Latest News - Part 12
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
Side Effects With Inhaled Corticosteroids: Systematic Review
The authors also showed that immediately after inhalation of 200 ^g of FP, there were significant amounts of FP in the esophagus (3.3 ^g). Even after 30 min, FP remained detectable and the amount of drug recovered was affected by whether the patient was prone or remained upright (0.67 ^g if the patient laid down immediately or 0.11 ^g if they remained standing). This study implies that if asthmatic patients do not go to sleep immediately after FP inhalation, the remaining FP in the esophagus decreases rapidly, thereby decreasing the risk of esophageal candidiasis. review
In addition, by changing the FP inhalation times to before breakfast and dinner, the remaining FP in the esophagus would be removed by the passage of food and would not remain in the esophagus. Thus, physicians need to be aware of the possibility of esophageal candidiasis with FP therapy and advise patients on how to potentially minimize their risk for this side effect.
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Side Effects With Inhaled Corticosteroids: Local Side Effects of ICS Therapy
A systematic review compared the dose response for oral candidiasis for FP with the dose response for preventing an exacerbation. The authors calculated the number of patients that needed to be treated to prevent withdrawal of therapy due to worsening of asthma symptoms vs the risk of oral candidiasis. In this analysis, the number of patients who avoided asthma exacerbation by taking FP increased with increasing daily doses of FP, although the dose-response curve was relatively flat, with little benefit in efficacy between FP at 500 ^g and 1,000 ^g. However, as the dose of FP increased, so did the risk of oral candidiasis. At a dose of 100 ^g, the difference between the number of additional patients that would need to be treated to avoid a loss of efficacy vs the number of patients that would need to be treated in order to see an additional case of oral candidiasis was 87 patients (Fig 1). In comparison, at an FP dose of 1,000 ^g, this difference had fallen to 21 patients, a narrow margin of tolerability (Fig 1). Thus, when increasing the dose of FP, the risk of oral candidiasis will increase much faster than the risk of an exacerbation will decrease. read
Side Effects With Inhaled Corticosteroids
Inhaled corticosteroids (ICS) are the cornerstone of asthma management and result in improved symptom control and quality of life for many patients. However, as for all medicines, the physician must achieve a balance between the potential benefits for the patient and the risk of side effects. For ICS therapy, the potential side effects may be local in the oropharyngeal cavity, or systemic due to absorption of ICS into the circulation through the lungs and GI tract. Increasing the dose of ICS in order to achieve improvements in asthma symptoms, or prolonged treatment over many years, will expose patients to an increased risk of side effects. http://cheap-asthma-inhalers.com/
Despite the publication of guidelines2’ stressing the importance of ICS, ICS are often underused. The major reason that physicians fail to prescribe ICS appears to be due to disagreement with recommendations, particularly regarding when the balance lies between their benefits and the risk of complications and side effects. In addition, patients’ fears of ICS may lead to a lack of adherence with prescribed therapy, which may expose them to the unnecessary risk of an asthma exacerbation. Although the nature of local side effects with ICS is fairly well described and understood, the impact of these side effects on patient quality of life and adherence to therapy may be underestimated. However, the most common concerns regarding ICS therapy relate to the potential systemic effects, which are often more serious, long term, and can be difficult to detect and treat.”
Influence of Two Different Interfaces for Noninvasive Ventilation Compared to Invasive Ventilation on the Mechanical Properties and Performance of a Respiratory System: Wasted Efforts
Racca et al recently studied the effectiveness of the helmet in a human model of resistive breathing, finding a higher inspiratory effort if the helmet was used compared to the face mask. In line with our data (Fig 5), the less effective unloading of the respiratory muscles in NIV-H was partially explained by the underassistance due to the long inspiratory delay time and the impaired pressurization rate during NIV-H. The pressurization may, however, be dependent on the amount of gas leakage and the maximal inspiratory flow of the respirator. Since gas leakage could almost completely be avoided in our lung model study, this may also offer an explanation for our favorable results regarding PTP with the use of a helmet.
In addition, rebreathing of CO2 with a helmet resulted in an almost doubled minute ventilation during resistive breathing and was therefore most likely the major cause for the increased work of breathing with the helmet. The problem of limited CO2 elimination has also been described in COPD patients, and was analyzed in an experiment showing increased CO2 concentrations within the helmet especially with demand flow systems. Both studies> imply that a continuous flow or flow-by system may be beneficial to reduce the inspiratory CO2 concentration and thus the risk of CO2 rebreathing. read only