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Drugs acting on the respiratory tract

Aerosol delivery Propellants Pulmonary delivery of drugs is the administration route of choice in respiratory diseases such as chronic obstructive pulmonary, disease and asthma. Different devices are available, including metered dose inhalers, dry powder inhalers, and nebulizers, and nearly 80% of asthmatic patients worldwide use metered dose inhalers (1R). Chlorofluorocarbon has been used as an aerosol propellant in metered dose inhalers; however, it depletes the ozone layer and is being replaced by more environment-friendly propellants. The first chlorofluorocarbon-free metered dose inhaler for asthma treatment was approved by the FDA in 1996 (2 R) and the European Union has set 2005 as a target date for the withdrawal of all chlorofluorocarbon-based inhalers (1R). In the USA, prescriptions for chlorofluorocarbon-free medications rose from 16.4 million in 1996 to 33.8 million in 2000 (2R). Most of the chlorofluorocarbon-free medications were steroids for nasal use (27.2 million). However, chlorofluorocarbon-containing medications still represented two-thirds of all prescriptions and increased from 63.0 to 67.6 million dispensed (2R ). The search for ozone-friendly propellants has concentrated on two hydrofluoroalkanes with physicochemical properties similar to the chlorofluorocarbons: hydrofluoroalkane 134a and hydrofluoroalkane 227 (1g ). A new generation of chlorofluorocarbon-free metered dose inhalers has been designed by the pharmaceutical industry to be equivalent to the currently marketed chlorofluorocarbon-containing inhalers in terms of efficacy, safety, and dose 9 2004 Elsevier B.V. All rights reserved.

Side Effects of Drugs, Annual 27 J.K. Aronson, ed. 172

delivered. This goal was achieved by using the Modulite | technology, by dissolving the drug in the propellant with the aid of a glycerol-like co-solvent (3R). Beclomethasone dipropionate and budesonide Modulite | formulations have been compared with equivalent chlorofluorocarbon products in small groups of healthy volunteers and asthmatic patients (4c): there was no significant difference in morning serum cortisol or urinary cortisol excretion, suggesting that the systemic availability of the inhaled corticosteroids with different propellants is similar Moreover, plasma profiles of beclomethasone dipropionate and B17MP were similar after inhalation of beclomethasone dipropionate Modulite | and beclomethasone dipropionatechlorofluorocarbon, suggesting that pulmonary delivery to the lung is comparable with the two propellants (4c). There have been three randomized, doubleblind studies in adult asthmatics of the efficacy and safety of a new beclomethasone dipropionate-hydrofluoroalkane 134a formulation, equivalent in dose per actuation to the currently marketed beclomethasone dipropionate chlorofluorocarbon products (5c-7c). Daily doses of beclomethasone dipropionate hydrofluoroalkane 134a 1000 # g over 12 weeks given by metered dose inhaler (5 c) or a spacer jet device (6 c) were equivalent in terms of safety and efficacy compared with beclomethasone dipropionate chlorofluorocarbon 1000 Izg. The same was true for doses of 400 #g (7c). In another study different doses of flunisolide hydrofluoroalkane were tested in 21 healthy adult volunteers for 4.5 days (170 lzg, 340 Izg, 680 Izg); there was a dose-related response after both single- and multiple-dose administration (8c). There was no accumulation of flunisolide with repeated dosing, suggesting that the systemic availability of flunisolide hydrofluoroalkane is low. A randomized, double-blind,

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placebo-controlled study with daily doses of 80 #g and 160 Izg over 12 weeks in 353 asthmatic children gave similar results (9c). Hydrofluoroalkane 134a and chlorofluorocarbon have been compared in two randomized, double-blind, placebo-controlled studies with salbutamol. Salbutamol 180 #g in hydrofluoroalkane 134a given 30 minutes before an exercise challenge was as safe and effective as 180 Izg in chlorofluorocarbon in 24 patients with documented exercise-induced bronchospasm (lOt). In 63 patients with mild to moderate asthma salbutamol in hydrofluoroalkane 134a or chlorofluorocarbon were of comparable efficacy without any difference in the incidence of adverse events ( l lC ). These results suggest that the transition from chlorofluorocarbon-containing to chlorofluorocarbon-free metered dose inhalers is possible without concerns about safety and efficacy

of the hypothalamic-pituitary-adrenal axis. As effective inhaled corticosteroid therapy is expected to cause detectable reductions in the physiological secretion of cortisol (12r), lowdose 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 hypothalamicpituitary-adrenal axis function (basal plasma cortisol concentrations and ACTH test) in doses from 0.25 to 1.0 mg (16c). However, inhaled fluticasone propionate by pressurized metereddose inhaler with a spacer in 62 children resulted in abnormal morning cortisol concentrations in 36% (17 using a low dose of 176 Izg/day; 43 using a high dose, over 880 Iz g/day ) (17c). The equivalence of inhaled corticosteroids based on equipotent (cortisol suppression) effects has been studied by the Asthma Clinical Research Network (ACRN). Six different inhaled corticosteroids 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 (18c). Steroid naYve people with asthma (n = 156) were enrolled at six centers and a 1week doubling dose design was used for each of the six inhaled corticosteroids 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 corticosteroids could only be performed at 10% cortisol suppression, because fluticasone did not cause higher suppression. The following equipotent doses (i.e. doses producing equal systemic cortisol suppression) were found: flunisolide 936 Izg; triamcinolone 787 #g; beclomethasone 548 Ixg; fluticasone dry powder: 445 Izg; budesonide 268 Izg; fluticasone metered dose inhaler 111 Izg. The ranking of systemic effects was very similar to that found earlier in a large meta-analysis (19M). In a randomized, double-blind study adult asthmatic patients took budesonide 800 I~g/day

Systemic availability of inhaled corticosteroids (SEDA-23, 175; SEDA-24, 185; SEDA-26, 187) The systemic availability of an inhaled corticosteroid 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 (12r). The different methods of assessing hypothalamic-pituitary--adrenal axis activity in patients using inhaled corticosteroids have been compared (13c). The AUC of serum cortisol concentrations was the most reliable method. There were significant positive correlations between AUC and the 8 a.m. serum and salivary cortisol concentrations. The authors favored the non-invasive method of salivary concentration measurement. However, 24-hour urine collection is not recommended, as it correlated only moderately well. This finding is consistent with the results of other studies. Urinary free cortisol estimation based on immunoassay after inhaled corticosteroids may be an unreliable surrogate marker of adrenal suppression, and studies using this method should be interpreted with caution (14c). Dry powder inhaler and pressurized metered-dose inhaler for administration of low-dose budesonide (400 Izg/day) have been compared (15"). Only the dry powder caused suppression

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over 12 weeks either by Easyhaler | (n = 103) or Turbuhaler | (n = 58) dry powder inhaler. The Easyhaler was equivalent to the Turbuhaler with regards to safety and efficacy, but was more acceptable to the patients (20c).

INHALED CORTICOSTEROIDS (SED-14, 512; SEDA-23, 178; SEDA-26, 186)

Risks of inhaled corticosteroids in children Inhaled corticosteroids are recommended as first-line therapy for persistent asthma in children, to reduce both asthma symptoms and inflammatory markers. Treatment should be begun early in the course of the disease, because inhaled corticosteroids can preserve airway function and prevent airway remodelling and subsequent irreversible airway obstruction (21M). Because asthma is a chronic disease requiring long-term treatment, it is very important to balance the safety and efficacy of inhaled corticosteroids to achieve optimal long-term results. Major safety concerns in children are the potential adverse effects on growth, adrenal function, and bone mass. Overall, the benefits of inhaled corticosteroids clearly outweigh their potential adverse effects and the risks of poor asthma control. However, high doses o f inhaled corticosteroids in children are still of concern (22M). It is o f utmost importance to use the lowest effective dose, to limit systemic availability by selecting drugs with high first-pass hepatic inactivation, and to instruct patients on proper inhalation technique. Moreover, the use of adjuvant asthma medications acting by different mechanisms can help to reduce inhaled corticosteroid dosages (21 M, 22M). These add-on therapies include leukotriene modifiers, long-acting beta2-agonists, cromoglicate and nedocromil, and in selected cases theophylline. These agents should be added to, but should not in any case replace, inhaled corticosteroid therapy (21 M, 22M). In recent years inhaled corticosteroids have been prescribed more and more in younger children at an earlier stage of their disease and for

A d r e n a l suppression in children

longer periods; children with severe asthma are also treated with larger doses than licensed. Therefore, considerations of their systemic effects are of importance. Symptomatic adrenal insufficiency has been reported in children after prolonged high-dose treatment with inhaled corticosteroids. 9 Fourboys 4-8 years old with symptomatic adrenal insufficiency had all used consistent high doses of fluticasone propionate 1000-1500 #g/day over extended periods (16 months to 5 years) (23A). They presented with acute hypoglycemia secondary to iatrogenic adrenal suppression, with abnormal ACTH tests, although none had Cushingoid features. 9 A 33-year-old man and three children (two girls, one boy, 7-9 years) presented with symptomatic adrenal insufficiency (24A). All three children had seizures because of hypoglycemia, and the man had a low blood pressure, nausea, and fatigue. In all cases ACTH tests were abnormal showing adrenal insufficiency. The children had used fluticasone propionate 500-2000 Izg/day and the man had recently switched from fluticasone propionate 1000-2000 #g/day to budesonide dry powder inhaler 800 lzg/day. Only one of the children had used oral glucocorticosteroids in the previous year 9 A 21-month-old boy had a hypoglycemia-induced seizure in the setting of adrenal suppression (25A). He had been given increasing doses of budesonide up to 2000 Izg qds and oral glucocorticosteroids until the age of 15 months. 9 A 32-month-old girl developed hypoglycaemic seizures (26A). She had been given fluticasone propionate 440-880 lzg/day and up to 5 months before the incident oral glucocorticosteroids. In addition to these case reports, there has been a survey of symptomatic adrenal suppression associated with inhaled corticosteroids in the UK (27c). Only 24% o f the questionnaires were returned (709 responses), and there were 28 cases of symptomatic adrenal suppression reported in children and five in adults (including the 10 cases discussed above). The children presented mostly with hypoglycemia and coma, whereas the adults mainly had lethargy and nausea. No obvious precipitating cause was found in 65% of the cases. In four children diagnosis was delayed by 3 months to 2 years. All but three patients had been treated with fluticasone propionate alone, but at high daily doses (children 500-2000 #g, adults 1000-2000 tzg). One child had used both fluticasone propionate and budesonide and one adult and one child used beclomethasone dipropionate. Different inhaled corticosteroids have recently been compared for their suppressing

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effects on the hypothalamic-pituitary-adrenal axis (18c ). In a large meta-analysis budesonide or beclomethasone dipropionate in doses of over 1500 tz g/day were associated with adrenal suppression in adults (19M ). In children, fluticasone propionate 200 Izg/day or budesonide 400 Izg/day caused detectable adrenal gland suppression (28c). For interpretation of the different studies it is very important to distinguish between detectable indicators for systemic drug action (i.e. reduced morning cortisol) and true suppression of the hypothalamicpituitary-adrenal axis, as determined by adrenal function tests (standard-dose or low-dose ACTH test), which are more predictive of possible systemic adverse effects (12r ). The fact that fluticasone propionate is involved in the vast majority of the published cases should be discussed further. The systemic concentration of an inhaled glucocorticoid depends on the absorbed fraction of the drug in the gut and in the lung. Swallowed fluticasone propionate is almost completely metabolized in the liver by CYP3A4 (first-pass effect over 99.9%) before reaching the systemic circulation; however, its metabolic clearance can be altered in patients with low CYP3A4 expression and activity ( 29c). Pulmonary absorbed fluticasone propionate is very potent; because of its pronounced lipophilicity it binds with higher affinity to glucocorticoid receptors and has a larger distribution volume and a longer half-life than other inhaled corticosteroids ( 30M ). These characteristics give it the potential of accumulating with multiple doses. Other factors that determine the absorbed fraction of inhaled corticosteroids include age of the child, as lung deposition of inhaled drugs increases with age (31M). Therefore, the minimum effective dose may fall as the child becomes older. Moreover, it is reasonable to hypothesize that systemic absorption will increase once asthma control is established (3U). Furthermore, patient adherence and inhaler technique are two factors that can have a large influence on the amount of corticosteroid inhaled and absorbed. However, the most important factor is the dose. The safety and efficacy of fluticasone propionate in children in daily doses of 100200 tzg have been demonstrated in many studies (33M). The doses in the case reports of symptomatic adrenal suppression have to be

considered as being excessively high. These reports reflect excessive dosing of inhaled corticosteroids, and in some cases a residual effect of previous oral glucocorticosteroid treatment cannot be excluded. The use o f excessive doses is empirical and not supported by the literature. All inhaled corticosteroids have a flat dose-response curve (34M). Extensive clinical experience with inhaled corticosteroids over the past 20 years has suggested that the risk of adrenal insufficiency with inhaled corticosteroids alone is very low when recommended doses are used (35M). To avoid symptomatic adrenal suppression, the lowest effective dose should always be used. Before automatically increasing the dose in refractory patients, the diagnosis should be reconsidered. Furthermore, a reduction in the dosage of inhaled corticosteroid can also be achieved with the addition of adjuvant therapies, such as leukotriene receptor antagonists and long-acting beta2adrenoceptor agonists (22M). Monitoring children using inhaled corticosteroids has recently been discussed (12r ). Children using low to moderate doses of inhaled corticosteroids (up to 200 Ixg of fluticasone propionate or budesonide) do not require routine hypothalamic-pituitary-adrenal axis measurement. In children using consistently higher doses (up to 400 lzg o f fluticasone propionate or budesonide) or using glucocorticoids by other routes, morning plasma cortisol should be monitored periodically because of the increased risk of clinically significant adrenal suppression. If cortisol concentrations are below 276 Izmol/l (100 #g/l), functional testing of the hypothalamic-pituitary-adrenal axis should be considered. Growth inhibition Oral glucocorticoids inhibit growth by blunting pulsatile growth hormone secretion, by decreasing insulin-like growth factor-1 activity, and by directly inhibiting collagen synthesis (36M ). Although inhalation reduces systemic exposure, concerns have been raised regarding the potential effects on growth and final height in children, especially when inhaled corticosteroids are used for long periods. A two-part review was published in 2002, addressing the difficulties of assessing the effects of asthma therapy on childhood growth and reviewing the published literature based on the authors' recommendations (37 M, 38M). In

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the first part, a simple classification system for growth studies was developed: 9 comparisons with placebo (type 1 studies); 9 comparisons with non-steroidal asthma therapy (type 2 studies); 9 comparisons with another inhaled corticosteroid (type 3 studies); 9 comparisons with "real life" asthma therapy (type 4 studies) (37M). In the context of these different study types, the authors also discussed the choice of end-point, key trial design issues, the selection and numbers of subjects in the active and control groups, the duration of assessments, and methods for measuring height and data analysis. They also elaborated specific recommendations regarding study duration, age~sexual maturity of the patients, exclusion criteria for height and growth velocity, permitted therapy during the study, the protocol for height measurement, the numbers of patients for adequate statistical power, and methods for statistical analysis (37M). In the second part, they selected 18 growth studies that included minimal criteria, such as selected control group, measured height by stadiometry, and at least a 12-month duration; they compared the design attributes of these studies with the described recommendations (38M). Of the 18 selected studies, 17 were susceptible to one or more important confounding factors; nevertheless, the outcomes of all 18 studies were considered to be consistent. In summary, impaired growth velocity was found with budesonide and beclomethasone dipropionate compared with placebo, non-steroidal treatment, and fluticasone propionate during 1-2 years of therapy, but none of the inhaled corticosteroids appeared to affect final height (38M). Growth in children treated with lowdose fluticasone propionate (up to 200 Ixg/day) for I year is similar to growth in those treated with placebo or non-steroidal therapy. Standard pediatric doses of inhaled corticosteroids (less than 800 Izg of budesonide and less than 400 Izg of budesonide or fluticasone) are considered not to affect growth adversely (35M, 39r). The risk of growth suppression depends on the dose, the administration regimen, and the delivery device. An important confounding .factor is the influence of non-adherence to inhaled corticosteroid

treatment (4Or). Sensitive and reliable measures of adherence should be applied when evaluating long-term effects on height. The time of dosing can influence the effect of inhaled corticosteroids on growth suppression in the prepubertal child, since GH secretion is generally confined to night-time. Therefore, once-daily morning dosing could be advantageous (41M). For clinical practice, the lowest effective dose should be achieved, and all children using inhaled corticosteroids should have their growth measured every 6 months, as this is a sensitive method of detecting significant systemic effects (35 M, 41M). These results apply to children over 4 years of age; for younger children only assumptions can be entertained and age-specific studies are needed (41M). Bone mineral density The adverse effects of oral corticosteroids on bone metabolism are well established. However, studies of the effects of inhaled corticosteroids on markers of bone mineral density have provided conflicting data (42M). A cross-sectional study in children (43 c) showed no significant difference in total and anteroposterior spine bone mineral density between children with asthma treated with longterm budesonide (20,0--800 ILg for at least 6 months; n = 52) and asthmatic children who had never used inhaled corticosteroids (n = 22). These results are in agreement with those of a larger cross-sectional study of the effects of long-term treatment (3-6 years, mean 4.5 years) with inhaled budesonide on total bone mineral density in children with asthma (n = 157). The results provided evidence that long-term treatment with inhaled corticosteroids in moderate dosages is unlikely to affect bone mineral density adversely in children with asthma (44M). However, a recent study of the association of clinical risk factors and bone density with fractures in 324 prepubertal children, of whom 32 had a fracture, suggested that for total fracture risk bone mineral density may be less important than clinical risk factors (45c). In a multivariate model incorporating age, weight, height, breast-feeding history, sports participation, and the use of inhaled corticosteroids, these factors accounted for 10% of the variability in the risk of fracture.

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Surprisingly, bone mineral density in the lumbar spine, femoral neck, and total body bone did not differ between those with or without fractures. More data on the effect of inhaled corticosteroids on bone mineral density in adults has been generated by the large randomized, multicenter, double-blind, placebo-controlled EUROSCOPE (European Respiratory Society Study on Chronic Obstructive Pulmonary Disease) study of 912 patients with chronic obstructive pulmonary disease randomly assigned to treatment for 3 years with budesonide 800 #g/day or placebo (46c). There were no significant differences in bone mineral density at L2-4 vertebrae, the femoral neck, trochanter, or Ward's triangle; nor did the fracture rate between budesonide-treated and placebo-treated patients differ. These findings are in contrast to recent data from the Lung Health Study, which showed that triamcinolone 1200 #g/day f o r 4 years was associated with a statistically significant 2% reduction in bone mineral density in the femoral neck compared with placebo (47M). It can be hypothesized that different corticosteroids have different systemic effects, and therefore different effects on bone metabolism. An alternative hypothesis is that these effects are dose-dependent (22M), support for which comes from a population-based case-control study o f 16 341 older patients with hip fractures (mean age 79 years) and 29 889 controls; recent use o f an inhaled corticosteroid was associated with a small dose-dependent increase in the risk o f hip fracture (48c).

inhibitors (n = 53 845) were the controls. Relative to controls oral corticosteroid users (n = 31 864) were more likely to develop diabetes mellitus, but there was no association between the use of inhaled corticosteroids (n = 38441) and diabetes mellitus. These results suggest that the use of inhaled corticosteroids in elderly people does not significantly increase the risk of diabetes mellitus.

Endocrine Diabetes mellitus The association between inhaled corticosteroids and the risk of diabetes mellitus in elderly people (over 65 years) has been investigated in two Canadian studies. In a nested case-control study of the association between current use of inhaled corticosteroids and the risk of using antidiabetic drugs among 21 645 subjects the risk of diabetes was not statistically significant (49r Moreover, there was no statistically significant increase in risk among users of high-dose beclomethasone compared with non-users. In a retrospective population-based cohort study using administrative databases, the association between oral and inhaled corticosteroid use and the onset of diabetes mellitus in the elderly was quantified (50c). Users of proton pump

Skin Contact allergy to corticosteroids is not rare in patients with atopic dermatitis. In patients with known contact allergy to budesonide allergic skin reactions can also occur when inhaled forms of the drug are used, as shown by a randomized, double-blind, placebo-controlled study in 15 non-asthmatic patients with budesonide hypersensitivity on patch testing (51 c). In four of seven patients who used inhaled budesonide, there was reactivation of the 6-week-old patch test sites and they had new distant skin lesions. No fare-up reactions were observed in the other 11 patients (three had used inhaled budesonide and eight placebo for 1 week). None of the patients developed respiratory symptoms; spirometry and peak expiratory flow rates remained normal. Drug interactions Interactions with other drugs can increase plasma concentrations of inhaled corticosteroids. Itraconazole, a potent inhibitor of CYP3A4, markedly increased plasma concentrations of inhaled budesonide (52c). Ritonavir, another potent inhibitor of CYP3A4, caused Cushing's syndrome in a patient using fluticasone propionate 1000 p.g/day (53A).

LEUKOTRIENE MODIFIERS (SEDA-24, 184; SEDA-25, 197; SEDA-26, 193)

Leukotriene receptor antagonists and Churg-Strauss syndrome Leukotriene receptor antagonists (montelukast, pranlukast, zafirlukast) were introduced in 1998. They have both anti-inflammatory and bronchodilator effects and are increasingly

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being used in patients with moderate to severe asthma in order to reduce corticosteroid dosages. In early clinical trials leukotriene receptor antagonists were generally well tolerated, but in the postmarketing phase they have been associated with the Churg-Strauss syndrome. Churg-Strauss syndrome is a rare disease, first described in 1951, characterized by the histological findings of eosinophilic tissue infiltration, extravascular eosinophil granulomas, and necrotizing vasculitis. It develops in patients with a history o f upper airway disease (especially allergic rhinitis and sinusitis) and asthma. There are different definitions of the syndrome, and it is important to know which definition is being used when the results of different incidence studies are being compared. Clinically the syndrome has been defined (54 R) as a combination of asthma, peripheral eosinophilia (over 1.5 x 109/1), and a systemic vasculitis involving two or more extrapulmonary organs. Recognized clinical risk factors include moderate to severe asthma, chronic sinusitis, and a recent reduction in systemic corticosteroid therapy (55R). An important feature is the phasic developmental pattern of the disease, and corticosteroid therapy suppresses some manifestations of the syndrome, leading to incomplete disease. Churg and colleagues labelled these cases "formes frustes" of Churg-Strauss syndrome (56~). Careful monitoring must be ensured when tapering corticosteroids in steroiddependent patients to avoid development of incomplete disease. In 2002 there were several reports of patients with Churg-Strauss syndrome who were using leukotriene receptor antagonists. 9 Two 50-year-old men, both using inhaled corticosteroids, presented with Churg-Strauss syndrome after taking montelukast for 4-5 months, not related to steroid tapering (57A). One had a history of asthma and recurrent sinusitis for 5 years with intermittent short-course oral corticosteroids and continued inhaled steroids, whereas the other had asthma for I year treated with only inhaled corticosteroids. 9 Two women (aged 60 and 62 years) with allergic rhinitis and asthma, one using inhaled corticosteroids and the other oral corticosteroids, developed Churg-Strauss syndrome after taking montelukast (58A). In the woman using oral steroids dosage reduction preceded the onset of the syndrome; in the woman using inhaled steroids there was no dosage reduction. The authors also presented the case of a 54-year-old man with a history

of Churg-Strauss syndrome who relapsed after taking montelukast. 9 A 50-year-old man with a history of severe asthma and tapering of prednisone took montelukast and developed an erythematous rash and mononeuritis multiplex; skin biopsy, confirmed the diagnosis of Churg-Strauss syndrome (59A). 9 A 54-year-old man with no history of corticosteroid therapy presented with systemic symptoms and a purpuric rash after taking zafirlukast; the diagnosis was Churg-Strauss syndrome (604). 9 An 18-year-old woman with childhood asthma using inhaled corticosteroids and zafirlukast developed Churg-Strauss syndrome 10 days after starting to use rokitamycin (61A). Of 22 asthmatic patients taking leukotriene receptor antagonists who developed ChurgStrauss syndrome, 13 had used zafirlukast, eight montelukast, and one pranlukast (62M). All had used inhaled or oral corticosteroids. The onset of the syndrome was at 2 days to 10 months after starting treatment with the leukotriene receptor antagonist; the interval between the last dose of oral steroids and the recognised onset of Churg-Strauss syndrome ranged from 3 days to 8 months. In severalpatients the signs and symptoms of Churg-Strauss syndrome became manifest after the start of leukotriene receptor antagonist treatment and tapering of inhaled~oral steroids (13 o f 23 patients). There are different explanations for the possible association between leukotriene receptor antagonist treatment and Churg-Strauss syndrome. The favored hypothesis is unmasking of Churg-Strauss syndrome (meaning either unmasking of a previously contained pathological condition or the clinical declaration of a "forme fruste") after reduction of corticosteroid dosage (55 R, 63r). This is supported by the fact that Churg-Strauss syndrome has also been reported in asthmatic patients who are tapering their doses of corticosteroid after the introduction of other antiasthmatic drugs (55 R). It seems unlikely that leukotriene receptor antagonists themselves provoke Churg-Strauss syndrome, since none of the established mechanisms o f adverse drug reactions provides a plausible explanation for the association (55R). The incidence of Churg-Strauss syndrome among asthmatic patients has been calculated in a cohort study of 36 230 patients with asthma (64c). The incidence rates of definite ChurgStrauss syndrome were 0--67 cases per million per year, depending on the definition used. The small number of cases did not allow subgroup

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analysis. The occurrence o f Churg-Strauss syndrome during leukotriene receptor antagonist therapy could therefore be coincidental, because the rate o f 64 cases per million patients per year in association with leukotriene receptor antagonists is comparable to the estimated rate of 18-74 cases per million patients per year in the asthma population observed before the introduction of these drugs (55 R, 62~t ), (63r). Large epidemiological studies, including data on corticosteroid-naive patients using leukotriene receptor antagonists, are needed to address this question further. In summa~, to date most authors agree that the most plausible explanation for ChurgStrauss syndrome during therapy with leukotriene receptor antagonists is an unmasking mechanism (i.e. progression of clinical symptoms when oral corticosteroids are avoided, withdrawn, or withheld) rather than a druginduced disease. However, physicians should be aware of the possible development of ChurgStrauss syndrome in patients with moderate to severe asthma who are tapering their corticosteroid dosages, because early recognition and effective treatment o f the syndrome is of the utmost importance.

BETA2-ADRENOCEPTOR AGONISTS

(SED-14, 500;

SEDA-24, 187; SEDA-25, 192; SEDA-26, 190)

Formoterol

(SED-14, 506;

SEDA-25, 194; SEDA-26, 191) In a post-marketing surveillance study of the long-acting beta2-adrenoceptor agonist formoterol in the UK using the technique of prescription event monitoring, exposure and outcome data in 5777 patients aged 3-96 years were collected (67c). The most commonly reported events, excluding those related to respiratory disease, were headache, tremor, palpitation, cramp, and nausea and vomiting, events known to be associated with betaz-adrenoceptor agonists (68 R). However, the frequencies of nausea and vomiting (1.3%) and pruritus (0.5%) differed from the frequencies reported in the premarketing trials.

Salbutamol

(SED-14, 502;

SEDA-23, 185)

Montelukast

(SEDA-24, 184;

SEDA-26, 193) D r u g overdose Since montelukast is a relatively new drug, few data are available on unintentional poisoning. This makes it difficult to determine which dosages require aggressive decontamination or simple monitoring. Acute montelukast overdose with doses up to at least 150 mg/day have been reported in children. In most of the reports no adverse events were reported; when they occurred, symptoms included thirst, somnolence, mydriasis, hyperkinesia, and abdominal pain. In two cases of unintentional poisoning with montelukast there were no symptoms in a 3-year-old child who took 80 mg or in a 5-year-old child who took 135 mg (65A). In adults, montelukast doses up to 20- to 90-fold greater than the recommended dose (10 mg/day), given for longer than 1 week, were well tolerated and no unexpected adverse events occurred (66M).

The short-acting beta2-adrenoceptor agonists have pharmacologically predictable adverse effects (tachycardia, tremor, plasma altered potassium and blood glucose concentrations) and unpredictable effects, including airway hyper-responsiveness (68R). Rare adverse reactions to salbutamol are also occasionally reported.

Nervous system The often reported observation by parents of asthmatic children that salbutamol causes hyperactivity has been investigated in 19 children before and after the inhalation of 5 ml of a nebulized solution (isotonic saline or salbutamol 5 mg); there was no statistically significant difference in activity (69c). The authors hypothesized that the supposed effect on the children's activity might be dose related or might reflect a propellant effect rather than being a consequence of salbutamol itself.

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Metabolic

Transient lactic acidosis/lactatemia has been reported as an adverse effect of inhaled salbutamol. In five patients who received 5 mg salbutamol by inhalation serum lactate concentrations were 3.2-8.0 mmol/1 and arterial blood pH values 7.34-7.43; after 24 h serum lactate concentrations returned to normal without specific treatment (70A). In two other cases high-dose salbutamol caused lactic acidosis, contributing to respiratory failure in one patient and complicating the assessment and management of acute severe asthma in the other (71A). Respiratory compensation for this primary metabolic acidosis, characterized by increased respiratory rate and effort, may be mistaken for increased respiratory distress due to asthma. Lactic acidosis in acute asthma can therefore lead to problems in asthma management, including unwarranted intensification of beta2-adrenoceptor agonist therapy and the initiation of premature or unnecessary mechanical ventilation. Musculoskeletal The question of whether salbutamol can cause a myopathy has recently been discussed (72A). 9 A 76-year-old asthmatic woman developed increasing weakness, proximal muscle cramps, and fatigue. She had been using salbutamol spray (600 r and tablets (10 mg/day) for 2 years, and for 6 months had also used inhaled formoterol 24 p.g/day. There were increases in creatine kinase (494 IU/1; reference range 0-130 IU/1), lactate dehydrogenase (350 1U/l; 0-300 IU/1), and aldolase (10 IU/1; 0-7.5 IU/1). Myopathy was confirmed electrophysiologically and histologically. The three medications were withdrawn and 2 days later her condition began to improve; the muscle pain and weakness disappeared within 3 weeks. The authors concluded that beta2-adrenoceptor agonist activity had been responsible for the deleterious muscle effects and they proposed that beta2-adrenoceptor agonists should be added to the list of drugs that can cause myopathies. However, the exact effects of beta2adrenoceptor agonists on human skeletal muscle are not clear. They have also been reported to increase muscle strength and have been used in patients with muscle weakness, including spinal muscular atrophy (73A). Drug overdose A 28-year-old woman took an overdose of oral salbutamol (100 mg of salbutamol BP solution) (74A). She developed

diabetic ketoacidosis, with a serum glucose concentration of 17 mmol/1 (308 mg/dl). Diabetic ketoacidosis induced by salbutamol overdose is uncommon in patients without diabetes; however, this patient had a family history of diabetes. A 4-year-old girl with accidental salbutamol intoxication (2.3 mg/kg) developed fever (38~ besides the classical signs of salbutamol intoxication (75A). Since she had no identifiable focus of infection the possibility of a thermogenic effect induced by increased adrenergic stimulation due to salbutamol intoxication was considered.

Terbutaline

(SED-14, 507;

SEDA-23, 186)

Nervous system

Acute paraparesis occurred after an injection of terbutaline sulfate for premature labor in a 26-year-old woman (76A).

ANTICHOLINERGIC DRUGS (SED-14, 499; SEDA-24, 192; SEDA-26, 194)

Tiotropium bromide The parasympathetic nervous system plays a major role in regulating bronchomotor tone. Bronchoconstriction due to increased parasympathetic bronchomotor tone is thought to be the major component of airway obstruction in patients with chronic obstructive pulmonary disease. Inhaled anticholinergic drugs, such as the quaternary ammonium compound ipratropium bromide, are therefore recommended as firstline bronchodilators in the treatment of chronic obstructive pulmonary disease. The most recently developed quaternary ammonium compound, tiotropium bromide, is an anticholinergic bronchodilator that binds with similar affinity to the three muscarinic receptor subtypes (77R). However, tiotropium dissociates more slowly from M1 and M3 receptors in bronchial smooth muscle than from M2 receptors. This results in a long half-life of the bound complex, allowing once-daily administration.

Drugs acting on the respirato~ tract

Chapter 16

The efficacy and safety of tiotropium have been studied in vitro and in early clinical trials, and dose-ranging studies have shown that tiotropium dry powder 18 p.g/day is safe and efficacious (77R-79R). Tiotropium is inhaled from the HandiHaler | a dry-powder, breathactivated inhaler system that delivers particles to the lung over a wide range of airflow limitations in patients with chronic obstructive pulmonary disease; it can be effectively delivered at inspiratory flow rates as low as 20 1/min (80c). Pharmacodynamic steady-state studies have shown that most of the bronchodilator activity is achieved with one to two doses within 48 hours, although a carryover effect on forced vital capacity was observed beyond 48 hours (81c). Several large, randomized, double-blind, controlled comparisons of tiotropium with placebo (82c), ipratropium (83c), and salmeterot (84 r ) have been published. In a multicenter, double-blind, placebo-controlled trial in patients with stable chronic obstructive pulmonary disease tiotropium 18 I.tg/ day for 1 year (n = 550) significantly improved lung function (mean trough FEV1, FVC, PEFR) and reduced dyspnea compared with placebo (n = 371) (82r Moreover, tiotropium recipients had better health status scores, fewer exacerbations of chronic obstructive pulmonary

181

disease, and fewer hospitalizations. There was no evidence of tachyphylaxis over one year. In a randomized, double-blind trial tiotropium 18 txg/day for 1 year (n = 356) was compared with ipratropium 160 p_g/day (n = 179) in patients with chronic obstructive pulmonary disease (83r Tiotropium maintained superior efficacy (FEVI and FVC) throughout the study, improved dyspnea, and reduced the number of exacerbations by 24%. In a placebo-controlled, double-blind study tiotropium 18 ~g/day for 6 months (n = 209) was compared with salmeterol 50 I.tg bd (n = 213) and placebo (n = 201) in 623 patients with moderate to severe chronic obstructive pulmonary disease (84r Tiotropium improved dyspnea and trough FEVI and FVC significantly more than salmeterol. The patients who used tiotropium had better quality-of-life scores than those who used satmeterol, but the difference was not statistically significant. In all these studies adverse events were comparable to those with placebo, except for dry. mouth, which was reported in 10-16% of patients (77 R, 8 2 c - 8 4 c ) . Since the quaternary structure of tiotropium limits its absorption through the mucous membrane of the respiratory and gastrointestinal tract, systemic adverse effects are in general minimal.

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