Introduction Biosynthesis Metabolism Receptors SAR Drugs Mechanism of action Uses of antihistamines Conclusion References

1. Presented By
Y.VEDAVATHI
(11AB1R0081)
Under the esteemed Guidance of
K.V.S.Santosh Kumar M.Pharm.
Vignan Pharmacy College
Affiliated to JNTU Kakinada, (Approved by AICTE,
PCI, New Delhi & Govt. of A.P)
Vadlamudi, Guntur (Dt.)
7/10/2014 1

2. Introduction
Biosynthesis
Metabolism
Receptors
SAR
Drugs
Mechanism of action
Uses of antihistamines
Conclusion
References
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3. HISTAMINE
• Histamine is a β-imidazolylethylamine derivative present in all
mammalian tissues.
• It was first discovered by SIR HENRY DALE.
• Its synthesis occurs in mast cells,parietal cells of gastric mucosa,
CNS, periphery.
• It functions as an autocoid & one of the mediator involved in the
allergic inflammatory responses.
• It has an important role in the regulation of gastric acid secretion.
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4. BIOSYNTHESIS OF HISTAMINE
HDC
HN N
NH2
H
COOH
HN N
H
S-HISTIDINE HISTAMINE
NH2
H
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5. BIOSYNTHESIS OF HISTAMINE
• Histamine is synthesized in cytoplasmic granules of its storage cells,
mast cells & basophils.
• It is formed from naturally occurring amino acid, S-histidine, via
the catalysis of the pyridoxal phosphate – dependent enzyme
histidine decarboxylase/ aromatic decarboxylase.
INHIBITORS OF HISTIDINE DECARBOXYLASE
α-fluoromethyl histidine
Certain flavonoids
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6. HN N
NH2
HN N
O
Imidazole acetic acid
Histamine
OH
SAH SAM
N N
NH2
CH3
N-Methyl histamine
N N
CH3
O
OH
N-Methylimidazole acetic acid
N N
O
OH
OH OH
O
OH
Imidazole acetic acid
riboside
HMT
DAO
DAO
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7. METABOLISM OF HISTAMINE
• Metabolism of histamine takes by the enzymatic inactivation.
• Enzymes that involve in the metabolism are:
1. Histamine N-methyl transferase(HMT)
2. Diamine oxidase.
• Histamine is metabolized as N- methylimidazole acetic acid ,
imidazole acetic acid riboside. Both are excreted through urine.
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8. IMPORTANCE OF HISTAMINE
It is not used therapeutically but in the past it has been used to test
acid secreting capacity of stomach.
To test bronchial hyperactivity in asthmatics.
For diagnosis of pheochromocytoma , but these pharmacological
tests are risky.
In pulmonary laboratories, histamine aerosol has been used as a
provocative test of bronchial hyperactivity.
To distinguish between real & pseudoanesthesia.
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9. RECEPTORS
• Histamine receptors are belonging to the family of G-Protein
coupled receptors.
• The sub types of histamine receptors are:
 H1
 H2
 H3
 H4
Myocardial
cells,pariet
al cells
CNS,myent
ric plexus,
gastric
mucosa
Spleen,thymus
,T-cells,
eosinophils.
RECEPTOR
LOCATION
H1 H2 H3 H4
Brain,GIT,CVS
Lymphocytes.
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10. HISTAMINE ANTAGONISTS
• Drugs that block the action of histamine at H1,H2,H3,H4 receptors
• The development of antihistamines began by the discovery of
PIPEROXAM.
1. Drugs that inhibits the histamine release.
2. Drugs that inhibits the action of released histamine
a. H1 antagonists(first,second&third generations)
b. H2 antagonists
c. H3 antagonists
7/10/2014 3.Drugs having dual action 10

11. GENERAL STRUCTURE OF ANTIHISTAMINES
X
Ar
Ar1
CH2 N
R
R1
n
STRUCTURAL REQUIREMENTS:
 Ar is aryl:
Phenyl, substituted phenyl,hetero aryl groups like
2- pyridyl.
 Ar1: Second aryl (or) aryl methyl group.
 X: Connecting atom of O, C, (or) N.
 (CH2)n: Carbon chain usually ethyl.
 NRR1: Basic, terminal amine functional group.
11 7/10/2014

12. DRUGS THAT BLOCK THE HISTAMINE RELEASE
O
O
O
OCH3
CH3
OCH3
KHELLIN
O
O
COO
OCH2CHCH2O
OH
O
O
COO Na
CROMOLYN SODIUM
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13. • These drugs act by stabilizing the mast cells & inhibit the release
of histamine & other mediators of inflammation.
• Natural product KHELLIN led to the development of bis
compounds.
• CROMOLYN nasal solution used for the prevention &
treatment of allergic rhinitis.
• Oral concentrate used to treat the histaminic symptoms of
mastocytosis.
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14. DRUGS THAT BLOCK THE RELEASED HISTAMINE
a) H1 ANTAGONISTS(FIRST GENERATION DRUGS):
• These are classical antihistamines.
• These are clinically used in the treatment of histamine mediated
allergic conditions like allergic rhinitis, allergic conjuctivitis etc.,
CLASSIFICATION:
a) Amino alkyl ethers.
b) Ethylenediamine derivatives.
c) Propyl amine derivatives.
d) Phenothiazine derivatives.
7/10/2014 e) Piperazine derivatives. 14

15. a) AMINO ALKYL ETHERS (ETHANOLAMINES)
General structure:
R
Ar
Ar1
O (CH2)2 N CH3
2
DRUG Ar Ar1 R CHEMICAL
DIPHENHYDRA
MINE
NAME
H N,N-Dimethyl
ethanamine.
15 7/10/2014

16. 2-[α-[2-
(dimethylamin
o)ethoxy]-α-
methylbenzyl
pyridine.
N
DOXYLA
MINE.
CLEMAST
INE.
Cl
2-[2-[1-(4-Chlo
Ro phenyl)-1-
Phenyl-ethoxy]
Ethyl]1-
Methyl pyrrol
Idine.
CH3
CH3
16 7/10/2014

17. STRUCTURE ACTIVITY RELATIONSHIP
These are characterized by presence of OXYGEN connecting moiety.
Most compounds in this series are simple N,N-dimethyl ethanolamine
derivatives.
CLEMASTINE differs from basic structural pattern.
Most amino alkyl ethers are optically active.
The drugs in this group possess significant anticholinergic activity,
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.
17 7/10/2014

18. b) ETHYLENEDIAMINE DERIVATIVES:
GENERAL STRUCTURE:
N CH2 CH2 N
R
R1
Ar
Ar1
DRUG Ar Ar1
CHEMICAL
NAME
TRIPELENN
AMINE
CH2
N
2-[Benzyl[2-(dime
Thylamino)ethyl]-
Amino]pyridine
METHAPY
RILENE
S
CH2 N
2-[2-(Dimethyl
Amino)ethyl]2-
Thienylamino
Pyridine.
18 7/10/2014

19. THONZYL
AMINE
H3CO CH2
N 2-[2-Dimethylamino
N
Ethyl](p-methoxy
Benzyl amino]
pyrimidine
SAR:
These are characterized by NITROGEN connecting atom.
Phenbenzamine was first clinically useful member.
Replacement of phenyl moiety of Phenbenzamine with a 2-pyridyl system
yielded “tripelennamine”
Replacement of benzyl group of tripelennamine with a 2-thienylmethyl
group provided methapyriline.
Replacement of tripelennamine with -2-pyridyl group with a pyrimidinyl
moiety yields thonzylamine.
The anticholinergic & antiemetic action of these compounds are low.
19 7/10/2014

20. C) PROPYLAMINE DERIVATIVES:
1. SATURATED ANALOGUES:
GENERAL STRUCTURE:
Ar
Ar1
CH2CH2 N CH3 2
DRUG Ar Ar1
CHEMICAL
NAME
PHENIRAMINE
N
2-[α-[2-Dimethyl
Amine ethyl]
Benzyl]pyridine.
20 7/10/2014

21. CHLORPHER
INAMINE Cl
N
2-[P-Chloro-α[2-
Dimethyl amino)
Ethyl]benzyl]-pyridine
SAR:
Phenyl substituent at P-position replaces with “Cl” is chlorpheniramine &
“Br” is bromopheniramine.
These halogenated pheniramines are more potent & have a longer duration
of action.
The agents in this class produce less sedation than the other classical
antihistamines.
21 7/10/2014

22. 2) UNSATURATED ANALOGUES:
N
Ar
Ar1
DRUG Ar Ar1
PYRROBUTAM
INE
TRIPROLIDINE
Cl CH2 N
CH3
22 N 7/10/2014

23. d) PHENOTHIAZINE DERIVATIVES:
GENERAL STRUCTURE:
S
N
R
CHEMICAL NAME
(±)10-[2-
(Dimethylamino)pro
pyl]phenothiazine
TRIMEPRAZI
NE
(±)10-[3-
(Dimethylamino)-2-
methylpropyl]phenothi
azine.
DRUG R
PROMETHAZ
INE
CH2
CH3
N(CH3)2
CH2 CH2N(CH3)2
23 CH3 7/10/2014

24. SAR
Phenothiazine derivatives that contain a 2/3 carbon branched alkyl chain
between alkyl chain between the ring system and terminal nitrogen atom.
This differs the phenothiazine’s from antipsychotic series in which an
unbranched propyl chain is required.
PROMETHAZINE, the parent member of this series is moderately potent &
with prolonged action & pronounced sedative side effects.
The combination of lengthening of side chain & substitution of lipophilic
groups in 2nd position of aromatic ring results in compounds with decreased
antihistaminic activity & increased psychotherapeutic properties.
METABOLISM:
These compounds undergo mono-di & N-dealkylation,sulfur oxidation,
aromatic oxidation at 3rd position to yield phenol & N-oxidation.
7/10/2014 24

25. DIBENZOCYCLOHEPTANES & DIBENZOCYCLOHEPTENES
N
CH3
.HCl
CYPROHEPTADINE
X
N
R
AZATIDINE
These are the phenothiazine analogues in which sulfur atom is replaced
by an isosteric vinyl group (cyproheptadine) or saturated ethyl bridge
25(AZATIDINE). 7/10/2014

26. e) PIPERAZINE DERIVATIVES:
GENERAL STRUCTURE:
N N
R
R1
CHEMICAL
NAME
CYCLIZINE 1-
(Diphenylmethyl
)-4-methyl
piperazine.
DRUG R R1
H CH3
26 7/10/2014

27. CHLORCYCLINE 1-(P-Chloro-α-
phenylbenzyl)-4-
methyl piperazine C l CH3
MECLIZINE C l
CH3
1-(P-Chloro-α-
Phenyl benzyl)
-4-(m-methyl
Benzyl)piperazine.
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.
27 Primary structural difference is nature of para aromatic ring sub7s/1ti0t/u20e1n4t.

28. MECHANISM OF ACTION
• H1 antagonists act by competitively inhibiting the effects of histamine
at H1 receptor.
• H1 receptor blockade results in decreased vascular permeability,
reduction of pruritus, relaxation of smooth muscle in the respiratory,
GIT.
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29. H1 ANTAGONISTS (FIRST GENERATION)
These are classical antihistamines.
These are clinically used in the treatment of histamine mediated
allergic conditions.
These are mainly used in allergic rhinitis, allergic conjunctivitis,
allergic dermatological conditions.
ADVERSE EFFECTS:
The main adverse effect of H1 antagonists first generation is SEDATION.
This is evidenced by drowsiness, diminished alertness.
This is due to their relative lack of selectivity for the PERIPHERAL H1
RECEPTOR,.
29 7/10/2014

30. SECOND GENERATION H1 ANTAGONISTS(NON-SEDATIVE)
OH OH
C N CH2CH2CH2CH
TERFENADINE
OH
C N CH2CH2CH2CH
C
COOH
OH
FEXOFENADINE
30 7/10/2014

31. CH N N
O
O OH
CETIRIZINE
Cl
• These have a relative low affinity for central H1 receptors & largely free
from sedation.
• The 2nd generation drugs have little affinity for muscarnic,adrenergic
receptors.
• TERFENADINE is a long acting H1 antagonist.
• FEXOFENADINE is a primary oxidative metabolite of TERFENADINE&
does not cross the BBB.
31 7/10/2014

32. THIRD GENERATION H1 ANTIHISTAMINES
N
Cl
N
COOC2H5
LORATIDINE
N
N
H
H COOH
CH3
ACRIVASTINE
 These are active metabolite derivatives of second generation drugs
intended to have increased efficacy with fewer adverse drug reactions.
32 7/10/2014

33. H2 ANTAGONISTS
HN N
CH2SCH2CH2NH C NHCH3
CH3
NCH
CIMETIDINE
N
S
N
CH2SCH2CH2NH C NH2
NH2
NH2
NSO2NH2
FAMOTIDINE
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34. O
CH2SCH2CH2NH C NHCH3
CH3
N CHNO2
CH3
RANITIDINE
S N
N
CH3
CH3
CH2SCH2CH2NH C NHCH3
CHNO2
NIZATIDINE
34 7/10/2014

35. SAR & STRUCTURAL REQUIREMENTS:
GENERAL FORMULA FOR H2 ANTAGONISTS:
BASIC
HETEROCYCLE
GROUP
FLEXIBLE
CHAIN/
AROMATIC RING
These are the result of modification of histamine structure.
The imidazole ring of histamine is not required for competitive antagonism
of histamine at H2
Separation of ring & nitrogen group with the equivalent of 4 carbon chain
is necessary for optimum antagonist activity.
The terminal nitrogen group should be polar,non-basic substituents for
maximal activity.
35 7/10/2014

36. SAR STRUCTURE
HN N
NH2
HISTAMINE:H1=H2 Agonism
5-Methylhistamine:H2>H1 Agonism
HN N
NH2
CH3
N-Guanylhistamine:Partial H2 agonist
(weak – antagonist)
HN N
NH C NH2
NH
36 7/10/2014

37. Burimamide:
Full H2 Antagonist.
low potency HN N
CH2CH2 NH C NHCH3
S
Metiamide:
Full H2 antagonist.
Higher potency HN N
S
CH2CH2 NH C NHCH3
S
CH3
CH CH2CH2 NH C NHCH3 3
Cimetidine:
Full H2 antagonist
Higher potency HN N
S
N
CN
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38. H3 ANTAGONISTS
General structure:
Hetero cycle A chain B chain Lipophilic
group
Polar group
DRUGS:
HN
N
S
 This THIOPERAMIDE was first potent H3 antagonist used to
treat sleep disorders.
N C
NH
THIOPERAMIDE
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39. H4 ANTAGONISTS
O
(CH3)2N(H2C)2HC
DOXEPINE
S
N
Cl
(CH2)3 N (CH3)2
CHLORPROMAZINE
This DOXEPINE, CHLORPROMAZINE are bind to the H4 receptor
with high affinity.
7/10/2014 39

40. DRUGS HAVING DUAL ACTION
H3C
N
N
N
Cl
O
AZELASTINE
O
O
HO
N
H3C
CH3
OLOPAT
IDINE
• Both the drugs having the action of antihistaminic & mast cell
stabilization.
• Both are used in allergic conjunctivitis.
40 7/10/2014

41. USES OF ANTIHISTAMINES
DRUG CHEMICAL STRUCTURE
ALLERGIC DISORDERS:
They effectively control certain immediate type of allergies like itching,
urticaria, seasonal hay fever, allergic conjunctivitis & angioedema of lips
eyelids etc.,
CETIRIZINE have adjuvant role in seasonal asthma.
OMEPRAZOLE
PRURITIS:
Antihistamines are first choice of drugs for idiopathic pruritus.
COMMON COLD:
LANSOPRAZOLE
They donot effect the illness but may afford sympatomatic relief by
anticholinergic & sedative actions.
As hypnotics eg: diphenhydramine & promethazine. 41 7/10/2014

42. PANTAPRAZOLE
As “anti-tussives” Eg: diphenhydramine.
As “anti-emetic” Eg: meclizine
In “parkinsonism” Eg: promethazine , diphenhydramine.
In drug induced “acute dystonias” Eg: diphenhydramine,
promethazine.
To treat “motion & morning sickness” Eg: cyclizine,
promethazine.
To treat “vertigo” conditions Eg: cinnarizine.
RABEPRAZOLE
42 7/10/2014

43. CONCLUSION
Histamine is an important chemical messenger that
exhibits significant physiological effects mediated
through its receptor. A thorough knowledge of drugs
is very much useful to treat the clinical conditions
arising due to imbalance of histamine in the body.
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44. REFERENCES
JOHN H.BLOCK & JOHN M WILSON& GISVOLD’S
Organic Medicinal & Pharmaceutical chemistry.
(Pg): 698 – 728
D.SRIRAM & P.YOGEESWARI -Medicinal chemistry.
(Pg): 278 – 302
BERTRAM G.KATZUNG, SUSAN B.MARTERS
ANTHONY J.TREVOR Basic & Clinical pharmacology
(Pg) : 277
K.D TRIPATHI Essentials of medical pharmacology.
(Pg): 159 – 160.
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45. FOYE’S Principles of medicinal chemistry.
(Pg) NO: 1045.
KATZUNG- Basic & clinical pharmacology.
(Pg) NO: 277.
7/10/2014 45

46. ACKNOWLEDGEMENT
• I would like to thank my guide
Mr. K.V.S. Santosh Kumar for his valuable
support and guidance.
• I also like thank our Principal Dr. P. Srinivasa
Babu and the seminar committee for their
valuable suggestions.
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47. 47 7/10/2014