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Antihistamines

The document discusses histamine, a key biological mediator involved in allergic responses and gastric acid regulation, detailing its biosynthesis, metabolism, receptors, and the drugs developed to antagonize its effects, known as antihistamines. It covers the mechanisms of action for H1, H2, H3, and H4 receptor antagonists, classifications of antihistamines, and their clinical uses for allergic conditions and other disorders. The conclusion emphasizes the importance of understanding histamine and its derivatives for effective clinical treatment of related conditions.

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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
Introduction Biosynthesis Metabolism Receptors SAR Drugs Mechanism of action Uses of antihistamines Conclusion References 7/10/2014 2
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 3
BIOSYNTHESIS OF HISTAMINE HDC HN N NH2 H COOH HN N H S-HISTIDINE HISTAMINE NH2 H 7/10/2014 4
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 5
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 7/10/2014 6
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 7
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 8
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. 9 7/10/2014
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
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
DRUGS THAT BLOCK THE HISTAMINE RELEASE O O O OCH3 CH3 OCH3 KHELLIN O O COO OCH2CHCH2O OH O O COO Na CROMOLYN SODIUM 7/10/2014 12
• 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 13
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
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
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
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
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
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
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
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
2) UNSATURATED ANALOGUES: N Ar Ar1 DRUG Ar Ar1 PYRROBUTAM INE TRIPROLIDINE Cl CH2 N CH3 22 N 7/10/2014
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
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
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
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
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.
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 28
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
SECOND GENERATION H1 ANTAGONISTS(NON-SEDATIVE) OH OH C N CH2CH2CH2CH TERFENADINE OH C N CH2CH2CH2CH C COOH OH FEXOFENADINE 30 7/10/2014
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
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
H2 ANTAGONISTS HN N CH2SCH2CH2NH C NHCH3 CH3 NCH CIMETIDINE N S N CH2SCH2CH2NH C NH2 NH2 NH2 NSO2NH2 FAMOTIDINE 7/10/2014 33
O CH2SCH2CH2NH C NHCH3 CH3 N CHNO2 CH3 RANITIDINE S N N CH3 CH3 CH2SCH2CH2NH C NHCH3 CHNO2 NIZATIDINE 34 7/10/2014
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
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
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 37 7/10/2014
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 7/10/2014 38
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
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
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
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
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 43
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 44
FOYE’S Principles of medicinal chemistry. (Pg) NO: 1045. KATZUNG- Basic & clinical pharmacology. (Pg) NO: 277. 7/10/2014 45
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 46
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