global strategy for asthma management and prevention

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GINA_WR_2006.qxp:GINA_WR_2006.qxp 7/20/07 4:12 PM Page 31lung function, decreases the use of rapid-acting inhaled 2 -agonists 57-59 , reduces the number of exacerbations 12,57-62 ,and achieves clinical control of asthma in more patients,more rapidly, and at a lower dose of inhaled glucocorticosteroidsthan inhaled glucocorticosteroids given alone 63 .This greater efficacy of combination treatment has led tothe development of fixed combination inhalers that deliverboth glucocorticosteroid and long-acting 2 -agonistsimultaneously (fluticasone propionate plus salmeterol,budesonide plus formoterol). Controlled studies haveshown that delivering this therapy in a combination inhaleris as effective as giving each drug separately 64, 65 . Fixedcombination inhalers are more convenient for patients, mayincrease compliance 66 , and ensure that the long-acting 2 -agonist is always accompanied by a glucocorticosteroid.In addition, combination inhalers containing formoterol andbudesonide may be used for both rescue and maintenance.Both components of budesonide-formoterol given asneeded contribute to enhanced protection from severeexacerbations in patients receiving combination therapy formaintenance 67 and provide improvements in asthmacontrol at relatively low doses of treatment 67-70 .Long-acting 2 -agonists may also be used to preventexercise-induced bronchospasm, and for this purposemay provide longer protection than rapid-acting inhaled 2 -agonists 71 . Salmeterol and formoterol provide a similarduration of bronchodilation and protection againstbronchoconstrictors, but there are pharmacological differencesbetween them. Formoterol has a more rapid onset of actionthan salmeterol 72, 73 , which may make formoterol suitablefor symptom relief as well as symptom prevention 68 .Side effects - Therapy with long-acting inhaled 2 -agonistscauses fewer systemic adverse effects—such ascardiovascular stimulation, skeletal muscle tremor, andhypokalemia—than oral therapy. The regular use of rapidacting 2 -agonists in both short and long acting forms maylead to relative refractoriness to 2 -agonists 74 . Dataindicating a possible increased risk of asthma-relateddeath associated with the use of salmeterol in a smallgroup of individuals 75 led to advisories from the US Foodand Drug Administration (FDA)‡ and Health Canada § thatlong-acting 2 -agonists are not a substitute for inhaled ororal glucocorticosteroids, and should only be used incombination with an appropriate dose of inhaledglucocorticosteroid as determined by a physician. A studyhas identified that the asthma of subjects with an unusualgenotype for the beta-adrenergic receptor (withsubstitution of arginine for glycine at position B-16) maydeteriorate with regular use of salmeterol whether or notadministered with inhaled glucocorticosteroids 76 .‡ http://www.fda.gov/cder/drug/infopage/LABA/default.htm§ http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2Theophylline.Role in therapy - Theophylline is a bronchodilator and,when given in a lower dose, has modest anti-inflammatoryproperties 77-79 . It is available in sustained-releaseformulations that are suitable for once- or twice-dailydosing. Data on the relative efficacy of theophylline as along-term controller is lacking. However, availableevidence suggests that sustained-release theophylline haslittle effect as a first-line controller 80 . It may provide benefitas add-on therapy in patients who do not achieve controlon inhaled glucocorticosteroids alone 81-83 . Additionally insuch patients the withdrawal of sustained-releasetheophylline has been associated with deterioration ofcontrol 84 . As add-on therapy, theophylline is less effectivethan long-acting inhaled 2 -agonists 85,86 .Side effects - Side effects of theophylline, particularly athigher doses (10 mg/kg body weight/day or more), aresignificant and reduce their usefulness. Side effects canbe reduced by careful dose selection and monitoring, andgenerally decrease or disappear with continued use.Adverse effects include gastrointestinal symptoms, loosestools, cardiac arrhythmias, seizures, and even death.Nausea and vomiting are the most common early events.Monitoring is advised when a high dose is started, if thepatient develops an adverse effect on the usual dose,when expected therapeutic aims are not achieved, andwhen conditions known to alter theophylline metabolismexist. For example, febrile illness, pregnancy, andanti-tuberculosis medications 87 reduce blood levels oftheophylline, while liver disease, congestive heart failure,and certain drugs including cimetidine, some quinolones,and some macrolides increase the risk of toxicity. Lowerdoses of theophylline, which have been demonstrated toprovide the full anti-inflammatory benefit of this drug 82 , areassociated with less frequent side effects, and plasmatheophylline levels in patients on low-dose therapy neednot be measured unless overdose is suspected.Cromones: sodium cromoglycate and nedocromilsodium.Role in therapy – The role of sodium cromoglycate andnedocromil sodium in long-term treatment of asthma inadults is limited. Efficacy has been reported in patientswith mild persistent asthma and exercise-inducedbronchospasm. Their anti-inflammatory effect is weakand they are less effective than a low dose of inhaledglucocorticosteroid 88 .Side effects - Side effects are uncommon and includecoughing upon inhalation and sore throat. Some patientsfind the taste of nedocromil sodium unpleasant.ASTHMA TREATMENTS 31
GINA_WR_2006.qxp:GINA_WR_2006.qxp 7/20/07 4:12 PM Page 32Long-acting oral 2 -agonists.Role in therapy - Long acting oral 2 -agonists includeslow release formulations of salbutamol, terbutaline, andbambuterol, a prodrug that is converted to terbutaline inthe body. They are used only on rare occasions whenadditional bronchodilation is needed.Side effects - The side effect profile of long acting oral 2 -agonists is higher than that of inhaled 2 -agonists, andincludes cardiovascular stimulation (tachycardia), anxiety,and skeletal muscle tremor. Adverse cardiovascularreactions may also occur with the combination of oral 2 -agonists and theophylline. Regular use of long-actingoral 2 -agonists as monotherapy is likely to be harmfuland these medications must always be given incombination with inhaled glucocorticosteroids.Anti-IgE.Role in therapy - Anti-IgE (omalizumab) is a treatmentoption limited to patients with elevated serum levels of IgE.Its current indication is for patients with severe allergicasthma 89 who are uncontrolled on inhaled glucocorticosteroids,although the dose of concurrent treatment hasvaried in different studies. Improved asthma control isreflected by fewer symptoms, less need for relievermedications, and fewer exacerbations 90,91 . Furtherinvestigations will likely provide additional clarification ofthe role of anti-IgE in other clinical settings.Side effects: As indicated by several studies involvingasthma patients between the ages of 11 and 50, whowere already receiving treatment with glucocorticosteroids(inhaled and/or oral) and long-acting 2 -agonists 89 ,anti-IgE appears to be safe as add-on therapy 92-94 .Systemic glucocorticosteroids.Role in therapy - Long-term oral glucocorticosteroidtherapy (that is, for periods longer than two weeks as aglucocorticosteroid “burst”) may be required for severelyuncontrolled asthma, but its use is limited by the risk ofsignificant adverse effects. The therapeutic index(effect/side effect) of long-term inhaled glucocorticosteroidsis always more favorable than long-term systemicglucocorticosteroids in asthma 95,96 . If oral glucocorticosteroidshave to be administered on a long-term basis,attention must be paid to measures that minimize thesystemic side effects. Oral preparations are preferred overparenteral (intramuscular or intravenous) for long-termtherapy because of their lower mineralocorticoid effect,relatively short half-life, and lesser effects on striatedmuscle, as well as the greater flexibility of dosing that permitstitration to the lowest acceptable dose that maintains control.Side effects - The systemic side effects of long-term oralor parenteral glucocorticosteroid treatment includeosteoporosis, arterial hypertension, diabetes, hypothalamicpituitary-adrenalaxis suppression, obesity, cataracts,glaucoma, skin thinning leading to cutaneous striae andeasy bruising, and muscle weakness. Patients with asthmawho are on long-term systemic glucocorticosteroids in anyform should receive preventive treatment for osteoporosis(Figure 3-2) 97-99 . Although it is rare, withdrawal of oralglucocorticosteroids can elicit adrenal failure or unmaskunderlying disease, such as Churg-Strauss Syndrome 54,100 .Caution and close medical supervision are recommendedwhen considering the use of systemic glucocorticosteroidsin patients with asthma who also have tuberculosis,parasitic infections, osteoporosis, glaucoma, diabetes,severe depression, or peptic ulcers. Fatal herpes virusinfections have been reported among patients who areexposed to these viruses while taking systemicglucocorticosteroids, even short bursts.Oral anti-allergic compounds.Role in therapy - Several oral anti-allergic compoundshave been introduced in some countries for the treatmentof mild to moderate allergic asthma. These includetranilast, repirinast, tazanolast, pemirolast, ozagrel,celatrodast, amlexanox, and ibudilast. In general, theiranti-asthma effect appears to be limited 101 , but studies onthe relative efficacy of these compounds are neededbefore recommendations can be made about their role inthe long-term treatment of asthma.Side effects - Sedation is a potential side effect of some ofthese medications.Other controller therapies.Role in therapy - Various therapeutic regimens to reducethe dose of oral glucocorticosteroids required by patientswith severe asthma have been proposed. Thesemedications should be used only in selected patientsunder the supervision of an asthma specialist, as theirpotential steroid-sparing effects may not outweigh the riskof serious side effects. Two meta-analyses of the steroidsparingeffect of low-dose methotrexate showed a smalloverall benefit, but a relatively high frequency of adverseeffects 102,103 . This small potential to reduce the impact ofglucocorticosteroid side effects is probably insufficient tooffset the adverse effects of methotrexate 104 . Cyclosporin 105and gold 106,107 have also been shown to be effective in32 ASTHMA TREATMENTS
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