The document discusses anti-histamines and their classification. It describes how histamine is synthesized and functions in the body. Anti-histamines work by blocking histamine receptors and are classified as first generation, second generation, or topical. First generation anti-histamines include amino alkyl ethers, ethylene diamine derivatives, piperazine derivatives, propylamine derivatives, and phenothiazine derivatives. Second generation anti-histamines have fewer side effects than first generation. The structures, names, and uses of several specific anti-histamines are provided.

1. ANTI-HISTAMINES
PREPARED BY
K.SATTANATHAN M.PHARM.,
ASST. PROFESSOR
DEPT. OF PHAMACEUTICAL CHEMISTRY

2. INTRODUCTION
Histamine is chemically – (2-( imidazolyl) ethyl amine)
Its synthesis occurs in many tissues, include mast cells, parietal cells of the gastric mucosa and
nervous system ( CNS)
Histamine function as three role
a. involved in allergic reaction
b. Regulation of the secretion of gastric acid
C. Role at axon in several region of CNS has established in the role in the regulation of
the sleeping and waking .
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3. INTRODUCTION
Metabolism of histamine is rapidly metabolized in vivo by two major pathways
1. N- methylation
2. Oxidation
Histamine receptors are found in various tissues( follow the table )
All of the histamine receptors appear to have constitutive receptor G protein signalling activity
dependent of the presence of histamine
histamine is a achiral molecule , histamine receptors is highly stereo selective toward chiral
molecule .
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4. Histamine release
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5. Introduction
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6. RECEPTORS OF HISTAMINE
S. RECEPTORS LOCATION FUNCTION
1. H1 Found on smooth muscle
of bronchi, endothelium,
uterus and central
nervous system tissue
CausNOes vaso dilation, broncho constriction, smooth
muscle activation, separation of endothelial cells and pain
and itching due to insect stings, the primary receptors
involved in allergic rhinitis symptoms and motion sickness
2. H2 Located on parietal cells Primarily regulate gastric acid secretion
3. H3 - Decreased neuro transmitter release: histamine, acetyl
choline, norepinephrine, serotonin
4. H4 Found primarly in the
thymus, small intestine,
spleen and colon. It is also
found on basophils and in
the bone marrow
-
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7. ANTI HISTAMINES
The first anti histamine piperoxan was discovered by Forneau and Bovet .
Piperoxan has important effects related to antagonism of norepinephrine at alpha adrenergic
receptor
Anti histamines specifilly H1 antihistamine are useful in the treatment of allergic responses and
inflammatory disorders.
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8. CLASSIFICATION OF ANTI HISTAMINES
Anti histamines
First generation
Second generation
Topical antihistamines
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9. CLASSIFICATION OF ANTI HISTAMINES
First
generation
• Amnio alkyl ethers EG: Diphenhydramine, carbinoxamine,
Doxylamine, Dimenhydrinate, Diphenylpyraline, Clemastine
First
generation
• Ethylene diamine derivaives: Eg., Tripelennamine, Pyrilamine,
Methapyrilene, thonzylamine
First
generation
• Piperazine derivatives: eg., Cyclizine, Chlorcyclizine,
Meclizine, Buclizine
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10. CLASSIFICATION OF ANTI HISTAMINES
First
generation
• Propyl amine derivative: Chlorpheniramine,
Pheniramioine, Triprolidine, Bromopheniramine,
Phenindamine
First
generation
• Phenothiazine derivatives: Promethazine, Trimeprazine,
Methdilazine
First
generation
• Dibenzo cycloheptenes : Cyproheptadine, azatadine
• Miscellaneous drugs: Diphenylpyraline, Dimethindene, Antazoline
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11. CLASSIFICATION OF ANTI HISTAMINES
SECOND
GENERATION
•Cetrizine, Loratidine, Fexofenadine,
Tesfenadine, Astemizole, Acrivasatine
TOPICAL ANTI
HISTAMINES
•Olopatadine, Levocarbastine, Emedastine,
Azelastine, Ketotifen, Epinastine
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12. General structure of H1 receptors
AMINO ALKYL ETHER ETHYLENE DI AMINE DERIVATIVES
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13. General structure of H1 receptors
PROPYLAMINE DERIVATIVES PHENOTHIAZINE DERIVATIVES
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14. General structure of H1 receptors
PIPERAZINE DERIVATIVES DIBENZO CYCLOHEPTENES
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15. General structure of H2 receptors and
proton pump inhibitors
H2 RECEPTORS PROTON PUMP INHIBITORS
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16. DIPHENHYDRAM
INE
IUPAC NAME:
[2-(diphenylmethoxy)ethyl]dimethylamine
Synonym:
pKa: 8.87
Log p: 3.65
Melting point: 161- 162
Bcs classification: 1
Uses:
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17. DOXYLAMINE
IUPAC NAME:
2-(alpha-(2-(dimethylamino)ethoxy)-alpha-methylbenzyl)
Synonym:
Dimethyl({2-[1-phenyl-1-(pyridin-2-yl)ethoxy]ethyl})amine
N,N-Dimethyl-2-[1-phenyl-1-(2-pyridinyl)ethoxy]ethanamine
pKa: 5.8 and 9.3
Log p:
Melting point: 103 – 108
Solubility data: freely soluble in water, slightly soluble in alcohol and
insoluble in ether.
Uses: symptomatic relief of hypersensitivity reactions and
in the treatment of pruritic skin disorders
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18. CLEMASTINE
IUPAC NAME: 2-(2-((p-chloro-alpha-methyl-alpha-
phenylbenzyl)oxy)ethyl)-1-methyl-,Pyrrolidine
SYNONYMN:
(2R)-2-{2-[(1R)-1-(4-chlorophenyl)-1-
phenylethoxy]ethyl}-1-methylpyrrolidine
Log P : 5.29
Melting point( In Celsius) : 178
USES : hay fever, rhinitis, allergic skin conditions,
and pruritus
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19. TRIPELENNAMINE
IUPAC:
pyridine 2-(benzyl(2-dimethylamino)ethyl)amino)
Synonym : 1,2-Ethanediamine, N,N-dimethyl-N'-
(phenylmethyl)-N'-2-pyridinyl-,
pKa: 8.76
Ph:
BCS classification:
Uses:
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20. CYCLIZINE
IUPAC NAME: 1- Benzhydryl-4-methyl
piperazine
SYNONYM: 1-((4-
Chlorophenyl)phenylmethyl)-4-
methylpiperazine hydrochloride
MELTING POINT: 105-107. 5
LOG P : 3
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21. CHLOR CYCLIZINE
IUPAC NAME: 1-((4-chlorophenyl)(phenyl)
methyl)-4-methyl pipeazine
Melting point: 216
Log p : 4.16
Pka: 7.63
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22. MECLIZINE
IUPAC NAME: 1-(p-chloro-α-phenylbenzyl)-4-
(m-methylbenzyl) piperazine
SYNONYM: 1-[(4-chlorophenyl)phenylmethyl]-4-
[(3-methylphenyl)methyl]-piperazine,
MELTING POINT: 217-224
LOG P: 5.59
Pka: 8.16
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23. BUCLIZINE
IUPAC NAME:
1-[(4-tert-butylphenyl)methyl]-4-[(4-
chlorophenyl)(phenyl)methyl]piperazine
PH: 7.1
PKA : 8.04
STOAGE : PROTECT FROM LIGHT
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24. CHLORPHENIRAMINE
IUPAC NAME:
[3-(4-chlorophenyl)-3-(pyridin-2-
yl)propyl]dimethylamine
SYNONYM: 2-(p-chloro-alpha-(2-
(dimethylamino)ethyl)benzyl)pyridine
maleate
MELTING POINT( IN CELSIUS) : 132 .5
PKA : 9.47
Dextro form of chlorpheniramine is more
potent than levo form
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25. PHENINRAMINE
IUPAC NAME:
Dimethyl[3-phenyl-3-(pyridin-2-
yl)propyl]amine
SYNONYM: 2-[alpha-[2-
Dimethylaminoethyl]benzyl]pyridine
MELTING POINT : 104-109
SOLUBILITY : WATER
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26. TRIPROLIDINE
IUPAC NAME:
2-[(1E)-1-(4-methylphenyl)-3-
(pyrrolidin-1-yl)prop-1-en-1-
yl]pyridine
SYNONYM: 2[1-(4-Methylphenyl)-3-(1-
pyrrolidinyl)-1-propenyl]pyridine
hydrochloride
MELTING POINT ( iin celsisus) : 115
E –triprolidine is more potent than Z-
triprolidine
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27. PROMETHAZINE
IUPAC NAME:
Dimethyl[1-(10H-phenothiazin-10-yl)propan-2-yl]amine
SYNONYM: N-(2'-Dimethylamino-2'-
methyl)ethylphenothiazine hydrochloride
MELTING POINT ( in Celsius) : 219
STEREO ISOMER : racemic compound
SOLUBILITY DATA : freely soluble in water
USES
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28. TRIMEPRAZINE
IUPAC NAME: dimethyl[2-methyl-3-(10H-
phenothiazin-10-yl)propyl]amine
MELTING POINT : 68
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29. CYPROHEPTADINE
IUPAC NAME:
1-methyl-4-
{tricyclo[9.4.0.0³,⁸]pentadeca-
1(15),3,5,7,9,11,13-heptaen-2-
ylidene}piperidine
Cypro heptadine is levo in form its
more potent than dextro form .
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30. AZITIDINE
IUPAC NAME:
1-(
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31. PHENTOLAMINE
IUPAC NAME:
2-methyl-5-phenyl-2,3,4,4a,5,9b-
hexahydro-1H indeno[1,2- }pyridine
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32. ASTIMAZOLE
IUPAC NAME: 1-(4- flurobenzyl)-N-(1-
(4- methoxy phenyl piperidin-3yl)1- H
benz imidazole 2- amine
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33. Loratidine
IUPAC NAME: Ethyl4- (8- chloro-5,6-dihydo-11 H- benzo
[5,6] cyclo hepta [1,2-b] pyridine-11-ylidine)
pipeeridine-1- carboxylate
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34. Cetrizine
IUPAC NAME:
2-(2-(4-((4-Chlorophenyl) (phenyl)methyl) piperazin-
1yl) ethoxy) acetic acid
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35. Cromolyn
sodium
IUPAC NAME:
Sodium 5,5’-((2-
hydroxypropane-1,3-
diyl)bis(oxy))bis ( 4 oxo-1,4-
dihydronaphthalene-2-
carboxylate)
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36. H2 BLOCKER
CIMETIDINE
IUPAC NAME:
2- cyano 1- methyl -3-[2-[[(5-methyl imidazol-4-
yl)methyl]- thio ]ethyl] guanidine
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37. FEMOTIDINE
IUPAC NAME:
N-( amino sulfonyl)-3-[[[2[(
diaminomethylene ) -amino]4-thiazolyl]
methyl] thio] propanimidamide
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38. RANITIDINE
IUPAC NAME:
N-[2-[[5-(dimethyl amino )methyl
]furfuryl]thio]ethyl]- N’-methyl 2- nitro -1, 1-
ethenediamine
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39. PROTON PUMP INHIBITORS
IN 1972 SWEDISH MEDICINAL CHEMIST DISCOVERED CERTAIN PYRIDYLMETHYL BENZIMIDAZOLE
SULFIDES( TIMOPRAZOLE ) WERE ACTIVE PROTON PUMP .
THE BENZIMIDIAZOLE PROTON PUMP INHIBITORS ARE PRODRUGS THAT ARE RAPIDLY
CONVERTED TO SULFENAMIDE INTERMEDIATE IN THE HIGHLY ACIDIC IN CONDITION OF
GASTRIC PARIETEL CELLS
IN THIS INTEMEDIATE INHIBIT THE PROTO PUMP VIA COVALENT INTERACTION WITH CYSTEINE
RESIDUE LOCATED ON THE LUMINAL SURFACE OF THE ALPHA SUBUNIT OF THE H+/K+ ATPASE
THE COVALENT BINDING RESULTS IN SPECIFIC AND ESSENTIALLY IRREVERSIBLE IN ACTIVATION
OF THE ENZYME LEADING TO INHIBITION OF GASTRIC ACID SECRETION .
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40. Pantoprazole
IUPAC NAME:
5-(difluromethoxy)-2[[(3,4-dimethoxy-2-
pyridinyl) methyl] sulfonyl]-1H
benzimidazole
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41. Omeprazole
IUPAC NAME:
5-methoxy-2-(((4-methoxy 3,5- dimethyl-
2-pyridinyl) methyl) sulfinyl) 1-H
benzimidazole
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42. Lansoprazole
IUPAC NAME:
2-[[[3-methyl-4-((2,2,)
trifluoroethoxy ) -2-pyridyl]
methyl] sulfinyl]1-H
benzimidazole
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43. Raberazole
IUPAC NAME:
2-([[4-(3-methoxy propoxy)-3-methyl-2-
pyridinyl] methyl] sulfinyl]-1H
benzimidazole
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44. Synthesis of DiPhenhydramine
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45. Synthesis of triprolidine
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46. Synthesis of Promethazine
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47. Mechanism action of h1 antagonist
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48. Mechanism of action of H2 receptor
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49. SAR OF ANTI HISTAMINES
X is a connecting atom, of O, C, N , the X connecting moiety may be saturated
Spacer between the central X and the amine, usually 2-3 carbons in length.
Ar is Aryl , it may be phenyl, substituted phenyl, or hetero aryl group ( pyridyl)
Ar’ is a second aryl or methyl group
Carbon chain on between terminal amine and X usually ethyl.
Extension of branching of this carbon may les active compounds
The terminal amine function is necessary for the anti histamine activity
The terminal amine is tertiary in nature. The terminal nitrogen atom is simple dimethyl amino moiety
The terminal amine may also form of hetero cyclic structure like, piperidine or piperazine
The amino moiety is basic with pKa ranging from 8.5 to 10 and thus presumed to be protonated when bound to a
receptor( the basic tertiary amine which are protonated at physiological pH)
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50. This Photo by Unknown Author is licensed under CC BY
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