Antiallergic drugs

Allergic reactions of the body are abnormally enhanced immune responses to an antigen, causing damage to the tissue of a sensitized microorganism. There are two types of mechanisms of allergic reactions: humoral and cellular. Humoral mechanism is based on the production of antibodies. The cellular one involves many immunocompetent cells. The immune response is generated during the interaction between phagocytes, regulatory lymphocytes (T-helpers and T-suppressosr), effector lymphocytes (cytotoxic T-cells, B-cells producing antibodies) and a number of other cells (including mast cells).

Lymphocytes activated by the antigen, as well as monocytes and macrophages produce bioactive peptidic compounds, regulating and enhancing the immune response – cytokines. Cytokines produced by lymphocytes are called lymphokines. Cytokines regulate interactions of immunocompetent cells and affect the course of the inflammatory process. They possess anti-proliferative, anti-microbial and anti-tumor effect. These are interleukins IL-1 - IL-6; interferons α and β, ɣ; colony stimulating factors, granulocyte-macrophage, granulocyte, macrophage; factor inhibiting macrophage migration; cytotoxins: tumor necrosis factor (α, β), lymphotoxins.

Hypersensitivity reactions are divided into: immediate reactions (expressed in minutes or hours); reaction of the delayed type (appear in 2 - 3 days or later). The immediate hypersensitivity reactions include bronchospasm, rhinitis, conjunctivitis, urticaria, anaphylaxis, drug thrombocytopenic purpura, serum sickness, Arthus phenomenon, and others. The reactions of immediate type are caused by the interaction of antigens with antibodies. Antibodies are produced by plasmocytes. Cytophilous antibodies are fixed to a number of high affinity receptor cells (mast cells, basophils, etc). The interaction of antibodies with allergen leads to tissue damage (from a variety of reversible functional changes to lysis and necrosis). The release of histamine, "slow reacting substance of anaphylaxis" (MRSA), bradykinin, serotonin, prostaglandins, platelet-activating factor (PAF), and others out of mast cells and basophils is typical for many allergic reactions.

Delayed type reaction. The delayed hypersensitivity reactions include tuberculin reaction, contact dermatitis, graft rejection, some types of autoimmune lesions. Delayed-type reactions are associated with cellular immunity and dependent on the presence of sensitized T-lymphocytes, having on their surface specific receptors that recognize antigens localized on macrophages, monocytes and other antigen-presenting cells and interact with them. A group of hormone-like substances is produced by thymus (for example, thymosin). It regulates the maturation of precursors of T-lymphocytes, proliferation and differentiation of mature T-lymphocytes. The mediators of delayed-type allergies are: interleukin - 2, lymphotoxin, a factor inhibiting the migration of macrophages (MIF), and others.

In case of an allergy (hypersensitivity) of an immediate type one uses:

1. The drugs that prevent the release of histamine and other biologically active substances out of sensitized mast cells and basophils. Such effect is typical for glucocorticoids, cromolyn sodium ketotifen, the drugs with β- adrenomimetic activity, euphylline.

2. The drugs preventing the interaction of histamine with sensitive tissue receptors - histamine H1 receptor (Dimedrol, дипразин and others.).

3. The drugs eliminating general symptoms of allergic reactions such as anaphylactic shock (drop in blood pressure, bronchospasm): adrenomimetics (adrenaline); broncholytics of myotropic action (euphylline).

4. The drugs reducing tissue damage: steroid anti-inflammatory drugs.

In case of an allergy (hypersensitivity) of a delayed type one uses:

1. The drugs suppressing immunegenesis (which suppress cellular immunity) - immunosuppressants: glucocorticoids, cyclosporine, tacrolimus, cytotoxic agents.

Antihistamines blocking H1-receptors

      Histamine is a biogenic substance involved in the development of allergies, inflammation; stimulates the secretion of HCl, dilates blood vessels, increasing their permeability, lowers blood pressure, increases the tone of the bronchi. Histamine interacts with H1 - H4 - receptors. Antiallergic effects are realized upon activation of histamine H1-receptors.

     H1- receptor blockers: diphenhydramine hydrochloride (dimedrol), дипразин (promethazine hydrochloride, pipolfen), Chloropyramine (suprastin), Phencarol (Quifenadine), diazolin (Mebhydrolin passilat, Omeryl), loratadine (Claritin).

Histamine receptor blockers are used for the first type allergic reactions: urticaria, skin itching, allergic conjunctivitis, rhinitis, angioneurotic edema. The main pharmacological effect – they eliminate or reduce the following types of action of histamine: increased tone of bronchial smooth muscle, intestine, uterus; lowering blood pressure (partially); increase in capillary permeability with the development of edema; flushing and itching.

Additional pharmacological effects: upon penetration into the CNS they have a sedative hypnotic effect. This is typical of dimedrol, diprasine, suprastin. Diprasine increases the effects of anesthetic drugs, opioids and local anesthetics. It reduces the temperature to a small extent. At very high doses of these drugs they cause motor and mental excitement, insomnia, tremor, increased reflex excitability.

Tavegil, phencarol and loratadine have an insignificant sedative effect, diazolin does not affect the central nervous system. Most drugs are characterized by anesthetic properties, expressed in varying degrees. Dimedrol lowers blood pressure due to its ganglioblocking effect. Diprasine blocks α- adrenergic receptors. Diprasine, Dimedrol and Suprastin have moderate inflammatory properties.

Н₁- receptor blockers of the 1^st generation

Diphenhydramine (Dimedrol).

Pharmacokinetics. When taken orally, it is rapidly and well absorbed, T1 / 2 is about 7 hours, duration of action – 4-6 hours. It crosses the blood-brain barrier, undergoes biotransformation in the liver and gets excreted by the kidneys.

Dosing regimen. It is prescribed to be used orally, IM, IV and topically (dermally, in the form of eye drops to the nasal mucosa), rectally. Oral tablets – 0,03-0,05g x 1-3 times / day. The course is 10-15 days. As a hypnotic drug – before the bedtime 0.03-0.05 g. IM – 1-5 ml of 1% solution (0.01-0.05 g); IV drip – 0.02-0.05 g in 75-100ml of physiological solution.

Contraindications. Angle-closure glaucoma, prostatic hypertrophy, pregnancy, lactation.

Dosage forms. Tablets – 0.02 g; 1% solution in 1 mL ampoules.

Diazolin (Diazolinum, Mebhydrolin)

Pharmacodynamics. Along with antihistamine action, it has an M-anticholinergic properties and properties of a local anesthetic. No sedative or hypnotic effects.

Pharmacokinetics. When taken orally, it is slowly absorbed, T1 / 2 is about 4 hours; biotransformation is in the liver and excretion – by the kidneys.

Dosing regimen. In tablets of 0.05-0.2 g, the course of treatment – 10-15 days.

Adverse reactions. Irritation of gastric mucosa, dizziness, blurred vision, urinary retention. In large doses – drowsiness and slow reaction rate.

Contraindications. Gastric ulcer, inflammatory diseases of the gastrointestinal tract, prostatic hypertrophy, angle-closure glaucoma.

Dosage forms. Tablets of 0.1 g; dragee – 0.05 - 0.1 g

Н₁- receptor blockers of the 2^nd generation

They do not practically penetrate the blood-brain barrier so there’s no significant effect on the CNS. There are no M-anticholinergic properties. They act longer (up to 24 hrs.) than first-generation drugs.

Phencarol (Phencarolum, Quifenadine)

Pharmacodynamics. It is low lipophilic tha’s why it slightly penetrates the blood-brain barrier. It does not only block the H1-receptors, but also reduces the amount of histamine in tissues because it activates diamine oxidase – an enzyme which inactivates histamine. The absence of m-anticholinergic action allows to prescribe it to patients with glaucoma and prostatic hypertrophy.

Dosing regimen. Taken orally after meal. The dose for adults is 0.025-0.05 g x 3-4 times / day. The course of treatment is 10-20 days.

Adverse reactions. With caution in case of severe diseases of the cardiovascular system, gastrointestinal tract (peptic ulcer disease), liver. Not recommended for women in the Ist trimester of pregnancy.

Dosage forms. Tablets of 0.025 and 0.05 g.

Loratadine (Claritin).

Pharmacodynamics. It is a long-acting drug. The duration of action is up to 24 hours. No pronounced sedation.

Pharmacokinetics. It is rapidly and completely absorbed. Cmax – 1.3-2.5 hour. T1/2 – 8 h. It does not get through the blood-brain barrier. It undergoes biotransformation in the liver to form the active metabolite – desloratadine, T1 / 2 of which is about 28 hours.

Dosing regimen. Tablets – 0.01 g x 1 time / day.

Side effects. Rarely – dry mouth, nausea, vomiting, increased appetite, sweating, arthralgia, myalgia, hyperkinesis.

Dosage form. Tablets of 0.01 grams and 0.1% syrup and suspension for oral administration. Desloratadine is a component of the drug Aerius.

Cetirizine (Zyrtec).

Pharmacodynamics. Long-acting drug.

Pharmacokinetics. It is rapidly and completely absorbed. Cmax is 1 h. T1 / 2 - 7-10 h. In case of renal dysfunction – 20 hours.

Dosing regimen. In tablets – 0.01 g x 1 time / day or 0.05 g x 2 times / day.

Side effects. Dry mouth, drowsiness, headache, dizziness, dyspepsia.

Dosage form. Tablets of 0.01 g, 1% solution for oral administration.

Immunogenesis suppressing drugs

They mainly inhibit cell-mediated immunity. The immunosuppressants include glucocorticoids, cyclosporin, tacrolimus, cytotoxic drugs.

Glucocorticoids exert an immunosuppressive effect suppressing the lymphocyte proliferation phase (especially T-lymphocytes). The antigen recognition is also inhibited. The production and action of interleukins and interferon ɣ- are reduced. They decrease the cytotoxicity of T-lymphocytes (killers). The formation of macrophage migration factor is inhibited. They have expressed anti-inflammatory activity. Glucocorticoids do not have an impact on the synthesis of specific antibodies and the formation of antigen-antibody complexes.

Cyclosporine (Sandimmune) – a peptide antibiotic. It inhibits an early stage of antigen-induced differentiation of T-lymphocytes and blocks their activation. It inhibits T-helper cells, reduces the production of interleukins (IL-2) and ɣ- interferon. The difference between Cyclosporine and cytotoxic drugs is in small blood inhibition. It is nephrotoxic and can interfere with liver function. It is used in case of organ and tissue transplants, can be also used in autoimmune diseases. Oral and IV administration.

Tacrolimus (FK-506, Prograf) refers to macrolide antibiotics. It inhibits activation of T-lymphocytes and IL-2 production. It is 100 times more active than cyclosporine. Used in organ transplantation. Administered enterally and IV. It is characterized by nephrotoxicity, neurotoxicity; it causes hypertension, dyspepsia, hyperglycemia and other side effects.

Alkylating drugs – cyclophosphan; antimetabolites – Azathioprine, methotrexate, merkaptourin, some antibiotics – actinomycin C. The immunosuppressive effect of cytotoxic drugs is associated with the influence on the division of immune cells and the suppression of the proliferative phase of the immune response.

Drugs that reduce tissue damage

     In allergic inflammation foci of aseptic inflammation are developing in tissues. The anti-inflammatory drugs of steroid and non-steroid nature are effective against these foci: glucocorticoids, NSAIDs.