Prof DR Dr Ariyanto Harsono SpA(K)
Definition: Impaired function of the nose after allergen exposure through IgE-mediated allergic inflammation
Prevalence: 10-25%
Impacts Social Quality of life Performance Schools Cost
2Prof DR Dr Ariyanto Harsono SpAK
1. Allergen
2.Aspirin
3.Polution
3Prof DR Dr Ariyanto Harsono SpAK
1. Allergen:-Inhalant House dust
Polen
Bulu hewan
Tungau
-Foods
4Prof DR Dr Ariyanto Harsono SpAK
Arachidonic Acid
Phospholiphase A
Cyccloxygenase Lipoxygenase
Prostaglandine
TXA
Prostacyclin
Leukotriene A
Leukotriene B
Leukotriene C
Aspirin
2. Aspirin
HETE,5-HETE, PAF5Prof DR Dr Ariyanto Harsono SpAK
P
Bacterial/ viral infectionCytokinesStress
P
P
P
C
C
N
C
C
C
NN
I-B
p50
ATP ADP
I-B kinase
PhosphoryIation of I-B kinase
NF-B
Degradation of I-Bin proteosome
Ubiquitination of I-B
Nucleus
NF-B - responsive gene
(Ub) n (Ub) n
Polution
3. Polution
Sel EpitelMakrofagSel TSel B Sel MastEosinofil
Gejala
Sitokin/Kemokin IL-4, IL-5, IL-13, IL-10, IL-3GM-CSF,EotaxinRANTES,TGF-TGF-
Mediator
Histamin,ProstaglandinLeukotrien
Bersin,Buntu,RinoreaGatal
Infiltrasi Sel Eosinofil
Inflamasi AlergiKo-morbid
7Prof DR Dr Ariyanto Harsono SpAK
8Prof DR Dr Ariyanto Harsono SpAK
9Prof DR Dr Ariyanto Harsono SpAK
10Prof DR Dr Ariyanto Harsono SpAK
11Prof DR Dr Ariyanto Harsono SpAK
Mast CellPreformed Mediator: Histamin, TNF- Protease,Kinin, ECFNew Generated Mediator: PGD, Leukotriene 12
Prof DR Dr Ariyanto Harsono SpAK
Mast Cells Mediate Allergic and Inflammatory Reactions
IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10,
IL-13, TNF, MIPs, IFN,
GM-CSF, TGF, bFGF,
VPF/VEGF, PGD2, LTB4, LTC4, PAF,
Serotonin,Heparin,
Chondroitin-sulfate,
Chymase, Tryptase,
Cathepsin G
Recruitment
Extravasation
Vasodilation
Activation
MC
Graphics courtesy of Prof. M. Maurer.13
Prof DR Dr Ariyanto Harsono SpAK
Granule contents:Histamine,TNF-Proteases, Heparin Lipid mediators:
ProstaglandinsLeukotrienes
Cytokine production:Specifically IL-4, IL-13
14Prof DR Dr Ariyanto Harsono SpAK
EosinofilMediator: MBP,ECP,EDN, Protease, PeroksidaseSitokin: TGF- TGF- 15Prof DR Dr Ariyanto Harsono SpAK
Eosinophil activated and prolonged life-span by IL-5
16Prof DR Dr Ariyanto Harsono SpAK
17Prof DR Dr Ariyanto Harsono SpAK
18Prof DR Dr Ariyanto Harsono SpAK
19Prof DR Dr Ariyanto Harsono SpAK
20Prof DR Dr Ariyanto Harsono SpAK
21Prof DR Dr Ariyanto Harsono SpAK
Keluhan Utama:-Rhinorrea -Itchy nose -Sneezing -Congestion
Gejala minor: Rabbit Nose Allergic Salute Nasal crease Allergic Shiner Toothy mouth (Adenoid Face)
22Prof DR Dr Ariyanto Harsono SpAK
LeukotrieN C4
Prostaglandin D2
Tryptase
HISTAMIN
CYTOKINEIL-1IL-3IL-4IL-5IL-6IL-13TNF-
KemokinIL-8EotaxinRANTES
Adhesion MoleculesP-selectinICAM
Early phaseResponse
• Sneezing• Itchy, watery eyes• Runny nose• Congestion• Itchy nose
Rapid phase Inflammatory Response
Overview: Symptoms of Allergic Rhinitis
Early phase Mediator
23Prof DR Dr Ariyanto Harsono SpAK
IncreaseVaskularPermebility /secretion Vascular obstruction
Mucosal Inflammation
Nasal obstruction
Rapid phase Mediators Vasodilatation
Mediators of allergic inflammation
Etiologic Factors of Congestion
24Prof DR Dr Ariyanto Harsono SpAK
25Prof DR Dr Ariyanto Harsono SpAK
26Prof DR Dr Ariyanto Harsono SpAK
27Prof DR Dr Ariyanto Harsono SpAK
28Prof DR Dr Ariyanto Harsono SpAK
29Prof DR Dr Ariyanto Harsono SpAK
30Prof DR Dr Ariyanto Harsono SpAK
31Prof DR Dr Ariyanto Harsono SpAK
32Prof DR Dr Ariyanto Harsono SpAK
33Prof DR Dr Ariyanto Harsono SpAK
Allergic Rhinitis and co-morbid conditions
Allergic rhinitis
Nasal polyps
Sleep disturbance, including sleep-disordered breathing
Rhinosinusitis (acute and chronic)
Asthma with AR
CongestionInflammation
CongestionInflammation
Common cold
34Prof DR Dr Ariyanto Harsono SpAK
35Prof DR Dr Ariyanto Harsono SpAK
36Prof DR Dr Ariyanto Harsono SpAK
37Prof DR Dr Ariyanto Harsono SpAK
38Prof DR Dr Ariyanto Harsono SpAK
39Prof DR Dr Ariyanto Harsono SpAK
40Prof DR Dr Ariyanto Harsono SpAK
41Prof DR Dr Ariyanto Harsono SpAK
42Prof DR Dr Ariyanto Harsono SpAK
43Prof DR Dr Ariyanto Harsono SpAK
•anamnesis•physical examination•Total IgE / Specific•Nasal mucosa smear eosinophils•Skin test•Nasal mucosa provocation test
44Prof DR Dr Ariyanto Harsono SpAK
•avoidance of allergens•education•pharmacotherapy•immunotherapy
45Prof DR Dr Ariyanto Harsono SpAK
ARIA = Allergic Rhinitis and its Impact on Asthma.Bousquet et al. J Allergy Clin Immunol. 2001;108 (5 suppl):S147.
ARIA Guidelines: Recommendations for Management
of Allergic Rhinitis
Mildintermittent
Moderatesevere
intermittent
Mildpersistent
Moderatesevere
persistent
Immunotherapy
Allergen and irritant avoidance
Intranasal decongestant (<10 days) or oral decongestant
Second-generation nonsedating H1 antihistamine
Leukotriene receptor antagonists
Local cromone
Intra-nasal steroid
46Prof DR Dr Ariyanto Harsono SpAK
Jenis obatbersin rinorea Buntu Gatal
hidungKeluhan mata
Antihistamin H1OralIntranasalIntraokuler
++++0
++++0
++0
+++++0
++0
+++
Kortikosteroid intranasal +++ +++ +++ ++ ++
KromolinIntranasalIntraokuler
+0
+0
+0
+0
0
++
DekongestanIntranasalOral
00
00
+++
+
00
00
Antikolinergik 0 ++ 0 0 0
Antilekotrien 0 + ++ 0 ++
Gejala
47Prof DR Dr Ariyanto Harsono SpAK
Jenis obatbersin rinorea Buntu Gatal
hidungKeluhan mata
Antihistamin H1OralIntranasalIntraokuler
++++0
++++0
++0
+++++0
++0
+++
Kortikosteroid intranasal +++ +++ +++ ++ ++
KromolinIntranasalIntraokuler
+0
+0
+0
+0
0
++
DekongestanIntranasalOral
00
00
+++
+
00
00
Antikolinergik 0 ++ 0 0 0
Antilekotrien 0 + ++ 0 ++
Gejala
48Prof DR Dr Ariyanto Harsono SpAK
Drugs Choice for nasal congestion
• Antagonist reseptor H1
• Dekongestan oral & topical
– pseudoefedrin
– fenilefrin
• Topical nasal Cortikosteroid
Nayak AS et al. Allergy. 2001;56:1077-80. 49Prof DR Dr Ariyanto Harsono SpAK
Desloratadin reduces nasal congestion Score
*P = 0.005†P = 0.01‡P = 0.001 dibanding plasebo
15
Waktu Terpapar Alergen (menit)
0
0.6
1.2
1.6
2.0
1.8
1.4
1
0.8
0.4
0.2
45 75 105 135 165 195 225 255 285 315 345
†
*
* † * † ††
†
* ††
*
†
*
† *
‡
‡‡ ‡ ‡
‡
SumbatanReduced
DesloratadinPlaseboR
erat
a pe
ruba
han
Skor
Su
mba
tan
Hid
ung
Horak F et al. J Allergy Clin Immunol. 2002;109:956-61.50Prof DR Dr Ariyanto Harsono SpAK
Treatment with desloratadine:
• Inhibition of allergic inflammatory mediators
• Reduces symptoms of nasal obstruction in the well-designed studies
• Improve nasal airflow, an objective measurement of the nasal obstruction
51Prof DR Dr Ariyanto Harsono SpAK
0
10
20
30
40
50
60
70
IL-6 IL-8 IL-3 GM-CSF
AERIUS
Cetirizine
Lippert U, et al. Exp Dermatol. 2000;9:118-124.
Per
cen
t in
hib
itio
nDesloratadine: Inhibition of Allergic
Inflammation
TNF-
Greater inhibition than Cetirizine
Inhibition of Mast Cell Cytokine Release
52Prof DR Dr Ariyanto Harsono SpAK
Food Does Not Alter the Oral Bioavailability of Desloratadine
Desloratadine 7.5 mg* after high-fat, high-calorie meal
Desloratadine 7.5 mg* after 10-hour fast
Mea
n D
eslo
rata
din
e P
lasm
a C
on
cen
trat
ion
(µ
g/L
)
0 4 8 12 16 20 240
1
2
3
4
Hour
Randomised, open-label, single-dose, 2-way crossover study (n = 18)
*The recommended daily dose for desloratadine is 5 mg.Gupta S et al. Clin Pharmacokinet. 2002;41(Suppl 1):7-12. 53Prof DR Dr Ariyanto Harsono SpAK
0 6 12 18 240
50
100
150
200
0
1
2
3
4
0 6 12 18 24
(µg
/L P
las
ma
)
Hours
FexofenadineDesloratadine
(ng
/mL
Pla
sm
a)
Banfield C et al. Clin Pharmacokinet. 2002:41:311-8.
Effect of Grapefruit Juice of Desloratadine and Fexofenadine
Hours
With Grapefruit Juice
Without Grapefruit Juice
54Prof DR Dr Ariyanto Harsono SpAK
0 4 8 12 16 20 240
1
2
3
4
5
6
Hour
DL 7.5 mg/d* + placebo
DL 7.5 mg/d* + erythromycin 500 mg TDS7
8
Mea
n D
eslo
rata
din
e P
lasm
a C
on
cen
trat
ion
(µ
g/L
) o
n D
ay 1
0
DL, desloratadine; TDS, three times daily.
*The recommended daily dose for desloratadine is 5 mg.Banfield C et al. Clin Pharmacokinet. 2002;41:29-35.
• Changes in AUC not clinically significant
• Steady-state levels of DL achieved by day 10 after both treatments
Desloratadine/ErythromycinDrug-Coadministration
55Prof DR Dr Ariyanto Harsono SpAK
ECG Pharmacodynamic Effects of Desloratadine
• Desloratadine 45 mg* single daily doses for 10 days; placebo crossover design
– No statistically significant differences in QTc observed
• No clinically relevant adverse events reported
*Nine times the recommended daily dose.ECG, electrocardiogram.Bousquet J, et al.Allergy 2004;59 (suppl.77):4-16 56Prof DR Dr Ariyanto Harsono SpAK
Desloratadine and EAACI/ARIA Criteria for Antihistamines
in Allergic Rhinitis
• AERIUS meets all EAACI-ARIA criteria for antihistamines required for the treatment of allergic rhinitis– Efficacy
• Effective in the treatment of intermittent and persistent rhinitis
• Effective for all nasal symptoms including nasal obstruction
• Improvement of eye symptoms
• Improvement in asthma symptoms
• Efficacy in pediatric and elderly patients
57Prof DR Dr Ariyanto Harsono SpAK
Desloratadine and EAACI/ARIA Criteria for Antihistamines
in Allergic Rhinitis
- Safety and tolerability/side effects• No sedation or cognitive or psychomotor impairment
• No anti-cholinergic effects
• No weight gain
• No cardiac side effects
• Studies should be carried out in young children and elderly patients to assess safety
• Prospective postmarketing safety analysis should be conducted
58Prof DR Dr Ariyanto Harsono SpAK
Jenis obatbersin rinorea Buntu Gatal
hidungKeluhan mata
Antihistamin H1OralIntranasalIntraokuler
++++0
++++0
++0
+++++0
++0
+++
Kortikosteroid intranasal +++ +++ +++ ++ ++
KromolinIntranasalIntraokuler
+0
+0
+0
+0
0
++
DekongestanIntranasalOral
00
00
+++
+
00
00
Antikolinergik 0 ++ 0 0 0
Antilekotrien 0 + ++ 0 ++
Gejala
59Prof DR Dr Ariyanto Harsono SpAK
Efficacy NASONEX in Pediatric Patients with Perennial Allergic Rhinitis
• 4-week, double-blind study (double blind)• With the extension of the 26-week, open-
label• Children 3-11 years• MFNS 100 mcg qd or placebo
60Prof DR Dr Ariyanto Harsono SpAK
Results Clinical Experience NASONEX in Children
• Mometasone furoate nasal spray (MFNS) 100 mcg qd is the optimal dose in children over 2 years
• Low potential for systemic effects• There is no short-term growth disorders• There is no evidence of HPA axis suppression• Well tolerated• Incidence of adverse events similar placebo
61Prof DR Dr Ariyanto Harsono SpAK
Efek Jangka Panjang Nasonex thd Mukosa Hidung
AA BB
Before MFNS TreatmentBefore MFNS Treatment After 12 Months of TreatmentAfter 12 Months of TreatmentWith MFNSWith MFNS
Minshall E, et al. Minshall E, et al. Otolaryngol Head Neck Surg. Otolaryngol Head Neck Surg. 1998;118(5):6481998;118(5):648
62Prof DR Dr Ariyanto Harsono SpAK
63Prof DR Dr Ariyanto Harsono SpAK
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