect of Rhinocort® has also been shown in clinical studies. Day et al (2000) demonstrated the onset of action of Rhinocort® Aqua™ to be 7 h, as measured by combined nasal symptom scores (Figure 3). In addition, runny nose and peak nasal inspiratory flow showed improvement 3 h after administration of Rhinocort® Aqua™ in this study (Day et al 2000).
  Figure 3. Nasal symptom scores after ragweed pollen exposure in 217 patients with seasonal allergic rhinitis following treatment with Rhinocort® Aqua™ 64 or 256 µg compared with placebo (Day et al 2000)
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- How effective is Rhinocort®?
  Rhinocort® is effective at very low doses. Although 64 µg is currently the lowest recommended daily dose for maintenance treatment, significant effects have been documented at once-daily doses as low as 32 µg/day (Figure 4; Meltzer 1998). Some patients require higher doses and the maximum approved label dose for adults is 256 µg.
  Figure 4. Nasal symptom scores in 478 patients with perennial allergic rhinitis following once-daily treatment with Rhinocort® Aqua™ (Meltzer 1998)
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- What factors influence the effects of Rhinocort® and other intranasal steroids?
  Several factors influence the local anti-inflammatory effects of intranasal steroids, including receptor affinity, as well as absorption and retention of corticosteroids in the nasal mucosa (Brattsand & Ingelf 1993). Many factors that are important for the systemic effects of intranasal corticosteroids are the same as those above, but also include systemic absorption from nasal mucosa, oral bioavailability, receptor affinity and retention in body tissues. Two basic features of intranasal corticosteroids influence most of the above factors, namely lipophilicity (or water solubility) and intracellular esterification, which are discussed in more detail below.
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- How does lipophilicity affect the efficacy of intranasal corticosteroids?
  High lipophilicity (low water solubility) is associated with high receptor affinity, high non-specific binding to airway tissues and low dissolution in mucosal fluids. However, low water solubility means that drugs may be cleared by ciliary activity before they can dissolve and be absorbed, leading to less absorption into mucosal tissues. Nasal ciliary clearance of saccharin was estimated to be 9 min in healthy volunteers and 10–12 min in patients with rhinitis (Schuhl 1995).
  
  Intranasal corticosteroids differ greatly in lipophilicity and water solubility (Table 1). Budesonide has comparatively high water solubility and dissolves readily in mucosal fluids. This means that it is not removed as extensively as more lipophilic corticosteroids by nasal mucociliary clearance.
  Table 1. Lipophilicity and water solubility of intranasal steroids; dissolution time of steroids in human bronchial fluid (Miller-Larsson et al 2003; Edsbäcker 2002)
  
  Corticosteroids that are more water soluble show fast and more complete absorption into airway tissues. In systemic compartments, however, greater water solubility generally results in a lower volume of distribution, less accumulation and more rapid elimination (Edsbäcker 2002). The high water solubility of budesonide makes Rhinocort® accessible to the nasal mucosa. The systemic bioavailability of Rhinocort® Aqua™ is 31.4% based on the delivered dose-to-subject (Thorsson et al 1999), most of which is absorbed through the nasal mucosa. However, the systemic bioavailability of the highly lipophilic intranasally administrated mometasone and fluticasone is low, with both <1% (Daley-Yates & Baker 2001; Derendorf et al 2002), which may be explained in terms of the much lower solubility of these corticosteroids in airway fluids, leading to extensive mucociliary elimination rather than nasal uptake. Thus, budesonide may provide an optimal balance between hydrophilic properties, ensuring solubility in nasal mucus, and lipophilic properties leading to substantial mucosal uptake and high nasal exposure to glucocorticosteroid receptors (Brattsand & Ingelf 1993).
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- What role does in vivo esterification have in the efficacy of Rhinocort®?
  The prolonged duration of action of budesonide can be attributed to in vivo fatty acid esterification (reviewed by Edsbäcker & Brattsand 2002), a feature of intranasal corticosteroids that can affect local and systemic effects (Figure 5). After absorption into the cell, budesonide can undergo reversible esterification with long-chain fatty acids, providing a local, inactive depot from which active budesonide is gradually released. Esterification occurs to a greater extent in the airways than in tissues, such as skeletal muscles and blood (Edsbäcker & Brattsand 2002), which results in improved local effects and reduced systemic effects. The prolonged residence time may be one of the key contributors to the high efficacy of once-daily dosing with low doses of Rhinocort®.
  Figure 5. In vivo esterification of budesonide (Miller-Larsson et al 1998; Weislander et al 1998)
  
  A recent study in human nasal mucosa (Petersen et al 2001) investigated tissue concentrations of single doses of Rhinocort® Aqua™ 256 µg and fluticasone propionate 200 µg, at various time points before and after administration. The study demonstrated that 2 h post-administration, the ratio of unesterified Rhinocort® Aqua™/fluticasone propionate in nasal biopsies – corrected for differences in given doses – was 3.5 (CI: 0.9–13.7; p=0.07), increasing to 13.7 (CI: 4.7–40.5; p<0.001) after 6 h. When both esterified and unesterified budesonide were measured, the ratio increased to 5.6 and 21.0 at 2 h and 6 h, respectively. This indicates that Rhinocort® Aqua™ provides higher mucosal concentrations of glucocorticosteroid than fluticasone propionate, partly as a result of better absorption into the nasal tissue, but also as a consequence of its prolonged retention.
  Find out more about budesonide esterification.
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- How important is receptor affinity in the efficacy of Rhinocort®?
  Receptor affinity is an important pre-requisite for the local anti-inflammatory effects of Rhinocort® in the airways. However, it is not the only factor in determining anti-inflammatory potency, as local kinetic factors, among others, are equally important. Several studies (e.g. reviewed by Edsbäcker & Szefler 1997; Brattsand 2002) have looked at relative receptor affinity for corticosteroids. Mometasone furoate and fluticasone propionate have the strongest receptor affinities (2.8 and 2.3, respectively), followed by budesonide (reference value 1.0) and the weakest affinities are seen with flunisolide, triamcinolone acetonide and beclomethasone dipropionate (0.2–0.5) (Brattsand 2002).
  
  In spite of their higher receptor affinities, fluticasone propionate and mometasone furoate are no more potent than Rhinocort® for the treatment of allergic rhinitis. Indeed, high receptor affinity is not the only determinant of potent local anti-inflammatory effects, as assessed by vasoconstriction or skin blanching tests. Budesonide has a topical potency similar to that of fluticasone propionate in the human skin vasoconstriction test (Figure 6; Andersson et al 1994) and around twice the potency of beclomethasone dipropionate (Johansson et al 1982).
  Figure 6. Topical potency of budesonide and fluticasone propionate in human skin vasoconstriction tests in 19 subjects (Andersson et al 1994)
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- What features of budesonide contribute to its low systemic effects?
  As mentioned above, the high water solubility of Rhinocort® Aqua™ results in a relatively high systemic availability of 31.4% (Thorsson et al 1999). However, the systemic half-life of budesonide is relatively short (2.8–4.5 h) (Ryrfeldt et al 1982; Thorsson et al 1999; 2001) compared with fluticasone propionate (7.8–12.5 h) (Mackie et al 1995; Thorsson et al 2001). Thus, budesonide is more rapidly eliminated showing little distribution into peripheral tissues compared with fluticasone propionate (Thorsson et al 2001). Systemic effects of intranasal steroids have been documented for both lipophilic and more water-soluble hydrophilic steroids (Lipworth & Jackson 2000); these data suggest that low systemic bioavailability does not guarantee an absence of adverse systemic effects.
  
  Another feature of budesonide that contributes to the low level of systemic effects is its metabolism (Figure 7) and elimination. There is no metabolic inactivation of budesonide in the nose, but it is rapidly metabolised in the liver (Edsbäcker et al 1985). In addition, the metabolites of budesonide are virtually inactive biologically.
  Figure 7. Metabolism of budesonide (Edsbäcker et al 1985)
  
  The systemic effects of Rhinocort® have been extensively investigated in both adults and children. For more information, please click here.
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- References
  Andersson M, Andersson P, Pipkorn U. Topical glucocorticosteroids and allergen-induced increase in nasal reactivity: relationship between treatment time and inhibitory effect. J Allergy Clin Immunol 1988; 82: 1019–1026.
  
  Andersson N, Klint S, Randwall G, et al. Equipotency of budesonide and fluticasone proprionate in the vasoconstriction assay. Crit Exp Allergy 1994; 24: 182, P67.
  
  Brattsand R, Ingelf J. Pharmacodynamic and pharmacokinetic basis for inhaled glucocorticosteroid (GCS) therapy in allergic rhinitis. In: Melillo G, O'Byrne PM, Marone G, eds. Respiratory allergy: advances in clinical immunology and pulmonary medicine. Amsterdam: Elsevier Science Publishers BV 1993: 129–136. Brattsand
  
  Brattsand R. Drug development of inhaled steroids. A pharmacologist's view based on experiences from the budesonide project. In: Schleimer RP, O'Byrne PMO, Szefler SJ, Brattsand R, eds. Inhaled steroids in asthma: optimizing effects in the airways. New York: Marcel Dekker, 2002: 3–33.
  
  Daley-Yates PT, Baker RC. Systemic bioavailability of fluticasone propionate administered as nasal drops and aqueous nasal spray formulations. Br J Clin Pharmacol 2001; 51: 103–105.
  
  Day JH, Briscoe MP, Rafeiro E, Ellis AK, Pettersson E, Åkerlund A. Onset of action of intranasal budesonide (Rhinocort® Aqua™) in seasonal allergic rhinitis studied in a controlled exposure model. J Allergy Clin Immunol 2000; 105: 489–494.
  
  Derendorf H, Daley-Yates PT, Pierre LN, Efthimiou J. Bioavailability and metabolism of mometasone furoate: pharmacology versus methodology. J Clin Pharmacol 2002; 42: 383–387.
  
  Edsbäcker S, Andersson KE, Ryrfeldt A. Nasal bioavailability and systemic effects of the glucocorticoid budesonide in man. Eur J Clin Pharmacol 1985; 29: 477–481.
  
  Edsbäcker S, Szefler SJ. Glucocorticoid pharmacokinetics: Principles and clinical applications. In: Schleimer RP, Busse WW, O'Byrne PM, eds. Inhaled glucocorticoids in asthma: mechanisms and clinical actions. Marcel Dekker, New York, 1997: 381–445.
  
  Edsbäcker S. Uptake, retention, and biotransformation of corticosteroids in the lung and airways. In: Schleimer RP, O'Byrne PMO, Szefler SJ, Brattsand R, editor(s). Inhaled steroids in asthma: optimizing effects in the airways. New York: Marcel Dekker, 2002: 213–246.
  
  Edsbäcker S, Brattsand R. Budesonide fatty-acid esterification: a novel mechanism prolonging binding to airway tissue. Review of available data. Ann Allergy Asthma Immunol 2002; 88: 609–616.
  
  Johansson S-Å, Andersson KE, Brattsand R, Gruvstad E, Hedner P. Topical and systemic glucocorticoid potencies of budesonide and beclomethasone dipropionate in man. Eur J Clin Pharmacol 1982; 22: 523–529.
  
  Laitinen LA, Laitinen A, Haahtela T. A comparative study of the effects of an inhaled corticosteroid, budesonide, and a beta 2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized double-blind, parallel-group controlled trial. J Allergy Clin Immunol 1992; 90: 32–42.
  
  Lipworth BJ, Jackson CM. Safety of inhaled and intranasal corticosteroids: lessons for the new millennium. Drug Saf 2000; 23: 11–33.
  
  Mackie AE, Ventresca GP, Moss JA, Bye A. Pharmacokinetics of intravenous fluticasone propionate in healthy subjects. Br Clin J Pharmacol 1995; 40: 198P.
  
  Mastruzzo C, Greco LR, Nakano K, et al. Impact of intranasal budesonide on immune inflammatory responses and epithelial remodeling in chronic upper airway inflammation. J Allergy Clin Immunol 2003; 112: 37–44.
  
  Meltzer EO. Clinical and antiinflammatory effects of intranasal budesonide aqueous pump spray in the treatment of perennial allergic rhinitis. Ann Allergy Asthma Immunol 1998; 81: 128–134.
  
  Miller-Larsson A, Mattsson H, Hjertberg E, Dahlbäck M, Tunek A, Brattsand R. Reversible fatty acid conjugation of budesonide. Novel mechanism for prolonged retention of topically applied steroid in airway tissue. Drug Metab Dispos 1998; 26: 623–630.
  
  Miller-Larsson A, Axelsson B-O, Brattsand R, Edsbäcker S, Ingelf J. Relative lipophilicity of budesonide, fluticasone propionate, mometasone furoate, and ciclesonide. Preference of variable lipophilicity in airways versus systemic compartment. Am J Respir Crit Care Med 2003; 167: A773.
  
  Nelson HS. Mechanisms of intranasal steroids in the management of upper respiratory allergic diseases. J Allergy Clin Immunol 1999; 104: S138–143.
  
  Petersen H, Kullberg A, Edsbäcker S, Greiff L. Nasal retention of budesonide and fluticasone in man: Formation of airway mucosal budesonide-esters in vivo. Br J Clin Pharmacol 2001; 51: 159–163.
  
  Ryrfeldt Å, Andersson P, Edsbäcker S, Tönnesson M, Davies D, Pauwels R. Pharmacokinetics and metabolism of budesonide, a selective glucocorticoid. Eur J Respir Dis Suppl 1982; 122: 86–95.
  
  Schuhl JF. Nasal mucociliary clearance in perennial rhinitis. J Investig Allergol Clin Immunol 1995; 5: 333–336.
  
  Thorsson L, Borgå O, Edsbäcker S. Systemic availability of budesonide after nasal administration of three different formulations: pressurized aerosol, aqueous pump spray, and powder. Br J Clin Pharmacol 1999; 47: 619–624.
  
  Thorsson L, Edsbäcker S, Källén A, Löfdahl CG. Pharmacokinetics and systemic activity of fluticasone via Diskus® and pMDI, and of budesonide via Turbuhaler®. Br J Clin Pharmacol 2001; 52: 529–538.
  
  Wieslander E, Delander EL, Järkelid L, Hjertberg E, Tunek A, Brattsand R. Pharmacologic importance of the reversible fatty acid conjugation of budesonide studied in a rat cell line in vitro. Am J Respir Cell Mol Biol 1998; 19: 477–484.
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