Pharmacology – ANTIHISTAMINES (MADE EASY)

Pharmacology – ANTIHISTAMINES (MADE EASY)

July 16, 2019 60 By William Morgan


in this lecture we’re gonna discuss
pharmacology of antihistamines but
before we do that let’s first talk about
what is histamine and what does it do so
histamine is a small molecule produced in
our bodies by decarboxylation of the
amino acid histidine it is widely
distributed throughout all tissues but
is particularly concentrated in the skin
lungs and gastrointestinal tract most of
histamine is generated and stored within
granules in mast cells located within
the tissues
basophils and eosinophils circulating in
the blood and enterochromaffin-like cells
located in the stomach lining now
there are three major conditions that
trigger the release of histamine first
allergic reaction so when an allergy-prone
individual for the first time comes into
contact with allergen such as ragweed
pollen their B-cells
will become activated and will form
plasma cells that produce large amounts
of ragweed immunoglobulin E antibodies
these antibodies abbreviated as IgE
firmly attach themselves to mast cells
now when that same person comes into
contact with ragweed pollen again the
binding of allergen to IgE antibodies
will trigger activation of the mast
cell which will then release granules
rich in histamine now let’s move on to
the second condition which triggers
histamine release that is tissue injury
so when tissue injury occurs the damaged
mast cells release chemical mediators
among them histamine which affect blood
vessels and nerves in the damaged area
finally the third major stimulus which
triggers histamine release can come from
drugs and foreign chemicals compounds
found in venoms
antibiotic bases dyes and alkaloids such
as morphine are a few examples that can
directly displace histamine from the
granule stores so now what does
histamine do following its release
well histamine exerts its effects by
binding to various types of histamine
receptors found on many different cells
throughout the body
to date four
types of histamine receptors have been
identified and these are H1 H2 H3 and H4
that being said in this lecture we’re
going to focus only on the first two
types as they’re the main targets of
clinically useful drugs so the first
type H1 receptors are expressed
primarily on vascular endothelial cells
smooth muscle cells as well as in the brain
and on peripheral nerve endings these
receptors mediate mainly inflammatory
and allergic reactions
so when histamine binds to vascular
endothelial receptors it causes blood
vessels to dilate thus making them more
permeable ultimately leading to redness
and edema now when histamine binds to
smooth muscle receptors particularly the
ones located in bronchioles it causes
bronchoconstriction histamine also acts
as a neurotransmitter within the central
nervous system
histamine binding to the H1 receptors in
the brain promotes among other things
wakefulness and appetite suppression
lastly histamine mediated stimulation of
peripheral nerve endings leads to pain
and itching sensations now let’s move on
to the histamine type 2 receptors so H2
receptors are expressed mainly on
gastric parietal cells when histamine
binds to these receptors it causes
increased gastric acid secretion now
let’s switch gears and let’s talk about
drugs that block the action of histamine
starting with H1 receptor blockers
classically referred to as
antihistamines so the H1 receptor
blockers can be divided into the older
or first generation agents and the newer
or second generation agents these agents
act as inverse agonists meaning they
bind to H1 receptor on a target tissue
and stabilize its inactive conformation
this leads to inhibition of histaminic
actions and gradual relief of allergy
related symptoms such as inflammation
itching runny nose and sneezing now the
general structure of the first
generation H1 antihistamines consists
of two aromatic rings
connected to a substituted ethylamine
group due to this lipophilic structure
first generation H1 antihistamine can
cross the blood-brain barrier and thus
cause sedation and potentially impair
cognitive function
additionally first generation agents
have relatively poor H1 receptor
selectivity and as a result they are
capable of occupying other receptors
such as cholinergic alpha-adrenergic and
serotonin receptors this leads to a
number of side effects for example
blockade of cholinergic receptors may
cause dry mouth blurred vision and
urinary retention blockade of alpha-adrenergic receptors
may cause
hypotension and reflex tachycardia
and lastly blockade of serotonin receptors
may cause increased appetite on the
positive side blockade of central
histamine and acetylcholine receptors
seems to be responsible for antiemetic
and anti-nausea effects examples of
first generation H1 antihistamine
include Brompheniramine
Chlorpheniramine Clemastine
Cyproheptadine Diphenhydramine
Doxylamine Hydroxyzine Meclizine and
Promethazine although all of these drugs
are useful in relieving allergy symptoms
some of them are often used for other
therapeutic indications for example
Diphenhydramine and Doxylamine are often
used in the treatment of insomnia while
Meclizine and Promethazine are more
often used in the treatment of nausea and
vomiting related to certain conditions
such as motion sickness now let’s move
on to the second generation H1
antihistamines
so unlike the first generation second
generation agents have bulkier and less
lipophilic structure therefore they
do not cross the blood-brain barrier as
readily furthermore they are much more
selective for the peripheral H1
receptors involved in allergies as
opposed to the H1 receptors in the
central nervous system as a result
second generation drugs provide the same
allergy symptom relief but with less
side effects such as sedation examples
of second generation H1
antihistamine include Cetirizine
Desloratadine Fexofenadine
Levocetirizine and Loratadine additionally
we can include in this group drugs that
have both antihistamine and mast cells
stabilizing effects namely Azelastine
and Olopatadine that are available in
ophthalmic and nasal formulations as
well as Ketotifen which is currently
available in ophthalmic formulation only
and as a side note here keep in mind that in some
medical literature
Ketotifen is classified as a
first generation antihistamine now
before we end let’s quickly discuss
histamine type 2 receptor blockers
also called H2 antagonists so in order
to understand how these drugs work first
we need to take a closer look at their
primary target that is acid producing
parietal cells of the stomach so
parietal cell has three types of
receptors which control acid production
that is acetylcholine receptor gastrin
receptor and histamine H2 type receptor now parasympathetic vagus nerve that
innervates the GI tract releases
acetylcholine which acts on acetylcholine
receptor to increase intracellular
calcium next gastrin which is a hormone
produced by G-cells located in the
pyloric glands acts on gastrin receptor
to just like acetylcholine increase
intracellular calcium
additionally gastrin stimulates nearby
enterochromaffin-like cells to
synthesize and secrete histamine finally
histamine secreted from
enterochromaffin-like cells acts on H2 receptor
to activate adenylyl cyclase leading
to increase of intracellular cyclic-AMP
levels now this increase in
intracellular cAMP and calcium
results in activation of protein kinases
which in turn stimulate hydrogen-potassium ATPase
this so called gastric proton pump
secretes hydrogen ions into the lumen of
stomach in exchange for potassium so H2 receptor antagonists selectively block
H2 receptor sites thus effectively
reduce the secretion of gastric acid
this makes them useful in treatment of
gastric ulcers and gastroesophageal
reflux disease
examples of H2 receptor antagonists
include Cimetidine Famotidine Nizatidine and Ranitidine in general these
drugs are well tolerated so adverse
effects are few and mild with the most
common being headache out of the four
Cimetidine is the most likely to
cause drug-drug interactions and side
effects some of which may include
gynecomastia and galactorrhea due to its
antiandrogenic and prolactin
stimulating effects and with that I
wanted to thank you for watching I hope
you enjoyed this video and as always
stay tuned for more