E

M

I

Ja

b

urlbomo

ianp

odrtLmio

D

crt

t(gaot

t

1

Arch Bronconeumol. 2013;49(7):279–281

w w w.archbronconeumol .org

ditorial

2–�2 Interaction: A Basis for Combined Bronchodilator Treatment�

nteracción M –� : bases para el tratamiento broncodilatador combinado

2 2

osé Luis López-Camposa,b

Unidad Médico-Quirúrgica de Enfermedades Respiratorias, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, Sevilla, SpainCentro de investigación en red de enfermedades respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain

Since the introduction of the first short-acting bronchodilatorsntil the present day, bronchodilator treatment has undergoneemarkable advances, with the appearance of new more potent,onger-acting molecules with a better safety profile. This growth inronchodilator drugs has significantly improved the treatment ofbstructive airways diseases, most notably chronic obstructive pul-onary disease (COPD), in which bronchodilation forms the basis

f pharmacological therapy.New long-acting �2-adrenergic receptor agonists (LABA) have

mproved pharmacodynamic parameters, increasing their potencynd efficacy.1 Similarly, the new long-acting muscarinic antago-ists (LAMA) also show improvements in their pharmacodynamicrofile, with longer duration and more rapid onset of action.2

Due to the good clinical results obtained with both familiesf bronchodilator drugs, the clinical effect that combining tworugs from different groups could have in COPD patients hasecently begun to be considered. In this respect, various clinicalrials have provided evidence on the effects of using a LABA and aAMA together.3–5 These studies have found a functional improve-ent resulting from their additive action, as well as a clinical

mpact with improvements in chronic symptoms but less impactn exacerbations.6,7

escription of the Problem

Although available evidence supports the use of combined bron-hodilator treatment in COPD, there are still some unknowns. In thisespect, a close review of the literature may reveal two phenomenahat require explanation.

The first stems from combination trials evaluating the func-ional effect of adding a twice daily LABA to a once daily LAMAtiotropium).3,5 These studies similarly describe a very illustrativeraph that shows the resulting functional improvement after the

ddition of the first and second dose of twice daily LABA in patientsn tiotropium treatment. However, attention must be drawn tohe fact that the second dose of LABA, the dose administered in

� Please cite this article as: López-Campos JL. Interacción M2–�2: bases para elratamiento broncodilatador combinado. Arch Bronconeumol. 2013;49:279–81.

E-mail address: lcampos@separ.es

579-2129/$ – see front matter © 2012 SEPAR. Published by Elsevier España, S.L. All right

the evening, achieves smaller functional improvements than thoseachieved with the morning dose.

This phenomenon may have several explanations. On one hand,the smaller effect of tiotropium 12 h after the onset of action meansthat the onset of bronchodilation after the second dose of LABAoccurs in a different part of the tiotropium action curve. Neverthe-less, although this is true, the bronchodilator impact is more minoreven if we take into account this decline in the action of tiotropium.8

Another possible explanation could be that the LABA acts differ-ently according to the time of day at which it is administered. In thisrespect, the existence of a circadian rhythm that influences airwaycalibre has been described. This circadian rhythm causes the cali-bre of the airways to become smaller during the night, regardlessof the state of sleep or wakefulness.9 To establish the importanceof this phenomenon, various studies have been conducted on theefficacy of bronchodilators according to the time of day at whichthey are administered. Although detailed analysis of their results isbeyond the scope of this editorial, most studies did not find majordifferences between administering a long-acting bronchodilatorin the morning or at night, when given separately.10,11 However,if we study the joint action of two bronchodilators, a once dailyLAMA (tiotropium) and twice daily LABA, we come across an inter-esting finding. A recent study explored the clinical efficacy of thecombination of tiotropium and formoterol, in order to study dif-ferent regimens according to the time of administration of bothdrugs (morning or evening) and the number of doses in the caseof formoterol (1 or 2 doses daily), so five treatment groups wereestablished.12 In this study, both treatment groups that receivedformoterol every 12 h plus tiotropium (one group in the morningand the other in the evening) obtained better efficacy in lung func-tion, symptoms and use of rescue medication than the other groups.However, patients with nighttime symptoms obtained a greaterbenefit in dyspnoea and use of rescue medication if the tiotropiumwas administered at night together with the formoterol instead ofin the morning.12 This finding had not been described previously,and suggests that the joint action of both bronchodilators is moreeffective when the administration of the two drugs is closer, whichconstitutes the second phenomenon that requires explanation.

In order to understand why this functional and clinicalimprovement occurs with the joint administration of a LABAand a LAMA, we must briefly recall the mechanism of action ofbronchodilators.

s reserved.

2 ncone

I

hrtTtecmp

trmewpcMw

bMatcttitm

M

tiocbitrfoitutifs

tiwtauatOa

1

1

1

1

1

80 J.L. López-Campos / Arch Bro

nteraction Between Adrenergic and Cholinergic Receptors

The mechanism of action of the �2 agonists is known andas been recently reviewed.13 Briefly, the stimulation of theseeceptors causes activation of G proteins coupled to the �2 recep-or, which in turn regulate the action of an adenylate cyclase.his enzyme mediates the conversion of adenosine triphosphateo cyclic adenosine monophosphate (cAMP). cAMP regulates thexpression of several cellular proteins, among which are the cal-ium channel, which in turn permits relaxation of the bronchialuscles. Therefore, adenylate cyclase and intracellular cAMP levels

lay a crucial role in the mechanism of action of the �2 receptors.There are currently five known types of muscarinic receptors,

ermed M1–M5.14 Of these, M1–M3 are expressed in the humanespiratory tract. Specifically, airway smooth muscle contains aixed population of M2 and M3 receptors. The main bronchodilator

ffect derived from their inhibition is related with the M3 receptors,hich through G proteins stimulate a phospholipase that in turnromotes the influx of calcium into the cell.15 However, despite thelear role of the M3 receptors in muscle contraction, the number of

3 receptors in the airways is much lower than the M2 receptors,ith a ratio of 4:1.16

The role of the M2 receptor in the action of the LAMAs has noteen sufficiently considered until now. However, the function of the2 receptors is key for understanding the interaction with the �2

drenergic receptors in the airways. It is known that the M2 recep-ors inhibit (via the G proteins) the generation and accumulation ofAMP in the cell, which is the mechanism of action of the �2 recep-or. Thus, stimulation of an M2 receptor would inhibit the action ofhe �2 receptor. Although the exact site of interaction where thisnhibition occurs is unknown, the relationship between both recep-ors contributes jointly to the contraction of the bronchial smooth

uscle.17

2–�2 Interaction: Clinical Implications

From the above, it appears that it would be plausible to suggesthat the effect of stimulating the �2 receptor would be greater dur-ng M2 receptor inhibition. To understand the clinical implicationsf this suggestion, we must remember the tiotropium pharma-odynamic studies. It is well known that tiotropium exerts itsronchodilatory action by inhibiting the M3 receptors. However,

t is equally certain that it also inhibits the M2 receptors, only thathis M2 inhibition is transient, with a half life of 3.6 h.8 Thus, M2eceptor inhibition and the subsequent release of �2 last barely aew hours, so if we want to take advantage of the potential benefitsf this M2–�2 interaction, it follows that both drugs must be admin-stered at the same time, in order for the M2 inhibition to unblockhe �2 receptor and allow it to have greater action on being stim-lated. This would explain the smaller effect of the second dose inhe LABA–LAMA combination studies,3,5 as it lacks this interactionn the second administration, or the greater clinical effect when theormoterol and tiotropium doses are given simultaneously in thetudy by Terzano et al.12

If this hypothesis is true, it would be advisable to use a LABAogether with a LAMA to be able to take advantage of the M2–�2nteraction. Thus, if once daily bronchodilators are administered, it

ould be reasonable to recommend their simultaneous adminis-ration at the same time of the day, instead of one in the morningnd the other at night. On the contrary, if a twice daily LABA issed, it would be reasonable to recommend the administration of

twice daily LAMA. At present there are two twice daily (salme-erol, formoterol) and one once daily LABAs (indacaterol) available.nly one once daily LAMA has been available to date (tiotropium),lthough new LAMA molecules have recently been approved with

1

umol. 2013;49(7):279–281

an administration profile every 12 h (aclidinium18) and every 24 h(glycopyrronium19). Clinical trials exploring the clinical relevanceof this interaction on combining once or twice daily bronchodilatorsare therefore required.

Conclusions

In recent years, we have been witnessing an expansion inthe development of bronchodilator drugs towards more potent,longer-lasting molecules with a better safety profile. Knowledgeof the mechanisms of action of both bronchodilator families,LABA and LAMA, provides us with information that helps us tounderstand the interaction between both, with a significant rolebetween the M2 and �2 receptors. Understanding this receptorinteraction is crucial for suggesting the optimal form of admin-istration of these drugs, so that the best clinical benefits can beobtained for patients. Future clinical studies must ascertain theclinical importance of this M2–�2 interaction in specific clinicalcontexts.

Conflicts of Interests

The author has received fees for giving lectures, scientific advice,participation in clinical studies and writing articles for (alphabet-ical order): Almirall, AstraZeneca, Bayer, Boehringer Ingelheim,Cantabria Pharma, Chiesi, Esteve, Faes, Ferrer, GlaxoSmithKline,MSD, Novartis and Pfizer.

References

1. Malerba M, Radaeli A, Morjaria JB. Therapeutic potential for novel ultralong-acting beta2-agonists in the management of COPD: biological and phar-macological aspects. Drug Discov Today. 2012;17:496–504.

2. Matera MG, Page CP, Cazzola M. Novel bronchodilators for the treat-ment of chronic obstructive pulmonary disease. Trends Pharmacol Sci.2011;32:495–506.

3. Van Noord JA, Aumann JL, Janssens E, Smeets JJ, Zaagsma J, Mueller A, et al.Combining tiotropium and salmeterol in COPD: effects on airflow obstructionand symptoms. Respir Med. 2010;104:995–1004.

4. Mahler DA, D’Urzo A, Bateman ED, Ozkan SA, White T, Peckitt C, et al. Concur-rent use of indacaterol plus tiotropium in patients with COPD provides superiorbronchodilation compared with tiotropium alone: a randomised, double-blindcomparison. Thorax. 2012;67:781–8.

5. Van Noord JA, Aumann JL, Janssens E, Verhaert J, Smeets JJ, Mueller A,et al. Effects of tiotropium with and without formoterol on airflow obstruc-tion and resting hyperinflation in patients with COPD. Chest. 2006;129:509–17.

6. Miles MC, Donohue JF, Ohar JA. Optimum bronchodilator combinations inchronic obstructive pulmonary disease: what is the current evidence? Drugs.2012;72:301–8.

7. Van der Molen T, Cazzola M. Beyond lung function in COPD management: effec-tiveness of LABA/LAMA combination therapy on patient-centred outcomes. PrimCare Respir J. 2012;21:101–8.

8. Disse B, Reichl R, Speck G, Traunecker W, Ludwig Rominger KL, Hammer R. Ba679 BR, a novel long-acting anticholinergic bronchodilator. Life Sci. 1993;52:537–44.

9. Spengler CM, Shea SA. Endogenous circadian rhythm of pulmonary function inhealthy humans. Am J Respir Crit Care Med. 2000;162:1038–46.

0. Calverley PM, Lee A, Towse L, van Noord J, Witek TJ, Kelsen S. Effect of tiotropiumbromide on circadian variation in airflow limitation in chronic obstructive pul-monary disease. Thorax. 2003;58:855–60.

1. Magnussen H, Verkindre C, Jack D, Jadayel D, Henley M, Woessner R, et al. Inda-caterol once-daily is equally effective dosed in the evening or morning in COPD.Respir Med. 2010;104:1869–76.

2. Terzano C, Petroianni A, Conti V, Ceccarelli D, Graziani E, Sanduzzi A, et al. Ratio-nal timing of combination therapy with tiotropium and formoterol in moderateand severe COPD. Respir Med. 2008;102:1701–7.

3. Rosenbaum DM, Rasmussen SG, Kobilka BK. The structure and function of G-protein-coupled receptors. Nature. 2009;459:356–63.

4. Caulfield MP, Birdsall NJ. International Union of Pharmacology. xvii. Clas-

sification of muscarinic acetylcholine receptors. Pharmacol Rev. 1998;50:279–90.

5. Belmonte KE. Cholinergic pathways in the lungs and anticholinergic ther-apy for chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;2:297–304.

ncone

1

1

1

J.L. López-Campos / Arch Bro

6. Roffel AF, Elzinga CR, Van Amsterdam RG, De Zeeuw RA, Zaagsma

J. Muscarinic M2 receptors in bovine tracheal smooth muscle: dis-crepancies between binding and function. Eur J Pharmacol. 1988;153:73–82.

7. Torphy TJ. Beta-adrenoceptors, cAMP and airway smooth muscle relaxation:challenges to the dogma. Trends Pharmacol Sci. 1994;15:370–4.

1

umol. 2013;49(7):279–281 281

8. Kerwin EM, D’Urzo AD, Gelb AF, Lakkis H, Garcia Gil E, Caracta CF, et al. Efficacy

and safety of a 12-week treatment with twice-daily aclidinium bromide in COPDpatients (ACCORD COPD I). COPD. 2012;9:90–101.

9. D’Urzo A, Ferguson GT, van Noord JA, Hirata K, Martin C, Horton R, et al. Efficacyand safety of once-daily NVA237 in patients with moderate-to-severe COPD:the GLOW1 trial. Respir Res. 2011;12:156.