Ghosh S, Debnath I, Bhunia S, Hazra S, Nandi S, Mandal S. K, Mallya S, Chakraborty S, Shaw A. R, Patra S, Khatun R. A Review on Mechanism of Histamine Mediated Allergic Reactions: Therapeutic Role, Safety, and Clinical Efficacy of Cetirizine in Modern Allergy and Other Diseases Management. Biomed Pharmacol J 2025;18(1).

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Manuscript received on :14-11-2024
Manuscript accepted on :15-01-2025
Published online on: 13-02-2025

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Plagiarism Check: Yes
Reviewed by: Dr. Moumita Hazra
Second Review by: Dr. M Mohan Varma
Final Approval by: Dr. Eman Refaat Youness

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Suman Ghosh¹, Ishita Debnath¹, Sobhanjan Bhunia¹ , Supriya Hazra¹ , Sumit Nandi^2* , Sudip Kumar Mandal³, Sneha Mallya⁴ , Souvik Chakraborty⁴ , Aditya Raj Shaw⁴ , Soumyadip Patra⁴and Rajia Khatun⁴

¹Department of Pharmaceutical Chemistry, Guru Nanak Institute of Pharmaceutical Science and Technology, Kolkata, West Bengal, India

²Department of Pharmacology, Gupta College of Technological Sciences, Asansol, West Bengal, India

³Department of Pharmaceutical Chemistry, Dr. B. C. Roy College of Pharmacy and Allied Health Sciences, Durgapur, West Bengal, India

⁴Department of Pharmaceutical Technology, Bharat Technology, Howrah, West Bengal, India

Corresponding Author E-Mail: sumitrx27@gmail.com

Abstract

Histamine-mediated allergic reactions are central to the pathogenesis of various allergic disorders, involving complex molecular mechanisms. Cetirizine, a second-generation antihistamine, functions as a potent H1 receptor antagonist and is widely utilized for the management of these conditions. This review comprehensively evaluated the molecular mechanisms underlying histamine release, its interaction with H1 receptors, and the subsequent allergic responses. It also analyzed the pharmacokinetics and pharmacodynamics of cetirizine, highlighting its high selectivity for H1 receptors and its minimal sedative effects. The clinical efficacy of cetirizine was demonstrated across several allergic conditions, including food allergies, atopic dermatitis, allergic conjunctivitis, and drug-induced hypersensitivities. In these contexts, cetirizine reduced histamine-mediated symptoms, such as pruritus and inflammation, and improved patient outcomes. Additionally, combination therapies involving cetirizine with other antihistamines, corticosteroids, or biologics were discussed, particularly in refractory or severe allergic cases. Despite its overall safety, this review also highlighted the adverse effects associated with long-term cetirizine use, particularly in special populations such as pediatric, elderly, and patients with renal impairment. Future perspectives emphasize the role of future research on cetirizine in personalized allergy treatment, emerging combination therapies with biologics, and its potential in prophylactic applications.

Keywords

Cetirizine; Clinical efficacy; Histamine; H1 receptor antagonist; Pharmacodynamics; Pharmacokinetics

Introduction

Cetirizine is a second-generation antihistamine primarily used to manage allergic reactions. Allergy development is a multifactorial process that begins during sensitization when particular allergens cause the formation of IgE antibodies. These IgE antibodies cause degranulation, which releases a number of mediators, including histamine, by binding to the high-affinity receptors (FcεRI) found on mast cells, basophils, and antigen-presenting cells (APCs) ^1,2. This process triggers immediate hypersensitivity reactions, which manifest as common allergic symptoms. Inducing allergic inflammation largely depends on effector Th2 cells, which release cytokines like IL-4, IL-5, and IL-13, which promote eosinophilia, mucus secretion, and recruitment of inflammatory cells, thereby exacerbating allergic responses ^3–5. Eosinophils and mast cells are crucial for the initiation and progression of allergic reactions, and histamine is one of the main mediators of acute hypersensitivity. In contrast, eosinophils contribute to chronic inflammation through the release of cytotoxic proteins ^6–8. Histamine release is a crucial phase in allergic responses, occurring when intracellular histamine stored in mast cell granules is released into the extracellular environment. This is initiated by antigen-antibody interactions, where FcεRI-bound IgE on mast cells stimulates tyrosine-protein kinase activation. This cascade leads to the phosphorylation of phospholipase Cγ and the subsequent intracellular calcium release, which facilitates granule fusion with the plasma membrane, releasing histamine. Histamine, synthesized from histidine by the enzyme L-histidine decarboxylase, acts as a potent signaling molecule by binding to H1, H2, H3, and H4 receptors, all belong to the GPCR family ^9–11. These receptors mediate various physiological and pathological processes, with H1 receptor activation playing a key role in allergic symptoms. Upon binding to the H1 receptor, histamine triggers a cascade involving Gq/11 protein activation and phospholipase C signaling, producing DAG and IP3. This promotes smooth muscle contraction, increases vascular permeability, as well as contributes to the hallmark symptoms of allergic responses, such as itchiness, bronchoconstriction, and tissue swelling. Cetirizine’s action as an H1 receptor antagonist effectively blocks this pathway, reducing the effects of histamine and alleviating allergy symptoms ^12,13. Cetirizine relieves symptoms associated with allergies, such as itching, swelling, and rhinorrhea, without causing the sedative effects commonly observed with first-generation antihistamines. Studies have demonstrated its effectiveness not only in traditional allergic conditions like hay fever and urticaria but also in newer allergies such as food allergies, atopic dermatitis, and allergic conjunctivitis ^14,15. Furthermore, cetirizine has shown a favourable safety profile in long-term use, making it suitable for a broad spectrum of patients with chronic allergic conditions. This review aims to provide a thorough analysis of the mechanisms underlying histamine-mediated allergic reactions, the molecular and pharmacological actions of cetirizine, and its clinical efficacy and safety profile, particularly in emerging allergic conditions.

Causes of allergy formation

Inflammatory mediators and a variety of cell types interact to produce an immunological cascade of allergy diseases. Sensitization, early-phase reactions, and late-phase responses are the three separate stages of the allergic response. Producing IgE-antibodies specific to allergens, which adhere to mast cell, basophil, and APCs surfaces to initiate degranulation and mediator release, is the initial stage of the sensitization phase. After that, allergen-specific CD4+Th2 cells undergo clonal proliferation and differentiation, enabling them to produce IL-4 and IL-13, two important factors of IgE production ¹⁶. IgE attaching to effector cells makes a patient more sensitive to a specific allergen. In the initial stages of the reaction, histamine, tryptase, eosinophil chemotactic factor, and newly synthesized molecules (PGD2, LCT4, bradykinin) are secreted by basophiles and mast cells ¹⁷. This explains why patients who demonstrate a preliminary allergy response also undergo a late-phase inflammatory response 4 to 24 hours after being exposed to allergens. A recurrence of the early-stage symptoms occurs during the later stage of the allergy response, which is marked by tissue damage as well as inflammation. Allergy disorders refer to the complex immune system responses to environmental antigens that result in inflammatory reactions with a prevalence of IgE specific to allergens and a T-helper-2 type cell. In essence, allergy is an inflammatory illness ¹⁸. Recent years have seen a substantial advancement in our knowledge of the cells and mediators that affect allergic inflammation. This information serves as the cornerstone for the more logical formulation of treatment concepts and the mitigation of allergy symptoms. Many different cells are involved in allergic inflammation. Three distinct cell types, though, appear to be particularly significant. These are the T-lymphocyte Th2-type, the mast cell, and the eosinophil granulocyte. Naive T cells differentiate into a variety of subsets, such as Th1, Th2, Th9, Th17, and Th22 type memory and effector cells, in large part due to cytokines, other substances, and the cells in the microenvironment ¹⁹. In the presence of allergic diseases, effector Th2 cells produce proinflammatory cytokines such as IL-25, IL-31, and IL-33 in addition to more common Th2 cytokines including IL-4, IL-5, IL-9, and IL-13. These cytokines sometime may cause mucus production, eosinophilia, the generation of IgE specific to allergens, as well as migration of inflammatory cells to inflammatory tissues. Primary effector cells are eosinophilia and mast cells in this aspect. Histamine release is one of the primary consequences of mast cell activation, which causes an immediate allergic reaction (Figure 1). When eosinophils are activated, several strong cytotoxic proteins are released extracellularly. The development of subacute and chronic allergy symptoms is significantly influenced by these proteins. In addition to macrophages, endothelial cells, neutrophil granulocytes, and epithelial cells are also crucial in allergic disorders ²⁰.

Figure 1:  The cascade of allergies. In addition to inducing degranulation, mast cell mediators such as cytokines also support lymphocyte activity, immune cell migration to inflammatory sites, and reciprocal communication with other inflammatory cells or their progenitors. Click here to view Figure

Mechanism involved in histamine release

Histamine is produced and released by various human cells, including lymphocytes, enterochromaffin cells, basophils, mast cells, platelets, and histaminergic neurons. Within intracellular granules of mast cells, histamine is retained by heparin and an acidic protein. Sodium ions (Na⁺) in the extracellular fluid exchange with histamine during granule extrusion via exocytosis, thus histamine releases ²¹.

Figure 2: Mechanism of Histamine release Click here to view Figure

The mechanism by which mast cells release histamine in response to an antigen-antibody reaction. Sensitized atopic individuals produce specific reaginic antibodies (IgE), which attach to the Fc epsilon receptor (FcɛRI) on mast cell surfaces. When the antigen bridge IgE molecules are challenged, tyrosine-protein-kinase (t-Pr-K) is transmembrane activated and phosphorylates phospholypase C𝛄. Inositol triphosphate (IP3) is produced upon hydrolysis of phosphotidyl inositol biphosphate (PIP2), which causes the calcium ion to be released between cells. Granule content is released exocytotically when the calcium ion causes the granule membrane to fuse with the mast cell’s plasma membrane. The granule contained a complex of negatively charged protein and heparin molecules with positively charged histamine. Histamine is released to act on target cells through cationic exchange with extracellular sodium. It is kept in granules or vesicles that are released upon activation. Dale and Laidlaw discovered histamine [2-(4-emidazolyl) ethylamine] in 1910, and in 1932 they ascertained that it was an intermediate of anaphylactic reactions ²². Histidine is converted to histamine, one of the biogenic amines, by the enzyme L-histidine decarboxylase (HDC), which requires pyridoxal phosphate (vitamin B6). A powerful modulator of many physiological responses is histamine. There are many types of histamine receptors like H1, H2, H3, H4, etc. Histamine is a biogenic amine. H1-receptor is a part of the GPCR superfamily. This superfamily is made up of almost 500 distinct membrane proteins that are connected by a structural pattern consisting of seven transmembrane helical regions. Histamine has various physiological and pathophysiological effects on histamine receptors ²³. Another recent study found that a protein called caspase-8 may play a role in the release of histamine from mast cells. Caspase-8 is an enzyme that is involved in cell death. The study found that mice lacking caspase-8 had increased levels of histamine in their blood.

Effect of histamine on H1 receptor

As H1 receptor binding induces smooth muscle contraction and vascular permeability H1 antagonist is the best choice for alleviating the effect of allergies. The human chromosome 3 encodes the H1 receptor, which is in charge of several symptoms and indicators of allergic diseases, including itchiness, rhinorrhea, asthma, and stiffness of the intestinal smooth muscle ²⁴. H1 activation is associated with Gq/11 GTP-hydrolysing protein that activates phospholipase C, then histamine binds with the H1 receptor. In turn, phospholipase C hydrolyzes phosphatidylinositol-4,5-bisphosphate to produce DAG and IP3, two more second messengers. DAG potentiates, and inositol phospholipid signaling pathways are stimulated. The activity of PKC releases stored Ca²⁺ ions into the cytoplasm through IP3 binding on the endoplasmic reticulum. Moreover, H1 stimulation can also activate two additional intracellular signaling pathways phospholipase D and A. It has recently been demonstrated that nuclear transcription factor κB (NFκB) can be activated by heme-regulated inhibitor (HRI) activation. Both contribute to the emergence of allergic illnesses. In the process of figuring out how histamine affects stomach acid secretion, the H2 receptor was discovered. After being cloned in dogs, it was subsequently discovered in various species. The H2 receptor is encoded by an intronless gene and has a protein with 358 to 359 amino acids. It is connected to both PKA and Gs ²⁵.

The somata, dendrites, and axons (varicosities) of histaminergic and other cells have H3 receptors, which function as a negative feedback loop to restrict the production and release of histamine as well as other transmitters such as acetylcholine, noradrenaline, and glutamate. Gi/o and high voltage-triggered Ca²⁺ channels, a common method for controlling transmitter release, are related to H3 receptors. The H3 receptor triggers the MAPK pathway by being negatively linked to cAMP.

Molecular mechanism of histamine

Histamine has a major impact on the CNS is now apparent because it was discovered that traditional antihistamines have sedative effects. In almost all animals’ histamine is released in brain cell ²⁶. However, the histamine content in cells varied between higher to lower vertebrates. In lower vertebrates, histamine is present in higher amounts because of their lower-developed cortex and cerebellum. Histamine-producing neurons can be found in the tuberomamillary nucleus (TMN), which is a component of the posterior hypothalamus in both humans and animals. Although the primary terminals of histamine secretors vary among species, they are all found in crucial regions of the CNS ²⁷. All mammals have moderate to intense histaminergic innervation in the cerebral cortex, amygdala, substantia nigra, and striatum. The tuberomammillary nucleus also sends histaminergic fibers to the retina and spinal cord, and the density of these projections in the thalamus and hippocampal regions varies. The afferent projection of the tuberomammillary nucleus comes from many areas among them the prominent source is the infralimbic cortex, lateral septum, preoptic nucleus. The primary sources of brainstem stimulation are the noradrenergic groups A1 to A3, the adrenergic cell groups C1 to C3, and the serotonergic groups B5 to B9. Only a few numbers of fibers, however, pass through the dopaminergic groups of the ventral tegmental area, substantia nigra, as well as locus coeruleus to reach the TM nucleus ²⁸.

Neurons use histamine synthesis and inactivation as the primary mechanisms for histamine transport and metabolism. The process is that when histidine is released into the body it enters neuron cells by L-amino-acid transporter. Histidine decarboxylase in neurons converts histidine into histamine. Formed histamine is brought into vesicles by VMAT-2. After the formation of histamine, inactivation of histamine occurs postsynaptically. After the release of histamine from VMAT-2 methylation occurs in postsynaps by Histamine methyltransferase and form Tele-methylhistamine. Tele-methylhistamine is a substance that has no effects like histamine. This methylation process is the main inactivation process of histamine ²⁹. Neuronal histamine has a relatively high turnover rate and a half-life that varies rapidly based on neuronal activity, usually lasting around 30 minutes.

Figure 3: Release of histamine in CNS  Click here to view Figure

Pharmacokinetic profile of Cetirizine

The oral dose has rapid absorption in the gut. The maximum plasma concentration achieved by cetirizine is 1-2 hours. The bioavailability of this drug is the same for any dosage formulation (tablet, syrup). There is no difference in the amount of absorption between the fed and fasted states, despite the possibility that the presence of food will accelerate absorption rate. The majority of the medication roughly 90% is bonded to albumin and other plasma proteins. Oral cetirizine is quickly absorbed into breast milk and tear fluid in allergic conjunctivitis patients; nevertheless, the medication is not easily absorbed through the blood-brain barrier. Elimination of cetirizine occurs via urine (70% of administered drug) rest small quantity is eliminated by faeces.

Pharmacodynamic profile of Cetirizine

Cetirizine, the carboxylate metabolite of hydroxyzine, is a zwitterion that may help to explain some of its characteristics, including its limited biotransformation potential, low to moderate lipophilicity, strong hydrogen-binding capacity, and restricted blood-brain barrier penetration. With very little affinity for several other receptor types, such as adrenergic and serotoninergic receptors, it is an extremely selective antagonist of the histamine H1 receptor ³⁰. In non-atopic and atopic adults as well as pediatric patients, oral cetirizine 10 mg administered once or more times suppressed histamine-induced wheal and flare reactions. Additionally, this drug shows a higher level of efficacy in comparison to therapeutic dosages of other antihistamine medications, including loratadine or ebastine. Cetirizine’s effects lasted for at least 24 hours, peaking between 4-8 hours in. Cetirizine 5-20 mg offered dose-dependent defense against histamine-induced respiratory. Despite reports of somnolence in clinical trials, cetirizine 10 mg once daily did not typically impair CNS function. Cetirizine did not affect an adult’s cognitive performance, a pediatric patient’s behavior, or their psychomotor milestones. Since cetirizine binds to histamine H1-receptors, many of the effects of histamine are effectively reversed.

Mechanism of action of Cetirizine

Although second generation H1 antihistamines are derived from first-generation H1 antihistamines, they have more benefits than the first generation of drugs because they have fewer sedative or anticholinergic effects. They do, however, also have negative effects, and some of them combine with other medications and substances. Cetirizine, a carboxylic acid with a racemic mix of R and S enantiomers, is derived from hydroxyzine. It is not metabolized in the liver and does not interact with any inducers or inhibitors of the CYP (cytochrome p450 system) ³¹. When cetirizine is given up to six times the recommended dosage, no changes have been seen in electrocardiography. Since cetirizine seems to be a P glycoprotein (Pgp) substrate, pharmacological interactions at this level are conceivable but not fully understood. When a person ages and develops renal or hepatic disorders, they must change their dosage. The sedative effects of traditional antihistamines, which function as H1 antagonists, are widely recognized. Cellular excitation is accomplished through Gq/11 and PLC activation, resulting in the formation of diacylglycerol (DAG) and Inositol 1,4,5-triphosphate [Ins(1,4,5)P₃], the two-second messengers. Inositol 1,4,5-triphosphate release stimulates dye-coupling via gap junctions and causes the supraoptic nucleus to express C-Fos ³². Within this nucleus, neurons expressing vasopressin have been reported to exhibit both enhanced after depolarizations and excitation. Studies on vasopressin, commonly referred to as antidiuretic hormone (ADH), shed light on the molecular mechanism underlying histamine-induced antidiuresis.

Figure 4: Mode of action of Cetirizine Click here to view Figure

Cetirizine induces an equilibrium shift to the off position by crosslinking sites on transmembrane domains IV and VI, stabilizing the receptor in the inactive state. Because they function on the receptor in the opposite way to histamine, H1-antihistamines are not receptor antagonists; rather, they are negative antagonists. As a result, “H1-antihistamines” is the recommended name to describe these medications instead of “histamine antagonists”.

Figure 5: A, Diagram illustrating the seven GPCR transmembrane domains for the H1 receptor in a cell membrane. Click here to view Figure

Cetirizine-based combination therapies with detailed case study information in other disease management

Cetirizine, a second-generation H1-antihistamine, is widely used for managing histamine-mediated allergic conditions due to its high selectivity for H1 receptors and minimal sedative effects compared to first-generation antihistamines. In clinical practice, cetirizine is often combined with other antihistamines, corticosteroids, leukotriene receptor antagonists, and even biologics to enhance therapeutic outcomes, particularly in patients who do not respond to monotherapy. The table depicts detailed information about cetirizine combination therapies, the doses of these combinations, and their bioactivity.

Table 1: Combination drug therapies with cetirizine, their dosages, and bioactivity in allergic conditions

Clinical Application with Detailed Examples from Recent Case Studies

Cetirizine with Loratadine

This combination is often used for patients with chronic urticaria or severe allergic rhinitis. Both cetirizine and loratadine are second-generation antihistamines that block histamine H1 receptors but have different pharmacokinetics. Combining them can extend the duration of symptom relief.

This combination was assessed in a clinical trial study conducted in 2022 on 120 people suffering from severe allergic rhinitis. In comparison to monotherapy, the results demonstrated a considerable improvement in symptom scores over an 8-week period, with patients reporting little drowsiness​. ^54,55

Cetirizine with Fexofenadine

Fexofenadine is another second-generation antihistamine with a strong safety profile. When combined with cetirizine, this duo provides enhanced histamine receptor blockade, which is effective in treating chronic idiopathic urticaria.

In a 2023 trial, cetirizine and fexofenadine were used in conjunction to treat 85 individuals with chronic idiopathic urticaria. The study found a 35% improvement in patient-reported itching and quality-of-life scores compared to cetirizine monotherapy​. ⁵⁶

Cetirizine with Ketotifen

Ketotifen, a mast cell stabilizer and H1 antihistamine, is commonly used in combination with cetirizine to treat more severe allergic reactions, such as chronic spontaneous urticaria. Ketotifen prevents mast cell degranulation, which complements cetirizine’s H1 receptor blockade.

A study involving pediatric patients with atopic dermatitis treated with cetirizine and ketotifen found a 45% reduction in flare-ups over 6 months. No significant sedation was observed, making it a viable option for long-term therapy. ⁵⁷

Cetirizine with Desloratadine

Desloratadine is the active metabolite of loratadine and provides potent, long-acting antihistaminic effects. This combination has been used for chronic allergic diseases where single antihistamine therapy is insufficient.

A 2021 randomized controlled trial reported on 60 children with severe allergic rhinitis. The cetirizine and desloratadine combination led to a 52% improvement in nasal congestion and sneezing after 4 weeks compared to a 35% improvement with desloratadine monotherapy​. ^58,59

Cetirizine with Cyproheptadine

Cyproheptadine, a first-generation antihistamine, is often added for patients with refractory symptoms despite second-generation antihistamine therapy. Cyproheptadine’s stronger sedative effects are offset by cetirizine’s minimal sedative profile, making it useful for nighttime symptom control.

A clinical case series from 2022 found that in patients with recalcitrant chronic urticaria, cetirizine and cyproheptadine combined therapy reduced symptoms by 60% over 12 weeks, with moderate drowsiness reported in 20% of patients​. ⁶⁰

Cetirizine with Chlorpheniramine

Chlorpheniramine, a first-generation antihistamine, is frequently combined with cetirizine for acute allergic responses, such as severe hay fever or drug-induced allergies. This combination provides quick symptom relief but often results in sedation.

In a study of 50 patients with acute allergic rhinitis, this combination provided faster relief than monotherapy. However, 30% of patients experienced mild sedation​. ^61–63

Cetirizine with Promethazine

Promethazine is a first-generation antihistamine with antiemetic properties, making it valuable for treating nausea and allergy symptoms simultaneously. This combination is often used in cases of drug-induced allergies where gastrointestinal symptoms are present.

In a 2023 study on drug-induced urticaria, the combination of cetirizine and promethazine improved symptom control in 85% of patients but caused sedation in nearly 40%, as reported in Indian Journal of Dermatology​. ⁶⁴

Cetirizine with Levocetirizine

Levocetirizine is an enantiomer of cetirizine, offering similar benefits but with even less sedative effect. Combining the two enhances histamine blockade while keeping sedation minimal. A 2023 case study involving patients with allergic conjunctivitis demonstrated significant improvements in eye redness and itchiness after 3 weeks of combination therapy. Patients reported no sedation​. ⁶⁵

Cetirizine with Montelukast

Montelukast is a leukotriene receptor antagonist that targets inflammatory pathways beyond histamine. This combination is commonly used in patients with asthma and allergic rhinitis, where both histamine and leukotriene pathways play a role.

In a large-scale study (2023), 120 patients with allergic rhinitis and mild asthma experienced significant reductions in both nasal and respiratory symptoms with this combination. The study highlighted an 85% improvement in daytime symptoms and minimal adverse effects​. ^66,67

Cetirizine with Omalizumab

Omalizumab, an anti-IgE monoclonal antibody, is effective in treating chronic spontaneous urticaria that is refractory to antihistamines. Combining it with cetirizine provides enhanced suppression of allergic responses by blocking IgE and histamine pathways.

In a 2023 case reports, a patient with severe urticaria unresponsive to antihistamines found that combining cetirizine and omalizumab resulted in a 75% reduction in urticarial flare-ups. No serious side effects were noted​. ⁶⁸

Cetirizine with Hydrocortisone

Hydrocortisone, a corticosteroid, is often combined with cetirizine in cases of severe allergic reactions, including drug-induced anaphylaxis. While this combination is highly effective, it is typically used for short durations to minimize corticosteroid-related adverse effects.

In a 2022 case report, a patient with severe food-induced anaphylaxis was treated with cetirizine and hydrocortisone. Symptom resolution occurred within 12 hours, though the patient was monitored for potential long-term corticosteroid effects​. ^69,70

Cetirizine with Azelastine

Azelastine, an intranasal antihistamine, is often combined with oral cetirizine for patients with conjunctivitis and allergic rhinitis. This combination allows for targeted nasal symptom relief and systemic control of histamine.

A case study in 2022 showed that combining azelastine nasal spray with oral cetirizine improved nasal congestion by 65% compared to monotherapy in 90 patients with moderate allergic rhinitis​. ^71–73

These illustrations offer strong proof in favor of using cetirizine in conjunction with other medications to treat a variety of allergic diseases, such as severe drug-induced allergies, allergic rhinitis, and chronic urticaria. This approach enhances therapeutic efficacy and optimizes patient outcomes by reducing symptoms while minimizing adverse effects. Starting with a detailed table after the introduction, as discussed, will provide an authoritative overview of these strategies, supported by clinical case studies and pharmacological mechanisms.

Clinical Studies of Cetirizine in the Management of Emerging Allergies

The increasing frequency of allergic illnesses around the world has led to their recognition as significant public health concerns. Traditionally, allergic rhinitis, asthma, and urticaria have been the focus of allergy management. However, emerging allergic conditions like food allergies, atopic dermatitis, drug-induced hypersensitivities, and allergic conjunctivitis are gaining attention due to their complexity, chronicity, and expanding range of allergens. Recent epidemiological data from large-scale studies have revealed a surge in these allergies, especially in developed and developing countries, driven by factors such as environmental changes, dietary habits, and immune system alterations ^74–77. Cetirizine is used in the treatment of various types of allergic conditions. Table 2 depicts numerous clinical trials of cetirizine in treating emerging allergies worldwide with recent studies.

Table 2: Clinical trial of Cetirizine with the updated outcomes (US National Library of Medicine. Available online: https://clinicaltrials.gov)

Therapeutic Applications of Cetirizine in Emerging Allergic Disorders

Cetirizine in Food Allergies

The rise in food allergies, particularly in children, has prompted investigations into the role of cetirizine as a potential therapy. Food allergies are IgE-mediated hypersensitivity reactions that can manifest as mild urticaria or, in severe cases, anaphylaxis. In clinical trials, cetirizine has shown efficacy in reducing symptoms of allergic reactions to common food allergens like peanuts, milk, and shellfish by stabilizing mast cells and reducing histamine-mediated responses. However, cetirizine’s role in preventing the progression of mild reactions to anaphylaxis remains an area of active research. Studies indicate that while cetirizine can mitigate symptoms like skin rashes and gastrointestinal discomfort, it should be used in conjunction with other therapies, such as epinephrine, in life-threatening allergic reactions ^78,79. 

Cetirizine in Atopic Dermatitis (AD)

AD a chronic inflammatory skin disorder, is another emerging condition in which cetirizine has demonstrated potential therapeutic benefits. Cetirizine has proven effective in reducing pruritus in AD patients by inhibiting histamine-mediated itching and reducing inflammatory markers like IL-4 and IL-13. Clinical studies have highlighted the beneficial effects of cetirizine in pediatric patients with AD, where it helps reduce the frequency and severity of flare-ups without causing sedation. Long-term treatment regimens involving cetirizine have also been explored in AD, demonstrating a favorable safety profile with a minimal incidence of adverse effects ^80,81.

Allergic Conjunctivitis and Cetirizine

Allergic conjunctivitis, a condition characterized by eye redness, tearing, and itching due to allergen exposure, has become increasingly prevalent, particularly in urban environments with high pollution levels. Cetirizine has been found effective in treating both seasonal and perennial allergic conjunctivitis. It works by reducing histamine-induced vasodilation and capillary permeability in the conjunctival tissues, thereby alleviating ocular symptoms. Recent randomized controlled trials have shown that cetirizine when used as an adjunct therapy alongside topical antihistamines, provides faster relief and a longer-lasting protective effect against allergen exposure compared to topical agents alone ^82,83.

Cetirizine in Drug-Induced Allergies

Drug-induced hypersensitivities, including allergic reactions to antibiotics, NSAIDs, and biologics, represent another category of emerging allergic disorders. While most drug-induced allergies involve immediate hypersensitivity mechanisms, some may progress to delayed hypersensitivity reactions. Cetirizine has been reported as an effective treatment for managing mild-to-moderate drug-induced allergic reactions, especially in hospital settings, where its rapid onset of action can be beneficial in acute management. Although cetirizine is effective in alleviating cutaneous symptoms, such as rash and angioedema, it is not sufficient for more severe reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis, where immunosuppressive therapies may be required ⁸⁴.

Adverse Effects of Cetirizine

Cetirizine, a second-generation antihistamine, is generally well-tolerated, but like any medication, it can have side effects. The profile of adverse effects is crucial for evaluating its safety and suitability for long-term use. Common Adverse Effects of Cetirizine are as follows:

Somnolence

Some patients may experience mild to moderate drowsiness even though cetirizine is less sedative than first-generation antihistamines. This results from its partial capacity to influence central histamine receptors and penetrate the blood-brain barrier ⁸⁵.

Dry Mouth

Reduced salivary secretion can lead to a sensation of dry mouth, which is a common side effect among antihistamines ⁸⁶.

Headache, Dizziness, and Allergic Reaction

Some users may experience headaches or dizziness, which could be attributed to the drug’s effects on the CNS. Although rare, cetirizine can cause allergic reactions such as rash, pruritus, and angioedema in some individuals ⁷⁷.

Gastrointestinal Symptoms

Sometimes, long-term cetirizine use has been linked to gastrointestinal side effects such as nausea, vomiting, abdominal pain etc. These effects are generally mild and transient ⁸⁷.

Safety Profile of Cetirizine

Safety Profile in Long-Term Use

Cetirizine, a second-generation antihistamine, has a well-established safety profile, particularly for its long-term use. This section provides an extensive review of its safety considerations based on clinical evidence and real-world data.

Clinical Evidence for Long-Term Safety

Cetirizine’s safety in long-term use has been evaluated in numerous clinical trials and observational studies. These studies typically span durations from several months to over a year and encompass various populations, including those with chronic allergic conditions like allergic rhinitis and chronic urticaria. Many researches demonstrated that daily administration of cetirizine for up to 12 months was generally well-tolerated, with no significant side effects beyond those reported in short-term studies ⁸⁸.

Tolerance and Efficacy

Unlike first-generation antihistamines, which can lead to tolerance with prolonged use, cetirizine maintains its efficacy over time. The term “Tolerance” describes a drug’s decreased effect after repeated use. Cetirizine’s consistent effectiveness is attributed to its selective H1 receptor antagonism and minimal penetration into the central nervous system, which helps preserve its therapeutic benefits and minimizes side effects such as sedation. This stability in effectiveness supports its role in chronic allergic conditions management ⁸¹.

Impact on Quality of Life (QoL)

Cetirizine use over time has been linked to better QoL for people with long-term allergy disorders. Studies have shown that cetirizine’s non-sedating profile, in contrast to first-generation antihistamines, contributes positively to patients’ daily functioning and overall well-being. The lack of significant sedative effects allows patients to maintain their normal activities and productivity, thus enhancing adherence to treatment and overall satisfaction ⁸⁹.

Safety Profile in Special Populations

Pediatric Population

Cetirizine is approved for use in 6-month-old infants, and long-term studies have shown it to be safe and effective in managing allergic symptoms in this group. Dosing adjustments are based on body weight, and continuous monitoring is recommended to ensure appropriate therapeutic levels and minimal side effects ⁹⁰.

Elderly Population

Age-related changes in renal function may cause cetirizine’s pharmacokinetics to shift in older people. Long-term use in this demographic requires dose adjustments and careful monitoring of renal function to prevent accumulation and potential toxicity. Clinical studies have demonstrated that cetirizine remains safe and effective in elderly patients when prescribed with appropriate dose modifications ⁹¹.

Patients with Renal Impairment

Cetirizine is mainly excreted via the kidneys, and its clearance can be significantly reduced in individuals with renal impairment. Long-term use in this population necessitates dose adjustments and regular monitoring of renal function to avoid the risk of drug accumulation. Evidence indicates that with proper dosage adjustments, cetirizine is safe for long-term use in patients with compromised renal function ⁹¹.

Patients with Hepatic Impairment

While cetirizine undergoes minimal hepatic metabolism, caution is advised in patients with severe liver dysfunction. Although long-term studies are limited in this population, the available data suggest that cetirizine can be used safely with appropriate dose adjustments and monitoring ⁹².

Future Directions for Cetirizine in Allergy Management

Personalized Allergy Treatment through Pharmacogenomics

Advances in pharmacogenomics offer significant potential in optimizing cetirizine therapy for allergic conditions. Cetirizine’s effectiveness and safety profile may be impacted by genetic variations in histamine receptors and drug-metabolizing enzymes, including those in the cytochrome P450 (CYP) family. Individual patient reactions to cetirizine, such as the requirement for dose modifications or alternate treatments, may be influenced by differences in the genes encoding H1 receptors or enzymes involved in drug metabolism. The use of genetic markers to guide therapy will allow for the development of personalized allergy management strategies, minimizing side effects and improving therapeutic outcomes. Future studies in pharmacogenetic testing may lead to precise, tailored cetirizine therapies, particularly for patients with unique metabolic profiles or severe allergic phenotypes ^93,94.

Combination Therapies with Immunotherapy and Biologics

While cetirizine is effective in controlling histamine-mediated symptoms, its ability to modulate the underlying immune response is limited. Combining cetirizine with allergen-specific immunotherapy and biologics targeting key immune pathways presents an innovative approach to more comprehensive allergy management. Immunotherapy, which desensitizes the immune system to specific allergens, can be paired with cetirizine to reduce the severity of immediate allergic symptoms during the desensitization process. Moreover, biologic agents like omalizumab and other monoclonal antibodies that inhibit IgE or other immune mediators offer synergistic benefits when used with cetirizine, addressing both acute and chronic aspects of allergic conditions. These combination therapies are currently under clinical investigation, with preliminary results suggesting improved efficacy and patient satisfaction, particularly in severe or refractory cases of allergic rhinitis, asthma, and atopic dermatitis ^95,96.

Prophylactic Use of Cetirizine in Allergy Management

The prophylactic use of cetirizine is a promising avenue for preventing allergic reactions in high-risk populations like individuals with occupational allergen exposure or those with seasonal allergies. Regular, preventive administration of cetirizine during peak allergen seasons may mitigate the severity of allergic episodes by maintaining continuous H1 receptor blockade. This approach could be particularly beneficial in cases of seasonal allergic rhinitis and asthma, where preemptive therapy reduces the need for corticosteroids and other more aggressive interventions. Additionally, research into long-term prophylactic use of cetirizine may reveal its potential to prevent allergy sensitization, particularly in pediatric populations prone to developing allergic diseases ⁹⁷.

Cetirizine as an Adjunct in Anaphylaxis and Asthma Management

Cetirizine’s potential role in anaphylaxis and asthma management is garnering attention, particularly as an adjunct to standard emergency treatments. In anaphylaxis, cetirizine can provide secondary symptom control post-epinephrine administration, particularly for urticaria, angioedema, and residual histamine-mediated symptoms. Research into the biphasic anaphylactic response a delayed recurrence of symptoms has identified cetirizine as a promising agent for preventing secondary allergic responses. Additionally, for allergic asthma, cetirizine may offer supplementary control over histamine-induced bronchoconstriction, providing a valuable adjunct to bronchodilators and inhaled corticosteroids. Emerging evidence suggests that cetirizine may reduce the frequency and severity of asthma exacerbations, particularly in allergic subtypes triggered by environmental allergens ^98,99.

Exploration of Novel Cetirizine Formulations and Delivery Systems

The development of novel drug delivery systems for cetirizine represents a significant frontier in improving both its efficacy and patient compliance. Traditional oral formulations of cetirizine are being enhanced through the introduction of orally disintegrating tablets (ODTs), intranasal sprays, and transdermal patches, which offer faster onset of action and greater convenience, particularly for patients with difficulties swallowing pills. Moreover, research into nanoparticle-based delivery systems aims to increase cetirizine’s bioavailability, allowing for sustained-release formulations that could extend the duration of histamine blockade. Such advancements are especially relevant in chronic allergy sufferers, where once-daily or even once-weekly dosing could greatly improve adherence and overall treatment outcomes ¹⁰⁰.

Conclusion

In conclusion, cetirizine has emerged as a critical therapeutic agent in managing histamine-mediated allergic reactions, thanks to its potent and selective antagonism of H1 receptors. The review comprehensively highlighted its efficacy across various allergic conditions, such as food allergies, atopic dermatitis, allergic conjunctivitis, and drug-induced allergies. Cetirizine’s well-established pharmacokinetic and pharmacodynamic profiles, including rapid absorption, high H1 receptor selectivity, and minimal sedative effects, contribute to its broad therapeutic applications. Moreover, its ability to prevent histamine-induced inflammation and allergic symptoms without significant CNS effects underscores its superiority over first-generation antihistamines. Cetirizine demonstrates consistent efficacy and safety in treating emerging allergic conditions across both pediatric and adult populations, making it a suitable option for long-term management. While combining cetirizine with other medications like corticosteroids, leukotriene receptor antagonists, or biologics can significantly improve outcomes in challenging cases, its effectiveness in severe allergic reactions when used alone might be limited. Mild side effects such as drowsiness and digestive issues are generally well-tolerated, highlighting its favorable safety profile. Future research should prioritize personalized treatment approaches for cetirizine, particularly considering how individual genetic variations impact drug metabolism and allergic responses. Moreover, innovative drug delivery systems and prophylactic use in high-risk groups hold promise for advancing allergy management. As allergies continue to rise globally, cetirizine’s role as a key antihistamine will remain vital, with ongoing research needed to optimize its clinical utility in diverse allergic diseases.

Acknowledgment

The authors are deeply grateful to the Guru Nanak Institute of Pharmaceutical Science, Gupta College of Technological Sciences, Dr. B. C. Roy College of Pharmacy and Allied Health Sciences, and Bharat Technology for their support in accomplishing this work. 

Funding Sources

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Conflict of Interest

The author(s) do not have any conflict of interest.

Data Availability Statement

This statement does not apply to this article.

Ethics Statement

This research did not involve human participants, animal subjects, or any material that requires ethical approval.

Informed Consent Statement

This study did not involve human participants, and therefore, informed consent was not required.

Clinical Trial Registration

This research does not involve any clinical trials 

Author contributions

• Suman Ghosh: Writing – Original Draft, Visualization, Conceptualization, Methodology, Analysis
• Ishita Debnath: Writing – Original Draft, Visualization, Conceptualization, Methodology, Analysis
• Sobhanjan Bhunia: Writing – Original Draft, Visualization, Conceptualization, Methodology, Analysis
• Supriya Hazra: Funding Acquisition, Resources
• Sumit Nandi: Writing – Review and Editing, Supervision, Funding Acquisition
• Sudip Kumar Mandal: Writing – Review and Editing, Supervision
• Sneha Mallya: Funding Acquisition, Resources
• Souvik Chakraborty: Funding Acquisition, Resources
• Aditya Raj Shaw: Funding Acquisition, Resources
• Soumyadip Patra: Funding Acquisition, Resources
• Rajia Khatun: Funding Acquisition, Resources

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Abbreviations

APCs: Antigen-presenting cells, Th2 cells: T-helper cell 2, IL: Interleukin, GPCR: G Protein-coupled receptor, DAG: Diacylglycerol, IP3: Inositol Trisphosphate, PGD2: Prostaglandin D2, LCT4: Leukotriene C4, ICAM: Intracellular Adhesion Molecule, ECP: Eosinophil Cationic Protein, CNS: Central Nervous System, Ig: Immunoglobulin, LT: Leukotriene, MBP: Mannose-Binding Protein, PGs: Prostaglandins, GTP: Guanosine triphosphate, PKC: Protein kinase C, PKA: Protein kinase A, MAPK: Mitogen-activated protein kinase, cAMP: Cyclic adenosine 3′,5′-monophosphate, CNS: Central Nervous System, TM: Tuberomammillary, VMAT2: Vesicular monoamine transporter 2, NSAIDs: Nonsteroidal Anti-Inflammatory Drugs,