DO OTCGn TREATMENT OF ASTHMA : FROM THE CHILD TO THE ADULT What is the role of beta-agonist bronchodilators in the day-to-day treatment of chronic asthma ?

The reported links of asthma morbid ity and mortality to the use of in ha led bc ta-agoni st brnnchod il ators are reviewed. Report s fro m the Saska tchewan Asth ma Epidemiology Project (SAEP) suggest that it is excess ive us e that is li nked to lifethreatening as thma and that patients at hi ghest ri sk can be identified by the ir increas ing use of these medications. Th is is the ma jor _justification for prescribing short ac ti ng hL·ta-agonists on an a. needed bas is , though there is ho th c linical and ex pe rimenta l evidence suggesting regular use of these agents may not be benefic ia l. New longer ac ting inhaled be ta-agonists des igned for regular use are be ing introducL·d and the ir exac t role remains to be de fi ned. Provisiona lly , the y appear to be useful in pa tients whose asthma is no t well controlled with optimal doses of inha led corti coste roi ds . T he use of these ne wer agents for the rel ie f of acute bronchospasm is contraindicated because of the ir slow onse t of ac ti on.

T I IE M EDICAL PROFES SION 11.\S EMB RACED WIT H GREAT confidence the selective hct:.12-agonist hronc hodilators such as salbut amo l, fen oterol and tc rbut al ine fo r the treatment o f bronc ho spasm .These agents ha ve g radua ll y replaced thcophy ll ines as first line therapy no t only for acute attacks of asthma w he re the ir preponderant rol e re ma ins undi sputed , Que) est le role des bronchodilatateurs betaagonistes dans le traitement quotidien de l'asthme chronique '? RESUME : Les liens rapportcs ent re la murt ali t0 et la mor-hidit0 de l' asthme ct !'utilisati on de bronchodilatatcurs bctaagonistes en inhalation sont passes en rL~vue.Des donnees pro vena nt du Saskatchewan Ep idem iology Projec t (S A EP} laissen t penser que c •est le ur utili sati on excessive qui est associcc a 1 'asthme quasi 111 onel, et que les pati ents ~t plus haul ri sque pc uve nt ctre iden ti fi es par lcur utili sa tion accrue de ces medicaments, Ccc i est la justi ficati on majeure po ur prescrirc des bcta-ago nistes ?t cou11e durcc d 'acti on au besoin.bien que des donnees lt la fo is cl ini qucs et cx pcrime ntal es la issent pc nser quc !' utili sation regul iere de ces agents pouJTait ne pas ctre benc fiq ue.De nouveaux b0ta-agonistcs a longue du ree d 'acti on, en inhalati on.mi s au poi nt pour une ut ili sati on rc.g ulicre sont presentc.s; !cur role ex act reste i\ ct re dcfini.Provisoirement.il s apparaissent etre ut iles chc1.les pati ents dont I 'asthme n 'est pas bien maftrise par des doses optimalcs de corti costero'ides en inhalati on.L' util isati on de ccs nouvea ux agents pour le sou lagcmcnt d'un bronchospasmc aigu est contrcindiquce tt cause de leur delai d' ac ti on pro longc.hut al so in the regula r treatme nt of the stable asthmatic ( I ).In this latter role , they have been used most freque ntl y on a continuo us bas is , ie. three to four times a day in orde r to m a inta in bro nchodilation th ro ughout the Jay and ni ght.The ~h o n durati on o f ac tion o f beta-agonist hro nchodi lators was seen as a drawback that li mited the effi cacy for the treatment ( 'orrcsp1111d('{I<'(' u11d U'f' rillls: Or l'iar,• l:.'rnst, Re,pirnton   i•plio11e (5 / 4) 398-69 74, Fax (5 of nig httime symptoms and was rL'sponsible for reJuceJ compl iance on the part of many patie nts.For th is reason .various pham1aceutical compan ies undertook programs to (k'vclop long acting be ta -agonist bronchodi lators.T wo of these, salmete rol and formoterol.were recently introduced into the European marke t. and salmeterol is now av;.iilable in CanaJa. An epidemic ur asthma de aths among young people in G reat Britain in th e mid-I %Os first raised the poss ibility that overuse of inhaled beta-agonist med ication could be hazanJous (2).Several agents in use at that time were nonsclecti vc beta-agonists such as isop renaline.The concern regarding their overuse contributed to the development of beta2 se lective agents that had fewer cardiac side cffcl"ls given thL• predominann: or beta I receptors in the heart.Much later, alann concerning the safety of the beta2 selective agents was set off by a stuJy published by C rane and colleagues in 1989 (3). which described an association betwee n the use of fen otcnil.one of the commonly used se lective be ta2-agon ists.and increased ri sk of J eath from ast hma in New Zealand wh ich, at the time.had one of the highest death rates anywhere in the world.The study design did not pe nnit conclusions to be drawn about olher bcta -agonists in common use such as sa lbutamol.Furthe rmo re, differences in the way the medicat ion history was obtaincJ in the c ases and conlrols suggested the possibility of bias.which rende red the rnnclusions of this sllldy conlrovcrsial.

SASKATCHEWAN ASTHMA EPIDEMIOLOGY PROJECT
The Saskatchewan Asthma Epidemiology Project was unde rtaken in respon.~c to this controversy.Th is stud y, based on examination of linked compute rized databases avai lable in the province of Sask atchewan.demonstrated a doseresponse relat ionship between the use of inhaled selective bcta2-agonists anJ the risk of fatal and near-fatal asthma (4).Since it appears obvious that patients with more seve re disease are likely to use more medications and are also more likely to experience adverse ou tcumes, the cases of fatal and near-fatal asthma from Saskatchewan were matched to controls with a similar his tory of prior hospitalization for asthma (prL' .Viously shuwn to hl: one nf the most impurtant risk factors for fatal and near-fata l asthma) as well as the prese nce of other diseases that mig ht affect Dutcomc.Furthermore. in ,1 subsequent analys is.cases of fatal and near-fatal asthma were compared with the same controls atkr accounting for the influence of additional markers of severi1y obtained from hospital and office charts.The association between beta2agon ists and risk of fatal and near-fata l asthma wa.~ unchanged atkr this additional adjustme nt for severity (5) .
Compleme ntary analyses or the whole cohort of over 12,000 patients suggest that the risk of major adverse outcomes is limited a lmost entirely to pa1ien1s overusing be taagoni st medications.that is.more than one inhale r per month (6).Fu rthe nnore, it appears that the pa1irn1s at highest risk can be identified by their inerl:asing use of inhaled betaagonists ove r a period of se veral months (7).This.therefore.formally rnnfirms clinical experience: asthmatic pati e nts Can Respir J Vol 2 Su ppl A Marcl1 1995 have a tendency to overuse inhaled hninch0Jih1tors because of the immed iate improvement of symptoms I hat they experi e nce, and thi s overuse worsens in paralle l wilh the ir clinical state.Furthe m1ore.this overuse of beta-agonists and other bronchodilators appears to be at tl1L' expense of the use nr inhaled corticosteroiJs which haVL'. in nmtrasl to betaago nists , the capac ity to improve the severity of asthma (8) and to decrease the risk of fatal and near-fatal attacks (l))_ The practice of prescribing inhaled bronchodilators to be taken on a regular basis was first se rious ly put into que •tion by the report of Sears and colleag ues in 1990 ( I 0).In a ra ndomized, double-blind crossover study.asthmat ic patients were found to be better controlled if they took the ir betaagonist fenoterol on an as needed basi s, compared with when they were taki ng thi s med ication regularly four ti mes a day.Some of the criteria used to judge asthma control were critici zed but a subsequent analysis confirmeJ the firsl impression by showing a rate of asthma exacerbations that was higher anJ a time to exacerbation th at was shorter among !hose subjec ts tak ing the inhaled beta-agoni st on a regular bas is ( 11 ).Van Sc hayck ( l 2) also reported tha t subjects who were taking bronchodilators on a regular basis had a greater fall in forced exp iratory volume in I s (FEV 1) over a I wo-year period compared with suhjects who were u.,ing their bro11chodilator on an as needed hasis only.

POSSIBLE MECHANISMS
If beta-agoni sts do indeed increase the risk of seve re attacks o f asthma.and if their regu lar use docs bring on worsening control of asthma, what arc the potential mechani sms?Tachyphy lax is to the bronchodilator effects of betaago nists docs not appear to be a proble m.The bronchodilator effe ct persis ts undimini shed for prolonged periods ( 13).An increase in nonspecific bronchial hy perresponsivcness to methac holine or histamine has been found in certain studi es examining the reg ul ar use of beta-agonist therapy in the treatment of asthma ( 14.1 5).S uch changes in bronchial responsiveness ra ised the possibility of a change in function of beta-agonist receptors when they are continuously stimulated.Evide nce for th is has been described fro m several sourn's recently.Ba i and coll eagues ( 16 ) descri bed defective rela xalion of smooth muscle after stimulation of the be ta receptors in patients who had di ed or asthma.Two g roup., independently repo rted decrea ••es in lhc protective effect or inhaled beta-ago ni sts on induced bronchoconstriction by methacholine.which acts directly on smooth muscle . .or by ade nosine monophosphatc, which ac ts via mast cells.among subjects who had been g iven e ither terbutalinc on a regular hasis or the long acting beta-agoni st salmetcrol fo r a pe rioJ of seven Jays and eight weeks , respectively ( 17, 18 ).Be l and Sterk ( 19) have suggested that while be ta-ago nists delay the onscl of bronchoconstric tion in response to an ago nist, the m;.ixima l degree of bronchial constriction is not decreased and the rate of bronc hoconstrietion may actually he increased.which could make attacks of asthma more preci pitow;.Page (20) has proposed that the stabili1.ation of mast

USEO Y•DO OTCC
cdls by bcta-agonists might prevent a liberation of heparin and a los s of its protect ive effect on bronchial epithelium.i\fost recently.Cockcro ft et al (21) showed that among ast hmatics.two wee ks of treatnll'nt with salbutamol increases the degree of bronc hoc onstriction in response to allergen.Thi s study is quite significant when one consi ders the very import ,rnt role of allergy in the majority of asthmatics during ch ildhood and yo ung adulthood.It seems that there ,m: several plausi ble mechanisms hy which the use of bronchodi lators on a rL•gular basis could be responsible for a worsen ing asthma that might res ult in in creased morbidity.Mitc hell (22) has expla ined how a small increase in bronchia l hype rrespons ive ness in the ge nera l population could bring about a largc increase in morbidity.which would he most apparen t in the most severe ast hmatics.
Following the epi de mic or asthma deat hs in the 1960s.much attention was given to the possible cardiotoxic effects of heta-agonist medications.specifically their arrhythmo-ge11ic potential.When the safet y of se lecti ve beta2-agonists came into question.numnous stud ies examined the rel at ive cardiotoxicity of the various beta2 selel"live agen ts.hy using ind irec t measures such as tachycardia.prolongation of the Q-Te in terv al on the electrocardiogram or the induction of hypo ka lemia (23 ).The importance of these phenomena in vivo.howeve r, has yet tu he demonstrated.It shou Id hL• pointed out that the great majority of asthma deaths occur after days and sometimes weeks of gradual deterioration and that at autopsy. the primary abnormality is an obliteration of < ,.Su issa S. Ernst P. Boiv in J F. ct al.A coho rt ,maly,is of e xcess mort a lity i11 ast hm a and the use 0 1• inhal ed f1-agoni s1' .Am J l{espir C rit Care Med !99-l : 1-l' -l :60-l-lll.

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the airway luml'!l by thicl,.. mucus enriched with infl am matory and epitheli al cells.T he importance of asphy xia as a mechanism fo r li fe-threaten ing asthma was also underlined recently by the study of Molfino ct al (24 ).Among patients comi ng to the emergency room in extremis, it was found that the predominant abnom1a li ty was resp iratory acidosis and not cardiac arrhythmia or hypokalcmia.

ROLE OF NEW BET A2-AGONISTS
What is the poten tial role of two new long acting beta2agon ists , salmete rol and formoterol. in the face of guidelines for the therapy of asthma .which now emphasiLc earl in use of ,mti-inflam rnatory therapy and the use of short acting beta-agoni sts as resc ue medication?The clinical e ffi cacy or these new agents whe n used continuously as bronchod ilators is c lear and impressive ( 25 ) and these newe r agents are oft en preferred by patients (26).Early evidence suggested these drugs might have significant anti-inflamm atory activity ( 27), but they have not been shown to di ffer from the currently av,1ilable agents such as sa lbutamol in this respect (28 ).Thus.