EASCOF EXPECTORANT

Indications

• Chronic bronchitis
• Asthma
• Bronchiectasis
• Pneumonia
• Respiratory tract infections with productive cough

Dosage

Children: Refer to the BNF for Children for specific paediatric dosing recommendations.

Adults: Refer to the BNF for specific dosing information.

Mechanism of action

Bromhexine aids in mucus clearance by reducing the viscosity of mucus and activating the ciliary epithelium, allowing secretions to be expelled from the respiratory tract. Additionally, bromhexine has been shown to inhibit the transmembrane serine protease 2 receptor (TMPRSS2), which plays a crucial role in viral respiratory diseases. This inhibition may help in preventing or treating various respiratory illnesses, including COVID-19, by blocking viral entry into cells.

Pharmacodynamics

Bromhexine thins airway secretions, thus improving breathing and alleviating discomfort associated with thick mucus in the airways. Its action is particularly beneficial in respiratory disorders where mucus obstruction is a significant issue.

Pharmacokinetics

Bromhexine is well absorbed after oral administration, with peak plasma concentrations typically reached within 1 to 2 hours. It is metabolized in the liver, primarily to ambroxol, which is its active metabolite. The elimination half-life of bromhexine is approximately 8 to 12 hours, and it is excreted mainly through urine. The pharmacokinetics can be influenced by factors such as liver function and concurrent medications.

Adverse effects

• Gastrointestinal disturbances
• Nausea
• Vomiting
• Diarrhea
• Allergic reactions

Precautions

• Use with caution in patients with peptic ulcer disease
• Monitor patients with asthma or bronchospastic conditions

Pregnancy

Bromhexine should be used during pregnancy only if clearly needed and after careful consideration of the potential benefits and risks.

Breast-feeding

Bromhexine is excreted in breast milk; caution should be exercised when administering to nursing mothers.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets
• Syrup
• Solution for inhalation

Indications

• Cough associated with respiratory tract infections
• Cough due to bronchial asthma
• Acute bronchitis
• Chronic obstructive pulmonary disease (COPD)
• Sinusitis

Dosage

Children: For children aged 6 to 12 years, the typical dosage is 100-200 mg every 4 hours as needed, not exceeding 1.2 g in 24 hours. For children aged 2 to 6 years, the dosage is generally 50-100 mg every 4 hours as needed, not exceeding 600 mg in 24 hours. Refer to the BNF for Children for specific dosing recommendations.

Adults: The usual adult dosage for guaifenesin is 200-400 mg every 4 hours as needed, not exceeding 2.4 g in 24 hours.

Mechanism of action

Guaifenesin is believed to work by increasing mucus secretion and acting as an irritant to gastric vagal receptors, which stimulates efferent parasympathetic reflexes. This leads to glandular exocytosis of less viscous mucus. Additionally, it may enhance respiratory tract fluid, thereby reducing the viscosity of secretions and improving ciliary action for more efficient mucus clearance.

Pharmacodynamics

As an expectorant, guaifenesin enhances the output of bronchial secretions and phlegm by decreasing their adhesiveness and surface tension. This results in an increased flow of less viscous gastric secretions, promoting ciliary action and converting unproductive coughs into more productive ones. Although it may also exhibit mild anticonvulsant and muscle relaxant properties, these effects are less well established.

Pharmacokinetics

Guaifenesin is rapidly absorbed from the gastrointestinal tract and reaches peak plasma concentrations within one hour of administration. It is metabolized in the liver, and its elimination half-life is approximately one hour. The drug is primarily excreted in the urine, mostly as metabolites.

Adverse effects

• Nausea
• Vomiting
• Dizziness
• Headache
• Rash

Precautions

• Use with caution in patients with chronic cough due to asthma, smoking, or emphysema
• Ensure adequate hydration while using

Pregnancy

Guaifenesin is categorized as pregnancy category C. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Guaifenesin is excreted in breast milk. Caution should be exercised when administered to breastfeeding women.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Oral syrup
• Tablets
• Extended-release capsules

Indications

• Topical analgesic for muscle and joint pain
• Cough suppressant in cough drops and lozenges
• Relief of minor throat irritation
• Cooling agent in various cosmetic and personal care products

Dosage

Children: Refer to BNF for Children for specific dosing guidelines, as doses may vary based on age and formulation.

Adults: For topical use, apply a thin layer to the affected area not more than 3 to 4 times daily. For cough drops, follow the product-specific instructions as per the formulation.

Mechanism of action

Menthol acts as an agonist for the transient receptor potential subtype M8 (TRPM8), a non-selective cation channel that is activated by cold temperatures. This activation leads to calcium influx in mast cells, inducing the release of histamine, which can trigger allergic responses such as urticaria, asthma, and rhinitis. Menthol's ability to induce histamine release via TRPM8 suggests potential therapeutic applications for TRPM8 antagonists in managing cold- and menthol-induced allergies.

Pharmacodynamics

Menthol produces a cooling effect by stimulating sensory neurons that convey cold sensations. It interacts with TRPM8 channels, leading to the activation of intracellular signaling pathways that can result in vasodilation and increased blood flow to the area of application. This cooling sensation can provide symptomatic relief in conditions characterized by pain or irritation.

Pharmacokinetics

Menthol is absorbed through the skin and mucous membranes, with systemic effects depending on the route of administration. Its bioavailability can vary, and it is metabolized primarily in the liver. The elimination half-life and excretion pathways have not been extensively characterized, but menthol is generally considered to have a rapid onset of action with effects lasting for a few hours.

Adverse effects

• Allergic reactions
• Urticaria
• Asthma
• Rhinitis
• Skin irritation

Precautions

• Use with caution in patients with known allergies to menthol or related compounds
• May exacerbate asthma in sensitive individuals

Pregnancy

There are no well-controlled studies of menthol in pregnant women. Menthol should be used during pregnancy only if clearly needed.

Breast-feeding

Menthol is excreted in breast milk. Caution should be exercised when administering to nursing mothers.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Topical ointment
• Cream
• Liquid

Indications

• Asthma
• Chronic obstructive pulmonary disease (COPD)
• Exercise-induced bronchospasm

Dosage

Children: Refer to the BNF for Children for specific dosing information.

Adults: Refer to the BNF for specific dosing information.

Mechanism of action

Sulbutamol exerts its effects by binding to beta-2 adrenergic receptors on the bronchial smooth muscle. This binding activates adenylate cyclase, leading to an increase in cyclic adenosine monophosphate (cAMP) levels. Elevated cAMP results in the phosphorylation of proteins that cause relaxation of smooth muscle, thus dilating the airways and facilitating easier breathing.

Pharmacodynamics

The primary pharmacodynamic effect of sulbutamol is bronchial smooth muscle relaxation, which results in bronchodilation. This effect is dose-dependent and can begin within minutes after administration, providing rapid relief from bronchospasm. Additionally, sulbutamol has some effects on other smooth muscles, such as those in the uterus and blood vessels, although these effects are not the primary therapeutic targets.

Pharmacokinetics

Sulbutamol is rapidly absorbed after inhalation, with peak plasma concentrations typically occurring within 30 minutes to 2 hours. Its bioavailability is affected by the route of administration; inhaled sulbutamol has a higher bioavailability compared to oral formulations due to first-pass metabolism. The drug is metabolized primarily in the liver, with a half-life of approximately 3 to 7 hours. Sulbutamol is excreted mainly in the urine as inactive metabolites.

Contra-indications

• Hypersensitivity to sulbutamol or any of its components
• Severe tachyarrhythmias
• Cardiac arrhythmias

Adverse effects

• Tremor
• Nervousness
• Palpitations
• Tachycardia
• Headache
• Dizziness
• Nausea
• Muscle cramps
• Hypokalemia
• Increase in blood glucose levels

Interactions

• Beta-blockers may reduce the effectiveness of sulbutamol
• Diuretics may increase the risk of hypokalemia
• Monoamine oxidase inhibitors (MAOIs) can potentiate the effects of sulbutamol
• Tricyclic antidepressants may enhance the cardiovascular effects

Precautions

• Use with caution in patients with cardiovascular disorders
• Caution in patients with hyperthyroidism
• Caution in patients with diabetes mellitus
• Risk of paradoxical bronchospasm

Pregnancy

Sulbutamol should only be used in pregnancy if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Sulbutamol is excreted in breast milk, caution is advised when administered to nursing mothers.

Storage

Store at room temperature, away from light and moisture. Do not freeze.

Formulations

• Inhalation aerosol
• Inhalation solution
• Tablet
• Syrup

Mechanism of action

Inflammation of the airways, increased mucus secretion, and altered mucociliary clearance are the hallmarks of various diseases of the respiratory tract. Mucus clearance is necessary for lung health; bromhexine aids in mucus clearance by reducing the viscosity of mucus and activating the ciliary epithelium, allowing secretions to be expelled from the respiratory tract. Recent have studies have demonstrated that bromhexine inhibits the transmembrane serine protease 2 receptor (TMPRSS2) in humans. Activation of TMPRSS2 plays an important role in viral respiratory diseases such as influenza A and Middle East Respiratory Syndrome (MERS). Inhibition of receptor activation and viral entry by bromhexine may be effective in preventing or treating various respiratory illnesses, including COVID-19. In vitro studies have suggested the action of ambroxol (a metabolite of bromhexine) on the angiogensin-converting enzyme receptor 2 (ACE2), prevents entry of the viral envelope-anchored spike glycoprotein of SARS-Cov-2 into alveolar cells or increases the secretion of surfactant, preventing viral entry.

Pharmacodynamics

Bromhexine thins airway secretions, improving breathing and discomfort associated with thick mucus in airways associated with a variety of respiratory conditions.

Mechanism of action

Although the exact mechanism of action of guaifenesin may not yet be formally or totally elucidated, it is believed that expectorants like guaifenesin function by increasing mucus secretion. Moreover, it is also further proposed that such expectorants may also act as an irritant to gastric vagal receptors, and recruit efferent parasympathetic reflexes that can elicit glandular exocytosis that is comprised of a less viscous mucus mixture. Subsequently, these actions may provoke coughing that can ultimately flush difficult to access, congealed mucopurulent material from obstructed small airways to facilitate a temporary improvement for the individual. Consequently, while it is generally proposed that guaifenesin functions as an expectorant by helping to loosen phlegm (mucus) and thin bronchial secretions to rid the bronchial passageways of bothersome mucus and make coughs more productive, there has also been research to suggest that guaifenesin possesses and is capable of demonstrating anticonvulsant and muscle relaxant effects to some degree possibly by acting as an NMDA receptor antagonist. Guaifenesin is thought to act as an expectorant by increasing the volume and reducing the viscosity of secretions in the trachea and bronchi. Thus it may increase the efficiency of the cough reflex and facilitate removal of the secretions; however, objective evidence for this is limited and conflicting. By increasing respiratory tract fluid, guaifenesin reduces the viscosity of tenacious secretions and acts as an expectorant. Guaifenesin, a commonly used agent for the treatment of cough, is termed an expectorant since it is believed to alleviate cough discomfort by increasing sputum volume and decreasing its viscosity, thereby promoting effective cough. Despite its common usage, relatively few studies, yielding contrasting results, have been performed to investigate the action and efficacy of guaifenesin. To evaluate the effect of guaifenesin on cough reflex sensitivity. Randomized, double-blind, placebo-controlled trial. Fourteen subjects with acute viral upper respiratory tract infection (URI) and 14 healthy volunteers. On 2 separate days, subjects underwent capsaicin cough challenge 1 to 2 hr after receiving a single, 400-mg dose (capsules) of guaifenesin or matched placebo. Measurements and results: The concentration of capsaicin inducing five or more coughs (C(5)) was determined. Among subjects with URI, mean (+/- SEM) log C(5) after guaifenesin and placebo were 0.92 +/- 0.17 and 0.66 +/- 0.14, respectively (p = 0.028). No effect on cough sensitivity was observed in healthy volunteers. /The/ results demonstrate that guaifenesin inhibits cough reflex sensitivity in subjects with URI, whose cough receptors are transiently hypersensitive, but not in healthy volunteers. Possible mechanisms include a central antitussive effect, or a peripheral effect by increased sputum volume serving as a barrier shielding cough receptors within the respiratory epithelium from the tussive stimulus.

Pharmacodynamics

Guaifenesin is categorized as an expectorant that acts by enhancing the output of phlegm (sputum) and bronchial secretions via decreasing the adhesiveness and surface tension of such material. Furthermore, guaifenesin elicits an increased flow of less viscous gastric secretions that subsequently promote ciliary action - all actions that ultimately change dry, unproductive coughing to coughs that are more productive and less frequent. Essentially, by decreasing the viscosity and adhesiveness of such secretions, guaifenesin enhances the efficacy of mucociliary activity in removing accumulated secretions from the upper and lower airway.

Mechanism of action

Exposure to low temperatures often causes allergic responses or urticaria. Similarly, menthol, a common food additive is also known to cause urticaria, asthma, and rhinitis. However, despite the obvious clinical implications, the molecular mechanisms responsible for inducing allergic responses to low temperatures and menthol have not been determined. Because a non-selective cation channel, transient receptor potential subtype M8 (TRPM8) is activated by cold and menthol, we hypothesized that this channel mediates cold- and menthol-induced histamine release in mast cells. Here, we report that TRPM8 is expressed in the basophilic leukemia mast cell line, RBL-2H3, and that exposure to menthol or low temperatures induced Ca(2+) influx in RBL-2H3 cells, which was reversed by a TRPM8 blocker. Furthermore, menthol, a TRPM8 agonist, induced the dose-dependent release of histamine from RBL-2H3 cells. When TRPM8 transcripts were reduced by siRNA (small interfering RNA), menthol- and cold-induced Ca(2+) influx and histamine release were significantly reduced. In addition, subcutaneous injection of menthol evoked scratching, a typical histamine-induced response which was reversed by a TRPM8 blocker. Thus, our findings indicate that TRPM8 mediates the menthol- and cold-induced allergic responses of mast cells, and suggest that TRPM8 antagonists be viewed as potential treatments for cold- and menthol-induced allergies. /DL-Menthol/ Menthol's characteristic cooling sensation is due, in part, to the activation of sensory neurons generally termed transient receptor potential (TRP) channels, in particular transient receptor potential melastatin family member 8 (TRPM8) and transient receptor potential subfamily A, member 1 (TRPA1). Menthol acts upon TRPM8 receptors by rapidly increasing intracellular calcium and mobilizing calcium flux through the channels to induce cold response signals at the application site. Aside from its cold-inducing sensation capabilities, menthol exhibits cytotoxic effects in cancer cells, induces reduction in malignant cell growth, and engages in synergistic excitation of GABA receptors and sodium ion channels resulting in analgesia. /DL-Menthol/ In recent years, the transient receptor potential melastatin member 8 (TRPM8) channel has emerged as a promising prognostic marker and putative therapeutic target in prostate cancer. We have found that forced overexpression of TRPM8 in PC-3 cells can inhibit the cell proliferation and motility probably through the TRPM8 activation. In this study, we aimed to investigate whether activating the TRPM8 channel by its selective agonist menthol can inhibit the proliferation and motility of androgen-independent prostate cancer (AIPC) with remarkable expression of TRPM8. Menthol is a naturally occurring compound, which has been widely used in cosmetics and pharmaceutical products, and also as flavoring in food. DU145 cells are androgen-independent but have a remarkable expression of TRPM8. The demonstration of the existence of TRPM8 and the absence of TRPA1 in DU145 cells provided the foundation for the following experiments, because both TRPM8 and TRPA1 are molecular targets of menthol. The outcome of MTT assay indicated that menthol inhibited the cell growth (p < 0.01). Cell cycle distribution and scratch assay analysis revealed that menthol induced cell cycle arrest at the G(0)/G(1) phase (p < 0.01). Furthermore, menthol inhibited the migration of DU145 cells by downregulating the focal-adhesion kinase. So it suggests that the activation of the existing TRPM8 channels may serve as a potential and pragmatic treatment for those AIPC with remarkable expression of TRPM8, and menthol is a useful compound for future development as an anticancer agent. /DL-Menthol/