HISTAMINE

Suman Kumar Mekap Asst. Professor, Pharmacology RIPS, Berhampur

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INTRODUCTION:

• Histamine is a biogenic amine, with a imidazoline ring

and act as a neurotransmitter. It is an autocoid- means that is a molecule secreted locally to increase or decrease activity of near by cells.

• It is involved in local immune responses as well as regulating physiological function in the gut.

• Histamine triggers the inflammatory response.

• Histamine is found in basophils and by mast cells found in nearby connective tissues.

• Histamine increases the permeability of the capillaries to white blood cells and other proteins, in order to allow them to engage foreign invaders in the affected tissues.

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SYNTHESIS AND METABOLISM OF

HISTAMINE:

• pathways for histamine formation in brain.

• -----pathways that can occur outside of the nervous system.

• HDC-histidine

decarboxylase; • HMT -histamine methyl

transferase; • DAO –diamine oxidase; • MAO-monoamine oxidase.

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DYNAMICS OF NEURONAL HISTAMINE

• 1)L-histidine (His) transport into nerve terminal. • 2)Histamine (HA) synthesis by histidine

decarboxylase. • 3)Formation of histamine containing vesicles. • 4)Histamine release by exocytosis. • 5)Activation of post-synaptic receptors. • 6)Feedback inhibition of histamine synthesis and

release by H3autoreceptors. • 7)Histamine transport by astrocytes(re-uptake by

nerve terminals has not been found).

8)Metabolism by histamine-N-methyl transferase (HMT).

9)Oxidation of t-MH (tele-methyl histamine) by monoamine oxidase-B.

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STORAGE AND RELEASE OF HISTAMINE:

• 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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• 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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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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Histamine metabolism

• Histamine metabolism takes place in the liver by oxidative pathway furtherly into inert byproducts.

• One major metabolite of histamine is METHYL-

IMIDAZOLE ACETIC ACID(MIAA) 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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Histamine excretion

• 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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MECHANISM OF ACTION:

• Histamine exerts its actions by combining with specific

cellular histamine receptors.

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H1 Receptor

• The H1 receptor activates G protein – mediated hydrolysis of phosphatidylinositol.

• Leads increased intracellular inositol trisphosphate(IP3)

• IP3 triggers the release of Ca2+

from intracellular stores.

Leads to increased intracellular DIACYLGLYCEROL(DAG).

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• IP3 up on releasing Ca2+ , there is an increase in cytosolic Ca2+ concentration and activating downstream pathways.

• DAG activates protein kinase C, leading to phosphorylation

of numerous cytosolic target proteins. • The increase in cytosolic Ca2+ causes smooth muscle

contraction. • H1 receptor stimulation also leads to the activation of NFkB

(nuclear factor kappa-light-chain-enhancer of activated B cells) , an important and ubiquitous transcription factor that promotes the expression of adhesion molecules and proinflammatory cytokines.

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VMAT- vesicular monoamine transporter HNMT -histamine n-methyl transferase HDC – histidine decarboxylase NMDAR- N-methyl-D-aspartate.

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H2 Receptor

• 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 enhanced proton- pump mediated delivery of protons into the gastric fluid.

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H3 Receptors

• LOCATION :- • H3 receptors are predominantly located on presynaptic

neurons in the distinct regions of the CNS, including the cerebral cortex, basal ganglia and the tubero mammillary nucleus of the hypothalamus.

• H3 receptors appear to function as both auto receptors and

hetero receptors, 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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• 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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H4 Receptors

• 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 C beta, and downstream events result in increased intracellular Ca2+.

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Agonists and Antagonists

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PHARMACOLOGICAL ACTIONS OF HISTAMINE:

• BLOOD VESSELS:

• Dilatation of small blood vessels, larger arteries and veins are

contracted mediated by H1. • HEART:

• Heart rat and force of contraction are increased (H2) and

negative dromotropic (slowing of A-V conduction) (H1) • VISCERAL SMOOTH MUSCLE:

• H1 mediated contraction & H2 mediated relaxation is also seen.

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• GLANDS: • Increased in gastric secretion mediated by increased cAMP

generation through H2 receptors. • SENSORY NERVE ENDINGS:

• Itching when injected via i.v. Higher concentrations cause pain.

• AUTONOMIC GANGLIA AND ADRENAL MEDULLA : • Stimulated and release adrenaline and cause rise in B.P

• CNS: • Cannot penetrate BBB. Intra cerebro ventricular administration

cause rise in B.P., cardiac stimulation, hypothermia, ADH release. These effects are both by H1 & H2 receptors.

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USES OF HISTAMINE: • Sleep regulation

• Suppressive effects

• Schizophrenia

• Betahistine is used to control vertigo in patients of

Meniere’s disease, acts by causing vasodilatation in internal ear. As diagnostic aid to test of acid secreting

capacity of stomach test bronchial hyperactivity in asthmatics

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