Category - Part 3
Side Effects With Inhaled Corticosteroids: Control and Monitoring of Side Effects Local Side Effects
The only other systemic side effect with ICS mentioned in the NAEPP 1997 guidelines was disseminated varicella infection. While oral corticosteroid use, with or without immunosuppression, has been associated with a high risk of severe varicella infection compared with case-matched control sub-jects, no causal relationship has been shown with ICS, despite sporadic case reports of severe varicella infections in patients receiving ICS.
The 1997 NAEPP guidelines suggested the following clinical interventions to mitigate the risk of, or treat, local side effects:
• Oral candidiasis (thrush): use a spacer/holding chamber, rinse mouth with water after inhalation, and administer ICS less frequently (twice daily vs four times daily). Topical or oral antifungal agents should be used to treat active infections. • Dysphonia: use a spacer/holding chamber, temporarily reduce dosage, or rest for vocal stress.
• Reflex cough and bronchospasm: use a slower inspiration rate and/or a spacer/holding chamber or pretreat with an inhaled (32-agonist.
Side Effects With Inhaled Corticosteroids: Systemic Side Effects in Children
Oral corticosteroids are a known risk factor for the development of subcapsular cataracts, with risk influenced by daily cumulative dose, age, and ethnic origin. The systematic review described above concluded that the risk of cataracts due to ICS was small and may only be relevant in elderly patients. Two studies not included in the systematic review generally support these findings. A study from 1993 found that the prevalence of subcapsular cataracts in 48 patients treated with long-term BUD or BDP (750 to 1,500 ^g/d) was 27%. However, the development of cataracts was correlated to prednisone but not ICS use. A study published in 2001, after the systematic review was compiled, suggested that the risk of cataracts with ICS may be related to age. An analysis of 103,289 subjects exposed to ICS vs 98,527 subjects in a control cohort found slightly higher incidence rates for cataracts in the ICS group compared with the nonexposed cohort (RR, 1.3; 95%, CI 1.1 to 1.5) after adjusting for age and gender. However, a relationship between heavy use of ICS and cataract risk that was most pronounced in subjects > 70 years old was also seen in subjects aged 40 to 49 years, but was absent in subjects aged < 40 years. add comment
Side Effects With Inhaled Corticosteroids: Risk of Systemic Side Effects
While safety data have been reported for many clinical trials, there are few studies that have been adequately powered, or have long enough follow-up periods, to assess long-term systemic side effects with ICS. A systematic review conducted in collaboration between the American College of Chest Physicians, the American Academy of Allergy, Asthma, and Immunology, and the American College of Allergy, Asthma, and Immunology examined the evidence for potential systemic complications of ICS therapy for asthma. Evidence published up to the end of the year 2000 was considered. The results are summarized in Table 2. In brief, there was relatively good evidence for the effect of ICS on skin thinning and bruising, with a dose-response relationship identified. In older adults, ICS appeared to reduce bone mineral density after long-term, high-dose therapy and increased the risk of cataracts and glaucoma, although the evidence was not conclusive. Click Here
Side Effects With Inhaled Corticosteroids: Asthma Clinical Research
Modern delivery systems, such as HFA-based pMDI inhalers, enhance drug targeting to the lungs. Thus, lower ICS doses can be used, such that the clinical response is maintained but systemic exposure reduced. For example, conversion from CFC to HFA as a propellant moved the dose-response curve for drugs delivered using the HFA device toward the left, so lower doses are required to achieve the same therapeutic effect.> Conversely, a 1:1 substitution of the CFC to the more recent HFA formulations may result in greater systemic exposure and a higher potential for side effects.> Therefore, recommended doses of HFA devices are lower than older CFC-containing formulations. Large-volume spacers have also been recommended as a means of improving lung deposition, allowing dose reduction and minimization of ICS systemic bioavailability in adults and children. this
Side Effects With Inhaled Corticosteroids: Systemic Side Effects With ICS Therapy Systemic Availability of ICS
ICS absorption into the systemic circulation occurs either through the lungs or by swallowing drug that is not inhaled but deposited at the back of the throat. Nevertheless, other factors need to be considered and these are discussed below.
The contribution of GI absorption to systemic ICS exposure is minimal compared with that of absorption through the lungs. ICS that are swallowed and absorbed in the gut will undergo hepatic first-pass metabolism, greatly reducing the amount of circulating drug. The degree of hepatic first-pass metabolism differs between ICS: FP and MF, 99%; BUD, 90%; TAA, 80 to 90%; and BDP, 60 to 70%. Theoretically, agents that are inactivated by hepatic first-pass metabolism should be safer. However, highly lipophilic drugs, such as FP and MF, will be taken up more readily into tissues than drugs that are less lipophilic, such as TAA and BUD.
Because more extensive tissue storage of ICS in an active form will result in a longer clearance time from the body, this not only may increase the duration of therapeutic effect but it also may increase the potential for increased systemic side effects should active drug continue to be released back into the circulation. There is another potential reason why there is an increased risk of systemic side effects with MF. In contrast to other ICS, MF generates an active metabolite (6^-OH MF) in the liver and an active degradation product (9,11-epoxy MF) in the lung and plasma. Even though MF itself has a low systemic bioavailability, these active metabolites will contribute to the overall potential for MF therapy to cause systemic side effects. It has been shown that MF does cause significant overnight urinary cortisol suppression, a marker for hypothalamic-pituitary-adrenal axis suppression, to a similar extent as FP.
Side Effects With Inhaled Corticosteroids: HFA
Inhaler device can also influence the occurrence of local side effects, mainly through determining the relative amount of drug deposited in the lungs vs the oropharynx. Ideally, a device should maximize the proportion of drug that reaches the lung; higher lung deposition reduces the required dose, and lower oropharyngeal deposition reduces the potential for oropharyngeal side effects. Two types of inhaler device are used by the majority of asthma patients. read
In a pMDI, the drug is dissolved or suspended in a propellant under pressure, and when activated releases a predetermined dose. A pMDI can be used with or without a spacer and can be manually or breath actuated. Use of a spacer device may improve lung deposition and reduce oropharyngeal deposition for patients with poor inhaler technique. The choice of propellant greatly influences drug deposition. Chlorofluorocarbon (CFC) propellants used to be ubiquitous, but concern over their effect on the depletion of ozone in the upper atmosphere has led to their replacement with hydrofluoroalkane (HFA). The use of HFA has had some additional benefits. Because particle sizes of < 5 ^m diameter will reach the lower airways when larger particles are deposited in the oropharynx, and because smaller particle sizes can be achieved with HFA, the use of HFA will likely lead to greater lung deposition, allowing lower doses, and lower oropharyngeal dep-osition. With CFC-based pMDI devices, lung deposition was approximately 10 to 20% depending on the exact device and method of measurement. In contrast, newer HFA-based inhalers are achieving levels of lung deposition 50%.
Side Effects With Inhaled Corticosteroids: Local Side Effects in Children
Similar findings for local side effects are seen for ICS/long-acting (3-agonist combination therapies. With BUD/formoterol, pharyngitis was seen in 6% of patients in clinical trials, with coughing in 5%. For FP/salmeterol, oropharyngeal candidiasis was seen in 2 to 4% of patients, hoarseness/dysphonia in 2 to 4%, throat irritation in 1 to 3%, and cough/breathing difficulties in 1 to 3%. In a comparative study of FP/salmeterol vs FP vs salmeterol vs placebo, there was no difference in the incidence of side effects between the ICS groups and the salmeterol group, except for a higher incidence of oral candidiasis for FP/salmeterol (10%) or FP alone (6%) vs salmeterol (3%) and placebo (< 1%).
Studies on local side effects in children are less common than for adults. However, a relatively large, prospective, observational, cross-sectional cohort study of 639 patients (75.9 ± 48.9 months old) with moderate-to-severe asthma showed that 61.5% of patients had at least one local side effect (Fig 2). More info