drugs
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
1
H
4
N
N
2
Histamine
Type of
receptor
Effect
Treatment
H1
G-protein coupled,
linked to
intercellular Gq,
which activates
phospholipase C
Mediate an increase
in vascular
permeability at sites
of inflammation
induced by histamine
Allergies, nausea,
sleep disorders
H2
G-protein coupled,
linked to
intercellular Gs
Stomach ulcers
H3
G-protein coupled,
possibly linked to
intercellular Gi
Neural presynaptic
receptor, may
function to release
histamine
Unknown
H4
Unknown, most
likely also Gprotein coupled
Unknown
In addition to
benefiting allergic
conditions, research in
the h4 receptor may
lead to the treatment
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.
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
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.
Adverse effect
1) Inhibition of CNS
2) Some first-generation H1
antagonists have strong
antimuscarinic actions (atropinelike 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
Ethylenediamines
Ethanolamines
Alkylamines
Piperazines
Tricyclics
Ethylenediamines
These were the first group of
clinically effective H1-antihistamines
Mepyramine (Pyrilamine)
http://en.wikipedia.org/wiki/Mepyramine
Ethanolamines
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
e)
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
Alkylamines
Chlorphenamine
Brompheniramine
(Dimetapp)
Alkylamines
Triprolidine
hydrochloride
Pheniramine (Avil)
http://en.wikipedia.org/wiki/Image:Triprolidine.svg
http://www.chiralpure.com/Figures/pheniramine.jpg
Piperazines
http://en.wikipedia.org/wiki/Image:Cyclizine.svg
Piperazines
Chlorcyclizine
Hydroxyzine
Piperazines
Meclizine
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 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://en.wikipedia.org/wiki/Image:Ketotifen.png
Tricyclics
Alimemazine (Vallergan)
Azatadine
(Optimine or Trinalin)
http://www.genome.jp/Fig/compound/C07774.gif
Astemizole (Hismantol)
This drug has a long duration
of action
It suppresses the formation of
edema and puritus
It doesnt cross the BBB
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
Terfenadine
(Seldane)
http://en.wikipedia.org/wiki/Image:Loratadin.svg
http://scienceblogs.com/moleculeoftheday/images/terfenadine.gif
Levocabastine
(Livostin)
Olopatadine
(Patanol)
http://en.wikipedia.org/wiki/Image:Azelastine.png
Levocetirizine (Zyzal)
Fexofenadine
(Allegra)
http://en.wikipedia.org/wiki/Image:Fexofenadine_Structure.png
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:
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)