The different stories:

a historical perspective
Georges M. Halpern, MD, PhD
Distinguished Professor of Pharmaceutical Sciences
Hong Kong Polytechnic University
Are all Antihistamines
the same ?
General History of Antihistamines
1910 Histamine discovered
1937 First antihistamines (AHs) synthesized
1942 Antihistamines introduced for clinical use
1943 First CNS effects of AHs reported
1955 Antiallergic effects of AHs described
1981 2nd generation AHs introduced
1986 Cardiotoxic effects of AHs reported
1991 Human H2 receptor cloned
1993 Human H1 receptor cloned
1998 H1 receptor polymorphism described
1999 Human H3 receptor cloned
2000 Human H4 receptor cloned
Modified from Simons FER.
Antihistamines, Chapter 51, in
Middleton's Allergy: Principles and
Practice, Mosby, 6th Edition, 2003
1910-1911: Discovery of Histamine
Henry Dale and Patrick
Laidlaw identified
and described the
properties of
histamine (from:
histos = tissue, with
an amine
constituent).
1937: First Animal Studies
Etienne Fourneau
synthesized the 1
st

AH (thymo-ethyl-
diethylamine); Daniel
Bovet, assisted by
Anne-Marie Staub
studied it.
It was found to be too
weakly active, and
too toxic for clinical
use.

1942: First Clinical Applications
Bernard N. Halpern
introduces the 1
st
AH
in human medicine:
Phenbenzamine
(Antergan).
Indications: allergic
rhinitis & asthma;
urticaria; blood
conservation.
Next Steps
Marked by intensive and diversified research
leading to notable differences between
commercially available antihistamines
different synthesis pathways, hence different classes
different chemical structures
different indications/uses in various diseases
different development objectives
different generations
different safety features
different antihistamine performance and efficacy
Different Classes of Antihistamines
Ethylenediamines:

Pyrilamine
(mepyramine)
Antazoline
Methapyrilene
Tripelennamine

Ethanolamines

Diphenhydramine
Clemastine
Diphenylpyraline
Doxylamine
Phenyltoxamine

Alkylamines:

Desbrompheniramine
Dexchlorpherniramine
Chlorpheniramine
Dimethindene
Pheniramine
Phenothiazines:

Promethazine
Methdilazine
Trimeprazine
Piperazines:

Cyclizine
Buclizine
Hydroxyzine
Meclizine
Piperidines:

Cyproheptadine
Azatadine
Loratadine
Different classes due to different mother molecules
Different Chemical Structures
Different Applications of Antihistamines
Allergy:
1
st
& 2
nd
generation H1-antihistamines
(chlorpheniramine, diphenylhydramine,
hydroxyzine, astemizole, terfenadine, cetirizine,
fexofenadine, loratadine, desloratadine,
levocetirizine)
Anti-Migraine:
cyproheptadine, ergotamine + diphenydramine,
pizotifen
Cough, Cold and Pain relief:
diphenhydramine, doxylamine
Different Applications of Antihistamines
Motion Sickness:
dimenhydrinate, hydroxyzine, promethazine
theoclate
Sedatives:
doxylamine succinate, diphenhydramine,
pyrilamine, promethazine hydrochloride,
mepyramine maleate, trimeprazine

Different uses due to different properties and
different development objectives
PK, lower drug-drug
interactions
Receptor affinity and
selectivity, efficacy
Safety, lower
cardiotoxicity
Different Development Objectives
General trend: improve tolerability and safety (less to
no sedation; reduce the cholinergic effects)
Targeted Molecules
for improvement
Type of Improvement
Loratadine

Hydroxyzine

Terfenadine

Astemizole
Objective Class
Piperidine

Piperazine

Piperidine

Piperidine
Isomer Purification


Levocetirizine

Active metabolite
Desloratadine

Cetirizine

Fexofenadine
No possible improvement
not even designed as an antihistamine; discovered
during research of calcium channel-blocking agents
Different Generation of Antihistamines
Antergan and Neo-Antergan
1
st
Generation:
pyrilamine, antazoline, tripelennamine, diphenhydramine,
clemastine, chlorpheniramine, triprolidine, promethazine,
mequitazine, hydroxyzine, cyclizine, azatadine, cyproheptadine
2
nd
Generation:
terfenadine, astemizole, cetirizine, acrivastine, ebastine,
levocabastine, loratadine, mizolastine
New or 3
rd
Generation:
levocetirizine, carebastine, desloratadine, fexofenadine
Different Safety Profiles
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withdrawn from the
market due to
cardiotoxicity
A set of AHs tested for toxicity (inhibition of cellular proliferation) by the MTS assay (Sussman NL et al. Cell
Notes, Issue 3, 2002: 7-10). All drugs tested in quadruplicate at 80m and all assays performed at 72 hrs.
Still on the market
Different Destinies
Some withdrawn from the market:
astemizole, terfenadine
Some failed to reach enough patients:
ebastine, levocabastine
Some quickly falling out of favour:
loratadine
Some are still going strong:
fexofenadine, cetirizine, desloratadine,
levocetirizine
Are all antihistamines the same ?
Apparently, they are NOT
Different synthesis pathways
Different development objectives
The uncertainty of whether a 3
rd
generation exists
or not is also related to the different development
histories and product characteristics

The diverse pharmacology, efficacy and
safety characteristics will be featured in
the presentations that follow mine