medical ppt
TRANSCRIPT
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.
.
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