Histamine is a biogenic amine that acts as a mediator of allergic and inflammatory processes. It is synthesized from the amino acid histidine and stored in mast cells and basophils. Upon stimulation, histamine is released from these cells and binds to four types of histamine receptors - H1, H2, H3, and H4. H1 receptors mediate smooth muscle contraction and inflammation. H2 receptors stimulate gastric acid secretion. H3 receptors inhibit neurotransmitter release in the brain. H4 receptors promote inflammation by activating immune cells. Histamine has widespread effects throughout the body and plays roles in gastric acid secretion, neurotransmission, and immune function.

1. BY
Y.Durga priyanka
M.pharmacy
y18MPHPY446.
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2.  Histamine is a biogenic amine.
 It is an autocoid- means that is a molecule secreted locally to increase or
decrease activity of near by cells.
 Histamine is a major mediator for allergic and inflammatory process; it also has
significant role in the regulation of gastric acid secretion, neurotransmission &
immune modulation.
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3.  Involved in local immune responses, as well as regulating physiological function in the gut and acting
as a neurotransmitter for the brain, spinal cord, uterus and high concentration in lungs & skin.
 Most histamine in the body is generated in cellular level granules in mast cells and in white blood
cells (leukocytes) called basophils.
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4.  Mast cells are especially numerous at sites of potential injury — the nose, mouth, and feet,
internal body surfaces, and blood vessels.
 Non-mast cell histamine is found in several tissues, including the brain as histaminergic neurons,
where it functions as a neurotransmitter.
 Another important site of histamine storage and release is the enterochromaffin-like (ECL) cells as
histaminocytes of the stomach.
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5. It is a aralalkylamino compound & A member of imidazole
which is a conjugate base of Histaminium.
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6.  The synthesis of histamine occurs in mast cells and basophils of
immune system, enterochromaffin – like (ECL) cells in gastric mucosa,
and certain neurons in the CNS that use histamine as neurotransmitter.
 Histamine is synthesized from the amino acid
L- Histidine.
 The enzyme HISTIDINE DECARBOXYLASE catalyzes the
decarboxylation of HISTIDINE to 2-(-4-imidazolyl) ethylamine, commonly
known as HISTAMINE.
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8.  Histamine storage and release can be divided into two pools :-
1. Slowly turning over pool.
2.Rapidly turning over pool.
 1.Slowly turning over pool :-
 Is located in mast cells and basophils.
 Histamine is stored in large granules in these inflammatory cells, and the release of histamine
involves complete degranulation of the cells.
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9.  Degranulation (Degranulation is a cellular process that releases antimicrobial cytotoxic or other molecules from secretory
vesicles called granules found inside some cells. It is used by several different cells involved in the immune system, including granulocytes and
mast cells) can be triggered by allergic processes, anaphlaxis (systemic mast cell degranulation can
cause the life-threatening condition) or cellular destruction from trauma, cold, or other insults.
 This pool is termed as Slowly turning over pool. Because several weeks are required to replenish
the stores of histamine after degranulation has occurred
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10. 2. Rapidly turning over pool :-
 Is located in gastric ECL cells and is histaminergic CNS neurons.
 These cells synthesize and release histamine as required for gastric acid secretion
and neurotransmission, respectively.
 Unlike mast cells and basophils, ECL cells and histaminergic neurons do not store
histamine.
 Instead, the production and release of histamine in these cells depend on physiologic
stimuli.
 In the gut, for example histidine decarboxylase is activated after the ingestion of food.
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11.  Histamine metabolism takes place in the liver by oxidative pathway furtherly into inert byproducts.
 One major metabolite of histamine is METHYL-IMIDAZOLE ACETIC ACID(IAA) formed by
methylation of imidazole ring.
 Other metabolite of histamine is imidazole actetate riboside(ImAA) formed by oxidative
deamination of IAA and conjugation with ribose.
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12.  In humans histamine is excreted from the urine.
 One major metabolite of histamine, ImAA( methyl imidazole acetic acid), can be
measured in the urine.
 And the level of the metabolite is used to determine the amount of histamine that
has been released systematically.
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14.  Histamine has a wide spectrum of actions involving many organs and organ system.
 These effects include actions on
smooth muscle,
vascular endothelium,
afferent nerve terminals,
heart,
gastro intestinal tract & CNS.
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15.  On smooth muscle, histamine causes some muscle fibres to constrict and others to relax.
 In human respiratory system , Histamine causes bronchoconstriction.
 Other smooth muscles – such as those in the bowel, bladder, iris, and utereus- also constrict on
exposure to histamine.
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16.  Histamine also constrict vascular endothelium cells.
 Histamine induced endothelial cells constriction causes these cells to separate from one another,
allowing release of plasma proteins and fluid from postcapillary venules and there by causes
edema.
 Thus, histamine is a key mediator of local responses at site of injury.
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17.  Peripheral sensory nerve terminals also respond to histamine.
 A direct depolarizing action of histamine on afferent nerve terminals leads to sensation of itch &
pain experienced after an insect bite for example.
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18.  The cardiac effects of histamine consists of minor increases in the force and rate of cardiac
contraction.
 Histamine enhances Ca2+ influx into cardiac cells, leading to increased ionotropy.
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19.  Histamine is one of 3 molecules that regulate acid secretion in the stomach, the other being gastrin
& acetylcholine.
 The primary role of histamine in the gastric mucosa is to potentiate Gastric – induced acid
secretion.
 Activation of histamine receptors in the stomach leads to an increase in intracellular Ca2+ in
parietal cells and results in increased secretion of HCl acid by gastric mucosa.
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20.  Finally, histamine functions as a neurotransmitter in the CNS.
 Histaminergic neurons originate in the tuberomamillary nucleus of the hypothalamus and
project diffusely throughout the brain & spinal cord.
 Although the functions of histamine in the CNS are not well understood.
 Histamine is belived to be important in the maintenance of sleep-wake cycles, cognitive processes(
attention,memory & learning), feeding behaviours( appetite suppression).
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21.  Histamine actions are mediated by the binding of histamine to one of four receptors subtypes:- H1,
H2, H3, H4.
 Histamine receptor subtypes are 7- transmembrane, G- protein coupled receptors.
 Let us study about each histamine receptor subtype individually.
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22.  LOCATION OF H1 RECEPTOR :-
 Located on vascular endothelial cells , smooth muscle cells and also on
post synaptic neurons in the tuberomamillary nucleus of the
hypothalamus, cerebral cortex, and limbic system.
 Tissue responses of H1 receptor stimulation includes edema,
bronchoconstriction, sensitization of primary afferent nerve terminals.
 In neurons appear to be involved in the control of circadian rhythms,
wakefulness, and energy metabolism.
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23.  The H1 receptor activates G protein –
mediated hydrolysis of phosphatidylinositol.
 Same.
Leads increased intracellular inositol
trisphosphate(IP3)
IP3 triggers the release of Ca2+ from intracellular
stores.
Leads to increased intracellular
DIACYLGLYCEROL(DAG).
same
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24.  IP3 up on releasing Ca2+ , there is an increase in cytosolic Ca2+ concentration and
activating downstream pathways.
 DAG activates protein kinase C, leading to phosphorylationof numerous cytosolic target
proteins.
 The increase in cytosolic Ca2+ causes smooth muscle contraction.
 H1 receptor stimulation also leads to the activation of NFkB , an important and ubiquitous
transcription factor that promotes the expression of adhesion molecules and
proinflammatory cytokines.
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25.  LOCATION :-
 These receptor subtype is located on Parietal cells in the gastric mucosa, cardiac muscle
cells, on some immune cells and on certain postsynaptic neurons in the CNS.
 The major function of the H2 receptor is to mediate gastric acid secretion in the stomach.
 H2 receptors on parietal cells activation of G protein dependent cyclic AMP cascade, leading to
enchanced proton- pump mediated delivery of protons into the gastric fluid.
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26.  LOCATION :-
 H3 receptors are predominantly located on presynaptic neurons in the distinct regions
of the CNS, including the cerebral cortex, basal ganglia and the tuberomammillary
nucleus of the hypothalamus.
 H3 receptors appear to function as both autoreceptors and heteroreceptors, there by
limiting the synthesis and release of histamine as well as other neurotransmitters,
including dopamine, Acetylcholine, norepinephrine, GABA and serotonin.
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27.  This complex interaction between histamine and various neurotransmitter systems contributes to
histamine’s wide spread effects on CNS functions, including wakefulness, appetite and memory.
 H3 receptors have also been localized in the peripheral nervous system and appear to limit
histaminergic actions in gastric mucosa and bronchial smooth muscle.
 The downstream effects of H3 receptor activation are mediated via a decrease in Ca2+.
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28.  LOCATION :-
 H4 receptors are localized to cells of hematopoietic origin, primarily mast cells, eosinophils &
basophils.
 H4 receptors are of particular interest because they are thought to play an important role in
inflammation.
 coupling of the H4 receptor to Gi/o leads to decreased cyclic AMP and activation of phospholipase
Cbeta, and downstream events result in increased intracellular Ca2+.
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29.  Up on activation of H4 receptors mediates histamine- induced leukotriene B4
production, adhesion molecule up- regualtion, and chemotaxis of mast cells,
eosinophils, and dendritic cells.
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30. Principles of pharmacology – HL sharma /kk sharma. Pg no-
344- 351.
PHARAMCOLOGY – lippincott illustrated review.pg no -393-
399.
PRINCIPLES OF PHARMACOLOGY – D.E. GOLAN.
IMAGES – Google search.
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