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What does endogenous histamine promote
wakefulness, sneezing, itching, bronchoconstriction, increasing gastric acid production
What must occur for Mast cells to degranulate
Must be sensitized by IgE
Need Ca2+ and ATP to degranulate
What kind of receptor are Histamine receptors
GPCR
Where are H1 receptors found
Smooth muscle, endothelium, nerve-endings, post-synaptic brain cells
What kind of GPCR are H1 receptors
Gq
What effects do H1 receptor activation have
vasodilation (smooth muscle)
Bronchoconstriction (endothelium)
Increase in capillary permeability → hives
Wakefulness (post-synaptic brain cells)
Pain and itching (nerve-endings)
Can cause intestinal contractions at high concentrations
Where are H2 receptors found
Gastric mucosa, Cardiac muscle, mast cells, post-synaptic brain cells
Where in gastric mucosa are H2 receptors found
in parietal cells
What kind of GPCR are H2 receptors
Gs
What effects do H2 receptor activation have
Increases gastric acid secretion
Vasodilation
Increase in Inotropy and Chronotropy
Negative feedback on mast cells
Where are H3 receptors found
Pre-synaptic brain cells
nerve endings
What kind of GPCR are H3 receptors
Gi/o
What effects do H3 receptor activation have
Act as negative feedback regulating histamine release
can inhibit acid secretion and lower appetite
Where are H4 receptors found
Mast cells
What kind of GPCR are H4 receptors
Gi/o
What is the triple response
scratch
Immediate capillary dilation forms red line
Flare
Redness around line as arterioles dilate, within minutes
Wheal
Pale firm wheal appears from fluid and plasma leaking our of capillaries
What effect does histamine have on capillaries
Vasodilation of arterioles → increases intracapillary pressure → leakiness of fluid → hives
What is cromolyn and what is it used for
Mast cell stabilizer used for prevention of asthma attack, mastocytosis, allergic rhinitis, allergic conjunctivitis
prevents increase of calcium in mast cells
What kind of antagonist are antihistamines
Most are inverse agonists
1st generation antihistamines MOA
Inverse agonist at H1 receptors, some antagonist effects at muscarinic, serotonin and adrenoreceptors
Can block Na+ channels
1st generation antihistamines therapeutic uses
itching, edema, bronchoconstriction, N/V, motion sickness, local anesthetic
1st generation antihistamines onset and duration
1-2 hours onset, 4-6 hour duration
1st generation antihistamine side effects
drowsiness, dry mouth, (anticholinergic), constipation, urinary retention
1st generation antihistamine contraindications
Glaucoma (narrow angle)
epilepsy, febrile seizures
caution if BPH
How is histamine made
From histidine via histidine decarboxylase
What are the main tautomers of histamine
NJ is 80% Npi is 20%
J - H is away from amine
Pi - H is close to amine
Forms Gauche tautomer
What is pathway 1 of histamine metabolism
N-methylation via HMT (methylates the far N)
Oxidation via MAO or DAO to Aldehyde
Oxidation via ALDH to acid
What is pathway 2 of histamine metabolism
DAO to aldehyde
ALDH to Acid
Acid ribosylation via PRT (at far N)
How do H1 receptors bind
Aspartic acid ionic bond with amine
Asparagine hydrophilic interaction with imidazole ring
Threonine H-bond to close N on imidazole
How do H2 receptors bind
Aspartic acid ionic bond with amide
Asparagine hydrophilic interaction with imidazole ring
Base on right Tautomerizes Nitrogens
What is essential for H2 receptor binding
ability of ligand to tautomerize, and imidazole ring
What are examples of ethyldiamines
tripenelennamine
What are examples of ethanolamines
diphenhydramine
What are examples of alkylamines
chlorpheniramine
What are examples of piperazines
Meclizine, hydroxyzine
What are examples of tricyclic antihistamines
chlorpromazine, promethazine, olopatadine
1st generation antihistamine SAR
2nd generation antihistamine SAR
What is terfenadine and fexofenadine
Loratadine use, class
Desloratadine use, class
Cetiriine use, class
Pitolisant Use, class
Promethazine Use, class
