ZEET COMBINATION PRODUCT ORAL LIQUID

Indications

• Pruritus
• Eczema
• Acne
• Rosacea

Dosage

Children: For children aged 12-17 years, apply up to 3 grams 3-4 times a day, ensuring coverage is less than 10% of body surface area.

Adults: Apply thinly to the affected area 1-2 times a day. Maximum application should cover less than 10% of body surface area, with a total daily maximum of 12 grams.

Mechanism of action

Levomenthol primarily activates the cold-sensitive TRPM8 receptors in the skin. This stimulation leads to a feeling of coolness by inhibiting calcium ion currents in neuronal membranes. Additionally, menthol may exhibit analgesic properties through kappa-opioid receptor agonism, further contributing to its pain-relieving effects.

Pharmacodynamics

Levomenthol is a covalent organic compound that can be synthesized or extracted from peppermint and other mint oils. It induces a cooling sensation when applied topically, inhaled, or ingested, by stimulating cold-sensitive receptors located in the skin. Notably, this effect occurs without a decrease in actual skin temperature, making it useful in topical formulations for managing discomfort.

Pharmacokinetics

Levomenthol is absorbed through the skin upon topical application. Its effects are localized, and it does not significantly enter systemic circulation when used as directed. The onset of action is typically rapid, providing immediate symptomatic relief from conditions like itching and irritation.

Contra-indications

• Severe heart disease
• Severe hepatic impairment
• Glaucoma
• Urinary retention
• History of mania or arrhythmias

Adverse effects

• Drowsiness
• Dizziness
• Headache
• Nausea
• Vomiting
• Dry mouth
• Dry eyes
• Diarrhea
• Constipation
• Skin reactions
• Altered taste
• Blurred vision
• Suicidal behaviors

Interactions

• Tricyclic antidepressants
• Other central nervous system depressants

Precautions

• Avoid application to large areas of the skin
• Use caution in patients with a history of psychiatric disorders
• Caution advised for driving and skilled tasks due to potential somnolence or dizziness

Pregnancy

Manufacturer advises use only if potential benefit outweighs risk.

Breast-feeding

Manufacturer advises use only if potential benefit outweighs risk.

Storage

Store in a cool, dry place, protected from light.

Formulations

• AquaSoothe 1% cream (Menthol 10 mg per 1 gram)
• AquaSoothe 2% cream (Menthol 20 mg per 1 gram)
• Arjun 0.5% cream (Menthol 5 mg per 1 gram)
• Arjun 1% cream (Menthol 10 mg per 1 gram)
• Dermacool 0.5% cream (Menthol 5 mg per 1 gram)
• Dermacool 1% cream (Menthol 10 mg per 1 gram)
• Menthoderm 0.5% cream (Menthol 5 mg per 1 gram)
• Menthoderm 1% cream (Menthol 10 mg per 1 gram)
• Menthoderm 2% cream (Menthol 20 mg per 1 gram)
• Menthoderm 5% cream (Menthol 50 mg per 1 gram)

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

• Allergic rhinitis
• Allergic conjunctivitis
• Urticaria

Mechanism of action

Diphenhydramine primarily functions by antagonizing H1 (Histamine 1) receptors located in various tissues, including the respiratory system, gastrointestinal tract, and central nervous system. By acting as an inverse agonist at H1 receptors, it mitigates the effects of histamine, thereby reducing allergic symptoms. As a first-generation antihistamine, it also crosses the blood-brain barrier, leading to sedative effects. Furthermore, diphenhydramine exhibits antimuscarinic activity by competitively antagonizing muscarinic acetylcholine receptors, contributing to its use in treating parkinsonian symptoms.

Pharmacodynamics

Diphenhydramine possesses anti-histaminic, anti-emetic, anti-vertigo, and sedative properties. Its antihistaminic action blocks the effects of histamine by competing for H1 receptor sites, preventing symptoms associated with histamine release. Its anti-emetic effects are due to inhibition at the medullary chemoreceptor trigger zone, while its anti-vertigo action arises from a central antimuscarinic effect on the vestibular apparatus and the vomiting center in the midbrain.

Pharmacokinetics

Diphenhydramine is well-absorbed following oral administration and reaches peak plasma concentrations within 1 to 2 hours. It is metabolized in the liver and has a half-life of approximately 4 to 8 hours, although this can vary based on individual factors. The drug is excreted primarily in the urine, with a significant portion eliminated as metabolites rather than unchanged drug. Due to its lipophilic nature, diphenhydramine readily crosses the blood-brain barrier, contributing to its sedative effects.

Contra-indications

• Severe asthma exacerbation
• Hypersensitivity to diphenhydramine or any of its components
• Newborns or premature infants

Adverse effects

• Drowsiness
• Dizziness
• Dry mouth
• Constipation
• Urinary retention
• Blurred vision
• Confusion

Interactions

• CNS depressants (e.g., alcohol, sedatives, tranquilizers) may enhance sedative effects
• MAO inhibitors can prolong and intensify anticholinergic effects

Precautions

• Use with caution in patients with glaucoma
• Prostatic hypertrophy
• Cardiovascular disease
• Elderly patients may be more sensitive to side effects

Pregnancy

Diphenhydramine should only be used during pregnancy if clearly needed. Consult a healthcare provider for advice.

Breast-feeding

Diphenhydramine is excreted in breast milk. Use caution when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets
• Capsules
• Liquid formulations
• Topical preparations

Indications

• Cough associated with colds
• Bronchitis
• Respiratory tract infections
• Other conditions with excessive mucus production

Dosage

Children: Refer to the BNF for Children for specific dosing guidelines based on age and

Adults: The typical adult dose is 200-400 mg orally every 4 hours as needed, not exceeding 2.4 g per day.

Mechanism of action

Guaifenesin is believed to function by increasing mucus secretion and acting as an irritant to gastric vagal receptors. This action recruits efferent parasympathetic reflexes that stimulate glandular exocytosis, resulting in a less viscous mucus mixture. Consequently, this may provoke coughing, facilitating the clearance of congealed mucopurulent material from obstructed airways, thereby improving respiratory function. Additionally, it is thought to enhance the output of phlegm and bronchial secretions by reducing their viscosity and adhesiveness, thus promoting ciliary action and improving the efficiency of the cough reflex.

Pharmacodynamics

Guaifenesin acts as an expectorant that enhances the output of phlegm and bronchial secretions by decreasing their adhesiveness and surface tension. By increasing the flow of less viscous gastric secretions, it promotes ciliary action, leading to more productive coughs. This mechanism ultimately aids in the removal of accumulated secretions from the upper and lower airways, making coughs less frequent and more effective.

Pharmacokinetics

Guaifenesin is rapidly absorbed from the gastrointestinal tract and is metabolized in the liver. It has a relatively short half-life, with peak plasma concentrations typically occurring within one hour of administration. The drug is eliminated primarily through renal excretion, with both unchanged drug and metabolites being excreted in the urine.

Adverse effects

• Nausea
• Vomiting
• Dizziness
• Headache
• Rash
• Gastrointestinal discomfort

Precautions

• Caution in patients with chronic cough associated with smoking, asthma, or emphysema
• Use with caution in patients with a history of gastrointestinal disorders

Pregnancy

Guaifenesin is categorized under FDA pregnancy category C. Risk cannot be ruled out; consult a healthcare provider.

Breast-feeding

Limited data available; exercise caution and consult a healthcare provider before use.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Oral solution
• Tablet
• Extended-release tablet
• Syrup

Mechanism of action

Menthol primarily activates the cold-sensitive TRPM8 receptors in the skin. Menthol, after topical application, causes a feeling of coolness due to stimulation of 'cold' receptors by inhibiting Ca++ currents of neuronal membranes. It may also yield analgesic properties via kappa-opioid receptor agonism.

Pharmacodynamics

Menthol is a covalent organic compound made synthetically or obtained from peppermint or other mint oils. Menthol induces a cooling sensation on the skin upon inhalation, oral ingestion, or topical application by stimulating the cold-sensitive receptors expressed on the skin, without actually causing a drop in the skin temperature.

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

Diphenhydramine predominantly works via the antagonism of H1 (Histamine 1) receptors. Such H1 receptors are located on respiratory smooth muscles, vascular endothelial cells, the gastrointestinal tract (GIT), cardiac tissue, immune cells, the uterus, and the central nervous system (CNS) neurons. When the H1 receptor is stimulated in these tissues it produces a variety of actions including increased vascular permeability, promotion of vasodilation causing flushing, decreased atrioventricular (AV) node conduction time, stimulation of sensory nerves of airways producing coughing, smooth muscle contraction of bronchi and the GIT, and eosinophilic chemotaxis that promotes the allergic immune response. Ultimately, diphenhydramine functions as an inverse agonist at H1 receptors, and subsequently reverses effects of histamine on capillaries, reducing allergic reaction symptoms. Moreover, since diphenhydramine is a first-generation antihistamine, it readily crosses the blood-brain barrier and inversely agonizes the H1 CNS receptors, resulting in drowsiness, and suppressing the medullary cough center. Furthermore, H1 receptors are similar to muscarinic receptors. Consequently, diphenhydramine also acts as an antimuscarinic. It does so by behaving as a competitive antagonist of muscarinic acetylcholine receptors, resulting in its use as an antiparkinson medication. Lastly, diphenhydramine has also demonstrated activity as an intracellular sodium channel blocker, resulting in possible local anesthetic properties. Antihistamines used in the treatment of allergy act by competing with histamine for H1-receptor sites on effector cells. They thereby prevent, but do not reverse, responses mediated by histamine alone. Antihistamines antagonize, in varying degrees, most of the pharmacological effects of histamine, including urticaria and pruritus. Also, the anticholinergic actions of most antihistamines provide a drying effect on the nasal mucosa. /Antihistamines/ H1 antagonists inhibit both the vasoconstrictor effects of histamine and, to a degree, the more rapid vasodilator effects mediated by activation of H1 receptors on endothelial cells (synthesis/release of NO and other mediators). /H1 Receptor Antagonists/ H1 antagonists suppress the action of histamine on nerve endings, including the flare component of the triple response and the itching caused by intradermal injection. /H1 Receptor Antagonists/ The first-generation antihistamines are widely prescribed medications that relieve allergic reactions and urticaria by blocking the peripheral histamine H(1) receptor. Overdose of these drugs often results in serious neuronal toxic effects, including seizures, convulsions and worsening of epileptic symptoms. The KCNQ/M K(+) channel plays a crucial role in controlling neuron excitability. Here, we demonstrate that mepyramine and diphenhydramine, two structurally related first-generation antihistamines, can act as potent KCNQ/M channel blockers. Extracellular application of these drugs quickly and reversibly reduced KCNQ2/Q3 currents heterologously expressed in HEK293 cells. The current inhibition was concentration and voltage dependent. The estimated IC(50) (12.5 and 48.1 microM, respectively) is within the range of drug concentrations detected in poisoned patients (30-300 microM). Both drugs shifted the I-V curve of KCNQ2/Q3 channel to more depolarized potentials and altered channel gating properties by prolonging activation and shortening deactivation kinetics. Mepyramine also inhibited the individual homomeric KCNQ1-4 and heteromeric KCNQ3/Q5 currents. Moreover, mepyramine inhibited KCNQ2/Q3 current in an outside-out patch excised from HEK293 cells and the inhibitory effect was neither observed when it was applied intracellularly nor affected by blocking phospholipase C (PLC) activity, indicating an extracellular and direct channel blocking mechanism. Finally, in cultured rat superior cervical ganglion (SCG) neurons, mepyramine reduced the

Pharmacodynamics

Diphenhydramine has anti-histaminic (H1-receptor), anti-emetic, anti-vertigo and sedative and hypnotic properties. The anti-histamine action occurs by blocking the spasmogenic and congestive effects of histamine by competing with histamine for H1 receptor sites on effector cells, preventing but not reversing responses mediated by histamine alone. Such receptor sites may be found in the gut, uterus, large blood vessels, bronchial muscles, and elsewhere. Anti-emetic action is by inhibition at the medullary chemoreceptor trigger zone. Anti-vertigo action is by a central antimuscarinic effect on the vestibular apparatus and the integrative vomiting center and medullary chemoreceptor trigger zone of the midbrain.

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.