Role of guaifenesin in the management of chronic bronchitis and upper respiratory tract infections

Abstract

Guaifenesin, a mucoactive drug, acts by loosening mucus in the airways and making coughs more productive. It is used for relief of wet cough and chest congestion due to the common cold, and remains the only legally marketed expectorant in the US (per OTC Monograph). An ingredient in numerous over-the-counter (OTC) cough/cold medications, guaifenesin has a secondary indication for use in stable chronic bronchitis (professional indication). Clinical pharmacology and patient studies support the clinical utility of guaifenesin in respiratory conditions where mucus hypersecretion is prevalent: acute upper respiratory tract infections (URTIs), stable chronic bronchitis, and possibly rhinosinusitis. Guaifenesin has a well-established and favorable safety and tolerability profile in adult and pediatric populations. Its dosing range (200-400 mg 4-hourly, up to 6× daily) allows flexible dose titration to allow an increase of plasma concentrations. Multiple daily doses are needed to maintain 24-h therapeutic effect with immediate-release formulations. Extended-release guaifenesin tablet formulations are available, providing convenience with 12-hourly dosing and portability compared to liquids. Guaifenesin is considered as a safe and effective expectorant for the treatment of mucus-related symptoms in acute URTIs and stable chronic bronchitis. Its clinical efficacy has been demonstrated most widely in chronic respiratory conditions, where excess mucus production and cough are more stable symptoms. Progress is being made to establish clinical models and measures that are more appropriate for studying symptomatic relief with guaifenesin in acute respiratory infections. This will help generate the up-to-date and high-quality data needed to optimize guaifenesin's effectiveness in established uses, and in new respiratory indications associated with mucus hypersecretion.

Keywords: Chronic bronchitis; Cough; Expectorant; Extended-release (ER) formulation; Guaifenesin; Mucoactive agents; Mucociliary clearance; over-the-counter (OTC); Mucus; Respiratory tract infections.

Fig. 1

Putative effects of guaifenesin on mucus in chronic or acute hypersecretory respiratory conditions. a The airway is composed of a mucus gel layer covering the epithelium, which includes ciliated cells, Clara cells, goblet cells and submucosal glands. The mucociliary complex can be subdivided into two layers – an upper mucus gel layer containing MUC5AC and MUC5B mucins, and a lower layer of periciliary fluid containing cell surface-tethered mucins. Mucociliary clearance (MCC) is effected by the rhythmic sweeping motion of cilia. Prolonged exposure to irritants such as cigarette smoke or allergens can lead to overproduction and hypersecretion of mucus. Guaifenesin has been postulated to promote mucociliary clearance via a number of mechanisms. (1) Indirect activation/stimulation of gastrointestinal vagal afferent nerves triggers reflex parasympathetic glandular secretion from submucosal glands and goblet cells (green stars), increasing hydration of mucus layer for more effective mucociliary clearance. Guaifenesin also affects secretion from goblet and Clara cells (red stars), resulting in (2) decreased mucin production and secretion (green circles, goblet cells; blue squares, Clara cells), and (3) reduced viscoelasticity of mucus, which increases the ability of ciliary movement to remove mucus. Together these changes serve to enhance MCC and mucus clearance. b–d Guaifenesin has direct effects on MCC-related processes in airway epithelial cells. In cultured human differentiated tracheobronchial epithelial cells, 24-h treatment with guaifenesin (2 or 20 μg/mL) significantly suppressed mucin production and mucin secretion (b), while 6-h treatment with guaifenesin (2–200 μg/mL) significantly enhanced mucociliary transport rates (c). At 1 h and 6 h after guaifenesin treatment (0–200 μg/mL), significant dose-dependent decreases were observed in mucus viscosity and elasticity at typical ciliary beat frequency (1 rad/s) (d), as measured by G*1 (vector sum of viscosity and elasticity at 1 rad/s). Panels b-d adapted from Seagrave et al., 2011 [13]

Fig. 2

Schematic pharmacokinetic profile of extended-release (ER) vs immediate-release (IR) guaifenesin formulations. Extended-release (ER) guaifenesin (blue line) attained bioequivalent plasma concentrations to those obtained with 3 immediate-release (IR) guaifenesin doses (orange line). The unique bi-layer tablet formulation comprises an IR layer that permits immediate release of guaifenesin to rapidly attain maximum plasma concentrations (C_max), and an ER layer that permits sustained release of guaifenesin to maintain prolonged blood plasma levels of guaifenesin over 12 h. Figure adapted from Vilson and Owen, 2013 [20]