AUTACOIDS PHARMACOLOGY
Histamine
• Histamine is endogenous to many mammalian
cell types, most notably mast cells in the skin &
lungs, parietal cells of the gastric mucosa, &
basophils.
• Histamine is also found in the CNS, where it
appear to be a NT.
• Secretion of gastric acid is markedly influenced
by histamine.
• Ag-Ab interactions, as well as several drugs
(ex. Morphine, Trimethaphan) stimulate release
of histamine from mast cells.
• Allergy symptoms such as Urticaria, nasal
congestion, asthma, & anaphylactic shock
are attributable at least in part to this amine.
• Histamine exert its effect by interacting with 2
distinct types of binding sites, designated H1
and H2 histamine receptors.
• H1 receptors are most responsible for allergy
responses, while H2 receptors mediate gastric
secretion.
• Both types of receptors are found in the brain,
& both receptor types probably mediate CV
actions of histamine.
• Histamine was adm. in the past as a test for
gastric secretion when pernicious anemia was
suspected.
• Betazole, a relatively H1-receptor-specific
analogue of histamine, was used in a similar
manner. However, SE that can be
life-threatening have made this use obsolete.
• Prostaglandin has now replaced histamine as
a test for gastric-acid secretory responses.
• Histamine use as provocative test in the dx of
Pheochromocytoma is also obsolete.
• Histamine stim. of the cells of the adrenal
medulla, coupled with an exaggerated reflex
response to histamine-induced hypotension,
results in massive release of catecholamines
in these individuals.
• Chemical assay of catecholamines are now
used.
• Adm. of Histamine can provoke all the
symptoms of allergy, including asthma and
anaphylactic shock.
• Persons who have allergies are esp. responsive
to histamine.
• Additional AE are HA, dizziness, hypotension,
exacerbation of peptic ulcer symptoms.
• Betazole causes fewer and less intense SE.
• The conventional or “classic” antihistamines
are H1-receptor antagonists.
Antihistamines
● H1-Receptor Antagonists :
● GN : Azatadine (Optimine)
● Brompheniramine (Dimetane)
● Chlorpheniramine (Chlor-Trimeton)
● Clemastine (Tavist)
● Cyproheptadine (Periactin)
● Diphenhydramine (Benadryl)
● Terfenadine (Seldane)
● Tripelennamine (Pyribenzamine)
● Triprolidine (Actidil)
H2-Receptor Antagonists :
● Cimetidine (Tagamet)
● Famotidine (Pepcid)
● Ranitidine (Zantac)
● Nizatidine (Axid)
• They are used extensively in the prevention &
control of allergic reactions.
• The most prominent SE is Sedation, although
recently developed agents such as Terfenadine
(Seldane) are reported not to cross the BBB.
• H2-antihistamines are also anticholinergic and
will produce dry mouth, urinary retention,
thickening of bronchial secretions, &
exacerbation of glaucoma.
• OTC sleeping aids & motion sickness
preventatives often contain antihistamines.
• H2 –receptor antagonists are used clinically
for their ability to suppress both daytime and
nocturnal gastric acid secretion in response to a
variety of stimuli (ex. Pentagastrin, insulin,
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 histamine & food ingestion).
• Tx & prevention of PUD , including those that
can occur with stress or with Zollinger-Ellison
Syndrome, are the major indications.
• During clinical development, Cimetidine
(Tagamet) appeared remarkably free of adverse
effects.
• However, post market surveillance revealed an
inhibition of hepatic metabolism that can result
in elevated serum levels of such drugs as
Diazepam, Warfarin, Theophylline, and
Propranolol.
• Although, H2-receptor antagonists do not
readily cross the BBB, Cimetidine can cause
mental confusion particularly in patients who
are elderly or have impaired renal function.
• Agranulocytosis and thrombocytopenia can
occur.
• Ranitidine and Famotidine have fewer
adverse CNS effects because they cross the
BBB poorly.
Serotonin
• Or 5-hydroxytryptamine (5-HT) is a
monoamine neurotransmitter, popularly thought
to be a contributor to feelings of well-being and
happiness.
• Biochemically, the indoleamine molecule is
derived from the AA tryptophan.
• This AA enter the body through diet found in
food such as nuts, cheese and red meat.
• Tryptophan deficiency can lead to lower
serotonin levels resulting to mood DO such as
anxiety & depression.
• However, it is also produced in CNS specifically
in the Raphe nuclei located in the brainstem.
• Serotonin is also stored in blood platelets and
is released during agitation and
vasoconstriction, where it acts as an agonist to
other platelets.
• Approximately 90% of the human body’s total
serotonin is located in the enterochromaffin
cells in the GIT, used to regulate intestinal
movements.
• Serotonin is secreted luminally and
basolaterally which leads to inc. serotonin
uptake by circulating platelets & activation after
stimulation, which give inc. stimulation of
myenteric neurons and GI motility.
• The remainder is synthesized in serotonergic
neurons of the CNS, where it has various
function including regulation of mood, appetite,
and sleep.
• Serotonin has cognitive functions including
memory and learning.
• Serotonin can serve as vasoconstrictor or
vasodilator while regulating hemostasis and
blood clotting.
• Vasoconstrictive property is mostly seen in
pathologic state affecting endothelium
(atherosclerosis and chronic HPN)
• In physiologic states, vasodilation occurs
through the serotonin mediated release of nitric
oxide from endothelial cells.
• It inhibits the release of NE from adrenergic
nerves.
• Is also a growth factor for some types of cells,
which may give it a role in wound healing.
• Is converted to melatonin in the pineal gland.
• Is metabolized mainly to 5-HIAA, chiefly by the
liver.
• Metabolism involves first oxidation by
monoamine oxidase to the corresponding
aldehyde. This is followed by oxidation by
aldehyde dehydrogenase to 5-HIAA , the indole
acetic acid derivative. The latter is then
excreted by the kidney.
• Smooth muscle :
• Increases motility of SI, stomach and LI may
also enhanced, but usual response is inhibition.
• Inhibitory responses are mediated by 5-HT
receptors located both in neural and muscle
cells
• 5-HT can directly stimulate the smooth muscle
of the uterus and bronchi to contract.
• Afferent nerves to the bronchi may also be
stimulated by 5-HT causing inc. in RR.
Eicosanoids
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