Antihistamines in Children: A Dermatological Perspective : Indian Journal of Paediatric Dermatology

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Review Article

Antihistamines in Children

A Dermatological Perspective

Kohli, Sakshi; Tayal, Richa; Goyal, Tarang

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Indian Journal of Paediatric Dermatology: Jan–Mar 2022 - Volume 23 - Issue 1 - p 8-23
doi: 10.4103/ijpd.ijpd_124_21
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Abstract

Introduction

Antihistamines are one of the most commonly used drugs in pediatric dermatology. They are primarily used in children in conditions such as urticaria, angioedema, anaphylaxis, atopic dermatitis (AD), insect bite reactions, and other cutaneous and systemic disorders associated with pruritus. Pediatric population encompasses a wide age group ranging from neonates, infants, toddlers to adolescents.[1] Hence, pediatric drug therapy must be based on specific parameters of that age group and not a blanket approach as there might be different pharmacokinetics at different ages for the same drug.[2]

First-generation antihistamines are still widely used in pediatric population despite numerous adverse effects and lack of adequate data on the efficacy and safety of these drugs in children. This can be attributed to the following facts:

  • Physicians assume them to be safe since they have been in use since decades
  • Pediatric formulations including syrups and drops are easily available over the counter.

The data on efficacy and safety of second-generation antihistamines, however, are well documented in pediatric population which encourages their routine use in the management of pediatric dermatoses.[3]

This article summarizes the pharmacological characteristics and clinical data on efficacy and safety of commonly used antihistamines in pediatric population. Recent updates on novel uses of antihistamines are also discussed.

Method of Acquiring Data

An extensive literature search was done using words such as “antihistamines,” “first-generation H1 antihistamines,” “second-generation H1 antihistamines,” “third-generation antihistamines,” “pediatric,” “children” “urticarial,” “atopic dermatitis,” “mastocytosis,” “hydroxyzine,” “cyproheptadine,” “chlorpheniramine,” “promethazine,” “diphenhydramine,” “ketotifen,” “cetirizine,” “levocetirizine,” “loratadine,” “desloratadine,” “fexofenadine,” “bilastine,” “ebastine,” “rupatadine,” “mizolastine.” All clinical trials, randomized double-blinded or single-blinded controlled trials, open-label studies, retrospective studies, reviews, case series, and case reports concerned with the use of antihistamines in pediatric population were screened. The articles which did not have relevant information were excluded. The selected articles were retrieved; the final manuscript was prepared, analyzed, and presented in a narrative fashion.

Histamine and its Receptors

Histamine is an endogenous biogenic amine formed by the decarboxylation of the amino acid histidine by the enzyme histidine decarboxylase.[4]

By its action on H1 receptors, histamine acts as a potent vasoactive agent, bronchial smooth muscle constrictor, stimulant of nociceptive itch nerves and promotes allergic immune response.[56] It regulates the gastric acid secretion through H2 receptors and plays an important role in neurotransmission and immunomodulation by activation of H3 and H4 receptors, respectively.

Antihistamines

Antihistamines act as an inverse agonist that binds to the same receptor binding site as histamine and not only antagonize the effects of histamine but also exert the opposite effect by suppressing spontaneous receptor signaling.[7]

Classification

Conventionally, H1 antihistamines have been classified into 6 chemical groups [Table 1].[8] However, the functional classification is more clinically relevant in today's scenario [Table 2].[9] Functionally, the H1 antihistamines are classified into first-generation (sedating) and second-generation (relatively nonsedating) drugs.

T1-3
Table 1:
Chemical classification of H1 antihistamines
T2-3
Table 2:
Functional classification of H1 antihistamines

A comparative account of the major differences between the properties of first and second-generation antihistamines is presented in Table 3.

T3-3
Table 3:
A comparative account of major differences between first-generation and second-generation antihistamines

Some authors have also proposed a new category of third-generation antihistamines with additional properties and less adverse effects, however, till date, there is no consensus with regard to the drugs included in this category.[17]

First-Generation Antihistamines

  • Most of the data for the use of first-generation antihistamines in children has been derived by extrapolation of data in adolescent/adult population assuming that efficacy results in adolescents/adults are also valid in children. However, as immune reaction in under 2 years of age is considered to be different than adults, specific efficacy studies are required targeting the pediatric population[18]
  • First-generation antihistamines can significantly influence a child's quality of life and school performance[19] by inducing sedation and cognitive impairment when taken during the day and poor sleep when taken during night[1320]
  • Physicians should also be watchful for anticholinergic side effects[21] of first-generation antihistamines such as
    • Dry mouth
    • Urinary retention
    • Constipation
    • Visual disturbances (mydriasis, photophobia)
    • Tachycardia
    • Drowsiness, confusion, and agitation (high-dose administration).
  • Despite the lack of supporting data, hydroxyzine is commonly used for the treatment of pruritus in children with chronic kidney disease (CKD). Since histamine is not the primary mediator of uremic pruritus and patients with CKD are at high risk of having prolonged QT interval, hydroxyzine is not recommended in the treatment of uremic pruritus[22232425]
  • In 2016, health Canada released a warning that hydroxyzine has been associated with QT interval prolongation and torsade de pointes which may lead to dizziness, palpitation, seizures, and sudden cardiac death in children.[26] Both the Food and Drug Administration (FDA)[27] and European medicines agency[28] have released similar warnings
  • Similarly, FDA has also released a black box warning regarding the use of phenergan (promethazine) in pediatric patients <2 years of age due to potential risk of fatal respiratory depression. Caution should also be exercised while administering promethazine in children aged 2 years and above.[29]

A brief account of the commonly used first-generation antihistamines is presented in Tables 4-6.

T4-3
Table 4:
Pharmacokinetics and drug interactions of commonly used first-generation antihistamines
T5-3
Table 5:
Licensing age, formulation, and dosages of commonly used first-generation antihistamines
T6-3
Table 6:
Indications, contraindications, and common side effects of first-generation antihistamines

Second-Generation Antihistamines

  • The poor receptor selectivity, high lipophilicity, and inadequate pediatric data of first-generation antihistamines led to a need of relatively safer, nonsedating, and well-documented group of drugs. The second-generation antihistamines were then introduced which offered an improved safety profile and were relatively less sedative.
  • Terfenadine and astemizole were the first of second-generation antihistamines marketed. However, due to reports of QT prolongation and life-threatening ventricular arrhythmias including torsade de pointes, FDA recommended discontinuation of both of these drugs. The risk of ventricular arrhythmia was more in patients who had either exceeded the FDA recommended daily doses or taken concurrently with a drug known to interfere with hepatic CYP3A4 isoenzyme activity or had significant liver dysfunction[1642]
  • At present, the rules are very stringent with regard to potential cardiotoxicity and newer antihistamines have to pass strict safety controls before being authorized for introduction into the market[18]
  • Among second-generation antihistamines, cetirizine,[43] desloratadine,[4445] fexofenadine,[46] levocetirizine,[47] rupatadine,[48] bilastine,[49] and loratadine[43] have been well studied in children and their safety profile is well established.

A brief account of the commonly used second-generation antihistamines is presented in Tables 7-9.

T7-3
Table 7:
Pharmacokinetics, food and drug administration approval status, and drug interactions of commonly used antihistamines
T8-3
Table 8:
Licensing age, formulation and dosages of commonly used second-generation antihistamines
T9-3
Table 9:
Indications, contraindications, sedative potential and common side effects of second-generation antihistamines

Urticaria

Antihistamines are the cornerstone for the treatment of both acute and chronic urticaria.

The latest 2018 EAACI/GA2 LEN/EDF/WAO[15] guidelines recommend the following key points for the management of urticaria:

  • The second-generation antihistamines should be the first line of treatment for urticaria
  • The use of first-generation antihistamines is no more recommended for the routine management of urticaria in both adults and children
  • Antihistamines should be taken on a regular basis and not as and when needed
  • Different second-generation antihistamines should not be used at the same time
  • Four fold-up dosing of second-generation antihistamines should be preferred before switching to other treatment options (cyclosporine and omalizumab) in case of unresponsive urticaria.

However, in children <12 years of age, there is a paucity of literature regarding up dosing, but nevertheless, considering the safety profile of second-generation antihistamines and various large controlled studies doubling of the recommended dose can be done.[82]

Cetirizine, fexofenadine, bilastine, ebastine, desloratadine, and rupatadine have been studied in urticaria up to fourfold the recommended dose in more than 12 years of age group and their safety has been established.[88899091929394959697]

Atopic dermatitis

  • The itch in AD is mediated by several mediators other than histamine, such as substance P, IL-31, protease, and gastrin-releasing peptides.[98] Since histamine is not the sole mediator, the usefulness of antihistamines in AD is controversial and debated. The 2019 guidelines on the management of AD in India suggest that a subset of patients of AD with allergic rhinitis and bronchial asthma benefit maximum from antihistamines[99]
  • The sedating properties of first-generation antihistamines have been used by physicians to ameliorate nocturnal itch by inducing sedation. Although they induce sedation but are also known to reduce rapid eye movement (REM) sleep. REM sleep deprivation affects higher cortical functions such as cognition, attention, and memory consolidation.[100] Moreover, their sedative effects persist well into the next day even when taken the night before[19]
  • In a study, atopic children treated with loratadine or placebo demonstrated better learning performance than those treated with diphenhydramine[101]
  • American academy of dermatology recommends against the use of nonsedating antihistamines in the absence of urticaria or rhinoconjunctivitis[102]
  • However, the National Institute of Health and Care Excellence guidelines for treating atopic eczema suggest 1-month trial of nonsedating antihistamines in children with severe itching.[7103] As there is no difference in treatment efficacy between sedative and nonsedative antihistamines, it is recommended that a nonsedating antihistamines should be selected.[98]

Cutaneous mastocytosis

Nonsedating H1 antihistamines have been recommended for the treatment of pruritus, flushing, urticaria, and tachycardia associated with mastocytosis in children. If necessary, sedating H1 antihistamines may be added on demand depending on severity of disease.[104105]

Cetirizine, mizolastine, desloratadine, fexofenadine, and levocetirizine have been shown to have anti-inflammatory and mast cell stabilizing properties.[2106107108]

Others

Antihistamines are useful as an adjunctive therapy in anaphylaxis, insect bite reactions and in the management of various other cutaneous and systemic disorders associated with pruritus.

Over dosage

First-generation antihistamines have frequently been associated with intoxication both accidental and intentional which can be life threatening particularly in children. Diphenhydramine has even been used as an agent of infanticide in the past.[109] The symptoms of intoxication vary from CNS depression in adults to paradoxical stimulation in the form of excitation, hallucinations, convulsions, and death in children.[3]

In the year 2020, FDA has issued a warning that taking higher than recommended doses of the common over-the-counter allergy medicine diphenhydramine (Benadryl) can lead to serious heart problems, seizures, coma, and even death. FDA recommends to keep these medicines out of reach from children to prevent accidental poisonings and misuse, especially when they are home more often due to COVID-19 pandemic.[110]

Second-generation antihistamines are relatively safer and have less side effects in therapeutic as well as overdose. Even with extremely high serum concentration observed in in vitro studies, second-generation antihistamines do not produce significant toxicity.

What's New in Antihistamines?

Antihistamines as an adjunctive treatment in Acne

H1 receptors have been identified on the sebaceous glands, and a possible role of histamine in the production of sebum has been implicated.[111112]

Antihistamines have been found to play an adjuvant role in the management of acne by the following mechanisms:

  • They reduce itching associated with acne by inhibiting the release of inflammatory mediators[113]
  • They have a synergistic effect with retinoids:
    • Retinoids reduce sebum in general with little effect on squalene while antihistamines are known to reduce squalene levels[111114]
    • Antihistamines reduce the associated adverse effects of retinoids such as itching and acne outbreaks.[115]

Antihistamines which have been studied to be effective as an adjunctive treatment in acne include loratadine,[116] levocetirizine,[113] and desloratadine.[112114115]

Modulation of antibiotic efficacy by antihistamines

Various authors have hypothesized the following mechanisms by which the antihistamines may enhance the effect of antibacterial drugs:

  • Inhibition of bacterial efflux pumps
  • Inhibition of biofilm formation
  • Alteration of biological membrane permeability because of surfactant like properties of antihistamines[117118]
  • Counteracting the effect of histamine produced under stress condition by some bacteria such as Lactobacillus reuteri and Escherichia coli.[119120]

El-Banna et al.[116] and Bruer et al.[119] have described the modulation of antibiotic efficacy by antihistamines in their in vitro studies on Klebsiella pneumonia and Escherichia coli.

Mepyramine,[119] promethazine,[116] diphenhydramine, and cetirizine[116] have been shown to increase the efficacy of some antibiotics.

These effects of modulation of antibiotic efficacy are seen primarily with first-generation antihistamines owing to their nonselective receptor binding. The second-generation antihistamines are more specific for H1 receptor and hence do not show these properties to that extent.

The authors have proposed that combined use of antihistamines and antibacterials might be a potential option to treat infectious diseases in the future and to reduce the absolute amount of antibacterials used therapeutically, although in vitro findings need to be confirmed in vivo.[116119]

Paradox with Antihistamines Treatment

Antihistamine-induced urticaria

Antihistamines are the first-line treatment for urticaria. However, paradoxically, there are reports of antihistamine-induced urticaria. Hypothesis such as haptenization of metabolites, abnormal routes of metabolism, antibody production, complement activation, cross reactivity between metabolites of various drugs, type 1 and type 4 hypersensitivity reactions has been proposed to explain this paradox.

If urticaria lesions tend to persist or worsen despite H1 antihistamine treatment, physician should keep in mind the possibility of this paradoxical effect of antihistamines. Various antihistamines which have been reported to induce urticaria are fexofenadine, loratadine, cetirizine, ebastine, and hydroxyzine.[121122123124125]

Antihistamine-induced paradoxical excitation and seizures

The major drawback of first-generation antihistamines is their sedative potential, however, in children, they are paradoxically known to cause excitation, irritability and can precipitate seizures, especially in known epileptics or cases of febrile convulsions.[98121126] It is hypothesized that first-generation antihistamines may reduce the seizure threshold by blocking the histamine activity in central nervous system.[127]

Third-generation antihistamines

Consensus group on new generation antihistamines (COGNA)[17] in support with British society of allergy and clinical immunology have made recommendations for a drug to classify as third-generation antihistamine, it should have the following properties:

  • Anti-inflammatory effects
  • High therapeutic index
  • Lack of cardiac toxicity
  • Minimal drug interactions
  • Lack of CNS effects
  • Additional effect other than being an H1 blocker.

Till date, no antihistamine drug has fulfilled all these criteria. Rico et al. have analyzed ebastine in light of COGNA recommendation and have suggested that it could be a step forward toward the quest for third-generation antihistamines.[77] Rupatadine also has additional anti-inflammatory effects and platelet-activating factor antagonistic activity apart from being an H1 blocker, however, due to CYP p450 metabolism, it has a potential for drug interactions.[84]

There still seems to be a long way before a novel antihistamine is developed that fulfills all the COGNA recommendations and be classified as a third-generation antihistamine in true sense.

Conclusion

Antihistamines are an important therapeutic class of drugs in children. Since pediatric population encompasses a wide age group, drug therapy in children should be evidence based.

In our department, the first choice of antihistamine in children is always a second-generation drug. Since the therapeutic efficacy of the various second-generation antihistamines is almost comparable, so the choice of drug in an otherwise healthy pediatric patient is dictated by other factors such as financial considerations, academic activities, and school performance. In situations where even mild sedative potential of drugs is undesirable such as school-going children, during examinations where learning performance might get affected, we prefer drugs as fexofenadine and bilastine.

Our preferred antihistamines for various age groups (not in order of preference)

In a pediatric patient with no associated systemic medical conditions,

  • 6 months to 2 years: cetirizine, levocetirizine, desloratadine, fexofenadine
  • 2 years to 6 years: cetirizine, levocetirizine, desloratadine, fexofenadine, loratadine
  • >6 years: cetirizine, levocetirizine, desloratadine, fexofenadine, loratadine, bilastine.
  • In children with associated systemic medical conditions:
  • Children with renal impairment:
    • 6 months to 6 years: desloratadine, fexofenadine (however, dose adjustment required in severe renal impairment)
    • 6 years: bilastine
  • Children with hepatic impairment:
    • 6 months to 6 years: levocetirizine, fexofenadine
    • >6 years: levocetirizine, fexofenadine, bilastine.
  • Children with cardiac impairment:
    • 6 months to 2 years: cetirizine, fexofenadine
    • >2 years: cetirizine, fexofenadine, loratadine.

As many novel antihistamines have now been introduced with additional properties and improved safety profile, it is imperative to raise concerns precluding the routine use of first-generation antihistamines in children. Further research with newer antihistamines focusing on specific pediatric age groups is warranted.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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                    Keywords:

                    Antihistamines in children; atopic dermatitis; newer antihistamines; pediatric; urticaria

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