Pharmacological Management: Inhaled Corticosteroids
Jeffrey M. Kintner, PharmD, and Elizabeth de la Riva-Velasco, MD
Introduction
Inhaled corticosteroids (ICS) are generally considered first-line therapy for all patients with persistent asthma.
Mechanism of Action
•The potent anti-inflammatory activity of ICS is likely related to their broad effect on many aspects of the inflammatory process.
•The primary action of the corticosteroid occurs at the cellular level, where the interaction with the glucocorticoid receptor leads to a reduction in multiple inflammatory substances (cytokines, chemokines, adhesion molecules, inflammatory enzymes, receptors, and proteins).
•Clinically, these actions translate into
—Reduced severity of asthma symptoms
—Better asthma control and an improvement in quality of life
—Improvement in peak expiratory flow and spirometry values
—Diminished airway hyperresponsiveness
—Prevention of exacerbations
—Reduction in systemic corticosteroid courses, emergency department care, hospitalizations, and death
Indications for Use
•ICS are indicated for the maintenance treatment of asthma as prophylactic therapy and are NOT indicated for the relief of acute bronchospasm.
•Both the National Asthma Education and Prevention Program and the Global Strategy for Asthma Management and Prevention guidelines consider ICS to be the superior long-term asthma control medication and are listed as the first-line agents of choice for persistent asthma.
Dosing
•A critical component of asthma management is frequent assessment of asthma control and subsequent adjustments to the therapeutic regimen.
• The goal of therapy is to achieve asthma control while minimizing exposure to medications.
•ICS are available in both a metered-dose inhaler (MDI) and a dry- powder inhaler (DPI); there are advantages and disadvantages to each dosage form.
—MDI contents are secured in a pressurized aerosol dispenser that is more resistant to changes in temperature and humidity, whereas storage of DPIs is critical to maintain potency.
—DPIs have the advantage of not requiring a holding chamber. While studies have shown that young children can develop sufficient inspiratory flow to activate DPIs to deliver sufficient medication, there is concern whether children will consistently use proper technique on a daily basis, over time. For this reason, many specialists limit DPIs to children at least 8–12 years of age and only after they are able to demonstrate proper technique in the office.
•Table 35-1 lists ICS doses and corresponding steroid potencies.
DPI, dry-powder inhaler; HFA, hydrofluoroalkane; ICS, inhaled corticosteroids; LABA, long-acting β2-adrenergic agonist; ND, no data.
Some of these products are a combination of inhaled corticosteroids and LABAs. The steroid referenced in addition to the LABA is indicated by the footnotes.
a Product contains formoterol.
b Product not approved for patients <12 years of age.
c Product contains salmeterol.
d Product contains vilanterol.
e Product not approved for patients <18 years of age.
f No guideline recommendations for ICS dosage form or specified age group.
Adverse Effects
•ICS have little systemic absorption and are subsequently associated with fewer and less severe adverse effects than orally administered glucocorticoids, which make them favorable chronic asthma control medications.
•However, their use is not completely devoid of adverse effects, which can occur both locally and systemically.
•Using a holding chamber and rinsing the mouth can minimize the risk of systemic and local adverse effects.
Systemic Adverse Effects
•While ICS are intended to act exclusively in the lungs, if a valved holding chamber (for an MDI) or spacer (for a DPI) is not used, approximately 80% of the doses inhaled do not reach their target destination but are deposited in the oropharynx, swallowed, and subsequently absorbed from the gastrointestinal tract.
•Most ICS have poor bioavailability (<1% for ciclesonide to 15% for beclometasone dipropionate) and, when subjected to first-pass metabolism, are converted into inactive metabolites.
• The remaining ICS is free for systemic absorption and is responsible for observed systemic adverse effects (Table 35-2).
| Table 35-2. Potential Systemic Adverse Effects of ICS | |
| Adverse Effect | Description |
| Adrenal suppression | Chronic administration of ICS may reduce cortisol secretion from the adrenal gland via negative feedback inhibition of the HPA axis. The degree of HPA suppression depends on the dose, duration, and frequency of ICS administration. Symptoms include Cushingoid features, anorexia, weight loss, fatigue, growth failure, and hypoglycemia. |
| Linear growth deceleration | ICS therapy may be associated with an adverse effect on linear growth in children. This adverse effect is dose dependent, occurs in the first several months of therapy, and is generally small and not progressive. This phenomenon may be confounded by the observation that poorly controlled asthma may also delay linear growth. The minor growth risks are considered to be outweighed by the respiratory benefits. |
| Reduction in bone mineral density | ICS have mild effects on bone mineral density that typically do not reach clinical significance. Children at highest risk are those with chronic disease, malnutrition, or use of long-term medications that reduce bone mineral density. |
HPA, hypothalamic-pituitary-adrenal; ICS, inhaled corticosteroids.
Local Adverse Effects
•Table 35-3 shows the most common local adverse effects associated with ICS.
•While not generally as serious as systemic side effects, they have the ability to affect patient quality of life and adherence to treatment and may mask symptoms of more serious disease.
•The incidences of local adverse effects are highly variable and are dependent on the type and/or dose of ICS used, the mode of delivery (MDI vs DPI), the use of valved holding chamber devices, and inhaler technique.
Strategies to Minimize Risks of Adverse Effects
•Recommend the routine use and cleaning of valved holding chambers with all MDIs, especially in children. For younger children who are unable to deeply inhale voluntarily, spacers with face masks are available.
•Advise patients to have the child “rinse and spit” and wash the face after administration of inhaled medications.
•Use the lowest effective dose of ICS that maintains asthma control to reduce unnecessary steroid excess
—There are few long-term head-to-head comparison studies with sufficient sample sizes to determine whether growth effects might be less with different brands overall or if an individual child might have improved growth if switched from 1 formulation to another.
| Table 35-3. Potential Local Adverse Effects of ICS | |
| Adverse Effect | Description |
| Dysphonia (hoarseness) | Has been reported in 5%–50% of patients using ICS. While the etiologic origin of dysphonia is unclear, it has been suggested that pharyngeal deposition of steroid particles may induce myopathy of vocal cord muscles, subsequently triggering bowing of the vocal folds on phonation. The risk of dysphonia may be dose dependent, and symptoms can be reversed after discontinuation of therapy. |
| Oropharyngeal candidiasis (thrush) | May result from local deposition of ICS particles on the mucosal surface of the oropharyngeal cavity. Thrush is thought to be the consequence of local immunosuppression or an increase in salivary glucose levels, which may stimulate growth of Candida albicans. Symptoms of thrush tend to be mild, and the primary clinical manifestation is local discomfort (altered taste sensation, sore throat, etc); however, the risk of fungemia increases in immunocompromised populations or if left untreated. Thrush can occur in ≤70% of patients using ICS, and risk increases at higher doses, with more frequent dosing, or in patients taking concomitant oral glucocorticoids and/or antibiotics. |
| Cough | Can occur in >30% of children treated with ICSs, although cough may be difficult to differentiate from poor asthma control. It has been proposed that coughing may be due to the exposure to excipient ingredients (specifically oleic acid) and nonspecific irritating properties of ICS. Dry-powder inhalers typically have a lesser incidence of coughing owing to a larger proportion of fine particles. |
| Perioral dermatitis | An erythematous, eczematoid eruption that occurs around the mouth, nostrils, or eyes has been described with ICS use, most notably with budesonide. Perioral dermatitis is thought to be due to a direct local effect of ICS on facial skin and occurs infrequently in children. Wash the face after the use of ICS to avoid this side effect. Topical erythromycin or metronidazole should be considered in severe cases. |
| Tongue hypertrophy | A seldom-reported adverse effect thought to be caused by ICS-induced hypertrophy and local fat accumulation. This phenomenon has been described in infants treated with nebulized beclometasone dipropionate and in asthmatic children treated with nebulized budesonide. Tongue hypertrophy resolves after cessation of ICS treatment. |
| Thirst sensation | Occurring in >20% of children using ICS, a thirsty feeling after delivery of the drug may be caused by throat irritation or as a manifestation of oral thrush. Combination treatment with a long-acting β2-adrenergic agonist may increase risk. |
•Before increasing the ICS dose, assess the following:
—Inhaler technique
—Adherence to the prescribed regimen
—Environmental control measures
—Whether the addition of a long-acting β2-adrenergic agonist, antileukotriene agent, or alternative adjunctive therapy to low- or medium-dose ICS should be considered, rather than using high-dose ICS to minimize steroid exposure
—Whether allergic sensitizations are being assessed and treated appropriately
Resources for Families
•Allergy & Asthma Network. www.allergyasthmanetwork.org
•American Academy of Allergy, Asthma, and Immunology. www.aaaai.org
•American Association for Respiratory Care. www.aarc.org
•American Lung Association. www.lung.org
•Association of Asthma Educators. www.asthmaeducators.org
•Asthma and Allergy Foundation of America. www.aafa.org
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