es
Outline
What is an antihistamine?
What causes allergies and what are
they, what is histamine?
History of antihistamines
Classes of antihistamines
Future of antihistamines and allergy
treatment in general
What is an antihistamine?
A drug that reduces or eliminates the effects
mediated by the chemical histamine
Histamine is released by your body during an
allergic reaction and acts on a specific histamine
receptor
True antihistamines are only the agents that produce
a therapeutic effect that is mediated by negative
modulation of histamine
The term antihistamine only refers to H1 receptor
antagonists
Antihistamines compete with histamine for binding
sites at the receptors. Antihistamine cannot remove
the histamine if it is already bound.
Allergies
Structure of Histamine
Mast Cells
Histamine is distributed in Mast
Cells in all peripheral tissues of the
body and basophils, which
circulate in the blood
ANTIGEN
IgE - Antibody
Induced Release
IgE
(food, penicillin,
venoms, etc)
Inhibitors
of
Release
(Cromolyn,
lbuterol)
PGs & LTs
Y Y
HA
H
A
HA
PROTEASES
Non-immune
Releasers
HA
HA
(opioids,
tubocurarine,
vancomycin etc)
HA
HA
HISTAMINE
Synthesis of Histamine
Formed from the amino acid Histadine in a
decarboxylation reaction with the enzyme
histidine decarboxylase
Occurs primarily in mast cells and basophils
http://www.fao.org/docrep/006/y4743e/y4743e0k.gif
Histamine receptors
Antihistam
ines
H1-
H2
H3
H1
H2
H3
H4
Type of
receptor
Effect
Treatment
G-protein coupled,
linked to
intercellular Gq,
which activates
PLC
G-protein coupled,
linked to
intercellular Gs
Mediate an increase
in vascular
permeability at sites
of inflammation
induced by histamine
Increases the release
of gastric acid
Allergies, nausea,
sleep disorders
G-protein coupled,
possibly linked to
intercellular Gi
Neural presynaptic
receptor, may
function to release
histamine
Unknown
Unknown, most
likely also Gprotein coupled
Unknown
In addition to
benefiting allergic
conditions, research in
the h4 receptor may
lead to the treatment of
autoimmune diseases.
(rheumatoid arthritis
and IBS)
Stomach ulcers
First antihistamine
Piperoxan
Discovered in 1933 by Jeff Forneau and
Daniel Bovent while developing a guinea
pig animal model of anaphylaxis.
They received the Nobel Prize in 1957
http://www.registech.com/images/ce.jpg
Piperoxan
Histamine
Agonists
H
HN
NH 2
H
HN
Histamine
NH 2
N
2methylhistamine
H1Agonist
CH 3
H3 C
HN
NH 2
N
H
HN
NH 2
N H3C
4methylhistamine
H2Agonist
(R)methylhistamine
H3Agonist
15
Antihistamines H1
Blockers
Ethylenediamines
Ar1
Ar2
(CH 2 )n
N
N
HN
N
CH 3
CH 3
CH 3
CH 3
SARPrototype
Phenbenzamine
Antazoline
16
R1
CH 3
H
O
CH 3
SARPrototype
R1isasmallgrouplikeH,CH3,OCH3
CH 3
N
Antihistamine SAR
CH 3
Diphenhydramine
(Benadryl)
Aminoalkylethers
Cl
O
NCH 3
Cl
Diphenylpyraline
N
N
CH3
Meclizine
GoodH1antagonist,butalso
goodantimuscarinic
Piperazine/N-heterocycle Series
Cl
CH3
O
Clemastine
(Tavist)
N CH3
19
Alkyl Amines
N
CH3
N
CH3
Cl
R = H Pheniramine
R = Cl Chlorpheniramine (Chlortrimeton)
R = Br Brompheniramine (Dimetane)
Pyrrobutamine (Pyronil)
N
N
N CH 3
CH3
H3 C
N
CH3
CH3
Triprolidine (Actidil)
Dimethindene (Forhistal)
Phenindamine (Nolahist)
22
Ethylenediamines
These were the first group of
clinically effective H1-antihistamines
Mepyramine (Pyrilamine)
http://en.wikipedia.org/wiki/Mepyramine
Ethanolamines
Diphenhydramine (Benedryl)
Oldest and most effective antihistamine on the
market
Ethanolamines
Carbinoxamine(Clistine)
Doxylamine succinate
Ethanolamines
Clemastine (Tavist)
Dimenhydrinate
(Dramamine)
Alkylamines
Isomerism is an important factor in this class of
drugs, which is due to the positioning and fit of
the molecules in the H1-receptor binding site
These drugs have fewer sedative and GI adverse
effects, but a greater incidence of CNS
stimulation
These drugs lack the spacer molecule (which is
usually a nitrogen or oxygen) between the two
aromatic rings and at least one of the rings has
nitrogen included in the aromatic system
Akylamines
Brompheniramine
(Dimetapp)
Chlorphenamine
http://redpoll.pharmacy.ualberta.ca/drugbank/drugBank/PC_IMAGE/APRD00832_ZOOM.gif
Akylamines
Triprolidine hydrochloride
Pheniramine (Avil)
http://en.wikipedia.org/wiki/Image:Triprolidine.svg
http://www.chiralpure.com/Figures/pheniramine.jpg
Piperazines
Cyclizine
http://en.wikipedia.org/wiki/Image:Cyclizine.svg
Piperazines
Chlorcyclizine
Hydroxyzine
Piperazines
Meclizine
It is most commonly
used to inhibit nausea
and vomiting as well as
vertigo, however it does
cause drowsiness
Cetirizine (Zyrtec)
http://redpoll.pharmacy.ualberta.ca/drugbank/drugBank/PC_IMAGE/APRD00354_ZOOM.gif
Tricyclics
These drugs are structurally related to tricyclic
antidepressants, which explains why they have
cholinergic side effects
Promethazine (Phenegran)
This drug has extremely strong
anticholinergic and sedative effects
It was originally used as an antipsychotic,
however now it is most commonly used as a
sedative or antinausea drug (also severe
morning sickness) and requires a prescription
http://upload.wikimedia.org/wikipedia/commons/c/c9/Promethazine.png
Tricyclics
Cyproheptadine
Ketotifen (Zaditor)
http://en.wikipedia.org/wiki/Image:Ketotifen.png
Tricyclics
Alimemazine (Vallergan)
Azatadine
(Optimine or Trinalin)
http://www.genome.jp/Fig/compound/C07774.gif
Mebhydrolin
Cl
CH 2 CH2 CH 2 N(CH 3 )2
NCH 3
Chlorpromazine
Fenthazine
N
CH2 CH2 N(CH 3 )2
N
N
N
OCH 3
H
Promethazine
(Pheregan)
N
CH2 CHN(CH 3 )2
CH3
Astemizole
(Hismanal)
36
Cl
N
N
CH3
Primethixene
Cl
N
OCH2CH 3
Loratadine (Claritin)
Desloratadine (Clarinex)
37
Astemiz
ole
N
N
N
N
OCH 3
H
Astemizole
(Hismanal)
Hismanal was FDA approved in 1988 as an antihistamine for allergy and hay fever
symptom relief. The FDA first warned consumers and healthcare providers of new
safety information regarding Hismanal February 9, 1998 due to the risk of death,
cardiovascular adverse events, anaphylaxis, and serious drug interactions.
In addition, Hismanal labeling was changed to stress avoiding the use of Hismanal in
combination with certain other medications and for liver disorder patients to
completely avoid its' use.
After a series of labeling changes and warnings Hismanal was recalled on June 21,
1999.
38
Antihistamines related to
butyrophenones
Terfenadine was discontinued when it became apparent that there was a high frequency
of heart arrythmia associated with the drug. Fexofenadine is a metabolite and is the
activated form responsible for antihistamine activity. In patients with compromised liver
metabolism, or when the presence of other drugs limited the metabolism of terfenadine,
persistent levels resulted in the observed arrythmias. Therefore, the fexofenadine
replaced terfenadine (1997).
Ventricular Arrythmias are not good!
OH
N
Haloperidol(Haldol)
Prototypebutyrophenoneantipsychotic
10xChlorpromazine
O
Cl
39
Butyrophenone-like
structures
OH
Terfenadine
(Seldane)
N
OH
[OX]
COOH
OH
N
Fexofenadine
(Allegra)
OH
H
Cl
OH
O
O
Cetirizine
(Zyrtec)
40
41
www.zyrtec.com
If you haven't gotten the relief you want from Claritin (loratadine), Clarinex
(desloratadine), or Allegra (fexofenadine HCl), ask your doctor if ZYRTEC is
right for you.
42
Structural Summary
Linking the first generation with Non-sedative
Antihistamines.
Big Picture - Bottom Line
Cl
O
CH3
CH3
CH3
Diphenhydramine
Meclizine
Cl
O
NH
Cl
N
OH
Desloratadine
Cetirizine
43
Astemizole (Hismantol)
This drug has a long duration
of action
It suppresses the formation
of edema and puritus
It doesnt cross the BBB
Terfenadine (Seldane)
Levocabastine
(Livostin)
Olopatadine
(Patanol)
Levocetirizine (Zyzal)
Fexofenadine (Allegra)
It was developed as an
alternative to Terfenadine
Fexofenadine was proven to be
more effective and safe
51
H2 Histamine
antagonists
Gastric receptors are pharmacologically distinct. The classic H 1 antagonists dont
interact with H2 receptors. Antihistamines are an important treatment for gastric
disorders; antacids, ulcer treatment, acid-reflux disease.
H
HN
NH 2
N
NH 2
N
NH
NTTautomerispreferredforH2
SARforHistamineH2ReceptorAntagonists
BasicHeterocycle
FlexibleChain
Polar,NeutralGroup
52
H3 C
CH3
N
N
CH3
CN
S
N
C(NH2)2
S
O
CH2 N(CH3) 2
Cimetidine
(Tagamet)
CH3
HN
Metiamide
(H2Selective)
H
HN
Burimamide
(Nonselective)
H3 C
CH3
CHNO2
Ranitidine
(Xantac)
NH2
NSO2 NH2
Famotidine
(Pepcid)
53
References
Cuss, F.M. Beyond the histamine receptor: effect of antihistamine on mast
cells. Clinical and Experimental Allergy Review 1999; 29: 54-59.
Devalia, J.L. and R.J. Davies. Effect of antihistamines on epithelial cells.
Clinical and Experimental Allergy Review 1999; 29: 64-68.
Mosges, R. and N. Krug. Efficacy of antihistamines: from the precision of
challenge models to the alchemy of clinical practice. Clinical and Experimental
Allergy Review 2006; 6: 20-24.
Tillement, J.P. Pharmacological profile of the new antihistamines. Clinical and
Experimental Allergy Review 2005; 5:7-11
http://www.netdoctor.co.uk/medicines/100002712.html
http://www.drugs.com
http://en.wikipedia.org/wiki/Antihistamines
http://www.drugbank.com