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Introduction Biosynthesis Metabolism Receptors SAR Drugs Mechanism of action Uses of antihistamines Conclusion References
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1
Y.VEDAVATHI
Under the esteemed Guidance of
K.V.S.Santosh Kumar M.Pharm.
Vignan Pharmacy College
Presented By
Affiliated to JNTU Kakinada, (Approved by AICTE, PCI, New Delhi & Govt. of A.P) Vadlamudi, Guntur (Dt.)
ANTIHISTAMINES
(11AB1R0081)
7/10/2014
2
Introduction BiosynthesisMetabolismReceptorsSARDrugsMechanism of actionUses of antihistaminesConclusionReferences
CONTENTS
7/10/2014
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.
7/10/2014
4
BIOSYNTHESIS OF HISTAMINE
S-HISTIDINE HISTAMINE
HDCHN N
NH2
HCOOH
HN NH
NH2
H
7/10/2014
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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
7/10/2014
6
HN N
NH2
HN N
O
Imidazole acetic acid
Histamine
OH
N N
NH2
CH3 N-Methyl histamine
N N
CH3
OH
O
N-Methylimidazole acetic acid
N NOOH
OHOH
O
OH
Imidazole acetic acidriboside
SAMSAH
DAO
7/10/2014
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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.
7/10/2014
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.
7/10/2014
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,parietal cells
CNS,myentric plexus, gastric mucosa
Spleen,thymus,T-cells, eosinophils.
RECEPTOR
LOCATION
H1 H2 H3H4
Brain,GIT,CVSLymphocytes.
7/10/20149
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
3.Drugs having dual action7/10/2014
GENERAL STRUCTURE OF ANTIHISTAMINES
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.
X
Ar
Ar1
CH2 N
R
R1
n
7/10/201411
12
DRUGS THAT BLOCK THE HISTAMINE RELEASE
O
O
O
OCH3
CH3
OCH3
KHELLIN
O
O
COO
OCH2CHCH2O
OH
O
O
COO Na
CROMOLYN SODIUM7/10/2014
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.
7/10/2014
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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.
e) Piperazine derivatives.7/10/2014
a) AMINO ALKYL ETHERS (ETHANOLAMINES)
General structure:R
Ar
Ar1
O (CH2)2 N CH32
DIPHENHYDRAMINE
DRUG Ar Ar1 R CHEMICAL NAME
HN,N-Dimethylethanamine.
7/10/201415
2-[α-[2-(dimethylamino)ethoxy]-α-methylbenzyl pyridine.
N
DOXYLAMINE.
CLEMASTINE.
Cl
2-[2-[1-(4-ChloRo phenyl)-1-Phenyl-ethoxy]Ethyl]1-Methyl pyrrolIdine.
CH3
CH3
7/10/201416
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.
7/10/201417
b) ETHYLENEDIAMINE DERIVATIVES:
GENERAL STRUCTURE:
N CH2 CH2 N
R
R1
Ar
Ar1
DRUG Ar Ar1CHEMICAL NAME
TRIPELENNAMINE
CH2
N
2-[Benzyl[2-(dimeThylamino)ethyl]-Amino]pyridine
METHAPYRILENE S
CH2 N
2-[2-(DimethylAmino)ethyl]2-Thienylamino Pyridine.
7/10/201418
THONZYLAMINE
CH2H3CO
N
N 2-[2-DimethylaminoEthyl](p-methoxyBenzyl 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.7/10/201419
C) PROPYLAMINE DERIVATIVES:
1. SATURATED ANALOGUES:
GENERAL STRUCTURE:
Ar
Ar1
CH2CH2 N CH3 2
DRUG Ar Ar1 CHEMICAL NAME
PHENIRAMINE
N
2-[α-[2-DimethylAmine ethyl]Benzyl]pyridine.
7/10/201420
CHLORPHERINAMINE 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.
7/10/201421
2) UNSATURATED ANALOGUES:
N
Ar
Ar1
PYRROBUTAMINE
TRIPROLIDINE
DRUG Ar Ar1
Cl CH2 N
CH3
N 7/10/201422
d) PHENOTHIAZINE DERIVATIVES:
GENERAL STRUCTURE:
N
S
R
CHEMICAL NAME
(±)10-[2-(Dimethylamino)propyl]phenothiazine
TRIMEPRAZINE
(±)10-[3-(Dimethylamino)-2-methylpropyl]phenothiazine.
DRUG R
PROMETHAZINE
CH2
CH3
N(CH3)2
CH2 CH2N(CH3)2
CH3 7/10/201423
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.
These compounds undergo mono-di & N-dealkylation,sulfur oxidation, aromatic oxidation at 3rd position to yield phenol & N-oxidation.
METABOLISM:
7/10/2014
DIBENZOCYCLOHEPTANES & DIBENZOCYCLOHEPTENES
N
CH3
CYPROHEPTADINE
.HCl
X
N
RAZATIDINE
These are the phenothiazine analogues in which sulfur atom is replaced
by an isosteric vinyl group (cyproheptadine) or saturated ethyl bridge
(AZATIDINE). 7/10/201425
e) PIPERAZINE DERIVATIVES:
GENERAL STRUCTURE:
N N
R
R1
CHEMICAL NAME
CYCLIZINE 1-(Diphenylmethyl)-4-methyl piperazine.
DRUG R R1
H CH3
7/10/201426
CHLORCYCLINE 1-(P-Chloro-α-phenylbenzyl)-4-methyl piperazineCl CH3
MECLIZINE ClCH3
1-(P-Chloro-α-Phenyl benzyl)-4-(m-methylBenzyl)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.
Primary structural difference is nature of para aromatic ring substituent.7/10/201427
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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.
7/10/2014
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,.
7/10/201429
SECOND GENERATION H1 ANTAGONISTS(NON-SEDATIVE)
C N CH2CH2CH2CH
OHOH
TERFENADINE
C N CH2CH2CH2CH
OH
C
COOH
OH
FEXOFENADINE
7/10/201430
CH N NO OH
O
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. 7/10/201431
THIRD GENERATION H1 ANTIHISTAMINES
These are active metabolite derivatives of second generation drugs
intended to have increased efficacy with fewer adverse drug reactions.
N
Cl
N
COOC2H5
LORATIDINE
N
NH
H COOH
CH3
ACRIVASTINE
7/10/201432
33
H2 ANTAGONISTS
HN N
CH2SCH2CH2NH C NHCH3CH3
NCH
CIMETIDINE
N
SN
CH2SCH2CH2NH C NH2
NH2
NH2
NSO2NH2
FAMOTIDINE
7/10/2014
O
CH2SCH2CH2NH C NHCH3
N CHNO2
CH3
CH3
RANITIDINE
S N
N
CH3
CH3
CH2SCH2CH2NH NHCH3C
CHNO2
NIZATIDINE
7/10/201434
SAR & STRUCTURAL REQUIREMENTS:GENERAL FORMULA FOR H2 ANTAGONISTS:
BASIC HETEROCYCLE
GROUP
FLEXIBLE CHAIN/
AROMATIC RINGPOLAR GROUP
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.
These are the result of modification of histamine structure.
7/10/201435
SAR STRUCTURE
HN N
NH2
HISTAMINE:H1=H2 Agonism
5-Methylhistamine:H2>H1 Agonism
HN N
NH2CH3
N-Guanylhistamine:Partial H2 agonist (weak – antagonist)
HN N
NH C NH2
NH
7/10/201436
Burimamide:Full H2 Antagonist. low potency HN N
CH2CH2 NH C NHCH3
S
Metiamide:Full H2 antagonist. Higher potency HN N
SCH2CH2 NH C NHCH3
S
CH3
Cimetidine:Full H2 antagonist Higher potency HN N
SCH2CH2 NH C NHCH3CH3
N
CN7/10/201437
38
H3 ANTAGONISTSGeneral structure:
Hetero cycle A chain B chain Lipophilicgroup
Polar group
DRUGS:
This THIOPERAMIDE was first potent H3 antagonist used to treat sleep disorders.
HN
NN C
S
NH
THIOPERAMIDE
7/10/2014
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H4 ANTAGONISTS
O
(CH3)2N(H2C)2HC
DOXEPINE
N
S
(CH2)3 N (CH3)2
Cl
CHLORPROMAZINE
This DOXEPINE, CHLORPROMAZINE are bind to the H4 receptor
with high affinity.
7/10/2014
DRUGS HAVING DUAL ACTION
N
H3C
NN
Cl
O
AZELASTINE
OO
HO
NH3C
CH3
OLOPATIDINE
• Both the drugs having the action of antihistaminic & mast cell
stabilization.
• Both are used in allergic conjunctivitis. 7/10/201440
DRUG CHEMICAL STRUCTURE
OMEPRAZOLE
LANSOPRAZOLE
USES OF ANTIHISTAMINES
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.
PRURITIS:
Antihistamines are first choice of drugs for idiopathic pruritus.
COMMON COLD:
They donot effect the illness but may afford sympatomatic relief by
anticholinergic & sedative actions.
As hypnotics eg: diphenhydramine & promethazine. 7/10/201441
PANTAPRAZOLE
RABEPRAZOLE
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.
7/10/201442
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.
7/10/2014
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 – 160.7/10/2014
45
FOYE’S Principles of medicinal chemistry.
(Pg) NO: 1045.
KATZUNG- Basic & clinical pharmacology.
(Pg) NO: 277.
7/10/2014
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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.
7/10/2014
7/10/201447
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