Antihistamine & CIU

Retno W. Soebaryo Allergy-Clin Immunology div., Dept. Dermato-venereology, Fac. of Medicine, Univ.of Indonesia, Jakarta

U rtic a ria Urticaria is a vascular reaction of the skin that result in localized edema in the dermis Classification : Chronic Idiopathic Urticaria / CIU (autoimmune U) intermitten idiopathic physical
food additives vasculitis

acute -----------< 6 weeks > -------------------- chronic

Chronic Idiopathic Urticaria - CIU

Problem in terms of etiology, pathogenesis, and treatment Causative agent is found in less than 25 % Include autoimmune urticaria Persist for several years Un-satisfaction for patients (QoL) & physicians

Introduction

What may play a role in todays allergies?

Pollution Indoor Lifestyle persistent allergen exposure2
(mould, cockroach)

New Allergens more and different allergens3

(spices, fruits, seeds ragweed)

Stressful Lifestyle neuroimmune responses4 susceptive to allerg"

Aggressive allergens1
(pollen)

evere s"mptoms

persistent s"mptoms

fre!uent s"mptom

#$Amato % et al& 'ur (esp ) 2**2+ 2*, -.3--. /iska 01 etal& ) Allerg" 2lin 3mmunol& 2**3+ 111, 24*-5 #utau % etal& 6resse 7ed 1444+ 28, 1553-4 9right () et al& 2urr :pin Allerg" 2lin 3mmunol 2**5+ 5,23-4

U rtic a ria

Pivotal event : -Mast cell degranulation Itching : mainly caused by histamine Wheal & flare : caused by other mediators

Urticaria

Angioedema

Histamine

* The major & last steps of allergic reactions * Bound on histamine receptors found on cellular surfaces of almost every tissue *Release from mast cells upon various trigger * Depends on the type of histamine receptors on the target cells

Histamine-receptors

In humans 4 subtypes of histamine receptor H1 H4 H1-r skin, bronchus, GI tract, smooth muscle H2-r gastric mucosal, uterus, brain H3-r bronchus, smooth muscle, brain H4-r brain, mast cells, eosinophils

Histamine receptors
H1 H2 gastric mucous Uterus, brain H3 H4

ptor

tion

Bronchus GIT, smooth musc ,brain tion smooth musc contract# cap #perm# pruritus

brain, bronchus, bm, thym smooth musc sp , ung, i!er, co on cap#permiab# brain b ! $i at# chemota% gastric#secrect bron&o&onstr# eos, mast mucous secreti 'negati!e LTB4 pro$ hipotension (ee$bac&) chemot#neutr micro!asc re ease IL1* neurogen +reg#immune (unction,

pain, hypotens# erythema erythem, hea$ach hea$ache in( am#me$# tachycar$ia mobi #In( am#ce

Immunomodulatory actions of histamine

Activation H1R promote Th1 responses Activation H2R inhibition of Th1 & Th2 Activation H4R mediates chemotaxis of neutrophil & eosinophil

Immunomodulatory actions of histamine

ander 0', ;ischoff 2, Allerg" 2lin 3mmunol 3nt < ) 9orld Allerg" :rg, 1-=4 (2**5)

Histamine H1-receptor
Responsible for the effects of histamine in allergic responses Stimulation of the receptor results: * in cellular responses * several other signaling pathways (phospholipase D and A2) * activate transcription factor NF-B allergic condition

Histamine H1-receptor

In the skin mediated effects: * contraction of postcapillary vein endothelial cells wheal * sensory nerve stimulation pruritus * neuropeptide stimulation neurogenic flare

Histamine H2-receptor

Elevating cyclic adenosine monophosphate (AMP) modulate cell function Dendritic cells (DC) maturation: * IL-10 & IL-12 polarization Th0 Th2 (IL-4 mast cell growth & mediator release)

Histamine H3-receptor

Expressed exclusively on brain Autoreceptor modulate histamine syntesis & release from histaminergic nerves Heteroreceptor for other amine neuro-transmitter: noradrenaline, serotonin, acethylcholine

Histamine H4-receptor

Close related to H3-receptor (58% identity on trans membrane region) Involved in chemotaxis of eosinophil and mast cell Stimulating LTB4 production chemotaxis of neutrophil Release of IL-16 from CD8+ lymphocyte Do not bind conventional H1 and H2 antihistamine therapeutic target for regulation of immune function particularly allergy

Mode of action

Histamine: * acting as agonist * combined with & stabilizes activated conformation of the receptor * shifting the equilibrium to activated state * cause a concentration-dependent increase in cell stimulation

Mode of action

2hurch 7>& Allerg" 2lin 3mmunol 3nt < ) 9orld Allerg" :rg, 1.=3 (2**4)

Mode of action

H1 antihistamine - -ompetiti!e antagonist * combined with the receptor no switch to active state * potency of antagonist depended on how well it competed with agonist for binding on the receptor

Mechanism of action

-hurch ./# 0 ergy - in Immuno Int 1 2 3or $ 0 ergy 4rg, 1*53 +2664,

Newer Anti-histamine H1

Rapid absorption Longer duration of action No sedating effect ( no blood-brain barrier passage) No anti-cholinergic effect No alcohol potentiation Non-toxic relatively

7e8er 0nti9histamine H1

Is not just symptomatic drugs An important anti-inflammatory effects (H4 on mast cell & eosinophil chemotaxis & accumulation in inflammatory allergic tissue)

0nti9in( amatory e((ect o( 0H

Achieved via: * mediator release & adhesion mol. expression * regulating release of cytokines & chemokines * inflammatory cell recruitment

Anti-inflammation effect

Anti-allergic effect of AH

synthesis & release of arach.acid metab (NF-B) adhesion mol (ICAM-1) on epith.cell & basophil histamine prod.& release by basophil chemotaxis & survival of eosinophil TNF-, IL-1, IL-6 (inflammatory cytokines) IL-4 & IL-13 (immunoreg. functions)

Antihistamines
First Generation Second Generation Third Generation

Chlorpheniramine Diphenhydramine Promethazine Hydroxyzine

Cetirizine Loratadine Astemizole Terfenadine

L !"C T#$#%#& Fexofendine &orastemizole Desloratadine

Handley D' Magnetti A, Higgins AJ. Therapeutic Advantages of Third Generation Antihistamines. Exp.Opin. nvest.!rugs "##$%&'&()"*+,-"*,+.

GPSRC AA 28 PROM TA 0406 GPRC AA 104 TA 1105 LCZ LCZ_XYZAL

The receptor occupancy concept

Receptor Occupancy (RO)

To produce an effect, drugs that act via receptors must reach receptor sites These drugs must occupy receptors Only free drug is pharmacologically active Only free drugs can cross biological membranes to interact with a given receptor

Free drug in plasma drug available to occupy receptors*

7edical 6harmacolog" and ?herapeutics 2**5, 2nd edition+ 2hapter 2, 1--48

Receptor Occupancy (RO) = proportion of receptors occupied by a drug

GPSRC AA 28 PROM TA 0406 LCZ_XYZAL

Citation on field study

Chronic Urticaria Treatment Evaluation (CUTE-Study) (Study A00394) A multicentre, double-blind, two parallel groups, randomized trial over four weeks of treatment to compare the clinical efficacy and safety of Levocetirizine 5 mg oral capsules once daily in the morning vs. Desloratadine 5 mg oral capsules once daily in the morning in subjects suffering from Chronic Idiopathic Urticaria (CIU)

Chronic Urticaria Treatment Evaluation (CUTE-Study)

Efficacy Analysis ITT Population: Mean Pruritus Severity Score
!raph of the "ean of the Pruritus Severity Score I## Population Pruritus Severity Primary ndpoint
3 Pruritus Severity Score pA&**1 2

2&22

2&2* nB431&18 nB443 1&*2 nB434

nB44. 1

* ;aseline #esloratadine 9eek 1 0evocetiri@ine

*B none+ 1B mild (present Cut not disturCing)+ 2B moderate (disturCing Cut not hampering da" time activities and=or sleep)+ 3B severe=intense (disturCing and hampering da"time activities and=or sleep ;arCaud A on Cehalf of 2D?' tud" %roup, 9A2 2**- (;angkok) 6oster Eo&, 51-

Chronic Urticaria Treatment Evaluation (CUTE-Study)

Efficacy Analysis ITT Population: Number of Wheals Score*
!raph of the "ean of the Num%er of Wheals Score I## Population

Num%er of Wheals
3 Num%er of Wheals Score pB&*54 2 1&85 nB44. 1 1&*5 nB443 * ;aseline #esloratadine nB448
$ * B none+ 1B A2* wheals =24h+ 2B 21 to 5* wheals=24h+ 3B F5* wheals=24h #ata on file

1&83 nB43*&4. nB434

G
0evocetiri@ine nB438

9eek 1

Chronic Urticaria Treatment Evaluation (CUTE-Study)

Efficacy Analysis ITT Population: Time to First Symptom Improvement Feeling after Drug Intake - Q1
&' h
&' h

)h

-h

)h

*+', h

(h
0evocetiri@ine (nB438)

(h
#esloratadine (nB448)

;arCaud A on Cehalf of 2D?' tud" %roup, 9A2 2**- (;angkok) 6oster Eo&, 51-

Chronic Urticaria Treatment Evaluation (CUTE-Study) Efficacy Analysis ITT Population: Impact of Urticaria on Quality of Sleep
.hanges of the Impact of /rticaria on 0uality of Sleep in the Levocetiri1ine group 2n3*-45

7aseline

1.&-H

33&.H

24&-H

12&1H

-&8H

6inal visit

5&8H 2&.H

-&-H

1-&1H

..&8H

*H

2*H Ier" much A lot

4*H 7oderatel"

.*H omewhat

8*H Eot at all

1**H

#ata on file

Chronic Urticaria Treatment Evaluation (CUTE-Study)

Adverse Events ITT Population: Drug related TEAEs Having an Incidence of at Least 1% in One of the Treatment Group

Levocetirizine (N=438) Dry mouth Fatigue Headache Somnolence 6 (1.4%) 12 (2.7%) 7 (1.6%) 26 (5.9%)

Desloratadine (N=448) 3 (0.7%) 12 (2.7%) 15 (3.3%) 13 (2.9%)

#ata on file

In summary

Understanding about the mechanism of action give more information how drug works Among the 4 histamine receptor H1-R & H4-R are the most important for allergic inflammation To produce an effect the drug must occupy the receptor Pro memory: antihistamine has an individual propensity