Antihistamine

Antihistamine
An antihistamine is a type of pharmaceutical drug that opposes the
activity of histamine receptors in the body. Antihistamines are sub
classified according to the histamine receptor that they act upon: the
two largest classes of antihistamines are H1-antihistamines and H2-
antihistamines. Antihistamines that target the histamine H1-receptor are
used to treat allergic reactions in the nose (e.g., itching, runny nose, and
sneezing) as well as for insomnia. They are sometimes also used to treat
motion sickness or vertigo caused by problems with the inner ear.
Antihistamines that target the histamine H2-receptor are used to
treat gastric acid conditions (e.g., peptic ulcers and acid reflux). H1-
antihistamines work by binding to histamine H1 receptors in mast
cells, smooth muscle, and endothelium in the body as well as in
the tubero-mammillary nucleus in the brain; H2-antihistamines bind
to histamine H2 receptors in the upper gastrointestinal tract, primarily in
the stomach.
Chemistry of histamine
Histamine (β-Aminoethyl imidazole or [2-(imidazol-4-yl)ethylamine])
is a hydrophilic molecule consisting of an imidazole ring with amino
group connected by two methylene groups. Analogs of histamine
activated the four classes of 4 histamine receptors (H1, H2, H3and H4).
2Methylhistamine and 4(5)-Methyl histamine have a preferential effect
onH1and receptors respectively. A chiral analog of histamine with
restricted conformational freedom (R)-α-methyl histamine is the
preferred strong and weak agonist of the H3 and H4 receptors
respectively.
 
Sites of histamine release
1. Mast cell site:
Pulmonary tissue
Skin
GIT(intestinal mucosa)

2.Non-mast cell site:

CNS
Epidermis of skin
GIT
Cells in regenerating or rapidly growing tissue
Basophills(in blood)
 Common First Generation Antihistamines
Generic Name Brand Name

Diphenhydramine Benadryl

Chlorpheniramine Chlortimeton, Allerest

clemastine fumarate Tavist-1

Dexbrompheniramine Drixoral

hydroxyzine Atarax, Vistaril

Second Generation Antihistamines

Generic Name Brand Name

Lortadine Claritin

fexofenadine Allegra

certirizine (light sedation) Zyrtec

Levocetirizine Xyzal

pseudoephedrine/loratadine Claritin-D

pseudoephedrine/fexofenadine Allegra-D

desloratadine Clarinex

azelastine (light sedation) Astelin

Olopatadine Patanase
Classification of antihistamines (H1 Antagonists ) :
1) First generation H1 antihistamines :  
 Ethanolamine - Diphenhydramine
 Piperidine - Cyproheptidine
 Phenothiazine - Promethazine
 Alkylamine - Chlorpheniramine
OH OH
 Piperazine - Hydroxyzine
C N CH2CH2CH2CH C
 2) Second generation H1 antihistamines :
 Terfenadine COOH
 Fexofenadine
 Astemizole
 Loratidine FEXOFENADINE
 Desloratidine
 Cetrizine

 3) Third generation H1 antihistamines : 

 Levocetrizine
Cyclizine :
 SAR:
 These are ETHYLENE DIAMINE derivatives.
 Connecting moiety(X) is CHN group.
 These are moderatly potent, with low incidence
of drowsiness. slow onset of action & exhibit
peripheral & central antimuscarnic activity.
 Primary structural difference is nature of para
aromatic ring substituent.
Chlorpheniramine
 SAR : Ar
 Phenyl substituent at P-position CH2CH2 N CH3 2
replaces with “Cl” is chlorpheniramine Ar1
&
CHEMICAL
 “Br” is bromopheniramine. DRUG Ar Ar1 NAME
2-[P-chloro-
 These halogenated pheniramines are Chlorpherina α[2-
mine dimethyl
more potent & have a longer duration amino)
Cl ethyl]benzyl]-
 of action.
N pyridine
 The agents in this class produce less
sedation than the other classical
 antihistamines.

Pyridine which undergoes alkylation by 4-chlorobenzylchloride, giving 2-(4-

chlorobenzyl)pyridine. Alkylating this with 2-dimethylaminoethylchloride in
the presence of sodium amide gives chlorphenamine. Alkylamine
Derivatives
Diphenhydramine
SAR:
 These are characterized by presence of
OXYGEN connecting moiety.
 Most compounds in this series are
simple N,N-dimethyl ethanolamine
 derivatives..
 Most amino alkyl ethers are optically R
active.
Ar O (CH2)2 N CH3
 The drugs in this group possess 2
significant anti-cholinergic activity, Ar1
which may enhance the H1 blocking
action on exocrine secretion.
 This amino alkyl ethers have to
penetrate the BBB and occupy central
H1 receptor resulting the
DROWSINESS
Phenothiazine Derivatives : Eg - Promethazine
SAR :
 Phenothiazine derivatives that contain a 2/3 S
carbon branched alkyl chain
 between alkyl chain between the ring N
system and terminal nitrogen atom. R
 This differs the phenothiazine’s from DRUG R CHEMICAL
antipsychotic series in which an NAME

 Branched propyl chain is required. Promethazine (±)10-[2-

 PROMETHAZINE, the parent member of CH2 N(CH3)2 (Dimethylamino
)
this series is moderately potent & propyl]phenothi
CH3 azine
 with prolonged action & pronounced
sedative side effects.
 The combination of lengthening of side
Syntesis of promethazine by alkylation of
chain & substitution of lipophilic phenothiazine using sodinum amide
 groups in 2nd position of aromatic ring
results in compounds with decreased
antihistaminic activity & increased
psychotherapeutic properties.
Synthesis, storage and metabolism of Histamine

Histamine is a dibasic vasoactive substance formed from the decarboxylation of the amino acid histidine by the
enzyme L-histidine decarboxylase

The main site of histamine storage in most tissues is the mast cells and basophil in the blood. In these
cells, histamine is synthesized and stored in secretory granules that are then carried through the axons
and stored in nerve terminals located in the median eminence or posterior pituitary gland. Histamine is
positively charged with the pH of approximately 5.5, and ionically complexed with negatively charged
acidic groups on other constituents of the secretory granule. Non-mast cell sites of histamine
formation or storage include the epidermis, gastric mucosa, neurons within the Central Nervous
System (CNS) and cells in regenerating or rapidly growing tissues. Histamine is released continuously
rather than stored because of rapid turnover at non-mast cell sites. Non-mast cell sites of histamine
production contribute significantly to the daily excretion of histamine metabolites in the urine.
Histamine normally ingested or formed by bacteria in the gastro intestinal tract (GIT), which is
metabolized rapidly and eliminated through the urine. Histamine is metabolized by histaminase
Or methylating enzyme Imidazole-N-methyl transferase