Pharmacology – ANTIHISTAMINES (MADE EASY)
18
September

By Adem Lewis / in , , , , , , , , , , , , , , , , , , , , , /


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


13 thoughts on “Pharmacology – ANTIHISTAMINES (MADE EASY)

  1. your videos are really wonderful and have helped me in many exams settings. I would be very glad if you could upload a video on anti-asthmatic drugs.

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