Antihistamin

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.

What are allergies?

Allergies are caused by a hypersensitivity reaction of the
antibody class IgE (which are located on mast cells in the
tissues and basophils in the blood)
When an allergen is encountered, it binds to IgE, which
excessively activates the mast cells or basophils, leading
them to release massive amounts of histamines.
These histamines lead to inflammatory responses ranging
from runny nose to anaphylactic shock
If both parents have allergies, you have a 70% of having
them, if only one parent does, you have a 48% chance
(American Academy of Asthma, Allergies and Immunology,
Spring 2003).

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

When it is released, histamine

causes inflammation by increasing
vasodilation, capillary permeability,
causing smooth muscle
contraction, mucus secretion, and
parasympathetic nerve stimulation

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

OTHER MEDIATORS (TNF,ILs)

ACUTE INFLAMMATORY RESPONSE

IMMEDIATE HYPERSENSITIVITY REACTION

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

[Link]

Histamine receptors

Antihistam
ines

H1-

Allergic responses. Watery eyes, congestion, etc. from allergies.

Anaphylaxis bronchial larynx constriction.
Skin allergic response reddening, rashes, welts.
Edema from injury.

H2

Gastric secretion. Important for ulcer treatment and acid reflux

H3

CNS receptors. There are also H1 receptors in the CNS.

Antihistamines may also cause the motion sickness. In general their

antimuscarinic effects are similar to that of scopolamine, although weaker.

The different Histamine receptors

Location

H1

Throughout the body, specifically

in smooth muscles, on vascular
endothelial cells, in the heart and
the CNS

H2

In more specific locations in the

body mainly in gastric parietal
cells, a low level can be found in
vascular smooth muscle,
neutrophils, CNS, heart, uterus
Found mostly in the CNS, with a
high level in the thalamus,
caudate nucleus and cortex, also
a low level detected in small
intestine, testis and prostate.
They were recently discovered in
2000. They are widely expressed
in components of the immune
system such as the spleen,
thymus and leukocytes.

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

Why is this important?

Allergies are very common in America, 50 million
people suffer from them (about 1 in 4 people)
Allergies are the 6th leading cause of chronic
disease and they cause the health care system
$18 billion annually
Over 60% of people with allergies develop
asthma as well
Keeping them under control is very important!!

Clinical Uses of Antihistamines

Allergic rhinitis (common cold)
Allergic conjunctivitis (pink eye)
Allergic dermatological conditions
Urticaria (hives)
Angioedema (swelling of the skin)
Puritus (atopic dermatitis, insect bites)
Anaphylactic reactions (severe allergies)
Nausea and vomiting (first generation H1antihistamines)
Sedation (first generation H1-antihistamines)

Adverse side effects

Associated with the first generation H 1-antihistamines and due
to their lack of selectivity for the H 1 receptor and anticholinergic activity. Side effects are due to CNS depression:
Sedation
Dizziness
Tinnitus (ringing in the ear)
Blurred vision
Euphoria
Uncoordination
Anxiety
Insomnia
Tremor
Nausea/ vomiting
Dry mouth/dry cough
Newer second generation H1-antihistamines are more
selective for the peripheral histamine receptors and have far
less side effects (drowsiness, fatigue, headache, nausea
and dry mouth)

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

[Link]

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

Classes of first generation H1 receptor

antagonist antihistamines
Ethylenediamine
s
Ethanolamines
Alkylamines
Piperazines
Tricyclics

Common Structural Features of classical

first generation antihistamines
2 aromatic rings, connected
to a central carbon,
nitrogen, or oxygen
Spacer between central
atom and the amine, usually
2-3 carbons in length. (Can
be linear, ring, branched,
saturated or unsaturated)
The amine is substituted
with small alkyl groups
Chirality at X and having the
rings in different planes
increases potency of the
drug

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

Antihistamines are stereospecific. A number of new,

single isomer drugs are being developed.

Antihistamines are structurally similar To SSRIs and to antipsychotics.

Notice the subtle difference between fluoxetine And several antihistamines.

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)

Long Duration, less sedation than ethylenediamines, ethanolamines. The

next best thing until the 2nd generation were developed.

22

Ethylenediamines
These were the first group of
clinically effective H1-antihistamines

Mepyramine (Pyrilamine)

[Link]

Ethanolamines

This class has significant anticholinergic side effects and

sedation, however reduced the gastroinestnal side effects

Diphenhydramine (Benedryl)
Oldest and most effective antihistamine on the
market

Available over the counter

Because it induces sedation, its used in
nonprescription sleep aids such as Tylenol PM
Also inhibits the reuptake of serotonin, which
led to the search for viable antidepressants with
similar structures (prozac)
[Link]

Ethanolamines
Carbinoxamine(Clistine)

Doxylamine succinate

Is used to treat Hay fever and is

especially popular to children
due its its mild taste

2nd in effectiveness of anti-allergy

activity only to Benadryl

After 21 reported deaths in

children under 2, its now only
marketed to children above 3
(FDA, June 2006)

Active ingredient in NyQuil

Potent anti-cholinergic effects
[Link]

Ethanolamines
Clemastine (Tavist)

Exhibits fewer side effects

than most antihistamines
Widely used as an
antiprurtic (stops itching)
[Link]
cgi-bin/[Link]?CARD=[Link]

Dimenhydrinate
(Dramamine)

Anti-emetic (anti nausea)

Also causes strong sedation
Readily crosses the BBB
[Link]

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

Originally used to prevent

allergic conditions
Shown to have antidepressant
properties and inhibit the
reuptake of serotonin
The first SSRI was made as a
derivative of chlorphenamine

Available over the counter

Used to treat the common cold
by relieving runny nose, itchy,
watery eyes and sneezing

[Link]

Akylamines
Triprolidine hydrochloride

Pheniramine (Avil)

Used to alleviate the symptoms

associated with allergies

Used most often to treat hay fever or

urticaria (hives)

Can be combined with other cold

medicine to relieve flu-like
symptoms

Antihistamine component of Visine-A

[Link]

[Link]

Piperazines

Structurally related to the ethylenediamines and the

ethanolamines and thus produce significant anti-cholinergic
effects
Used most often to treat motion sickness, vertigo, nausea and
vomiting

Cyclizine

Used to treat the symptoms associated

with motion sickness, vertigo and post-op
following administration of general
anaesthesia and opiods

[Link]

Mechanism of inhibiting motion sickness

is not well understood, but it may act on
the labyrinthine apparatus and the
chemoreceptor trigger zone (area of the
brain which receives input and induces
vomiting)

Piperazines
Chlorcyclizine

This drug is used to treat

motion sickness
[Link]

Hydroxyzine

In addition to treating itches and

irritations, its an anitemetic, a weak
analgesic and an anxiolytic (treat
anxiety)
[Link]

Piperazines
Meclizine

It is most commonly
used to inhibit nausea
and vomiting as well as
vertigo, however it does
cause drowsiness

Cetirizine (Zyrtec)

This drug treats indoor and

outdoor allergies and is safe to
use in children as young as 2

[Link]

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
[Link]

Tricyclics
Cyproheptadine

This drug both an antihistamine and an

antiserotonergic agent
It is a 5-HT2 receptor antagonist and also
blocks calcium channels
Used to treat hay fever and also to
stimulate appetite in people with anorexia
It is also rarely used to treat SSRI induced
sexual dysfunction and also Cushings
Syndrome (high level of cortisol in the blood)
and migraine headaches
[Link]

Ketotifen (Zaditor)

This drug is available in two forms: an

ophthalmic form used to treat allergic
conjunctivitis or itchy red eyes and an oral
form used to prevent asthma attacks
It has several adverse side effects including
drowsiness, weight gain, dry mouth,
irritability and increased nosebleeds

[Link]

Tricyclics
Alimemazine (Vallergan)

This drug is used to treat itchiness

and hives that results from allergies
Since it causes drowsiness, it is
useful for rashes that itch worse at
night time
It is also used to sedate young
children before operations
[Link]

Azatadine
(Optimine or Trinalin)

This drug is used to treat symptoms

of allergies and the common cold
such as sneezing, runny nose, itchy
watery eyes, itching, hives and
rashes

[Link]

Rigid Analogs (I)

A Cl at the 2-position weakens H1 activity relative to antimuscarinic activity and D2
antagonist activity

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

Rigid Analogs (II)

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

Allegra Propaganda - [Link]

41

[Link]

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

Second generation H1-receptor

antagonists
These are the newer drugs and they are much more selective
for the peripheral H1-receptors involved in allergies as opposed
to the H1-receptors in the CNS
Therefore, these drugs provide the same relief with many fewer
adverse side effects
The structure of these drugs varies and there are no common
structural features associated with them
They are however bulkier and less lipophilic than the first
generation drugs, therefore they do not cross the BBB as
readily
Recent studies have also showed that these drugs also have
anti-inflammatory activity and therefore, would be helpful in
the management of inflammation in allergic airways disease
(Devalia and Davies).

Second generation H1-receptor

antagonists
Acrivastine (Semprex-D)

Astemizole (Hismantol)
This drug has a long duration
of action
It suppresses the formation
of edema and puritus
It doesnt cross the BBB

This drug relieves itchy

rashes and hives
It is non-sedating because it
does not cross the BBB

It has been taken off the

market in most countries
because of adverse
interactions with erythromycin
and grapefruit juice

Second generation H1-receptor

antagonists
Loratadine (Claritin)

Terfenadine (Seldane)

It is the only drug of its class

available over the counter

It was formerly used to treat

allergic conditions

It has long lasting effects and does

not cause drowsiness because it
does not cross the BBB

In the 1990s it was removed from

the market due to the increased
risk of cardiac arrythmias

Second generation H1-receptor

antagonists
Azelastine
(Astelin or Optivar)

Levocabastine
(Livostin)

Olopatadine
(Patanol)

It is a mast cell stablilizer

Available as a nasal spray
(Astelin) or eye drops for pink
eye (Optivar)

Both of these drugs are used as eye

drops to treat allergic conjunctivitis

Third generation H1-receptor

antagonists
These drugs are derived from second generation antihistamines
They are either the active enantiomer or metabolite of the second
generation drug designed to have increased efficacy and fewer
side effects

Levocetirizine (Zyzal)

This drug is the active enantiomer of cetirizine and is

believed to be more effective and have fewer adverse
side effects.
Also it is not metabolized and is likely to be safer than
other drugs due to a lack of possible drug interactions
(Tillement).
It does not cross the BBB and does not cause
significant drowsiness
It has been shown to reduce asthma attacks by 70% in
children

Third generation H1-receptor

antagonists
Deslortadine (Clarinex)

It is the active metabolite of

Lortadine
Even though it is thought to be
more effective, there is no
concrete evidence to prove this

Fexofenadine (Allegra)

It was developed as an
alternative to Terfenadine
Fexofenadine was proven to be
more effective and safe

The future of antihistamines

The anti-inflammatory activity of second generation
antihistamines, about which little is known, will
continue to be researched and possibly lead to an
effective alternative to corticosteriods in the
treatment of allergic airways conditions.
The action of the H4 receptor will also continue to be
researched and will possibly lead to effective
treatment of autoimmune dieseases.
Creating antihistamines with higher selectivity and
less adverse side effects will continue to be the goal

2005 Nobel Prize

Press Release: The 2005 Nobel Prize in Physiology or Medicine
3 October 2005
The Nobel Assembly at Karolinska Institutet has today decided to award
The Nobel Prize in Physiology or Medicine for 2005
jointly to
Barry J. Marshall and J. Robin Warren
for their discovery of
"the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease

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

H2 Histamine antagonists. - Structures

H
HN

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
[Link]
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