histamine pharmacology Flashcards
overview of histamine
histamine and histamine receptor aagonists have no clinical use, just need to know its actions and uses of antihistamines.
is a basic amine, found in most tissues, but present in high concentrations in places where the body is contact with the outer environment
where is histmine synthesised (5)
- mast cells
- basophils
- ECL cells in the gastric mucosa
non-mast cell histamine
4. “histaminocytes” in the stomach
5. histaminergic neurons
what is the process of synthesis of histamine?
- histidine decarboxylated (L-histidine decarbyoxylase) into histamine.
- released from mast cells by exocytosis, undergoes rapid metabolism by the liver into a inert metabolite, imidazole acetic acid (ImAA)
- there are 2 pathways either undergo ring methylation to form methyl-ImAA (via N-methytransferase) or undergo oxidative demination then conjugation with ribose to become ImAA-ribose
triggers of histamine release
released (exo) from mast cells in response on inflammatory or allergic reactions and stimuli include the complement proteins C3a and C5, which interact with specific surface receptors, and released when there is a rise in cytosolic [Ca2+]
how is histamine stored and released?
there are slowly turning over pools and rapidly turning over pool.
slowly turning over pools are mast cells and basophils.
rapidly turning over pools are gastric ECL and histaminergic neurons.
slowly turnig over: histamine stored as an inactive ionic complex with proteoglycan (macroheparin) in large granules, and released by complete degranulation of the cell. takes a few weeks to replenish the stores.
rapidly turning over: do not store histamine, but synthesisse and releaase as its requried. histidine decarxylase is activated upon the ingestion of food
how many receptor types are there?
4, H1-4
What does H1-4 mediate generally?
H1: allergic inflammatory responses
H2: gastric acid secretion
H3: neurotransmission
H4: immunoodulatory
Which is Gq/s/i?
H1: Gq
H2: Gs
H3: Gi
H4? increase IP3 but decreases cAMP
why can histamine causes wheal and flare response?
- vasodilation of vascualr smooth muscle
- contraction of endothelial cells
- sensitisation of nereves
hence leading to redness, oedema and pain
how does histamine cause (i) bronchiolar smooth muscle constraction and (ii) vasodilation
(i) Ca2+ influx into L-type channels, phosphorylation of myosin light chain, increased contraction of smooyh muscle. Asthma patients may be 1000 fodl more senstive to histamine mediated bronchoconstriction.
(ii) Ca2+ influx, triggers NO release to into the vacscular smooth muscle cells, causing vasodilation, but the vascular smooth muscles themselves contraction. Dilation of smooth muscle leads to vasodilation, contraction of endothellal vascular cells causes fluid / plasma leadkage
what are the cardiac effects of histamine
- increased contractility - increased Ca2+ influx, leading to stronger contraction
- increased HR - increases the slope of phase 4 depolraisation, reaching the threshold more easily
- barorecptor reflex - activation ofthe reflex due to the vasodilation happening elsewhere in the body, and this changes the heart rate to compensate for hte change in blood pressure
what are the smooth muscle effects
- bronchoconstriction
- post capillary venule relaxation - increase in Ca2+ causes relaxation by inducing ht release of NOO
- vascular smooth muscle vasodilation - terminal arteriole dilation
what are the gastrointestinal effects
stimualtion of H+/K+ ATPase on the luminal membrane of parietal cells of hte gastric mucosa, causing increased gastric acid secreion
increase in cAMP also causes increased salivation
what are the skin responses (triple response)
- reddening: vasodilatino of small arterioles and relaxatino of pre-cepillaru sphincters
- wheal: incraesed permeability of post-capillary venules
- flare: surrouds the whea;
axoanl reflex: stimulateion of snesory neurons which evokes the antidromic impulse, through neighbouring branches of same nerve, releasing vasodilators (calcitonin gene releated peptide) CGRP
what is the pathology of histamine
- initial exposure to the allergen results in priming
- TH2 cells recognise the allergen and release IL-4 to stimulate B plasma cells to produce and release IgE, which binds to the Fc receptor on mast cells, priming mast cells.
- Upon subsequent exposure, the IgE is still bound to the Fc receptor, and the allergen binds to IgE, resultling in mast cell degranulation and release of histamine
- IgE-mediated hypersensitivity is type 1 and is esponsbel fro the allergies
