The different stories:The different stories:a historical perspectivea historical perspectiveThe different stories:The different stories:

a historical perspectivea historical perspective

Georges M. Halpern, MD, PhDDistinguished Professor of Pharmaceutical Sciences

Hong Kong Polytechnic University

Are all Antihistamines Are all Antihistamines the same ?the same ?

Are all Antihistamines Are all Antihistamines the same ?the same ?

General History of AntihistaminesGeneral 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 Henry Dale and Patrick Laidlaw identified Laidlaw identified and described the and described the properties of properties of histamine (from: histamine (from: histoshistos = tissue, with = tissue, with an amine an amine constituent).constituent).

1937: First Animal Studies

Etienne Fourneau Etienne Fourneau synthesized the 1synthesized the 1stst AH AH (thymo-ethyl-(thymo-ethyl-diethylamine); Daniel diethylamine); Daniel Bovet, assisted by Bovet, assisted by Anne-Marie Staub Anne-Marie Staub studied it. studied it.

It was found to be too It was found to be too weakly active, and too weakly active, and too toxic for clinical use.toxic for clinical use.

1942: First Clinical Applications

Bernard N. Halpern Bernard N. Halpern introduces the 1introduces the 1stst AH AH in human medicine: in human medicine: Phenbenzamine Phenbenzamine (Antergan). (Antergan). Indications: allergic Indications: allergic rhinitis & asthma; rhinitis & asthma; urticaria; blood urticaria; blood conservation.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

EthanolaminesEthanolamines

Diphenhydramine Clemastine Diphenylpyraline Doxylamine Phenyltoxamine

  Alkylamines:Alkylamines:

Desbrompheniramine Dexchlorpherniramine Chlorpheniramine Dimethindene Pheniramine

Phenothiazines: Phenothiazines:

Promethazine Methdilazine Trimeprazine

Piperazines:

Cyclizine Buclizine Hydroxyzine Meclizine

Piperidines:

Cyproheptadine Azatadine Loratadine

Different classes due to different “mother” moleculesDifferent classes due to different “mother” molecules

Different Chemical Structures

Different Applications of AntihistaminesDifferent Applications of Antihistamines Allergy:

– 1st & 2nd 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

Different uses due to different properties and different development objectives

PK, lower drug-drug interactions

Receptor affinity and selectivity,

efficacySafety, lower cardiotoxicity

Different Development ObjectivesDifferent Development Objectives General trend: improve tolerability and safety (less to

no sedation; reduce the cholinergic effects)

Targeted Molecules for improvement

Type of Improvement

Type of Improvement

Loratadine

Hydroxyzine

Terfenadine

Astemizole

ObjectiveClass

Piperidine

Piperazine

Piperidine

Piperidine

Isomer Purification

Levocetirizine

Active metabolite

Desloratadine

Cetirizine

FexofenadineNo possible improvement

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

Different Generation of Antihistamines

Antergan and Neo-Antergan

1st Generation:

pyrilamine, antazoline, tripelennamine, diphenhydramine, clemastine, chlorpheniramine, triprolidine, promethazine,

mequitazine, hydroxyzine, cyclizine, azatadine, cyproheptadine

1st Generation:

pyrilamine, antazoline, tripelennamine, diphenhydramine, clemastine, chlorpheniramine, triprolidine, promethazine,

mequitazine, hydroxyzine, cyclizine, azatadine, cyproheptadine

2nd Generation:

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

2nd Generation:

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

New or 3rd Generation:

levocetirizine, carebastine, desloratadine, fexofenadine

New or 3rd Generation:

levocetirizine, carebastine, desloratadine, fexofenadine

Different Safety Profiles

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withdrawn from the market due to cardiotoxicity

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

Still on the market

Different Destinies Some withdrawn from the market: Some withdrawn from the market:

– astemizole, terfenadineastemizole, terfenadine

Some failed to reach enough patients: Some failed to reach enough patients: – ebastine, levocabastineebastine, levocabastine

Some quickly falling out of favour: Some quickly falling out of favour: – loratadineloratadine

Some are still going strong:Some are still going strong:– fexofenadine, cetirizine, desloratadine, levocetirizinefexofenadine, cetirizine, desloratadine, levocetirizine

Are all antihistamines the same ?

Apparently, they are NOTApparently, they are NOT– Different synthesis pathwaysDifferent synthesis pathways– Different development objectivesDifferent development objectives– The uncertainty of whether a 3The uncertainty of whether a 3rdrd generation exists or not generation exists or not

is also related to the different development histories and is also related to the different development histories and product characteristicsproduct characteristics

The diverse pharmacology, efficacy and safety characteristics will be featured in the

presentations that follow mine