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)

• 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

Symptoms

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

Histamine/Receptors Biology

• 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

Historical Aspects

Overview of 4 Histamine Receptors

.

Receptor Location Activities

Nasal Symptoms Produced

H1

Blood vessels, sensory nerves(smooth muscle bronchi, GI tract, cardiac tissue, endothelium, CNS)

Increases vascular permeability, stimulation sensory nerves of airways, eosinophil chemotaxis, smooth muscle contraction in bronchi and GI tract, stimulation of vagal nerve receptors producing reflex smooth muscle contraction in airways, decreased AV node conduction time, enhancement of release of histamine and arachidonic acid derivatives, nitric oxide formation

Sneezing, itching, rhinorrhea, and perhaps some degree of nasal congestion via increased vascular permeability with leakage of fluid into the tissues and vasodilatation

H2

Vascular bed, epithelium of mucosa of nose, submucosal glands in nose, mucosa of stomach, CNS, cardiac tissue, uterus, smooth muscle

Stimulate mucous glands in airways, increases vascular permeability, direct chronotropic effect on atrium and inotropic action on ventricle, relaxation of esophageal sphincter, stimulation of suppressor T-cells, decrease in neutrophil and basophil chemotaxis and activation, proliferation of lymphocytes, activity of NK cells

Potentially increase nasal airway swelling, producing nasal decongestion

H3

Presynaptic nerves in the peripheral sympathetic adrenergic system, nasal submucosal glands, CNS (histaminergic nerves), airways, GI tract

Suppression of norepinephrine release at presynaptic nerve endings, stimulates nasal submucosal gland secretion, opposes bronchoconstriction and gastric acid

Can produce nasal congestion by prevention of nor-epinephrine release and activity on adrenergic post-synaptic receptors

H4

Eosinophils, mast cells, basophils neutrophils, nasal turbinates (nerves), lung colon, epicanthus, bone marrow, spleen, liver

Chemotaxis and chemokinesis of mast cells and eosinophils, enhancement of the activity of other chemoattractants (e.g., chemokines) on eosinophils, upregulation of adhesion molecules

Could enhance the inflammatory response to nasal allergen exposure

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.

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Mechanism of Allergic Reaction

IgEproduction

Allergens

T- and B-cellinteraction

Cellular infiltration• Eosinophils• Neutrophils• Monocytes• Basophils

Chemical mediators

HistamineLeukotrienes

Prostaglandin D2

Kinins

Early-phase reactionsymptoms

• Itching

• Sneezing

• Rhinorrhea

• Nasal congestion

Late-phase reactionsymptoms

• Nasal congestion

• Nasal hypersensitivity

• Rhinorrhea

Mast Cells

Cell mediatores and syptomes of rhinitis

Rhinorrhoea

Sneezing

HistamineEndothelin

MEDIATORS

Blockage

HistamineLeukotrienes

Endothelin

Histam

ine

Endothelin

HistamineLeukotrienes B4/C4/D4

Prostaglandins D2/E2/I2

Kinins

Itching

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

AR and Comorbid Airway Disease

AllergicRhinitis

Economic 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

Societal Impact of Allergic Rhinitis

Allergic Rhinitis (AR)

The treatment of allergic rhinitis combines:

• Environmental controls (allergen avoidance)

• Pharmacotherapy

• Immunotherapy

• Education

Recommendations from ARIA

Bousquet J, et al. Allergy 2002;57:841–855.

Allergic Rhinitis (AR)

• 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

Environmental Control Measures

Allergic Rhinitis (AR)

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

Pharmacologic Therapy

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

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

Allergic Rhinitis (AR): Pharmacotherapy

DrugRhinorrhe

a Nasal Itch SneezingCongestio

n Ocular Sxs

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 MedicationsGroup name / Generic name Mechanism of Action Side Effects

Topical H1-antihistamines

azelastine; olopatadine

• Block H1-receptor/ inverse agonist

• Some anti-allergic activity for azelastine

• Minor local side-effects• Azelastine: most common side effect is bitter

taste

Oral H1-antihistamines (Second

generation):acrivastine; cetirizine; desloratadine;

fexofenadine; levocetirizine; loratadine

• Block H1-receptor/ inverse agonist

• Some anti-allergic activity• No development of tachyphylaxis

• Acrivastine, cetirizine, levocetirizine have sedative effects

• No anticholinergic effect• No cardiotoxicity for products still available

Intranasal corticosteroidsbeclomethasone; budesonide;

ciclesonide; flunisolide; fluticasone furoate; fluticasone propionate;

mometasone; triamcinolone

• Reduce nasal inflammation• Reduce nasal hyperreactivity

• Minor local side-effects (nasal irritation, bleeding occur; rare septal perforation)

• Growth concerns

Oral/intramuscular (IM) glucocorticosteroids

dexamethasone; hydrocortisone;methylprednisolone; prednisolone;

prednisone; triamcinolone

• Potently reduce nasal inflammation

• Reduce nasal hyperreactivity

• Systemic side-effects common for IM drugs• Depot injections may cause local tissue

atrophy

Local chromones (intranasal/intraocular)

nedocromil sodium; cromolyn sodium

• Mechanism of action poorly known

• Minor local side-effects• Excellent safety

Oral decongestantsphenylephrine hydrochloride;

pseudoephedrine hydrochloride

• Sympathomimetic drug • Relieve symptoms of nasal

congestion

• Hypertension, palpitations, restlessness, agitation, tremor, insomnia, headache, dry mucous membranes, urinary retention, exacerbation of glaucoma, thyrotoxicosis

Intranasal decongestantsoxymetazoline hydrochloride;phenylephrine hydrochloride

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

less intense• Rhinitis medicamentosa

Intranasal anticholinergicsipratropium bromide

• Anticholinergics block exclusively rhinorrhea

• Minor local side-effects, dry nasal membranes

• Almost no anticholinergic activity

Oral leukotriene antagonists (LTRA)montelukast sodium; zafirlukast

• Block cysteinyl leukotriene receptor

• Excellent safety

Combination Therapy for AR

Combination Therapy Therapeutic Considerations

Oral antihistamine with oral decongestant More effective relief of nasal congestion than antihistamines alone

Oral antihistamine with oral LTRA

• 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

Antihistamine, oral with intranasal antihistamine

Combination may be considered, although controlled studies of additive benefit lacking

Antihistamine, oral with intranasal corticosteroids

Combination may be considered, although supporting studies limited and many studies unsupportive of additive benefit of adding an antihistamine to an intranasal steroid

Intranasal anticholinergic with intranasal corticosteroid

Concomitant use of ipratropium bromide nasal spray and an intranasal corticosteroid is more effective for rhinorrhea than administration of either drug alone

Intranasal antihistamine with intranasal corticosteroid

• 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

LTRA, oral with intranasal corticosteroid Subjective additive relief in limited studies, data inadequate

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

Mechanism of actionAzelastine hydrochloride Fluticasone propionate

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

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)

• 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

Guidelines

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

Onset of Action

• 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

For Selected Intranasal Sprays

Buck ML. Pediatr Pharm. 2001;7.

Intranasal vs. Oral Antihistamines: Second Generation

P<.001 vsplacebo

Intranasal Intranasal Antihistamines Antihistamines

Leading Oral Leading Oral AntihistaminesAntihistamines

Treats symptoms from seasonal allergies (indicated for SAR) Treats symptoms from environmental irritants (indicated for VMR) Relieve nasal itching, sneezing, and rhinorrhea Relieves nasal congestion without added decongestant

Topical administration Well-tolerated with low discontinuation rates Documented anti-inflammatory properties

Impr

ovem

ent f

rom

Bas

elin

e TN

SS a

fter

2

Wks

of T

xl S

pray

vs.

Flu

ticas

one

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

Intranasal Antihistamines vs. Intranasal Corticosteroids: Azelastine AND Fluticasone

2-Week Treatment in Patients with SAR and Moderate-Severe Symptoms

-37.9*

-27.1-24.8

*p=0.042 vs. fluticasone and p=0.016 vs. azelastine

Combination = Fluticasone AND 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

-37.9*

-27.1

*Azelastine + Fluticasone; P<.05 vs Fluticasone

†Azelastine + Fluticasone; P<.05 vs Azelastine

TNSS=Total Nasal Symptom Score

Azelastine + Fluticasone Fluticasone Azelastine

Imp

rovem

en

t (%

)

50 †

0

10

20

30

40

TNSS Congestion Itchy Nose

Runny Nose

Sneezing

*†

*†

*†*

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