Expectorants

Under physiological conditions, bronchial secretion is one of the essential requirements for normal function of the bronchial tree. The production of bronchial secretion and its movement in the proximal direction (from the bronchi to the trachea) is a protective function of the respiratory system. Bronchial secretion not only mechanically protects the epithelium of the bronchial tree — it condenses inhaled air, humidifies it, normalizes its temperature, traps and clears dust — but also has bacteriostatic properties (preventing bacterial multiplication).

The bronchial mucosa is covered with multilayered ciliated epithelium consisting of ciliated, goblet, basal and intermediate cells. Synchronized oscillatory movements of the ciliated cells drive the clearance of bronchial secretion. Each ciliated cell has about 200 cilia beating at 15 strokes per second. Their oscillations move bronchial mucus along the tracheobronchial tree at 4–10 mm per minute.

In healthy individuals, the bronchial secretion produced by the bronchial mucosa ranges from 0.1 to 0.75 ml per kg of body weight. The person does not feel excess mucus because there is a special clearance mechanism — the mucociliary transport (mucociliary clearance). Its existence is of great importance in protecting the bronchi from bacterial invasion: because of ciliated-epithelium beating, a bacterium entering the bronchial lumen moves across the surface of 10 mucosal cells per second, so its contact with a single cell does not exceed 0.1 s, making bacterial invasion of the bronchial epithelium difficult. In patients with tracheobronchial disease — e.g. bronchial asthma — mucociliary clearance speed is reduced by 10–55%.

Bronchial secretion consists of mucus produced by the bronchial glands and by the goblet cells of the surface epithelium of the bronchi, and includes a special protein-mucopolysaccharide substance — surfactant — secreted by alveolar cells. Surfactant participates in regulating the rheological properties (flow) of bronchial secretion and thus improves its clearance along the pulmonary epithelium.

Physically, bronchial secretion is a multi-component colloidal solution made of two layers (phases): the upper (thick) gel, about 2 μm thick, and the lower (liquid) sol, 2–4 μm thick, in which the cilia swim and contract. The gel (insoluble phase) has a fibrillar structure and is formed by a macromolecular glycoprotein complex. The sol (soluble phase) contains electrolytes, biologically active substances — including enzymes and their inhibitors.

When mucociliary clearance does not provide adequate drainage of the tracheobronchial tree, productive cough occurs, becoming an important part of the defensive response. Often cough alone cannot provide adequate bronchial drainage — expectorants and/or mucolytics are therefore used.

Expectorant and mucolytic therapy is symptomatic and has two main goals:

• reduce sputum viscosity to ease its clearance;
• increase the activity of the ciliated epithelium of the tracheobronchial tree to improve bronchial drainage.

In respiratory illness the activity of the airway epithelial cells decreases while sputum secretion and viscosity increase. Coughing out viscous sputum becomes harder. Beyond its own protective role, excess or overly viscous sputum impairs gas exchange and creates conditions for bacterial growth — hence the need for products that stimulate expectoration or thin sputum.

Classification of expectorants

By mechanism of action, expectorants fall into two groups:

1. reflex-acting expectorants;
2. direct-acting expectorants.

Reflex-acting expectorants. Substances that irritate stomach receptors and cause vomiting at high doses have an expectorant action at low doses. These include preparations of thermopsis (e.g. Thermopsis lanceolata), marshmallow root (Althaea officinalis), senega root (Polygala species), licorice root (Glycyrrhiza glabra/uralensis), and Jacob’s-ladder rhizome with roots (Polemonium coeruleum). The expectorant effect is due to alkaloids, saponins and essential oils contained in these plants.

Mechanism: at doses that do not cause vomiting, irritation of stomach receptors reflexively alters the bronchial mucosa. Sputum secretion increases and viscosity decreases. Clearance is further aided by increased ciliary activity.

Herbal origin does not guarantee safety. Ipecac preparations, for example, significantly increase bronchial secretion and trigger the gag reflex. Thermopsis also enhances the gag and cough reflexes, so it is avoided in infants and children with CNS disease — it may cause aspiration, asphyxia, atelectasis or worsen cough-related vomiting. Anise, licorice and oregano have a marked laxative effect and are not recommended in children with diarrhea. Menthol can cause laryngospasm leading to acute asphyxia. Consequently, some agents in this group are not indicated in young children — for example, menthol-containing Bronchosan or Thermopsis.

This group also includes mainly emetic agents (apomorphine, lycorine) that have an expectorant effect at low doses.

Example preparations: Thermopsis lanceolata herb; Dry adult cough mixture (thermopsis + licorice extract + sodium bicarbonate + sodium benzoate + ammonium chloride + anise oil); Cough tablets (thermopsis + sodium bicarbonate); Dry thermopsis extract; Chest herbal blends No. 1 and No. 3; Glycyram (glycyrrhizic acid salt from licorice); Jacob’s-ladder rhizome with roots; Licorice root; Althaea syrup; Althaea root; Mukaltin (althaea polysaccharides).

Direct-acting expectorants include mucolytics that reduce sputum viscosity on direct contact. Two subgroups:

1. secretomotor (stimulating expectoration);
2. secretolytic / mucolytic (thinning sputum).

Subgroup 1 includes:

1. Iodide salts (NaI, KI). Given orally as 2–3% solutions, they are excreted by the bronchial mucosa, aiding expectoration and lowering viscosity.
2. Essential oils (anise, fennel, eucalyptus, turpentine). In pediatrics, ammonia-anise drops are still often used — the ammonia has a reflex expectorant action, the anise oil a direct effect.
3. Sodium bicarbonate — its alkaline properties reduce mucus viscosity. Effective by inhalation.

Subgroup 2 — the mucolytic group — is the largest and includes drugs that thin sputum by depolymerizing its polymers:

1. Acetylcysteine
2. Ambroxol (Lazolvan, Ambrobene)
3. Bromhexine

By entering the sputum they disrupt protein, nucleic-acid and other polymer molecules that make sputum viscous — sputum becomes more fluid and is easier to cough up. Some mucolytics also stimulate bronchial glands and promote surfactant secretion — the substance that lines alveoli and prevents their collapse.

The first drugs of this group were enzymatic preparations — trypsin, chymotrypsin, ribonuclease — with serious adverse effects (bronchospasm, hemoptysis, destruction of interalveolar septa in α1-antitrypsin deficiency). They are no longer used. Today enzymatic mucolytics are represented by α-DNase (dornase alfa, Pulmozyme), used in cystic fibrosis.

In recent years the main mucolytics used widely in pediatrics are cysteine derivatives: acetylcysteine (ACC), bromhexine, ambroxol (AmbroHEXAL, Lazolvan, Ambrobene), carbocisteine. A feature of their action is that they thin sputum without significantly increasing its volume. Acetylcysteine, carbocisteine, bromhexine and ambroxol break the disulfide bonds of the acid mucopolysaccharides of the sputum gel, thinning it and reducing its adhesiveness.

Acetylcysteine (ACC) also thins pus, stimulates the synthesis of secretion by mucous cells (which lyses fibrin and blood clots) and enhances glutathione synthesis in lymphoid cells of the airway mucosa — aiding their functional maturation and boosting the detoxification activity of the mucosal cellular apparatus. In children ACC is usually given orally, as it is well absorbed and effective concentrations are quickly reached in the lungs. In surgical and endoscopic practice ACC is also used endotracheally via slow instillations and, when necessary, parenterally — intramuscularly or intravenously. Action starts in 30–60 minutes and lasts up to 4 hours. In asthma the drug should be used with great caution because it can cause bronchospasm.

Bromhexine hydrochloride reduces sputum viscosity by breaking down the acid mucins of the bronchial gel. It also stimulates the production of neutral polysaccharides and the release of lysosomal enzymes by the bronchial glands. Importantly, bromhexine stimulates the synthesis of surfactant (an anti-atelectasis factor) by type II alveolar pneumocytes — making the alveoli more stable during respiration and the bronchial mucus easier to clear. Bromhexine’s pharmacokinetics are dose-dependent — it can accumulate with repeated administration, especially in renal failure, since it is excreted by the kidneys. Its metabolism and activity depend on liver function. It is mainly given orally in age-dependent increasing doses; inhaled and parenteral (IM/IV) routes are also used. After inhalation of 2 ml the effect starts in 20 minutes and lasts 4–8 hours. Bromhexine itself has an antitussive effect — which may be undesirable in asthma and cystic fibrosis, so bronchodilators should be co-administered.

Ambroxol hydrochloride (AmbroHEXAL, Lazolvan, Ambrobene) is an active metabolite of bromhexine. It is significantly more potent than bromhexine, especially in increasing surfactant synthesis — besides stimulating synthesis, it blocks its degradation — hence its stronger effect on mucociliary clearance. Ambroxol is available as tablets, extended-release capsules, syrup and inhalation solution.

ACC, AmbroHEXAL and bromhexine can be widely used for coughs caused by lower-respiratory-tract illnesses, especially in children up to five years old — whose increased bronchial-secretion viscosity is the main factor in cough and bronchial obstruction. The tendency to insufficient surfactant synthesis justifies the use of agents such as AmbroHEXAL in neonatology.

Carbocisteine is also a cysteine derivative. A feature of its pharmacology is that, besides a mucolytic effect, it changes the ratio between acid and neutral sialomucins, bringing it closer to normal; it also reduces the number of goblet cells and decreases mucus production. It acts at every level of the respiratory tract — bronchial, nasopharyngeal, paranasal sinus and middle-ear mucosae — hence its widespread use in otorhinolaryngology. Elimination is mainly renal and takes about 3 days.

Given carbocisteine’s profile, certain precautions are needed in pediatrics: it is not recommended to combine with other antitussives or drugs that suppress bronchial gland function (central antitussives, macrolide antibiotics, first-generation antihistamines) and with constipation.

Guaifenesin-based antitussives are widely used today. Guaifenesin is an intermediate between expectorants and mucolytics. It is the basis of Coldrex-Broncho, Tussin (combined product with caramel, glycerin, citric acid, sodium benzoate, corn syrup) and Stoptussin (with the central antitussive butamirate and guaifenesin). The usual dose is 100–200 mg every 4 hours. Guaifenesin-based products are mainly used in children over 3.

Indications. Expectorants of various types are used in inflammatory airway and lung diseases with dry cough or cough with viscous, hard-to-clear sputum (bronchitis, pneumonia, bronchiectasis, asthma, etc.). For purulent sputum, mucolytics are more effective than other expectorants. Efficacy is enhanced by abundant fluid intake. Reflex-acting agents should be taken every 2–3 hours because their action is brief. If needed, expectorants are combined with antitussives and — in conditions involving increased bronchial tone (e.g. asthma) — with bronchodilators. In respiratory infections expectorants are used alongside antibacterial therapy.

Note: this reference summary covers the main groups and representative agents; it is not a complete monograph on every preparation mentioned in the Russian source.