Green, Robin J

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CLINICAL PRACnCESAMJFORUMADVERSE EFFECTS OF ICSSYSTEMIC EFFECTS OF INHALEDSTEROIDS AND THEIR RELEVANCEIN CHILDREN WITH ASTHMARobin JGreenAsthma is a common condition with a well-describedpathology and consequent treatment principles. Some therapiesare very effective in controlling not only symptoms of thedisease but also the disease itself, and yet in children treatmentof this condition remains contentious.Asthma is defined by the ational Heart, Lung and BloodInstitute as 'a chronic inflammatory disorder of airways, inwhich many cells play a part, including mast cells andeosinophils in susceptible individuals. This causes symptomswhich are usually widespread but variable, airflow obstructionthat is often, but not always, reversible spontaneously or withtreatment, and causes an associated increase in airwayresponsiveness to a variety of stimuli'.' The implication of thisdefinition and most others is that asthma is an inflammatorydisorder. This holds true for all forms of the disease, even whenit is mild. Hence the most important treatment should bedirected at inflammation2 and the most effective anti-inflammatory agent is the corticosteroid,' both in adults and inchildren.For many years oral corticosteroids controlled asthma veryeffectively but at huge cost in terms of unwanted side-effects.The introduction of inhaled corticosteroids (ICS) provided asafer alternative to oral steroids; and their use has been shownto reduce the need for systemic steroids. ICS are successful indecreasing nonspecific bronchial hyperresponsiveness.'"sufficiently to control asthma symptoms over a period of time.Despite this apparent answer to the problem of asthma,many practitioners are reluctant to use ICS in children becauseof so-called 'adverse effects'. Drug effects, however, includeboth adverse (or undesired) effects and beneficial effects, and inaddressing the role of ICS in the management of childhoodasthma, some clarity is required on the balance between thesetwo extremes.Robin Green is a paediatric pulmonologist in privatepractice at Sunninghill Hospital in Johannesburg. He isactive in the ationa! Asthma Education Programme, theSouth African Allergic Rhinitis Working Group, the SouthAfrican Pulmonology Society and the Allergy Society ofSouth Africa.July 199 ,Vol. , No. SAMJAt the outset it should be stated that measurable systemiceffects are not equivalent to clinically relevant systemic side-effects. Simple detection of the drug in the blood or a measuredchange in a physiological variable does not necessarily denotean adverse event. In addition measurable systemic activity isdependent on the sensitivity of the method used. Few truestudies have looked at the clinical relevance of adverse events,and most opponents of res have lumped all systemic activityunder adverse events.The systemic effect of rcs depends on the amount of drugsystemically absorbed from both the gastro-intestinal tract(GIT) and the intrapulmonary airway. Factors influencingsystemic activity include the amount swallowed (roughly 80%of a metered dose), the affinity of the drug for receptors, andespecially selectivity for the glucocorticoid receptors,metabolism in the circulation and liver (oral bio-availability),activity of metabolites and systemic clearance. The fraction thatis absorbed in the pulmonary circulation is also systemicallyactive.A number of strategies have been employed to minimise thesystemic activity of ICS. These include reducing the amountswallowed, through manipulating the inhaler technique, or byusing a spacer, or by mouth washing after use. The intrinsicstructure of the ICS can be altered to increase receptor affinity,increase glucocorticoid receptor affinity, increase first-passmetabolism, reduce activity of metabolites and increasesystemic clearance. These manouvres have been employed withthe newer generation ICS. Spacer devices (Fig. 1) should beconsidered an integral part of rcs therapy in children, and thespacer used should be that recommended by the manufacturerfor the particular drug, as mixing and matching deliversinconsistent dosages.Fig. 1. Child using an inhaled steroid via a Babyhaler spacer.It has largely been in children that adverse effects have beenof concern to practitioners treating asthma, with growth theimportant variable. Surrogate markers for the systemic effectsof rcs have included measures of hypothalamopituitary axis(HPA) activity, biochemical markers of bone mineralisation,1 SAMJFoRUMshort-term growth, and of course growth over time. The degreeof HPA axis suppression is dependent on a number ofvariables, including dose of lCS, duration of action, frequencyof administration, time of day administered and route ofadministra tion.A number of tests have been employed to 'measure' thesystemic effect of ICS. These include both basal adrenal activityand the more sen:sitive stimulation tests. When interpretingsuch tests it must be remembered that normal cortisol secretionvaries during the course of the day, that laboratory studies maynot reflect physiological changes, that many tests are difficultto perform, and that often changes noted are within the normalrange for a particular test.With regard to the effect of ICS on the HPA axis, conflictingresults' reported may be due to uncontrolled studies, previoususe of oral steroids, variable duration of treatment, variableinhaler systems and different measuring methods. Some ofthese studies indicated that significant effects on basal adrenalfunction (cortisol secretion) can be detected at doses of ICSaround 400 pg per day. However, no clinically reievantendocrine effects have been reported in children who havereceived such therapy for many years.The mechanism of the effect of rcs on growth is not fullylmderstood, but may involve both an indirect effect on growthhormone secretion, and a direct effect on bone metabolism.Important considerations in this regard are that the rate ofgrowth in childhood and final height are determined by theimpact of a range of environmental factors on genetic potential.In addition growth measurement is subject to error, especiaJJywhen growth velocity is low (mid-childhood), where error in3-monthJy intervals may be as high as 50%. Compoundingvariables for height determination are seasonal changes, year-by-year changes, time of onset of puberty, effect of asthma(many asthmatic children have a slower growth rate thannormal children and a physiological delay in puberty whichdoes not affect final adult height), severity of asthma,' andlastly the effect of oral steroid use.Although short-term growth studies, usually involvingknemometry, report variable rates of lower limb growth withICS, long-term follow-up studies have been few. Three suchstudies found no long-term effect (up to 6 years) on growthwith variables doses of rcs (up to 1100 pg/m'/d).6 Inconclusion, it appears that knemometry (short-term) studiesshow effects of lCS on growth (of the lower leg) at doses from400 pg/d, that long-term statural growth is not affected at thisor higher doses, and that knemometry may be oversensitive formeasurement of this sort.7The use of bone turnover to reflect systemic adverse events isbased on the understanding that systemic glucocorticoidtherapy has a deleterious effect on the skeleton, leading todecreased bone mass and ultimately to osteoporotic fractures·Thirty to fifty per cent of patients receiving long-term (overyears) treatment with doses of prednisone of 7.5 -10 mg perday would develop skeletal fractures.'"Numerous methods are available for assessing boneturnover, both biochemical and radiological. Bone densitometryis the latest and probably the most practical, but like the othertests described, it is associated with a number of problems.Bone metabolism (like asthma itself) is influenced by diseasestates, activity, diet and the confounding effect of oral steroids.Although short-term studies in general have found ICS tohave no effect on systemic measures of bone metabolism,n.n itis the long-term effects that would be more important. Fewstudies have been performed in children, but in one sentinelstudy Agertoft and Pedersen13 found no change in bone densityin children after 4.5 years (mean dose of rcs 691 pg/d)compared with steroid-naIve asthmatics.In conclusion, while there is no indication of increased risk ofosteoporosis or fractures in children on ICS, it is wise to aim forthe lowest dose with long-term treatment. However, at theonset of treatment of asthma use of high-dose rcs is becominga popular way of gaining initial control of the disease.BENEFICIAL EFFECTS OF ICSIt has become common practice to discuss adverse events dueto lCS as the sole marlifestation of drug activity. This is not thecase. Many beneficial systemic effects are known or becomingobvious.As has been discussed, uncontrolled asthma can cause poorgrowth in childhood and delayed puberty, and this effect ismagnified by the need for repeated courses of oral steroids.There is evidence that growth is improved with ICS. Short-termgrowth was marginally better in a fluticasone propionate-treated group than in a placebo control group (N = 13) (notstatistically significant)," and this probably reflects an overallimprovement in health.Three studies comparing asthmatic patients given ICS earlywith patients in whom the introduction of lCS was delayeddemonstrated increasing loss of lung function with increasingdelay in introduction of lCS.";'17 This would impact on cost andnumber of exacerbations, and could have future medicolegalimplications.An exacerbation of asthma, especially a severe exacerbation,is a serious illness. There is evidence that treatment with ICS(fluticasone propionate) results in fewer exacerbations thantreatment with sodium cromoglycate17 and has a Significantlygreater effect than treatment with ~-agonists,'6and togetherwith the benefits of improved long-term control and quality oflife, the cost of rcs is lower than that of some other agents,such as sodium cromoglycate. m:D·CO CLUSIONConcerns about the systemic unwanted effects of ICS havegreatly limited their use, especiaJJy in children. The adverseeffects of inhaled glucocorticosteroids are dose-related, withSAMJFoRUMIlittle or no evidence of clinically relevant systemic unwantedeffects at doses of < -lOO J.Ig/ d. In most patients optimal asthmacontrol can be maintained with these or lower doses. There arecurrently no anti-inflammatory drugs that are as effective asinhaled glucocorticosteroids in the first-line treatment ofasthma.In children with asthma it is reassuring to note thatguidelines for management now advocate the use of ICS in allseverities of persistent disease" (and not just for severeasthma), and that with the newer inhaled corticosteroids anddelivery devices (fluticasone propionate or budesonideturbuhaler) equal effect may be achieved at half the dose ofboth BDP and budesonide in a metered dose inhaler1Y.201. l\;ational Heart Lung and Blood lnstitute. lntemational Coru.en~u3Report on DJagnlhl:> andManagement of Asthma Clm EIp AIlL-rgy 1992; 22; suppl I, 1-722. Warner JO. t.:se of comcosteroids 10 children with asthma Eur Roplr Rf'i.' 1993; 3: 326-3183. Bames!\c. Ad\-anc~ in inhaled ~teroid therap~. ElIr Rop" Rn' 199·t -I: 295-300.-I Geddes 0\.1 Inhaled cortic05teroids: Benefits and risk.. Thorax 1992.47: .;Q.4-W75. Clarke PS The effect of beclomethasone diproplOnate on bronchial hyperreach""lty. 1 A...Umll)1982; 190 91-93.Ryan G, Lahmer K.o\.1, Juniper EF. Roberts RS, Hargreave FE. Etiect of Mlomt'tha30nediproplonate on bronchial responsiveness to histamine in controlled nOl1.'>terold-dependentasthma I Al/agy Om ImmutWl 19 5; 75: 25-30.7. Pedersen S. Sdfety aspech of corticosleroids in children. Eur Rr.;pir RtT 199-·'. 4: 33....13.Agertott L. Pedersen Effects of long-term treatment with an Inhaled corticosteroid ongro" th and pulmonary funcuon m asthmatic children_ R.esptr Med 199·4, : 373-381.9. Toogood JH, Hod3man AB Effecb of inhaled and oral cortic03teroicb on bone_ AIIII Allt''X1I1991.67,87-90.10. Lukert BP. Ratsz lG. Glucocorticoid-induced osteoPOrtklJlo: pathogen6b and m<ll1dgt?'m~m.Alln IlItern Mid 1990; 112: 35.2·.36-t11. Wolthers OD, Ris.s BJ. Pederson . Bone tumO\·er in asthmatic children treated .....ith oral orinhaled budesonide. P(tJiiJtr PlllmmJOll993; 16: J...t1·J...t6.12. Kinberg KA. Hopp RJ. Bi\"en RE, GaJlagher Je. Bone mineral deru.ity in normal andasthmatic children JAll~ Clm Immll1roJ 1994; 94: -I~97.13. Agertoft L, Peder.,en S. Bone denSity in childhOCld dunng long~t€'rm treatment withbudesonide. EllT R6plT J 1993; 6: 2615.14. ~1acKenzje CA, WalesJKH. Growth In asthmatic children. BAJ/I991; 202: -116.15. Haahtela T. Alanko K. Muitari A, if al. The supenonty of combmation beclomethasone andsalbutamol over standard dosing of salbutamol in the treatment of chronic asthma. AnnAll<rgy 1989, 6Z, 63-66.16. Selroos 0, Pietinalho A. Lofroos A-B, Ri~ka H. Effect of early versus late IOtenenhon withInhaled corticosteroid!) m asthma. Chot 1995; 108: 121S-123·t17 Price JE WeHer PH Comparison of Outicasone propionate and ~ium cromogl:cate for thetreatment of childhood aSlhma (an open parallel study). Rrsptr Med 1995,89:- 362-36818. Van ~n-Zand .. het EB, Hughes ~ID, Waalren~HI. Duisennan EJ. Pocock 5J. Kerreb~in KFEffects of 22 months of treatment with inhaled corticosterolds and/or ~·a~onist on lungfunction, aU"Way responsiveness and symptoms in children With asthma. Am Rev Resptr Db1992. U6, 547-554.19 Bntbh Thoracic Sociel}. The British Guidelines on asthma mana~ement.ThoTl1x 1997; 32;suppll 1· 2120. Veln A3peren P. Fitzgera!d D, ~1ellis C. Honner M, Smith l, Ambler G Ruhcasone propionate(FP) TXj mcg/day i.3 as effectl\-e <b bedomethasone dipropionate (BDP) 1 500 mc~/da~ IIIpaediatric asthma (Abstract). EllT &sPIT J 1996; 9: II-ls.DRUG ALERTROCHE WITHDRAWS POSICORRoche announced on Monday 8 June 1998 the voluntarywithdrawal of the antihypertensive and anti-anginalmedication, Posicor (mibefradil), and is advisingphysicians to propose alternative therapies to theirpatients.This action is based on evolving informationconcerning the potential for drug interaction, some ofthem serious, which may occur when Posicor is takentogether with some other medications. The decisionfollows analysis of the preliminary results of a 3-yearlong-term study of Posicor in congestive heart failure-this demonstrated no significant difference beh-veenPosicor and placebo when added to standard therapy inthis patient population, but did provide furtherinformation on drug interaction .. In both hypertension and chronic angina pectoris,Posicor has proved to be consistently effective and welltolerated when used appropriately. However, thecombination of Posicor and some other commonly useddrugs, among them cardiovascular agents, may increasethe frequency of the side-effects of these othermedications.In principle, drug interactions can be addressed byappropriate labelling; however, in the case of Posicor,Roche believes that the complexity of such prescribinginformation would make it too difficult to implement.As patient well-being is of the highest priority to Roche,the company has preferred to voluntarily withdraw thecompound from all markets.The company is working closely with regulatoryauthorities to appropriately inform physicians and otherhealth care professionals of its decision.Patients hould not simply discontinue treatment withPosicor; instead they should promptly consult theirphysicians about appropriate alternative therapy. Inaddition, patients should not add any new medicationto their present treatment without consulting theirphysicians.Enquiries: Kelvyn Henry, Public Affairs Director, te!(011) 928- 73-1 or (011) 974-5335.July 199 , Vol. '0.7SAMJ

Systemic effects of inhaled steroids and their relevance in children with asthma

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Systemic effects of inhaled steroids and their relevance in children with asthma

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