Symbicort® and Asthma – Mechanism of Action and Device

Symbicort® – Mechanism of action

Symbicort® contains the bronchodilator formoterol and the glucocorticosteroid budesonide. These have different modes of action and show additive effects in terms of reduction of asthma exacerbations [1,2]. The specific properties of these two components allow the budesonide plus formoterol combination to be used as a maintenance treatment for asthma, or as both maintenance and reliever therapy.

Find out more about Symbicort mode of action in COPD .

Budesonide – Mechanism of action

When inhaled, budesonide exerts a dose-dependent anti-inflammatory action in the airways, resulting in reduced symptoms and fewer asthma exacerbations [3,4]. The severity of adverse effects with inhaled budesonide are less severe than with systemic corticosteroids [5]. The exact mechanism responsible for the anti-inflammatory effect of glucocorticosteroids is unknown.

Formoterol – Mechanism of action

Inhaled formoterol, a selective long-acting ß2-agonist (LABA) bronchodilator, results in rapid and long-acting relaxation of bronchial smooth muscle in patients with reversible airways obstruction [6-8]. The bronchodilating effect is dose dependent, with an onset of effect within 1–3 minutes [6,7]. Studies performed in both stable and acute severe asthma confirm that formoterol works as fast as salbutamol or terbutaline [8,9] and faster than salmeterol [6]. The duration of effect is at least 12 hours after a single dose [6,7].

Symbicort Turbuhaler®

Symbicort effectively delivers budesonide and formoterol to the airways. Symbicort is delivered via the easy-to-use, inspiratory flow-driven inhaler, Turbuhaler® [10]. Due to the unique Turbuhaler vortex design of the mouth piece, Turbuhaler achieves effective administration of the drug and delivers a high high fraction of fine particles (< 4.7 aerodynamic diameter) to the lungs [11].

Compared with other dry powder inhalers such as Diskus™, Turbuhaler delivers a greater proportion of every dose as fine particles to the airways resulting in greater lung deposition [11-14]. The fine particle dose and lung deposition achieved with Turbuhar are similar to that seen with the pressurised metered dose inhaler Modulite® [11,15].

Turbuhaler delivers a high proportion of fine particles to the airways

Data are not direct treatment comparisons
1. Dhillon S, Keating GM. Drugs 2006;66: 1475–83.
2. Borgstrom L, et al. Int J Clin Pract 2005;59: 1488–95.

Turbuhaler deposits a high proportion of drug in the lungs

Data are not direct treatment comparisons
1. Dhillon S, Keating GM. Drugs 2006;66: 1475–83.
2. Borgstrom L, et al. Int J Clin Pract 2005;59: 1488–95. 

Turbuhaler can be used effectively by almost all asthma patients, regardless of age or clinical setting. Even young children and patients with severely impaired lung function have sufficient peak inspiratory flow values to be able to use Turbuhaler effectively [16,17]. Clinically effective drug delivery is achieved with relatively low inspiratory flow rates (about 30 L/min) [10].

Why can Symbicort® be used as maintenance and reliever therapy?

With Symbicort SMART, patients take a regular maintenance dose of Symbicort consisting of budesonide and formoterol and additional inhalations of Symbicort as needed. When additional inhalations are required, Symbicort allows an increased dose of both components, thereby addressing the underlying inflammation as well as offering effective symptom relief with every inhalation [18].

Symbicort can replace the use of a short-acting ß2-agonist (SABA) as it works as fast and effectively as salbutamol in relieving severe bronchoconstriction [19]. This rapid onset of effect means that patients feel the benefit of Symbicort very quickly – patients have confirmed that they feel relief from breathlessness within the first minute of taking Symbicort [20]. 

Onset of effect of Symbicort is similar to salbutamol [19]

Increasing both the dose and frequency of budesonide is beneficial in asthma that is poorly controlled [21]. Temporarily increasing the dose of budesonide at the first sign of worsening asthma effectively manages an exacerbation as well as regular higher doses of budesonide [22].

Clinical studies show that patients using Symbicort SMART experience fewer daily symptoms, experience less night-time awakenings and have fewer severe exacerbations compared with traditional fixed maintenance doses of inhaled corticosteroid (ICS)/LABA combination therapies plus as-needed SABA [23,24] – Read more about Symbicort asthma efficacy. The reduction in exacerbations seen with Symbicort SMART suggests that the timing of the budesonide dose may be a crucial factor; lung tissue concentrations decline between maintenance doses [25,26] and therefore budesonide taken as needed may supplement the tissue concentrations at a time when the concentration is suboptimal.

Symbicort SMART aims to provide a dose of medication that is appropriate to the level of inflammation, treating the underlying inflammation with every inhalation. Furthermore, increasing the dose of budesonide and formoterol at the first sign of asthma symptoms may prevent the development of exacerbations.

Symbicort SMART aims to provide a dose of medication that is appropriate to the level of inflammation, treating the underlying inflammation with every inhalation

Can other combination therapy inhalers be used as both maintenance and reliever therapy?

Due to its unique properties, Symbicort is currently the only ICS/LABA combination that is approved to be used as maintenance and relief in one inhaler. This is because both budesonide and formoterol show a clear dose response (i.e. higher doses have a greater effect). This approach is not possible with a combination product containing the LABA salmeterol (such as Seretide [salmeterol/fluticasone]), due to the lack of dose response for salmeterol. In addition, the onset of effect of Symbicort is faster than Seretide [27] and comparable with traditional relievers such as salbutamol [19].

Symbicort has a faster onset of effect than Seretide [27]

References

1. Barnes PJ. Scientific rationale for inhaled combination therapy with long-acting beta2-agonists and corticosteroids. Eur Respir J 2002;19:182-191.
2. Barnes PJ. Scientific rationale for using a single inhaler for asthma control. Eur Respir J 2007;29:587-595.
3. Busse WW, Chervinsky P, Condemi J, et al. Budesonide delivered by Turbuhaler is effective in a dose-dependent fashion when used in the treatment of adult patients with chronic asthma. J Allergy Clin Immunol 1998;101:457-463.
4. Adams N, Bestall J, Jones PW. Budesonide at different doses for chronic asthma. Cochrane Database Syst Rev 2001;CD003271.
5. Global Initiative for Asthma. Global strategy for asthma management and prevention - updated 2008. 
6. Palmqvist M, Persson G, Lazer L, et al. Inhaled dry-powder formoterol and salmeterol in asthmatic patients: onset of action, duration of effect and potency. Eur Respir J 1997;10:2484-2489.
7. Ringdal N, Derom E, Wahlin-Boll E, et al. Onset and duration of action of single doses of formoterol inhaled via Turbuhaler. Respir Med 1998;92:1017-1021.
8. Seberova E,.Andersson A. Oxis (formoterol given by Turbuhaler) showed as rapid an onset of action as salbutamol given by a pMDI. Respir Med 2000;94:607-611.
9. Boonsawat W, Charoenratanakul S, Pothirat C, et al. Formoterol (OXIS) Turbuhaler as a rescue therapy compared with salbutamol pMDI plus spacer in patients with acute severe asthma. Respir Med 2003;97:1067-1074.
10. Selroos O, Borgstrom L, Ingelf J. Performance of Turbuhaler(R) in Patients with Acute Airway Obstruction and COPD, and in Children with Asthma : Understanding the Clinical Importance of Adequate Peak Inspiratory Flow, High Lung Deposition, and Low In Vivo Dose Variability. Treat Respir Med 2006;5:305-315.
11. Borgstrom L, Asking L, Thorsson L. Idealhalers or realhalers? A comparison of Diskus and Turbuhaler. Int J Clin Pract 2005;59:1488-1495.
12. Agertoft L,.Pedersen S. Lung deposition and systemic availability of fluticasone Diskus and budesonide Turbuhaler in children. Am J Respir Crit Care Med 2003;168:779-782.
13. Asking L, Maayan C, Petterson G. Flutide Diskus less consistent than Pulmicort Turbuhaler with respect to in vitro fine particle dose proportionality. Am J Respir Crit Care Med 2009;163:A441.
14. Thorsson L, Edsbacker S, Kallen A, et al. Pharmacokinetics and systemic activity of fluticasone via Diskus and pMDI, and of budesonide via Turbuhaler. Br J Clin Pharmacol 2001;52:529-538.
15. Dhillon S,.Keating GM. Beclometasone dipropionate/formoterol: in an HFA-propelled pressurised metered-dose inhaler. Drugs 2006;66:1475-1483.
16. Stahl E, Ribeiro LB, Sandahl G. Dose response to inhaled terbutaline powder and peak inspiratory flow through Turbuhaler in children with mild to moderate asthma. Pediatr Pulmonol 1996;22:106-110.
17. Brown PH, Ning AC, Greening AP, et al. Peak inspiratory flow through Turbuhaler in acute asthma. Eur Respir J 1995;8:1940-1941.
18. Humbert M, Andersson TL, Buhl R. Budesonide/formoterol for maintenance and reliever therapy in the management of moderate to severe asthma. Allergy 2008;63:1567-1580.
19. Balanag VM, Yunus F, Yang PC, et al. Efficacy and safety of budesonide/formoterol compared with salbutamol in the treatment of acute asthma. Pulm Pharmacol Ther 2006;19:139-147.
20. van der Woude HJ, Boorsma M, Bergqvist PB, et al. Budesonide/formoterol in a single inhaler rapidly relieves methacholine-induced moderate-to-severe bronchoconstricion. Pulm Pharmacol Ther 2004;17:89-95.
21. Toogood JH, Baskerville JC, Jennings B, et al. Influence of dosing frequency and schedule on the response of chronic asthmatics to the aerosol steroid, budesonide. J Allergy Clin Immunol 1982;70:288-298.
22. Foresi A, Morelli MC, Catena E. Low-dose budesonide with the addition of an increased dose during exacerbations is effective in long-term asthma control. On behalf of the Italian Study Group. Chest 2000;117:440-446.
23. O'Byrne PM, Bisgaard H, Godard PP, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005;171:129-136.
24. Rabe KF, Atienza T, Magyar P, et al. Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet 2006;368:744-753.
25. Jendbro M, Johansson CJ, Strandberg P, et al. Pharmacokinetics of budesonide and its major ester metabolite after inhalation and intravenous administration of budesonide in the rat. Drug Metab Dispos 2001;29:769-776.
26. Miller-Larsson A, Mattsson H, Hjertberg E, et al. Reversible fatty acid conjugation of budesonide. Novel mechanism for prolonged retention of topically applied steroid in airway tissue. Drug Metab Dispos 1998;26:623-630.
27. Palmqvist M, Arvidsson P, Beckman O, et al. Onset of bronchodilation of budesonide/formoterol vs. salmeterol/fluticasone in single inhalers. Pulm Pharmacol Ther 2001;14:29-34.