COPD: New Treatments

Chronic obstructive pulmonary disease(COPD) is the fourth leadingcause of chronic morbidity and mortalityin the United States.¹ Its prevalenceand impact are increasing,and the World Bank/World HealthOrganization has projected that it willrank fifth in 2020 as a global burdenof disease.^2,3 The economic and publichealth impact of COPD is staggering,because this chronic conditionrequires long-term care, frequentoffice visits, and use ofemergency department and hospitalservices. Thus, there is a pressingneed to discover new therapies thatcontrol symptoms and prevent diseaseprogression.An increased understanding ofthe pathophysiologic mechanisms ofCOPD has helped researchers identifypotential targets for new treatments.These include many chemoattractantsand cytokines that drive the inflammatoryresponses in COPD; the signaltransduction pathways activated duringthese processes; the mediators released,including proteases and oxidants;and the cellular responses thatlead to abnormalities in tissue functions,such as mucociliary clearanceand repair.Increased interest in COPD isalso reflected in the number of importantpulmonary guidelines thathave been published since 1974 atboth local and international levels.⁴Pharmacologic and nonpharmacologicmeasures are aimed at improvingthe quality of care for patients whohave COPD, with smoking cessationmandatory for all patients to slow theprogression of lung function loss.Our focus here is on the pharmacologicoptions for COPD. We identifythe currently available agents and outlineappropriate treatment strategies.We also highlight new areas of researchthat may help guide managementin the future.CLASSIFICATIONOF COPDIn the Global Initiative for ChronicObstructive Lung Disease (GOLD)guidelines, COPD is defined as a "diseasestate characterized by airflowlimitation that is not fully reversible.The airflow limitation is usually bothprogressive and associated with anabnormal inflammatory response ofthe lungs to noxious particles andgases."5 The guidelines also provide asimple classification of disease severityinto 4 stages (Table 1); this stagingsystem can help guide treatment(Table 2).The major physiologic abnormalityin COPD is expiratory airflow limitation,which is measured best byspirometry. Airflow has, therefore, becomethe international measure bywhich most drugs are considered forthe management of COPD. Althoughseveral recent trials have highlightedother useful end points, such as qualityof life, exacerbation frequency, exerciseperformance, and survival,therapies have been based on objectiveimprovements in expiratory airflow.Current pharmacologic therapyis used mainly to control symptoms; itmay also reduce the frequency andseverity of exacerbations, improvehealth status, and improve exercisetolerance.PHARMACOTHERAPYAn effective COPD managementplan includes 4 components: assessingand monitoring disease, reducing riskfactors, managing stable COPD, andmanaging exacerbations.⁵ Once COPDhas been diagnosed, the treatmentgoals are:

• Prevention of disease progression.
• Symptom relief.
• Improvement in exercise tolerance

and health status.

• Prevention and treatment of complicationsand exacerbations.^5,6

Bronchodilators.

The hallmarkof COPD is airflow obstruction, whichleads to incomplete expiration. Duringexertion, patients with emphysemamay experience a significant amount ofair trapping, which leads to hyperinflation(dynamic hyperinflation) withauto-peak end-expiratory pressurephenomenon. Hyperinflation attributableto incomplete lung emptying-especiallywith exercise-leads to a furtherincrease in intra-alveolar pressureand decreased inspiratory capacity; itaffects the operation of the inspiratorymuscles and results in dyspnea. Bronchodilators are central toCOPD symptom management.

^7-10

These agents improve airflow by decreasingairway smooth muscle tone;as a result, improved emptying of thelungs at rest and during exercise leadsto a reduction in dynamic hyperinflation.11 Generally, bronchodilators aregiven on an as-needed or a regularbasis to relieve persistent or worseningsymptoms or on a regular basis to preventor reduce symptoms.The major side effects are dosedependent.Both oral and inhaled formulationsare available, but the latter ispreferable, because adverse effects areless likely to occur and resolve morequickly after treatment has stopped.Tailor bronchodilator therapy to thespecific patient

(Table 3)

.

Anticholinergics.

Contributing factorsthat lead to bronchial obstructionin COPD include mucus hypersecretionand an increased bronchial muscletone, which is mediated by cholinergicmechanisms. The anticholinergicbronchodilators decrease vagal cholinergictone, which is the main reversiblecomponent of COPD; hence,they are usually the first-line drugs inthe management of COPD.Anticholinergic drugs block muscarinicreceptors on airway smoothmuscle and, possibly, on submucosalgland cells. Autoradiographic mappingand functional studies have shown M1(Hm1), M2 (Hm2), and M3 (Hm3) receptorsin human airways, and thesereceptors appear to have differentphysiologic functions.

¹²

M1 receptors in parasympatheticganglia facilitate cholinergic neurotransmissionand, thus, enhance cholinergicbronchoconstriction, whereasM3 receptors on airway smooth musclecells and glands mediate bronchoconstrictionand mucus secretion.M2 receptors on cholinergic nerveendings inhibit the release of acetylcholineand act as feedback inhibitoryreceptors (autoreceptors). In humanairways, blockade of M2 receptors resultsin increased acetylcholine release

(Figure 1).

Because ipratropium is a comparativelynonselective muscarinic an-tagonist, it blocks M2 receptors aswell as M1 and M3 receptors, and increasedacetylcholine release mayovercome the blockade of muscarinicreceptors in the muscle. This hasprompted a search for selective muscarinicreceptor antagonists that blockeither just M3 or both M1 and M3receptors.Tiotropium is a novel, potent,long-lasting muscarinic antagonist.Like ipratropium, tiotropium has a positivelycharged quaternary ammoniumstructure that is responsible for its limitedsystemic absorption. Studies withcloned human muscarinic receptorshave shown that tiotropium bindsequally well to M1, M2, and M3 receptors.However, when comparedwith other muscarinic antagonists, itdissociates very slowly from M1 andM3 receptors and more rapidly fromM2 receptors.

^13,14

Takahashi and colleagues

¹⁵

confirmed the long durationof action of tiotropium in binding studieswith cholinergic neural responsesin both guinea pig and human airwaysin vitro.Maesen and colleagues

¹⁶

demonstratedthe dose-dependent bronchodilatoryefficacy and duration ofaction of tiotropium in patients withCOPD.In a well-controlled study, Littnerand associates

¹⁷

administered tiotropiuminhalation powder once daily to stablepatients with COPD (mean forcedexpiratory volume in 1 second [FEV1],1.08 L [42% of predicted]) and evaluateddose-response characteristics. Tiotropiumwas shown to be safe and effectivein once-daily doses rangingfrom 4.5 to 36 ?g, and patients had improvedspirometric results comparedwith patients given placebo.In patients with COPD, tiotropiumprovides a dose-related bronchodilatationthat persists for more than 24hours

(Figure 2).

¹⁶

Long-term studieson the safety and efficacy of 18 ?g oftiotropium once daily are being conducted.This drug, which has beenfiled with the FDA for approval, is likelyto be a useful addition to COPDtherapy.β

₂

-

Agonists.

If the outcome of anticholinergictherapy is not optimal,add an inhaled short-acting β

₂

-agonist.These bronchodilators improve lungfunction, reduce symptoms, and protectagainst exercise-induced dyspneain patients who have COPD.

^18,19

Theprincipal action of β

₂

-agonists is torelax airway smooth muscle via activationof adenylate cyclase in the muscle,which, in turn, increases the concentrationof intracellular cyclic adenosinemonophosphate (AMP).

²⁰

Albuterol, a short-acting β2-agonist,has proved a major advance intherapy in the 30 years it has beenused to treat and prevent the symptomsof COPD. This drug usually isadministered via metered-dose inhaler(MDI), dry-powder inhaler, or nebulizer,but also is available in an oral formulation.Albuterol remains the standardbronchodilator for the treatmentof COPD-related acute bronchospasmand acute exacerbations of chronicbronchitis.The main disadvantage of a firstgenerationβ

₂

-adrenergic agonist, suchas albuterol, is short duration of action(2 to 4 hours), which requires thedrug to be administered several timesa day. Other short-acting β

₂

-agonists(metaproterenol, pirbuterol, terbutaline)are listed in

Table 3.

The need for long-acting bronchodilatorsin patients who have asthmaand COPD was met with salmeterol

²¹

and formoterol.

²²

Salmeterol hasprolonged, specific binding to a secondaryexocite on the β

₂

-adrenergicreceptor, resulting in repeated stimulationof the active site, which leads tolonger efficacy.In an attempt to increase theaffinity of agonists for the β

₂

-adrenergicreceptor, formoterol was developed.The exact mechanism by whichformoterol exerts prolonged effects onlung function is unknown but may involveinteraction with the membranelipid bilayer.

²³

Both salmeterol and formoterolinduce bronchodilatation. Celik and associates

²⁴

demonstrated that after 10minutes, formoterol induced clinicallyand statistically significant improvementin FEV1 compared with placebo,whereas salmeterol required 20 minutesto induce significant improvement.Both of these long-acting β

₂

-agonistshave a 12-hour duration of action andare appropriate for twice-daily use.The long-acting β

₂

-agonists haveother effects that may be beneficial.Salmeterol inhibits airway smoothmuscle proliferation and inflammatorymediator release. It also exertsnon-smooth muscle effects, such asstimulation of mucociliary transport,cytoprotection of respiratory mucosa,and attenuation of neutrophil recruitmentand activation.

²⁵

Formoterol hasnot been evaluated for such effects.Treatment with long-acting β

₂

-agonistsmay reduce the number and severity ofexacerbations; thus, it may reduce theoverall cost of health care for patientswith COPD. In addition, long-acting β

₂

-agonists, which can be used twice daily(in contrast to short-acting β

₂

-agoniststhat must be used 4 times per day),may improve patient compliance.

Methylxanthines.

The effects androle of xanthine derivatives in the treatmentof COPD remain controversial.However, if the outcome of therapy isnot optimal, adding 100 to 900 mg oftheophylline per day to the regimen ofipratropium with or without a β

₂

-agonistcan be considered.Because methylxanthines arenonspecific inhibitors of all phosphodiesteraseenzyme subsets, they have awide range of toxic effects. Toxicity inxanthine derivatives is dose-relatedbecause the toxic-therapeutic ratiois small. Theophylline is the mostwidely available methylxanthine, andit is metabolized by cytochrome P-450mixed-function oxidases. Clearance oftheophylline decreases with age, anda number of drugs and physiologicvariables affect its metabolism.The phosphodiesterase inhibitorshave been reported to have a widerange of nonbronchodilator actionsthat may help the COPD patient.Mahler

²⁶

showed a reduction inbreathlessness in patients who receivedtheophylline. Kirsten and coworkers

²⁷

found that cessation of theophyllinetherapy resulted in significant(

P

28,29 butwhether this reflects changes in dynamiclung volumes or a primary effecton the muscle is not clear. Resultssuggest that theophylline is effective insome patients with COPD and supportits use for patients who remain symptomaticdespite the use of inhaledbronchodilators.Second-generation inhibitors ofphosphodiesterase 4 (PDE4) havebeen evaluated. The earliest medications,such as rolipram, demonstratedmarked anti-inflammatory and bronchodilatoryeffects in vitro and invivo,

³⁰

but use of these compoundswas limited by GI side effects. NovelPDE4 inhibitors that maintain the antiinflammatoryand bronchodilatory activityof rolipram with fewer side effectsare being sought. Currently, roflumilast,piclamilast, and cilomilast arebeing investigated.

³¹

Bronchodilator combinationtherapy

. Anticholinergics, β-agonists,and phosphodiesterase inhibitors havedifferent mechanisms of action, andthe relative importance of each ofthese may differ at various airwaysites. Thus, β-agonists may increasecyclic AMP and mutually potentiatethe action of methylxanthines that inhibitcyclic AMP breakdown. Crosstalkbetween muscarinic cholinergicreceptors and β-agonist receptors maypromote synergies between agentsthat act at these sites.Clinical trials have supported thecombined use of bronchodilators.

³²

Ipratropium has been given effectivelywith several short-acting bronchodilators,and an MDI combining ipratropiumand albuterol was approved by theFDA for use in 1996. When added tosalmeterol, ipratropium therapy resultsin further bronchodilatation. This potentiationmay last up to 10 hours-well beyond the usual duration of actionof ipratropium. Theophylline alsohas been used effectively in combinationwith ipratropium and with shortandlong-acting β-agonists.

³³

Corticosteroids.

In COPD, systemiccorticosteroids are recommendedfor treatment of acute exacerbationsonly, and several studies haveshown benefits in this setting.

³⁴

Extendedtreatment for 8 weeks is notmore beneficial than treatment for 2weeks.Four large studies evaluated thelong-term effects of inhaled corticosteroidson lung function decline.

^35-38

The principal outcome measure for allthe studies was longitudinal declinein FEV1. Investigators showed that inhaledcorticosteroids did not slow thedecline in lung function that characterizesCOPD and that regular treatmentwith these drugs is appropriate onlyfor symptomatic patients with documentedspirometric responses or forthose with FEV1 of less than 50% ofpredicted and persistent exacerbationsrequiring treatment with antibiotics ororal corticosteroids.

^5,6

However, in the Inhaled Steroidsin Obstructive Lung Disease (ISOLDE)trial, which assessed patients with themost severe disease, a significant reductionin exacerbation frequency wasnoted.

³⁹

This was associated with a reductionin the rate of decline in healthstatus. Reduction of exacerbations withinhaled corticosteroids was confirmedin a prospective study with exacerbationsas the primary outcome.

⁴⁰

Currentrecommendations, therefore, suggestthat inhaled corticosteroids can beused to help prevent exacerbations, particularlyin patients with severe pulmonaryfunction abnormalities who areat increased risk for exacerbations orsevere exacerbations.

^5,6

Inhaled corticosteroids can resultin a modest improvement in airflow inCOPD patients, but these improvementsare considerably smaller thanthose seen with bronchodilators. Nevertheless,if dyspnea persists despitemaximal treatment with bronchodilators,a trial with inhaled corticosteroidsis reasonable

(Table 4)

. This trial mayrequire at least 3 months to discernbenefit. Trials with oral corticosteroidsare no longer recommended.

FUTURE DIRECTIONS

We believe that combining drugswith different mechanisms and durationsof action will occupy a centralrole in future management of COPD.The availability of combination therapyshould help enhance patient complianceand result in cost savings.There is an urgent need to developnew drugs that will offer significantimprovement in airflow and arrestlong-term decline in lung function inpatients with COPD. The developmentof drugs with low bioavailability, longdurations of action, predictable side effects,and targeted pharmacologic effectswill improve symptomatic managementof this disease.Future COPD treatments willlikely be based on mechanisms thatare distinct from those of current therapies.A better understanding of thebasic pathophysiologic processes underlyingthe inflammation and tissueremodeling that are characteristic ofCOPD has created novel therapeuticopportunities.The agents that are being investigatedcan block various aspects ofthe inflammatory response, attenuatethe effect of inflammatory mediators,modulate tissue destruction, andstimulate tissue restoration. Thesedrugs may alter the natural courseof COPD and, potentially, reversephysiologic compromise.

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