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Are all Antihistamines the same ?. The different stories: a historical perspective. Georges M. Halpern, MD, PhD Distinguished Professor of Pharmaceutical Sciences Hong Kong Polytechnic University. 1910 Histamine discovered. 1937 First antihistamines (AHs) synthesized.

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the different stories a historical perspective

Are all Antihistamines the same ?

The different stories:a historical perspective

Georges M. Halpern, MD, PhD

Distinguished Professor of Pharmaceutical Sciences

Hong Kong Polytechnic University

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

General History of Antihistamines

Modified from Simons FER. Antihistamines, Chapter 51, in Middleton's Allergy: Principles and Practice, Mosby, 6th Edition, 2003

1910 1911 discovery of histamine
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
1937: First Animal Studies

Etienne Fourneau synthesized the 1st 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
1942: First Clinical Applications

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

next steps
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
Different Classes of Antihistamines

Different classes due to different “mother” molecules

different applications of antihistamines
Different 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 antihistamines10
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 development objectives

Class

Active metabolite

Isomer Purification

PK, lower drug-drug interactions

Piperidine

Piperazine

Piperidine

Piperidine

Desloratadine

Cetirizine

Fexofenadine

Levocetirizine

Receptor affinity and selectivity, efficacy

Safety, lower cardiotoxicity

No possible improvement

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

Different Development Objectives
  • General trend: improve tolerability and safety (less to no sedation; reduce the cholinergic effects)

Type of Improvement

Targeted Molecules for improvement

Objective

Loratadine

Hydroxyzine

Terfenadine

Astemizole

different generation of antihistamines

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

New or 3rd Generation:

levocetirizine, carebastine, desloratadine, fexofenadine

Different Generation of Antihistamines

Antergan and Neo-Antergan

different safety profiles

Still on the market

withdrawn from the market due to cardiotoxicity

Different Safety Profiles

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 80m and all assays performed at 72 hrs.

different destinies
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
Are all antihistamines the same ?
  • Apparently, they are NOT
    • Different synthesis pathways
    • Different development objectives
    • The uncertainty of whether a 3rd 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