Ambroxol, Acetylcysteine

Pharmacological properties

Ambroxol hydrochloride is a mucolytic and expectorant, it has a pronounced expectorant, anti-inflammatory, immunomodulating, antioxidant and slight antitussive effect. stimulates the serous cells of the glands of the bronchial mucosa, increases the amount of mucous secretion and thus changes the disturbed ratio of serous and mucous components. this leads to the normalization of the rheological parameters of sputum, reducing its viscosity and adhesive properties. directly stimulates the motor activity of the ciliated epithelium of the bronchi, prevents its adhesion and improves mucociliary evacuation of sputum. Ambroxol increases the content of surfactant in the lungs, and also prevents its destruction in pneumocytes. Ambroxol does not cause bronchial obstruction, but rather improves the function of external respiration. It is proved that the drug reduces the hyperreactivity of the muscles of the bronchi of patients with asthma. Ambroxol has an anti-inflammatory effect, antioxidant properties, stimulates local immunity and the renewal of the natural layer of surfactant. when taking Ambroxol, patient complaints of cough and sputum are significantly reduced according to the intensity of treatment.

Acetylcysteine ​​is a mucolytic and expectorant. Due to the free sulfhydryl group, it breaks the bisulfide bonds of sputum mucopolysaccharides, which leads to a decrease in the viscosity of bronchial secretions. Increases mucociliary clearance. It has an antioxidant effect due to the ability to bind free radicals. Increases the synthesis of glutathione, which is an important factor in detoxification; due to this property, acetylcysteine ​​is used for the treatment of acute poisoning with paracetamol, phenols, aldehydes and other substances.

Pharmacokinetics

Ambroxol hydrochloride. The absorption of ambroxol hydrochloride from oral forms of non-prolonged action is fast and quite complete, with a linear dose-response in the therapeutic range. The maximum plasma levels are reached after 1–2.5 hours with oral administration of rapid release dosage forms.

Distribution. When taken orally, the distribution of ambroxol hydrochloride from the blood to the tissues is quick and pronounced, with a maximum concentration of the active substance in the lungs.

Metabolism and excretion. About 30% of the dose after oral administration is excreted through presystemic metabolism. Ambroxol hydrochloride is metabolized mainly in the liver by glucuronidation and digestion to dibromanthranilic acid (about 10% of the dose). After 3 days of oral administration, about 6% of the dose is excreted unchanged in the urine, about 26% of the dose in conjugated form.

T_½ from blood plasma is about 10 hours.

In patients with impaired liver function, the excretion of ambroxol hydrochloride is less, which causes a 1.3–2 times higher level in blood plasma.

Age and gender do not have a clinically significant effect on the pharmacokinetics of ambroxol hydrochloride, so dose adjustment is not required.

Eating does not affect the bioavailability of ambroxol hydrochloride.

Acetylcysteine. After oral administration, acetylcysteine ​​is rapidly and completely absorbed and metabolized in the liver with the formation of cysteine, a pharmacologically active metabolite, as well as diacetylcysteine, cystine, and subsequently mixed disulfides. Bioavailability is very low - about 10%. C_max in blood plasma is achieved 1-3 hours after administration. Plasma protein binding is about 50%. Acetylcysteine ​​is excreted by the kidneys in the form of inactive metabolites (inorganic sulfates, diacetylcysteine).

T_½ determined mainly by rapid biotransformation in the liver and is about 1 hour. In case of decreased liver function T_½ extended to 8 hours

Indications

Treatment of acute and chronic diseases of the respiratory tract, accompanied by a violation of bronchial secretion and secretion evacuation: including in acute and chronic bronchitis, hobl, pneumonia, bronchiectatic disease, BA, cystic fibrosis, laryngitis, tracheitis.

In case of shock syndrome in adults, for the prevention and treatment of complications after surgical interventions on the lungs, when caring for a tracheostomy, before and after bronchoscopy.

Application

Tablets. doses for adults and children over the age of 12 years: 1 tablet 3 times a day.

Do not exceed recommended dose.

The duration of treatment should not exceed 5-7 days without consulting a doctor.

Sachet. Dissolve the contents of 1 sachet in ½ cup of water and drink.

Doses for adults and children over the age of 12 years: 1 sachet 3 times a day.

Do not exceed recommended dose.

The duration of treatment should not exceed 5 days without consulting a doctor.

Contraindications

Hypersensitivity to ambroxol, acetylcysteine ​​or other components that make up the drug. peptic ulcer of the stomach and duodenum in the acute stage. hemoptysis, pulmonary hemorrhage.

Side effects

On the part of the immune system: hypersensitivity reactions, including anaphylactic reactions or even shock, rash, urticaria, reactions from the mucous membranes, angioedema, fever, dyspnea, pruritus, etc.

From the skin and subcutaneous tissue: erythema, eczema, severe skin lesions - Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyells syndrome).

From the digestive system: dry mouth, salivation, heartburn, nausea, vomiting, dyspepsia, stomatitis, abdominal pain, diarrhea, constipation, halitosis.

From the respiratory system: rhinorrhea, dry airway, bronchospasm (mainly in patients with hyperreactivity of the bronchial system, which is associated with AD).

From the urinary system: dysuria.

On the part of the organ of hearing: ringing in the ears.

From the nervous system: headache.

From the cardiovascular system: tachycardia, arterial hypotension.

With the use of acetylcysteine, the occurrence of bleeding, which was most often associated with the development of hypersensitivity reactions, was very rarely reported; cases of anemia, hemorrhage. There have been cases of decreased platelet aggregation, but there is no clinical evidence for this.

When taking the drug in the form of a powder for oral suspension, it is possible to develop a mild laxative effect due to the content of mannitol (E421).

special instructions

Several severe skin reactions (Stevens-Johnson and Lyella syndromes) have been reported that coincide in time with the use of Ambroxol hydrochloride or acetylcysteine. in most cases, they could be explained by the severity of the underlying disease in patients with / or the simultaneous use of another drug. Also at the initial stage of Stevens-Johnson Syndrome or Lyell Syndrome, patients may have non-specific flu-like symptoms, such as fever, aches, rhinitis, cough and sore throat. mistakenly, for such nonspecific symptoms, symptomatic treatment with cough and cold preparations can be used. therefore, when new lesions of the skin or mucous membrane appear, you should immediately seek medical help and stop taking Ambroxol hydrochloride.

Since ambroxol can enhance mucus secretion, the drug should be used with caution in case of impaired bronchial motility and increased mucus secretion (for example, with such a rare disease as primary ciliary dyskinesia).

The use of acetylcysteine ​​causes a dilution of the bronchial secretion. If the patient is not able to cough up sputum effectively, postural drainage and broncho-aspiration are necessary.

Use with caution in patients with AD, with a history of gastric and duodenal ulcers.

Use with caution in patients with impaired renal function, severe liver disease (namely, the interval between use should be increased or the dose should be reduced); in patients with severe renal failure, the accumulation of metabolites that form in the liver is expected.

Pulmobriz, a powder for oral suspension, contains aspartame, which is a source of phenylalanine, so the drug should not be used in patients with phenylketonuria.

Use during pregnancy and lactation. The drug is not recommended for use in the first trimester of pregnancy.

There is no relevant data on the teratogenic effect of ambroxol hydrochloride and acetylcysteine ​​on the fetus, therefore, it is possible to use the drug in the II – III trimesters of pregnancy only when the expected benefit to the mother outweighs the potential risk to the fetus.

Since ambroxol hydrochloride and acetylcysteine ​​pass into breast milk, it is undesirable to take the drug during lactation. If necessary, the appointment of the drug should stop breast-feeding.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. There is no data on the effect on the reaction rate when driving vehicles or other mechanisms.

Children. Use in children over the age of 12 years.

Interactions

Synergism of acetylcysteine ​​with bronchodilators is noted.

Acetylcysteine ​​reduces the hepatotoxic effect of paracetamol; can be a donor of cysteine ​​and increase the level of glutathione, which helps detoxify free oxygen radicals and certain toxic substances in the body.

The use of ambroxol increases the concentration of antibiotics amoxicillin, cefuroxime, erythromycin and doxycycline in sputum and bronchopulmonary secretion.

The simultaneous use of the drug and cough suppressants can lead to excessive accumulation of mucus due to inhibition of the cough reflex. Therefore, such a combination is possible only after a careful assessment by the doctor of the ratio of the expected benefit and the possible risk of use.

When used simultaneously with antibiotics such as tetracycline (with the exception of doxycycline), ampicillin, amphotericin B, cephalosporins, aminoglycosides, their interaction with the thiol group of acetylcysteine ​​is possible, which leads to a decrease in the activity of both drugs. Therefore, the interval between the use of these drugs should be at least 2 hours. This does not apply to cefixime and loracarbef.

Activated carbon reduces the effectiveness of acetylcysteine.

The simultaneous administration of nitroglycerin and acetylcysteine ​​can lead to an increase in the vasodilating effect of nitroglycerin.

Acetylcysteine ​​affects histamine metabolism, therefore, long-term therapy should not be prescribed to patients with histamine intolerance, as this can lead to symptoms of intolerance (headache, vasomotor rhinitis, pruritus).

The use of acetylcysteine ​​can change the results of quantitative determination by the colorimetric method and the results of determination of ketones in urine.

When the powder for oral suspension comes in contact with metals or rubber, sulfides with a characteristic odor are formed, so glassware should be used to dissolve the drug.

Overdose

There are no data on cases of overdose of dosage forms of acetylcysteine ​​intended for oral administration.

Ambroxol is well tolerated after parenteral administration in doses up to 15 mg / kg / day and after oral administration up to 25 mg / kg / day. In case of overdose with Ambroxol, no severe signs of intoxication were noted. Cases of short-term anxiety and diarrhea, hypersalivation have been reported. Children are at risk of hypersecretion.

By analogy with preclinical studies, excessive overdose can lead to hypersalivation, nausea, vomiting, and a decrease in blood pressure.

Treatment. Urgent measures, such as stimulating vomiting and gastric lavage, are not generally indicated and should be used in case of acute intoxication. Symptomatic treatment is recommended.

Storage conditions

Keep out of the reach of children in the original packaging at a temperature not exceeding 25 ° c.

Actual information

Acute bronchitis is an inflammatory disease of the bronchial mucosa without damage to the lung tissue (Tsarev VP, 2013).

About 5% of adults annually suffer at least 1 episode of acute bronchitis, and up to 90% of them seek medical help. Viruses are the main cause, causing 95% of adult cases of acute bronchitis (Graham Worrall, 2008).

In the course of bronchitis has an acute (2-3 weeks) and prolonged (more than 1 month) course.

According to the localization of acute bronchitis, proximal (tracheobronchitis) and distal (bronchiolitis) are distinguished (Tsarev V.P., 2013).

The mechanism of acute bronchitis:

1) the attachment of a virus or bacteria to the wall of the bronchus;

2) the death of the cylindrical epithelium of the bronchus, a decrease in mucociliary clearance;

3) exposure of irritant receptors (quickly adapting), hidden in the mucous membrane of the bronchus;

4) chemotaxis to these receptors of lymphocytes and neutrophils, the occurrence of edema and hypersecretion of mucus (Tsarev V.P., 2013).

The main symptoms of acute bronchitis:

• cough - the first few days are dry, and later on - a tendency to wet;
• sputum is first transparent, then it becomes yellow (the attachment of bacterial microflora);
• rhinitis and nasal congestion, begin a few days before coughing;
• feeling of tiredness;
• muscle pain;
• wheezing or whistling when breathing;
• fever (Alex H. Gifford, 2018).

Sputum is a mucous discharge (pathological secretion) from the bronchi and trachea. It consists of glycoproteins called mucins, whey proteins with an admixture of cell debris and bacteria. The cilia of the ciliated epithelium of the respiratory tract provide a constant secretion movement and removal of excess mucus. Sputum is usually removed reflexively during coughing (Bruce K. Rubin, 2014).

Pulmobriz - a two-component drug that has a mucolytic (thinning sputum) and expectorant effect.

It has a pronounced anti-inflammatory effect, has a bactericidal effect, reduces swelling of the bronchi, dilutes sputum and thereby contributes to its effective evacuation from the lumen of the bronchi, facilitating breathing and improving the patients condition. Its active ingredients: ambroxol hydrochloride and acetylcysteine.

Ambroxol hydrochloride, a metabolite of bromhexine, increases the amount of mucous secretion, improves the process of coughing, and facilitates a productive cough (Kardos P. et al., 2018).

Ambroxol hydrochloride has been used for a relatively long time in the treatment of various respiratory diseases. It has an anti-inflammatory effect - inhibits the activity of neutrophils, reduces the formation of free radicals and the release of hydrolytic enzymes; antioxidant - inhibits lipid peroxidation; antibacterial - inhibits (prevents) the attachment of bacteria to the surface of the bronchi (Cataldi M. et al., 2013); immunomodulatory effect - reduces the content of eosinophils and cytokines in bronchoalveolar lavage; promotes rapid evacuation of mucus from the bronchi; it has a local anesthetic effect due to blockade of the sodium channels of the cell membrane (Kardos P. et al., 2018).

Acetylcysteine ​​is a derivative of the amino acid cysteine, it belongs to mucolytics. The main value of acetylcysteine ​​is its antioxidant and stabilizing activity (Santus P. et al., 2014). Two mechanisms of its antioxidant action have been identified:

1.Indirect - acetylcysteine ​​is converted to cysteine, which, in turn, increases the concentration of glutathione in the body. Glutathione is a tripeptide consisting of glutamic acid, cysteine ​​and glycine, it is an important factor in chemical detoxification and plays a key role in maintaining the redox status of cells (Santus P. et al., 2014).

2. Direct - acetylcysteine ​​contains a free sulfhydryl group ((-SH) -group), which is involved in protecting the body from oxidative processes (Santus P. et al., 2014).

The mechanism for reducing the severity of inflammation is the inhibition of the nuclear factor Kappa-B, the suppression of the activation of B-lymphocytes and the decrease in the synthesis of cytokines (Yanping Pei et al., 2018). Antimicrobial properties - acetylcysteine ​​is able to break down bacterial biofilms (Yanping Pei et al., 2018).

Acetylcysteine ​​and Ambroxol hydrochloride are still of great interest to researchers. For the first time they began to be used in pulmonology. A number of long-term studies prove the diversity of the effects of these drugs.

Acetylcysteine ​​has antimicrobial activity. It has been proven that treatment with acetylcysteine ​​reduces the percentage of exacerbation of the disease and the addition of bacterial microflora in patients with chronic bronchitis. Acetylcysteine ​​therapy was carried out in a group of patients with chronic bronchitis. Then a bronchoscopy was performed with sputum collection in this group of patients and in the control group, where acetylcysteine ​​therapy was not carried out. The results showed: in the sputum of patients in the group receiving acetylcysteine, a significantly smaller number of pathogenic bacteria was determined compared with the control group (Riise G.C. et al., 1994).

Ambroxol has anti-inflammatory properties. This confirmed the study, which provoked the development of pneumonia in rats by the intrapulmonary administration of quartz. A dose of 0.91 mg / kg / day of Ambroxol hydrochloride was administered to rats. The indicators of the inflammatory process of the lungs and the proliferation of lymphatic follicles around the bronchioles, as well as the general indicators were significantly lower in those rats that were administered Ambroxol hydrochloride than in the group that did not receive this drug (Shohei Kanie et al., 2018).

Pulmobriz - a drug that combines the properties of its active ingredients. It belongs to the group of drugs prescribed for cough and respiratory infections. This is a combined mucolytic drug used in pulmonology.

Indications

Following published reports of hypersensitivity reactions and severe skin adverse reactions possibly related to ambroxol, the European Union Pharmacovigilance Risk Assessment Committee (PRAC) in April 2014 initiated a safety review of ambroxol in all its recorded indications, which was completed in 2016 g.

Clinical experience gained as a result of randomized clinical and observational (a clinical study in which the researcher collects data by simply observing events in their natural course) studies suggests that Ambroxol is a safe and well-tolerated drug for the treatment of bronchopulmonary diseases with a well-balanced and favorable risk and benefit profile. All reported side effects were mild and self-limiting (Cazan D. et al., 2018).

Acetylcysteine, an acetylated version of the amino acid L-cysteine, is a source of sulfhydryl (-SH) groups and is converted into metabolites in the body that can stimulate the synthesis of glutathione (has antioxidant properties), promoting detoxification and acting directly on free radicals. Historically, it was prescribed as a mucolytic agent for various respiratory diseases; however, it also appears to have a beneficial effect under conditions characterized by decreased levels of glutathione or oxidative stress (a condition in which there are too many free radicals in the body), such as HIV infection, cancer, heart disease, and cigarette smoking.

Contraindications

Children under 12 years old.

Hypersensitivity to ambroxol hydrochloride, acetylcysteine ​​or any of the components of the drug.

Contraindications are also bleeding from the pulmonary vessels; varicose veins of the esophagus.

Powder composition Pulmobriz includes aspartame, which is metabolized to phenylalanine. For this reason, patients with phenylketonuria should use a tablet form of the drug.

Lactose monohydrate is also an auxiliary substance. Pulmobreeze. Therefore, the use of the drug is undesirable in lactase deficiency.

Application, doses

Pulmobriz sachet. Adults and children over the age of 12 years - 1 sachet 3 r / day. Pour the contents of one sachet into a container, add 100-200 ml of warm boiled water (1 cup) and drink.

Pulmobriz tablets. Adults and children over the age of 12 years - 1 tablet 3 r / day, drinking plenty of fluids.

Interactions

Acetylcysteine ​​is compatible with drugs that expand the bronchi. It inhibits the toxic effect of paracetamol due to the formation of glutathione, which absorbs unbound radicals.

When prescribing the drug with antibiotics (such as tetracycline, ampicillin, cephalosporin antibiotics, aminoglycosides), the antibiotic interacts with the sulfhydryl group of acetylcysteine. This reaction leads to a decrease in the activity of both drugs. Therefore, if an antibiotic is prescribed in combination with Pulmobrizom, then the interval between taking the drugs is at least 2 hours. However, this reaction was not detected with antibiotics cefixime, doxycycline.

Reception of activated carbon and other sorbents completely eliminates the effectiveness of acetylcysteine.

When combined with nitroglycerin, acetylcysteine, which is part of Pulmobreezepotentiates the vasodilating property of nitroglycerin.

Side effects

Immunological reactions, including anaphylaxis, rash, redness and itching of the mucous membranes, Quinckes edema, dyspnea. Digestive disorders are manifested in the form of hypo- or hypersalivation, nausea, vomiting, inflammation of the oral mucosa, diarrhea, constipation, numbness of the oral mucosa. Bronchospasm, frequent urination are also possible; headache, dysgeusia - impaired perception of taste buds, hearing impairment; tachycardia, arterial hypotension.

Taking the drug during pregnancy is undesirable, since its effect on the embryo is not fully understood. Admission is possible in situations where the intended benefit to the mother outweighs the potential risk to the fetus. Given that this combination drug is able to pass into breast milk, it is not recommended to prescribe therapy Pulmobrizom breastfeeding women.

findings

Pulmobriz - It is an effective multicomponent mucolytic with an expectorant effect, which has a moderate antimicrobial and anti-inflammatory effect.

Its two main components - Ambroxol hydrochloride - a mucolytic, a stimulant for the production of surfactant (a mixture of surfactants), an anti-inflammatory agent, and acetylcysteine ​​- an antioxidant that exhibits an expectorant effect. Pulmobriz It has proven itself in the treatment of acute bronchitis, symptomatic treatment of COPD, is used in preparation for bronchoscopy and after it, as a prevention of complications after tracheostomy.