Curriculum vitae

NAME: Dr. Asnominanda, SpTHT-KL

Place & date of birth: Payakumbuh, Indonesia, February 4th 1966

Qualification:
 Head of ENT Dept of Central Indonesia Air Force Hospital Jakarta
(2004 – now)

EDUCATION:
Dokter, Faculty of Medicine, University of Indonesia, 1992
ENT Specialist, University of Padjadjaran, 2003.

Adress : Jalan Suyani No. 1 Komplek Trikora Halim Perdanakusuma,

Indonesia
Phone : 62 21 8579927; HP: +62 8159638630
Email : mingtht_007@yahoo.co.id

1
 The Role of
Antihistamine
in Allergic Rhinitis
Management
An Update Review Article: ARIA 2007 & 2008

Asnominanda
Head of ENT-HNS Dept
Central Indonesia Air Force Hospital Jakarta

Presented at RSPAU Morning Meeting

Jakarta
Juny 22th 2009

2
 Allergic rhinitis is a symptomatic
disorder of the nose induced after
allergen exposure by an immuno-
globuline E (IgE)-mediated inflammation
of the membranes lining the nose.1:1

(1) It was defined in 1929.1:2

(2) The three cardinal symptoms in nasal
reactions occurring in allergy are :
a. sneezing, itching
b. nasal obstruction
c. mucous discharge
1. ARIA 2008 Update (in collaboration with the World Health
Organization, GA2LEN* and AllerGen
3
Burden of AR :1

Allergic rhinitis is a global health

problem that causes major illness
and disability worldwide (all
countries, all ethnic groups, all
socioeconomic conditions and of all
ages).
The prevalence of allergic
sensitization is often higher than
50% of the population (in some age
groups, in many countries).
4
Burden of AR :1 (cont)

 AR occurs in over 500

million people around the
world (A conservative estimate).
 AR affects social life, sleep,
school and work, and QOL.
 The economic impact of AR
(direct costs and indirect
costs) is high.

5
Allergic inflammation is a systemic disease
and shows co-morbidities several organs.

Asthma

Atopic
Dermatitis Allergic
Rhinitis

6
 The Allergic March of systemic allergic
diseases.1:(1,2,3)
Age

Asthma
School
age
Allergic
Rhinitis
2 years Atopic
Dermatitis
6 months

Kulig M et al. J Allergy Clin Immunol. 2000;106:832-9. 4 7

Plaschke P et al. Am J Respir Crit Care Med. 2000;162:920-4. 5
 Complications of Allergic Rhinitis

• Rhinosinusitis, Nasal Polyps

• Pharyngitis, Laryngitis
• Otitis Media, Otitis Externa
• Conjunctivitis
• Exacerbation of Asthma, Bronchitis, Vertigo,
Migraine, Eczema
• Impaired Olfaction / Taste, Sleep Apnea,
Facial Growth Abnormalities in Children (all from
nasal obstruction)

8
Risk factors for allergic rhinitis:1,2
Indoor and outdoor inhalant
allergens cause allergic rhinitis:
Major outdoor allergens include
pollens and molds.
Major indoor allergens include mites,
animal danders, insects and molds.
These are the causes why
prevention of allergic symptoms is
difficult.
9
 Pathophysiology of Allergic Disease

• 1. Host sensitization to allergen

• 2. IgE production by host
• 3. Mast cell sensitization
• 4. Allergen provocation by further
• exposure after sensitizing event
• 5. Mediator release:
Histamine, kinins, leukotrienes, cytokines
• 6. End-organ response

10
 Types of Rhinitis - 1

• Seasonal allergic rhinitis (classic hayfever with

spring, summer &/or fall symptoms)
• Perennial allergic rhinitis (mite, mold,
cockroach, animal dander)
• Infectious rhinitis (virus, bacteria, fungi)
• Occupational rhinitis (latex)
• Chemical / irritative rhinitis (perfumes, strong
odors, fine particles)
• Anatomic rhinitis (nasal drainage obstruction
by septum, etc.)
 Perennial Rhinitis
• Fungi/mold:
– Exposure peaks accompany activities such as
harvesting, cutting grass and leaf raking.
• Pet Dander (cats, dogs):
– Can linger up to 4 months after pet removal.
• House dust mites:
– Live in bedding, carpets and upholstery.
– Dietary preference: human epidermal scales.
• Cockroaches:
– Respiratory allergy
– Important allergen in inner-city asthma. 12
 Pathophysiology of Allergic
Inflammation: Sensitization
Phase 1 : Sensitization

Allergens
Antigen-presenting
cell

Processed
allergens

CD4
T cell
B cell

IgE antibodies
Plasma cell

Naclerio, RM. New Engl J Med 1991:325; 860-9

 Pathophysiology of Allergic
Inflammation: Clinical Disease
Phase 2 : Clinical Disease
Early Late
Inflammation Inflammation
Allergens

Late-phase Resolution
IgE antibodies reaction
Cellular
infiltration Hyper-
Mast responsiveness Complications
cell
Eosinophils
Mediator release Basophils Priming
Nerves Monocytes
Blood Irreversible
vessels Lymphocytes
Glands disease (?)

Sneezing
Rhinorrhea
Congestion
 The update theory on allergic Inflammation

Th0 Th0
Activate M/DC
Inducing CMI:
IFN-γ, IL-2, M cell
TNF-β, ect (-)
as APC Humoral immunity
(+)
Allergic diseases:
IL-4, IL-13, IL-5, dll

(+) (-) (+)

(-) (+)
(-) T Reg (-)
(+) Eos &
IL10/ (-) Baso
B cells TGFβ
ASIT B cells Accumu-
IgG4 & IgA pro- lation
duction IgE produc-
Adapted from Creticos 1998 & Akdis et al 2005)
tion 15
(Modified by Sumarman, 2009)
 Hypothesis of allergic inflamation
on T Reg and T-cell responses. (Till et al. J Allergy Clin Immunol 2004;113:1025-34)

+
+ +
-
- -
-
-
-
-
+ -
Reduced EOS accumulation
+ Inducing effect of ASIT
- Inhibiting effect of ASIT
16
IgE

FcεRI expression Eosinophil survival

and and activation
IgE-dependent
mast cell activation

IL-10
IgE-dependent
antigen
presentation IL-10 produced by
T Reg
IL-10 is another effective
inhibitive indicator of
Cytokines and
allergic inflammation proliferation
The potential anti allergic properties of IL-10 (produced by Treg) on different limbs of the
allergic immune response. (Till et al. J Allergy Clin Immunol 2004;113:1025-34) (7)
EOS = Eosinophil; T reg = T regulatory cell. 17
DIAGNOSTIC OF ALLERGIC
DISEASES:
Subjective test: Symptoms and
its severity & Family allergic
history
Objective tests for the diagnosis
of IgE-mediated allergy: 1:53–55
18
DIAGNOSTIC OF ALLERGIC DISEASES:
Objective :
1. Physical examination
2. Laboratory &/or Skin Testing for the
diagnosis of IgE-mediated allergy:
Skin prick test (SPT)
Serum-specific IgE
Other working test:1:57
o nasal function test
o specific nasal challenge test
o specific bronchial challenge test
o specific food challenge test
19
Physical Examination of Allergy Patient

• Eyes: conjunctivitis, Dennie’s lines, “shiners”

• Ears: otitis media or externa, retracted
tympanic membrane from ET dysfunction
• Nose: boggy / pale nasal mucosa, clear / thin
mucoid rhinitis, turbinate hypertrophy, polyps,
transverse nasal crease from “allergic salute”
• Throat: prominent lymphoid patches
(cobblestoning), lateral pharyngeal bands
 R = “Shiners” & nasal obstruction (mouth
breather) from nasal edema & venous congestion ,
L = Dennie’s Lines

R L
 ARIA Classification & Allergic Rhinitis
Intermittent
• Symptoms < 4 days per week
• or Symptoms < 4 weeks
Mild
Normal sleep
& no impairment of daily
activities, sport, leisure
& normal work and school
& no troublesome symptoms
Persistent
• > 4 days per week
• and > 4 weeks
Moderate–severe
One or more items
• Abnormal sleep
• Impairment of daily
activities, sport, leisure
• Abnormal work and school
• Troublesome symptoms
 Classification of Allergic Rhinitis according to ARIA
according to Subjective symptoms
1. Intermittent means that the symptoms are present:
 <4 days a week
 Or for <4 consecutive weeks
2. Persistent means that the symptoms are present
 More than 4 days a week
 And for more than 4 consecutive weeks
3. Mild means that none of the following items are present:
 Sleep disturbance
 Impairment of daily activities, leisure and/or sport
 Impairment of school or work
 Symptoms present but not troublesome
4. Moderate/severe means that one or more of the following
items are present:
 Sleep disturbance
 Impairment of daily activities, leisure and/or sport
 Impairment of school or work
 Troublesome symptoms
27
Recommendations of the ARIA
workshop (2008):1 (continue)

The combine treatment strategy of

AR :
 Education
 Allergen avoidance (when possible)
Pharmacotherapy
 Allergen specific immunotherapy

28
Air Filtration: Personal, Room, House, Car
Pharmacotherapy
Management in
Allergic Rhinitis
& its Co-
morbidities
 Treatment of Allergic Rhinitis

Type of Drug Action

Antihistamines Block histamine
Intranasal Steroids Local anti-inflammatory
Cromolyn sodium Stabilizes mast cells
Decongestants Vasoconstriction
Leukotrienes Block cytokine action
Immunotherapy Competing antibodies
IgE specific agents Bind IgE, block receptor
sites, etc.
Figure 10. Management of allergic rhinitis in
the pharmacy [from Ref. (1:1154)]. 32
 Fig.5.
Treatment
strategy:
1. Adapted from:
Allergic Rhinitis
and its Impact on
Asthma (ARIA)
2008 Update.
Allergy. European
JACI. Supl 86.Vol
63.2008
 Management of Allergic Rhinitis
Options Common in a Stepwise Approach
Moderate-
severe
Mild persistent
Moderate- persistent
severe
Mild intermittent
intermittent
Intranasal corticosteroid
Cromolyn Sodium
Patient
Patient education
education andand allergen
allergen and irritant avoidance
avoidance
Intranasal decongestant (<10 days) or oral decongestant
Oral or local nonsedating
antihistamine
Immunotherapy, if other therapies fail
Oral vasoconstrictors:

Are at risk when using oral

sympathomimetic decongestants
patients with:1
Glaucoma
Hyperthyroidism
Elderly men with urinary retention
(prostate enlargement)
Hipertension
Cardiac disease
Pseudoephedrine was recently banned
(not allowed use) for Olympic athletes.1:27
 Oral H1-antihistamines.1
H1-blockers or H1-antihistamines :
block histamine at the H1-receptor level
(neutral antagonists or inverse
agonists;1:1538).
Some also possess additional
antiallergic properties. 1:(1539)
 *
Mechanism of action
PROPERTIES 1 2 3
4 5 6 7
8 9 10 11
12 13 14 15
16 17 18 19
20 21

1 2 3

H1 receptor
POTENCY

4 5 6 7
8 9 10 11
12 13 14 15
16 17 18 19
20 21 22 23
24 25 26 27
28 29 30 31

Histamine
Histamine
SAFETY PROPERTIES  EFFICACY

1 2 3
4 5 6 7
8 9 10 11
12 13 14 15
Antihistamine
16 17

1 2 3
4 5 6 7
8 9 10 11
12 13 14 15
16

1 2 3
4 5 6 7 Antihistamine
8 9 10 11 Histamine binding
12 13 14 15 prevents
16 17 18 19
20 21 histamine
1 2 3
cell activation
binding
OTHERS

4 5 6 7
8 9 10 11
12 13 14 15
16 17 18 19
20 21 22 23 Symptoms No activation, No symptoms
24 25 26 27
28 29 (sneezing, rhinorrhoea, pruritus)
PROPERTIES 1 2 3
4 5 6 7
8 9 10 11

History of antihistamines
12 13 14 15
16 17 18 19
20 21

1 2 3 Second generation AH
POTENCY

4 5 6 7

First generation AH
®
Xyzal
8 9 10 11
12 13 14 15
16 17 18 19
20 21 22 23 desloratadine
24 25 26 27
28 29 30 31
Staub terfenadine fexofenadine
Bovet
SAFETY PROPERTIES  EFFICACY

1 2 3
4 5 6 7
cetirizine
8 9 10 11 phenbenzamine loratadine
12 13 14 15 chlorphenyramine astemizole
16 17

1 2 3
4 5 6 7
8 9 10 11
12 13 14 15
16
1937 1942 1979 1988 1996 2001

Anti-histaminic effect
1 2 3
4 5 6 7
8 9 10 11
12 13 14 15 Anti-cholinergic effect
16 17 18 19
20 21
1 2 3
OTHERS

4 5 6 7
8 9 10 11
12 13 14 15
Sedative effect
16 17 18 19
20 21 22 23
24 25 26 27
28 29
Oral H1-antihistamines are:
Effective against symptoms mediated
by histamine :
Rhinorrhoea
Sneezing
Nasal itching and
Eye symptoms
Less effective on nasal congestion
(Histamine is minor factor).1:(1229)
Their clinical effect in trials of
perennial rhinitis lasting 4 weeks and
over is usually small.
Table 17. Glossary of medications used in allergic rhinitis:1 [adapted from Ref. (1155)]

Name and Generic name Mechanism Side effects Comme

also known of action nts
as:
First gene- Chlorphenyramine Blockage of 1st genera
ration Oral (1476, 1482) H1-receptor
Some anti- tion AH1:
H1-AH:1 allergic activity Sedation is
Clemastine (1483)
Should be common
Dimethindene maleate used TID
No develop- and/or anti
(1484) ment of cholinergic
Hydroxyzine tachyphylaxis effect
Ketotifen (1485)
Oxatomine (1485,
1486)

40
First-generation oral H1-
antihistamines side effects:
CNS side effects: sedation and
fatigue.1:(116, 2225).
Paradoxical hyperactivity
(insomnia and irritability may
also occur in infants and very
young children).
Often has a further reducing effect
upon cognitive function.1:(2226)
Anticholinergic properties.1
Table 17. Glossary of antihistamines (AH) used in AR:1 [adapted from Ref. 1:(1155)]
Name and Generic name Mechanism Side effects Comments
known as of action
Blockage No sedation for Preferred for
Second Acrivastine (1452–1454) most drugs their efficacy
Azelastine (1455) of H1-
genera- receptor No anticholin- /safety ratio
and
tion Oral Cetirizine (1456–1460) Some anti- ergic effect
pharmaco
No cardiotoxic- kinetic:
H1-AH:1 Desloratadine (1461–1464) allergic ity for products Rapidly
Ebastine (1465–1467) activity still available effective (<1 h)
Can be Acrivastine has on nasal and
Fexofenadine (1468–1471) used OD sedative effects ocular
No symptoms
Levocetirizine (1066, 1108, Mequitazine has Moderately
1472) develop- an anticho-linergic effective on
ment of effect nasal
Loratadine (1473, 1474) tachyphy- Oral azelastine congestion
Mequitazine (1475, 1476) laxis may induce
Mizolastine (1477, 1478) sedation and a
Rupatadine (1479–1481)
bitter taste

42
The safety of second generation of
H1-antihistamine:1
No sedation, no cognitive or psychomotor
impairment.
No anti-cholinergic effects.
No weight gain.
No cardiac side-effects.
Possible use in pregnancy and breast feeding.
Studies should be carried out on young
children and elderly patients to assess safety.
Prospective post marketing safety analyses
should be conducted.
Use of the newer second generation
of H1-AH:
Counteracts the feeling of
malaise caused by AR
May improve learning ability in
AR.
Pharmacokinetic studies of the
second generation H1-AH have been
performed on children, but few
studies have been carried out on
infants.1:(116, 2227–2229)
Cetirizine, fexofenadine and
levocetirizine are not metabolized
to any extent.
Second-generation H1- anti
histamine which are effective and
safe in long term treatment of AR
in children, are:1:(2230–2232)
Cetirizine
levocetirizine and
loratadine
Pharmacodynamics of second
generation of H1-antihistamine:1

Rapid onset of action.

Long duration of action – (the 24-
h dosing period), enabling once-
daily administrations (OD).
No likelihood of development of
tolerance (tachyphylaxis).
 Combination therapy H1-
antihistamine with intranasal
glucocorticosteroids.1
Combination between drugs has
been tested, good result, use of oral
H1-antihistamines and intranasal
glucocorticosteroids.1:1099, 1594, 1595
 Corticosteroids (intranasal)
• Mechanism:
– reduce inflammation
– suppress neutrophil chemotaxis
– mildly vasoconstrictive
– reduce intracellular edema
• Effect: reduce nasal blockage, pruritis,
sneezing and rhinirrhea.
 Corticosteroids (continued)
• intranasal: acts locally.
• goal: control sx with lowest possible dose.
• >90% achieve symptomatic relief.
• most effective when started several days
before exposure and used on regular basis.
• therapeutic efficacy within 1-3 days, but max
efficacy may take up to 3 weeks.
• compliance is critical.
Side effects: nasal irritation, bleeding (nasal
septal perforation).
 SIMPULAN:
1. Kemanan dari second generation of H1-
antihistamine adalah tidak
memiliki/menimbulkan:
a. Efek sedasi
b. Gangguan kognitif atau psikomotor
c. Efek anti-cholinergic
d. Peningkatan berat badan
e. Cardiac side-effects.
2. Second generation H1- antihistamine
dimungkinkan penggunaan pada
kehamilan dan menyusui

50