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MEDICAL SCIENCES / «ШУШМУМ-ШУГМаУ» #14(173), 2023
MEDICAL SCIENCES
УДК : 615.357.065:615.451.35(048.8)
Koloskova Olena Kostyantynivna,
Bukovinian State Medical University PhD, Pprofessor of Department of Pediatrics and Children Infectious Diseases
of, Teatralna Sq., 2, Chernivtsi, Ukraine,58002 Buryniuk- Hloviak Khrystyna Petrivna Bukovinian State Medical University PhD, Assistant of Department of Pediatrics and Children Infectious Diseases
of, Teatralna Sq., 2, Chernivtsi, Ukraine,58002 DOI: 10.24412/2520-6990-2023-14173-14-17 PERCEPTIONS REGARDING SIDE EFFECTS OF INHALATED GLUCOCORTICOSTEROIDS
(LITERATURE REVIEW)
Abstract.
Since bronchial asthma remains an actual disease today, the question of treatment of this ailment becomes important. As you know, the main role in the therapy of bronchial asthma is played by inhaled glucocorticoster-oids. However, despite the fact that these drugs are the safest for use, the question of the occurrence ofpossible side effects is important, especially with long-term and high-dose courses of treatment in preschool and school-aged children.
Keywords: Bronchial asthma, treatment, inhaled glucocorticosteroids, children.
The prevalence of bronchial asthma (BA) is 118% in the population in different countries of the world [1]. The problem of increasing the incidence of BA in different age groups remains relevant for many years [2-3]. Considering such data, the development of effective treatment schemes for bronchial asthma is one of the most urgent problems of modern allergology. The main goal of treatment of patients with BA is to achieve and maintain its controllability. Among the important components of the general control of BA are: prevention of a decrease in lung function, occurrence of unwanted side effects of drugs and reduction of the risk of exacerbations. The main drugs in the treatment and prevention of this disease are inhaled glucocorticosteroids (IGS). Against the background of the anti-inflammatory effect of IGS in the respiratory tract, their hyperreactivity to nonspecific provocative factors decreases [4], lung function normalizes, the quality of life of patients improves, the frequency and severity of BA symptoms and asthmatic attacks, which lead to hospitalization or death, decrease [5]. However, despite the fact that these drugs are the safest for use, the question of the occurrence of possible side effects is important, especially with long-term and high-dose courses of treatment in preschool and school-aged children.
In his review, B. Lipworth [6] shows the dose dependence of the side effects of IGS. However, caution should be exercised when comparing the side effects of different drugs because different studies used different methods of assessing them. But after stabilization of asthma, it is always desirable to titrate glucocorticosteroids to the minimum effective dose to reduce the likelihood of systemic effects and optimize the benefit-risk ratio.
However, high doses of IGS are recommended for patients with treatment-resistant asthma that is poorly controlled with medium doses of IGS, even in combination with other basic treatment drugs. However, the use of high doses of IGS may be associated with the occurrence of systemic side effects, and a number of researchers believe that this thesis has already lost the signs of discussion [7].
Such undesirable effects include, in particular, the occurrence of osteoporosis [8], growth retardation in children [9], thinning of the skin [10], posterior subcapsular cataracts [11], glaucoma [12], [13].
Figure 1 shows the relationship between the occurrence of side effects and the dose of IGS used (according to G Russel, 2006) [14]
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Dose
Fig. 1. The relationship between the dose and side effects of the use ofIGS
Local side effects, including candidiasis of the oropharyngeal mucosa, dysphonia, reflex cough, and bronchospasm, are also associated with the use of IGS. Other less frequent side effects include perioral dermatitis, pharyngitis, and thirst [15],[16]. Compared to systemic side effects, local side effects of IGS are generally considered to be infrequent and of minor concern. Such side effects (hoarseness, dysphonia, oral candidiasis, cough, etc.) are well documented in adults, where they have been shown to cause rapid clinical discomfort for patients and potentially alter treatment compliance [17],[18]. Studies and publications about the local side effects of ICS in children appear in the literature occasionally [19] - [20].
Factors affecting the development of local side effects are represented by: (a) drug residue in the oropharynx, which depends on the inhalation technique, type of inhaler, etc.; (b) type of drug used (prodrugs, for example ciclesonide, vs active drugs); (c) frequency of use of IGS; and (d) dose of IGS. Ways to avoid local side effects should include the use of minimally sufficient doses of corticosteroids and the frequency of inhalations, rinsing the mouth and oropharynx each time after inhalation, using a spacer, using prodrugs that are not associated with side effects from the oropharynx [21].
The use of high doses of corticosteroids can be accompanied by systemic side effects, the most alarming of which is inhibition of the functional activity of the hypothalamic-pituitary-adrenal axis [22]. In particular, it has been shown that the current use of high doses of corticosteroids increases the risk of developing adrenal insufficiency [23]. The development of adrenal insufficiency was studied in 10 randomized, single- or doubleblind controlled trials in adults and children who received 3 or more doses of IGS. The presence of hypo-function of the adrenal cortex was established in 7 out of 8 studies using fluticasone (from 9% to 78%), in 1 of 5 budesonide trials (14% to 46% depending on trial), in 2 of 2 beclomethasone trials (6% and 36%), and in 1 of 2 triamcinolone trials (34%). Using a meta-analysis of 27 studies, the equivalent of adrenal hypofunction for prednisolone at a dose of 10 mg and fluticasone at a dose of 1 mg was established, as well as an increase in the risk of adrenal insufficiency with the use of fluticasone compared to beclomethasone (in 1.9 times), triamcinolone (in 3 .7 times) and budesonide (4.3 times) [24], [25].
However, changes in carbohydrate metabolism as a manifestation of adrenal insufficiency or hyperinsu-linism in asthma in children against the background of long-term IGS therapy, especially in high doses, are extremely insufficiently described in the literature.
A. J. Drake sang. [26] reported four cases of acute hypoglycemia on the background of AD as a clinical sign of iatrogenic adrenal insufficiency caused by inhaled fluticasone propionate. It has been shown that children receiving high doses of inhaled steroids may have symptomatic hypoglycemia secondary to adrenal insufficiency. Hypoglycemia, first of all, accompanies the course of metabolic stress, especially during infection. Hypoglycemia occurs as a result of impaired glu-coneogenesis, since cortisone is known to be a counter-insular hormone that enhances the recovery of liver enzymes that control gluconeogenesis and stimulates glucagon secretion. Deficiency of cortisol, thus, limits the availability of glucose in the cell during fasting. ToddG.R. and sang (2002) described three children aged 7 to 9 years who received inhaled GCS in doses of 500-2000^g/day for a period of 5 months to 5 years and who were hospitalized for hypoglycemic seizures (blood glucose ranged between 23, 4 and 32.4 mg/dL) [27].
Contrary to this, a number of studies conducted in the adult population of patients have shown that taking IGS can provoke the development of diabetes or the progression of already diagnosed diabetes [28].
An increase in the concentration of glucose in the blood is a well-known complication with the oral administration of corticosteroids, since these drugs increase gluconeogenesis and reduce the utilization of glucose by the liver and adipocytes due to a decrease in insulin binding. According to a number of scientists [29], in contrast to adults, the appointment of IGS in children is not accompanied by a violation of glucose tolerance, as evidenced by normal values of the glucose tolerance test and HbA1c.
Despite the belief that fluticasone dipropionate causes fewer side effects and is safer than other inhaled corticosteroids [30] due to limited oral absorption and a large first hepatic passage [31], the work of other researchers has shown that its high inhaled doses are associated with delayed growth [32] and inhibition of adrenal function [33]. The effect of IGS on growth rates was investigated in 6 double-blind, randomized con-
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trolled trials in which growth rates were delayed for be-clomethasone compared to placebo (in 2 RCTs; mean decrease 1.0 cm/year at 7 months, p<0.001; 1.08 cm /yr for 12 months, p<0.05), for salmeterol over 12 months (1 RCT; 1.4 cm/year, P <0.01), as well as for theophylline over 12 months (1 RCT; 1.6 cm /year, p = 0.001). No effect on growth rates was observed for fluticasone (1 RCT) at 12 months, or for the addition of budesonide to salbutamol at 22 months (1 RCT). Two studies have shown that the final height of adults who used IGS in childhood was not negatively affected.
Other systemic side effects of long-term use of high-dose corticosteroids include growth retardation in children, decreased bone mineral density, eye side effects (glaucoma and cataracts), thinning of the skin and bruising, and an increased risk of infectious complications. The connection of IGS with the development of pneumonia, the risk of bone fracture, the occurrence of tuberculosis and diabetes is described. A large retrospective study evaluated the dose-effect association between the dose of IGS and the risk of developing pneumonia, lower respiratory tract infection, and tuberculosis. [34], [35].
However, studies of bone mineral density in 2 longitudinal studies (1 of middle-aged subjects for 12 months and 1 of children for 6 months) treated with be-clomethasone and 1 RCT of middle-aged subjects treated with budesonide or beclomethasone, did not show any negative effect of these drugs on bone density.
Undesirable effects of IGS on the part of the organ of vision and skin showed a strong connection between a high dose of drugs and posterior subcapsular cataract, as well as between an increased risk of cataract development and the dose of medication, the age of patients and their ethnic origin. 1 RCT showed a weak correlation of high-dose IGS with an increased risk of ocular hypertension or open-angle glaucoma, and 3 studies showed an association between IGS (especially beclomethasone) and skin bruising.
Interestingly, in one of the studies, the frequency of exacerbations and hospitalizations in patients with COPD was lower in the group of patients treated with ICS based on the assessment of the level of eosinophils in the sputum (anti-inflammatory treatment was started or escalated if the eosinophils in the sputum were more than 3%, and was reduced or canceled if eosinophils were not noted in the sputum.
On the other hand, given that the morbidity associated with excess body weight in both adults and children is increasing worldwide [36], excess body weight associated with impaired carbohydrate and lipid metabolism is currently one of the main factors the risk of unceasing growth of general morbidity and reduction of life expectancy worldwide, which is recognized by the WHO [37]. The development of negative effects of excess body weight is associated with the formation of insulin resistance, long-term oxidative stress and an increase in the concentration of various (adipo) cytokines and inflammatory markers, which ultimately leads to the development of endothelial dysfunction, an increase in cardiovascular diseases and a high risk of other diseases [38]. There are many data in the literature that IGS can lead to the formation of iatrogenic Cushing's syndrome [39]. Previously, iatrogenic Cush-ing's syndrome was established only after long-term
use of high doses of corticosteroids, or when they were combined with antiretroviral drugs or antidepressants.
A multicenter study conducted by French scientists J.-C. Dubus and sang. (2001) showed that more than 60% of children and infants receiving IGS had at least one local side effect in daily life [40]. Such a high level of IGS-induced adverse events contradicts the results of a questionnaire, according to which only 3% of adults and adolescents had frequent local oropharyngeal side effects [41].
In view of the above, further study of clinical-instrumental markers associated with disorders of carbohydrate metabolism, the function of the hypothalamic-pituitary-adrenal axis and the regulation of phosphorus-calcium metabolism, as pathogenetic features of the course of bronchial asthma in children against the background of long-term basic anti-inflammatory therapy with inhaled glucocorticosteroids, is presented promising, as its results can become the basis for the development of new ways to differentiated basic therapy.
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