Rethinking the Treatment of Allergic Rhinitis: The Role of Intranasal

Treatment of allergic rhinitis

The role of intranasal antihistamine
thToo Drugs” or a Novel Class?
 Prevalence of allergic
rhinitis
Prevalence of asthma
Objectives

• Describe patient's perspective of burden of allergic rhinitis

(AR) and unmet needs
• Discuss new place of intranasal antihistamines as first-line
therapies and compare and contrast this class of
medication to traditionally available medications
• Discuss potential for intranasal antihistamines to provide
relief superior to second-generation oral antihistamines
• Explain how intranasal antihistamines fit into the latest
guidelines
 Allergic Rhinitis (AR)
Symptoms

• Rhinitis is characterized by ≥1 of the following nasal

symptoms: congestion, rhinorrhea (anterior and
posterior), sneezing, and itching.
• Symptoms of AR may occur:
 Only during specific seasons
 Perennially with or without seasonal exacerbation
 Episodically after specific aeroallergen exposures
• Severity of AR ranges from mild and intermittent to
seriously debilitating
Wallace DV, et al. J Allergy Clin Immunol 2008; 122: S1-S84.
Histamine/Receptors Biology
Historical Aspects

• 1863: Mast cell first described (characterized in 1879 by

Ehrlich)
• 1910: Dale and Laidlaw smooth muscle and vessel
contraction
• 1927: Best found in human tissue
• 1927: Lewis demonstrated “H”-substance was released from
skin by antigen/antibody
• 1966-1983: discovery of 3 separate receptors
• 2000→present: discovery of 4th receptor and understanding of
the signaling process
 Overview of 4 Histamine Receptors
Receptor Location
H1 Blood vessels, sensory nerves Increases vascular permeability, stimulation
(smooth muscle bronchi, GI
tract, cardiac tissue,
endothelium, CNS)
Activities Nasal Symptoms
Produced
Sneezing, itching,
sensory nerves of airways, eosinophil rhinorrhea, and perhaps
chemotaxis, smooth muscle contraction in bronchi and some degree of nasal
GI tract, stimulation of vagal nerve receptors producing congestion via increased
reflex smooth muscle contraction in airways, decreased vascular permeability
AV node conduction time, enhancement of release of with leakage of fluid into
histamine and arachidonic acid derivatives, nitric oxide the tissues and
formation vasodilatation

H2 Vascular bed, epithelium of Stimulate mucous glands in airways, increases Potentially increase
mucosa of nose, submucosal vascular permeability, direct chronotropic effect on nasal airway swelling,
glands in nose, mucosa of atrium and inotropic action on ventricle, relaxation of producing nasal
stomach, CNS, cardiac tissue, esophageal sphincter, stimulation of suppressor T-cells, decongestion
uterus, smooth muscle decrease in neutrophil and basophil chemotaxis and
activation, proliferation of lymphocytes, activity of NK
cells
H3 Presynaptic nerves in the Suppression of norepinephrine release at Can produce nasal
peripheral sympathetic presynaptic nerve endings, stimulates nasal congestion by
adrenergic system, nasal submucosal gland secretion, opposes prevention of nor-
submucosal glands, CNS bronchoconstriction and gastric acid epinephrine release and
(histaminergic nerves), airways, GI activity on adrenergic
tract post-synaptic receptors
H4 Eosinophils, mast cells, Chemotaxis and chemokinesis of mast cells and Could enhance the
basophils neutrophils, nasal eosinophils, enhancement of the activity of other inflammatory response
turbinates (nerves), lung colon, chemoattractants (e.g., chemokines) on to nasal allergen
epicanthus, bone marrow, spleen, eosinophils, upregulation of adhesion molecules exposure
liver
Abbreviations: AV, atrioventricular; CNS, central nervous system; GI, gastro-intestinal; H1, H1-receptor; H2, H2-receptor; H3, H3-receptor; H4,
H4-receptor, NK cells, natural killer cells.

.
 Mechanism of Allergic Reaction

Chemical mediators Early-phase reaction

Mast Cells symptoms
Histamine • Itching
Allergens Leukotrienes • Sneezing
Prostaglandin D2 • Rhinorrhea
IgE Kinins
production • Nasal congestion

Late-phase reaction
T- and B-cell Cellular infiltration
symptoms
interaction • Eosinophils
• Neutrophils • Nasal congestion
• Monocytes • Nasal hypersensitivity
• Basophils
• Rhinorrhea

.
Cell mediatores and syptomes of
rhinitis

Sneezing

Itching

His othe
En
tam lin
d
Rhinorrhoea Histamine

in e
MEDIATORS
Histamine Endothelin
Leukotrienes Histamine
Endothelin Leukotrienes B4/C4/D4
Prostaglandins D2/E2/I2
Kinins
Blockage
 AR and Comorbid Airway Disease

Allergic
Rhinitis

Spector SL. J Allergy Clin Immunol. 1997;99:S773-S780.

Economic Impact of Allergic Rhinitis
Societal Impact of Allergic Rhinitis

• 28 million restricted days

• 800,000 days off work
– Days with decreased productivity unknown
• 2 million school days lost
• 20% symptomatic > 9 months/year
• 50% symptomatic > 4 months/year
 Allergic Rhinitis (AR)
Recommendations from ARIA

The treatment of allergic rhinitis combines:

• Environmental controls (allergen avoidance)
• Pharmacotherapy
• Immunotherapy
• Education
Bousquet J, et al. Allergy 2002;57:841–855.
Allergic Rhinitis (AR)
Environmental Control Measures

• Common allergic triggers: dust mites/insect emanations, fungi,

animal dander, pollens
• Dust mite: humidity control, bedding covers, HEPA filtration,
vacuuming of carpet, use of acaricides
• Indoor fungus: removal of moisture, replacement of contamination
materials, use of dilute bleach on nonporous surfaces
• Pollen: limit exposure to outdoors when high counts are present
• Animal dander: most effectively managed by avoidance
• Rhinitis triggered by irritants (e.g., tobacco smoke and
formaldehyde): best treated by avoidance
 Allergic Rhinitis (AR)
Pharmacologic Therapy

Selection of pharmacotherapy for patient

depends on multiple factors including:
•Type of rhinitis (e.g., allergic, nonallergic, mixed, episodic)
•Most prominent symptoms
•Symptom severity
•Patient age

Wallace DV, et al. J Allergy Clin Immunol 2008; 122: S1-S84.

 Allergic Rhinitis (AR): Pharmacotherapy

Selection of pharmacotherapy for patient depends on multiple factors including:

• Type of rhinitis (e.g., allergic, nonallergic, mixed, episodic)
• Most prominent symptoms
• Symptom severity
• Patient age
Drug Rhinorrhe Nasal Itch Sneezing Congestion Ocular Sxs
a
Antihistamines + + + -/+ +
(oral and nasal)
Nasal steroids + + + + -/+
Decongestants - - - + -
(oral and nasal)
Leukotriene modifier + -/+ + -/+ -/+
Mast cell stabilizer -/+ -/+ -/+ -/+ -
Nasal anticholinergics + - - - -
Ophthalmic topical - - - - +
Wallace DV, et al. J Allergy Clin Immunol 2008; 122: S1-S84.
 FDA-Approved Medications
Group name / Generic name Mechanism of Action Side Effects
Topical H1-antihistamines • Block H1-receptor/ inverse agonist • Minor local side-effects
azelastine; olopatadine • Some anti-allergic activity for • Azelastine: most common side effect is bitter
azelastine taste

Oral H1-antihistamines (Second • Block H1-receptor/ inverse agonist • Acrivastine, cetirizine, levocetirizine have
generation): • Some anti-allergic activity sedative effects
acrivastine; cetirizine; desloratadine; • No development of tachyphylaxis • No anticholinergic effect
fexofenadine; levocetirizine; loratadine • No cardiotoxicity for products still available

Intranasal corticosteroids • Reduce nasal inflammation • Minor local side-effects (nasal irritation,
beclomethasone; budesonide; ciclesonide;• Reduce nasal hyperreactivity bleeding occur; rare septal perforation)
flunisolide; fluticasone furoate; fluticasone • Growth concerns
propionate; mometasone; triamcinolone

Oral/intramuscular (IM)
glucocorticosteroids
dexamethasone; hydrocortisone;
methylprednisolone; prednisolone;
prednisone; triamcinolone
• Potently reduce nasal inflammation • Systemic side-effects common for IM drugs
• Reduce nasal hyperreactivity • Depot injections may cause local tissue
atrophy

Local chromones • Mechanism of action poorly known • Minor local side-effects

(intranasal/intraocular)
nedocromil sodium; cromolyn sodium
Oral decongestants
phenylephrine hydrochloride;
pseudoephedrine hydrochloride
• Excellent safety
• Sympathomimetic drug • Hypertension, palpitations, restlessness,
• Relieve symptoms of nasal agitation, tremor, insomnia, headache, dry
congestion mucous membranes, urinary retention,
exacerbation of glaucoma, thyrotoxicosis

Intranasal decongestants • Sympathomimetic drug • Same side-effects as oral decongestants, but

oxymetazoline hydrochloride; less intense
phenylephrine hydrochloride • Rhinitis medicamentosa
Intranasal anticholinergics • Anticholinergics block exclusively • Minor local side-effects, dry nasal
 Combination Therapy for AR
Combination Therapy
Oral antihistamine with oral decongestant
Oral antihistamine with oral LTRA
Antihistamine, oral with intranasal
antihistamine
Antihistamine, oral with intranasal
corticosteroids
Intranasal anticholinergic with intranasal
corticosteroid
Intranasal antihistamine with intranasal
corticosteroid
LTRA, oral with intranasal corticosteroid
Wallace DV, et al. J Allergy Clin Immunol 2008; 122: S1-S84.
Therapeutic Considerations
More effective relief of nasal congestion than antihistamines alone
• May be more effective than monotherapy with antihistamine or LTRA
• Less effective than INS
• An alternative treatment for patients unresponsive to or not compliant
with INS
Combination may be considered, although controlled studies of additive
benefit lacking
Combination may be considered, although supporting studies limited and
many studies unsupportive of additive benefit of adding an antihistamine
to an intranasal steroid
Concomitant use of ipratropium bromide nasal spray and an intranasal
corticosteroid is more effective for rhinorrhea than administration of either
drug alone
• Combination may be considered based on limited data
• Inadequate data about optimal interval between administration of the 2
sprays
• For mixed rhinitis, there may be significant added benefit to the
combination of an intranasal antihistamine with an intranasal
corticosteroid
Subjective additive relief in limited studies, data inadequate
 Mechanism of action
Azelastine hydrochloride
 H1-receptor antagonist
 broad spectrum of antiallergic and
anti-inflammatory activity.
 inhibitory effects on the synthesis of
leukotrienes, kinins, and cytokines and
the generation of superoxide free
radicals
Fluticasone propionate
 synthetic steroid of the
glucocorticoid
 mimics the naturally-occurring
hormone
 exerts its beneficial effects by
inhibiting several types of cells and
chemicals involved in allergic,
immune
and inflammatory responses.
 Allergic Rhinitis (AR)
Guidelines

• May be considered as 1st line treatment for AR and NAR

• Have rapid onset of action
• Are efficacious and equal to or superior to 2nd generation
antihistamines for treatment SAR
• Have been associated with a clinically significant effect on
nasal congestion
• Are generally less effective than INS
• May provide added benefit in combination

Wallace et al. J Allergy Clin Immunol 2008; 122: S1-S84.

 Onset of Action
For Selected Intranasal Sprays

• Azelastine: 15 – 30 minutes
• Olopatadine: within 30 minutes
• Beclomethasone: within 3 days
• Budesonide: 24 hours
• Ciclesonide: 12 – 24 hours
• Flunisolide: 4 – 7 days
• Fluticasone propionate: 12 hours – 3 days
• Mometasone: 12 hours – 3 days
• Triamcinolone: 24 hours
Buck ML. Pediatr Pharm. 2001;7.
 Intranasal vs. Oral Antihistamines:
Second Generation

Intranasal Leading Oral

Antihistamines Antihistamines
Treats symptoms from seasonal  
allergies (indicated for SAR)
Treats symptoms from environmental 
irritants (indicated for VMR) P<.001 vs
placebo
Relieve nasal itching, sneezing, and  
rhinorrhea
Relieves nasal congestion without 
added decongestant
Topical administration 
Well-tolerated with low discontinuation  
rates
Documented anti-inflammatory 
properties
Intranasal Antihistamines vs. Intranasal Corticosteroids:
Azelastine AND Fluticasone
2-Week Treatment in Patients with SAR and Moderate-Severe Symptoms

Combination =
Fluticasone
AND Azelastine
TNSS after 2 Wks of Txl Spray
Improvement from Baseline

vs. Fluticasone

-24.8
-27.1

-37.9*
p=0.042 vs. fluticasone and
*

p=0.016 vs. azelastine

Least-Squares Mean Values for 14
Study Days
Ratner PH, et al. Ann Allergy Asthma Immunol. 2008;100:74-81.
 Azelastine AND Fluticasone:
TNSS and Individual Symptoms

Azelastine + Fluticasone Fluticasone Azelastine

50 †
Improvement (%)

*†
40 *†
*
*†
30

20
-27.1
10

0 -37.9*
TNSS Congestion Itchy Runny Sneezing
Nose Nose
*Azelastine+Fluticasone; P<.05vsFluticasone

†Azelastine+Fluticasone; P<.05vsAzelastine

TNSS=Total Nasal SymptomScore

Ratner PH, et al. Ann Allergy Asthma Immunol. 2008;100:74-81.

 Recommendations

1-Patients with persistent rhinitis should be evaluated for asthma

2- Patients with persistent asthma should be evaluated for

rhinitis

3- A strategy should combine the treatment of upper and lower

airways in terms of efficacy and safety