Mechanism of action
Glucocorticoids have the widest spectrum of anti-inflammatory activity. Their effects are mediated primarily through genomic mechanisms (regulation of gene expression).
- Blockade of inflammatory mediators: The drugs stimulate the synthesis of lipocortin, which inhibits the enzyme phospholipase A2. This stops the release of arachidonic acid from cell membranes and halts the synthesis of leukotrienes and prostaglandins. Additionally, GCs suppress the gene responsible for the synthesis of COX-2.
- Immunosuppression: The function of macrophages, T- and B-lymphocytes is inhibited. The production of pro-inflammatory cytokines (IL-1, IL-2, IL-4) and immunoglobulin E (IgE) is reduced.
- Effect on mast cells: The number of IgE receptors decreases, cell membranes are stabilized, which prevents degranulation and histamine release. The drugs also prevent the expansion of the mast cell clone.
- Inhibition of cellular migration: The synthesis of intercellular adhesion molecules is suppressed, preventing leukocytes and monocytes from infiltrating the bronchial tissues.
- Permissive action: GCs increase the sensitivity of bronchial $\beta_2$-adrenergic receptors to circulating adrenaline, enhancing its bronchodilator effect.
Pharmacokinetic features
Inhaled formulations are designed so that the drug acts directly within the bronchi (topical action).
The main pharmacokinetic advantage of the group is high presystemic elimination. The fraction of the drug that is inevitably swallowed with saliva and absorbed into the systemic circulation is rapidly degraded during its first pass through the liver. This minimizes the risk of severe systemic side effects typical of oral steroids. Nevertheless, long-term administration carries the risk of suppressing endogenous glucocorticoid production via negative feedback.
Main representatives of the group
The drugs are intended for systematic (maintenance) treatment. Efficacy is observed only with regular use.
- Beclometasone: Prototype of the group. It is a halogenated steroid (containing a chlorine atom that enhances activity). The maximum therapeutic effect is achieved on days 5–7. Administered 2–4 times a day.
- Budesonide: Non-halogenated drug. It has an acetal group that increases lipophilicity and receptor affinity. It acts longer (administered 1–2 times a day), but the onset of effect is slower (1–2 weeks). Specific side effects include CNS effects (nervousness, excitability, depression). Systemic absorption is about 28%.
- Flunisolide: Similar to beclometasone, but has pronounced presystemic metabolism, resulting in a bioavailability not exceeding 40%.
- Fluticasone: Kinetic profile is close to budesonide, systemic absorption is about 20%.
«Soft» glucocorticoids
This is a new trend in pharmacology aimed at developing drugs with an improved safety profile. A prominent representative in pulmonology is ciclesonide.
Chemically, it is a non-halogenated esterified steroid that acts as a prodrug. Upon accidental ingestion, its bioavailability is negligible (0.5–1%). Upon reaching the lung tissue, it is converted by local esterases into the active metabolite — desisobutyryl-ciclesonide — which possesses potent anti-inflammatory activity.
Advantages of ciclesonide: administered only once daily, extremely well tolerated, and significantly less suppression of endogenous cortisol production compared to classical agents (e.g., fluticasone).
Briefly: answers to topical questions
What systemic side effects can develop with long-term use of inhaled corticosteroids?
Long-term use of inhaled corticosteroids may lead to systemic adverse events. These include:
- Pneumonia — increased risk in patients with COPD; this is a class effect for the ICS group.
- Osteoporosis and fractures — risk is noted in patients receiving high doses of ICS long-term.
- Diabetes mellitus — initiation of ICS treatment is associated with an increased risk of its development.
- Suppression of endogenous glucocorticoid production via a negative feedback mechanism.
Which drugs from the inhaled corticosteroid group are halogenated?
Among inhaled corticosteroids, the halogenated drug is beclometasone.
- Beclometasone contains a chlorine atom in its structure and is a halogenated steroid.
- Budesonide is a non-halogenated glucocorticoid.
- Ciclesonide is an esterified steroid containing no halogens.
Which drugs (bronchodilators) are most commonly combined with inhaled corticosteroids in the maintenance therapy of asthma?
In the maintenance therapy of bronchial asthma, inhaled corticosteroids are combined with long-acting $\beta_2$-agonists (LABAs).
- Salmeterol is used in a fixed combination with fluticasone, for example in Seretide Diskus.
- Formoterol can be used in combination with ICS in maintenance therapy, and the ICS + formoterol combination is also used as-needed via a single inhaler (MART).
- Adding a LABA to an ICS may allow for a reduction in the ICS dose.
To remember the cascade of GC action on arachidonic acid, use the chain: Glucocorticoids → Lipocortin → Phospholipase A2 Block (GLP).
Class and exam questions
Why are inhaled GCs not used to relieve an acute asthma attack?
Their onset of action is slow (ranging from days to weeks) because it is based on genomic effects and altered protein synthesis. Acute relief requires fast-acting agents, such as inhaled $\beta_2$-adrenergic agonists.
Why is rinsing the mouth recommended after ICS inhalation?
To wash away residual drug from the mucous membrane. The local immunosuppressive action of steroids can lead to oral and pharyngeal candidiasis (fungal infection) and cause dysphonia (hoarseness).
What is the permissive action of GCs?
This is the ability of glucocorticoids to restore and increase the sensitivity of bronchial $\beta_2$-adrenergic receptors to endogenous adrenaline and administered bronchodilators.
What else to study on this topic
- Combination drugs for the treatment of bronchial asthma (Seretide, Berodual, Intal Plus)
- Systemic (resorptive) glucocorticoids and their side effects
- Therapy of concomitant allergic conditions (antihistamines)
- Mast cell membrane stabilizers and antileukotriene drugs
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