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