Cetirizine in pediatric practice
In the development of allergic reactions, mediators of various chemical structures play a significant role - biogenic amines (histamine, serotonin), leukotrienes, prostaglandins, kinins, chemotactic factors, etc. In recent years, new drugs with antimediator effects - leukotriene receptor antagonists - have been synthesized and introduced into clinical practice , 5-lipoxygenase inhibitors, antichemotactic agents. However, the main chemical mediator of allergic inflammation is histamine, so histamine type 1 receptor (H1R) blockers play an important role in the control of atopy [2]. Antihistamines were one of the first medications for the treatment of allergies; their effectiveness has long been well studied, although attitudes towards them have changed, as well as their place in therapy and rehabilitation programs [3]. The first drugs of this group, available for use in clinical practice, were developed back in the 40s of the last century; since that time, H1R blockers have become traditional in the treatment of atopic diseases [4]. Currently, the doctor has many H1R antagonists with different properties in his arsenal. First generation antihistamines (diphenhydramine, chloropyramine, clemastine, promethazine, mebhydrolin, dimethindene, cyproheptadine, etc.) are competitive H1R blockers; their binding to the receptor occurs quickly and is reversible. Therefore, to achieve the main pharmacological effect, high doses are required, which leads to an increase in the incidence of side effects. The short duration of action of these drugs requires their repeated use throughout the day. First generation antihistamines in therapeutic doses have a blocking effect on other receptors (cholinergic receptors, adrenergic receptors), which explains the unwanted side effects associated with their use, in particular the negative effect on the cardiovascular system, vision, urinary system, gastrointestinal tract, central nervous system [5]. First-generation H1R antagonists impair cognitive function, negatively affect learning, disrupt sleep, are cardiotoxic, and pose a risk of potentially fatal overdose [6]. High incidence of adverse reactions (drowsiness, dizziness, headache, impaired coordination of movements and concentration, decreased blood pressure, increased heart rate, stomach pain, constipation, nausea, vomiting, difficulty urinating, decreased visual acuity, increased body weight), formation tachyphylaxis and the need for dosing several times a day significantly limit the use of 1st generation antihistamines in pediatric practice [7,8]. 2nd generation H1R antagonists (acrivastine, astemizole, azelastine, cetirizine, ebastine, loratadine, etc.) selectively inhibit histamine receptors, inhibit the early and late phases of the allergic reaction, and combine antihistamine, antiallergic and anti-inflammatory activity [9,10]. They do not penetrate the blood-brain barrier, do not have a sedative effect and have a higher safety profile. The drugs have a rapid onset of action, a long-lasting therapeutic effect, have a longer half-life, and are prescribed once a day. They do not cause the development of tachyphylaxis; with long-term use, their therapeutic activity does not decrease, and therefore there is no need to change the drug [11]. It is suggested that they may be beneficial and improve the quality of life of patients with asthma and concomitant allergic rhinitis, although further research is needed [12]. A special place among 2nd generation antihistamines is occupied by cetirizine hydrochloride (Zyrtec®), synthesized in 1987. It is a metabolite of hydroxyzine, a representative of the first generation of piperazine antihistamines. Three important indicators characterize Zyrtec®: high specificity for H1R, low level of metabolism and the existence of an effect independent of H1R blockade on cells involved in the immune response. This substance binds to a small extent to serotonin, dopamine and α-adrenergic receptors. Cetirizine (Zyrtec®) is considered the standard antihistamine and antiallergic drug, since it has the ability to inhibit the release of histamine from mast cells and basophils, inhibit the activation of eosinophils and epithelial cells of the airways, suppressing the expression of intercellular adhesion molecules (ICAM-1), slow down platelet aggregation and the release of leukotrienes various types of cells under the influence of allergenic and non-allergenic stimuli. The effect of reducing leukotriene levels when using cetirizine is due to a decrease in the movement of leukotriene-producing cells (eosinophils, basophils and macrophages) to the site of the allergic response. Cetirizine penetrates the blood-brain barrier to a small extent and does not have a pronounced sedative effect. The drug is characterized by renal elimination: 70% is excreted unchanged in the urine within 72 hours. The half-life is 10 hours in adults and 7 hours in children. Cetirizine does not inhibit the cytochrome P450 CYR3A4-mixed function oxygenase system, which reduces its metabolic conversion in the liver. Characterized by a low volume of distribution (0.56 l/kg) and high ability to penetrate the skin. After a single use, the effect of the drug appears within 20 minutes. in half of the patients, after 24 hours the concentration of cetirizine in the skin is equal to or even slightly higher than the concentration in the blood. With a course of up to 8 weeks. a constant level in the blood is achieved within 3 days; subsequently, the drug does not accumulate and the rate of elimination does not change. Currently, out of 40 H1R blockers, the pharmacokinetics of only 11 have been described in children [13], with especially few studies in young children. Zyrtec® is one of the most studied drugs in young patients, including infants, so its use is possible from 6 months of age. As part of the ETAC™ (Early Treatment of the Atopic Child) study on a large group of children (343 children aged 14–46 months, weighing 8.2–20.5 kg), it was shown that the pharmacokinetics of cetirizine are not affected by eosinophilia, sensitization to allergens, AD, gastroenteritis and diarrhea, taking other medications. The drug has no toxic effects and is safe when used in children. Valid for 24 hours, this allows cetirizine to be prescribed once a day. in children over 2–6 years old, which is very convenient, especially at an outpatient appointment. Cetirizine has some properties that are unique to other antihistamines. A steroid-sparing effect has been described for it: with the simultaneous administration of cetirizine and inhaled corticosteroids in patients with bronchial asthma, the dose of corticosteroids may be reduced or not increased, despite contact with the allergen. Cetirizine, in addition to blocking H1R, suppresses the skin response to platelet-activating factor, which gives it advantages over other drugs for skin manifestations of allergies [15,16]. This has been confirmed in numerous clinical comparative studies: the ability to accumulate in the skin allows the drug to relieve itching and hyperemia more effectively than drugs such as ebastine, epinastine, terfenadine, fexofenadine and loratadine [17–19]. Cetirizine is traditionally used in the treatment of urticaria [17,20]; Recent studies have shown that double the dose of cetirizine may be effective in patients with urticaria refractory to the usual dose [21]. In most cases, urticaria associated with the use of non-steroidal anti-inflammatory drugs can be prevented by cetirizine, which opens new possibilities for the treatment of pain and rheumatic disorders [22]. Cetirizine (Zyrtec®) is the only antihistamine with a proven ability to prevent the formation of AD, which was shown in a large, long-term, prospective, randomized, double-blind, placebo-controlled study, ETAC™. [23]. It involved more than 800 children from 13 countries (56 clinical sites) aged 1 to 2 years who had symptoms of atopic dermatitis, which within 18 months. took the drug for the next 18 months. were under observation. Placebo or Zyrtec® (10 mg/ml) at a dose of 0.25 mg per 1 kg of child’s body weight was prescribed 2 times a day. as an oral solution. The results of this study made it possible to clarify the place of the drug in the treatment and prevention of AD. First, good control of allergic skin lesions has been shown. In particular, according to the SCORAD index, the severity of atopic dermatitis decreased after 18 months. in both groups (p<0.001). But children receiving placebo were more likely to require additional use of other antihistamines (24.9% vs. 18.6%, p=0.03). In the subgroup of patients with a SCORAD index value≥25, the corticosteroid-sparing effect was statistically significant (in the placebo group 35.1 versus 25.8 in the Zyrtec® group; p=0.014). Taking the drug had a preventive effect on urticaria - the number of children who developed it during the study was significantly lower in the main group (in the placebo group - 16.2%, in the Zyrtec® drug group - 5.8%; p<0.001) [24]. The preventive effect against bronchial asthma was expressed in the fact that treatment with cetirizine, started in the first and second years of life in patients with atopic dermatitis who had hypersensitivity to inhaled allergens, significantly reduced the number of cases of subsequent bronchial asthma - by 50% in those sensitized to grass pollen and by 40% in those sensitized to house dust. 18-month follow-up results. showed that in children receiving cetirizine, the reduction in the risk of developing bronchial asthma was maintained. Thus, the use of cetirizine prevents or delays the development of bronchial asthma in every second child from a high-risk group (with atopic dermatitis, family history and sensitization to pollen and house dust mites) [25]. The drug occupies an important place in the treatment of allergic rhinitis, including in young children [26]. The administration of Zyrtec® for seasonal allergic rhinitis in children aged 2–6 years helped to reduce clinical symptoms and restore nasal patency. When using the drug Zyrtec® for the treatment of seasonal allergic rhinoconjunctivitis in children aged 6 to 12 years, a reverse development of symptoms of rhinitis and conjunctivitis was observed. For allergic rhinitis, cetirizine has a more effective effect compared to other antihistamines. A randomized, double-blind comparative study assessed the duration of the effect of cetirizine (10 mg once a day) and fexofenadine (180 mg once a day) after exposure to ragweed pollen in patients with seasonal allergic rhinitis [27]. The drugs demonstrated similar speed of onset of action and control of rhinitis symptoms within 5 hours after the first dose compared to placebo. However, after 21–24 hours, the effectiveness of cetirizine was 33% higher, as well as after 40 minutes. after the second dose, compared with fexofenadine. The advisability of taking cetirizine for acute allergic reactions to food has been proven. It begins to relieve symptoms as quickly and effectively as diphenhydramine, but has a longer duration of action [28]. The drug, compared to other new antihistamines, begins to work faster in other types of acute allergic reactions, including anaphylactic ones [20]. The use of drugs in young children always requires careful study of their safety and impact on cognitive activity. In adult patients, it has been shown that Zyrtec may influence the speed of information processes in the central nervous system, but these effects are not significant for the occurrence of cognitive deficits [29]. The effect of long-term use of the drug Zyrtec® in a high dose (0.25 mg/kg 2 times/day for 18 months) on behavior and cognitive abilities was assessed in the already mentioned ETAC™ study, which used well-validated and standardized behavioral questionnaires (Behavior Screening Questionnaire) and cognitive activity (McCarthy Scales of Children's Abilities), the age of acquisition of psychomotor skills was recorded. Analysis of the results did not reveal significant differences in behavior and cognitive performance between children receiving placebo and Zyrtec® during treatment and during follow-up, which confirms the absence of adverse effects on behavior and learning processes associated with prolonged use of Zyrtec® in young children age with atopic dermatitis [30]. There were no clinically significant differences in the neurological status or state of the cardiovascular system between the groups of children receiving Zyrtec® and placebo; In patients taking Zyrtec®, not a single case of prolongation of the QT interval was identified. Concomitant use of Zirtec® with macrolides did not affect the QT interval and the level of liver enzyme activity. The possibility of using cetirizine was studied in pregnant women in the first trimester of pregnancy: in a prospective observational cohort study, compared with the control group, the drug did not increase the number of congenital malformations (OR 1.07; CI 0.21–3.59), the frequency of spontaneous abortions ( OR 0.97; CI 0.54 – 1.65), preterm birth (OR 0.76; CI 0.35–1.5), and the weight of newborns did not differ (p = 0.13), which allows us to consider the drug the drug is relatively safe in the first trimester of pregnancy [31]. Cetirizine (Zyrtec®) is included in the list of vital and essential drugs [32] and is approved by the FDA [33]. The original drug cetirizine hydrochloride - Zyrtec® (UCB Pharma) has a release form convenient for use in children - drops for oral administration. Prescribed to children aged 6 to 12 months. 5 drops 1 time/day, from 1 year to 2 years – 5 drops 2 times/day, from 2 to 6 years – 5 drops 2 times/day. or 10 drops 1 time/day. Children over 6 years old – 20 drops or 1 tablet (10 mg) 1 time/day. Thus, Zyrtec® is indicated for allergic rhinitis, allergic conjunctivitis, urticaria, Quincke's edema and dermatoses manifested by itching and rashes. The possibility of long-term use allows us to recommend the drug for the secondary prevention of AD in case of combined pathology. The high effectiveness and safety of cetirizine (Zyrtec®), confirmed by scientific research, allows its widespread use in pediatric practice, including in young patients at increased risk of developing bronchial asthma. Literature 1. Balabolkin I.I. Current problems of childhood allergology at the present stage // Pediatrics. – 2012. – T. 91, No. 3. – P. 69–75. 2. Kondurina E.G., Zelenskaya V.V. Antihistamines in the control of atopic diseases in children // Breast Cancer. – 2012. – T. 20, No. 2. – P. 56–57. 3. Gushchin I.S. Prospects for improving the antiallergic action of H1-antihistamines // Attending physician. – 2009. – No. 5. 4. Emelyanov A.V., Kochergin N.G., Goryachkina L.A. History and modern approaches to the clinical use of antihistamines // Clinical dermatology and venereology. – 2010. – No. 4. – P. 62–70. 5. Tuzlukova E.B., Ilyina N.I., Luss L.V. Antihistamines // Russian Medical Journal. – 2002. – T. 10, No. 5. – P. 269–272. 6. Church M., Maurer M., Simons F. et al. Risk of first-generation H1-antihistamines: a GA2LEN position paper // Allergy. 2010. No. 65. R. 459–466. 7. Goryachkina L.A. Modern antihistamines in the treatment of allergic diseases // Russian Medical Journal. – 2001. – T. 9, No. 21. – P. 945–950. 8. Korovina N.A., Cheburkin A.V., Zakharova I.N. and others. Antihistamines in the practice of a pediatrician (a guide for doctors). – M., 2001. – 48 p. 9. Geppe N.A., Snegotskaya M.N., Kolosova N.G., Bykhovets E.A. Modern antihistamines and acaricidal drugs in the fight against allergic diseases // Terra Medica. – 2004. – No. 4. – P. 18–24. 10. Revyakina V. A. Antihistamines in clinical practice. Discussion questions. A doctor’s view of common medications // Attending physician. – 2010. – No. 7. 11. Malakhov A.B., Volkov I.K., Malakhova-Kapanadze M.A. Antihistamines and their place in the treatment of allergic diseases // Handbook of a polyclinic doctor. – 2007. – T. 5, No. 1. – P. 23–28. 12. Bachert C., Maspero J. Efficacy of second–generation antihistamines in patients with allergic rhinitis and comorbid asthma // J. Asthma. 2011. Vol. 48(9). P. 965–973. 13. Simons FE ETAC Study Group. Population pharmacokinetics of levocetirizine in very young children: the pediatricians' perspective // Pediatr.Allergy Immunol. 2005. Vol. 16(2). P. 97–103. 14. Hussein Z., Pitsiu M., Majid O. et al. ETAC Study Group. Retrospective population pharmacokinetics of levocetirizine in atopic children receiving cetirizine: the ETAC study // Br. J. Clin. Pharmacol. 2005. Vol. 59(1). P. 28–37. 15. Smirnova G.I. Antihistamines in the treatment of allergic diseases in children. – M., 2004. – 64 p. 16. Gushchin I.S. Cetirizine is a standard H1-antihistamine // www.health-medix.com. - 2009. - No. 5 (61). - S. 60–70. 17. Belsito D. Second - Generation Antihistamines for the Treatment of Chronic Idiopathic Urticaria // J. Drugs Dermatol. 2010. Vol. 9, is. 5. P. 503–512. 18. Grant J., RietHuisen J., Moulart B., Devos Ca Double - Blind, Randomized, Single - Dose, Crossover Comparison of Levocetirizine with Ebastine, Fexofenadine, Loratadadine, Miz STINE, and PLACEBO: Suppression of Histamine - Induced Wheal - And –Flare Response During 24 Hours in Healthy Male Subjects // Annals of Allergy, Asthma, & Immunology. 2002. Vol. 88. P. 190–197. 19. Kavosh E., Khan D. Second - Generation H1 - Antihistamines in Chronic Urticaria. An evidence - bassed Review // Am. J. Clin. Dermatol. 2011. Vol. 12 (6). P. 361–376. 20. Banerji A., Long A., Camargo Jr.C. Diphenhydramine Versus NonSedating Antihistamines for Acute Allergic Reactions: A Literature Review // Allergy and Asthma Procededings. 2007. Vol. 28, No. 4. P. 418–426. 21. Okubo Y., Shigoka Y., Yamazaki M., Tsuboi R. Double Dose of Cetirizine Hydrochloride Is Effective for Pathicaria Resistant: A Proospective, RandomIstive , non - blanded, Comparative Clinical Study and Assessment of Quality of Life // J. Dermatolog. Treat. 2011. Vol. 24. 22. Asero R. Cetirizine Premedic Prevents Acute Urticaria Induction by Weak Cox -1 Inhibitors in Multiple Nsaid Reactors // EUR. Ann. Allergy Clin. Immunol. 2010. Vol. 42 (5). P. 174–177. 23. Simons F. Prospective, Long - Term Safety EvalUtion of the H1 - RECEPTOR ANTAGONIST CETIRIZINE in VERY YOUNG Children with Atopic Dermatitis. ETAC Study Group. Early Treatment of the Atopic Child // J. Allergy Clin. Immunol. 1999. Vol. 104 (2 pt 1). P. 433–440. 24. Diepgen Tl Early Treatment of the Atopic Child Study Group. Long - Terment with Cetirizine of infants with atopic dermatitis: a multi - coutry, double - bland, randomized, Placebo - Controlled trial (The etac trial) Diatr. Allergy Immunol. 2002. Vol. 13(4). P. 278–286. 25. Girina A.A., Plandelikov A.L. "Atopic march" and antihistamines: Is preventive therapy possible? // RMG. - 2012. - No. 2. - S. 72–75. 26. Phan H., Moeller M., Nahata M. Treatment of allergic rhinitis in infants and children. Efficacy and Safety of Second - Generation Antihistamines and the Leukotriene Receptor Antagonist Montelukast // Drugs. 2009. Vol. 69 (18). P. 2541–2576. 27. Day J., Briscoe M., Rafeiro E. et al. RANDOMIZED DOBLE - BLIND COMPARISON of Cetirizine and Fexofenadine after Pollen Challenge in the Environment Exposure Unit: Duration of Effect in Subjects hinitis // Allergy Asthma Proc. 2004. Vol. 25 (1). P. 59–68. 28. Park J., Godbold J., Chung D. et al. Comparison of Cetirizine to Diphenhydramine in the Treatment of Accute Food Allergic Reactions // J. Allergy Clin. Immunol. 2011. Vol. 128 (5). P. 1127–1128. 29. Van Ruitenbeek P., Vermeeren A., Riedel Wj Histamine H1 Receptor Antagonist Cetirizine Impairs Working Memory Processing Speed, But Not Episodic Memory // Br. J. Pharmacol. 2010. Vol. 161 (2). P. 456–466. 30. Stevenson J., Cornah D., Evrard P. et al. ETAC Study Group. Long - Term EvalUtion of the Impact of the H1 - RECEPTOR ANTAGONIST CETIRIZINE On the Behavior, Cognitive, and Psychomotor Development of Very Young Children with Atopic Dermatitite IS // Pediatr. Res. 2002. Vol. 52 (2). P. 251–257. 31. Weber - Schoendorfer C., Schaefer C. The Safety of Cetirizine During Pregnancy. A Prospective Observational Cohort Study // Reprod. Toxicol. 2008. Vol. 26. P. 19–23. 32. The state register of drugs. - 2012. - Moscow: MZ and SR RF (Internet version www.drugreg.ru). 33. FDA Approvs Zyrtec for nonprescription use in adults and children - November 21, 2007.
