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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
Throughout the body, G-protein Mediate an Allergies,
H specifically in smooth coupled, linked increase in nausea, sleep
muscles, on vascular to intercellular vascular disorders
1 endothelial cells, in the Gq, which permeability at
heart and the CNS activates sites of
phospholipase inflammation
C induced by
histamine
In more specific locations G-protein Increases the Stomach ulcers
H in the body mainly in coupled, linked release of gastric
gastric parietal cells, a low to intercellular acid
2 level can be found in Gs
vascular smooth muscle,
neutrophils, CNS, heart,
uterus
Found mostly in the CNS, G-protein Neural Unknown
H with a high level in the coupled, presynaptic
thalamus, caudate nucleus possibly linked receptor, may
3 and cortex, also a low level to intercellular function to
detected in small intestine, Gi release
testis and prostate. histamine
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
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
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 of the drug
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(Clistine) Doxylamine succinate
Used to alleviate the symptoms Used most often to treat hay fever or
associated with allergies urticaria (hives)
Can be combined with other cold Antihistamine component of Visine-A
medicine to relieve flu-like
symptoms
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
http://en.wikipedia.org/wiki/Image:Chlorcyclizine.png http://en.wikipedia.org/wiki/Image:Hydroxyzine.png
Piperazines
Meclizine Cetirizine (Zyrtec)
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)
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 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
It has been taken off the
market in most countries
because of adverse
interactions with
This drug relieves itchy erythromycin and grapefruit
rashes and hives juice
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) Terfenadine (Seldane)
It is the only drug of its class It was formerly used to treat allergic
available over the counter conditions
It has long lasting effects and does In the 1990s it was removed from
not cause drowsiness because it does the market due to the increased risk
not cross the BBB of cardiac arrythmias
http://en.wikipedia.org/wiki/Image:Loratadin.svg http://scienceblogs.com/moleculeoftheday/images/terfenadine.gif
Second generation H1-
receptor antagonists
Azelastine Levocabastine
Olopatadine
(Livostin)
(Astelin or Optivar)
(Patanol)
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 (Clarinex) Fexofenadine (Allegra)
Cimetidine (Tagamet)
Ranitidine (Zantac)
Famotidine (Pepcid)
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)