Pharmacological properties

Pharmacodynamics. Ambroxol a hydrochloride — mucolytic and expectorant, renders the expressed expectorant, anti-inflammatory, immunomodulatory, antioxidant and insignificant antibechic action. stimulates serous cells of glands of a mucous membrane of bronchial tubes, increases amount of mucous secretion and thus changes the broken ratio of serous and mucous components. it leads to normalization of rheological indicators of a phlegm, reducing its viscosity and adhesive properties. directly stimulates physical activity of a ciliary epithelium of bronchial tubes, prevents its adhesion and improves mukotsiliarny evacuation of a phlegm. Ambroxol increases surfactant content in lungs and also prevents its destruction in pnevmotsita. Ambroxol does not cause a bronkhoobstruktion, and on the contrary, improves function of external respiration. it is proved that medicine reduces hyperreactivity of muscles of bronchial tubes of patients with asthma. Ambroxol has anti-inflammatory effect, antioxidant properties, stimulates local immunity and resumption of a natural layer of surfactant. at intake of Ambroxol, complaints of patients to cough and a phlegm considerably decrease according to intensity of treatment.

Acetylcysteinum — mucolytic and expectorant. At the expense of free sulfhydryl group breaks bisulfite links of mucopolysaccharides of a phlegm that leads to decrease in viscosity of a bronchial secret. Increases mukotsiliarny clearance. Has antioxidant effect due to property to connect free radicals. Increases synthesis of glutathione which is an important factor of a detoxication; thanks to this property Acetylcysteinum is applied to treatment at sharp poisonings with paracetamol, phenols, aldehydes and other substances.

Pharmacokinetics

Ambroxol hydrochloride. Hydrochloride Ambroxol absorption from oral forms of not prolonged action fast and rather full, with linear dependence on a dose in the therapeutic range. The maximum levels in blood plasma are reached in 1-2.5 h at oral administration of dosage forms of fast release.

Distribution. At oral administration hydrochloride Ambroxol distribution from blood to fabrics fast and expressed, with the maximum concentration of active agent in lungs.

Metabolism and removal. About 30% of a dose after oral administration are removed by presistemny metabolism. Ambroxol the hydrochloride is metabolized mainly in a liver by a glyukuronization and splitting to dibromantranilovy acid (about 10% of a dose). In 3 days of oral administration about 6% of a dose are removed with urine in not changed look, about 26% of a dose — in the conjugated form.

T _½ about 10 h

make

blood plasma At patients with an abnormal liver function hydrochloride Ambroxol removal less that causes 1.3-2 times above than the level in blood plasma.

Age and sex have no clinically significant impact on hydrochloride Ambroxol pharmacokinetics therefore dose adjustment is not required.

Meal does not affect bioavailability of Ambroxol of a hydrochloride.

Acetylcysteinum. After oral administration Acetylcysteinum quickly and completely is soaked up and exposed to metabolism in a liver with formation of cysteine, pharmacological an active metabolite and also diacetylcysteinum, cystine, and further — the mixed disulfides. Bioavailability very low — about 10%. The C _max in blood plasma is reached in 1–3 h after reception. Linking with proteins of blood plasma — about 50%. Acetylcysteinum is emitted with kidneys in the form of inactive metabolites (inorganic sulfates, diacetylcysteinum).

T _½ is defined p mainly by fast biotransformation in a liver and makes about 1 h. In case of depression of function of a liver of T _½ lasts up to 8 h.

Indication

Treatment of the sharp and chronic respiratory diseases which are followed by violation of bronchial secretion and evacuation of a secret: including at acute and chronic bronchitis, hobl, pneumonia, a bronchoectatic disease, oh, a mucoviscidosis, laryngitis, tracheitis.

At a syndrome of shock lungs at adults, for prevention and treatment at complications after surgeries on lungs, at care for a tracheostoma, before and after a bronkhoskopiya.

Use

Tablet. doses for adults and children are aged more senior than 12 years: on 1 tablet 3 times a day.

should not exceed the recommended dose.

Duration of treatment should not exceed

5–7 days without consultation with the doctor.

Sachet. To dissolve contents of 1 sachet in ½ glasses of water and to drink.

for adults and children 12 years are aged more senior than

Dose: on 1 sachet 3 times a day.

should not exceed the recommended dose.

Duration of treatment should not exceed

5 days without consultation with the doctor.

Contraindication

Hypersensitivity to the Ambroxol, Acetylcysteinum or other components which are a part of medicine. a peptic ulcer of a stomach and duodenum in an aggravation stage. pneumorrhagia, pulmonary bleeding.

Side effects

from the immune system: reactions of hypersensitivity, including anaphylactic reactions or even shock, rash, urticaria, reactions from mucous membranes, a Quincke's disease, fever, dispnoe, an itch, etc.

from skin and hypodermic cellulose: an erythema, eczema, severe damages of skin — Stephens's syndrome — Johnson and a toxic epidermal necrolysis (Lyell's disease).

from digestive system: dryness in a mouth, salivation, heartburn, nausea, vomiting, dyspepsia, stomatitis, an abdominal pain, diarrhea, a lock, an unpleasant smell from a mouth.

from a respiratory system: a rhinorrhea, dryness of airways, a bronchospasm (mainly at patients with hyperreactivity of a bronchial system which is associated with OH).

from an urinary system: dysuria.

from an organ of hearing: a ring in ears.

from nervous system: headache.

from a cardiovascular system: tachycardia, arterial hypotension.

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At use of Acetylcysteinum it was very seldom reported about developing of bleedings which were most often connected with development of reactions of hypersensitivity; cases of anemia, hemorrhage. Noted cases of decrease in aggregation of platelets, however it does not have clinical confirmation.

At administration of medicament in the form of powder for oral suspension the development of easy laxative action because of the maintenance of a mannitol (E421) is possible

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Special instructions

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It was reported about several heavy reactions from skin (Stephens's syndromes — Johnson and a layell) which coincided using Ambroxol of a hydrochloride or Acetylcysteinum. in most cases they could be explained with weight of a course of a basic disease at patients with / or simultaneous use of other medicine. also at an initial stage of a syndrome of Stephens — Johnson or a Lyell's disease at patients can be nonspecific, similar to symptoms of flu, symptoms, such as fever, ache, rhinitis, cough and sore throat. mistakenly at such nonspecific simpotoma it is possible to perform symptomatic treatment by medicaments against cough and cold. therefore at emergence of new damages of skin or mucous membrane it is necessary to ask immediately for medical care and to stop intake of Ambroxol of a hydrochloride.

As Ambroxol can strengthen slime secretion, medicament should be used with care at violation of bronchial motility and the strengthened slime secretion (for example at such rare disease as primary tsiliarny dyskinesia).

Use of Acetylcysteinum causes fluidifying of a bronchial secret. If the patient is not capable to cough up effectively a phlegm, are necessary a postural drainage and bronkhoaspiration.

With care to use medicament at patients with OH, with ulcer of stomach and duodenum in the anamnesis.

to Apply

with care at patients with renal failures, a serious illness of a liver (namely it is necessary to increase an interval between application or to lower a dose); at patients with a heavy renal failure the accumulation of metabolites which are formed in a liver is expected.

composition of the medicine Pulmobriz, powder for oral suspension, include aspartame which is a phenylalanine source therefore medicament should not be used at patients with phenylketonuria.

Use during pregnancy and feeding by a breast. Drug is not recommended to be used in the I trimester of pregnancy.

do not have

relevant data of rather teratogenic influence of Ambroxol of a hydrochloride and Acetylcysteinum on a fruit therefore it is possible to use medicament in the II-III trimesters of pregnancy only in case the expected advantage for mother exceeds potential risk for a fruit.

As Ambroxol the hydrochloride and Acetylcysteinum get into breast milk, it is undesirable to take the medicament during feeding by a breast. In case of need prescribing of medicine it is necessary to stop feeding by a breast.

Ability to influence speed of response at control of vehicles or work with other mechanisms. There are no data on influence on speed of response at control of vehicles or other mechanisms.

Children. To apply at children 12 years aged are more senior.

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Interaction

notes synergism of Acetylcysteinum with bronchial spasmolytics.

Acetylcysteinum reduces hepatotoxic action of paracetamol; can be the donor of cysteine and increase the level of glutathione which promotes a detoxication of free radicals of oxygen and certain toxic substances in an organism.

Use of Ambroxol increases concentration of antibiotics of amoxicillin, a tsefuroksim, erythromycin and doxycycline in a phlegm and a bronchopulmonary secret.

Simultaneous use of medicine and the means oppressing cough can lead

to excess accumulation of slime owing to oppression of a tussive reflex. Therefore such combination is possible only after careful assessment by the doctor of a ratio of the expected advantage and possible risk of application.

At simultaneous application with such antibiotics as tetracycline (except for doxycycline), ampicillin, Amphotericinum B, cephalosporins, aminoglycosides, their interaction with thiol group of Acetylcysteinum is possible

that leads to decrease of the activity of both medicines. Therefore the interval between use of these medicines has to make not less than 2 h. It does not concern a tsefiksim and a lorakarbef.

Activated carbon reduces efficiency of Acetylcysteinum.

Concomitant use of nitroglycerine and Acetylcysteinum can lead

to strengthening of vazodilatiruyushchy effect of nitroglycerine.

Acetylcysteinum influences metabolism of a histamine therefore patients should not appoint long therapy with intolerance of a histamine as it can lead to emergence of symptoms of intolerance (a headache, vasomotorial rhinitis, an itch).

Use of Acetylcysteinum can change

results of quantitative definition by a colorimetric method and results of definition of ketones in urine.

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At contact of powder for oral suspension with metals or rubber form sulfides with a characteristic smell therefore for dissolution of medicine it is necessary to use glasswares.

Overdose

Is not present data on cases of overdose of the dosage forms of Acetylcysteinum intended for intake.

Ambroxol is well transferred by

after parenteral application in doses up to 15 mg/kg/days and after oral administration up to 25 mg/kg/days. In case of overdose, Ambroxol noted heavy symptoms of intoxication. It was reported about cases of short-term concern and diarrhea, hypersalivation. The risk of hypersecretion is characteristic of children.

excessive overdose can lead

By analogy with preclinical trials to hypersalivation, nausea, vomiting and decrease in the ABP.

Treatment. Urgent measures, such as stimulation of vomiting and gastric lavage, in general are not shown and have to be applied in case of sharp intoxication. Symptomatic treatment is recommended.

Storage conditions

to Store

out of children's reach in original packing at a temperature not above 25 °C.

Relevant information

Acute bronchitis is an inflammatory disease of a mucous membrane of bronchial tubes without defeat of pulmonary fabric (tsarev accusative, 2013).

About 5% of adults annually transfer at least 1 episode of an acute bronchitis, and up to 90% from them ask for medical care. Viruses are a basic reason, causing 95% of cases of an acute bronchitis in adults (Graham Worrall, 2008).

In a course the bronchitis has sharp (2–3 weeks) and long (more than 1 month) a course.

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On localization of an acute bronchitis proximal (tracheobronchitis) and distal (bronchiolitis) (V.P. Tsarev, 2013).

Origins of an acute bronchitis:

1) attachment of a virus or a bacterium to a bronchial tube wall;

2) death of a cylindrical epithelium of a bronchial tube, decrease in mukotsiliarny clearance;

3) exposure of the irritantny receptors (quickly adaptive) hidden in a mucous membrane of a bronchial tube;

4) a chemotaxis to these receptors of lymphocytes and neutrophils, developing of hypostasis and hypersecretion of slime (V.P. Tsarev, 2013).

Main symptoms of an acute bronchitis:

• cough — the first few days dry, and further — a trend to damp;
• a phlegm at first transparent, then it gains yellow color (accession of bacterial microflora);
• rhinitis and congestion of a nose, begin some days before appearance of cough;
• feeling of fatigue;
• muscle pain;
• rattle or whistle at breath;
• fervescence (Alex H. Gifford, 2018).

Phlegm is a mucous discharge (pathological secret) from bronchial tubes and a trachea. It consists of glycoproteins which are called mucins, serum proteins with impurity of the cellular remains and bacteria. Cilia of a ciliary epithelium of airways provide the constant movement of a secret and removal of excess of slime. The phlegm is removed generally reflex, during cough (Bruce K. Rubin, 2014).

Pulmobriz — two-component medicine which renders mucolytic (diluting a phlegm) and expectorant action.

It differs in the expressed anti-inflammatory action, has bactericidal effect, reduces hypostasis of bronchial tubes, dilutes a phlegm and by that promotes its effective evacuation from a gleam of bronchial tubes, facilitating breath and improving a condition of the patient. Its active ingredients: Ambroxol hydrochloride and Acetylcysteinum.

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

hydrochloride relatively is applied long ago by

Ambroxol in treatment of various respiratory diseases. It has anti-inflammatory effect — brakes activity of neutrophils, reduces education of free radicals and release of hydrolytic enzymes; antioxidant — inhibits peroxide oxidation of lipids; antibacterial — inhibits (prevents) attachment of bacteria to the surface of bronchial tubes (Cataldi M. et al., 2013); the immunomodulatory effect — reduces the maintenance of eosinophils and cytokines in bronchoalveolar lavage; promotes fast evacuation of slime from bronchial tubes; renders the local anesthetizing effect due to blockade of natrium channels of a cellular membrane (Kardos P. et al., 2018).

Acetylcysteinum is derivative cysteine amino acids, it treats mucolytics. The main value of Acetylcysteinum consists in its antioxidant and stabilizing activity (Santus P. et al., 2014). Two mechanisms of its antioxidant action are revealed:

1. Indirect — Acetylcysteinum turns into cysteine which, in turn, increases concentration of glutathione in an organism. Glutathione is the tripeptide consisting of glutaminic acid, cysteine and glycine, it is an important factor of a chemical detoxication, plays a key role in maintenance of the oxidation-reduction status of cages (Santus P. et al., 2014).

2. A straight line — Acetylcysteinum contains free sulfhydryl group ((-SH) - group) which participates in protection of an organism against oxidizing processes (Santus P. et al., 2014).

Mechanism of reduction of expressiveness of inflammation consists in inhibition of a nuclear factor kappa-V, suppression of activation of B-lymphocytes and decrease in synthesis of cytokines (Yanping Pei et al., 2018). Antimicrobic properties — Acetylcysteinum is capable to split bacterial biofilms (Yanping Pei et al., 2018).

Acetylcysteinum and Ambroxol a hydrochloride still are of huge interest to researchers. For the first time their began to apply in pulmonology. A number of long-term researches proves a variety of effects of these medicinal substances.

Acetylcysteinum has antimicrobic activity. It was proved that treatment by Acetylcysteinum reduces percent of exacerbation of a disease and accession of bacterial microflora at patients with chronic bronchitis. Therapy by Acetylcysteinum in group of patients with chronic bronchitis was carried out. Then the bronkhoskopiya with a phlegm fence in this group of patients and in control where therapy by Acetylcysteinum was not carried out was carried out. Results showed: in a phlegm at patients in the group receiving Acetylcysteinum was defined the smaller quantity of pathogenic bacteriums in comparison with control group is considerable (Riise G.C. et al., 1994).

Ambroxol has anti-inflammatory properties. It confirmed a research in which provoked development of pneumonia in rats by intra pulmonary introduction of quartz. To rats the hydrochloride Ambroxol dose in a dose of 0.91 mg/kg/days was entered. Indicators of inflammatory process of lungs and proliferation lymphatic a follicle around a bronchiole and also the general indicators were much lower at those rats to which entered Ambroxol a hydrochloride, than in group which did not receive this medicine (Shohei Kanie et al., 2018).

Pulmobriz — medicine which combines properties of the active ingredients entering it. It treats to group of the medicines appointed at cough and respiratory infections. It is the combined mucolytic medicament used in pulmonology.

Indications

After the published messages about reactions of hypersensitivity and heavy skin side reactions, perhaps, connected with Ambroxol, the Committee on risk assessment in the field of pharmacovigilance of the European Union (PRAC) in April, 2014 initiated the overview of safety of Ambroxol in all its registered indications which the Clinical experience accumulated as a result of randomized clinical and observation (clinical trial in which the researcher collects data by simple observation of events in their natural course) researches was finished in 2016

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, allows to assume that Ambroxol is safe and well transferable means for therapy of bronchopulmonary diseases with well balanced and favorable profile of risk and advantage. All registered side effects were easy and self-limited (Cazan D. et al., 2018).

Acetylcysteinum, acetylized option of amino acid of L-cysteine, is a source sulphhydryl (-SH) - groups and turns in an organism into the metabolites capable to stimulate glutathione synthesis (has antioxidant properties), promoting a detoxication and affecting directly free radicals. Historically it developed that it was appointed as mucolytic cure for various respiratory diseases; however, apparently, it also makes favorable impact in the conditions which are characterized by decrease in level of glutathione or an oxidizing stress (state at which in an organism there are too much free radicals), such as HIV infection, cancer, heart troubles and smoking of cigarettes.

Contraindications

Age of children up to 12 years.

Hypersensitivity to Ambroxol to a hydrochloride, Acetylcysteinum or any of medicine components.

Contraindication are also bleeding from pulmonary vessels; gullet varicosity.

Pulmobriz enters composition of powder aspartame which is metabolized in phenylalanine. For this reason for patients with phenylketonuria it is worth applying the tableted medicine form.

Lactose monohydrate is excipient Pulmobriz too . Therefore use of medicine is undesirable at a lactose intolerance.

Use, doses

Pulmobriz sachet. Adults and children are aged more senior than 12 years — on 1 sachet 3 r / days. To pour out contents of one bag in capacity, to add 100–200 ml of warm boiled water (1 glass) and to drink.

Pulmobriz tablets. Adults and children are aged more senior than 12 years — 1 tablet 3 r / days, washing down with enough liquid.

Interactions

Acetylcysteinum is compatible to the medicines expanding bronchial tubes. It inhibits toxic effect of paracetamol due to formation of glutathione which absorbs untied radicals.

When prescribing medicine with antibiotics (such as tetracycline, ampicillin, antibiotics of a tsefalosporinovy row, aminoglycosides) the interaction of an antibiotic to sulfhydryl group of Acetylcysteinum happens. Such reaction leads to decrease of the activity of both medicines. Therefore if the antibiotic combined with Pulmobrizy , then an interval between administration of medicaments — not less than 2 h is appointed. However this reaction is not revealed with antibiotics tsefiksimy, doxycycline.

Intake of activated carbon and other sorbents completely levels efficiency of Acetylcysteinum.

At the combined appointment with nitroglycerine Acetylcysteinum which is a part Pulmobriz , exponentiates vasodilating property of nitroglycerine.

Side effects

Immunological reactions, including an anaphylaxis, rash, reddening and an itch of mucous membranes, a Quincke's edema, dispnoe. Disturbances from digestive system are shown in the form of hypo - or hypersalivations, nausea, vomitings, inflammations of a mucous membrane of a mouth, diarrhea, constipation, numbness of a mucous membrane of an oral cavity. The bronchospasm, urination increase are also possible; a headache, a dysgeusia — violation of perception of flavoring receptors, a hearing disorder; tachycardia, arterial hypotension.

Administration of medicament during pregnancy is undesirable

as its action on an embryo is up to the end not studied. Reception is possible in those situations when the expected advantage for mother exceeds potential risk for a fruit. Considering that this combined medicine is capable to get to breast milk, it is not recommended to appoint therapy Pulmobrizy to the women nursing.

Conclusions

Pulmobriz is the effective multicomponent mucolytic with expectorant action having moderate antimicrobic and anti-inflammatory effect.

its two the main a component — Ambroxol a hydrochloride — a mucolytic, a stimulator of production of surfactant (mix of surfactants), anti-inflammatory drug, and Acetylcysteinum — the antioxidant showing expectorant effect. Pulmobriz proved in treatment of sharp bronchitis, symptomatic therapy of HOBL, is applied by preparation for a bronkhoskopiya and after its carrying out as prevention of complications after tracheostomy.