Pharmacokinetics of inhaled glucocorticosteroids

GLUCOCORTICOID DRUGS

Toolkit

Strengths and weaknesses of this study

1) Extensive search of two databases with random sample extraction

2) Inclusion of both analytical and RCTs conducted in children and adults with asthma

3) Heterogeneous nature of studies and outcome measures available for analysis

4) Failure to properly assess differences in effects when using different drugs, using different types of inhalers, and differences in reactions depending on the dose of the drug taken.

LOCAL APPLICATION OF GLUCOCORTICOIDS

Local use of glucocorticoids makes it possible to create a high concentration of the drug in the pathological focus and significantly reduce the risk of developing systemic adverse reactions.

Types of local administration of glucocorticoids:

• inhalation (into the lungs or nasal cavity),
• intraarticular, periarticular,
• intradermal (in scars),
• epidural,
• intracavitary (intrapericardial, intrapleural and others),
• rectal,
• external (skin, eyes, ears).

INHALATION ADMINISTRATION

Inhaled glucocorticoids are currently the most effective method of preventive

, maintenance therapy of bronchial asthma.
Their use is based on a powerful local anti-inflammatory effect
.
In addition, when used for several months in patients with bronchial asthma, they reduce hyperreactivity of the respiratory tract
, weakening the spasmogenic effects of many biologically active substances (histamine, bradykinin, acetylcholine, adenosine), cold and damp air, and carbon dioxide.
Inhaled glucocorticoids are considered as the drugs of choice in patients with moderate-severe asthma
, which, despite increasing doses of inhaled beta2-adrenostimulants, is characterized by persistent deterioration, the presence of uncontrolled symptoms, and decreased respiratory function [13].

For inhalation administration, beclomethasone, flunisolide, budesonide, triamcinolone acetonide and fluticasone are used. Their comparative characteristics are presented in table. 10

Inhaled glucocorticoids should not be used

to
relieve an attack
of bronchial asthma, since their effect develops slowly, over 1 week, and the maximum effect is observed approximately 6 weeks from the start of therapy.

Table 10.

Comparative characteristics of inhaled glucocorticoids. Applied Therapeutics, 1995 [8] with additions

Pharmacokinetics

When administered by inhalation, only 10-20% of glucocorticoids reach the respiratory tract, while 80-90% is retained in the oral cavity and then swallowed. After absorption in the gastrointestinal tract, a significant part of the drug undergoes first-pass metabolism.

A spacer is used to increase the percentage of drug penetration into the bronchi. It is a plastic reservoir, the narrowed part of which is attached to the inhaler, and the expanded part has a tip that is inserted into the mouth.

Adverse reactions

Systemic reactions.

Inhaled glucocorticoids practically do not cause systemic adverse reactions inherent in oral drugs. Low systemic activity is associated with their rapid inactivation in the liver and, partially, in the lungs. Only with long-term use in high daily doses can they inhibit the hypothalamic-pituitary-adrenal system. In addition, it is possible to develop osteoporosis in women and growth retardation in children.

Local adverse reactions

are observed rarely, as a rule, in the form of
dysphonia
and
oropharyngeal candidiasis
. Dysphonia is caused by myopathy of the laryngeal muscles, is reversible and goes away when the drug is discontinued. Atrophic changes in the epithelium of the respiratory tract were not observed even when using beclomethasone for 10 years.

Risk factors for the development of candidiasis

are improper use of the inhaler, old age, inhalations more than 2 times a day, simultaneous use of antibiotics and/or glucocorticoids orally.
Preventive measures:
use the drug before meals, rinse the mouth and throat after inhalation, use a spacer.

Intranasal administration

Intranasal administration of glucocorticoids is used for the prevention and treatment of seasonal allergic rhinitis

, as well as with recurrent
polyposis
of the nasal cavity and paranasal sinuses. Due to their powerful local anti-inflammatory effect, glucocorticoids reduce symptoms such as runny nose, burning sensation in the nose, sneezing, and nasal congestion. If nasal congestion is very severe, topical decongestants can be used for 3-5 days before using them.

When administered intranasally, glucocorticoids are well tolerated. Sometimes there may be a tingling sensation in the nose or sneezing, and in rare cases, hemorrhagic nasal discharge. These phenomena usually pass quickly and do not require discontinuation of the drug. When using budesonide, the development of contact perinasal allergic dermatitis has been described.

Intranasal administration of glucocorticoids is contraindicated

with hemorrhagic diathesis and a history of repeated nosebleeds.

results

• The systematic review included 18 studies (7 RCTs and 11 analytical studies).
• A meta-analysis of analytical studies did not reveal any significant correlation between the use of ICS and the incidence of fractures in children (OR 1.02, 95%, CI 0.94-1.10, in 2 studies) and adults (OR 1.09, 95%, CI 0.45-2.62, in 4 studies).
• Based on the results of 3 RCTs and 4 analytical clinical trials, bone mineral density in the lumbar spine was determined in children, and according to the results of the meta-analysis conducted by the authors, there was no significant decrease in indicators with the use of ICS.
• Three RCTs and four analytical studies measured lumbar spine bone mineral density and femoral bone mineral density in adults taking ICS, and the meta-analysis found no significant reductions compared with controls.

PREPARATIONS FOR INHALATION ADMINISTRATION

BECLOMETASONE

It is the most common inhaled glucocorticoid and is considered the “gold standard”. Has minimal systemic effect. However, with long-term use of beclomethasone in doses of 1000-2000 mcg/day in adult patients, moderate effects of osteoporosis were observed, comparable to those with long-term oral administration of prednisolone in daily doses of 5-10 mg.

Dosage:

• inhalation - 200-1600 mcg/day in 2-3 doses, and there is a tendency to use high doses of the drug;
• intranasally - 100 mcg 2 times a day in each half of the nose.

Release forms:

• metered dose inhalers containing in one dose 50, 100 ( aldecin, beclat, beclomet, becotide
  ) and 250 mcg (
  beclocort-forte, beclofort
  ) of beclomethasone dipropionate;
• becodisk
  is a special form of release of beclomethasone in the form of a powder in single doses of 100 and 200 mcg, located in rotadisks (foil blisters), which are inhaled using a special inhaler (diskhaler);
• metered-dose inhalers for intranasal administration containing 50 mcg of beclomethasone dipropionate (aldecine, beconase, beclomet-nasal, gnadione)
  .

FLUNISOLIDE

It is inferior in local activity to beclomethasone and is used in higher doses. The likelihood of systemic action is higher, and the development of oral candidiasis is less common.

Dosage:

• inhalation 1000-2000 mcg/day in 2 divided doses;
• intranasally for adults - 50 mcg in each half of the nose 2-3 times a day, for children - 25-50 mcg in each half of the nose once a day.

Release forms:

• metered dose inhaler with spacer containing 250 mcg of flunisolide (Inhacort)
  ;
• metered dose inhaler for intranasal use containing 25 mcg of flunisolide (Sintaris)
  .

BUDESONIDE

It has an increased affinity for glucocorticoid receptors (15 times higher than prednisolone) and has low systemic bioavailability (10-15%), since it is almost 90% inactivated in the liver during the first pass. Less effect on adrenal function than beclomethasone.

When administered inhaled, budesonide has a slightly stronger effect than beclomethasone. Used in the same doses as beclomethasone dipropionate.

High effectiveness of budesonide was noted in children with severe acute laryngotracheobronchitis (“false croup”). The drug is administered using a stationary inhaler (nebulizer) at a dose of 2 mg. The effect develops within 1 hour.

Release forms:

• metered dose inhalers containing 50 and 100 mcg (Pulmicort)
  and 200 mcg
  (Benacort)
  of budesonide in one dose;
• metered dose intranasal inhalers containing 50 mcg of budesonide (rhinocort)
  .

TRIAMCINOLONE

In terms of glucocorticoid activity, triamcinolone acetonide is 8 times superior to prednisolone, although triamcinolone itself is only 20% more active. Like other inhaled glucocorticoids, it is quickly inactivated in the liver. However, the likelihood of systemic effects is higher than with fluticasone or budesonide.

Dosage:

• inhalation – 600-800 mcg/day in 3-4 doses, maximum – 1600 mcg/day; children aged 6-12 years – 300-800 mcg/day, maximum – 1200 mcg/day.

Release forms:

• Azmacort
  is a metered dose inhaler with a built-in spacer containing 100 mcg of triamcinolone acetonide in one dose. The presence of a built-in spacer is convenient for patients.

FLUTICAZONE

Newest inhaled glucocorticoid. It has the greatest affinity for glucocorticoid receptors, approximately 2 times greater than budesonide. It has a powerful local anti-inflammatory effect, 2 times stronger than that of beclomethasone. Fluticasone has slightly greater systemic activity than budesonide (despite lower bioavailability), but this is only apparent when very high doses are given. When fluticasone is used in dry powder form, systemic effects are significantly reduced. Controlled studies have shown that even at a dose of 2000 mcg/day, fluticasone does not affect blood cortisol levels.

Used in 2 times lower doses than beclomethasone. But when using fluticasone, lung function improves much faster – within 3-5 days.

Dosage:

• inhalation 100-500 mcg/day in 2 doses, in children over 5 years of age the maximum dose is 1000 mcg/day.

Methods

• The information search was carried out in two databases MEDLINE and EMBASE since July 2013. In December 2014, it was updated with the latest data from PubMed.
• The authors selected randomized clinical trials (RCTs) and controlled analytical studies that compared the effects of ICS (for at least 12 months) with the effects of other therapies in patients with asthma.
• A meta-analysis was conducted to determine odds ratios (ORs) for fractures and standard deviations of bone mineral density.
• Heterogeneity was assessed using I2.

Methods

Study selection criteria:

• The goal is to study important but infrequent bone side effects.
• At least 20 patients taking one of the types of ICS
• Duration - at least 12 months

Inclusion criteria for RCTs:

• RCT in parallel groups
• Participants included patients with asthma of varying degrees of severity
• In the main group, ICS was used as therapy, in the control group - other drugs recommended for asthma, or a combination of ICS with long-acting β-agonists, or only the latter.
• The aim was to assess the risk of fractures or changes in bone mineral density

Inclusion criteria for analytical studies:

• case-control
• prospective
• retrospective cohort

informative from the point of view of assessing the risk of fractures or changes in bone mineral density in patients taking ICS (main group) and taking alternative drugs (control group).

Exclusion criteria:

• Studies that included mixed groups of patients (asthma/COPD), the results of which were not reported separately for each disease
• Cross-sectional studies
• Studies that took into account only the effect of oral glucocorticosteroids without taking into account the effect of inhaled ones

Search strategy:

• The authors of the article searched MEDLINE and EMBASE in June 2013, using the general strategy of searching for various side effects associated with ICS use.
• In December 2014, the data was updated through a more targeted search on PubMed
• The reference lists of included studies were carefully manually reviewed to identify any other articles that might be useful.

Selection strategy:

• Two reviewers (Menaka Thavarajah and Patricia Blanco) independently double-checked all titles and abstracts of articles and excluded all that were not RK or analytical studies of the effects of ICS in patients with asthma.
• The full texts of potentially relevant articles were further reviewed and the selection criteria were tightened. Only articles related to bone side effects were selected
• A third reviewer (Yoon K Loke or Andrew M Wilson) made the final decision on inclusion or exclusion of the article from the review.

Study characteristics and data extraction

• Two reviewers (Menaka Thavarajah and Patricia Blanco) independently selected results that had a primary focus on fracture risk and a second and final reviewer that focused on changes in lumbar spine bone mineral density or femoral bone mineral density.
• A third reviewer (Yoon K Loke or Andrew M Wilson or Daniel Gilbert) corrected any discrepancies after cross-checking the source of the article.

Risk of estimation bias

• Two reviewers independently assessed reports of blinding of patients and staff, generation of random sequences, concealment of patient allocation order, withdrawal from study participation, or discontinuation of follow-up.
• To assess the validity of the relationship between the development of adverse effects and the use of ICS, information was extracted on the sample of participants, duration of use of these drugs and results, as well as methods for accounting for systematic errors in analytical studies.
• Funnel plots and skewed distributions were used to assess bias, provided that the meta-analysis included data from more than 10 studies, and to assess the absence of heterogeneity.

Statistical analysis

• Study data were pooled using Review Manager (RevMan) V.5.3.2 (Nordic Cochrane Centre, Copenhagen, Denmark)
• The inverse variance method was used to combine data regarding absolute fracture risks and standard deviation in bone mineral density (g/cm2)
• In accordance with the recommendations of the Cochrane guidelines, data with a confidence level of less than 95% were excluded.
• Statistical heterogeneity was assessed using I2, with I2 > 50% indicating a significant level of heterogeneity
• If a study included more than one control group (consisting of patients not taking ICS), when possible, preference was given to comparing ICS with placebo rather than comparing ICS with active drugs such as nedocromil, montelukast and sodium cromoglycate
• When studying combined dosage forms, a separate comparative analysis was carried out of the combination of ICS with another drug and this drug alone
• If the study included several types of ICS in different dosages, they were combined by the authors of the meta-analysis, as recommended by the Cochrane guidelines
• No preliminary protocol was kept.