Clinical and pharmacological group:
Beta adrenomimetics
Glucocorticosteroids
Included in the list (Order of the Government of the Russian Federation No. 2782-r dated 12/30/2014):
Vital and Essential Drugs
ONLS
ATX:
R.03.A.K Sympathomimetics in combination with corticosteroids or other drugs, excluding anticholinergics
R.03.A.K.06 Salmeterol and fluticasone
Pharmacodynamics:
Your-asthma-info.com stimulates β2-adrenergic receptors, which are located in the membranes of smooth muscle cells of the bronchi, uterus, gastrointestinal tract, detrusor of the bladder, blood vessels (vessels of skeletal muscles, lungs, coronary vessels). In this case, the smooth muscles of the bronchi relax, the tone and contractile activity of the myometrium, bladder, gall bladder and bile ducts, motility and tone of the stomach and intestines decrease, blood vessels expand.
Salmeterol is lipophylene, due to which it not only penetrates well into the membranes of smooth muscle cells of the bronchi, but also lingers in the lipid layer of the membranes, creating a kind of depot of the substance in the immediate vicinity of the receptor. This delays the activation of β2-adrenergic receptors (apparently, a small diffusion rate through the lipid layers of the membrane determines the delayed onset of the action of the substance on the receptor and is the reason for the slow development of the effect of the drug).
The relaxation of smooth muscles during stimulation of β2-adrenergic receptors coupled with Gs-proteins stimulating adenylate cyclase is associated with an increase in cAMP level and activation of cAMP-dependent protein kinase in smooth muscle cells. cAMP-dependent protein kinase A inhibits the kinase of myosin light chains, as a result of which phosphorylation of myosin light chains is disrupted and its interaction with actin does not occur. cAMP-dependent protein kinase A inhibits phospholamban (a Ca2 + -ATPase inhibitor), as a result, the activity of Ca2 + -ATPase, transporting Ca2 + from the cytoplasm to the sarcoplasmic reticulum, increases in smooth muscle cells, and the concentration of cytoplasmic Ca2 + decreases. All this leads to a decrease in tone and contractile activity of smooth muscles. It is possible to increase the level of glucose in the blood, since β2-adrenergic receptors control the process of glycogenolysis in the liver and skeletal muscles and the secretion of insulin in the pancreas, and upon stimulation they activate phosphorylase and increase the breakdown of glycogen, resulting in an increase in blood glucose.
The secretion of insulin during stimulation of β2-adrenergic receptors increases.
The anti-inflammatory effect of fluticasone is due to interaction with intracellular glucocorticoid receptors – the formation of dimers of the glucocorticoid-glucocorticoid receptor complex (releasing the receptor from bonds with heat shock proteins 70 and 90 and immunophilin). After which the activated receptor penetrates into the nucleus, binding to glucocorticoid-sensitive regulatory elements of DNA – a specific effect on gene expression (activation and suppression). And interaction with other protein transcription factors, including NFκB and AP-1, which regulate the expression of many proteins of the immune system, leads to suppression of the expression of genes encoding certain cytokines, collagenase, and stromelysins.
Pharmacokinetics:
After inhalation, 10-20% of the dose of salmeterol reaches the lower respiratory tract. The rest of the dose remains in the inhaler, settles on the mucous membrane of the oropharynx and then is swallowed. The fraction settled on the mucous membrane of the respiratory tract is absorbed into the lung tissue and blood, but is not metabolized in the lungs.
The degree of binding to plasma proteins is about 10%.
It is metabolized in the liver and excreted mainly in the urine unchanged and in the form of phenolic sulfate. The swallowed portion of the inhaled dose is absorbed from the gastrointestinal tract and undergoes active metabolism during the “first passage” through the liver, turning into phenolic sulfate. The elimination half-life is more than 5 hours. It is excreted with feces mainly in the form of metabolites.
The bioavailability of fluticasone is 30% (with aerosol inhalation) and 13.5% (with powder inhalation). Communication with proteins 91%, with transcortin insignificant. Liver biotransformation (CYP3A4), one inactive metabolite is known. The elimination half-life makes 7-8 h after intravenous administration; elimination with feces and urine (<5% as metabolites).
Indications:
Bronchial obstructive diseases:
patients receiving maintenance therapy with long-acting β2-adrenoreceptor agonists and inhaled corticosteroids;
with persisting symptoms of the disease during therapy with inhaled corticosteroids;
regularly using bronchodilators, which are indicated for therapy with corticosteroids).
ICD-10
Contraindications:
Hypersensitivity, children under 4 years old.
Carefully:
Pulmonary tuberculosis, fungal, viral or bacterial infections of the respiratory system, thyrotoxicosis, pheochromocytoma, diabetes mellitus, uncontrolled hypokalemia, IHSS, uncontrolled arterial hypertension, arrhythmia, prolongation of the QT interval on the ECG, hypoxia of various origins, cataracts, glaucoma, hypostasis, hypothyroidism, lactation period.
Pregnancy and lactation:
The FDA category of action for the fetus is C.
In studies on Dutch rabbits, the use of salmeterol was associated with the development of a cleft of the upper palate in the fetus, curvature of the extremities, and delayed ossification of the frontal bones. In studies on New Zealand rabbits, the use of salmeterol orally in a dose 1600 times higher than the doses recommended for treating people (per 1 m2 of body surface) only led to a delay in the ossification of the frontal bones. The use of salmeterol in rats at a dose 160 times the dose recommended for the treatment of humans (per 1 m2 of body surface) was not accompanied by a significant adverse effect on the fetus.
There is no evidence of penetration into breast milk. It is found in milk of lactating rats in a concentration comparable to that in blood plasma.
Dosage and administration:
Inhalation. The initial dose of the drug is determined based on the dose of fluticasone, which is recommended for the treatment of a disease of this severity. Then, the initial dose should be gradually reduced to the minimum effective dose.
Adults and adolescents 12 years of age and older: 2 inhalations (25 μg salmeterol and 50 μg fluticasone) 2 times a day, or 2 inhalations (25 μg salmeterol and 125 μg fluticasone) 2 times a day, or 2 inhalations (25 μg salmeterol and 250 μg fluticasone) 2 times a day, or 1 inhalation (50 μg salmeterol and 100 μg fluticasone) 2 times a day, or 1 inhalation 50 μg salmeterol and 250 μg fluticasone) 2 times a day, or 1 inhalation (50 μg salmeterol and 500 mcg of fluticasone) 2 times a day.
Children from 4 to 12 years: 2 inhalations (25 μg salmeterol and 50 μg fluticasone) 2 times a day or 1 inhalation (50 μg salmeterol and 100 μg fluticasone) 2 times a day.
In case of impaired liver and kidney function, as well as elderly patients, dose reduction is not necessary.
Side effects:
Salmeterol: paradoxical bronchospasm, irritation of the mucous membranes of the oral cavity or throat, change in taste (dysgeusia), hypokalemia, nervousness, abdominal pain, nausea, vomiting, hyperglycemia, tremor, palpitations, headache, arrhythmias (including atrial fibrillation supraventricular tachycardia and extrasystole), arthralgia, allergic reactions (skin rash, angioedema), skeletal muscle cramps.
Fluticasone: hoarseness, dysphonia, irritation of the pharyngeal mucosa, candidiasis of the oral cavity and pharynx, paradoxical bronchospasm, skin allergic reactions.
With prolonged use in high doses, the systemic effects of fluticasone may be noted: decreased adrenal cortex function, osteoporosis, growth retardation in children, cataracts, glaucoma.
Overdose:
Symptoms: tremor, headache, tachycardia, suppression of adrenal function.
Treatment: selective beta-blockers, drug withdrawal, (after a few days, adrenal function is restored on its own).
Interaction:
Beta-blockers reduce the effectiveness of inhibitors of the enzyme CYP3A4 (including ketoconazole, ritonavir), increase the concentration of fluticasone in the blood plasma.
Special instructions:
Composition – salmeterol – 25-50 mcg; fluticasone – 100-500 mcg.
Not suitable for the relief of acute attacks of bronchial asthma. Apply as a basic therapy for the failure of monotherapy.
Compared to increasing the dose of inhaled glucocorticoids, the combination does not improve the safety profile and clinical course of asthma, but the FVD improves.
Compared with monotherapy with long-acting β2-adrenergic agonists, they reduce the frequency of COPD attacks, but increase the risk of pneumonia.
Compared with monotherapy with inhaled glucocorticoids, the frequency of COPD attacks is reduced by 9.
Compared to placebo, they improve the quality of life for COPD.
The addition of long-acting β2-adrenergic agonists reduces the need for inhaled glucocorticoids with the same level of control of bronchial asthma.
Monitoring: growth and development in children; inhalation techniques, lung function; bone densitometry, ophthalmic status during therapy for more than 6 weeks (risk of cataracts, glaucoma, infectious diseases), tonometry.
In terms of effectiveness, it is comparable to the combination of formoterol + budesonide.