Systemic side effects of inhaled corticosteroids in patients with asthma Respiratory Medicine (2006) 100, 1307–1317 Department of Pulmonary & Critical Care Medicine, KyungHee Medical Center R3 Yang BH

Introduction (I) Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment. Asthma is a problem worldwide, with an estimated 300 million affected individuals. Although from the perspective of both the patient and society the cost to control asthma seems high, the cost of not treating asthma correctly is even higher.

Introduction (I) Pharmacological therapies to prevent and control asthma Pharmacological therapies to prevent and control asthma Glucocorticoids are the most potent and consistently effective. Glucocorticoids are the most potent and consistently effective. Inhaled corticosteroids (ICS) are the first-line treatment of choice for persistent asthma. Reduction of the airway hyperresponsiveness Prevention of the acute exacerbations Improved of the lung function Decreased symptom severity High dose of ICS High dose of ICS Systemic side effects Systemic side effects Local adverse effects Local adverse effects

1.Oropharyingeal deposition 1.Mouth washing 2.Spacer devide with a MDI 3.Dry-powder inhaler 2.Pharmacokinetics parameter 1.Rate of systemic clearance 2.Volume of distribution 3.Half-life 4.accumulation

HPA (hypothalamic-pituitary-adrenal) -axis suppression

By down-regulating ACTH production By down-regulating ACTH production Adrenal crisis after complete suppression of HPA-axis function Adrenal crisis after complete suppression of HPA-axis function Most serious adverse effect Most serious adverse effect Adrenal insufficiency after ICS therapy Adrenal insufficiency after ICS therapy Use of ICS in excess of the currently recommended guidelines Several studied for HPA-axis function Several studied for HPA-axis function Uncontrolled Uncontrolled Previous oral corticosteroid therpy Previous oral corticosteroid therpy Treatment duration Treatment duration Inhaler types Inhaler types Methods to assess HPA-axis suppression Methods to assess HPA-axis suppression

1. HPA-axis suppression exists in normal individuals and asthmatic patients treated with high-dose ICS. 2. The extent of HPA-axis suppression 1.Dose 2.Duration 3.Timing of corticosteroid administration

Measures of HPA-axis suppression Static tests : not predicting clinical adrenal suppressions Static tests : not predicting clinical adrenal suppressions Cortisol levels in the morning Cortisol levels in the morning Wide variation among individuals Wide variation among individuals Baseline levels before starting ICS treatment Baseline levels before starting ICS treatment Same time, repeated test Same time, repeated test Circadian rhythm of cortisol Circadian rhythm of cortisol Free urine cortisol excretion Free urine cortisol excretion Dynamic tests Dynamic tests Corticotrophin adrenocorticotropic hormone test Standard 250 μg cosyntropin test Low dose cosytropin test with 0.5 mg/m 2 cosyntropin Insulin tolerance test Metyrapone stimulation tests

Bone density and osteoporosis Glucocorticoids →↓bone formation,↑ bone resorption by direct actions on osteoblasts and osteoclasts → bone calcium loss via urine → decreased vitamin D-mediated calcium absorption in gut ICS therapy at low to moderate doses is not associated with a reduction in BMD in children. However, prolonged HPA-axis suppression and any effect on bone metabolism in children administered high-dose ICS remain to be examined. Long-term ICS use results in BMD reductions that could lead to increases in fractures in adults.

Cataracts and glaucoma The risk of subcapsular and nuclear cataract development related to ICS use seems minimal in asthmatic children, although the risk may be greater in older patients. Therefore, no firm link between cataract formation and ICS use has been made to date, and longer follow-up regarding this important potential adverse effect seems warranted. The risk of glaucoma following ICS therapy is most likely small, and future studies might be helpful in defining a definitive link between ICS use and glaucoma in the elderly.

Skin thinning and bruising Patients treated with high-dose ICS had significantly thinner skin. A Finnish study of asthmatic patients suggested that inhaled budesonide decreases skin collagen synthesis within a short period of time (6 weeks). ICS therapy, especially with high doses, increased the risk of easy bruising. Although sex was indicated to be a factor in this study because women reported easy bruising at a higher frequency versus men, men treated with ICS also had a higher relative risk for bruising than women. Roy et al. studied the prevalence of skin bruising in relation to adrenocortical function and ICS therapy in 100 asthmatic patients.

Cicleosonide (Alvesco ® ) The newest generation of ICSs, is inhaled as an inactive parent compound, which is then hydrolyzed to its active form, desisobutyryl-CIC (des-CIC) Several favorable pharmacokinetic characteristics Low oral bioavailability Rapid clearance High serum protein binding that would limit systemic exposure and side effects Potent glucocorticoid receptor-binding activity in the lung Short-term and longterm studies with ciclesonide 160–640 μg/day in the morning or evening did not suppress serum or 24-h urinary cortisol. However, no data for ciclesonide are available for other systemic side effects such as skin thinning, bruising, and fracture, and studies are necessary to further investigate long-term effects.