**4. Antihistamines**

Histamine is one of the main mediators of allergic reactions occurring as a result of contact between the allergen and the nasal mucosa. Its actions are not limited to triggering of the signs and symptoms of the early phase of the allergic reaction but are also implicated in the release of multiple proinflammatory cytokines, with a vasoactive effect that favors arrival in the nasal zone of a range of cellular elements that characterize allergic inflammation.

Antihistamines inhibit the effects of histamine at H1 receptors. Histamine is a physiologically active, endogenous substance that binds to and activates histamine H1 and H2 receptors in the respiratory tract (including the nose), the gastrointestinal tract, brain, adrenal medulla, skin vasculature, and the heart (Golightly & Greos, 2005).

#### **4.1 Oral antihistamines**

The antihistamines exert a number of effects upon the histamine receptor. On one hand, it is now clear that all known antihistamines act as reverse agonists, inactivating the intracellular actions of the receptor. On the other hand, antiinflammatory effects have been demonstrated for these drugs, explained by modulation of nuclear factor NF-κB, such as the inhibition of ICAM-1 expression or action upon the bradykinins (Leurs et al, 2002).

Antihistamines are classified (Handley et al, 1998) as first generation (sedating, including chlorpheniramine, diphenhydramine, promethazine, and hydroxyzine) and newer. The newer antihistamines are sometimes referred to as second generation (relatively nonsedating, including terfenadine, astemizole, loratadine, cetirizine, and levocetirizine) and third generation (including fexofenadine, norastemizole, and descarboethoxyloratadine) (Table 2).

Antihistamine drugs are the most commonly used pharmaceutical group. The effective use of anti-H1 (in its oral, intranasal and ophthalmic presentations) for the treatment of AR

Nevertheless, is cautioned that nasal irrigation with saline solutions could no longer be considered a mere adjunct treatment of rhinosinusitis (Brown & Graham, 2004). Despite

Metson lends support to the conviction that saline irrigation improves breathing and adds, more importantly, that it lengthens the time between relapses (Metson, 2004). Daily saline irrigation improves the quality of life of patients with sinusitis, decreasing symptoms and

Nasal irrigation is a simple and inexpensive treatment that improves symptoms of a variety of sinonasal diseases, reduces the use of resources and helps minimise resistance to antibiotics (Papsin & McTavish, 2003). Also, nasal lavage improves endoscopic imaging of nasal mucosa and the quality of life of patients with chronic rhinosinusitis (Taccariello et al, 1999). The nasal lavage increases mucociliary flow, dilutes thick secretions, relieves irritated mucous membranes, eliminates crusts and foreign bodies, facilitates the healing of mucous membranes, reducing the need for blowing and improving the sense of smell. The sinus irrigation by itself prevented the need for surgery in 58% of patients with chronic sinusitis

Histamine is one of the main mediators of allergic reactions occurring as a result of contact between the allergen and the nasal mucosa. Its actions are not limited to triggering of the signs and symptoms of the early phase of the allergic reaction but are also implicated in the release of multiple proinflammatory cytokines, with a vasoactive effect that favors arrival in

Antihistamines inhibit the effects of histamine at H1 receptors. Histamine is a physiologically active, endogenous substance that binds to and activates histamine H1 and H2 receptors in the respiratory tract (including the nose), the gastrointestinal tract, brain,

The antihistamines exert a number of effects upon the histamine receptor. On one hand, it is now clear that all known antihistamines act as reverse agonists, inactivating the intracellular actions of the receptor. On the other hand, antiinflammatory effects have been demonstrated for these drugs, explained by modulation of nuclear factor NF-κB, such as the inhibition of

Antihistamines are classified (Handley et al, 1998) as first generation (sedating, including chlorpheniramine, diphenhydramine, promethazine, and hydroxyzine) and newer. The newer antihistamines are sometimes referred to as second generation (relatively nonsedating, including terfenadine, astemizole, loratadine, cetirizine, and levocetirizine) and third generation (including fexofenadine, norastemizole, and descarboethoxyloratadine)

Antihistamine drugs are the most commonly used pharmaceutical group. The effective use of anti-H1 (in its oral, intranasal and ophthalmic presentations) for the treatment of AR

the nasal zone of a range of cellular elements that characterize allergic inflammation.

adrenal medulla, skin vasculature, and the heart (Golightly & Greos, 2005).

ICAM-1 expression or action upon the bradykinins (Leurs et al, 2002).

being effective and safe, it is underused.

the use of medication (Rabago et al, 2002).

over a year (Hartog et al, 1997)

**4. Antihistamines** 

**4.1 Oral antihistamines** 

(Table 2).


\* Doxepin has dual H1- and H2- antihistamine activities and is classified as a tricyclic antidepressant.

Table 2. H1-antihistamines: chemical and functional classification (modified: Simons, 2004; Simons & Akdis, 2009; Simons & Simons, 2011).

(seasonal or perennial) in children or adults is backed by significant evidence from published clinical trials (ARIA).

In the new classification of rhinitis and in the clinical practice guidelines promoted in the ARIA document, oral anti-H1 is recommended for use in intermittent and persistent mild AR, and combined with topical corticosteroids in persistent moderate/severe AR. It shows good response in seasonal AR, where symptoms mediated by histamines predominate and ocular symptoms are common. In persistent AR, in which congestion is significant, anti-H1 has a moderate effect.

Oral antihistamines may cause subclinical side effects not noticed by the patient (somnolence, decreased coordination, etc.). This does not happen with the new non-sedating antihistamines, but generally up to 50% of patients self-medicate (Storms, 1997).

Treatment with antihistamines in AR is almost universally accepted. In fact, the treatment of seasonal AR in children: The results of placebo-controlled trials of cetirizine (Allegra et al, 1993; Masi et al, 1993; Ciprandi et al, 1997a; Ciprandi et al, 1997b; Pearlman et al, 1997) and fexofenadine (Wahn et al, 2003) demonstrated significant improvements in symptoms with the study drug compared with placebo. Active-control studies compared cetirizine (Charpin

Treatment of Allergic Rhinitis:

**4.2.1 Levocabastine** 

efficacy is similar and that it has fewer side effects.

Hernández et al, 1995a; Conde Hernández et al, 1995b).

**5. Mast cell membrane stabilising drugs** 

**5.1 Disodium cromoglycate** 

ARIA Document, Nasal Lavage, Antihistamines, Cromones and Vasoconstrictors 73

studies have compared azelastine nasal spray with other oral antihistamines, finding that its

Conde Hernandez et al compared the safety and efficacy of two antihistamines, azelastine in nasal spray and oral ebastine, for 14 days. Authors found no significant differences between the two treatments, considering both to be effective in the treatment of seasonal AR (Conde

Berlin et al compared the efficacy of topical nasal corticosteroids with antihistamines in nasal spray (azelastine), and found that the results with topical nasal corticosteroids were clearly superior for managing nasal symptoms of rhinitis. The authors recommended topical

The first antihistamine developed for nasal application, levocabastine is a highly selective histamine antagonist of the H1 receptor, and acts immediately (Janssens et al, 1991). Since it is eliminated through the kidneys, it should be used with caution in renal patients. It does not sedate or boost the effects of alcohol. The dose is 2 applications of 0.5 mg each every 12 hours in each nostril. It is more powerful than chlorpheniramine (Dechant & Goa, 1991) and similar to other oral antihistamines [loratadine (Swedish GP Allergy Team, 1994) and terfenadine (The Livostin Study Group, 1993)] and disodium cromoglycate (Fisher, 1994).

In 1995, a study was published on 21 patients with AR sensitised to mites. The patients were treated with topical levocabastine, and a reduction of inflammatory mediators and nasal hyperreactivity was observed. The authors concluded that it was an effective antagonistic of H1 receptors, with immediate clinical response and few anti-inflammatory properties (de Graaf-in´t Veld et al, 1995). Previously in 1991, other spanish authors showed the efficacy of

Applied topically, these drugs are very useful in mild and moderate AR, as they lack systemic effects and are very well tolerated. To achieve effectiveness, appropriate application methods must be used so that an even distribution of the medication is achieved, especially if there is

Derived from the natural chromone Khellin, disodium cromoglycate (DSCG) is extracted

It is a dual chromone joined by a flexible chain. The chromone chain has a hydrogen atom

It is administered by inhalation because it is absorbed poorly orally. It has a plasma half-life


levocabastine in seasonal AR using a double-blind study (Palma-Carlos et al, 1991).

abundant rhinorrhoea (Okuda et al, 1985). The main drugs being used are:

from the *Ammi visnaga* plant, and was synthesised by Fisons (Cox, 1967).

of 80 minutes, and it reaches maximum levels in 20 minutes.

substituted by a sodium atom. It is a white powder that is barely water-soluble.

nasal corticosteroids as a first-line treatment of perennial AR (Berlin et al 2000).

et al, 1995) and loratadine (Boner et al, 1989) to first-generation antihistamines, with no significant differences between groups.

Various studies were identified which examined the efficacy of newer antihistamines among children with perennial AR (Baelde & Dupont, 1992; Jobst et al, 1994; Charpin et al, 1995; Pearlman et al, 1997; Sienra-Monge et al, 1999; Ciprandi et al, 2001; Yang et al, 2001; Lai et al, 2002; Wahn et al, 2003; Ciprandi et al, 2004; Hsieh et al, 2004). In three studies with active controls, cetirizine improved symptoms compared with placebo arms and compared with ketotifen and oxatomide (Lai et al, 2002). Cetirizine was comparable to montelukast in one study (Hsieh et al, 2004), but similar in efficacy in another (Chen et al, 2006). Three fairquality, placebo-controlled studies (Baelde & Dupont, 1992; Jobst et al, 1994; Ciprandi et al, 2001) found cetirizine efficacious for nasal symptoms, particularly at a dosage of 10 mg daily (either at bed time or divided doses twice daily) for children 6 to 12 years.

#### **4.2 Topical (intranasal) antihistamines**

Up until the late 80s, antihistamines had not yet been developed for local application. In the last 20 years, several clinical trials have been carried out on local application of various new generation antihistamines. Their marketing and use started almost 15 years ago.

#### **4.2.1 Azelastine**

Azelastine hydrochloride was initially researched for use in bronchial asthma, and is currently used in the symptomatic treatment of seasonal AR and for acute exacerbations of perennial AR. It is administered in an aqueous solution as a nasal spray, and was initially administered orally.

Clinical evaluation of its efficacy and side effects were carried out in several multicentre studies (Weiler & Meltzer, 1997). It does not affect driving ability or handling of machinery, but may occasionally irritate the mucous membrane and cause epistaxis.

One of the first studies with azelastine was published by Dorow, who performed two studies with pollen-allergic patients. The first study compared azelastine with a doubleblind placebo in 16 patients over one week. Significant improvement was noted in the group using the drug, with a decrease in sneezing (*P*<.01) and nasal pruritus (*P*<.01). There were no significant improvements in nasal congestion and hydrorrhoea (Dorow et al, 1993).

The second study was a double-blind comparison of 36 patients treated with either azelastine or budesonide for 15 days. There were no significant differences between the groups.

Weiler studied the effects of pre-treatment with azelastine in nasal provocation with grass pollens. Mean percent improvements in the total symptom complex severity scores for azelastine were statistically significant (*P*≤.05) or showed a trend toward statistical significance (*P*<.05 or *P*≤.10) versus placebo from the second through the first ten hours after the initial dose and for each of the last five hours of the second day, demonstrating a rapid onset of action and sustained efficacy over the 2-day study period (Weiler & Meltzer, 1997).

Grossman performed a double-blind study of 199 patients with perennial AR for 8 weeks, obtaining significant improvement when compared to placebo (Grossman et al, 1994). Other studies have compared azelastine nasal spray with other oral antihistamines, finding that its efficacy is similar and that it has fewer side effects.

Conde Hernandez et al compared the safety and efficacy of two antihistamines, azelastine in nasal spray and oral ebastine, for 14 days. Authors found no significant differences between the two treatments, considering both to be effective in the treatment of seasonal AR (Conde Hernández et al, 1995a; Conde Hernández et al, 1995b).

Berlin et al compared the efficacy of topical nasal corticosteroids with antihistamines in nasal spray (azelastine), and found that the results with topical nasal corticosteroids were clearly superior for managing nasal symptoms of rhinitis. The authors recommended topical nasal corticosteroids as a first-line treatment of perennial AR (Berlin et al 2000).
