Histamines and Antihistamines Flashcards
name the H2 blockers
cimetidine
ranitidine
famotidine
nizatidine
What is the name of the enzyme responsible for converting histidine to histamine?
L-histidine decarboxylase
Describe the structure of histamine and its important components.
ethylamine chain is important for drug behavior at H1 receptors
imidazole ring is important for action at H2 receptors
Discuss the metabolism of histamine.
oxidative deamination by N-methyltransferase and MAO (and other dehydrogenases)
finally turned into an acetic acid derivative
histaminase (diamine oxidase) is another pathway
diamine oxidase
found in high concentrations in the digestive tract
important for metabolizing ingested histamine
general sites of action of histamine
non-vascular smooth muscle
vascular smooth muscle (and sensory nerve endings in man)
gastric acid secretion
isolated heart peparations
possible neurotransmitter roles
effect of histamine on non-vascular sooth muscle
all are H1 effects
bronchoconstriction - smooth muscle very sensitive
intestinal smooth muscle contracts - high doses can cause diarrhea
effect of histamine on vascular smooth muscle
effects all mediated by H1
triple response of lewis due to skin trauma
triple response of Lewis
redness - direct dilatation
flare - indirect dilatation
wheal - edema
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triple response of Lewis - redness
direct dilatation of blood vessels
reflected as a local red spot appearing within seconds after injection or injury
immediate effect mediated by H1 receptors
at higher doses, a sustained H2 component participates in redness
triple response of Lewis - flare
indirect dilatation reflected as an irregular reddish area that develops slowly and extends beyond the original redness by about 1 cm
occurs indirectly via an axon reflex whereby histamine or injury excites sensory nerve terminals from the skin
impulses then travel up sensory nerve into spinal cord and also diverge via an axon collateral, which releases substance P
substance P binds to mast cells and release histamine, causing the flare
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triple response of Lewis - wheal
edema at injection site and the area of initial redness becomes raised due to increased permeability of small blood vessels, causing edema
effect of histamine on gastric acid secretion
in very low doses, histamine causes secretion of gastric juice from parietal and chief cells of the mucosa respectively (H2 mediated)
enterochromaffin-like (ECL) cells
paracrine cells that release histamine to induce parietal cells to release HCl
gastrin and ACh are other stimulants that cause these cells to release histamine
effect of histamine on isolated heart preparations
increases the rate and force of cardiac contraction (via H2 receptors) and slows conduction int he AV node (via H1 receptors, this is a minor effect)
may be important in producing arrhythmias during allergic reactions
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the effect of histamine on neurons
most important clinical effects of the H1 antihistamines int he CNS are due to blockade of muscarinic receptors
What cells contain histamine?
mast cell and the basophilic leukocyte
What makes up the secretory granules of mas cells?
histamine
proteases
heparin
cytokines
alpha-tryptase
a neutral protease found in the mast cell granule
What cytokines are found in mast cell granules?
ECF-A - eosinophil chemotactic factor of anaphylaxis
TNFs - tumor necrosis factors
anaphylaxis
the physiological stimulus to secretion of mast cells
leads to type I immediate hypersensitivity
Describe the signaling pathway that causes mast cells to release their granules and their contents.
- IgE antibodies become fixed to mast cells
- exposure to antigen triggers binding to antibodies
- phophorylation of interaction leads to activation of phospholipase C
- causes IP3 synthesis and calcium liberation from storage sites in the ER
- CRAC channels open in response to increased calium
- increased cytoplasmic calcium concentrations promote exocitosis and dissociation of the component parts of the granules
urticaria pigmentosa
a disease characterized by huge numbers of mast cells in the skin
when touched, may set of an exaggerated triple response
calcium dependent process, also activating phospholipase A2
detection of alpha-tryptase and histamine metabolites as well as prostaglandin metabolites in the urine
anaphylactoid - not IgE mediated