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Clinical and pharmacological group:

• Beta-adrenomimetics
• Glucocorticosteroids

ATX:

• R.03.A.K Sympathomimetics in combination with corticosteroids or other drugs, excluding anticholinergic drugs
• R.03.A.K.06 Salmeterol and fluticasone

Pharmacodynamics:

Salmeterol stimulates β2-adrenoreceptors that are located in the membranes of smooth muscle cells of the bronchi, uterus, GI tract, detrusor of the bladder, and blood vessels (skeletal muscle vessels, lungs, coronary vessels). This results in relaxation of bronchial smooth muscles, decreased tone and contractile activity of myometrium, urinary bladder, gallbladder and bile ducts, motility and tone of the stomach and intestines, and dilation of blood vessels.

Salmeterol is lipophilic, so it not only penetrates well into the membranes of bronchial smooth muscle cells, but also stays in the lipid layer of the membranes, creating a kind of depot of the substance in the vicinity of the receptor. This delays the activation of β2-adrenoreceptors (apparently, the low rate of diffusion through the lipid layers of the membranes determines the delayed onset of action of the substance on the receptor and is the reason for the slow development of the drug effect).

The relaxation of smooth muscles upon stimulation of β2-adrenoreceptors conjugated with Gs-proteins that stimulate adenylate cyclase is associated with an increase in the level of cAMP and activation of cAMP-dependent protein kinase in smooth muscle cells. cAMP-dependent protein kinase A inhibits myosin light chain kinase, as a result, phosphorylation of myosin light chains is impaired and its interaction with actin does not occur. cAMP-dependent protein kinase A inhibits phospholamban (Ca2+-ATPase inhibitor), resulting in increased activity of Ca2+-ATPase in smooth muscle cells that transports Ca2+ from the cytoplasm to the sarcoplasmic reticulum, and decreased concentration of cytoplasmic Ca2+. All this leads to decrease of tone and contractile activity of smooth muscles. Blood glucose levels may increase as β2-adrenoreceptors control the process of glycogenolysis in the liver and skeletal muscles and insulin secretion in the pancreas, and their stimulation activates phosphorylase and increases glycogen breakdown, resulting in increased blood glucose levels.

Insulin secretion increases when β2-adrenoreceptors are stimulated.

The anti-inflammatory effect of fluticasone is due to the interaction with intracellular glucocorticoid receptors - formation of dimers of the glucocorticoid-glucocorticoid receptor complex (receptor release from the bonds with heat shock proteins 70 and 90 and immunophilin). This is followed by penetration of the activated receptor into the nucleus, binding to glucocorticoid-sensitive regulatory elements of DNA - specific influence 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 some cytokines, collagenase and stromelysins.

Pharmacokinetics:

After inhalation, 10-20% of the dose of salmeterol reaches the lower respiratory tract. The remainder of the dose remains in the inhaler, is deposited on the oropharyngeal mucosa and then swallowed. The fraction deposited on the respiratory mucosa is absorbed into the lung tissues 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 with urine unchanged and in the form of phenol sulfate. The ingested part of the inhaled dose is absorbed from the gastrointestinal tract and undergoes active metabolism during "first passage" through the liver, turning into phenolic sulfate. The elimination half-life is more than 5 hours. It is excreted in the faeces mainly as metabolites.

Bioavailability of fluticasone is 30% (when aerosol inhalation) and 13.5% (when powder inhalation). Protein binding is 91%, with transcortin insignificant. Biotransformation in the liver (CYP3A4), one inactive metabolite is known. Half-life is 7-8 h after intravenous administration; elimination with feces and urine (<5% as metabolites).

Indications:

Bronchoobstructive disorders:

• Patients receiving maintenance therapy with long-acting β2-adrenoreceptor agonists and inhaled GCS;
• with persisting symptoms of the disease against the background of therapy with inhaled GCS;
• regularly using bronchodilators, who are indicated for GCS therapy).

Contraindications:

Hypersensitivity, children under 4 years of age.

With caution:

Pulmonary tuberculosis, fungal, viral or bacterial respiratory infections, thyrotoxicosis, pheochromocytoma, diabetes, uncontrolled hypokalemia, IGSS, uncontrolled arterial hypertension, arrhythmia, QT interval prolongation on ECG, hypoxia of various genesis, cataracts, glaucoma, hypothyroidism, osteoporosis, pregnancy, lactation period.

Pregnancy and lactation:

The FDA fetal action category is C.

In studies on Dutch rabbits, use of salmeterol was associated with the development of cleft palate, limb curvature, and delayed frontal bone ossification in the fetus. In studies on New Zealand rabbits, oral administration of salmeterol at a dose 1600 times higher than the doses recommended for the treatment of humans (based on 1 m2 of body surface) resulted only in delayed ossification of the frontal bones. Salmeterol administration in rats at a dose 160 times the recommended dose for treatment in humans (based on 1 m2 of body surface) was not accompanied by a significant adverse effect on the fetus.

There is no information on penetration into breast milk. Detectable in milk of lactating rats at concentrations comparable to those in blood plasma.

Directions for use and dosages:

Inhaled. The initial dose of the drug is determined on the basis of the dose of fluticasone recommended for treatment of the disease of a given 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 daily, or 2 inhalations (25 µg salmeterol and 125 µg fluticasone) 2 times daily, or 2 inhalations (25 µg salmeterol and 250 µg fluticasone) 2 times daily 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 µg fluticasone) 2 times a day.

Children from 4 to 12 years: 2 inhalations (25 mcg salmeterol and 50 mcg fluticasone) 2 times a day or 1 inhalation (50 mcg salmeterol and 100 mcg fluticasone) 2 times a day.

There is no need to reduce doses in patients with hepatic and renal dysfunction and in elderly patients.

Side effects:

Salmeterol: paradoxical bronchospasm, irritation of the mucous membranes of the mouth or throat, changes in taste sensation (dysgeusia), hypokalemia, nervousness, abdominal pain, nausea, vomiting, hyperglycemia, tremor, palpitation, headache, arrhythmias (including including atrial fibrillation, supraventricular tachycardia and extrasystole), arthralgia, allergic reactions (skin rash, angioedema), skeletal muscle cramps.

Fluticasone: hoarseness of the voice, dysphonia, irritation of the pharyngeal mucosa, candidiasis of the mouth and throat, paradoxical bronchospasm, skin allergic reactions.

When prolonged use in high doses, systemic effects of fluticasone may be noted: decreased adrenal cortical function, osteoporosis, growth retardation in children, cataracts, glaucoma.

Overdose:

Symptoms: tremor, headache, tachycardia, suppression of adrenal function.

Treatment: selective beta-adrenoblockers, drug withdrawal, (in a few days the adrenal function restores itself).

Interaction:

Beta-adrenoblockers reduce the effectiveness of CYP3A4 enzyme inhibitors (including ketoconazole, ritonavir), increase the plasma concentration of fluticasone.

Special indications:

Composition - salmeterol, 25-50 mcg; fluticasone, 100-500 mcg.

Not suitable for relieving acute attacks of bronchial asthma. Use as basic therapy when monotherapy is ineffective.

Compared with increasing the dose of inhaled glucocorticoids, the combination does not improve the safety profile and the clinical course of asthma, but the parameters of the BFD are improved.

Compared with monotherapy, long-acting β2-adrenomimetics reduce the frequency of COPD attacks but increase the risk of pneumonia.

Compared with inhaled glucocorticoids monotherapy, reduce the frequency of COPD attacks by 9.

Compared with placebo improve quality of life in COPD.

The addition of long-acting β2-adrenomimetics reduces the need for inhaled glucocorticoids at the same level of bronchial asthma control.

Monitoring: growth and development in children; inhalation technique, lung function; bone densitometry, ophthalmic status on therapy over 6 weeks (risk of cataracts, glaucoma, infections), tonometry.

It is comparable to formoterol + budesonide combination in efficacy.

By: Dr. Adil Shujaat