Do airway clearance mechanisms influence the local and systemic effects of inhaled corticosteroids?

doi:10.1016/j.pupt.2007.08.005

Pulmonary Pharmacology & Therapeutics

Volume 21, Issue 2, April 2008, Pages 247-258

https://doi.org/10.1016/j.pupt.2007.08.005 Get rights and content

Abstract

The role of airway clearance in inhaled drug therapy is complex. Disease-induced bronchoconstriction results in a central drug-deposition pattern where mucociliary clearance is most efficient. When drug-induced bronchodilation is achieved, deposition and uptake becomes more peripheral, and because there is less mucociliary clearance in the periphery, this will lead to an unintentional increase in lung exposure and enhance the risk of systemic side effects. In addition, mucociliary clearance is pathologically reduced in both asthma and chronic obstructive pulmonary disease. Among inhaled corticosteroids, rate of dissolution and lung uptake differs considerably. For the slowly dissolving, lipophilic steroids, the contribution of mucociliary clearance to these findings appears significant, and variability in lung and systemic exposure resulting from variable mucociliary function appears to be amplified. In addition, dose optimisation of non-stable asthma becomes more complex. The present review highlights the impact of mucociliary clearance on inhaled corticosteroid disposition and identifies critical areas where more research is needed.

Introduction

Inhaled corticosteroids (herein abbreviated as inhaled steroids or merely steroids) maintain their position as the most effective anti-inflammatory single treatment for asthma. Inhaled steroid formulations differ, however, in terms of dosing recommendations, lung deposition, intrinsic potency and local and systemic side effects. These aspects have been highlighted for inhaled steroids in numerous original papers and reviews [1], [2], [3]. There are, however, some steroid properties that have been scrutinised in less detail and for which the clinical implications remain dubious. One such aspect is the suggested impact of airway clearance on steroid uptake, which has been discussed in terms of safety [4], [5] but not in terms of lung dose or therapeutic ratio. This paper summarises observations of differences between inhaled steroids in regional lung deposition and uptake, discusses conceivable mechanisms for the observed differences and for the first time puts these into a clinical context. The purpose is to highlight some neglected principles of inhaled steroid therapy and propose research areas where more information should be generated.

Section snippets

Overview of observations

Several studies have demonstrated a difference in systemic exposure and systemic pharmacodynamics between asthmatic patients and healthy subjects for the inhaled steroid fluticasone propionate (fluticasone) (Table 1). Using cortisol production as an indirect measure of systemic drug exposure of fluticasone, Weiner et al. [6] showed a linear decrease in cortisol production when comparing asthmatic patients with normal lung function to those with varying degrees of pulmonary obstruction following

Lung dose and its relation to local and systemic exposure

For most inhaled drug formulations the major proportion of the inhaled aerosol will impact in the oral cavity and oropharynx; this portion is swallowed and handled by the body as an oral administration. Since most inhaled steroids are designed to have low oral bioavailability, the systemic uptake of the swallowed fraction will generally be negligible. The remaining portion of the inhaled aerosol will reach the lungs and deposit on the lung surface, or be exhaled. The exhaled fraction of an

Deposition of inhaled corticosteroids

The amount of steroid reaching the lung from a specific substance/inhaler combination equals the fraction of the inhaled aerosol that is not impacted and retained in the throat at inhalation. Throat impaction depends on throat geometry and inhalation flow rate, parameters that do not differ between healthy subjects and asthmatics or COPD patients [23]. For metered dose inhalers with spacers, the amount and particle size distribution of the aerosol is independent of subject factors. Thus, for

Mucociliary clearance

Mucociliary clearance is of fundamental importance for removal of secretions and foreign particles that have been deposited in the airways. The overall principle of the system is simple: the ciliated cells in the epithelium transport the mucus with deposited particles in a proximal direction and eventually the mucus is expectorated or swallowed. In respect to drug inhalation, aerosolised drug deposited in the lung will either penetrate the mucus and become absorbed or follow the mucus and

Dissolution of inhaled drugs in mucosal fluids

Most of the findings discussed earlier pertain to the transport of insoluble particles; there has been less attention on the fate of substances such as pharmaceutical agents, which possess different degrees of solubility. Solubility and pulmonary absorption may differ considerably between different compounds used as inhalation therapy, depending on their molecular weight, water/lipid partition, polar surface area and hydrogen bond properties [60], [61]. As a general rule, solubility in lung

Modelling of lung deposition

A further understanding of these findings is provided by a mathematical simulation study [69] in which pulmonary bioavailability following inhalation was modelled as a function of regional lung deposition pattern, mucociliary clearance rate and particle dissolution rate. Olsson et al. [69] found that the pharmacokinetic observations by Brutsche et al. [8] could be explained by a more central deposition pattern in a bronchoconstricted lung leading to increased mucociliary clearance for a slowly

Discussion and clinical relevance

As presented above, studies with the lipophilic corticosteroids fluticasone and mometasone have documented a substantial difference in absorption and systemic glucocorticoid activity between healthy subjects and patients with asthma, and within groups of asthmatic patients with varying disease severity [6], [8], [9], [10], [11], [12], [15], [71]. No, or negligible, impact of asthma severity on the uptake and cortisol effects was noted for the much less lipophilic compound budesonide [9], [10],

Concluding remarks

Many factors may influence the clinical effects of inhaled therapy, including inter-individual variation in inhaler use and differences in the devices themselves when used in everyday practice. That said, this review of available data suggests that airway-clearance mechanisms (mainly mucociliary clearance) play an important role in the disposition of inhaled steroids. To date, most studies addressing this phenomenon have compared the two currently most prescribed inhaled steroids, fluticasone

Acknowledgement

Editorial assistance was provided by Ian Wright, PhD, Wright Medical Communications Ltd., UK.

Disclosure of possible conflict of interest: Staffan Edsbäcker is a full-time employee at AstraZeneca.

Per Wollmer has received a research grant from AstraZeneca.

Olof Selroos was a full-time employee of AstraZeneca until 2001. Thereafter he has performed consultancy work for AstraZeneca Research and Development in Lund and has been invited as speaker to symposia organised by AstraZeneca.

Lars Borgström

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ReviewDo airway clearance mechanisms influence the local and systemic effects of inhaled corticosteroids?

Abstract

Introduction

Section snippets

Overview of observations

Lung dose and its relation to local and systemic exposure

Deposition of inhaled corticosteroids

Mucociliary clearance

Dissolution of inhaled drugs in mucosal fluids

Modelling of lung deposition

Discussion and clinical relevance

Concluding remarks

Acknowledgement

Ann Allergy Asthma Immunol

Respir Med

Chest

Ann Allergy Asthma Immunol

Lancet

J Allergy Clin Immunol

J Allergy Clin Immunol

Chest

Int J Pharmaceut

Respir Med

Ann Occup Hyg

Br J Dis Chest

Chest

Eur J Pharmacol

J Pharm Sci

Int J Pharm

J Allergy Clin Immunol

Respir Med

J Allergy Clin Immunol

Respir Med

Safety of inhaled and intranasal corticosteroids: lessons for the new millennium

Drug Saf

Systemic effects of inhaled corticosteroids in children

Curr Opin Pediatr

The presence of emphysema does not affect the systemic bioactivity of inhaled fluticasone in severe chronic obstructive pulmonary disease

Br J Clin Pharmacol

Comparison of the systemic effects of fluticasone propionate and budesonide given by dry powder inhaler in healthy and asthmatic subjects

Thorax

Pharmacokinetics and systemic activity of fluticasone via Diskus and pMDI, and of budesonide via Turbuhaler

Br J Clin Pharmacol

Plasma concentrations of fluticasone and budesonide following inhalation: the effect of methacholine induced airflow obstruction

Br J Clin Pharmacol

Plasma concentrations of inhaled corticosteroids in relation to airflow obstruction in asthma

Br J Clin Pharmacol

Pharmacokinetics and systemic effects of inhaled fluticasone propionate in chronic obstructive pulmonary disease

Br J Clin Pharmacol

Comparative bronchial vasoconstrictive efficacy of inhaled glucocorticosteroids

Eur Respir J

Plasma concentrations of fluticasone propionate and budesonide following inhalation from dry powder inhalers by healthy and asthmatic subjects

Thorax

The inhalation device influences lung deposition and bronchodilating effect of terbutaline

Am J Respir Crit Care Med

Importance of inhalation device on the effect of budesonide

Arch Dis Child

Efficacy of inhaled fluticasone propionate in asthma: results from topical and not from systemic activity

Am J Respir Crit Care Med

Uptake, retention, and biotransformation of corticosteroids in the lung and airways

Degree of throat deposition can explain the variability of lung deposition of inhaled drugs

J Aerosol Med

On the use of dry powder inhalers in situations perceived as constrained

J Aerosol Med

Performance of Turbuhaler® in patients with acute airway obstruction and COPD, and in children with asthma: understanding the clinical importance of adequate peak inspiratory flow, high lung deposition, and low in vivo dose variability

Treat Respir Med

Mucociliary clearance in adult asthma

Am Rev Respir Dis

Regional lung deposition and clearance of 99mTc-labeled beclomethasone-DLPC liposomes in mild and severe asthma

Chest

Influence of airway calibre on the intrapulmonary dose and distribution of inhaled aerosol in normal and asthmatic subjects

Eur Respir J

Principles underlying ciliary activity in the respiratory tract. II. A comparison of nasal clearance in man, monkey and other mammals

Arch Otolaryngol

Mucin exocytosis

Am Rev Respir Dis

Review
Do airway clearance mechanisms influence the local and systemic effects of inhaled corticosteroids?

Performance of Turbuhaler^® in patients with acute airway obstruction and COPD, and in children with asthma: understanding the clinical importance of adequate peak inspiratory flow, high lung deposition, and low in vivo dose variability