Corticosteroids—glucocorticoids, inhaled

Systemic availability of inhaled glucocorticoids

The systemic availability of an inhaled glucocorticoid represents the additive and complex combination of pulmonary and gastrointestinal drug absorption. Absorption is influenced by many factors, including delivery device, the use of a spacer, the particle size of the inhaled drug, and the absorption and metabolism of the swallowed drug [ ].

In healthy volunteers, high doses of both budesonide and fluticasone were readily absorbed after inhalation from a metered-dose aerosol [ ]. Fluticasone is extensively metabolized by the liver, so measurable concentrations of parent drug in the systemic circulation reflect efficient absorption across the lung. Lower doses of these inhaled glucocorticoids also result in some systemic absorption, reflected in effects on the hypothalamic–pituitary–adrenal axis [ ].

The extent of absorption of inhaled glucocorticoids tends to be less in asthmatic subjects than in healthy volunteers. In a study of fluticasone (500 micrograms via a dry powder device) in asthmatic patients with a wide range of severity, there was a highly significant linear correlation between lung function (expressed as percentage predicted FEV ₁ ) and the absolute magnitude of adrenal suppression [ ]. In 11 patients with moderately severe asthma (mean FEV ₁ 54% predicted), who took fluticasone 1000 micrograms/day via a metered-dose inhaler with a spacer, the systemic availability of fluticasone was significantly less (10%) than in 13 healthy controls (21%). The plasma fluticasone concentrations (expressed as AUC) correlated positively with gas transfer [ ]. In contrast, there was no difference in plasma concentrations of fluticasone and budesonide between 15 mild asthmatics (mean FEV ₁ 81% predicted) and healthy volunteers after inhalation of 1000 micrograms of either drug with single or repeated dosing [ ]. Taken together, these studies suggest that patients with severe asthma are protected from the systemic adverse effects of high doses of inhaled glucocorticoids, owing to airways obstruction and reduced lung availability. However, as their lung function improves with continued use of the inhaled glucocorticoids, it is likely that the lung availability of inhaled glucocorticoid will increase. This likely outcome is a compelling argument for reducing the dose of inhaled glucocorticoids to a lowest dose that maintains optimal control of asthma and optimal lung function.

Plasma concentrations have been measured in 13 healthy subjects and eight patients with mild asthma using inhaled fluticasone propionate 1000 micrograms bd via Diskus or pressurized metered-dose inhaler and of budesonide 1000 micrograms bd daily via Turbuhaler for 7 days. Twenty-four-hour plasma cortisol concentrations were determined to assess the systemic activity of fluticasone propionate and budesonide. At steady state, the systemic availability of budesonide via Turbuhaler (39%) was significantly higher than that of fluticasone propionate via Diskus (13%) or inhaler (21%). Fluticasone propionate had a larger distribution volume and slower rates of absorption and clearance. Despite a significantly higher pulmonary availability of budesonide via Turbuhaler, plasma cortisol suppression was less than that of fluticasone propionate via inhaler and similar to that of fluticasone propionate via Diskus. There were no differences between healthy subjects and patients with mild asthma in subgroup analyses. However, this study had some limitations as the doses of fluticasone propionate and budesonide were not equipotent, fluticasone being twice as potent as budesonide [ ].

The effects of fluticasone 1500 micrograms/day and budesonide 1600 micrograms/day, both by dry powder inhalation, on three systemic markers (urinary concentrations of total cortisol metabolites, morning serum cortisol, and osteocalcin concentrations) have been investigated in 46 healthy and 31 asthmatic subjects [ ]. Urinary total cortisol metabolite concentrations represented the most sensitive marker of the systemic effects of inhaled glucocorticoids, and were lower in healthy subjects treated with fluticasone than in asthmatic patients, suggesting greater systemic availability of fluticasone in healthy subjects. A similar correlation was not found for budesonide. Fluticasone impaired the hypothalamic–pituitary–adrenal axis more than budesonide, while budesonide significantly lowered serum osteocalcin concentrations, which reflect osteoblastic activity. The authors suggested that different inhaled glucocorticoids have different effects on the hypothalamic–pituitary–adrenal axis and bone metabolism. This study also had its limitations given that the fluticasone and budesonide doses were not equipotent [ ].

The safety and efficacy of fluticasone, beclomethasone dipropionate, and budesonide have been compared in a randomized trial in 133 patients with chronic severe asthma who required at least 1750 micrograms per day of beclomethasone/budesonide [ ]. The patients were randomized to their regular beclomethasone/budesonide or to fluticasone at about half the dose for 6 months. The patients who used fluticasone had a better safety profile, especially with regard to adrenocortical function and bone turnover, while maintaining asthma control. There were significant increases in morning serum cortisol concentrations, the urine cortisol:creatinine ratio, serum osteocalcin, and the serum (deoxy)-pyridinoline:creatinine ratio only with fluticasone, suggesting less suppression of the hypothalamic–pituitary–adrenal axis. The 2:1 potency ratio for clinical efficacy of fluticasone and budesonide/beclomethasone seems to be maintained even at doses of 2000 micrograms per day or higher.

Since many patients with allergic asthma also have rhinitis, they may be taking both inhaled glucocorticoids for their asthma and intranasal formulations for their hay fever. The total systemic availability of glucocorticoids has been studied after the addition of intranasal therapy in patients already taking inhaled glucocorticoids [ ] in 12 moderately severe asthmatic subjects (mean FEV ₁ 84% predicted), who were randomized in a placebo-controlled, two-way, crossover comparison of inhaled fluticasone (880 micrograms bd) plus intranasal fluticasone (200 micrograms od), inhaled triamcinolone (800 micrograms bd) plus intranasal triamcinolone (220 micrograms od), and respective placebos. Both the inhaled glucocorticoids caused significant suppression of adrenocorticoid activity, although the addition of intranasal formulations did not produce further significant suppression. There were more individual subjects with abnormally low cortisol values when intranasal fluticasone was added. These findings suggest that the dose of intranasal glucocorticoids should be taken into account (particularly if used in the long term) when considering the systemic availability of glucocorticoids used in the treatment of asthma and hay fever.

The concept of the L:T ratio in inhalation therapy is a useful one, where L represents the local or lung availability of an inhaled drug and T the total systemic availability. This ratio will be affected by differences in first-pass metabolism. Another important variable that determines the L:T ratio is the inhalation device. The L:T ratio for budesonide is 0.66–0.85, depending on the method of inhalation [ ].

Another way of describing the L:T ratio concept is that of “pulmonary targeting.” Drug properties that improve pulmonary targeting include slow absorption from the lungs, low oral systemic availability, and rapid systemic clearance.

budesonide = beclomethasone dipropionate > triamcinolone acetonide = flunisolide. Potency differences can be overcome by giving a larger dose of the less potent drug. However, comparisons between glucocorticoids must measure the systemic effects as well as the lung effect of each dose [ ].

Inhalation devices

The importance of the inhalation device has been shown in studies of beclomethasone. Pressurized metered-dose inhalers containing chlorofluorocarbons produce relatively large particles that deposit less than 10% of the delivered dose in the lungs, primarily in the large airways, more than 90% being deposited in the oropharynx. A hydrofluoroalkane beclomethasone multidose aerosol (Qvar 3 M Pharmaceuticals) delivers a smaller particle size. More than 50% is deposited in the lungs in animal and mechanical models. This has been confirmed using radiolabelled Qvar in patients with asthma and in healthy volunteers. In these subjects, 50–60% of the dose is deposited throughout the airways and about 30% in the oropharynx. The breath-activated Autohaler provides lung deposition equivalent to an optimally used Qvar inhaler, by automatically delivering drug early in the inhalation. Neither of these devices is improved by the addition of a spacer [ ].

Both inhaled and swallowed fractions cause significant systemic activity, the degree of which depends on the inhaler device used. In one study, systemic activity was greater using a dry power inhaler (52%) than a pressurized metered-dose inhaler with a large volume spacer (28%) [ ]. It was recommended that when high-dose beclomethasone is used, a pressurized metered-dose inhaler with a large volume spacer would help in limiting potential adverse effects.

The systemic availability of inhaled budesonide has been measured in 15 healthy volunteers, using an open crossover design. Each subject was given three treatments, intravenous budesonide 0.5 mg, inhaled budesonide (from a metered-dose inhaler with a Nebuhaler) 1 mg (200 micrograms × 5) plus oral charcoal, and inhaled budesonide 1 mg without oral charcoal. The treatment order was randomized. The mean systemic availability of inhaled budesonide compared with intravenous budesonide was 36% with charcoal and 35% without charcoal, indicating that the absorption of budesonide from the gastrointestinal tract did not contribute to its systemic availability. Pulmonary deposition was 36% with charcoal and 34% without. When the inhaler was used incorrectly, that is, the canister was shaken only before the first of the five inhalations, systemic availability fell by 50%. This shows that the performance of each inhaler is very dependent on proper use [ ].

The available studies suggest that fluticasone is more effective than beclomethasone, triamcinolone, or budesonide. However, budesonide delivered by Turbuhaler has equivalent efficacy to fluticasone delivered by metered-dose inhaler or Diskhaler, and is more effective than beclomethasone. When comparative safety is considered, budesonide and triamcinolone delivered by metered-dose inhaler have less systemic activity than fluticasone. Beclomethasone and fluticasone delivered by metered-dose inhaler are equivalent. Budesonide delivered by Turbuhaler has less systemic activity than fluticasone delivered by Diskhaler [ ].

The equivalence of inhaled glucocorticoids based on equipotent (cortisol suppression) effects has been studied by the Asthma Clinical Research Network (ACRN). Six different inhaled glucocorticoids and matched placebos (beclomethasone chlorofluorocarbon, budesonide dry powder inhaler, fluticasone dry powder inhaler, fluticasone chlorofluorocarbon metered-dose inhaler, flunisolide chlorofluorocarbon, and triamcinolone chlorofluorocarbon) were compared by measuring their systemic effects [ ]. Glucocorticoid-naïve patients with asthma (n = 156) were enrolled at six centers and a one-week doubling dose design was used for each of the six inhaled glucocorticoids and matched placebos to a total of four doses. The best outcome variable for the reliable assessment of a systemic effect was the 12-hour AUC of the hourly overnight plasma cortisol measurements from 8 p.m. to 8 a.m. Microgram comparisons of the glucocorticoids could only be performed at 10% cortisol suppression, because fluticasone did not cause higher suppression. The following equipotent doses (that is, doses producing equal systemic cortisol suppression) were found: flunisolide 936 micrograms; triamcinolone 787 micrograms; beclomethasone 548 micrograms; fluticasone dry powder: 445 micrograms; budesonide 268 micrograms; and fluticasone metered-dose inhaler 111 micrograms. The ranking of systemic effects was very similar to that found earlier in a large meta-analysis [ ].

Dry powder inhaler and pressurized metered-dose inhaler for administration of low-dose budesonide (400 micrograms/day) have been compared [ ]. Only the dry powder caused suppression of the hypothalamic–pituitary–adrenal axis. As effective inhaled glucocorticoid therapy is expected to cause detectable reductions in the physiological secretion of cortisol [ ], low-dose budesonide by pressurized metered-dose inhaler is probably not effective. In another study, budesonide inhalation suspension, developed for nebulization to meet the specific needs of infants and young children, did not cause significant suppression of hypothalamic–pituitary–adrenal axis function (basal plasma cortisol concentrations and corticotropin test) in doses from 0.25 to 1.0 mg [ ]. However, inhaled fluticasone propionate by pressurized metered-dose inhaler with a spacer in 62 children resulted in abnormal morning cortisol concentrations in 36% (17 using a low dose of 176 micrograms/day; 43 using a high dose, over 880 micrograms/day) [ ].

In a randomized, double-blind study, adult asthmatic patients took budesonide 800 micrograms/day over 12 weeks either by Easyhaler (n = 103) or by Turbuhaler (n = 58) dry powder inhaler. The Easyhaler was equivalent to the Turbuhaler with regard to safety and efficacy, but was more acceptable to the patients [ ].

Local adverse reactions

The local adverse reactions of inhaled glucocorticoids have been studied in a prospective, cross-sectional, cohort study in 639 asthmatic children using beclomethasone (721 micrograms/day) or budesonide (835 micrograms/day) for at least one month [ ]. The local adverse effects included cough (40%), thirst (22%), hoarseness (14%), dysphonia (11%), oral candidiasis (11%), perioral dermatitis (2.9%), and tongue hypertrophy (0.1%). A spacer doubled the incidence of coughing.

Potent glucocorticoids in high local doses increase the risk of local infection and even promote atrophy of the bronchial mucosa. The latter effect has not proved clinically important, but there is an increased incidence of oropharyngeal candidiasis. The incidence varies depending on the population studied and the criteria used to make the diagnosis; candidiasis can affect 13–71% of patients, the highest incidence being seen with doses up to 0.8 mg. Candidiasis rarely requires treatment or withdrawal of the drug. Local measures, such as gargling immediately after inhalation of the aerosol, and the use of a large-volume spacer are effective in reducing the incidence of this complication. However, candidiasis can result in dysphonia.

A local myopathy caused by inhaled glucocorticoids can also cause dysphonia. However, patients with asthma have more dysphonia and vocal fold pathology than healthy controls and inhaled glucocorticoids can improve the voice in some patients [ , ].

In some patients, the propellant used in certain aerosols can cause acute bronchoconstriction [ ].

Budesonide

Inhaled budesonide has been studied in the management of moderately severe, acute asthma in children [ ]. After treatment with nebulized terbutaline, 11 children were randomly allocated to receive one dose of either budesonide 1600 micrograms by Turbuhaler or prednisolone 2 mg/kg. There was no significant difference in the improvement of the pulmonary index score or peak expiratory flow rate. Children treated with budesonide had an earlier clinical response than those given prednisolone. Prednisolone caused a fall in serum cortisol concentration. The authors concluded that children with moderately severe asthma attacks could be effectively treated with a short-term course of inhaled budesonide, starting with a high dose and reducing over the following week.

In 81 patients with acute asthma, mean age 38 years, inhaled budesonide 1600 micrograms bd via Turbuhaler was compared with oral prednisolone (40 mg on day 1, reducing to 5 mg by day 7) in a randomized, double-blind, parallel-group design [ ]. The mean increase in FEV ₁ from baseline to day 7 was 17% with budesonide and 18% with prednisolone. Mean values of morning peak expiratory flow rate increased from day 1 to day 7 by 67 l/second with budesonide and by 57 l/second with prednisolone. There were no statistically significant differences between the groups in either symptoms or the number of doses of rescue medication. The authors concluded that high-dose inhaled budesonide may be a substitute for oral therapy in the treatment of an acute attack of asthma.

The effect of supplementary inhaled budesonide in acute asthma has been evaluated in a randomized, double-blind comparison with standard treatment in 44 children aged 6 months to 18 years with a moderate to severe exacerbation of asthma [ ]. Prednisone 1 mg/kg orally and nebulized salbutamol (0.15 mg/kg) every 30 minutes for three doses and then every hour for 4 hours were given to all children. In addition, each child was given 2 mg of nebulized budesonide or nebulized isotonic saline. There was a more rapid discharge rate in the budesonide group. There were no adverse effects. The authors concluded that nebulized budesonide may be an effective adjunct to oral prednisone in the management of moderate to severe exacerbations of asthma.

Fluticasone

Inhaled fluticasone 500 micrograms bd from a pressurized metered-dose inhaler for 6 months has been compared with placebo in a randomized, double-blind trial in 280 patients with COPD, aged 50–75 years [ ]. There was no significant difference in the number of patients who suffered one or more exacerbations. Moderate or severe exacerbations occurred significantly more often with placebo than with fluticasone. Diary-card scores, morning peak expiratory flow rate, clinic FEV ₁ , FVC, and mid-expiratory flow all improved significantly with fluticasone. Scores for median daily cough and sputum volume were significantly lower with fluticasone than with placebo. At the end of treatment, patients using fluticasone had increased their 6-minute walking distance significantly more than those using placebo. Fluticasone propionate was tolerated, as well as placebo, with few adverse effects and no clinically important effect on mean serum cortisol concentration. The authors suggested that inhaled glucocorticoids may have an important place in the long-term management of patients with COPD.

Sensory systems

Psychological

High doses of oral glucocorticoids can cause adverse psychiatric effects, including mild euphoria, emotional lability, panic attacks, psychosis, and delirium. There have been sporadic case reports of similar reactions in patients using inhaled glucocorticoids. Of 60 preschool children with a recent diagnosis of asthma taking inhaled budesonide 100–200 micrograms/day, nine had suspected psychological adverse events after 18 months, according to their parents [ ]. The symptoms reported were irritability, depression, aggressiveness, excitability, and hyperactivity. These adverse events disappeared when the medication was terminated or reduced and recurred when budesonide was restarted at higher doses. Most of the symptoms occurred within 2 days from starting the high dose (200 micrograms 2–4 times a day).