Cough: Friend or Foe?

Introduction

According to epidemiological studies, the prevalence of cough in the general population is closely linked to smoking rates and ranges from 5% to 40%. (1) Cough is also the most common reason patients seek medical attention from family physicians, pulmonologists, or allergists/immunologists. (2)

Depending on its duration, cough is classified as either acute or chronic, with chronic cough defined as lasting longer than eight weeks. A productive cough is accompanied by the expectoration of bronchial secretions, whereas a non-productive cough occurs without effective mucus clearance.

Although cough is a normal protective reflex that helps remove secretions and foreign material from the airways, it is often perceived by patients as a disease that should be eliminated as quickly as possible. This expectation is understandable, as observational studies have shown that persistent cough can significantly impair quality of life, mood, and work productivity. (3)

Nevertheless, experts emphasize that cough should only be suppressed when it is particularly troublesome, prolonged, and the underlying cause cannot be effectively treated. Expectorant therapy is recommended when thick bronchial secretions are difficult to clear, as it facilitates mucus clearance while preserving the protective function of coughing. This raises an important clinical question: does cough help or harm? When should it be suppressed, and when should it be supported?

Causes of Cough

Both acute and chronic diseases may cause cough. Acute cough is most commonly associated with viral infections of the upper or lower respiratory tract, although bacterial infections may also be responsible.

Identifying the cause of chronic cough is often more challenging. Studies have shown that in 18–64% of patients, chronic cough results from more than one underlying condition. (4)

The most common causes include smoking, the use of angiotensin-converting enzyme (ACE) inhibitors, gastroesophageal reflux disease (GERD), asthma, and upper airway cough syndrome (previously known as postnasal drip syndrome). Chronic cough may also occur as a manifestation of psychosomatic disorders or malignant disease.

Persistent cough lasting several weeks or months may develop after a respiratory tract infection. It is believed that residual airway inflammation leaves the respiratory epithelium more vulnerable, increasing cough receptor sensitivity and bronchial hyperresponsiveness.

Physiology, Pathogenesis, and Clinical Course

The respiratory epithelium consists of ciliated epithelial cells and mucus-producing goblet cells. Airway secretions are composed of two distinct layers that perform different physiological functions.

A low-viscosity aqueous layer covers the ciliated epithelial cells, protecting and hydrating them. Above this lies a sticky, more viscous mucus layer that traps inhaled particles such as viruses, bacteria, and dust, preventing them from reaching the lower respiratory tract.

Surfactant, the third key component of airway secretions, improves the interaction between the aqueous and mucus layers, facilitating efficient mucus transport and clearance.

Mucociliary clearance is one of the respiratory tract's primary defense mechanisms. Coordinated movement of the cilia continuously transports mucus and trapped particles out of the airways. However, smoking, air pollution, respiratory infections, and inadequate hydration can impair mucociliary function, reducing mucus clearance and creating favorable conditions for bacterial growth.

Inflammatory and infectious airway diseases also alter the composition of airway secretions. Production of the thick mucus layer increases, while the aqueous layer and surfactant decrease. As a result, secretions become thicker, more viscous, and more difficult to expectorate.

Under these circumstances, coughing becomes an essential secondary defense mechanism. Its primary physiological function is to clear the airways of accumulated secretions and foreign material.

Mechanical and chemical stimuli—including foreign bodies, mucus, cold air, irritant gases, and bradykinin—activate cough receptors and afferent nerve fibers located within the respiratory epithelium. These signals travel via the vagus nerve to the cough center in the brainstem. Efferent impulses are then transmitted through the vagus nerve, the phrenic nerve (n. phrenicus), and spinal motor nerves to the diaphragm and chest wall muscles.

The resulting sudden contraction of these muscles increases intrathoracic pressure to as much as 300 mmHg. When the glottis opens, air is expelled at extremely high velocity—reported to reach up to 500 miles per hour. (5) These powerful forces mechanically dislodge and expel thick respiratory secretions.

The marked rise in intrathoracic pressure also produces transient hemodynamic effects similar to external chest compression. (6) Consequently, severe coughing episodes may lead to syncope, cardiac rhythm disturbances, inguinal hernias, or worsening gastroesophageal reflux.

Cough Treatment

Successful cough management depends primarily on treating its underlying cause. Acute cough often resolves spontaneously without causing significant discomfort, and if it is not troublesome, pharmacological treatment is usually unnecessary. Chronic cough, however, is more persistent and frequently requires additional, sometimes empirical, treatment.

Several classes of medications are used in the management of cough, including antihistamines, bronchodilators, cough suppressants, and expectorants or mucolytic agents.

In patients with acute or prolonged cough who have difficulty clearing thick, viscous respiratory secretions, expectorants and mucolytics are recommended to reduce mucus viscosity and facilitate its removal.

Ambroxol Hydrochloride

Ambroxol hydrochloride is one of the most widely used and extensively studied expectorant medications. It is the only active metabolite of bromhexine. (7) Ambroxol has been shown to facilitate expectoration by reducing mucus viscosity and promoting its clearance from the airways. (8)

In addition to its mucolytic action, experimental studies have demonstrated antioxidant, anti-inflammatory, and antiviral properties that may contribute to its therapeutic effects.

Inflammation of the respiratory tract is a normal pathophysiological and immunological response to injury caused by viruses, bacteria, or other physical and chemical irritants. Depending on the underlying cause, inflammatory cells accumulate within the airway mucosa and submucosa, releasing cytokines, chemotactic factors, proteolytic enzymes, and reactive oxygen species.

Leukotriene B4 (LTB4) is one of the most important chemoattractants for monocytes, macrophages, and neutrophils during acute, particularly viral, respiratory inflammation. (9) In vitro studies have shown that ambroxol significantly reduces LTB4 release from activated monocytes and neutrophils. (10)

Interleukin-8 (IL-8), another important inflammatory mediator, plays a key role in neutrophil recruitment and is particularly relevant in chronic obstructive pulmonary disease (COPD). Experimental studies have demonstrated that ambroxol reduces IL-8 release from human airway epithelial cells. (11)

Ambroxol has also been shown to inhibit the production and release of several other inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), IL-4, IL-6, and IL-13. (12) In experimental mouse models, its anti-inflammatory activity has been reported to be comparable to that of dexamethasone. (13)

Oxidative stress is another consequence of prolonged airway inflammation. Activated inflammatory cells generate reactive oxygen species to combat infection, but excessive production may damage healthy respiratory epithelium and lung tissue. Gillissen and colleagues demonstrated that ambroxol reduces the release of reactive oxygen species from activated polymorphonuclear cells. (14) Similar antioxidant effects have been confirmed in several additional in vitro studies. (15–17)

Influenza A virus is a major cause of respiratory tract inflammation and epithelial injury. Experimental studies in mice conducted by Yang and colleagues demonstrated that ambroxol suppresses influenza virus replication while promoting the production of antiviral immunoglobulins A (IgA) and G (IgG). (18)

Overall, experimental studies using cell cultures and animal models suggest that ambroxol possesses multiple biological activities that influence airway inflammation and its consequences. However, the clinical significance of these additional properties has yet to be fully established.

Clinical studies have consistently demonstrated that ambroxol hydrochloride is an effective and well-tolerated expectorant.

In one randomized, double-blind clinical trial, patients with acute or chronic bronchitis received ambroxol hydrochloride 45 mg/day or placebo for 15 days. Bronchial secretion volume and viscosity were evaluated throughout the study. Patients treated with ambroxol produced a greater volume of sputum, and by the end of treatment, sputum viscosity was significantly lower than in the placebo group. These findings clearly demonstrated that ambroxol reduces mucus viscosity and promotes bronchial secretion clearance.

The exact mechanism responsible for mucus thinning remains incompletely understood. It has been suggested that ambroxol stimulates production of both the aqueous airway surface layer and pulmonary surfactant. (20)

Improved mucus clearance also enhances mucociliary transport. Weiss and colleagues evaluated whether ambroxol could improve mucociliary clearance in patients with chronic obstructive pulmonary disease (COPD). (21) Patients received ambroxol hydrochloride 90 mg/day or placebo for four days. Mucociliary clearance was assessed using scintigraphic monitoring of inhaled technetium-labelled aerosol. Aerosol clearance from the lungs was significantly faster in patients receiving ambroxol than in those receiving placebo.

In another randomized, double-blind, placebo-controlled study, Germouty and colleagues treated patients with acute or obstructive pulmonary disease using ambroxol hydrochloride 120 mg/day for 10 days. (22) Ambroxol rapidly reduced sputum viscosity, increased expectoration from the first day of treatment, and significantly improved cough severity within three days. Patients receiving placebo experienced much slower clinical improvement.

A small two-week clinical trial involving patients with asthma treated with ambroxol hydrochloride 90 mg/day found that the drug did not increase bronchial hyperresponsiveness. (23) These findings suggest that ambroxol may be safely used in patients with asthma when clinically indicated.

In contrast, another commonly used mucolytic agent, acetylcysteine, should be used cautiously in asthma because it may increase bronchial reactivity and worsen asthma symptoms. (24)

Cough frequently accompanies bacterial respiratory tract infections requiring antibiotic therapy. Therefore, it is important to understand whether concomitant mucolytic therapy influences antibiotic bioavailability or effectiveness.

Several in vitro studies have shown that acetylcysteine may reduce the activity of certain antibiotics. (25) Consequently, acetylcysteine is generally recommended to be administered at least two hours before or after antibiotic treatment.

Fraschini and colleagues conducted a clinical study involving patients with COPD who were treated for respiratory tract infections using amoxicillin, erythromycin, or cefuroxime. Patients additionally received either ambroxol hydrochloride 90 mg/day or placebo. Four hours after antibiotic administration, antibiotic concentrations in bronchial secretions were significantly higher in patients receiving ambroxol than in those receiving placebo. Although this study did not determine whether these differences translated into improved clinical outcomes, the findings suggest that ambroxol may enhance antibiotic penetration into bronchial secretions.

Another clinical study involving patients with acute exacerbations of chronic bronchitis treated with amoxicillin found that combining ambroxol hydrochloride 90 mg/day with antibiotic therapy resulted in faster clinical improvement. By the third day of treatment, patients receiving ambroxol reported less coughing, easier sputum expectoration, and lower sputum neutrophil counts. Comparable improvement occurred later in the placebo group.

Published clinical studies consistently indicate that ambroxol hydrochloride is well tolerated.

In 2003, a large post-marketing surveillance study conducted in Germany evaluated the safety of ambroxol hydrochloride under routine clinical conditions. (27) The study included 2,664 patients who purchased ambroxol syrup from pharmacies. Only 2.5% reported mild adverse events, most commonly involving gastrointestinal or skin-related symptoms. At the end of treatment, 97% of patients rated the drug's tolerability as "very good" or "good," while 92% rated its effectiveness as "very good" or "good."

Summary

Cough is a symptom associated with numerous acute and chronic diseases. Its development is closely linked to impaired mucociliary clearance. When mucus transport is compromised, coughing becomes an important secondary defense mechanism that promotes secretion clearance and helps protect the respiratory tract against infectious complications.

Therefore, when cough is associated with retained bronchial secretions, expectorant therapy should be considered. Ambroxol hydrochloride is a well-studied, effective, and well-tolerated mucolytic agent. Its ability to reduce mucus viscosity, improve mucociliary clearance, and facilitate expectoration supports its use in both acute and chronic cough.

Cough suppressants should be reserved for selected situations in which persistent cough is particularly distressing and the underlying cause cannot be eliminated.

Article prepared by Dr. Jolita Kudirkienė

Literature references are available from the editorial office.

LT/Fla/2014/03