Antihistaminics-Medicinal Chemistry

Introduction, Classification, Synthesis, Mechanism of action and uses of antihistaminics. Histamine 2 receptor antagonist, Proton pump inhibitors

1. Dr. Gopal Krishna Padhy

2. Histamine [4-(2-aminoethyl)imidazole]occurs in mast cell ,
blood basophiles and acid secreting parietal cells.

OD.

Antigens derived from food products, pollens, dust and human
hair releases histamine and causes serious allergic reaction.

The physiological action of histamine is due to their action on
histamine receptors (H,, H,, H; & H,)

3. Antihistaminic agents:
These are drugs which competitively antagonise the
action of histamine at H, receptor.

2 4 fs
CH) —CHy—N
CH

Diphenhydramine Hydrochloride

TUPAC: N, N-dimethyl-(2-diphenylmethoxy)ethylamine

4. Hs
Cho O tN 6 Ny
CH-O-CHy—CHy-N 2 cl
CH3 eget ve
BC” 3 45 Y
o

Dimenhydrinate

Complex of N, N-dimethyl (2-diphenylmethoxy) ethylamine
and 8-chlorotheophylline

y
N
a Ron")

CH;

Clemastine Fumarate
IUPAC: 2-[2-[1-(4-chlorophenyl)-1-
phenylethoxy]ethyl]-1-methylpyrrolidine

5. CH- re: CH; . HCl
O ”

Diphenylpyraline hydrochloride
TUPAC: 4-(benzhydryloxy)-N-methylpiperidine

Hs

H>— Seal

CH;

o 2 CH
C-C—0-C

ZN

o)

Doxylamines Scuccinate

IUPAC: N, N-dimethyl-2-(1-phenyl-1-pyridin-2-ylethoxy)

ethanamine

6. Ethylen

CH;

cH, CH;

Tripelennamine

TUPAC: N-benzyl -N',N'-dim ethyl-N-2-pyridylethylenediamine

7. Cl

o 23
1724

CH-N N-CH3 -HCI
© *
6 5
Chlorcyclizine hydrochloride
TUPAC: 1-[(4-chlorophenyl)-

phenylmethyl]-4-

methylpiperazine

cl

4" zu
i 2"

2 23
a" FR

CH-N N-CHa
a4
‘> 2 3cH;

Meclizine hydrochloride

TUPAC: 1-[(4”-chlorphenyl)
phenylmethyl]-4-[(3’-methylbenzyl)

phenyl]piperazine

8. Buclizine Hydrochloride

IUPAC: 1-[(4-chlorophenyl)-
phenylmethyl]-4-[(4-tert-

butylphenyl)methyljpiperazine

9. CH-N N—CH2CH2-0-CH2COOH
2 ri Es

Cetirizine

TUPAC: 2-[2-[4-[(4-chlorophenyl)-
phenylmethyl]piperazin-1-yl]ethoxyJacetic acid

10. H'-C-N N—CH2CH2-0-CH2COOH
2 2 És

Levocetirizine

2-[2-[4-[(R)-(4-chlorophenyl)-
phenylmethyl]piperazin-1-yljethoxy]acetic acid

11. Saturated analogs
pi

BQ y 3
NA 3 2 1 Ma
2 CH-CH¿—CH¿—N

INCH;

cl
Chlorpheniramine maleate

IUPAC: 3-(p-chlorophenyl)-3-(2'-pyridyl)propyldimethylamine

12. Unsaturated derivatives

«5% Y Triprolidine
TUPAC: trans-1-(4+"-methylphenyl)-1-(2'-pyridyl)-3-

pyrrolidinoprop-1-ene

5 10] CH;
She CHN

20H, CH;
mn

Promethazine

10-(2’-dimethylaminopropyl)phenothiazine

13. BR!

5 Mo 4 CHs
CHa H- = N
120,3

\

CH3

Trimeprazine

IUPAC: 10-(3’-dimethylamino-2'-

methylpropyl) phenothiazine

14. Cyproheptadine
hydrochloride

TUPAC: 4-(dibenzo[a,d]cyclohepten-5-ylidene)-

1-methylpiperidine
A

Azatidine

maleate

TUPAC: 11-(1-Methyl-4-piperidinylidene)-5,6-dihydro-5H

benzo[1, 2]cyclohepta[3,4-b]pyridine

15. Loratadine

IUPAC: 1-Piperidinecarboxylic acid, 4-(8-
chloro-5,6-dihydro-11H-
benzo[5,6]cyclohepta[1,2-b]pyridin-11-

ylidene)-, etyl ester

16. Astemizole Bohs

IUPAC: 1-[(4-fluorophenyl)methyl]-N-[1-[2-(4-

methoxyphenyl) ethyl]-4-piperidinyl]-benzimidazol-2-

amine

17. Cromolyn sodium

TUPAC: disodium ; 5-[3-(2-carboxylato-4+-
oxochromen-5-yl)oxy-2-hydroxypropoxy]-+-
oxochromene-2-carboxylate

18. H, Receptor

19. Receptor

hese are found on parietal cells located in the stomach lining.
Histamine action at these receptors stimulates the release of gastric
acid, excess of which can result in gastroenteritis.

«e These receptors are also found on heart, uterus and vascular
smooth muscle cells. Histamine reacting with the receptor at these
places encourages smooth muscle relaxation.

“This also found on neutrophils (one type of white blood cell).
Histamine inhibits antibody and cytokine production by reacting

h these receptors.

Receptor

‘hese are present throughout the nervous system, though most

bly in the central nervous system.

‘hey regulate histamine in the body, by inhibiting the further

hesis of histamine.

20. H4 Receptor

«e Discovered in 2001, these receptors regulate the levels of

white blood cell release from bone marrow.
«+ They are located in the thymus, small intestine, spleen, the
colon, bone marrow and basophils.

21. Gastric acid
secretion

Blood
vessels to
dilate

e.
« >

Contraction of
Itchiness respiratory ways

22. room cnn
Bra

CH, — CHB

r
Light NazCOs, 140 °C
-HBr

Diphenyl methane

E

Diphenhyeramine HCI 25mg | Anthistamine

ume ©

POTES

Q om
CH—0 CH2CH2N,
© j

Ha

[o

a.
O E

CH—OCH; CH N,
‘CH.

23. o Diphenhydramine predominantly works via the antagonism
of H1 (Histamine 1) receptors . It reverses the effects of
histamine on blood capillaries, reducing allergic reaction
symptoms .

© Moreover, it readily crosses the blood-brain barrier and
inversely agonizes the H, CNS receptors, resulting in
drowsiness, and suppress the medullary cough center.

O Furthermore, diphenhydramine also acts as an

antimuscarinic . It behave as a competitive antagonist of

muscarinic acetylcholine receptors, resulting in its use as an

antiparkinson medication.

Indicated for use in treating sneezing, runny nose,
itchy/watery eyes, itching of nose or throat, insomnia,
pruritis, urticaria, insect bites/stings, allergic rashes, and

nausea

24. Y

Dimenhydrinate

CHs 6 N7
CH-0-CH—CHyN 5
CH; Le
3 14° 9

MOA: Dimenhydrinate is a competitive antagonist at the

histamine H1 receptor, which is widely distributed in the
human brain. Dimenhydrinate's anti-emetic effect is probably
due to H1 antagonism in the vestibular system in the brain.

Uses: Dimenhydrinate is indicated for the prevention and

treatment of nausea, vomiting, or vertigo of motion sickness.

25. Doxylamines Scuccinate

CHs

H3C-C—O-CH,—CHy-N

CH:
IN 3

Se 5

IUPAC: N,N-dimethyl-2-(1-phenyl-1-pyridin-2-ylethoxy)
ethanamine
MOA: Dimenhydrinate is a competitive antagonist at the
histamine H1 receptor. It has pronounced sedative properties.

Uses: It is used in allergies and as an antitussive, antiemetic,

and hypnotic.

26. Y

Clemastine fumarate

Ha

k COOH .
ate O-CHy— o). ( bravest Tablets
COOH

MOA: It works via the antagonism of H, (Histamine 1)
receptors . It reverses the effects of histamine on blood
capillaries and reduces allergic reaction symptoms.

Uses: Used in hay fever, rhinitis, allergic skin conditions, and

pruritus. It causes drowsiness.

27. Diphenylpyraline hydrochloride

cH-o-{ N-cH, . HCI

MOA: It works via the antagonism of H, (Histamine 1)
receptors . It reverses the effects of histamine on blood

capillaries and reduces allergic reaction symptoms.

Uses: allergic rhinitis, hay fever, and allergic skin disorders.

28. Y

Tripelennamine

MOA: Tripelennamine binds to the histamine H1
receptor. This blocks the action of endogenous histamine,
which subsequently leads to temporary relief of the
negative symptoms brought on by histamine.

Uses: Used for the symptomatic relief of hypersensitivity

reactions, coughs, and the common cold.

29. Chlorcyclizine hydrochloride

a.

CH-N N-CH,
©
MOA: It works via the antagonism of H, (Histamine 1)
receptors . It reverses the effects of histamine on blood

capillaries and reduces allergic reaction symptoms.

Chlorcyclizine also has some local anesthetic,
anticholinergic, and antiserotonergic properties, and can be
used as an antiemetic.

Uses: used to treat urticaria, rhinitis, pruritus, and other
allergy symptoms.

30. Meclizine hydrochloride

cl

Boag

MOA: Meclizine is a histamine H, antagonist with antiemetic
and antivertigo properties. It also exhibits anticholinergic,

central nervous system depressant, and local anesthetic effects.

Uses: It is used in the symptomatic treatment of motion

sickness and control of vertigo associated with vestibular

system diseases.

31. Y

Buclizine Hydrochloride

cl

CH-N N-CH, HCI
©

MOA: Buclizine is a histamine H, antagonist with antiemetic

and antivertigo properties. It also exhibits anticholinergic,

central nervous system depressant, and local anesthetic effects.

Uses: It is used in the symptomatic treatment of motion
sickness and control of vertigo associated with vestibular

system diseases.

32. Y

<= o

Chlorpheniramine maleate

*Chlorpheniramine Maleate
Sustained Release Tablels
CH CPM-SR
Pa

Sony

CH—CH¿—CH¿—N

EZ
Who bots

MOA: Chlorpheniramine binds to the histamine H1 receptor.
This blocks the action of endogenous histamine, which
subsequently leads to temporary relief of the negative
symptoms brought on by histamine.

Uses: Used for the symptomatic relief of hypersensitivity

reactions, coughs, and the common cold.

33. Triprolidine

© ©
Ho )-E-cHs + HCHO + wo) — Ho—{_)-6-cH,-cH NC)

1-(p-tolyl)ethanone |
|

D

2

N° Li

OH
om

HC )-c=cl—cH, re Ho )- Och]

INN
EN N

| DS
N

MOA: Triprolidine binds to the histamine H1 receptor. This
blocks the action of endogenous histamine, which
subsequently leads to temporary relief of the negative
symptoms brought on by histamine.

Uses: Used for the symptomatic relief of hypersensitivity

reactions, coughs, and the common cold.

34. Phenindamine Tartarate

COOH
OH

CT wos Leon
Now's COOH

MOA: Phenindamine blocks the effects histamine in the body. It appear

to compete with histamine for histamine H1- receptor sites on effector

cells. The antihistamines antagonize those pharmacological effects of

histamine which are mediated through activation of H1- receptor sites

and thereby reduce the intensity of allergic reactions and tissue injury
response involving histamine release.

Uses: It is used to treat sneezing, runny nose, itching, watery eyes, hives,

rashes, itching, and other symptoms of allergies and the common cold

35. Phenergan’

25mg bits

C113 : as Coo

H
Diphenylamine CI—CH)-CH—N®
NaNH2 CH, CH

1-chloro-2-(dimethylamino)propane

C0 ee O

CH3

N
CHy-CH—NC Ha

‘cH, ch HN

CH;
$ CH, CH

36. MOA:

OPromethazine is a an antagonist of histamine H1

, post-

synaptic mesolimbic dopamine, alpha adrenergic, muscarinic,
and NMDA receptors.

OThe antihistamine action is used to treat allergic reactions.

Antagonism of muscarinic and NMDA receptors contri
its use asa sleep aid, as well as for anxiety and tension.
OAntagonism of histamine H1, muscarinic, and do
receptors in the medullar y vomiting center

promethazine useful in the treatment of nausea and vom

Uses: to treat rhinitis, allergic conjunctivitis, a

pute to

yamine
make

1tin,

I.

lergic

rg

reactions to blood or plasma, dermog raphism, anaphylactic

S
reactions, sedation, nausea, vomiting, pain, motion sic

and allergic skin reactions.

kness,

37. Y

Trimeprazine Tartarate

ae
N CH3

| À
CH3-CH-CH,—N

\

CH3 CH3

MOA: Trimeprazine binds to the histamine H1 receptor. This
blocks the action of endogenous histamine, which

subsequently leads to temporary relief of the negative

symptoms brought on by histamine.

Uses: Used for the symptomatic relief of hypersensitivity
reactions, pruritus (itching) and urticaria (some allergic skin
reactions).

38. Cyproheptadine hydrochloride a
Cyproheptadine Tables IP (Img)

Ciplactin 4
> iy
Cipla LA

N

CH3
MOA: Cyproheptadine competes with free histamine for binding at HA-
receptor sites This antagonizes the effects of histamine on HA-rec eptors,
leading to a reduction of the negative symptoms brought on by histamine
HA-receptor binding. Cyproheptadine also competes with serotonin at
receptor sites in smooth muscle in the intestines and other locations
Antagonism of serotonin on the appetite center of the hypothalamus may
account for Cyproheptadine's ability to stimulate appetite
Uses: Allergic rhinitis, rhinitis, urticaria and angioedema and

dermatographism.

39. Azatadine maleate

N

CHs
MOA: Antihistamines such as azatadine appear to compete with
histamine for histamine H1- receptor sites on effector cells. The
antihistamines antagonize those pharmacological effects of histamine
which are mediated through activation of H1- receptor sites and
thereby reduce the intensity of allergic reactions and tissue injury

response involving histamine release

Uses: For the relief of the symptoms of upper respiratory mucosal

congestion in perennial and allergic rhinitis, and for the relief of nasal

congestion.

40. Astemizole

‘OCH;

MOA: Astemizole competes with histamine for binding at H,-
receptor sites in the GI tract, uterus, large blood vessels, and
bronchial muscle. This reversible binding of astemizole to H,-
receptors suppresses the formation of edema, flare, and

pruritus resulting from histaminic activity.

Uses: Astemizole was indicated for use in the reliev ing allergy

symptoms, par ticularly rhinitis and conjunctivitis.

41. NOC 45802-650-78

Loratadine
Tablets,
Antihistamine

e Hour Rel

Y
Y.

u

Original Prescription Strength
Non-Drowsy"

When taken as rected

See Drag Facts ane.

42. Cetirizine PS cn sts
cl ya eb pá
a eb ye’ ys

AS à a

E

o À (etzine Hydrochloride Tablet IP (i)
CH-N = N—CH,CH,-O-CH,COOH Okacet

Cipla

MOA: Cetirizine, a metabolite of hydroxyzine, is an antihistamine drug.
Its main effects are achieved through selective inhibition of peripheral
H1 receptors. It compete with histamine for histamine H1- receptor
sites on effector cells. The antihistamines antagonize those
pharmacological effects of histamine which are mediated through

activation of H1- receptor sites and thereby reduce the intensity of

allergic reactions and tissue injury response involving histamine release

Uses: For the relief of the symptoms of upper respiratory mucosal
congestion in perennial and allergic rhinitis, and for the relief of nasal

congestion, Chronic urticaria

43. Levocetirizine
CI

Q

HON |—CH¿CH2-0-CH2COOH
©
MOA: It compete with histamine for histamine H1- receptor sites on
effector cells. The antihistamines antagonize those pharmacological

effects of histamine which are mediated through activation of H1-

receptor sites and thereby reduce the intensity of allergic reactions anc
pt t 1 there 1 tl t ty of allerg t 1

tissue injury response involving histamine release

Uses: For the relief of the symptoms of upper respiratory mucosal
congestion in perennial and allergic rhinitis, and for the relief of nasal

congestion, Chronic urticaria.

44. Cromolyn sodium

MOA: It inhibits degranulation of mast cells, subsequently
preventing the release of histamine and slow-reacting substance

of anaphylaxis (SRS-A), mediators of type I allergic reactions. It

also may reduce the release of inflammatory leukotrienes. It

may act by inhibiting calcium influx.
Uses: For the management of patients with bronchial asthma.
Also used in the treatment of vernal keratoconjunctivitis, vernal

conjunctivitis, and vernal keratitis.

45. SN
MOTS

NO: =
TUPAC: 1-N'-[2-[[5-[(imethylamino)methylffuran-2- (22728
yljmethylsulfanyljethyl]-1-N-methyl-2-nitroethene-1,1-
diamine

MOA:

46. Cimetidine

'CH¿SCH¿CH¿NH—C—NHCHg,
NCN

TUPAC: 1-cyano-2-methyl-3-[2-[(5-methyl-1H-
imidazol-4-yl)methylsulfanyl]ethyl]guanidine

CH

OH
‘we Hs = CH) NHp 0 CH2-CH2NH2
U
E wf
À

N-CN

® cimetidine Tablets

CIMWELL 200

a s

SN CN

oe

SHCH3

N-CN

H
S-CH2-CH2NH-C-N-CH3 a S-CH2-CHaNH-C-S-CH,

N

él E

NT CH
e

47. MOA: It antagonise the action of histamine at its H, receptor.
Cimetidine reduces the secretion of gastric acid by reversible
binding to histamine (H2) receptors, which are found on
gastric parietal cells. This process leads to the inhibition of
histamine binding to this receptor, causing the reduction of

gastric acid secretion.

Uses: It is used in the treatment of duodenal ulcer, gastric

ulcer, gastroesophageal reflux disease (GERD) and acid

indigestion. It is also used in multi drug treatment protocol

for eradication of H. py roli in treatment of peptic ulcer.

48. N CH3S CH2-CH2-C-NH2
H2N wr NSO;NH:
As Es 2
HN
IUPAC: 3-[[2-(diaminomethylideneamino)- 1, 3-thiazol-4-

yl]methylsulfany!]-N'-sulfamoylpropanimidamide

MOA:

49. Omeprazole

4
H3CO
BY

OCH;
TUPAC: 5-methoxy-2- {[(4-methoxy-3, 5-dimethylpyridin-2-

yl)methyl]sulfinyl} - 1 H-benzimidazole

Hydrochloric acid (HCI) secretion into the gastric lumen is a
process regulated mainly by the H(+)/K(+)-ATPase of the
proton pump. Omeprazole inhibits secretion of acid from the

gastric parietal cells by irreversibly inhibiting the enzyme H*-K*
ATPase.

50. H+K+ATPAse

Uses
Omeprazole is used in the treatment of duodenal ulcer, gastric

ulcer, gastroesophageal reflux disease (GERD) and acid

indigestion. Omeprazole is also used in multi drug treatment

protocol for eradication of H. pyroli in treatment of peptic ulcer.

51. (Lansoprazole

TUPAC: 2-(([3-Methyl-4-(2,2,2-trifluoroethoxy)-2-
pyridinyl]methyl}sulfinyl)-IH-benzimidazole

Hydrochloric acid (HCI) secretion into the gastric lumen is a
process regulated mainly by the H(+)/K(+)-ATPase of the
proton pump. Lansoprazole inhibits secretion of acid from the
gastric parietal cells by irreversibly inhibiting the enzyme H*-K*
ATPase.

52. Lansoprazole is used to reduce gastric acid secretion
and is approved for short term treatment of active gastric
ulcers, active duodenal ulcers and gastroesophageal reflux
disease (GERD) and acid indigestion.

Rabeprazole

E Rabeprazole Gastro-resistant Tablets IP

Mankind»

IUPAC: 2-[[4-(3-methoxypropoxy)-3-
methylpyridin-2-yl]methylsulfinyl]- 1H-

benzimidazole

53. Hydrochloric acid (HCI) secretion into the gastric lumen is a
process regulated mainly by the H(+)/K(+)-ATPase of the
proton pump. Rabeprazole inhibits secretion of acid from the
gastric parietal cells by irreversibly inhibiting the enzyme H*-
K* ATPase.

Rabeprazole is used to reduce gastric acid secretion and

is approved for short term treatment of active gastric ulcers,

active duodenal ulcers and gastroesophageal reflux disease
(GERD) and acid indigestion.

54. Pantoprazole

IUPAC: 6-(difluoromethoxy)-2-[(3,4+-dimethoxypyridin-2-
yl)methylsulfinyl]-1H-benzimidazole

Hydrochloric acid (HCl) secretion into the gastric lumen is a
process regulated mainly by the H(+)/K(+)-ATPase of the
proton pump. Pantoprazole inhibits secretion of acid from the
gastric parietal cells by irreversibly inhibiting the enzyme H*-K*

ATPase.

55. Uses: Pantoprazole is used to reduce gastric acid secretion

and is approved for short term treatment of active gastric

ulcers, active duodenal ulcers and gastroesophageal reflux
disease (GERD) and acid indigestion.