Untitled

Intranasal Corticosteroid
Prapaporn Pornsuriyasak, M.D.*, Paraya Assanasen, M.D.**
*Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, **Department of Otorhinolaryngology,
Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
Siriraj Med J 2008;60:90-95
E-journal: http://www.sirirajmedj.com
Rapidly metabolized intranasal corticosteroid (INS), elastase, and plasminogen activator. Furthermore, lympho-
with high topical potency and low systemic bioacti- cyte proliferation and delayed type hypersensitivity are vity, was introduced for perennial rhinitis in 1974 also inhibited by corticosteroids in vitro.
and found to be as effective as corticosteroids admini- The role of corticosteroids in the management of stered systemically.These second-generation INSs allergic rhinitis is influenced by their effect on the inflam- include beclomethasone dipropionate (BDP), budesonide matory cells and chemical mediators that are released in (BUD), flunisolide (FLU), fluticasone propionate (FP), the early- and late-phase allergic responses. The early- triamcinolone acetonide (TAA), mometasone furoate (MF), phase allergic response is characterized by an initial period and fluticasone furoate (FF). Although these INSs represent of sensitization to a specific allergen. Subsequent exposure improvements relative to earlier topical corticos-teroids, to the inciting allergen causes cross-linking of IgE antibodies they do vary from one to the other in potency and systemic located on the surface of mast cells residing in the nasal bioactivity. For example, MF is equal in potency to FP mucosa, which results in mast cell degranulation and the and is considered to be the most potent INS to date and release of various chemical mediators, such as histamine.
has almost undetectable systemic availability. FF, the most These mediators cause the infiltration of inflammatory recently introduced INS, is a novel, enhanced-affinity cells in the peripheral blood to the site of exposure. The glucocorticoid with potent anti-inflammatory activity ensuing cascade of events is termed the late-phase allergic administered in a unique side-actuated device. Among the response and is characterized by hyper-reactivity of the therapeutic indications for INS are seasonal and perennial allergic rhinitis, nonallergic rhinitis, acute and chronicrhinosinusitis, rhinitis medicamentosa, and nasal poly- Pharmacokinetics
Pharmacokinetics are the processes that ultimately determine the concentration of the drug at the receptor Mechanism of action
site. The volume of distribution is the fluid volume required Corticosteroids are highly effective in mitigating to contain the entire drug at the same concentration existing inflammation. The ability to modulate the expression of in the blood and is a measure of relative tissue uptake.
various arms of the immune response has led to widespread Clearance is the rate of elimination by all routes relative use in various inflammatory states. Corticosteroids act to the concentration of drug in the blood and is a measure primarily by regulating protein synthesis. Whether adminis- of the elimination capacity. The half-life is the relation tered topically or systemically, the unbound steroid molecule between volume of distribution and clearance and is the enters the cytoplasm of corticosteroid-responsive tissues time it takes for the plasma concentration to be reduced by passively diffusing across the cell membrane. In the by 50%. Factors included in half-life are the time to reach cytoplasm, it binds to a glucocorticoid receptor forming a steady state and the decay rate from steady-state complex that undergoes a conformational change. In concentrations. Bioavailability is the amount of drug that addition, corticosteroids stabilize lysosomal membranes, reaches the systemic circulation. In the case of drugs that block the effect of migratory inhibitory factor, decrease are administered locally, such as the INS, the term systemic permeability, and inhibit pro-inflammatory cytokine availability is more appropriate. A reference formulation production, including that of interleukin (IL)-1, IL-2, the is used to calculate the extent of systemic availability.
IL-2 receptor, interferon (IFN)-α, tumor necrosis factor The term absolute systemic availability is used when (TNF), and various colony-stimulating factors (CSFs) such intravenous dosing is used as the standard. These kinetic as IL-3. Even in very low concentrations, corticosteroids properties are described as the absorption, distribution, can inhibit the synthesis of a variety of pro-inflammatory metabolism, and excretion properties of the drug. Although enzymes, including the macrophage products, collagenase, INS is applied topically, a significant portion can beabsorbed systemically. The goal of INS design is to achievea high ratio of topical to systemic activity because this Correspondence to: Paraya Assanasen increases the potential for desired therapeutic effects relative E-mail: paraya.assanasen@gmail.com to undesired systemic effects (therapeutic ratio).
90
Delivery device
TABLE 1. Systemic availability after intranasal corticosteroid
Delivery devices have evolved to meet specific requirements for efficacious and tolerable delivery of INS.
Systemic availability (%)
The Freon-propelled aerosols first used to deliver INS distributed the drug poorly. Metered-dose pump sprays were used to deliver FP solubilized in polyethylene glycol and propylene glycol, although this approach caused nasal stinging. Aqueous pump sprays and pure powder formula-tions are now the more common methods of deliverybecause the intranasal distribution of drug is more favorable poorly absorbed into the systemic circulation because of than with a pressurized aerosol. Delivery of aqueous their lipophilicity. When the area under the concentration- suspensions by pump spray provides better drug deposition time curve after intranasal administration is compared with at the ciliated mucous membrane rather than the nonciliated that for intravenous administration, the absolute systemic anterior when compared with pressurized aerosol. Studies availability can be calculated4 (Table 1). For both FP and with TAA indicate greater systemic levels when administered MF, the systemic availability is very low. It is important in an aqueous rather than aerosol formulation for allergic to remember that, in many cases, the plasma concentration rhinitis.1 Actual quantitative comparisons of drug delivered of the drug was below the limit of quantification of the by different devices are complicated by the large amounts of drug deposited in the nozzle of pressurized aerosols.
However, there appears to be approximately the same Distribution
degree of symptom reduction by pressurized aerosols and Once in the systemic circulation, many corticosteroids aqueous pump sprays.2 After intranasal administration, there are highly bound by plasma albumin. The degree of plasma is nasociliary clearance of the drug into the throat.
protein binding for several corticosteroids has been Approximately 80% of the drug is available for absorption determined, including TAA (71%), FLU (80%), BDP (87%), at the nasal mucosa. Significant amounts of drug (10% to BUD (88%), FP (90%), and MF (>90%).5 Binding to 20%) remained in the target areas of the frontal cavity plasma proteins, primarily albumin, is generally greater with the more lipophilic corticosteroids. The volume ofdistribution is a classic pharmacokinetic parameter derived Absorption
from intravenous drug administration. It reflects the tissue There are two aspects of absorption regarding the distribution of the drug, with higher amounts indicating INS. One is topical absorption at the target site (the nose) greater amounts of drug either protein bound or in peripheral that determines therapeutic efficacy and the other is systemic tissue outside of the systemic circulation. As the lipophilicity absorption (Fig 1). Systemic absorption either occurs from of a corticosteroid increases, so does the volume of distribu- the fraction of INS swallowed and subsequently absorbed through the gastrointestinal tract or from the fractionabsorbed into the blood at the nasal mucosa. The amount Metabolism
of drug reaching target tissues and exerting a therapeutic BDP is a prodrug metabolized by many tissues, effect relative to the amount reaching the systemic circulation including the nose, into the more active metabolite, beclome- is a measure of safety for topically applied drugs, such as thasone monopropionate (BMP). Compared with a corticos- teroid receptor affinity of 1 for dexamethasone, the relative Some corticosteroids (e.g. BUD) are well absorbed binding affinity of BDP is 0.53, whereas that of the through the nasal mucosa directly into the systemic metabolite, BMP, is almost 25-fold greater.5 In a study circulation. In contrast, FP and MF are believed to be that compared the relative binding affinities of MF, FP,BUD, and TAA with dexamethasone (dexamethasonebinding affinity was defined as 100), all of the corticosteroidshad greater binding affinity than did dexamethasone. MFshowed the highest affinity for the corticosteroid receptorwith a relative binding affinity, followed by FP, BUD,and TAA.5 Systemic absorption of the swallowed portion of the dose may be inactivated by the first-pass effect (i.e., meta-bolism of the drug by the liver before entering the systemiccirculation). Rapid inactivation in the gastrointestinal tractminimizes systemic activity from the swallowed portion.
As a result, the oral bioavailability of FP is low becauseof poor absorption from the gastrointestinal tract and anextensive first-pass metabolism. MF also undergoes extensivemetabolism in the liver; consequently, systemic absorptionis extremely low (Fig 1).6 Elimination
Fig 1. The fate of intranasal corticosteroid. The amount of intranasal
Half-life is a function of clearance rate and volume.
corticosteroid that reaches the systemic circulation is the sum of After multiple doses of a drug, the plasma concentration the nasal and oral bioavailable fractions. The majority of the rises until it reaches a steady-state concentration. As a drug is swallowed, and systemic bioavailability is determined by general rule, it takes about 5 half-lives for a drug to reach the absorption from the gastrointestinal tract and the degree of its steady-state concentration during repeated dosing. The greatest half-life value currently reported is for FP. MF Siriraj Med J, Volume 60, Number 2, March-April 2008 91
has the second-greatest half-life, followed by BUD, FLU, rhinitis or when nasal congestion is a major component and may be an alternative to antihistamines. Clinical data Most pharmacokinetic analyses are performed on show that INS is highly effective in treating the symptoms healthy adults, and few data exist for children. When the of seasonal and perennial allergic rhinitis and non-allergic pharmacokinetic parameters of BUD were investigated in rhinitis and in preventing the onset of symptoms in such children (10 to 13 years of age), the half-life (1.5 hours) patients.12 INS is significantly more effective than leuko- was shorter and the weight-adjusted clearance was triene-receptor antagonists alone or leukotriene-receptor approximately 50% higher than those values previously antagonists combined with antihistamine in the treatment reported for adults.7 The authors postulate that this finding of grass pollen-induced rhinitis.13 In agreement with this may be the result of a higher hepatic blood flow in chil- finding, meta-analyses of 11 randomized controlled trials dren. Assuming that this suggestion is correct, more rapid show that leukotriene-receptor antagonists did not differ systemic elimination in children compared with adults from antihistamines and were less effective than INS in would be expected for other high clearance drugs, including reducing nasal symptoms and improving rhinoconjunctivitis quality of life of patients with allergic rhinitis.14 INS hasalso been shown to relieve ocular symptoms in patients Implications of pharmacodynamics
with allergic rhinoconjunctivitis.15 One likely mechanism Pharmacokinetic parameters such as systemic is probably the modulation of a naso-ocular neurogenic availability, clearance, and half-life can be used to assess reflex. Rhinitis therapy has been reported to improve the the relative systemic exposure to INS. The expectation subjective and objective measures of asthma. Data from a that low systemic exposure results in minimal adverse large managed care organization collected to analyze patients systemic effects has been examined by monitoring sensitive with asthma and concomitant rhinitis revealed patients systemic indexes, such as hypothalmic-pituitary-adrenal who used INS had a significantly lowered risk of both (HPA) axis effects. The second-generation INS causes asthma-related emergency department treatment visits and minimal systemic effects at recommended doses, with the hospitalizations.16 Nonsedating antihistamine use showed possible exception of FP, which showed significant no significant trend toward reduced visits in this study.
suppression of overnight urinary cortisol when compared Patients using both INS and second generation antihistamines with TAA and BDP. Reviews of intranasal administration had a further reduction over patients using INS alone.
of BDP, BUD, FLU, FP, and MF indicate no detectable However, the efficacy of INS on asthma outcomes in effects on measures of HPA axis function at recommended patients with rhinitis and asthma was recently evaluated doses, which is in agreement with rapid hepatic metabolism by meta-analyses of 14 randomized controlled trials.17 INS of these INSs.4 Therefore, the improved pharmacokinetic tended to improve asthma symptoms and forced expiratory parameters of the second-generation INS maximize efficacy volume in one second (FEV ), but the results did not Clinical use of INS
3) Rhinosinusitis
1) Allergic fungal sinusitis
Rhinosinusitis is defined as inflammation of the Atopy, continuous antigenic exposure, and inflammation paranasal mucous membranes, which leads to nasal all play roles in the perpetuation of the disease. The obstruction, poor drainage, and nasal infection. Classic mainstay of any combination treatment for allergic fungal symptoms of acute rhinosinusitis include nasal congestion, sinusitis remains surgical removal of the allergic mucin purulent discharge, fever, headache, facial pain, and and fungal elements along with creation of the sinuses.
post-nasal drip. Being an anti-inflammatory drug, INS As a single modality, functional endoscopic sinus surgery appears to be a rational approach to relieve nasal and results in a high rate of recurrence, and therefore medical possibly sinus ostial obstruction in rhinosinusitis. Study therapy is mandatory. This intervention can occur preopera- data indicate that concomitant administration of INS with tively in the form of corticosteroid administration to decrease antibiotic in the treatment of acute rhinosinusitis is more the intranasal polyposis and inflammation. In addition, effective, in terms of symptom relief, than antibiotic therapy corticosteroids should be administered postoperatively alone.18, 19 Moreover, in patients with acute, uncomplicated both topically and systemically, but the duration and rhinosinusitis, INS alone produced significant symptom optimal dosing remain unclear. Multiple studies8-11 have improvements versus amoxicillin and placebo, without shown improvement in symptoms as well as increased predisposing the patient to disease recurrence or bacterial time to recurrence and improvement in overall recurrence rates with corticosteroid administration, and the data seem Chronic rhinosinusitis (CRS) is broadly regarded as to support a longer period than a shorter one.
inflammation of the nose and paranasal sinuses lastinglonger than 12 weeks. Neutrophils, macrophages, lympho- 2) Allergic rhinitis
cytes, and eosinophils are among the characteristic inflamma- Allergic rhinitis is a hypersensitivity to inhaled allergens, tory cells infiltrating the sinus mucosa in CRS. Ultimately, with symptoms including congestion, rhinorrhea, sneezing, the inflammatory process leads to fibrosis, thickening of and nasal itching. Corticosteroids are the most potent the mucosa, and obstruction of the ostiomeatal complex.
preparations available for relief of the symptoms of nasal In the treatment of CRS, INS is a staple of treatment.
allergy since they alter the course of both the early and Steroids in topical and systemic forms have been used late phases of allergic rhinitis and reduce hyperactivity of widely in the treatment of CRS. Their use should improve nasal mucosa. They minimize allergic inflammation by patency of the ostiomeatal complex by way of reduction decreasing capillary permeability, stabilizing lysosomal in mucosal swelling. The myriad actions of corticosteroids, membranes, blocking the effect of migratory inhibitory and especially their ability to reduce airway eosinophil factors, and suppressing portions of the arachidonic acid infiltration by directly preventing increased viability and cascade. INS is then a first line of treatment for allergic activation of eosinophils and indirectly to reduce secretion rhinitis especially in patients with moderate-to-severe allergic of chemotactic cytokines by nasal mucosa, make them an 92
TABLE 2. Treatment with intranasal corticosteroid in persistent rhinosinusitis without nasal polyposis
Effect on symptoms
Other effects
mRNA for IL-4, and IL-5significantly improved mucociliary clearancesignificantly improved obvious choice. To date, five randomized control trials the genome of all inflammatory cells. This decreases have investigated the use of topical corticosteroids in cytokines and chemokines known to be derived from CRS.21-25 Two of these trials involved intrasinus instal- lymphocytes, eosinophils, and other inflammatory cells lation.21,22 The other three involved topical treatment23-25 that are part of the inflammatory events in nasal polyposis.30 Four of the five trials demonstrated significant impro- These resulted in reduced symptoms of rhinitis, improved vement in symptoms with no evidence of increased infection nasal breathing and reduced size and number of polyps, although INS appears to have less effect on improving the Another common problem in CRS is olfactory sense of smell. Thus, corticosteroids form the mainstay dysfunction. Rather than being only an obstructive of medical treatment. Surgery is reserved for severe and phenomenon from mucosal edema or polyps (transport non-responding nasal polyposis patients.
disorder), hyposmia or anosmia resulted in part from the Systemic (oral, intramuscular, or intravenous) corticos- direct effects of inflammatory processes on the olfactory teroids can reduce the size of nasal polyps to an extent epithelium, the surface of the olfactory receptors, or the that is comparable with surgery. Often a systemic burst is olfactory mucus bathing the receptors (sensory disorder).
used to shrink large obstructive polyps to provide more Aside from decreasing edema and improving the nasal area to apply INS therapy. Treatment with topical steroid airway in CRS, systemic steroids also seem to affect nasal drops in patients who had nasal polyposis and CRS olfactory neuron function in certain cases, perhaps by also had improved symptom scores, improved nasal airflow, decreasing inflammatory cytokines. The side effects of decreased polyp volume, and obviated the need for surgery systemic steroids make their prolonged use impractical for in about half of the treated patients.31 INS reduces polyp continuous treatment of olfactory loss. Unfortunately, INS, recurrence and the requirement for repetitive sinonasal which is safe for long-term daily use, does not have surgery and should be used in the long term.32, 33 equivalent beneficial effects on olfaction.26 In supporting The patient with the tetrad of symptoms including this concept, approximately 50% of anosmic patients with nasal polyps, asthma, aspirin intolerance, and CRS has CRS undergoing sinus surgery alone would have a persistent been classified as having ASA triad or Samterûs triad.
postoperative olfactory deficit. They were unresponsive to These patients have often had multiple polypectomies, INS, but most of these patientsû sense of smell was restored and the aggressive postoperative medical management of with oral steroids.27 In recalcitrant rhinosinusitis, new these patients is paramount to delay recurrence of polyposis.
intranasal/intrasinus catheters have recently been developed Clinical experience has generally shown a good response to allow the direct application of steroid formulations into to oral steroids in these patients. The need for oral steroids the maxillary sinus.28 Intranasal applications of steroids may be offset by using a higher concentration of nasal have been shown to decrease the levels of inflammatory mediators in the local milieu of the sinus as well as inserum.29 5) Eustachian tube dysfunction and/ or otitis media
with effusion
4) Nasal polyp
Eustachian tube dysfunction and / or otitis media with Nasal polyposis is a disease of the nasal and paranasal effusion (OME) is common and may cause hearing loss mucous membranes. It is characterized by edematous, semi- with associated developmental delay in children. The use translucent masses arising from the mucosal lining of the of topical flunisolide has been reported to accelerate the middle nasal meatus. The presenting symptoms of nasal return of normal eustachian tube function in allergic polyposis are nasal congestion, difficulties in breathing, children.34 Recently, the effectiveness of INS in promoting post-nasal drip, and loss of sense of smell. The etiology is the resolution of effusions has been assessed by meta- multifactor, and the exact pathophysiology is unknown.
analyses of randomized controlled trials. It was found that However, T-cells and their cytokine profiles in nasal polyps INS alone or in combination with an antibiotic lead to a are of clinical significance, since the use of topical anti- quicker resolution of OME in the short term. However, inflammatory agents, such as corticosteroids, may have a there is no evidence of a long term benefit from treating beneficial effect because of their ability to down-regulate OME or associated hearing loss with INS.35 Siriraj Med J, Volume 60, Number 2, March-April 2008 93
6) Posttraumatic olfactory dysfunction
studies corroborate results from those seen in adults and Although injury to the olfactory neurons or their cortical demonstrate that use in children (age > 3 years) is safe projections cannot be treated medically, some posttraumatic conductive olfactory deficits can. Direct trauma to thesinonasal region may lead to mucosal edema or hematoma 2) Effects on growth and bone metabolism
formation. Local administration of steroids improves olfac- Studies have shown that INS administered at recom- mended doses is not associated with impairment in growth To yield the greatest benefit, INS must be delivered and subsequent final adult height. However, these studies into a relatively patent airway. Thus, if large polyps, are limited since there have been no prospective, long- severe septal deviation, or marked mucosal edema are term data analyzing the effect of regular INS use on final present, the sprays are less effective. Once treatment is adult height.45 This is currently being facilitated by gradually begun, the patient must continue the therapy for at least lowering ages of approval for the use of INS by the 1 to 2 weeks (the time required for maximum effect to be evident) and often longer. Intermittent or as-needed dosages The effects of INS on bone metabolism are a specific are less effective. Evaluation of patients at regular intervals concern in certain patient groups such as children, the by the treating physician is necessary to detect undesirable elderly, postmenopausal women, and those receiving steroids local or systemic corticosteroid effects.
for other concurrent conditions. These patients are moresusceptible to the potential adverse effects of steroid use Use of INS in children
as their thresholds may more readily be reached or exceeded.
There has been a rise in INS usage with the recognition However, current studies that have evaluated the effects that long-term treatment is beneficial for seasonal and of INS on bone metabolism have also been limited by the perennial rhinitis. Although the use of INS to treat allergic lack of long-term studies. As with growth effects, it is rhinitis is generally thought to be associated with minimal difficult to assess the effects of INS on bone, due to serious adverse events in adults, increased long-term use confounding factors such as nutritional status and underlying in children has raised concerns about the potential for disease. Short-term studies in both children and adults, pediatric-specific effects, such as growth suppression. A however, demonstrate no significant effect on bone mineral 1-year study showed that use of 168 μg BDP aqueous nasal spray twice daily resulted in a significant suppressionof growth in children compared with placebo.38 However, 3) Ocular changes
other similar studies have shown no suppression of bone The risk of ocular side effects appears to be negligible growth in children after 1 year of treatment with the due to the low systemic bioavailability of most available recommended pediatric dose of MF nasal spray (100 μg daily)39 or with BUD (200 μg twice daily).40 4) Infection
Adverse effects
Use of INS has not been associated with infectious A. Systemic adverse effects
complications23,47 although other forms of inhaled steroids 1) Effects on the HPA axis
(such as those used in asthma) are associated with The vast majority of data in the literature indicate oropharyngeal candidiasis and have infrequently been that therapeutic doses of INS have very minimal effects associated with infectious complications.48-50 on the HPA axis function. The time of administrating thedose has demonstrated a variable effect on the HPA axis.
B. Local adverse effects
A few studies have shown that doses administered in the INS has been associated with several local side effects late afternoon and evening affect the normal and nocturnal such as epistaxis, dryness, and burning. These local side decrease in plasma cortisol concentrations.41 From a practical effects occur in approximately 5% to 10% of patients and viewpoint, the long-term clinical history of INS therapy is occur with most available INS preparations. Studies have informative. Clinically significant suppression of the HPA focused on the effects of these drugs on the nasal mucosa.
axis because of INS therapy alone appears to be exceedingly Initial concerns regarding atrophy of the nasal mucosa rare. Detectable suppression of childhood growth was with chronic topical steroid use were addressed in a study observed when an INS with relatively poor first-pass evaluating the long-term effects of the newer generation, inactivation was administered twice daily continuously more potent INS on nasal mucosa histology. The use of throughout the year.6 Of note, most currently available MF and FP over a 12-month period demonstrated no INS preparations are given once-daily in the morning and evidence of atrophy or metaplasia.51,52 There have been a thus, do not have significant adverse effects on the circardian few case reports of septal perforations associated with rhythm of the HPA axis.42 A major concern to clinicians INS use53, but this complication occurs mostly with the is prescribing INS to children. Several studies have very early preparations and can be avoided with appropriate demonstrated a similar safety profile of INS with respect use of these agents. The general recommendation is to to the HPA axis, as that observed in adults.43,44 These spray the contents toward the lateral nasal wall as opposedto the septum to maximize the anti-inflammatory action TABLE 3. Lower age limits for licensed prescription of intranasal
on the nasal mucosa while avoiding the potential dryness, crusting, and bleeding from the septum.
Active component
Trade name
Lower age limit
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Source: http://www.rcot.org/pdf/Intranasal%20Corticosteroid%20(2).pdf