ANTIHISTAMINIC & ANTIALLERGIC DRUGS

Biosynthesis of histamine
H H
HN L-histidine HN
COOH H
N H2N N H2N
decarboxylase
Histidine Histamine

2-(Imidazol-4-yl)ethylamine

Antihistamines 1
Histamine receptors
H1 receptors are found in smooth muscle of the bronchi, gut and
uterus, its stimulation leads to constriction.
H2 receptors are found in the stomach, its stimulation leads to
increase production and secretion of gastric acid.
.H3 receptors regulate the release of histamine
Classification of Antihistaminic Drugs

H1 Receptor antagonists

Inhibitors of Histamine Inhibitors of Released

Release Histamine
Antihistamines 2
A- Inhibitors of histamine release
These agents that prevent the release of histamine from mast cell
and do not block the effect of histamine at its receptors

1- Chromolyn sodium (IntalTM)

1
NaOOC O O COONa
2

OH
O O O O

Cromolyn Sodium (Intal)

It is used prophylactically for bronchial asthma and seasonal allergic

rhinitis and used also topically for allergic conjunctivitis.
Antihistamines 3
2- Ketotifen fumarate (Zaditen®)
** It is a potent selective H1-receptor antagonist that also prevents
the release of histamine from mast cells.
** It is approved to be used as a prophylactic agent against itching
of the eye due to allergic conjunctivitis.
** It is used as systemic antiallergic agent for treatment of
seasonal allergic rhinitis, hay fever and bronchial asthma.

O
9 10
8 1
S
7
2
6 4
5 3

N
CH3
Antihistamines 4
B- Inhibitors of released histamine
1st Generation Antihistamines
Uses
Hay fever, rhinitis, urticaria and food allergy.

Side effects
Sedation, blurred vision, dry mouth, urinary retention and
.constipation

Antihistamines 5
:General Structure of H1-Antagonists
Ar1 R1
X Spacer N
Ar2
R2
Ar = Phenyl, substituted phenyl, thienyl or pyridyl.
X = N………….. Ethylenediamines series
= C-O………. ethanolamine ether series
= C……………Alkylamines
Spacer is two or three carbon atoms, ring, branched, saturated,
unsaturated.

R = small alkyl, aralkyl group.

Antihistamines 6
 1- Ethylenediamines
CH3
N CH3 3
N N
N N 2
CH2 N
1 H
Tripelennamine Antazoline
Nomenclature of tripelennamine
N,N-Dimethyl-N’-benzyl-N’-(2-pyridyl)ethylenediamine

Nomenclature of antazoline
2-imidazoline dihydrogen phosphate-]N-(Benzylanilino)methyl[-2
They contain the ethylenediamine spacer, while antazoline contains
imidazoline group in space of the alkyl tertiary amine.
Antihistamines 7
 Ethanolamine ether antihistamines -2
Diphenhydramine H3C
N CH3

(2-Benzhydryloxyethyl)dimethylamine CH O

Synthesis of diphenhydramine
CH3
CH O CH2 CH N
Br2 HO K2CO3 2 CH3
CH Br + CH3
N
Light
CH3 140oC

Antihistamines 8
Related Compounds

H3C H3C H3C

Br N CH3 Cl N CH3
N CH3
CH3
CH O CH O C O
N

Bromdiphenhydramine Chlordiphenhydramine Doxylamine

CH3
Cl C O N
CH3

Clemastine

Antihistamines 9
SAR of ethanolamine ethers
1- Structural analogues with various ring substituents (Me, OMe,
Cl, Br) in one of the aromatic rings are also active.
2- The 8-chlorotheophyllinate salt of diphenhydramine was
marketed as dimenhydramine (Dramamine®) for treatment of
motion sickness.
O
CH3 H3C
CH O CH2 CH N
2 N NH
CH3 Cl
O N N
H3C

3- Compounds with methyl group α- to the ether function affords the

related compound doxylamine, in which the aromatic groups are
H 3C
phenyl and 2-pyridyl. N CH3
CH3
C O
N
Antihistamines doxylamine 10
4- Clemastine, a homologous with an additional carbon atom
between the oxygen and the basic nitrogen is a recent addition to this
group with less sedative properties.

CH3
Cl C O N
CH3

Clemastine
(TavistTM)

5- Clemastine is marketed as the R,R and S,S-enantiomeric pairs,

and are more potent than the R,S and S,R enantiomers of the other
diasterioisomers. CH3
Cl C O N
CH3

Antihistamines Clemastine 11
6- Introduction of an alkyl group at C-2’ of one aromatic ring results
in significant changes in selectivity. With increasing alkyl size (alkyl,
Et, iPr, t-Bu) at the C-2’, large decreases in antihistaminic activity
and increases in anticholinergic activity are observed.

7- Introduction of these alkyl substituents at C-4’ decreases the

anticholinergic activity and yields small increases in antihistaminic
activity.
e.g. orphenadrine, the (2’-methyl substituted analogue of
diphenhydramine) is marketed for use as antiparkinsonism because
of its central anticholinergic properties.

CH CH3
O CH2 CH
2 N
CH3
CH3
Antihistamines Orphenadrine 12
8- An inverted rearrangement of carbon and oxygen atoms in ethanolamine ethers
afforded significantly different pharmacologic properties and led to a series of
very potent serotonin reuptake inhibitors (antidepressant).
10- Replacement of O with S leads to significant decrease in antihistaminic
properties.

CH3
CH OCH2CH2N
CH3
CH3
OCH2CH2N
CH3
Phenyltoloxamine Diphenhydramine
(Antihistamine)

F3C

CH3 O
CH SCH2CH2N CH CH2CH2NHCH3
CH3

Fluoxetine
Weak antihistamine (Serotinin reuptake inhibitor)
Antihistamines 13
 3- Alkyl Amines
Compounds where a carbon atom replaces the heteroatom spacer
in the general structure. e.g. pheniramine, chlorpheniramine and
brompheniramine.
N
CH3
N
CH3
R
R=H Pheniramine
R = Cl Chlorpheniramine
R = Br Brompheniramine
Nomenclature for pheniramine
1-(N,N-Dimethylamino)-3-pheny-3-(2-pyridyl)propane
Antihistamines 14
 Piperazines -4

CH N N CH2CH2OCH2CH2OH CH N N CH2CH2OCH2COOH

Cl Cl
Hydroxyzine (AtaraxTM) Cetrizine (ZyrtecTM)

Cetrizine is the metabolite of hydroxyzine, it is usually classified

with the second generation non-sedating antihistamines.
The amphoteric nature of cetrizine having both tertiary nitrogen
and carboxylic acid functional group, appears to be associated
with decreased, but not absent sedative side effects.

Antihistamines 15
 Tricyclic H1-Antihistamines -5
In this group, the two aryl groups in the general structure are
connected to each others through additional atom, e.g. heteroatom
like S or O, or a short one or two carbon chain. The earliest potent
tricyclic antihistamines were phenothiazines. e.g: Promethazine
(PhenerganTM).
S

N
CH3
N N
H3C CH3 CH3
Promethazine (PhenerganTM) Cyproheptadine (Periactin)

10-(2-Dimethylamino-1-propyl)phenothiazine

Antihistamines 16
Second generation non-sedating H1-antihistamines

CH3
HO C N C COOH
CH3
OH

R = COOH Fexofenadine

Nomenclature of fexofenadine
4-[1-Hydroxy-4-[4-(hydroxydiphenylmethyl)]-1-piperidinyl]butyl-
α,α-dimethylbenzene acetic acid

Antihistamines 17
 Loratidine
Loratidine is structurally related to cyproheptadine. It is
metabolized to the descarboethoxy metabolite, which has potent
histamine H1 receptors blocking activity.

Cl
N

N
COOCH2CH3
Loratidine (Claritine)

Antihistamines 18