This (AR) type of hypersensitivity reaction occurs by immunoglobulin E (IgE). 17 IgE release is a reaction of cytokine secretion (Interleukin) that occurs when numerous inflammatory cells (mast cells, T cells, CD4 macrophages and infiltrated eosinophils, etc.) are exposed to the allergen. 18

When individual remain unguarded to allergen mostly airborne dust, faeces of mite, cockroach residue, mould, pollens, food, and animal hackles then IgE is secreted by plasma which initiates the release of cysteinyl leukotrienes, prostaglandin D2 and histamine etc. This release is responsible for triple response (dilation of arteriole, flare and increase of vascular permeability) and for critical characteristics of AR which is itching, runny nose, red eyes, sneezing, nasal pruritus, air flow obstruction, blockage and mucous secretion. These symptoms appear within minutes after exposure. 19 The pathogenesis of AR is shown in Figure 1.

Figure 1

There are different ways to classify rhinitis.

It is very difficult to fit patients in one system so nowadays according to symptoms like duration and severity they are classified as shown in Table 2.

AR is differentiated in two ways, first by what pathophysiological mechanism it arises and the second intensity of the critical symptoms or observable features. Personalized medicine is also drug of choice nowadays. 20, 21

Duration and severity can be estimated using numerical values (with 0 representing none, 1 for mild or less than 30min, 2 moderates, 3 for severe condition). They are judged according to interferences with daily activity. 22

Many factors are responsible for AR. Some components that must be examined to suspect main allergen are shown in Table 3.

Diagnosis is easy when symptoms are clearly observed after exposure to the triggering allergen. Spirometer and computed tomography are used to detect subclinical asthma and sinusitis respectively. 22 Basically, AR diagnosis depends on indication of sensitivity, presence of IgE in serum and by positive epicutaneous skin test where triple response is observed using allergen extracts. 23

It is also diagnosed according to its typical history and “sneezers and runners”. Some tests are mentioned below to test nasal obstruction

The main aim of any drug is relief of symptom. The rationale for treatment choice mostly depends on its level of efficacy, affordability and presence of drug in WHO essential list of drugs. 26

If we see the therapeutic option presented possibility to treat AR it incorporates avoidance, Pharmacotherapy (intranasal corticosteroid, leukotriene receptor antagonist, antihistaminic, decongestants, mast cell stabilizer, cromolyn) and allergen immunotherapy. 8, 17 Every line of treatment has different pharmacological response, advantages and disadvantages as shown in Table 4.

Histamine is biological amine (L-histidine) produced by decarboxylation in presence of enzyme histidine decarboxylase (HDC). 29 Basically histamine receptors are of 4 sub types (heptahelical G-protein coupled receptors) namely H1 (chromosome 3) (anti-allergic & anti-inflammatory), H2 (gastric acid related disorder), H3 (cognitive disorder) and H4 (immune and inflammatory disorder). Histamine is responsible for contraction of smooth muscle, gastric acid secretion, neurotransmitter activity (itching and sneezing), glandular secretions (rhinorrhea) in nose and enhancement of vascular permeability (edema and blockage). Histamine through the H1 release down regulates humoral immunity and upregulates TH1 proliferation, interferon-production, cellular adhesion molecule expression, and chemotaxis of eosinophils and neutrophils. Through transcription factor, nuclear factor-kB, they also decrease antigen presentation, expression of proinflammatory cytokines and cell adhesion molecules, and chemotaxis. 30

Effect of food (grapefruit juice) and drug is also observed on antihistaminic response of drug. Ketoconazole, cyclosporine, verapamil, itraconazole, erythromycin, azythromycin or rifampin alter the plasma concentration of drug. 31 It is main key which is responsible of immunomodulation, allergy [generation of (IgE)], inflammation, haematopoiesis, cell proliferation embryonic development, regeneration, and wound healing. Histamine exposure leads to erythema, pruritus, nasal congestion, flushing, headache, hypotension, tachycardia and bronchoconstriction. 32

Symptoms occur due to activation of H1-receptor-coupled G_q/11 which trigger inositol phospholipid signalling pathway and increases intracellular calcium concentration by formation of Inositol-1,4,5-triphosphate (InsP3) and diacylglycerol (DAG). Phospholipase D and phospholipase A2 are also activated. 33

Histamine producing neuron (~64000) presents tuberomammillary nucleus of the human brain in cerebrum, cerebellum, posterior pituitary and spinal cord and released when activated. 34

As present in brain H1-receptors responsible for circadian sleep/wake cycle, reinforcement of learning and memory, fluid balance, suppression of feeding, control of body temperature, control of cardiovascular system and mediation of stress-triggered release of ACTH and β-endorphin from the pituitary gland. 35

H1 antihistaminics are inverse agonist/neutral antagonist or receptor antagonists still a theory to justify. Antihistaminic is effective and safe in treatment of nasal itch, watery eye, sneezing and rhinorrhoea but less effect on nasal congestion. It is popular in children (aged 3-13) specially. 28

H1 antihistamines are extensively used in relieving from different condition such as seasonal and perennial allergic rhinitis, urticaria, mild-moderate seasonal asthma and angioedema etc.

According to classification both first and second generation antihistaminics are over the counter (OTC) drug. But choosing second generation is for considering it on daytime also and have more advantage which will be discussed later. 22

These drugs are usually classified as older ‘first-generation H1-antihistamines’. They are widely used in the treatment of allergic rhinitis, allergic conjunctivitis, urticaria, cough, cold and insomnia. They cross (blood brain barrier) BBB easily but show poor selectivity toward receptor. As they are derived from the same chemical stem from which cholinergic muscarinic antagonists, tranquillizers, antipsychotics and antihypertensive agents were developed so has side effect of these drugs. Drowsiness, sedation, somnolence, fatigue, hang-over are also observed with altered sleep/wake cycle. 36

It is also reported that whenever accident happen excluding alcohol/drug there is always first-generation H1-antihistaminic was found in post-partum report. Study shows there were 338 accidents (6% of total) where the pilot’s blood sample was found to contain first-generation H1-antihistamine responsible for plane crash.

Many first-generation H1-antihistamines are found dangerous to children like in US promethazine comes with ‘boxed warning’ and from studies in 3000 patients, diphenhydramine (cardiac repolarization) and chlorpheniramine were reported causing 27 and 11 deaths, respectively. 37

First-generation H1 antihistamines are highly liposoluble, they have low molecular weight and a high degree of affinity for cerebral H1 receptors, as a result sedation occurs frequently, even at therapeutic doses. 38

They also show adverse effect on cardiac system like Cardiac arrhythmias caused by hydroxyzine, diphenhydramine, orphenadrine, pheniramine and chlorpheniramine while promethazine cause syncopal attacks with frequent ventricular tachycardia and torsade de pointes. On CNS Seizure was also observed in cases of hydroxyzine, diphenhydramine and orphenadrine. 39

Second-generation H1 antihistamines, in contrast, have high molecular weight, low liposolubility and low affinity for cerebral H1 receptors. Therefore, the majority of compounds in this generation, at therapeutic doses, are apparently devoid of significant side effects on the CNS. 37

Second-generation compounds act as inverse agonist. They are less sedating due to limited penetration to BBB and also highly specific to H1 receptor. Hopefully there is no report found related to accident related to second-generation H1-antihistamines side effect. They also have additional anti-allergic properties different from antihistaminic activity. 39, 40 It is used in the treatment of Allergic rhinitis, Atopic dermatitis, Acute and chronic urticaria, Insect bites, stings and Seasonal asthma with allergic rhinitis. They also produce rapid onset of action. 41

In patients with AR, H1 antihistamines improve itching, sneezing and watery rhinorrhoea except nasal obstruction. They affect on symptoms nasal and ocular both. 40 All second-generation H1 antihistamines, with the exception of cetirizine, levocetirizine and fexofenadine, are metabolized via the cytochrome system. The P4503A (CYP3A) cytochrome, is known to be involved in the metabolism of many drugs used on humans. 42

After oral administration at usual dosages, they rapidly achieve peak concentration in tissues. The majority of them begin to act within 1 to 2 hours after administration, with effects up to 24 hours, and hence can be taken once a day. Their activity does not diminish with regular, daily use for prolonged periods. These compounds maintain the capacity both to suppress the wheal and flare induced by histamine and to control the symptoms of persistent allergic rhinitis and chronic urticaria, for weeks and months. 43

It is observed that second generation H1 antihistaminic show adverse effect on cardiac system. But three drugs namely cetirizine, levocetirizine and fexofenadine are safe. The other problem like drying of mouth, tachycardia and urinary retention which is reported in use of First generation H1 antihistaminic are countered by second generation. 44

These reports contrast markedly with the report of an 18-month-old boy, weighing only 13 kg, who drank approximately 18 ml of cetirizine solution, corresponding to a dose of 180 mg, some 50 times the recommended dose. The toddler tolerated the overdose with virtually no complications. Levocetirizine and loratadine also show same result. 45

The most frequently used Four second-generation H1 receptor antagonists are desloratadine, loratadine, fexofenadine, cetirizine and levocetirizine. 46

Second generation antihistaminics also have some side effect related to cardio and CNS disorder like Astemizole, Desmethylastemizole, Terfenadine (also observed convulsion) and Fexofenadine shows prolonged QT effect. Different comparative tolerability of second/third generation H1 antihistaminic drugs is shown in Table 5.

Levocetirizine (Xyzal^®) ‘third generation’ is the active R-enantiomer of cetirizine with chemical formula C₂₁H₂₅ClN₂O₃ and chemical name of piperazine class. 46 It is 2-(2-{4-[(R)-(4-chlorophenyl) (phenyl)methyl] piperazin-1-yl} ethoxy) acetic Acid as shown in fig 2.

Figure 2

Levocetirizine (5mg) has demonstrated a 2-fold higher affinity, less sedative effect 48 for the human H1-receptor compared to cetirizine, and an approximately 30-fold higher affinity than dextrocetirizine. 49

Comparison of the neurological event like somnolence (2.3, 0), nervousness (1.3, 0.4) and fatigue(3.3,0) between cetirizine and levo cetirizine were found respectively.

A New Drug Application (NDA) to the United States Food and Drug Administration (FDA) for approval of levocetirizine was granted in May, 2007. Comparative studies shows that levocetirizine had a higher clinical response rate than loratadine in allergic rhinitis, and a more pronounced and longer lasting inhibition of histamine mediated wheal and flare skin reactions than loratadine 10 mg. 47 Many studies demonstrate that the antihistaminic properties noted for cetirizine in the management of seasonal and perennial allergic rhinitis are probably due to the levocetirizine enantiomer. 50

It is selective, potent, oral histamine H1 antagonist of the latest generation receptor which is allowed for symptomatic treatment of chronic idiopathic urticaria, seasonal allergic rhinitis, and hay fever. Levocetirizine is non-sedating, selective histamine H1 receptor antagonist, with antihistamine, antiangiogenic and additional anti-inflammatory activities. 46, 50

Levocetirizine have lower volume of distribution may be due to high protein binding compared to both isomers. Great configurational stability of levocetirizine is also observed in body. 51

The most frequently used second-generation H1 receptor antagonists are desloratadine, loratadine, fexofenadine, cetirizine and levocetirizine. 46

Binding-affinity constants were found to be 0.9 nmol/L for desloratadine, 5.0 nmol/L for fexofenadine and 0.6 nmol/L for levocetirizine at a pH of 5.8. Increasing the pH to 7.4 resulted in a binding affinity constant of 7.4 nmol/L for levocetirizine. Desloratadine has a higher H1 receptor affinity than other second-generation antihistamines at nearly 200 times that of fexofenadine, >50 times that of loratadine and cetirizine, and three times that of levocetirizine. 52

In 2005, Potter published a 4-wk clinical trial of the efficacy and safety of levocetirizine and health-related quality of life in children aged 6–12 yr with perennial allergic rhinitis.⁴ His study showed that levocetirizine had significant improvement in 2- and 4-week of total four symptom scores compared with a placebo. In conclusion, a 12-wk treatment program showed that cetirizine was more efficacious than levocetirizine. Twice daily for oral intake of levocetirizine may be an alternative way to well control the symptoms of perennial allergic rhinitis in age 6- to 12-yr-old children. 53

Fexofenadine and levocetirizine are devoid of any clinically relevant anticholinergic activities but desloratadine (due to high potency). 54

Levocetirizine is approved in the US and EU for relief of symptoms of SAR, perennial/persistent AR and CIU patients aged ≥6 years. 46, 53

Levocetirizine has shortest onset of action as compared to other drugs. But on CNS effects like somnolence, drowsiness and psychomotor impairment was reported high for levocetirizine compared to other. 46

Desloratadine, fexofenadine and levocetirizine are not considered to be significant P-gp inhibitors. On long use decrease plasma concentration and bioavailability is observed in case of desloratadine. 46

Levocetirizine does not undergo extensive metabolism. It is notably not metabolized by the Cytochrome P450 system. It does not show any drug -drug interaction either. 51

Comparison of these drugs for every age shows that levocetrizine is suitable in every age especially for younger ones. Even compared to its isomer there is no need to increase dose in children for clearance issue.

Levocetirizine undergoes a low degree of first pass metabolism in the liver; it is metabolized to a limited extent by oxidative dealkylation to metabolite with negligible antihistaminic activity. It is approximately 93% bound to plasma proteins and has a plasma elimination half-life of 8-9 h that does not change with multiple dosing. Food had no effect on the extent of levocetirizine exposure (AUC) but T_max was delayed by 1.7 hours and C_max was decreased by 23% in the presence of food. 50, 51, 55, 56

As compared to cetirizine is shows high selectivity and twice affinity for H1 receptors. It is rapidly absorbed have prolonged effect as prescribed once a day(5 mg/day). 47 Levocetirizine have significant improvement in nasal flow and symptom score compare to other. Additionally, it also uses in prevention of immediate and late symptoms resulting from insect bites. Levocetirizine does not interact significantly with any of the muscarinic receptor subtypes and therefore does not exhibit strong anticholinergic effects. It is safe and well-tolerated compound compare to other. It does not cause sedation or other harmful effects on cognitive and psychomotor abilities of healthy volunteers. In patients with persistent AR and chronic idiopathic urticaria, it significantly enhances quality of life and reduces the cost of prolonged treatment. 40, 48

There are many types of formulation of Levocetirizine nowadays available which show good effectiveness and safety for long term use as compare to other drug shown in table 6.

The pharmacological characteristics of antihistaminics show that second generation are better as compare to first generation. They show less toxic and sedative effect. Second generation H1 antihistaminics are highly effective and safe with lesser interaction. Many type of such formulation are available in market related to treat AR. But most promising molecules are fexofenadine, loratadine and levocetirizine. If we compare these three, levocetirizine has many plus like used in insect bite, anti-inflammatory with zero drug-drug interaction and safest in paediatric purpose. The active component levocetirizine (R-isomer) possesses almost ideal pharmacological and pharmacokinetic properties as an antihistamine with low incidents of CNS side effects, because compared to cetirizine (88-90%), levocetirizine (91.2%) have high protein binding show low volume of distribution which decrease risk of drug-drug interaction and dose-dependent toxicity. Levocetirizine could serve as a good example for medicinal chemists to design zwitterion drugs from an acidic, basic or neutral lead molecule for various biological targets, particularly those requiring low CNS penetration for avoiding obvious CNS side-effects. It is an extensively investigated antihistamines for safety and efficacy in children of different ages ranging from 6 months to 12 years. Compared with cetirizine, desloratadine, fexofenadine and mizolastine; levocetirizine seems to have a favourable PK profile with respect to absorption, plasma protein binding or volume of distribution, suggesting a potentially greater therapeutic index for this antihistamine. Real-life studies have indicated good satisfaction levels with levocetirizine for the majority of patients.