MedChem Histaminergics

What does endogenous histamine promote

wakefulness, sneezing, itching, bronchoconstriction, increasing gastric acid production

What must occur for Mast cells to degranulate

1. Must be sensitized by IgE

2. 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

1. scratch

   Immediate capillary dilation forms red line

2. Flare

   Redness around line as arterioles dilate, within minutes

3. 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

N^J is 80% N^pi is 20%

J - H is away from amine

Pi - H is close to amine

Forms Gauche tautomer

What is pathway 1 of histamine metabolism

1. N-methylation via HMT (methylates the far N)

2. Oxidation via MAO or DAO to Aldehyde

3. Oxidation via ALDH to acid

What is pathway 2 of histamine metabolism

1. DAO to aldehyde

2. ALDH to Acid

3. 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

tripelennamine

• 1st gen

What are examples of ethanolamines

diphenhydramine

• 1st gen

What are examples of alkylamines

chlorpheniramine

• 1st gen

What are examples of piperazines

Meclizine, hydroxyzine

• First gen

Cetirizine

• Second gen

What are examples of tricyclic antihistamines

promethazine, olopatadine

• 1st gen - sedative

• Have longer duration of action

Loratadine, Desloratiadine

• 2nd gen

1st generation antihistamine SAR

1. 2 Aromatic rings in different planes

2. X a linker between the rings

3. A 2-4 atom spacer between X and Amine (2 is ideal)

4. Ionizable Amine with small groups

2nd generation antihistamine SAR

Similar to First generation but they are often zwitterionic and good substrates for PGP pumps (lipophilic around amine)

What is terfenadine and fexofenadine

Terfenadine is a prodrug to fexofenadine.

Avoid fexofenadine if pregnant

Terfenadine was removed due to QT prolongation

• Used for allergic rhinitis and urticaria

Loratadine use, class

Prodrug to desloratadine

Tricyclic Antihistamine

CYP3A4 metabolized

Used for allergic rhinitis and urticaria

Desloratadine use, class

Used with isotretinoin for acne

tricyclyic antihitamine

Cetirizine use, class

Piperazine antihistamine

Metabolite of hydroxyzine

Used for urticaria and allergic rhinitis

Pitolisant Use, class, metabolism

H3 Antagonist for narcolepsy

Used to increase endogenous Histamine levels to promote wakefulness

CYP2D6 metabolized

Promethazine Use, class, Warnings

Tricyclic Antihistamine

Used for allergic rhinitis, Conjunctivitis, NV, Motion sickness

Don’t use if under 2 due to fetal respiratory failure

What happens if you inject Hydroxyzine IV

Hemolysis

What’s the difference between chlorpromazine and Promethazine

Both are tricyclic compounds.

Chlorpromazine is an antipsychotic, signified by its unbranched 3 carbon spacer

Promethazine is an antihistamine, signified by its 2 carbon, branched spacer

What metabolizes Pitolisant

CYP2D6 and CYP3A4

How do first generation antihistamines cause sedation

By inhibitng Na+ chanels

What other eceptors do first generation antihistamines interact with

Muscarinic, serotonin, adenoreceptors, NA channels

What other channels do ethyl diamines affect

NET and SERT (hence fluozetine’s similar structure)