Histamine/Antihistamines

Correct Numbering and structure of histamine

Bioactive form of histamine

N distal (80%)

The ______ histamine tautomer is the major tautomer

• small vascular vessel dialtion

• vascular permeability

• bronchi CONSTRICTION

• Intestine contraction

• Gastric acid secretion

• Stimulate nerve ending (pain and itching)

• Wakefulness, cognition, food consumption

Biological effects of histamine

H1 receptor (smooth muscle, endothelial cells - allergy effects) AND H2 receptors (Gastric parietal cells - gastric acid secretion)

Biological targets of histamine

methyl (CH3)

When you add a _____ group to histamine’s structure, it changes potency from H1 receptor from 100 to 0.2 (uneven receptor potencies! 40 to 0.2!!)

Histidine decarboxylase

Histidine is transformed into HISTAMINE by _____ (takes away the COOH)

1. Histamine synthesis inhibitors

2. Histamine release inhibitors

3. Histamine receptor antagonists

Three class types of antihistamines

Inhibiting histidine decarboxylase; alpha-methylhistidine + Brocresine

Inhibitors of histamine synthesis work by ____, and examples of them are____

• Preventing bronchial asthma

• Prevent exercise-induced bronchospasm

• Prevent seasonal allergic rhinitis 

Examples: Cromolyn sodium, Khellin, Nedocromil sodium

Inhibitors of histamine release work by preventing the release of histamine (like from mast cells) and have indications for ____ 

Binding reversibly to histamine binding site (competitive antagonist) and examples are H1 receptor antagonists and H2 receptor antagonists

Histamine receptor antagonists work by _____

3 subclasses of the H1 receptor antagonists

1. Aryl group domain

2. Spacer domain

3. Alkyl amine domain

The 3 sections/domains of a H1 antagonist structure (SAR)

S configuration (think left handed gun) 

The ____ configuration is more active for the aryl group domain in H1 receptor antagonists

decreased; branching

For the spacer domain, the more carbons in the middle, the activity is _____ , and the same effect happens with ____ as well. Most agents have 4 to 5 carbons between aryl and N group

tertiary amine; quaternary charged amine

For the Alkyl amine domain for Histamine H1 antagonists, the ____ amine has optimal activity, while the ____ amine is also still active but not optimal 

Increased anticholinergic effects - dry mouth, blurred vision, urinary retention ,etc.

The quaternary amine in the amine domain of H1 antagonists is still active but NOT preferred because

Ethanolamines; S enantiomer

The _____ subclass of H1 receptor antagonists are typically used for allergic reactions (benadryl and daramamine are examples), and the ___ enantiomer is the most potent

antihistamines; SSRI’s

Ethanolamines can also become _____ or _______

two nitrogen’s connected by CH2-CH2

Ethylenediamines have these two key structures

Meclizine(top); Hydroxyzine (bottom)

____ and ____ are examples of H1 antagonist ethylenediamines

Structure of H1 antagonist subclass - propylamines

S isomer (d-isomer)

The____ isomer of H1 antagonists subclass propylamines is the most potent

Fenethazine, promethazine, and chlorpromazine

Three examples of tricyclic compounds that resemble H1 antagonist antihistamines

substituting ketone and halogen group with reduction (ketone) and bulky group (halogen)

For second gen non-sedating antihistamines, they are made by _________

Ventricular arrhythmias

Regular second gen antihistamines can have these effects

CYP450

To have 2nd gen antihistamines without arrhythmia side effects, the 2nd gens were metabolized into new drugs by ______

96% protein bound

20 hr half life

DOA: up to several weeks

CARDIAC ARRHYTHMIA!!!

Characteristics of Astemizole (withdrawn in 1999)

Loratidine; Cetirizine

_____ and ____ have no cardiac arrhythmias (2nd gens)

Structure of Loratidine

Structure of Cetirizine

Hydroxyzine

____ can become cetirizine by oxidizing the terminal alcohol 

They might form zwitterionic species which have limited BBB penetration, thus less sedationa ctivity

Why do 2nd gen antihistamines become “non-sedating”?

Azelastine; active metabolite

____ is a dual H1-receptor antagonist and mast cell stabilizer (2nd gen) and was made a nasal spray/ophthalmic due to an _____ in the oral version

Azelastine structure

Olopatadine structure

Cimetidine

Summary of SAR of antihistamines