Histamines Drenan Exam 4 Flashcards
What is histamine synthesized from?
Histidine
What cells release histamine?
Mast cells, eosinophils, and basophils (skin, nose, mouth, lungs, intestine) Histaminergic neurons (CNS, stomach)
What are the two pathways for histamine metabolism? How fast does it happen?
Oxidation or methylation: metabolized in minutes
How is histamine stored?
Within storage granules that contain polysaccharide, heparin, chondroitin, and proteases in addition to histamine.
What are the mechanisms for histamine release?
Thermal stress, mechanical stress, venoms, organic bases, antigen-mediated.
What immunoglobulin is most important to histamine release?
IgE
What are the steps of antigen-mediated histamine release?
Antigen presentation to B cells causes production of IgE, which binds to mast cels via FCeR. Antigen binding to IgE causes FCeR clustering, which leads to calcium influx through CRAC channels. Calcium required for degranulation.
What G protein is coupled to the H1 receptor? What is the effect?
Gq – causes calcium mobilization and NO/cGMP production
What G protein is coupled to the H2 receptor? What is the effect?
Gs – stimulates cAMP production
What G protein is coupled to the H3 receptor? What is the effect?
Gi/o – inhibits cAMP and activates MAPK (CNS more)
What are the three effects of histamine on the heart?
Positive inotropic effect (H2 myocytes), positive chronotropic effect (H2 SA node), and reflex tachycardia due to vasodilation.
How does histamine affect SA node cells?
Stimulates H2 receptors, increasing cAMP, which increases HCN activity, leading to more depolarization and higher heart rate
How does histamine affect cardiac myocytes?
Stimulates H2 receptors, increasing cAMP, which increases PKa activity and calcium channels. Increased calcium, enhanced contraction.
What type of blood vessel does histamine constrict?
Veins
How does histamine cause vasodilation?
Activates H1 in endothelial cells, which stimulates NO production. Also acts on H2 to stimulate cAMP which somehow contributes to vasodilation too.
Of the two mechanisms for histamine vasodilation, which receptor has a higher affinity for histamine? Which receptor has a longer effect?
H1: higher affinity
H2: longer binding (effect)
What is a potentially negative effect of histamine vasodilation?
Increased capillary permeability, which can cause edema.
How does histamine cause edema?
H1-mediated endothelial contraction leads to tight-junction disruption. Liquid, proteins, and cells can slip through. More small vessels than large.
What effect does histamine have on the respiratory system?
Bronchoconstriction (H1–Gq)
What effect does histamine have in the stomach?
Vagus cholinergic activation causes release of histamine, which acts on H2 receptors in parietal cells to stimulate proton pump.
What skin response is histamine responsible for?
The flare and wheal response (triple response of lewis)
What are three important signs of anaphylaxis?
Increase in heart rate, drop in blood pressure, shortness of breath. Due in part to histamine.
What type of inhibition do histamine antagonists have?
Inverse agonism
Which histamine antagonists look more like histamine–H2 antagonists or H1 antagonists?
H2 antagonists
What is the molecular basis for the second generation antihistamines having less sedation?
Increased hydrophilicity decreases CNS access
What two second generation antihistamines are the active metabolites of the original marketed antihistamines?
Fexofenadine and cetirizine (metabolites of terfenadine and hydroxyzine). Cetirizine may block other parts of inflammatory response.
What H1 antagonists are more often used for motion sickness?
Meclizine, promethazine, dimenhydrinate
What are potential adverse effects of H1 antagonists?
Sedation, N/V, anticholinergic, local anesthetic, antiserotonin (HA), a adrenergic antagonism (hypotension), extrapyramidal effects (dystonia, akathisia)
Can sedation and peripheral antihistamine activity be correlated?
No
How do histamine antagonists cause sedation?
Antagonism of histaminergic neurons involved in arousal and wakefulness.
What are the anticholinergic effects of histamine antagonists? Positive and negative.
Anti-emetic, decreased urination, dry mouth
What are first choice agents for PUD and GERD?
H2 antagonists
