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PHARMACY UPDATE Antihistamine use in children

Downloaded from on June 9, 2015 - Published by PHARMACY UPDATE . Antihistamine use in children Roisin Fitzsimons,1,2 Lauri-Ann van der Poel,1 William Thornhill,3. George du Toit,1,2 Neil Shah,4,5 Helen A Brough1,2. AR in In the UK, the Phase 3. 1. children 's Allergy Service, Guy's ABSTRACT. and St. Thomas' NHS. This review provides an overview of the use of (2002 2003) ISAAC study found a Foundation Trust, London, UK. 2. Department of Asthma, Allergy antihistamines in children . We discuss types of prevalence of AR symptoms and and Respiratory Science, King's histamine receptors and their mechanism of 16% eczema symptoms in 6-year-old to College London, London, UK. 3. action, absorption, onset and duration of action 7-year-old Hospital admissions Evelina children 's PHARMACY , of first-generation and second-generation for food allergic reactions in the UK have Guy's and St. Thomas' NHS. Foundation Trust, London, UK H(1)-antihistamines, as well as elimination of increased by 500% between 1990 and 4.

Table 1 Summary of the more commonly used H(1)-antihistamines licensed for use in children First-generation H(1)-antihistamines The most common adverse effect of the first-generation H(1)-antihistamines is central nervous system depression, with effects varying from …

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1 Downloaded from on June 9, 2015 - Published by PHARMACY UPDATE . Antihistamine use in children Roisin Fitzsimons,1,2 Lauri-Ann van der Poel,1 William Thornhill,3. George du Toit,1,2 Neil Shah,4,5 Helen A Brough1,2. AR in In the UK, the Phase 3. 1. children 's Allergy Service, Guy's ABSTRACT. and St. Thomas' NHS. This review provides an overview of the use of (2002 2003) ISAAC study found a Foundation Trust, London, UK. 2. Department of Asthma, Allergy antihistamines in children . We discuss types of prevalence of AR symptoms and and Respiratory Science, King's histamine receptors and their mechanism of 16% eczema symptoms in 6-year-old to College London, London, UK. 3. action, absorption, onset and duration of action 7-year-old Hospital admissions Evelina children 's PHARMACY , of first-generation and second-generation for food allergic reactions in the UK have Guy's and St. Thomas' NHS. Foundation Trust, London, UK H(1)-antihistamines, as well as elimination of increased by 500% between 1990 and 4.

2 Department of H(1)-antihistamines which has important In the last decade, the body of Gastroenterology, Great Ormond implications for dosing in children . The rationale knowledge of the safety and efficacy of H. Street Hospital, London, UK. 5. TARGID, Catholic University of for the use of H(1)-antihistamines is explored for (1)-antihistamines has increased substan- Leuven, Leuven, The Netherlands the relief of histamine-mediated symptoms in a 6. variety of allergic conditions including: non- Correspondence to anaphylactic allergic reactions, atopic eczema Dr Helen A Brough, HISTAMINE AND THE ALLERGIC. children 's Allergy Service, Guy's (AE), allergic rhinitis (AR) and conjunctivitis, RESPONSE. and St Thomas' NHS Foundation chronic spontaneous urticaria (CSU) and whether Trust, 2nd Floor, Stairwell B, Histamine is a fundamental mediator in they have a role in the management of South Wing, Westminster Bridge the pathophysiology of allergic condition intermittent and chronic cough, anaphylaxis, Road, London SE1 7EH, UK; in the smooth muscle, mucosa and skin food protein-induced gastrointestinal allergy and (figure 1).

3 On allergen exposure, an asthma prevention. Second-generation H(1)- RF and L-AvdP have contributed antigen cross-links specific immunoglobin antihistamines are preferable to first-generation equally. E (IgE) bound to the surface of mast cells H(1)-antihistamines in the management of non- and basophils and leads to degranulation Received 28 February 2014 anaphylactic allergic reactions, AR, AE and CSU. with release of histamine and other pro- Revised 17 July 2014 due to: their better safety profile, including Accepted 28 July 2014 inflammatory mediators. Once released, minimal cognitive and antimuscarinic side effects Published Online First histamine binds to G-protein-coupled 21 August 2014 and a longer duration of action. We offer some receptors on a wide variety of cells within guidance as to the choices of H(1)-antihistamines the surrounding tissues and vasculature. available currently and their use in specific clinical settings. H(1)- Antihistamine class, availability, licensing, age and dosing TYPES OF HISTAMINE RECEPTORS.

4 Administration, recommended indications in Four types of histamine receptors have allergic conditions and modalities of delivery for been identified, which have varying the 12 more commonly used H(1)-antihistamines degrees of responsibility for mediating an in children are also tabulated. allergic 6 H1 and H2 recep- tors are present on a wide range of cells (endothelial, epithelial, smooth muscle, INTRODUCTION neurons and cells of the innate and H(1)-antihistamines are among the most acquired immune system) and when in an commonly prescribed medicines in chil- active state, stimulate both the early Indications include acute allergic phase of an allergic response (vasodilata- reactions in food allergy, allergic rhinitis tion leading to erythema, swelling and (AR) and chronic spontaneous urticaria hypotension) and the late-phase response, (CSU); they are also used for relief of by upregulating cytokine production and histamine-mediated symptoms, but are cell-adhesion molecules, leading to a not the drug of first choice, in the proinflammatory 5 H(2)-receptor context of atopic eczema (AE) and ana- antagonists, such as ranitidine, work pri- To cite: Fitzsimons R, van der phylaxis.

5 The International Study for marily on gastric mucosa, inhibiting Poel L-A, Thornhill W, et al. Asthma and Allergies in Childhood gastric secretion. H3 and H4 receptors Arch Dis Child Educ Pract Ed (ISAAC) has shown a world-wide trend are less widely expressed but are inducers 2015;100:122 131. for increasing symptoms of eczema and of pruritus and proinflammatory immune 122 Fitzsimons R, et al. Arch Dis Child Educ Pract Ed 2015;100:122 131. Downloaded from on June 9, 2015 - Published by PHARMACY UPDATE Figure 1 Effects of histamine in allergic disease. 5 The therapeutic potential of targeting with 30% cetirizine and a negligible amount for fexo- these new histamine receptors is yet to be fully fenadine using positron emission tomography. These older H(1)-antihistamines may therefore be used for nausea ( promethazine), migraine ( pizotifen) and as Antihistamine DRUGS AND MECHANISM OF preoperative medication, but the multiple receptor ACTION binding also means potential for related adverse effects Nobel Prize winner Daniel Bovet, a Swiss-born Italian (table 1).

6 Pharmacologist, is best known for his synthesis and In the 1980s, new H(1)-antihistamines were devel- testing of antihistamines in 1937. Antihistamines were oped to be minimally sedating or non-sedating, with once considered histamine receptor antagonists; limited blood-brain barrier penetration by addition of however, they have been reclassified as inverse ago- a carboxylic moiety with a protonated amine, redu- nists that have an affinity for G-protein-coupled hista- cing the drug's blood-brain barrier penetration cap- mine receptors, to which they bind, returning acity and increasing H(1) Consensus on equilibrium to the cell and reducing the effects of an the use of these second-generation allergic 5 H(1)-antihistamines, thereby, H(1)-antihistamines was published in Some inhibit respiratory, vascular and gastrointestinal texts refer to the active metabolites derived from smooth muscle constriction and decrease second-H(1)-generation antihistamines as third- histamine-activated salivary and lacrimal gland generation' H(1)-antihistamines (desloratadine, levoce- secretions.)

7 Tirizine and fexofenadine), but they are more com- H(1)-antihistamines are generally categorised as old monly classified under the second-generation or first-generation or new, second-generation H(1)- H(1)- Antihistamine category. antihistamines. The first generation of H(1)-antihistamines have poor receptor selectivity for PHARMACOKINETICS AND. the H(1)-receptor, occupying muscarinic cholinergic, PHARMACODYNAMICS OF H(1)-ANTIHISTAMINES. -adrenergic, serotonin receptors and ion 8 Absorption Additionally, first-generation H(1)-antihistamines are Despite the longevity of their use, little is known lipophilic, facilitating crossing of the blood-brain about the pharmacokinetics and pharmacodynamics barrier into the central nervous 8 Studies of first-generation H(1)-antihistamines in young chil- looking at the binding to H(1)-receptors in the brain in dren and infants. Second-generation H. adults have shown between 50% and 90% occupancy (1)-antihistamines have been studied more extensively by first-generation H(1)-antihistamines,9 compared in older children and adults, and in the case of Fitzsimons R, et al.

8 Arch Dis Child Educ Pract Ed 2015;100:122 131. 123. Table 1 Summary of the more commonly used H(1)-antihistamines licensed for use in children 124. PHARMACY UPDATE The most common adverse effect of the first-generation H(1)-antihistamines is central nervous system depression, with effects varying from slight drowsiness to deep sleep. Paradoxical stimulation may occasionally occur, especially at high doses. These sedative effects, when they occur, may diminish after a few days of treatment. Other first-generation H(1)- Antihistamine side effects include headache, psychomotor impairment and anti-muscarinic effects, such as dry mouth, thickened respiratory-tract secretions, blurred vision, urinary difficulty or retention, constipation and increased gastro-oesophageal reflux. First-generation Other rare side effects of first-generation H(1)-antihistamines include hypotension, palpitation, arrhythmias, extrapyramidal effects, dizziness, confusion, depression, sleep disturbances, H(1)-antihistamines tremour, convulsions, hypersensitivity reactions (including bronchospasm, angio-oedema, anaphylaxis, rashes, and photosensitivity reactions), blood disorders and liver dysfunction.

9 Proprietary forms Availability Licensed indication Licensing age children 's dose1 (oral doses). Downloaded from on June 9, 2015 - Published by Chlorphenamine Non-proprietary P Symptomatic relief of allergy such as hay fever, urticaria, food allergy, Liquid 1 month 2 years 1 mg twice daily (Chlorpheniramine) Piriton GSL drug reactions, relief of itch associated with chickenpox 1 18 years 2 6 years 1 mg every 4 6 h, max. 6 mg daily Allerief Tabs 6 12 years 2 mg every 4 6 h, max. 12 mg daily 6 18 years 12 18 years 4 mg every 4 6 h, max. 24 mg daily Hydroxyzine Atarax POM Pruritus 1 18 years 6 months 6 years initially 5 15 mg at night, increased if Ucerax necessary to 50 mg daily in 3 4 divided doses 6 12 years initially 15 25 mg at night, increased if necessary to 50 100 mg daily in 3 4 divided doses Fitzsimons R, et al. Arch Dis Child Educ Pract Ed 2015;100:122 131. 12 18 years initially 25 mg at night, increased if necessary to 100 mg in 3 4 divided doses Ketotifen Zaditen POM Symptomatic relief of allergy, such as allergic rhinitis (AR) 3 18 years 3 18 years 1 mg twice daily eye drops POM eye drops seasonal allergic conjunctivitis 3 18 years 3 18 years apply twice daily Zaditen Promethazine hydrochloride Non-proprietary POM Symptomatic relief of allergy, such as hay fever, insomnia associated with 2 18 years 2 5 years 5 mg twice daily or 5 15 mg at night Phenergan urticaria and pruritus 5 10 years 5 10 mg twice daily or 10 25 mg at night 10 18 years 10 20 mg 2 3 times daily or 25 mg at night increased to 25 mg twice daily if necessary Second-generation Generally, the second-generation H(1)-antihistamines have little or no side effect of drowsiness or antimuscarinic effect.

10 H(1)-antihistamines Cetirizine Non-proprietary GSL Hay fever, chronic idiopathic urticaria, atopic eczema 2 18 years 1 2 years 250 mg/kg twice daily Piriteze P 2 6 years mg twice daily Benadryl for POM 6 12 years 5 mg twice daily children 12 18 years 10 mg once daily Loratadine Non-proprietary GSL Symptomatic relief of allergy, such as hay fever, chronic idiopathic 2 18 years 2 12 years Loratadine P urticaria under 30 kg 5 mg once daily Allereze, Clarityn POM over 30 kg 10 mg once daily 12 18 years 10 mg once daily Fexofenadine Non-proprietary POM Symptomatic relief of seasonal AR 6 18 years 6 12 years 30 mg twice daily Telfast symptomatic relief of chronic idiopathic urticaria 12 18 years 120 mg once daily 12 18 years 180 mg once daily Continued Fitzsimons R, et al. Arch Dis Child Educ Pract Ed 2015;100:122 131. Table 1 Continued Downloaded from on June 9, 2015 - Published by Proprietary forms Availability Licensed indication Licensing age children 's dose1 (oral doses).


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