Histamine Pharmacology and GI Disease Flashcards
(44 cards)
How is histamine made and what cofactor is required?
Made via decarboxylation of L-histidine via histidine decarboxylase
Requires pyridoxal phosphate (Vitamin B6) as cofactor
Why is histamine referred to as an “autacoid” and what are its major effects?
It is a local hormone -> must be degraded quickly
Effects: Vasodilation, increased vascular permeability, gastric secretion, and smooth muscle contraction.
It is also chemoattractant for inflammatory cells, and causes platelet aggregation / complement activation
Where is histamine primarily found in the blood and in the tissues?
In the blood - basophils
In the tissues - mast cells
Where is histamine stored? What is it stored with?
Stored in metachromatic secretory granules, complexed as an inactive componud with heparin and chondroitin sulfate
Where is turnover of histamine very rapid?
In non-mast cells:
Enterochromaffin-like cells, brain, etc
What is the function of enterochromaffin-like cells and what inhibits it?
They release histamine to stimulate gastric acid secretion
Inhibited by D cells in the antrum which release somatostatin in response to low pH
Stimulated by gastrin-production from G cells, which are also inhibited by somatostatin
How is histamine degraded and what its major breakdown product?
Degraded by liver by an N-metyhltransferase enzyme + monoamine oxidase
Forms methylimidazole acetic acid (MIAA) -> can be seen in urine
What is the immunologic cause of histamine secretion?
Hypersensitivity reaction -> B cells put IgE on mast cells and basophils, which degranulate in response to antigen
What are the mechanical and chemical causes of histamine release?
Mechanical - scratches or exposure to sunlight (skin turns red)
Chemical - Increased intracellular calcium causes exocytosis
What drug blocks the release of histamine from mast cells directly?
Cromolyn sodium (sodium cromoglycate), bocks influx of divalent cations including Ca+2
What do Compound 48/80 and polymyxin B do?
They act as ionophores, resulting in influx of Ca+2 and resultant histamine release
How do many therapeutic compounds stimulate histamine release?
Cause the dissociation of histamine from heparin-bound complex inside the granules (includes tubocurarine and radiocontrast dies)
What type of receptors are the histamine receptors? How many forms are there?
GPCR
There are H1-H4
H3 is presynaptic in brain
What is the mechanism of the H1 receptor and where are they found?
Found on smooth muscle of gut and bronchi, on endothelium, and in brain.
Gq -> cause contraction and bronchoconstriction (test for asthma) via Ca+2
Remember histamine causes contraction of GI smooth muscle
Where are H2 receptors found? What’s their mechanism?
Gastric mucosa (parietal cells), cardiac muscle cells, “mast cells”
Gs -> increase cAMP
What does cardiovascular histamine release cause?
Increased heart rate (H2) and decreased blood pressure (H1) -> reason why you feel flushed, get a headache, and feel warm
What causes hives?
Histamine-induced edema
Why does histamine cause itching?
H1-receptor mediated stimulation of sensory nerve endings (insect stings / venoms)
The “allergy pills” and “sleep aids” we know of -> what is their mechanism of action?
H1 receptor inverse agonist (reduce the histamine receptor functioning even below baseline)
What are the first generation antihistamines for rhinitis? What is their drawback?
Diphenyhydramine and chlorpheniramine
They put people to sleep as well as treat allergies
What is allegra and why is it used over terfenadine? How is it metabolized?
Second generation antihistamine called fexofenadine
Used over terfenadine because it does not cause Torsades de pointes (Ventricular arrhythmia)
Metabolized via CYP3A4
What are the motion sickness first generation antihistamines? How do they work?
Meclizine (antivert), Dimenhydrinate (dramamine)
Work via blocking H1 receptor in CNS (between inner ear and brainstem)
What is the third generation antihistamine?
Levocetirizine (zyrtec purified)
What is Claritin?
Loratidine
