Histamine and antihistamine

drugs

Department of Pharmacology & Therapy

Faculty of Medicine Universitas Kristen Indonesia
Email: farmakoterapi.uki@gmail.com
 Introduction

Autacoids
histamine
serotonin
endogenous peptides
prostaglandins
leukotrienes
 Aims
After you have taken this lecture, you
are:
Understand the history of hitamine
and anti-histamine
Know the profiles of some
antihistamine
Know the use and side effects of anti
histamine
 Introduction
Distribution:
The primary site the mast cell granules (or
basophils)
Mast cells are important in that they
release histamine in response to potential
tissue injury
Other sites
central nervous system
:neurotransmitter
the fundus of the stomach: major acid
secretagogues
 Histamine

NH2

5 4

1 3
N N
H
2
Sir Henry Dale,
Penemu histamin
Histamine
 Types of Histamine receptors
Location Type of Effect Treatment
receptor

H1
Throughout the body, specifically G-protein coupled, Mediate an increase Allergies, nausea,
in smooth muscles, on vascular linked to in vascular sleep disorders
endothelial cells, in the heart and intercellular Gq, permeability at sites
the CNS which activates of inflammation
phospholipase C induced by histamine

H2
In more specific locations in the G-protein coupled, Increases the release Stomach ulcers
body mainly in gastric parietal linked to of gastric acid
cells, a low level can be found in intercellular Gs
vascular smooth muscle,
neutrophils, CNS, heart, uterus

H3
Found mostly in the CNS, with a G-protein coupled, Neural presynaptic Unknown
high level in the thalamus, possibly linked to receptor, may
caudate nucleus and cortex, also intercellular Gi function to release
a low level detected in small histamine
intestine, testis and prostate.
In addition to
H4
They were recently discovered in Unknown, most Unknown
2000. They are widely expressed likely also G- benefiting allergic
conditions, research in
in components of the immune protein coupled
the h4 receptor may
system such as the spleen, lead to the treatment
Histamine: Storage and Release

Immunologic Release:
The most important mechanism for
histamine release is in response to an
immunological stimulus.
In mast cells, if sensitized by surface
IgE antibodies, degranulate when
exposed specific antigen.
Degranulation means liberation of the
contents of the mast cell granules,
including histamine.
Degranulation is involved in the
immediate (type I) allergic reaction.
Mechanical/Chemical Release:
A second type of release occurs
following chemical or mechanical
injury to mast cells.
In these injuries caused
degranulation
Mechanism of Action
Histamine mediates its effects by
interacting with receptors.
Receptor Types H1, H2,and H3
types.
 Pharmacological effects of Histamine

1)Histamine promotes (intestinal and

Bronchiolar ) smooth muscle contraction
which is an H1 receptor mediated effect

2)Histamine significant increase in gastric

acid and gastric pepsin secretion which
is an H2 receptor mediated effect

3) Vasodilation of arterioles and

precapillary sphincters which is an
H1and H2 receptor mediated effect
 Increase the systole
dilation the small vein and small
artery
Increase the gastric acid secretion
Mainly contract the smooth
muscle,especially in bronchus
 Histamine antagonists

receptor antagonists:
selective blockade of
histamine receptors (H1, H2,
H3 types)
 H1 receptor antagonists
First-generation
diphenhydramine
promethazine
chlorpheniramine
Second-generation
orally active, hepatic
metabolism
H1 receptor blockers:
competitive antagonism
 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
H1-antihistamines)
Sedation (first generation H1-
antihistamines)
http://www2.nphs.wales.nhs.uk/icds/documents/conjunctivitis2.jpg
 Therapeutic uses
1 Allergic Reactions:
allergic rhinitis , Atopic
dermatitis, hay fever,
urticaria
2 Motion sikness:
vestibular disturbances
 Therapeutic uses

3)Sedation and hypnotics. :

these agents to be used has
sleep-aids, i.e. hypnotics.
The newer H1 antagonists, by
contrast, cause minimal or no
sedation.
1. Difenhidramin -> bersifat sedativ, antiemetik,
antivertigo
2. Klorfeniramin -> untuk alergi
3. Prometazin -> untuk obat batuk
4. Dimenhidrinat -> untuk mabuk perjalanan dan
muntah-muntah waktu hamil
5. Antazolin -> alergi pada mata dan hidung
6. Feniramin -> meredakan batuk
7. Siproheptadin -> menambah nafsu makan
8. Mebhidrolini Napadisilat -> gatal-gatal pada
alergi dan tidak bersifat menidurkan
9. Setrizina HCL -> rinitis alergi, perineal rinitis
10.Loratadine -> rinitis alergi, rasa gatal pada
hidung dan mata, rasa terbakar pada mata.
 Adverse effect
1) Inhibition of CNS

2) Some first-generation H1
antagonists have strong
antimuscarinic actions (atropine-
like effects)

3) others: Second-generation
overdosage: may induce cardiac
arrhythmias
 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
Classes of first generation H1 receptor
antagonist antihistamines
Ethylenediamines
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
 Ethylenediamines
These were the first group of
clinically effective H1-antihistamines

Mepyramine (Pyrilamine)

http://en.wikipedia.org/wiki/Mepyramine
 Ethanolamines
This class has significant anticholinergic side effects and
sedation, however reduced the gastrointestnal side effects

Diphenhydramine (Benadryl)
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)

http://en.wikipedia.org/wiki/Image:Diphenhydramine_Structure.png
 Ethanolamines
Carbinoxamine(Clistin Doxylamine succinate
e)

Is used to treat Hay fever and is 2nd in effectiveness of anti-allergy

especially popular to children due activity only to Benadryl
its its mild taste
Active ingredient in NyQuil
After 21 reported deaths in
children under 2, its now only Potent anti-cholinergic effects
marketed to children above 3
(FDA, June 2006) http://en.wikipedia.org/wiki/Image:Doxylamine.png
 Ethanolamines
Clemastine (Tavist) Dimenhydrinate
(Dramamine)

Exhibits fewer side effects

than most antihistamines Anti-emetic (anti nausea)
Widely used as an antiprurtic
Also causes strong sedation
(stops itching)
Readily crosses the BBB
http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-
bin/getCard.cgi?CARD=APRD00875.txt http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=APRD00924.txt
 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
 Alkylamines
Chlorphenamine Brompheniramine
(Dimetapp)

Originally used to prevent

allergic conditions
Available over the counter
Shown to have antidepressant
properties and inhibit the Used to treat the common cold by
reuptake of serotonin relieving runny nose, itchy, watery
The first SSRI was made as a eyes and sneezing
derivative of chlorphenamine
http://redpoll.pharmacy.ualberta.ca/drugbank/drugBank/PC_IMAGE/APRD00832_ZOOM.gif
 Alkylamines
Triprolidine Pheniramine (Avil)
hydrochloride

Used to alleviate the symptoms
associated with allergies
Can be combined with other cold
medicine to relieve flu-like
symptoms
Used most often to treat hay fever or
urticaria (hives)
Antihistamine component of Visine-A

http://en.wikipedia.org/wiki/Image:Triprolidine.svg http://www.chiralpure.com/Figures/pheniramine.jpg
 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
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)
http://en.wikipedia.org/wiki/Image:Cyclizine.svg
 Piperazines
Chlorcyclizine Hydroxyzine

In addition to treating itches and

irritations, its an anti emetic, a weak
This drug is used to treat motion analgesic and an anxiolytic (treat
sickness anxiety)

http://en.wikipedia.org/wiki/Image:Chlorcyclizine.png http://en.wikipedia.org/wiki/Image:Hydroxyzine.png
 Piperazines
Meclizine Cetirizine (Zyrtec)

It is most commonly used This drug treats indoor and

to inhibit nausea and outdoor allergies and is safe to use
vomiting as well as in children as young as 2
vertigo, however it does
cause drowsiness
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 anti nausea drug (also severe
morning sickness) and requires a prescription

http://upload.wikimedia.org/wikipedia/commons/c/c9/Promethazine.png
 Tricyclics
Cyproheptadine Ketotifen (Zaditor)

This drug both an antihistamine and an

antiserotonergic agent This drug is available in two forms: an
It is a 5-HT2 receptor antagonist and also ophthalmic form used to treat allergic
conjunctivitis or itchy red eyes and an oral
blocks calcium channels
form used to prevent asthma attacks
Used to treat hay fever and also to stimulate
It has several adverse side effects including
appetite in people with anorexia
drowsiness, weight gain, dry mouth,
It is also rarely used to treat SSRI induced irritability and increased nosebleeds
sexual dysfunction and also Cushings
Syndrome (high level of cortisol in the blood)
and migraine headaches
http://en.wikipedia.org/wiki/Image:Cyproheptadine.png http://en.wikipedia.org/wiki/Image:Ketotifen.png
 Tricyclics
Azatadine
Alimemazine (Vallergan) (Optimine or Trinalin)

This drug is used to treat itchiness

and hives that results from allergies
This drug is used to treat symptoms of
Since it causes drowsiness, it is allergies and the common cold such as
useful for rashes that itch worse at sneezing, runny nose, itchy watery
night time eyes, itching, hives and rashes
It is also used to sedate young
children before operations

http://www.genome.jp/Fig/compound/C07172.gif http://www.genome.jp/Fig/compound/C07774.gif
 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
 Second generation H1-
receptor antagonists
Acrivastine (Semprex- Astemizole (Hismantol)
D) This drug has a long duration
of action
It suppresses the formation of
edema and puritus
It doesnt cross the BBB
It has been taken off the
market in most countries
because of adverse
interactions with erythromycin
This drug relieves itchy and grapefruit juice
rashes and hives
It is non-sedating because it
does not cross the BBB

http://en.wikipedia.org/wiki/Image:Acrivastine.svg http://en.wikipedia.org/wiki/Image:Astemizole.png
 Second generation H1-
receptor antagonists
Loratadine (Claritin)
It is the only drug of its class
available over the counter
It has long lasting effects and does
not cause drowsiness because it does
not cross the BBB
http://en.wikipedia.org/wiki/Image:Loratadin.svg
Terfenadine
(Seldane)
It was formerly used to treat allergic
conditions
In the 1990s it was removed from
the market due to the increased risk
of cardiac arrythmias
http://scienceblogs.com/moleculeoftheday/images/terfenadine.gif
 Second generation H1-
receptor antagonists
Azelastine Levocabastine
Olopatadine
(Livostin)
(Astelin or Optivar)
(Patanol)

It is a mast cell stablilizer

Available as a nasal spray
(Astelin) or eye drops for
Both of these drugs are used as eye drops
pink eye (Optivar)
to treat allergic conjunctivitis

http://en.wikipedia.org/wiki/Image:Azelastine.png http://en.wikipedia.org/wiki/Image:Levocabastine.png
 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
http://en.wikipedia.org/wiki/Image:Levocetirizine.png
 Third generation H1-
receptor antagonists
Deslortadine Fexofenadine
(Clarinex) (Allegra)

It was developed as an alternative

It is the active metabolite of
to Terfenadine
Lortadine
Fexofenadine was proven to be
Even though it is thought to be
more effective and safe
more effective, there is no
concrete evidence to prove this
http://en.wikipedia.org/wiki/Image:Desloratadine.png http://en.wikipedia.org/wiki/Image:Fexofenadine_Structure.png
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
 H2 receptor antagonists

Cimetidine (Tagamet)

Ranitidine (Zantac)

Famotidine (Pepcid)
 Clinical uses

Peptic Ulcer and Duodenal

Disease

Gastric Ulcer: reduce symptoms

promote healing for benign
gastric ulcers

Gastroesophageal Reflux
Disorder (erosive esophagitis)
 Clinical uses

Hypersecretory Disease:
Zollinger-Ellison syndrome:
acid hypersecretion --
caused by gastrin-secreting
tumor
Systemic mastocytosis and
multiple endocrine adenomas:
 adverse effects
Generally well tolerated
Most common adverse effects:
diarrhea , dizziness ,
somnolence , headache , rash,
thrombocytopenia ,
neutropenia , aplastic anemia)
 adverse effects
cimetidine --------CNS effects
(uncommon): elderly: confusion
states, delirium, slurred speech
(most associated with
cimetadine)

---------antiandrogenic effects
---------Blood
Dyscrasias (granulocytopenia ,
thrombocytopenia ,
neutropenia , aplastic anemia)