Introduction of histamine

Introduction of histamine

• 1.
  H1 & H2Antagonists Presented By Vivek Ajit Nimkar. M.Pharm Ist Sem. University Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur.440033.
• 2.
  Contents  Introduction tohistamine  Biosynthesis of histamine  Metabolism  Receptors of histamine  H1 Antihistaminics  Mechanism of action  H2 antihistaminics  Uses  Recent advances  References 20-12-2017 UDPS,RTMN University,Nagpur 2
• 3.
  Introduction To Histamine. •Histamineis the β-imidazolylethylamine derivative present in all mamalians tissue. •It was first discovered by Sir Henry Dale. •It’s synthesis occurs in mast cells, CNS, Parietal cells of gastric mucosa, and periphery. •It functions as autocoid and one of the mediator involved in the inflammatory allergic responses. •It has an important role in gastric acid secretion. 20-12-2017 UDPS,RTMN University,Nagpur 3
• 4.
  Biosynthesis of Histamine •Histamine is synthesized in cytoplasmic grannules of storage cells,mast cells, basophils. • It’s formed from naturally ocurring amino acid S-histidine via the catalysis of pyridoxal phosphate –dependant enzyme histidine decarboxylase • Inhibitors Of histidine decarboxylase are α-Fluromethylene and certain flavonoids 20-12-2017 UDPS,RTMN University,Nagpur 4
• 5.
  Metabolism Of Histamine •Metabolism of histamine taking place by enzymatic inactivation . • Enzymes responsible for metabolism are 1)Histamine N-methyl transferase(HMT) 2)Diamine oxidase (DAO). • Histamine metabolised as N-methyl imidazole acetic acid ,imidazole acetic acid riboside. 20-12-2017 UDPS,RTMN University,Nagpur 5
• 6.
  20-12-2017 UDPS,RTMN University,Nagpur6
• 7.
  Receptors Of Histamine Histaminereceptors belongs to the G-protein coupled receptor. Subtypes of histaminic receptors  20-12-2017 UDPS,RTMN University,Nagpur 7 RECEPTORS H1 H2 H3 H4 LOCATION Brain, CVS, GIT, Lymphocytes Myocardial cells, Parietal cells. CNS, myenteric plexus, gastric mucosa. Spleen, thymus, T- cells.
• 8.
  Antihistaminics Drugs that blocksthe release of histamine at H1,H2,H3,H4 receptors. Drugs that blocks the action of released histamine. H1 antagonists(first ,second & third (newer) generation). H2 antagonists. 20-12-2017 UDPS,RTMN University,Nagpur 8
• 9.
  H1 Antihistaminics – SAR: Generalstructure of H1 antihistaminic is as follows 1)Aryl groups (Ar): – Diaryl substitution is essential for H1 antihistaminic activity. And must be co-planarity. – Aryl substitution is as follows Ar -phenyl & heteroaryl -2-pyridyl. Ar1-Aryl or aryl methyl group. 2)Nature of “X”: – C in case of pheniramine series and its steriospecific due to chirality. – N (ethylene diamine) – O (amino alkyl ether) 20-12-2017 UDPS,RTMN University,Nagpur 9
• 10.
  3)Alkyl side chain: mostof antihistaminic drugs have ethylene chain and branching to this chain leads to decrease in activity. 4)Terminal “N “atom: Should in 3° amine form for maximum activity. It may be sometimes a part of heterocyclic ring. basicity with pKa 8.5-10 20-12-2017 UDPS,RTMN University,Nagpur 10
• 11.
  H1 antihistaminics First Generation(1G): These are classical drugs Clinically these are used in histamine mediated allergic rhinitis and cojuctivitis 20-12-2017 UDPS,RTMN University,Nagpur 11
• 12.
  Amino alkyl ethers(Ethanolamines) General Structure: Drugs Ar Ar1 R Chemical Name Diphenhydra mine -H N,N- dimethyletha namine. Doxylamine -CH3 2(2- dimethylami no ethoxy)- methyl benzyl pyridine. 20-12-2017 UDPS,RTMN University,Nagpur 12
• 13.
  Ethylenediamine derivative Drugs ArAr1 Chemical Name Tripelennamine 2(2-dimetyl amiono)ethyl amino pyridine. methpyrilene 2(2- (dimethylamino )ethyl)-2- thionylamino pyridine.20-12-2017 UDPS,RTMN University,Nagpur 13
• 14.
  Propylamine derivative Drugs ArAr1 Chemical name pheniramine 2(2- dimethylamino)et hyl benzyl pyridine Chlorpheniramine 20-12-2017 UDPS,RTMN University,Nagpur 14
• 15.
  Phenothiazine Derivatives Drugs RChemical Name Promethazine (±)10(2-dimethyl amino propyl) phenotiazine. Trimeperazine (±)10(3-dimethyl amino-2-methyl propyl)phenothiazin e. 20-12-2017 UDPS,RTMN University,Nagpur 15
• 16.
  Piperazine Derivative Drug RR1 Chemical Name Cyclizine H CH3 1-(diphenyl methyl)-4-methyl piperazine Meclizine Cl 1-P-chloro-α- phenyl benzyl)-4- (m-methyl benzyl)piperazin e. 20-12-2017 UDPS,RTMN University,Nagpur 16
• 17.
  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. 20-12-2017 UDPS,RTMN University,Nagpur 17
• 18.
  Adverse Effects • Themain 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. 20-12-2017 UDPS,RTMN University,Nagpur 18
• 19.
  Second Generation Drugs 20-12-2017UDPS,RTMN University,Nagpur 19
• 20.
  20-12-2017 UDPS,RTMN University,Nagpur20 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.
• 21.
  20-12-2017 UDPS,RTMN University,Nagpur21 These are active metabolite derivatives of second generation drugs intended to have increased efficacy with fewer adverse drug reactions.
• 22.
  Fexofinadine Levocetirizine 20-12-2017 UDPS,RTMN University,Nagpur22
• 23.
  H2 Antihistaminics SAR: 20-12-2017 UDPS,RTMNUniversity,Nagpur 23  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 other heterocyclic ring (furan,thiophene,thiazole) enhances potency.  The terminal nitrogen group should be polar, non-basic substituent for maximal activity.  These are the result of modification of histamine structure.
• 24.
  Effect of GuanidineGroups 20-12-2017 UDPS,RTMN University,Nagpur 24 • Mode of action : These drugs blocks the H+_ K+ ATPase channel and receptor. which releases gastric acid in stomach on stimuli.
• 25.
  20-12-2017 UDPS,RTMN University,Nagpur25 This made the guanidine analogue (top) the first example of a guanidine having pure antagonist activity. E.g. Guanyl histamine which is weak H2 antagonist .
• 26.
  H2 Antithistaminics 20-12-2017 UDPS,RTMNUniversity,Nagpur 26
• 27.
  20-12-2017 UDPS,RTMN University,Nagpur27
• 28.
  Uses of Antihistaminics •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. 20-12-2017 UDPS,RTMN University,Nagpur 28
• 29.
  • 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 20-12-2017 UDPS,RTMN University,Nagpur 29
• 30.
  Recent advances inantihistaminic drugs H1 antihistaminics • Dexbrompheniramine • Clemastine • Carbinoxamine 20-12-2017 UDPS,RTMN University,Nagpur 30
• 31.
  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. 20-12-2017 UDPS,RTMN University,Nagpur 31
• 32.
  20-12-2017 UDPS,RTMN University,Nagpur32