Antihistamines 101 Munich 06-05

8/11/2019 Antihistamines 101 Munich 06-05

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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 ?


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1910-1911: Discovery of Histamine

Henry Dale and Patrick

Laidlaw identified

and described theproperties of

histamine (from:

histos= tissue, withan amine

constituent).


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1937: First Animal Studies

Etienne Fourneau

synthesized the 1st

AH (thymo-ethyl-

diethylamine); DanielBovet, assisted by

Anne-Marie Staub

studied it.

It was found to be too

weakly active, and

too toxic for clinical

use.


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1942: First Clinical Applications

Bernard N. Halpern

introduces the 1stAH

in human medicine:

Phenbenzamine

(Antergan).

Indications: allergic

rhinitis & asthma;urticaria; blood

conservation.


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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


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Different Classes of Antihistamines

Ethylenediamines:

Pyrilamine

(mepyramine)

Antazoline

Methapyri lene

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


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Different Chemical Structures


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Different Applications of Antihistamines

Allergy:1st& 2ndgeneration 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


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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


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PK, lower drug-drug

interactions

Receptor affinity and

selectivity, efficacy

Safety, lowercardiotoxicity

Different Development Objectives

General trend: improve tolerability and safety (less tono sedation; reduce the cholinergic effects)

Targeted Molecules

for improvementType of Improvement

Loratadine

Hydroxyzine

Terfenadine

Astemizole

ObjectiveClass

Piperidine

Piperazine

Piperidine

Piperidine

Isomer Purification

Levocetirizine

Active metabolite

Desloratadine

Cetirizine

Fexofenadine

No possible improvement

not even designed as an antihistamine; discoveredduring research of calcium channel-blocking agents


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Different Generation of Antihistamines

Antergan and Neo-Antergan

1stGeneration:

pyrilamine, antazoline, tripelennamine, diphenhydramine,

clemastine, chlorpheniramine, triprolidine, promethazine,mequitazine, hydroxyzine, cyclizine, azatadine, cyproheptadine

2ndGeneration:

terfenadine, astemizole, cetirizine, acrivastine, ebastine,levocabastine, loratadine, mizolastine

New or 3rdGeneration:

levocetirizine, carebastine, desloratadine, fexofenadine


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Different Safety Profiles

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Numberofviablec

ells(absorbance)

cetiriz

ineco

ntrol

fexofe

nadine

diphen

hydram

ine

chlor

pheni

ramine

hydro

xyzine

lorata

dine

terfen

adine

astem

izole

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. CellNotes, Issue 3, 2002: 7-10). All drugs tested in quadruplicate at 80m and all assays performed at 72 hrs.

Still on the market


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Are all antihistamines the same ?

Apparently, they are NOT

Different synthesis pathways

Different development objectives

The uncertainty of whether a 3rdgeneration 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

Antihistamines 101 Munich 06-05

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