Flunisolide (Flunisolidum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Glucocorticosteroids

Included in the formulation
АТХ:

R.03.B.A   Glucocorticoids

R.03.B.A.03   Flunisolide

Pharmacodynamics:

It has anti-allergic, anti-inflammatory, immunosuppressive and anti-shock effects.

Interaction with intracellular glucocorticoid receptors - the formation of dimers of the glucocorticoid-glucocorticoid receptor complex.

The steroid hormone complex with the receptor is transported to the nucleus of the cell. In the nucleus this complex interacts with effector elements localized on the acceptor sites of the chromatin (genes). As a result of the interaction, stimulation or inhibition of gene expression occurs; this leads to a change in the synthesis of matrix RNA and proteins.

The anti-inflammatory effect of flunisolide is due to several factors.

1. The drug induces the synthesis of lipocortin, which inhibits the activity of phospholipase A2. Inhibition of phospholipase-mediated A2 hydrolysis of membrane phospholipids of damaged tissues prevents the formation of arachidonic acid. The disruption of the formation of arachidonic acid actually means inhibition of the synthesis of prostaglandins, since arachidonic acid is a substrate for further metabolism along the cyclooxygenase pathway, and also along the lipoxygenase pathway, with appropriate inhibition of leukotriene synthesis.

2.The anti-inflammatory effect of glucocorticoids is potentiated by their ability to inhibit the expression of COX-2 genes, which also leads to a decrease in the synthesis of prostaglandins in the inflammatory focus, including pro-inflammatory prostaglandins E2 and I2.

3. Flunisolide inhibits the expression of molecules of intercellular adhesion in the endothelium of blood vessels, violating the penetration of neutrophils and monocytes into the focus of inflammation. After the introduction of glucocorticoid, an increase in the concentration of neutrophils in the blood (due to their entry from the bone marrow and the restriction of migration from the blood vessels) is noted. This causes a decrease in the number of neutrophils in the site of inflammation.

The drug inhibits the transcription of cytokine genes that stimulate the inflammatory and immune response (IL-1, IL-2, IL-6, IL-8), as well as tumor necrosis factor (and some others). Also, a decrease in the transcription rate and an increase in the degradation of the receptor genes for IL-1 and IL-2, inhibition of the transcription of the metalloproteinase (collagenase, elastase, etc.) genes involved in increasing the permeability of the vascular wall in the processes of scarring and destruction of the cartilaginous tissue in joint diseases.

Immunosuppressive action is due to inhibition of transcription of DNA encoding the main histocompatibility complex, pro-inflammatory cytokines and inhibition of proliferation of T lymphocytes. It leads to a decrease in the number of T-lymphocytes and their influence on B-lymphocytes, inhibits the production of immunoglobulins. Reduces formation and increases the breakdown of the components of the compliment system.

The antiallergic effect is associated with the inhibition of the synthesis of mediators of allergy, degranulation of mast cells and the release of mediators of allergy, in connection with which it is effective in allergic reactions of immediate type.

Restores the sensitivity of adrenoreceptors to catecholamines. Accelerates the breakdown of proteins and reduces their concentration in the plasma, inhibits the utilization of glucose by peripheral tissues and stimulates gluconeogenesis in the liver, potentiates the formation of enzyme proteins in the liver, erythropoietin, fibrinogen, surfactant, lipomodulin. It leads to the redistribution of fat, increases the formation of triglycerides and higher fatty acids. Reduces absorption and potentiates the excretion of calcium; delays sodium and water.

The mechanism of the antishock effect of flunisolide is associated with a decrease in the synthesis of the platelet activating factor (a shock mediator), as well as a decrease in extra-neuronal capture and an increase in the pressor effect of catecholamines.

Pharmacokinetics:

After inhalation, 1 mg bioavailability is about 40%, as it undergoes rapid transformation in the pulmonary ways with the formation of sigma-beta-hydroxy metabolites and the metabolism of the first passage through the liver. Because of high presystemic metabolism when administered, bioavailability is even lower. Do not accumulate in the body, even when taking maximum doses. The half-life is 1.8 hours.

The connection with plasma proteins is moderate (albumin and transcortin). Biotransformation in the liver to less active metabolites (CYP3A4). The half-life is 90-120 minutes. Elimination by the kidneys (50%), with feces (50%).

Indications:Bronchial asthma, chronic obstructive bronchitis, allergic rhinitis.
ICD-10

X.J30-J39.J30   Vasomotor and allergic rhinitis

X.J40-J47.J44   Other chronic obstructive pulmonary disease

X.J40-J47.J45   Asthma

Contraindications:Hypersensitivityacute bronchoconstriction,asthmatic status (as a primary means), non-asthmatic bronchitis, viral, bacterial and fungal infections of the oral cavity and bronchi, active tuberculosis, pregnancy (I trimester), lactation, children's age (up to 5 years).
Carefully:With intranasal application: recent surgical interventions in the nasal cavity, recent nose trauma, the presence of nasal septic ulcers, recurrent nasal bleeding.
Pregnancy and lactation:

Recommendations FDA category C. A means of choice during pregnancy in the US (large clinical experience of use). Standard doses of inhaled glucocorticoids, as a rule, do not cause abnormalities on the part of the fetus. Qualitative and well-controlled studies on humans have not been conducted. In pharmacological doses can cause placental insufficiency, deficiency of fetal body weight, stillbirth. Teratogenic effect is not confirmed. Studies in animals have revealed an increase in the frequency of cleft palate, placental insufficiency, spontaneous abortion and delayed intrauterine development of the fetus. In newborns whose mothers received inhaled glucocorticoids during pregnancy,it is necessary to exclude adrenal insufficiency. The drug is contraindicated in the first trimester of pregnancy.

There is no information on the penetration into breast milk. When inhaled, concentrations often do not reach the detection limit in breast milk. To decide on the use during breastfeeding on the basis of a comparison of risk and benefit.

Dosing and Administration:

Bronchial asthma. People with moderate asthma are prescribed 750 mcg 2 times a day, persons with asthma of mild and moderate severity - 1000 mcg once a day, if necessary up to 2000 mcg per day.

When chronic obstructive pulmonary disease - aerosol inhalation by 500 mcg 2 times a day, if necessary up to 2 mg per day.

Year-round (50 mcg in each nasal passage 3 times a day) and seasonal (50 mcg in each nasal passage 2 times a day) allergic rhinitis (including hay fever).

In children, prevention and treatment allergic and vasomotor rhinitis.

Inhalation (spray). 5-14 years - 25 micrograms (1 injection) into each nostril 3 times a day, then lower the dose to the supporting one. 14-18 years - 50 mcg (2 injections) into each nostril 2 times a day, if necessary up to 3 times a day, then lower the dose to the supporting one.

Side effects:

For inhalation use: dryness or irritation in the oral cavity, dryness or irritation of the throat, flu-like symptoms, pharyngitis, laryngitis, dysphonia (dose-dependent effect), cough, headache; oropharyngeal candidiasis, bruising (high doses), fatigue, weakness, malaise, insomnia, dizziness, weight gain, abdominal pain, nausea or vomiting, constipation or diarrhea, chest pain, palpitation, tachycardia, arrhythmias, cystitis, allergic reactions, swelling of the face, fingers, ankles, feet, lower extremities, unpleasant taste sensations; esophageal candidiasis, gastroenteritis, slowing of growth rates in children, osteoporosis (more than 1500 μg / day - a significant decrease in bone mineral density), cataract (increased risk of development of posterior subcapsular cataract with prolonged treatment with high doses), hypertension, hypercortisy, hyperglycemia, menstrual irregularities , fever, mental disorders (anxiety, aggressive reactions, depression, psychosis), rectal bleeding, nosebleeds, hemorrhagic rash and thinning of the skin (400-2000 μg per day), fainting,adrenal insufficiency (suppression of adrenal function in the therapy at a dose of 1500 micrograms per day, however the sensitivity in individuals varies greatly), pneumonia, bronchoconstriction, allergic reactions, decreased sense of smell and taste, increased glaucoma risk, or increased intraocular pressure during prolonged treatment with high doses of , oppression of the hypothalamic-pituitary-adrenal system [minimal at a dose of <1500 μg per day in adults, 400 μg per day in children].

Intranasal administration: weak and transient burning, dryness or other irritation in the nasal and pharyngeal cavity, sneezing attacks, headache, scabbing in the nasal cavity, epistaxis, persisting rhinorrhea and nasal congestion, lacrimation, sore throat, hoarseness, cough, lethargy, dizziness, nausea or vomiting, stomach pain, loss of sensation of taste or smell, candidiasis of the nasal cavity and pharynx, atrophic rhinitis, ulceration of the nasal mucosa, nasal septum perforation, conjunctivitis, increased intraocular pressure, glaucoma, cataract, we echnye pain, shortness of breath, allergic reactions, tinnitus.

Overdose:

Symtomas: Nausea, vomiting, sleep disorders, euphoria, agitation, depression. With prolonged use in high doses - osteoporosis, fluid retention in the body, increased blood pressure and other signs of hypercorticism, including Itenko-Cushing syndrome, secondary adrenal insufficiency.

Treatment: against the background of the gradual withdrawal of the drug maintenance of vital functions, electrolyte balance correction, antacids, phenothiazines, Li + preparations; with the syndrome of Itenko-Cushing - aminoglutethimide.

Interaction:

Alcohol, NSAIDs - increased risk of bleeding (including hemorrhagic stroke) and ulceration of the gastric mucosa.

Aminoglutethimide - suppression of adrenal function (additional glucocorticoid administration is required).

Amphotericin B (parenterally), inhibitors of carbonic anhydrase - risk of severe hypokalemia.

Antiglaucoma means - Correction of dose due to glaucocorticoid proglacomoids.

Anticholinergics, special atropine - risk of intraocular hypertension.

Acetazolamide - The risk of hypernatremia, edema, hypocalcemia (osteoporosis).

Anabolic steroids, androgens - risk of edema, severe acne.

Antidepressants tricyclic - aggravation of steroid-dependent disorders of the psyche. Do not apply!

Anticoagulants indirect (coumarin and indanedione derivatives), anticoagulants direct, thrombolytics - risk of hemorrhagic stroke.

Antithyroid drugs, thyroid hormones - Correction of the dose of glucocorticoids due to reduced clearance in hypothyroidism and increased - in the hyperthyroid state.

Asparaginase - increase of its toxic effects.

Vaccines, live viruses or other immunization - pharmacological (immunosuppressive) doses glucocorticoids lead to stimulation of replication of live viruses, an increase in the risk of developing viral diseases, a decrease in the formation of antibodies to the vaccine.

Diuretics - reduction of their natriuretic and diuretic effects, hypokalemia.

Inhibitors of acetylcholinesterase - risk of severe weakness in myasthenia gravis (cancellation 24 hours before the start of therapy glucocorticoids).

Isoniazid, mexiletine - Increase in clearance of isoniazid, mexiletine, decrease in plasma concentration (dose adjustment).

Immunosuppressive drugs - risk of infection.

Carbamazepine, ephedrine, phenobarbital, phenytoin, rifampicin - increase in clearance glucocorticoids.

Ketoconazole - lower ground clearance glucocorticoida (increased risk of side effects).

Contact lenses - increased risk of infection.

Macrolides - lower ground clearance glucocorticoida.

Mitotan - increasing the dose glucocorticoida.

Non-depolarizing muscle relaxants - risk of respiratory depression (due to hypokalemia, induced by glucocorticoidami).

Oral antidiabetic agents and insulin - correction of the dose of one or both drugs in combination. Correction of an antidiabetic remedy after cessation of glucocorticoid therapy.

Cardiac glycosides - the risk of their overdose and arrhythmia due to hypokalemia.

Somatotropin - inhibition of the growth stimulating response to somatotropin.

Means or products that contain a large number of sodium - risk of edema and hypertension.

Means, inducing liver enzymes - increased clearance of glucocorticoids.

Means that stimulate activity liver enzymes - reduction of effects glucocorticoids by increasing their metabolism.

Folic acid - increased demand for folate with long-term therapy glucocorticoids.

Estrogen-Containing Oral Contraceptives - Increase in clearance and decrease in half-life glucocorticoids (dose adjustment).

Special instructions:

Use minimally effective doses to prevent systemic effects. With increasing doses, the bronchi's ability to relax is increased.

Rinsing of the mouth and throat after each inhalation - prevention of oral candidiasis, hoarseness and throat irritation. Do not swallow water after rinsing.

The use of a spacer reduces the likelihood of developing candidiasis, dysphonia, increases drug delivery to the lower respiratory tract and local activity of the glucocorticoid.

Instructions
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