Mast cell blocking drugs. Mast cell membrane stabilizers

A group of drugs that prevent mast cell degranulation. They are most effective when used in advance, proactively, since they are not able to block the action of released biologically active substances. The maximum effect occurs within 2-14 days from the start of use. Therefore, and also due to its good tolerance, they can be recommended for long-term use.

Sodium cromoglicate (cromohexal, lecrolin, lomuzol, opticrom, vividrin) is widely used in the form of 2% eye drops for the treatment and prevention of ocular symptoms of allergic diseases, as well as allergic conjunctivitis itself, including seasonal allergic conjunctivitis, perennial allergic conjunctivitis and vernal keratoconjunctivitis. Adults and children are prescribed a 2% cromoglycate solution, 1 drop in each eye 2-6 times a day. When using the drug, quickly passing pain or local irritation is possible. Contraindications: individual intolerance.

Currently, there is no evidence of an adverse effect of cromoglycate on the fetus. However, the use of the drug during pregnancy requires serious clinical indications. It may be excreted in breast milk, but adverse effects on the child are unlikely due to insignificant systemic absorption of the drug. Nedocromil inhibits the activation and release of mediators from a large number of inflammatory cells: eosinophils, neutrophils, mast cells, monocytes, macrophages and platelets. Eye drops in the form of a 2% solution of nedocromil (Tilavist) help suppress the activation of the cellular reaction in the conjunctiva. The scope and dosage are the same as for cromoglycate. Side effects (swelling of the nasal mucosa and irritation) are quite rare. The drug does not have a sedative effect and does not interact with alcohol. allergic eye antihistamine immunosuppressant

Alomide eye drops contain a 0.1% solution of lodoxamide. Lodoxamide stabilizes mast cells and also inhibits the migration of eosinophils and the release of mediators from them into the corneal tissue, making it effective against allergic and autoimmune lesions of the cornea. Alomide is well tolerated and is used in the same cases as cromoglycate. Prescribing lodoksamide is advisable for chronic and subacute pollinous conjunctivitis, marginal keratitis, allergic conjunctivitis caused by cosmetics, household chemicals, food products, medicines, and wearing contact lenses. Alomide is used in adults and children over 4 years of age, 1 drop in each eye 4 times a day. After instillation, a transient burning sensation, itching, and lacrimation may occur. Contraindications: individual intolerance.

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Mast cell membrane stabilizers

Cromolyn sodium is the safest drug that can be used as an additional therapy in cases of incomplete elimination of rhinitis symptoms during treatment with antihistamines.

They go well together.

Cromolyn sodium does not cause rebound symptoms, stabilizes mast cell membranes, effectively prevents allergic reactions of the reagin type, inhibits the release of allergy mediators from sensitized mast cells as a result of the antigen-antibody reaction, exhibits a protective effect not only against allergens, but also against nonspecific factors - triggers that can cause degranulation of mast cells (sulfur dioxide, nitrogen oxides, cold air, physical effort).

The use of cromolyn sodium is especially important when allergic rhinitis is combined with bronchial asthma, with hidden obstruction of the bronchial tree, since its pharmacological and therapeutic effects can reduce the hyperreactivity of the mucous membrane of the bronchial tree.

The various forms of sodium cromoglycate offered are designed for local action, directly on the shock organ, where the concentration of the allergen is highest.

Currently, there is a wide selection of sodium chromoglycate in the form of various forms - aerosols of lomuzol for the nasal mucosa, drops of opticrom for the mucous membranes of the eyes, capsules of nalcrom in cases of rhinitis developing against the background of sensitization to food allergens.

Aqueous solutions of sodium cromoglycate are preferable in cases of pronounced hyperreactivity of the mucous membrane of the bronchial tree to nonspecific factors - triggers, since intal "spinhaler" in the form of a dry substance (microcrystals) in aerosols on a mechanical basis causes a coughing reaction or coughing when inhaled.

As is known, intal significantly enhances the therapeutic effect of adrenomimetics and glucocorticoids when combined in cases of treating patients with bronchial asthma. Therefore, when allergic rhinitis and bronchial asthma are combined, Intal Plus and Ditek are successfully used. Thanks to the combination of 0.1 mg of fenoterol and 2 mg of disodium chromoglycate in the composition of ditek for bronchial asthma, not only a bronchodilator, but also an anti-inflammatory effect is achieved, and their severity is higher than when using the drugs separately.

As we indicated, the therapeutic effectiveness of non-sedating antihistamines in the form of a spray (allergodil, histimet), intal aerosols for allergic rhinitis depends on the availability of the nasal mucosa for topical drugs. In this regard, before using them, it is advisable to use decongestants (vasoconstrictors) in the form of 1-2 drops of naphthyzine (0.05% solution), galazolin (0.1% solution), norepinephrine (0.2% solution), mezatone (1 % solution) or ephedrine (2% solution).

Currently, oral decongestants are proposed that do not have the side effects of these adrenergic agonists, which are combined with second-generation antihistamines.
Clarinase, unlike the above decongestants, acts longer, does not cause damage to the nasal mucosa, promotes the rapid disappearance of nasal breathing obstruction, and opens the surface of the mucous membrane for Intal aerosols. One Clarinase tablet contains 5 mg of loratadine and 60 mg of pseudoephedrine.

Use with caution in patients over 60 years of age, with diseases of the cardiovascular system, diabetes mellitus, and not prescribed to children under 12 years of age.

Anticholinergic drugs

With year-round rhinitis on a cholinergic basis, the ability to degranulate mast cells with the release of histamine in response to the influence of nonspecific factors sharply increases, and activation of B lymphocytes with the expression of IgE is possible.

Atrovent (ipratropium bromide) is a competitive antagonist of acetylcholine, capable of suppressing cholinergic reactions by blocking their receptors. Unlike atropine, it has a predominantly local effect. Atrovent in the form of a nasal aerosol is prescribed 2 inhalations of 20 mcg (two presses on the valve of the aerosol can) into each nostril 2-3 times a day for 4-8 weeks. The clinical effect occurs within a day and after discontinuation of the drug can last up to a year.

Nonspecific hyposensitizing therapy

Histaglobulin is a preparation containing 6 mg of human gamma globulin and 0.1 μg of histamine hydrochloride in 1 ml of isotonic sodium chloride solution. Helps stabilize cell membranes, enhance histamine inactivation by increasing histaminase activity, binding histamine to tissue and blood proteins, and increases tissue tolerance to histamine. Courses of treatment with histaglobulin are carried out on the eve of the expected development of hay fever, cold idiopathic rhinitis, and with mild year-round rhinitis.

The methods and methods of administering histaglobulin may be different. Histaglobulin is administered subcutaneously 1 ml 2 times a week - for a course of 10-12 ml. Repeated courses - after 3-5 months. There are methods for gradually increasing the dose - 0.2, 0.4, 0.6, 0.8, 1.0 ml every other day, and then 1.6-1.8-2.0 ml after 3-4 days.

The method of intradermal administration (most suitable for idiopathic cold rhinitis - on the eve of the expected cold season) is carried out every other day, increasing the volume of administration each time by 0.1 ml, starting from 0.1 ml and up to 1 ml (five times 0.2 ml, since it is impossible to administer a larger volume intradermally), then after 3 days with an increase in volume by 0.2 ml and so on up to 1.6 ml.

Allergoglobulin is placental gamma globulin in combination with gonadotropin. Has a high ability to bind free histamine. A single dose for deep intramuscular injection is 5-10 ml after 15 days for seasonal or year-round rhinitis. There are 4 injections per course.

For rhinitis, phonopuncture with splenin ointment is indicated, which is carried out from paranasal points in continuous or pulsed mode for 1-2 minutes per point with an intensity of 0.4 W per 1 sq. cm. Composition of splenin ointment: splenin - 10 ml, citral 1% - 1 ml, lanolin - 5 ml, Vaseline - up to 100 ml.

Anti-inflammatory, antiallergic, antiproliferative therapy

Early registration of allergic rhinitis, their careful treatment with antihistamines, non-steroidal anti-inflammatory drugs - mast cell membrane stabilizers and decongestants often do not allow changing their initial course.

The proposed stepwise scheme for the treatment of seasonal and year-round rhinitis, given in the International Consensus Report on the diagnosis and treatment of rhinitis, therefore involves the use of more powerful anti-allergic, anti-inflammatory, anti-proliferative drugs - local glucocorticoid aerosols.

Glucocorticoids do not allow pathological changes in allergic rhinitis to develop into a self-destructive process involving the mucous membrane of the bronchial tree. However, the systemic effects of oral glucocorticoids (decreased adrenal function, glucocorticoid dependence, increased catabolism of muscle proteins, proteins of various cellular formations, including osteoclasts, the phenomenon of hypercorticism - Itsenko-Cushing syndrome, steroid diabetes, osteoporosis, etc.) restrained their use.

The emergence of a new generation of inhaled glucocorticoids, which have predominantly local and minimal systemic effects (subject to an adequate anti-inflammatory dose of the drug, the duration of the course of treatment, and the use of modern treatment technology), has significantly expanded the indications for their use.

The use of glucocorticoids is justified, since in small doses (up to 400 mcg), in short courses (for seasonal rhinitis up to 2 weeks, for year-round rhinitis up to 8 weeks) they allow you to transfer the course of the disease to a milder phase - dramatically improve the patient’s quality of life, enhance efficiency in subsequent stages, antihistamines and weaker anti-inflammatory drugs (nedocromil sodium).

Inhalation through a special nozzle for the nose reduces the systemic effect of these glucocorticoids to a low probability, especially since they do not penetrate from the nasal cavity into the distal parts of the lung.
Inhaled glucocorticoids include beclometazone dipropionate (becotide, aldecin), flunisolide (ingacort), triamcinolone (asmocort), fluticasone (flixotide, flixonase), budesonide (pulmicort), nasonex (mometasone dipropionate).

Pharmacokinetics and pharmacological effects of these drugs, according to Barnes, Pederson (1993), Demoly, Chung (1996), Rrteid et al. (1996), allow us to give preference to budesonide, since its transmembrane transport is difficult (absorption from the entry of an inhalation dose into the bloodstream is up to 10% - less than other glucocorticoids penetrate the alveolar epithelium), it is more strongly bound by plasma proteins than others (up to 88%), and is subject to intense metabolism (transformation) in the liver (microsomal oxidation with the help of cytochrome P 450) with conversion into inactive compounds.

Budesonide (rhinocort) prevents an allergen-induced reaction of the nasal mucosa, is offered in the form of a metered aerosol Mite (one breath 50 mcg, most often used to treat allergic rhinitis) and Forte (one breath 200 mcg, used in the treatment of bronchial asthma).

Comparing the clearance and half-life of the above-mentioned glucocorticoids, we can conclude that, along with budesonide, preference should be given to fluticasone and nasonex, the half-life of which is approximately 2 times higher than that of flunisolide and triamcinolone acetonide (2.8-3.1-, respectively). 3). Along with this, fluticasone and nasonex have an extremely low ability to penetrate into the bloodstream after inhalation administration from the surface of the nasal mucosa.

Flixonase is a nasal spray in the form of an aqueous suspension of microionized fluticasone propionate, secreted by a nasal adapter, per injection - 50 mcg of fluticasone. Flixonase is intended for the treatment and prevention of allergic rhinitis. Local anti-inflammatory activity of fluticasone is 2 times higher than that of beclomethasone propionate, and 4 times higher than that of triamcinolone acetonide.

Nasonex (mometasone furoate monohydrate) is a water-containing inhaler spray for intranasal use. Each time the dispenser button is pressed, approximately 100 mg of mometasone furoate suspension containing mometasone furoate monohydrate in an amount equivalent to 50 mcg of the chemically pure drug is released.

Nasonex is a glucocorticosteroid for local use, the local anti-inflammatory effect of which in such doses is not accompanied by systemic effects. This is due to the negligible bioavailability of Nasonex (< 0,1 %), крайне малой всасываемостью.

In cell culture studies, it was shown that mometasone furoate inhibits the synthesis and release of IL-1, IL-6, suppresses the synthesis of IL-4 and IL-5, tumor necrosis factor alpha, reduces the level of eosinophilic infiltration in the bronchioles and bronchioles and the content of eosinophils in washouts during bronchioloalveolar lavage, significantly suppresses the release of leukotrienes from leukocytes of patients with allergic diseases.

The dosage of the drug is usually two inhalations (50 mcg each) into each nostril once a day (total daily dose 200 mcg). After achieving a therapeutic effect for maintenance therapy, you can reduce the dose to one inhalation in each nostril (total daily dose of 100 mcg).

We conducted a study in 20 patients with seasonal (for 2 weeks) and 32 patients with year-round (duration of treatment - 60 days) rhinitis and found a high therapeutic effect of Nasonex - complete involution of rhinitis symptoms in 96% of cases. Patients with seasonal rhinitis practically did not need further treatment during the flowering season. In patients with year-round rhinitis, after stopping treatment, the degree of freedom remained high for up to 6-8 months and the need for other drugs was 2-4 times lower.

Thus, treatment of patients with allergic rhinitis should be carried out depending on sensitization to the allergen, the severity of rhinitis, and allergic reactions outside the nasal mucosa. In the system of treatment measures, primary and secondary prevention are important, since limiting contact with the allergen plays a decisive role in the success of general treatment measures.

The scheme of stepwise therapy given below by N.G. Astafieva, L.A. Goryachkina (1998) reflects, in our opinion, the general concept of the approach to the treatment of rhinitis.

As for stepwise therapy in the case of year-round rhinitis with sensitization to household allergens, the approach will be the same in cases where specific allergen vaccination was not carried out or was carried out with a satisfactory result.

It should be noted that in most cases, with year-round allergic rhinitis with a mild persistent course, there is a need to use inhaled glucocorticoids, since, despite measures aimed at limiting contact with household allergens, excluding active and passive smoking, limiting contact with other nonspecific irritants, including Following a hypoallergenic diet, regression of the disease cannot be achieved.

In terms of differential diagnosis of allergic rhinitis and approaches to their treatment, we present a rhinitis treatment regimen given in the International Consensus Report on the Diagnosis and Treatment of Rhinitis (1990), modified and adapted using Nasonex aerosols.

N. A. Skepyan

Mast cell membrane stabilizers are widely used to treat patients with mild or moderate bronchial asthma, as well as allergic rhinitis.
The group of mast cell membrane stabilizers includes ketotifen and cromone derivatives - cromoglycic acid and nedocromil.

Mechanism of action and pharmacological effects
The mechanism of action of mast cell membrane stabilizers is due to inhibition of the release from target cells, especially from mast cells, of allergy mediators - histamine and other biologically active substances. The release of these substances from mast cell granules occurs when an antigen interacts with an antibody on the cell surface. It is assumed that ketotifen and cromones indirectly inhibit the entry into the cell of Ca2+ ions necessary for degranulation, blocking the conductivity of membrane channels for Cl- ions, and also inhibit phosphodiesterase and the process of oxidative phosphorylation.
Inhibition of the function of allergy target cells makes it possible to use these drugs to prevent attacks of bronchial asthma induced by allergens, physical activity and cold air. With their regular use, there is a decrease in the frequency and severity of exacerbations of bronchial asthma, a decrease in the need for bronchospasmolytic drugs, and prevention of the onset of symptoms of the disease caused by physical activity.

Rice. 1. Mechanism of action of mast cell membrane stabilizers

Ketotifen has antianaphylactic and antihistamine effects, inhibits the release of inflammatory mediators (histamine, leukotrienes) by mast cells and basophils, is a calcium antagonist, and eliminates β-adrenergic receptor tachyphylaxis. It reduces airway hyperresponsiveness associated with platelet-activating factor or allergen exposure; suppresses the accumulation of eosinophils in the respiratory tract. The drug also blocks H1-histamine receptors.

Cromoglycate sodium prevents the development of the early and late phases of allergen-induced bronchial obstruction, reduces bronchial hyperreactivity, and prevents bronchospasm caused by physical activity, cold air and allergen inhalation. However, it does not have bronchodilator and antihistamine properties. The main mechanism of its action is the inhibition of the release of allergic mediators from target cells, preventing the early and late stages of the allergic reaction in response to immunological and other stimuli in the lungs. It is known that sodium cromoglycate acts on the bronchial receptor apparatus, increases the sensitivity and concentration of β-adrenergic receptors. The drug blocks reflex bronchoconstriction by inhibiting the activity of C-fibers of the sensory endings of the vagus nerve in the bronchi, which leads to the release of substance P and other neurokinins. The latter are mediators of neurogenic inflammation and cause bronchoconstriction. Prophylactic use of sodium cromoglycate inhibits reflex bronchospasm caused by stimulation of sensitive nerve C-fibers.

Nedocromil sodium similar in chemical structure and mechanism of action to sodium cromoglycate, however, as experimental and clinical studies have shown, nedocromil sodium is 4-10 times more effective than sodium cromoglycate in preventing the development of bronchial obstruction and allergic reactions. Nedocromil sodium is able to suppress the activation and release of allergy mediators from a larger number of immunocompetent cells (eosinophils, mast cells, basophils, macrophages, platelets), which is associated with the effect of the drug on the chloride channels of cell membranes. It inhibits the IgE-dependent secretion of histamine and prostaglandin D2 from human mast cells, prevents the migration of eosinophils from the vascular bed and inhibits their activity. The drug restores the functional activity of ciliated cells and blocks the release of eosinophilic cationic protein by eosinophils.

International name:

Dosage form: An aqueous solution for inhalation in 2 ml ampoules containing 2 mg of intal. “Bikromat aerosol” is also available in 15 g cylinders. Contains 200 single doses of intal, 1 mg per dose.

Indications: Bicromat is effective in patients with bronchial asthma and has a preventive effect when used before the development of an attack of bronchial asthma. ...

Broniten

International name: Ketotifen

Dosage form:

Pharmachologic effect:

Indications:

Vividrin

International name: Cromoglicic acid

Dosage form: 1 ml of solution contains disodium cromoglycate 20 mg. Eye drops: in dropper bottles of 10 ml, 1 bottle in a box. Nasal aerosol: in bottles with a dosing device of 15 ml, in a box 1 bottle.

Pharmachologic effect: antiallergic, membrane stabilizing. Blocks the penetration of calcium ions into mast cells, prevents their degranulation and release of biologically active substances, incl. allergy mediators.

Indications: Eye drops: allergic conjunctivitis. Nasal aerosol: allergic rhinitis (year-round and seasonal).

Denerel

International name: Ketotifen

Dosage form: eye drops, capsules, syrup, tablets

Pharmachologic effect: Stabilizer of mast cell membranes, has moderate H1-histamine blocking activity, suppresses the release of histamine, leukotrienes from basophils...

Indications: Prevention of allergic diseases: atopic bronchial asthma, allergic bronchitis, hay fever, allergic rhinitis, allergic dermatitis, urticaria, allergic conjunctivitis.

Zaditen

International name: Ketotifen

Dosage form: eye drops, capsules, syrup, tablets

Pharmachologic effect: Stabilizer of mast cell membranes, has moderate H1-histamine blocking activity, suppresses the release of histamine, leukotrienes from basophils...

Indications: Prevention of allergic diseases: atopic bronchial asthma, allergic bronchitis, hay fever, allergic rhinitis, allergic dermatitis, urticaria, allergic conjunctivitis.

Zaditen SRO

International name: Ketotifen

Dosage form: eye drops, capsules, syrup, tablets

Pharmachologic effect: Stabilizer of mast cell membranes, has moderate H1-histamine blocking activity, suppresses the release of histamine, leukotrienes from basophils...

Indications: Prevention of allergic diseases: atopic bronchial asthma, allergic bronchitis, hay fever, allergic rhinitis, allergic dermatitis, urticaria, allergic conjunctivitis.

Zerosma

International name: Ketotifen

Dosage form: eye drops, capsules, syrup, tablets

Pharmachologic effect: Stabilizer of mast cell membranes, has moderate H1-histamine blocking activity, suppresses the release of histamine, leukotrienes from basophils...

There are few disciplines in medicine in which diagnosis and treatment are as closely linked as in allergology. The most accurate diagnosis and identification of a causally significant allergen determines the treatment algorithm: elimination of contact with the allergen, drug relief of the allergic reaction that has occurred and, if possible, further ASIT, social adaptation and patient education (Table 3-1).

Table 3-1. General principles of allergy treatment

Elimination measures aimed at eliminating contact with the allergen, ASIT and immunomodulatory treatment are described in the relevant chapters. This chapter will discuss the main groups of drugs used for the treatment of AD (based on the State Register of Medicines, vol. 1, as of January 1, 2006).

MAST CELL MEMBRANE STABILIZERS

Classification membrane stabilizing drugs (see Table 3-2):

♦local action - cromone derivatives: cromoglycic acid, nedocromil sodium, lodoxamide;

♦systemic action, with an antihistamine effect - ketotifen.

MECHANISM OF ACTION AND PHARMACOLOGICAL EFFECTS

It is assumed that ketotifen and cromones act as agonists of the corresponding cellular receptors. These drugs block the entry of chlorine ions into mast cells, thereby preventing the entry of calcium ions into the cell, which ensure the process of degranulation of these cells. Due to this membrane-stabilizing effect, the release of histamine, LT and other mediators is blocked. Drugs also have a suppressive effect on other cells involved in allergic inflammation. Thus, the pharmacological effects of drugs are as follows:

♦suppression of the release of mediators from mast cells under the influence of allergens and nonspecific irritants (reduction of specific and nonspecific hyperreactivity);

♦decrease in permeability of mucous membranes;

♦inhibition of the activity of eosinophils, macrophages, neutrophils and platelets;

♦blockade of both early and late phases of the allergic response;

♦decrease in the sensitivity of afferent nerve fibers, blockade of reflex bronchoconstriction.

Cromones, by blocking the release of mediators, interrupt allergic inflammation, reduce the permeability of mucous membranes, block reflex bronchospasm, inhibit the immediate reaction of the bronchi to the allergen, and this property is more pronounced in nedocromil sodium. Cromolyn derivatives reduce allergen-specific and nonspecific reactivity of mucous membranes in AR, AK, and BA. Their use prevents the development of bronchospasm from various provoking factors: physical activity, cold air, and certain chemicals. The membrane-stabilizing effect of cromoglycic acid and nedocromil sodium also extends to processes not related to allergies. For example, cromoglycic acid inhibits cough caused by angiotensin converting enzyme (ACE) inhibitors - enalapril and captopril.