Anti-histamines Flashcards
histamine
Almost all mammalian tissues contain histamine in amounts ranging from less 1 to more than 100 mg/g. Concentrations in plasma and other body fluids generally are very low, but human cerebrospinal fluid contains significant amounts. The mast cell is the predominant storage site for histamine in most tissues; the concentration of histamine is particularly high in tissues that contain large numbers of mast cells, such as the skin, the mucosa of the bronchial tree, and intestinal mucosa. However some tissues synthesize and turn over histamine at a remarkably fast rate, even though their steady-state content may be modest.
histamine synthesis
Histamine is synthesized in vivo by decarboxylation of the amino acid L-histidine, which is catalyzed by pyridoxal phosphate-dependent enzyme, L-histidine decarboxylase. Most of the histamine in tissues is stored in an inert form at the site of synthesis. Very little preformed histamine exists in a freely diffusible form. When histamine is released from its storage site, it becomes active but is rapidly converted to inactive metabolites.
catabolism of histamine
The first is the oxidative deamination pathway, which is catalyzed by diamine oxidase and leads to the formation of imidazole acetic acid.
The second pathway involves the methylation of the tele-nitrogen in the imidazole ring, which is catalyzed by histamine-N-methyltransferase and results in the formation of t-N-methylhistamine
In the periphery, both pathways contribute to the metabolism of histamine, but in the CNS the methylation pathway predominates
histamine storage
The major sites of histamine storage and release are the mast cells. Other sites include basophils and neurons in the CNS.
Histamine is distributed throughout the body, indicating that the sites of synthesis and storage also widely distributed. However, the greatest concentration of histamine occur in the skin, lungs, and gastrointestinal tract mucosa and correspond to the density of mast cells.
Basophils and mast cells are similar, in that both have high-affinity IgE binding sites on their plasma membranes and both store histamine in secretory granules.
mast cells
Histamine exists in mast cells granules as an ionic complex with a proteoglycan, mostly heparin sulfate, but also with chondroitin sulfate E.
Histamine in basophils is stored in granules as an ionic complex, predominantly with the proteoglycan chondroitin monosulfate.
histamine release
The release of histamine and many other mediators from mast cells and basophils is common during allergic disorders but also can be induced by drugs and endogenous polypeptides (bradykinin and substance P)
Histamine is released from mast cells and basophils by two general processes of degranulation (1) cytolytic and (2) noncytolytic
cytolytic
cytolytic release of histamine from mast cells occurs when the plasma membrane is damaged. This type of release is energy-independent, does not require intracellular Ca++, and is accompanied by the leakage of cytoplasmic contents
Noncytolytic
this type of release can be induced by a variety of compounds. It is generally thought, though not unequivocally established, that this form of release is evoked by the specific binding of a ligand to a receptor in the plasma membrane of the mast cell of basophil. In contrast to cytolytic release, noncytolytic release requires ATP for energy, depends on changes in the concentration of free intracellular Ca++, and is accompanied by the leakage of cytoplasmic contents.
Noncytolytic release is characterized by exocytosis of the secretory granules.
histamine receptors
H1, H2 and H3 subtypes
H1and H2 receptors have been cloned and shown to belong to the superfamily of G-protein-coupled receptors.
H3- who knows??? Very little research upon the structure and functions of this receptor subtype.
H1 receptors
H1 receptors are coupled to phospholipase C, and their activation leads to formation of inositol-1,4,5,-triphosphate (IP3) and diacylglycerols from phospholipids in the cell membrane; IP3 causes a rapid release of Ca++ from the endoplasmic reticulum. Diacylglycerols ( and Ca++) activates Ca++/ calmodulin-dependent protein kinases and phospholipase A2 in the target cell to generate the characteristic response.
CV system
Loosely referred to as “capillary dilation” this is the characteristic action of histamine on the vascular tree, and it is the most important in humans. Vasodilatation involves both H1 and H2 receptors distributed throughout the resistance vessels in most vascular beds. Activation of either H1 or H2 receptors can elicit maximal vasodilation, but the responses differ in their sensitivity to histamine, in the duration of the effect, and in the mechanism of their production.
H1 & H2
H1 receptors (on endothelial cells) have the higher affinity for histamine and mediate a dilator response that relatively rapid in onset and short lived. Mechanism : increased Ca++-----phospholipase A2----nitric oxide diffuses to the smooth muscle---activates guanylyl cyclase and causes the accumulation of cyclic GMP----stimulation of a cyclic GMP-dependent protein kinase and a decrease in intracellular Ca++ are thought to be involved in the relaxation caused by this nucleotide. Activation of H2 receptors (on vascular smooth muscle cells)causes dilation that develops more slowly and is more sustained. Mechanism :vasodilation produced by activation of Cyclic AMP.
INCREASED “CAPILLARY” PERMEABILITY
This classical effect of histamine on the fine vessels in outward passage of plasma protein and fluid into the extracellular spaces, an increase in the flow of lymph and its protein content, and formation of edema, H1 receptors are important for this response. MECHANISM: histamine causes the endothelial cells to contract and separate at their boundaries and thus to expose the basement membrane, which is freely permeable to plasma protein and fluid.
‘TRIPLE RESONSE’
If Histamine is injected intradermally, it elicits a characteristic phenomenon known as the “triple response”. It consists of (1) a localized red spot, extending for a few millimeters around the site of injection, that appears within a few seconds; (2) a brighter red flush or “flare” extending about 1cm or so beyond the original red spot and developing more slowly; (3) a wheal that is discernible in 1 to 2 minutes and occupies the same area as the original small red spot at the injection site.
The red spot results from the direct vasodilatory effect of histamine, the flush is due to histamine-induced stimulation of axon reflexes that cause vasodilation indirectly, and the wheal reflects histamine’s ability to cause edema.
HISTAMINE SHOCK
Histamine given in large doses or released during systemic anaphylaxis causes a profound and progressive fall in blood pressure. As the small blood vessels dilate, they trap large amounts of blood, and as their permeability increases, plasma escapes from the circulation. Resembling surgical or traumatic shock, these effects diminish effective blood volume, reduce venous return and greatly lower cardiac output.
