Asthma control lies in balancing therapeutic benefits, adverse effects of inhaled corticosteroids

February 2006

This month’s Pharmacology Consult continues with a theme similar to January’s: adverse effects of corticosteroid use. I reviewed adverse effects of systemically administered corticosteroids in the January column. This month I will review potential adverse effects of orally inhaled corticosteroid (ICS) therapy. As with orally administered corticosteroid use, the potential for significant adverse effects cannot be ignored, given the wide pharmacological and physiologic effects that corticosteroids may have. It can be quite difficult for caregivers and clinicians alike to consider these adverse effects and place them in a proper, patient-specific perspective, balancing the therapeutic benefits and potential adverse effects of corticosteroid therapy.

ICS are the most effective long-term controller agents for the treatment of asthma in children. They are recommended as “preferred treatment” for all severity classifications (mild, moderate, severe) of persistent asthma for children and adults by the National Asthma Education and Prevention Program (NAEPP) Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma (2002). Positive therapeutic benefits of ICS use include improved spirometry, reduced airway hyperresponsiveness, improvements in symptoms scores and symptom frequency, fewer courses of oral corticosteroids and reduced need for acute care visits or hospitalizations. Thus, the benefits of ICS therapy are well documented and recognized. However, concerns for significant, systemic adverse effects by caregivers or clinicians may diminish or negate these therapeutic benefits of ICS.

Common, local adverse effects

Common adverse effects of ICS, which generally are of mild clinical significance, include cough, dysphonia and thrush. Rinsing the mouth with water and spitting after use is recommended to reduce these effects. The use of a spacer device, or holding chamber, when appropriate, with certain ICS product delivery devices will also reduce these adverse effects by trapping larger particles from dose actuation (and prevention of oropharynx deposition). These larger particles, due to their size, become trapped in the oropharynx and are not delivered to the lungs. Proper product-specific technique of use is also an important means to reduce oropharyngeal deposition and increase pulmonary delivery of ICS.

Systemic bioavailability

Several factors determine the amount of drug from each dose of ICS that becomes systemically available, with the potential for systemic adverse effects. Although numerous systemic adverse effects may result, two effects, which are important concerns to caregivers and clinicians, include growth and hypothalamic-pituitary-adrenal axis (HPA) suppression. These adverse effects will be reviewed in more detail below.

Six different ICS agents are currently available in the United States: beclomethasone dipropionate (QVAR HFA, IVAX), budesonide (Pulmicort Turbuhaler, Pulmicort Respules; AstraZeneca), flunisolide (AeroBid, Roche), fluticasone propionate (Flovent HFA, GlaxoSmithKline), mometasone furoate (Asmanex Twisthaler, Schering-Plough) and triamcinolone acetonide (Azmacort, Kos Life).

These products differ by delivery device, technique of use, dose, drug particle size, drug potency and gastrointestinal and pulmonary delivery, among other factors. Differences in potency are compensated for by differences in dosing among the available ICS (ie, because fluticasone is more potent than triamcinolone, its dosing is less than triamcinolone). The ICS products are generally considered equivalent in clinical effectiveness.

Systemic bioavailability, or the amount of drug absorbed into the blood for systemic delivery (with the potential for adverse effect), is determined by absorption from both the gastrointestinal and pulmonary systems. Even with proper product technique of use, most drugs from ICS deposits in the oropharynx, and swallowed. The amount of a dose delivered to the lungs may range from 10% with use of a metered-dose inhaler (MDI) product to greater than 50% with the newer MDI HFA (hydrofluoroalkane) products. Newer products with HFA propellant more efficiently deliver (compared with the older chlorofluorocarbon [CFC] propellant) drug to the lungs, as HFA-based propellant contains a larger proportion of smaller drug particles. Drug particles less than 5 µm are delivered to lung, while larger particles are swallowed.

The use of a spacer device can double the amount of drug delivered to the lungs. The potential for systemic availability exists for swallowed drugs. Fortunately, however, most swallowed drug undergoes significant first-pass hepatic metabolism, resulting in reduced pharmacologic effect. The ICS products differ in the extent of first-pass metabolism, especially with fluticasone, which has the highest rate: 99% of swallowed drug is metabolized prior to reaching the systemic circulation.

Inhaled drug delivered to the lungs provides therapeutic benefit, but some are also available for absorption to the systemic circulation. The difference in systemic availability is dependent upon delivery device and propellant, gastrointestinal availability, drug potency and extent of first-pass metabolism.

Although low oral bioavailability and enhanced pulmonary deposition is generally desirable, this is balanced by consideration of complete systemic drug availability from pulmonary deposition. Thus, a combination of several factors determines the amount of active drug that is available from the different ICS products for potential systemic adverse effects: inhalation device, delivery propellant, dose, drug potency, technique of use, amount of drug swallowed, amount of drug delivered to the lungs and extent of first-pass metabolism.

HPA suppression

The potential adverse effects that ICS may have on HPA function have been extensively evaluated. Numerous studies have differed in methods to determine HPA function, complicating study comparison. Commonly employed tests, such as morning cortisol concentration determination or standard cosyntropin testing, are not sensitive to assess HPA function, and are poorly predictive of adrenal suppression. Even more sensitive tests of HPA function, however, such as 24-hour area under the concentration curve for plasma cortisol measurement, do not accurately predict clinical adrenal suppression. This complicates interpretation of studies reporting reduction in adrenal function after ICS use. The low-dose cosyntropin test and insulin-induced hypoglycemia test more accurately assess HPA function; these newer tests are more difficult to perform.

A review of these publications indicates that low-medium doses of ICS allow enough drug to reach systemic circulation to result in mild suppression of HPA function. Data from longer-term (12 months or more) studies have mostly been favorable, indicating no cumulative adverse effects of low-medium doses of ICS use. Several studies have evaluated cumulative effects of ICS use on HPA function. Although one study of beclomethasone (336 µg/day for 12 months) demonstrated some cumulative effective upon HPA function, several other published studies of similar or longer duration have not found evidence of HPA suppression. One frequently published researcher of ICS use (Allen) does not recommend routine monitoring of HPA function in children receiving low-medium doses of ICS. Clinical adrenal insufficiency and adrenal crisis have rarely been documented from ICS use.

A frequently cited publication includes case reports of adrenal crisis noted from a survey of prescribing clinicians in the United Kingdom (Todd). Of nearly 3,000 surveys sent to ICS-prescribing clinicians, 33 patients (28 children) met the diagnostic criteria for adrenal crisis. Of these 28 children, 23 presented with hypoglycemia (13 with decreased levels of consciousness or coma, nine with coma and convulsions and one fatal case). Of the 33 patients described, 30 had been receiving fluticasone. However, it is important to note that the mean dose of all children receiving fluticasone was 980 µg/day (range 500 to 2,000), which is well above the “high-dose” range of more than 400 to 440 µg/day as set forth in the NAEPP report. As a follow-up to this report, Todd later reported on an additional seven cases (five children) of ICS-induced adrenal crisis (including one additional childhood death). Dosages used by these children were reported as similar to those in the original report.

In summary, low-medium doses of ICS are not likely to result in clinically significant adverse effects of HPA function. Children at increased risk for significant adverse effects include those receiving high doses of ICS and children receiving low-medium doses of ICS in addition to frequent corticosteroid therapy by other routes of administration (eg, nasal inhalation or topical). Periodic plasma cortisol levels should be assessed in children at higher risk for adverse effects.

Growth suppression

The potential for growth suppression from ICS use may be of paramount concern to parents and caregivers of children with asthma. Aware that orally administered corticosteroids may cause significant growth retardation, some parents may envision their children as “small adults” after years of corticosteroid use (by any route), and thus clinicians should be prepared to accurately educate parents on how ICS may affect growth, if at all.

Numerous published studies have evaluated the potential for ICS to affect growth, and many means of growth assessment have been used (eg, knemometry, one- to five-year growth velocity by stadiometry). Certainly, the longer the duration of assessment, the higher the clinical significance, as growth assessment over several months may not necessarily predict final adult height attainment.

Several published studies of intermediate duration (one to three years) have revealed that low-medium doses of beclomethasone (and likely equipotent doses of other ICS) can decrease growth in prepubertal children by approximately 1 cm (range 0.5-1.5 cm). The most useful data, long-term follow-up of children receiving ICS throughout childhood until adult height is attained, have not been gathered from a controlled trial. The best data currently available comes from the CAMP study (2000), a controlled, prospective trial that evaluated children with mild-moderate asthma for four to six years. Budesonide (medium dosing) therapy was compared with nedocromil and placebo, and was associated with 1.1-cm growth suppression in the first year of therapy. Although this effect did not occur after the first year for the remainder of the study, no catch-up growth was seen at the study conclusion. The researchers projected final adult height and concluded that no differences existed among the budesonide and comparative groups (nedocromil and placebo).

Additional information from an expert panel report (2003) from the American College of Chest Physicians, the American Academy of Allergy, Asthma and Immunology and the American College of Allergy, Asthma and Immunology states that ICS use is associated with a decrease in the short-term growth rate in children, and that the overall effect is small and may not be sustained with long-term therapy. The panel also addressed adult height and concluded that adult height attained by children with asthma is not different from children without asthma (based upon published cohort studies).

Conclusion

When considering the evidence for therapeutic benefit and adverse effect from ICS use, it is relatively clear that the balance is likely to be tilted toward therapeutic benefit in most children. ICS are very effective therapeutic drugs to control asthma; uncontrolled asthma due to lack of use of effective drug therapy may lead to a poor quality of life (ie, missed school, frequent symptoms), reduced growth (uncontrolled moderate persistent asthma may adversely affect growth) or even death.

The occurrence of HPA suppression from long-term ICS use, while possible, is unlikely to be clinically significant when low-moderate doses are used. This risk increases, however, when high-dose ICS are used, or when additional long-term corticosteroids are used (given by other routes of administration). Clinicians should consider periodic monitoring of HPA function for these children. Clinicians prescribing long-term high-dose ICS should consider adjunctive drug therapy (eg, long-acting inhaled ß-agonists) in an attempt to lower the ICS dose to the lowest effective dose, as well as referral to a subspecialist for additional care.

Although data are not complete to address the question of ICS use affecting final adult height, the evidence to date is encouraging. Regardless of the ICS dose prescribed, it would be wise for clinicians to frequently monitor patients’ growth patterns. When prescribing ICS, clinicians should educate patients and caregivers on the appropriate use (eg, scheduled dosing), role and technique of use to improve drug delivery to the lungs. As well, educating patients and caregivers on the potential adverse effects of ICS use and their clinical significance, along with the likelihood for therapeutic gain, is essential.

For more information:

• Allen DB. Inhaled steroids for children: effects on growth, bone, and adrenal function. Endocrinol Metab Clin North Am. 2005;34:555-564.
• Tattersfield AE, Harrison TW, Hubbard RB, Mortimer K. Safety of inhaled corticosteroids. Proc Am Thorac Soc. 2004;1:171-175.
• Kelly HW, Nelson HS. Potential adverse effects of the inhaled corticosteroids. J Allergy Clin Immunol. 2003;112:469-478.
• Leone FT, Fish JE, Szefler SJ, West SL. Systematic review of the evidence regarding potential complications of inhaled corticosteroid use in asthma: collaboration of American College of Chest Physicians, American Academy of Allergy, Asthma, and Immunology and American College of Allergy, Asthma, and Immunology. Chest. 2003;124:2329-2340.
• Todd GR. Adrenal crisis due to inhaled steroids is underestimated. Arch Dis Child. 2003;88:554-555.
• National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma update on selected topics—2002. J Allergy Clin Immunol. 2002;110:S141-S219.
• Todd GR, Acerini CL, Ross-Russell R, et al. Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Arch Dis Child. 2002;87:457-461.
• The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedorocromil in children with asthma. N Engl J Med. 2000;343:1054-1063.
• Reed CE, Offord KP, Nelson HS, et al. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma. The American Academy of Allergy, Asthma and Immunology Beclomethasone Dipropionate-Theophylline Study Group. J Allergy Clin Immunol.1998;101:14-23.

• Edward A. Bell, PharmD, BCPS, is an associate professor of pharmacy practice at Drake University College of Pharmacy and a clinical specialist at Blank Children’s Hospital, Des Moines, Iowa.