New Zeet

Uses

Bromhexineis used for the treatment of respiratory disorders associated with productive cough. These include; tracheobronchitis, bronchitis with emphysema, bronchiectasis, bronchitis with bronchospasm, chronic inflammatory pulmonary conditions and pneumoconiosis.

Diphenhydramine is used for the treatment of followings:

• Seasonal, perennial, vasomotor rhinitis
• Urticaria, angioneurotic oedema, anaphylaxis
• Pruiritic conditions
• Premedication for emesis and motion sickness
• Miscellaneous like meniere's disease and parkinsonism

Guaifenesin is an expectorant commonly found in OTC products for the symptomatic relief from congested chests and coughs associated with cold, bronchitis, and/or other breathing illnesses.

Guaifenesin is an expectorant that is indicated for providing temporary symptomatic relief from congested chests and coughs which may be due to a cold, bronchitis, and/or other breathing illnesses .

New Zeet is also used to associated treatment for these conditions: Bronchiectasis, Common Cold, Cough, Cough caused by Common Cold, Nasal Congestion, Whooping Cough, Airway secretion clearance therapyAllergic Rhinitis (AR), Allergic cough, Allergies, Anaphylaxis, Angioedema, Common Cold, Common Cold/Flu, Conjunctival irritation, Cough, Cough Variant Asthma, Cough caused by Common Cold, Eye allergy, Fever, Insect Bites, Insect Stings, Insomnia, Irritative cough, Itching of the nose, Itching of the throat, Motion Sickness, Nasal Congestion, Oral Mucositis, Pain, Parkinsonian Syndromes, Pollen Allergy, Productive cough, Pruritus, Rash, Rhinorrhoea, Sinus Congestion, Sinus headache, Skin Irritation, Sneezing, Sunburn, Symptoms of Acute Bronchitis Accompanied by Coughing, Upper respiratory tract hypersensitivity reaction, site unspecified, Urticaria, Dermatographism, Dry cough, Watery itchy eyes, Airway secretion clearance therapy, ExpectorantAllergic Reaction, Asthma, Asthma, Allergic, Bronchial Asthma, Bronchitis, Bronchospasm, Chronic Bronchitis, Chronic Obstructive Respiratory Diseases, Common Cold, Cough, Cough caused by Common Cold, Coughing caused by Allergies, Coughing caused by Flu caused by Influenza, Drug Allergy, Emphysema, Fever, Flu caused by Influenza, Food Allergy, Headache, House dust allergy, Irritative cough, Laryngitis, Nasal Congestion, Nasal Congestion caused by Common Cold, Phlegm, Pollen Allergy, Productive cough, Rash, Rhinorrhoea, Sneezing, Sore Throat, Tracheitis, Urticaria, Whooping Cough, Acute Rhinitis, Chest congestion, Chills occurring with fever, Dry cough, Excess mucus or phlegm, Mild to moderate pain, Minor aches and pains, Airway secretion clearance therapy, Expectorant

How New Zeet works

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.

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 .

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 .

Dosage

New Zeet dosage

BromhexineTablet:

Adults and children over 10 years: 8-16 mg 3 times daily. Children 5-10 years: 4 mg 3 times daily.

BromhexineSyrup:

Adults: The recommended daily dose is 2 to 4 teaspoonful 3 times. Initially 4 teaspoonful 3 times daily and then as required.

Children: Suggested dosage for children under 2 years is 1/4 teaspoonful 3 times daily, for 2-5 years 1/2 teaspoonful 3 times daily and for children aged 5-10 years 1 teaspoonful 3 times daily.

Adult-

• Most allergic conditions: 25-50 mg three times a day with a further 50 mg at night.

Children-

• 1 to 5 years of age: 5 mg i.e., 2.5 ml of elixir 4 times a day
• More than 6 years of age: 10 mg i.e. 5 ml of elixir 4 times a day

Side Effects

Gastrointestinal side-effects may occur occasionally with Bromhexine and a transient rise in serum aminotransferase values has been reported. Other reported adverse effects include headache, dizziness, sweating and skin rash.

Side effect includes sedation, dizziness, tinnitus, fatigue, ataxia, blurred vision, diplopia, euphoria, and epigastric discomfort.

Toxicity

The oral LD50 of bromhexine in rats is 6 g/kg. The observed symptoms of accidental overdose with bromhexine are consistent with the known adverse effects of bromhexine, including headache, nausea, and vomiting, among other symptoms. Provide symptomatic treatment and contact poison control services if an overdose is confirmed or suspected.

Overdose is expected to result in effects similar to the adverse effects that are ordinarily associated with the use of diphenhydramine, including drowsiness, hyperpyrexia, and anticholinergic effects, among others . Additional symptoms during overdose may include mydriasis, fever, flushing, agitation, tremor, dystonic reactions, hallucinations and ECG changes . Large overdose may cause rhabdomyolysis, convulsions, delirium, toxic psychosis, arrhythmias, coma and cardiovascular collapse . Moreover, with higher doses, and particularly in children, symptoms of CNS excitation including hallucinations and convulsions may appear; with massive doses, coma or cardiovascular collapse may follow .

Although diphenhydramine has been in widespread use for many years without ill consequence, it is known to cross the placenta and has been detected in breast milk . This medication should therefore only be used when the potential benefit of treatment to the mother exceeds any possible hazards to the developing fetus or suckling infant .

Pharmacokinetic studies indicate no major differences in the distribution or elimination of diphenhydramine compared to younger adults . Nevertheless, diphenhydramine should be used with caution in the elderly, who are more likely to experience adverse effects . Avoid use in elderly patients with confusion .

The results of a review on the use of diphenhydramine in renal failure suggest that in moderate to severe renal failure, the dose interval should be extended by a period dependent on Glomerular filtration rate (GFR) .

After intravenous administration of 0.8 mg/kg diphenhydramine, a prolonged half-life was noted in patients with chronic liver disease which correlated with the severity of the disease . However, the mean plasma clearance and apparent volume of distribution were not significantly affected .

LD₅₀=500 mg/kg (orally in rats). Considerable overdosage can lead to myocardial infarction (heart attack), serious ventricular dysrhythmias, coma and death.

The most prevalent signs and symptoms associated with an overdose of guaifenesin have been nausea and vomiting .

Although adequate and well-controlled studies in pregnant women have not been performed, the Collaborative Perinatal Project monitored 197 mother-child pairs exposed to guaifenesin during the first trimester . An increased occurrence of inguinal hernias was found in the neonates . However, congenital defects were not strongly associated with guaifenesin use during pregnancy in 2 large groups of mother-child pairs .

Moreover, guaifenesin is excreted in breast milk in small quantities . Subsequently, caution should be exercised by balancing the potential benefit of treatment against any possible risks .

Additionally, an LD₅₀ value of 1510 mg/kg (rat, oral) has been reported for guaifenesin .

Precaution

Since mucolytics may disrupt the gastric mucosa so Bromhexine should be used with care in patients with a history of peptic ulceration.

Caution should be exercised with patients in whom drowsiness is undesirable e.g., drivers, machine operators. Concomitant consumption of alcohol or central nervous system (CNS) depressants will potentiate drowsiness.

Interaction

Diphenhydramine administration significantly reduces the absorption of the antituberculous agent para-aminosalicyclic acid (PAS) from the gastrointestinal tract. CNS depressants may potentiate the sedative action of Diphenhydramine. Anticholinergic drugs may potentiate Diphenhydramine’s anticholinergic side effects.

Volume of Distribution

After intravenous administration in a pharmacokinetic study, bromhexine was found to be widely distributed. Bromhexine is known to cross the blood-brain barrier; small concentrations may cross the placenta. The average volume of distribution of bromhexine was 1209 ± 206 L (19 L/kg). Lung tissue concentrations of bromhexine two hours after a dose were 1.5 to 3.2 times higher in bronchial tissues than plasma concentrations. Pulmonary parynchema concentrations were 3.4 to 5.9 times higher when compared to plasma concentrations.

Diphenhydramine is widely distributed throughout the body, including the CNS . Following a 50 mg oral dose of diphenhydramine, the volume of distribution is in the range of 3.3 - 6.8 l/kg .

The geometric mean apparent volume of distribution of guaifenesin determined in healthy adult subjects is 116L (CV=45.7%) .

Elimination Route

After oral administration, bromhexine demonstrates linear pharmacokinetics when given in doses of 8-32 mg. Bromhexine is readily absorbed in the gastrointestinal tract at a rapid rate. This drug undergoes extensive first-pass effect in the range of 75-80%. The bioavailability is therefore reduced to approximately 22-27%.

Diphenhydramine is quickly absorbed after oral administration with maximum activity occurring in approximately one hour . The oral bioavailability of diphenhydramine has been documented in the range of 40% to 60%, and peak plasma concentration occurs about 2 to 3 hours after administration .

Studies have shown that guaifenesin is well absorbed from and along the gastrointestinal tract after oral administration .

Half Life

Following single oral doses ranging from 8 and 32 mg, the terminal half-life of bromhexine has been measured between 6.6 and 31.4 hours.

The elimination half-life ranges from 2.4-9.3 hours in healthy adults . The terminal elimination half-life is prolonged in liver cirrhosis .

The half-life in plasma observed for guaifenesin is approximately one hour .

Clearance

The clearance of bromhexine ranges from 843-1073 mL/min, within the range of the hepatic circulation.

Values for plasma clearance of a 50 mg oral dose of diphenhydramine has been documented as lying in the range of 600-1300 ml/min .

The mean clearance recorded for guaifenesin is about 94.8 L/hr (CV=51.4%) .

Elimination Route

After a dose of bromhexine was administered during a pharmacokinetic study, approximately 97% of the radiolabeled dose was detected in the urine; under 1% was detected as the parent drug.

The metabolites of diphenhydramine are conjugated with glycine and glutamine and excreted in urine . Only about 1% of a single dose is excreted unchanged in urine . The medication is ultimately eliminated by the kidneys slowly, mainly as inactive metabolites .

After administration, guaifenesin is metabolized and then largely excreted in the urine .

Pregnancy & Breastfeeding use

Pregnancy Category B. Bromhexine has been taken by a large number of pregnant women and women of child bearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.

It is not known whether bromhexine is excreted in breast milk or whether it has a harmful effect on the breastfeeding infant. Therefore it is not recommended for breast feeding mothers unless the potential benefits to the patient are weighed against the possible risk to the infant.

Category B: There are no adequate and well controlled studies in pregnant women using diphenhydramine hydrochloride. Therefore, diphenhydramine hydrochloride should be used in pregnancy only if clearly needed. Diphenhydramine hydrochloride has been reported to be excreted in breast milk and thus, use of diphenhydramine hydrochloride in lactating mother is not recommended.

Contraindication

Contraindicated to those who are hypersensitive to Bromhexine Hydrochloride.

Known hypersensitivity to Diphenhydramine Hydrochloride, Ammonium chloride is contra-indicated in presence of impaired hepatic or renal function.

Acute Overdose

Symptoms: Impaired consciousness; psychosis, seizures, antimuscarinic symptoms (e.g. mydriasis, tachycardia, tachyarrhythmias), resp failure, rhabdomyolysis; acute delirium with visual and auditory hallucination (topical).

Management: Supportive and symptomatic treatment. Convulsions and marked CNS stimulation may be treated with IV diazepam.

Storage Condition

Store below 25° C. Protect from light. Keep the container tightly closed.

Store between 15-30° C. Protect from moisture.

Innovators Monograph

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