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過敏性鼻炎治療的新趨勢
高雄榮總耳鼻喉部
紀昭全 醫師
May, 2007
鼻炎的分類


Allergic rhinitis (過敏性鼻炎)
Nonallergic rhinitis (非過敏性鼻炎)



infectious rhinitis (感染性鼻炎)
其他:
 Hormonal rhinitis: hypothyroidism,pregnancy,oral
contraceptives, menstrual cycle
 Occupatiohal rhinitis
 Drug-induced rhinitis (藥物性鼻炎)
 Atrophic rhinitis (萎縮性鼻炎)
vasomotor rhinitis (血管運動性):

idiopathic rhinitis , (Postnasal drip? Chronic rhinitis?)
Allergic rhinitis (過敏性鼻炎)



Seasonal allergic rhinitis: pollens,molds
(outdoor allergens)
Perennial allergic rhinitis: dust mites,
molds, and animal dander (indoor
allergens)
Often co-exist
In collaboration with the World Health Organization
ARIA program
First phase:

Development of evidence-based guidelines
during a workshop held at WHO in
December 1999 (J Allergy Clin Immunol,
suppl, Nov 2001).

Document has been endorsed by several
allergy, respiratory, ENT and paediatric
associations.
ARIA program
Second phase:

To produce materials to help improve
delivery of care to those with rhinitis.
In particular a pocket guide

To implement ARIA guidelines

To update the workshop report
ARIA
The classification "seasonal" and
"perennial" allergic rhinitis
has been changed to
"intermittent" and "persistent"
allergic rhinitis
ARIA Classification


Duration of symptom
Presentation with severity
ARIA Classification
Intermittent
. < 4 days per week
. or < 4 weeks
Persistent
. ≥ 4 days per week
. and ≥ 4 weeks
Moderate-severe
Mild
normal sleep
& no impairment of
daily
activities,
sport, leisure
& normal work and
school
& no troublesome
symptoms
one or more items
. abnormal sleep
. impairment of daily
activities, sport,
leisure
. abnormal work and
school
. troublesome
symptoms
PATHOPHYSIOLOGY (1)


Basophils and mast cells release histamine during the
early-phase reaction, whereas basophils alone are
considered the predominant source of histamine in
the late-phase response.
Histamine is the major mediator released after
immunological challenge by mast cells and
basophils.
PATHOPHYSIOLOGY (2)

Other important components of the earlyphase and late-phase allergic response are
cytokines, interleukin (IL) 3, IL-4, IL-5, IL-6,
and IL-8, and the cellular adhesion
molecules such as intercellular adhesion
molecule 1 (ICAM-1) and E selectin,
leukotrienes, and prostaglandins.
Pharmacotherapy




Antihistamine
Corticosteroid: intra-nasal , oral
Decongestant: topical , oral
Mast cell destablizer
first-generation H1antihistamines



diphenhydramine and chlorpheniramine, are
available as over-the-counter preparations,
whereas others, such as hydroxyzine, are
available by prescription.
poor receptor selectivity for the H1-receptor
and block muscarinic receptors, causing
substantial anticholinergic effects
dry mouth, constipation, urinary retention, and
tachycardia, and conferring an overall
unfavorable risk-benefit ratio.
second-generation, H1antihistamines



Since 1980, produced more specific
H1-receptor selectivity
faster onset of action, longer
duration of action, greater potency,
or fewer adverse events.
Can not cross BBB (blood-brain
barrier)
Available US SecondGeneration Antihistamines




Desloratadine
Loratadine
Cetirizine
Fexofenadine
5(mg/d)
10(mg/d)
10(mg/d)
180(mg/d)
ANTIALLERGIC AND ANTIINFLAMMATORY EFFECTS

newer-generation oral antihistamines have been shown to
have a range of additional antiinflammatory properties; however,
the mechanism of action for these
effects remains unclear.
Effect of Denosin ® on PMA/ionophoreinduced cytokine release from human
mast cell
70
Desloratadine
Dexamethasone
Percentage Inhibition
60
Cetirizine
50
40
30
20
10
0
IL-6
IL-8
TNF-α
IL-3
GM-CSF
UNDESIRABLE
PHARMACOLOGICAL EFFECTS



Drug Interactions
Central Nervous System Effects
Cardiotoxicity
What is a drug interaction？
Definition :
Refers to an event with a negative patients’
consequence that is associated with the specific
combination of two or more drugs. Wider ranging
definition may include any or all of the following :
Drug-drug interaction
Drug-disease state interaction
Drug-food interaction
Drug interaction-a big problem
Drug interaction are responsible for 3% to 10%
of admissions of older patients to the hospital
in USA.
When two for four different drugs are taken,
the potential for interaction is 6%, but the risk
increases to 50% with five drugs and to almost
100% with eight drugs.
The Fatal Drug-Drug Interaction
Product
Brand
Name
Launch
Withdrawal from USA
Terfenadine
Teldane
1985
1997
Astemizole
Hismanal
1988
1999
Ketoconazole, erythromycin, marcolides
--- Torsades de points
The findings of drug-food
Interaction in antihistamine
Object drug
Food
Effect
Astemizole
Food
Reduce absorption by 60%
fexofenadine
Grapefruit/
Apple/Orange
juice
Reduce bioavailability by
60~80%
The findings of drug-drug
interaction in antihistamine
Object
Drug
Cetirizine
Fexofenadine
Loratadine
Precipitant
drug
Effect
Adverse reaction
Theophylline
Decrease cetirizine
clearance
Somnolence, fatigue, dry mouth
Droperidol
Prolong the QT interval
Risk of cardiotoxicity
erythromycin
Increased AUC
No change in QTc interval.
Cimetidine
Erythromycin
Ketoconazole
Increase loratadine serum
concentration
Nefazodone
QTc prolongation
No significant adverse effects
Predispose individuals to torsades
de pointes, the arrthmia
Denosin ®
pharmacokinetics
Denosin ® with multiple pathways
in Allergic Rhinitis
Anti-allergic effect
Anti-inflammatory effect
Decongestion effect
Immune-modulating effect
Denosin ® with the higher affinity and
potency due to the slow dissociation
%Maximum specific binding
100
90
Norastemizole
Desloratadine
80
Cabastine
70
Loratadine
Terfenadine
60
Cetirizine
Ebastine
50
Astemizole
40
Fexofenadine
30
20
10
0
-11
-10.5
-10
-9.5
-9
-8.5
-8
-7.5
-7
Inhibitor, M
-6.5
-6
-5.5
-5
Inhibition of [3H ]desloratadine to human H1 receptor expressed on
CHO membranes by various antihistamine
ref : European J.Pharmacology 449
(2002)229~237
The Rank Order of Potency Among
Antihistamines
Norastemizole > Desloratadine
> Carebastine > Cetirizine
> Terfenadine > Astemizole
> Ebastine
> Loratadine
> Fexofenadine
ref : European J.Pharmacology 449 (2002)229~237
Denosin ®
Desloratadine is the only antihistamine
with least drug-drug interaction due to
without CYP450 metabolism, which
contributed to safety of complicated
therapy in allergic diseases.
Lack of Interaction Between
Denosin ® and Erythromycin
10
1
Desloratadine+placebo
Desloratadine +erythromycin
3-OH desloratadine + placebo
3-OH desloratadine +erythromycin
0.1
0
4
8
12
16
20
24
Mean plasma desloratadine and 3-hydroxy (3-OH) desloratadine comcentrations
on day 10 following oral administration of 7.5mg desloratadine with erythromycin
or with placebo to healthy adult volunteers(n=24)
ref : Clin Pharmacokinetics 2002;41 Suppl.29-35
Lack of Interaction Between
Denosin ® and Ketoconazole
Mean(± SEM) plasma desloratadine concentration-time profile Day 10 following
oral administration of 7.5mg desloratdine with ketoconazole or with placebo to
healthy adult volunteers(n=24)
ref : Clin Pharmacokinet 2002;41 Suppl1:37~44
Comparison with other
Antihistamines
Difference of Pharmacokinetics in
Denosin ® v.s Loratadine
Desloratadine
Loratadine
Potency
++++
++
Decongestion effect
++++
_
Drug interaction
with CYP3A4 inhibitors (Macrolide, antifungals)
with CYP2D6 inhibitors(H2-blocker,)
No
No
First-pass Metabolism
No
Metabolite
T1/2
3-OH desloratadine
↑ Plasma Concentration
↓ Plasma Concentration
Yes
>13 metabolites
27 hr
7.8 hr
Onset
1 hr
2 hr
Sedation
2.1%
8%
NHI price
12.2/ tab
12/ tab
Comparison with other antihistamines
Desloratadine
Levocetirizine
Potency
++++
Decongestion effect
++++
++
+
No
No
No available
No available
Potentially
Potentially
Drug interaction
with CYP3A4 inhibitors
(Macrolide, antifungals)
with CYP2D6 inhibitors
(H2-blocker)
++
Fexofenadine
No
+
First-pass Metabolism
No
T1/2
27 hr
7 hr
14.4 hr
Onset
1 hr
0.8 hr
1-2 hr
Sedation
2.1%
NHI price
$ 12.2/ tab
No available 14%?
$ 11.8/ tab
No
1.8%
$16.2/ 180mg tab
$6/60mg tab
Denosin ® meets
ARIA / EAACI criteria
ARIA/EAACI criteria for
antihistamine



Potent and selective H1 receptor blockade
Additive anti-allergic activities
No clinically relevant pharmacokinetic interference by foods,
medications or intestinal transport proteins
 No known interaction with Cytochrome P450 (CYP3A)
 No known interaction with disease to avoid toxic reactions
 Efficacy for all nasal symptoms including nasal obstruction
 Improvement of eye symptoms
 Improvement of asthma symptoms(short term studies)
 Reduction of asthma exacerbations(long term studies)
 An improvement of pulmonary function tests, FEV1
and peak flow rates are usually not altered.
ARIA/EAACI criteria for
antihistamine

No sedation or cognitive or psychomotor impairment
 No anti-cholinergic effects, no weight gain
 No cardiac side effects
 Possible use in pregnancy and breast feeding
 Rapid onset of action, long duration, at least persistence
24-h dosing period, so the drug can be administration once a
day

No likelihood of development of tolerance(tachyphylaxis)
Indication
Allergic rhinitis
Chronic idiopathic urticaria
Dosage and Usage
Over 12 years old.
In patients with liver or renal impairment,
a starting dose of one 5mg tablet every other
day.
Pregnancy
Pregnancy Category C
Contraindications
Denosin®(desloratadine) is contraindicated in
patients are hypersensitive to this medication
or any its ingredients, or to loratadine.
Second generation antihistamine
2o
Antihistamine
(oral)
Cetirizine
(Metabolite of
hydroxyzine)
Desloratadine
(Metabolite of
loratadine)
Fexofenadine
(Metabolite of
off-market
terfenadine)
Protein
binding
93%
82-89%
60-70%
Half-life
Elimination
t ½(hours) t ½(hours)
7-10
17.23-24
16-23
8.3
27
14.4
Pregnancy
category
B
C
C
Cardiac
K+
channel
blocking
No
Metabolism
Renal or
hepatic
impaired
Limited 1st
pass,
70%/10%
unchanged in
urine/feces
Decrease
dose by
50%
No
Extensive 87%
No
adjustment
Possible
Limited 1st
pass,Unchange
d 80%,/1%
feces/urine
Decrease
dose by
50% and
dose qd
High CYP
3A4,lower CYP
2D6, 40%/,40%
urine/feces
Decrease
interval to
Loratadine
97%
7.8-11
8.4 to 28 for
B
No
every
metabolite
day
Source:Drug and Comparisons Facts accessed 05/24/04, Renwick et al,1999, Marttila et al,1999, Horak etother
al, 1999.
Treatment conclusion


1st line
 Basic
 Antihistamine
 Intranasal corticosteroids
 Additive
 Decongestants
 Leukotriene-receptor antagonist
 Nasal irrigation
 Intranasal anticholinergic
2nd line
 Immunotherapy
 Subcutaneous
 Sublingual
 Oral/depot corticosteroid
+antihistamine
J Allergy Clin Immunol
2006;118:985-998.
Treatment of allergic rhinitis (ARIA)
Allergic Rhinitis and its Impact on Asthma
moderate
severe
intermittent
mild
persistent
moderate
severe
persistent
mild
intermittent intra-nasal steroid
local chromone
oral or local non-sedative H1-blocker
intra-nasal decongestant (<10 days) or oral decongestant
allergen and irritant avoidance
immunotherapy
外科手術在鼻過敏的角色





冷凍治療
Submucosa turbinectomy
CO2 laser
KTP laser
radiofrequency
Submucosa delivery of RF energy
Creation of coagulation lesion
Tissue volume reduction
Thanks!