histamine physiology, receptors and antihistamines

see also:

• autacoids
• allergy and hypersensitivity reactions
• anaphylaxis
• antihistamines (H1)
• allergic rhinitis
• pharmacology main index

• 1st detected (with ACh) in ergot extracts as stimulants of uterus, but later both proved to be contaminants of ergot due to bacteria;
• 1st isolated from body 1927 in various tissues hence histamine;
• Almost all mammalian tissues contain it - mainly stored in mast cells where it is synthesised from histidine via L-histidine decarboxylase & then store it in secretory granules along with heparin, ECF-A, NCF-A & certain enzymes which is exocytosed if i/cell. [Ca] is increased;
• Turnover rate of histamine in granules is slow & when tissue depletion occurs, may take weeks for normal levels to return;
• Histamine is rapidly made & continuously released in non-mast cell sites:
  • epidermal cells; gastric mucosa cells; CNS; rapid turnover cells;
• Histamine is metabolised to inactive metabolites (urine excreted) by:
  • histamine-N-methyltransferase ⇒ N-methylhistamine which is converted by MAO to N-methyl imidazole acetic acid;
  • nonspecific diamine oxidase (DAO) ⇒ imidazole acetic acid

• mast cell response in immunity:
  • H1:
    • bronchoconstriction, rapid vasodilation, increased capillary permeability, contraction GIT;
    • stimulate afferent vagal N endings ⇒ reflex bronchospasm;
    • NB. in man most bronchospasm via other mediators;
  • H2:
    • slow, sustained vasodilation; (? increased capill.perm.); bronchodilation
  • triple response of Lewis (1927):
    • local red spot few sec⇒1min due to local histamine;
    • brighter flare 1cm slowly due to his-ind. axon reflex;
    • wheal in 1-2 min. due to oedema;
• CNS neurotransmitter:
  • H1: reg. of drinking, T, ADH, BP, pain perception;
  • H3: presyn.reg. synth./release of his. in his.N terminals
• Gastric histamine secretion ⇒ main factor in incr. parietal acid secret.(H2);
• Epidermal release ⇒ pain/itch via stim. of nerve endings (H1);

• coupled to phospholipase C
  • ⇒ synth. of IP3 & diacylglycerols from Plipids in cell membrane;
    • IP3 ⇒ rapid Ca release from ER;
    • DAG & Ca activate:
      • Ca/calmod.-depend. protein kinases
        • ⇒ eg. myosin light chain kinase ⇒ contraction;
      • Plipase A2: (eg. on vasc. endothelial cells)
        • ⇒ eg. local prod. EDRF incr. ⇒ vasodilatation;
        • ⇒ eg. incr. PGI2 ⇒ vasodilatation;
• H1 antagonists:
  • see antihistamines (H1)

• coupled to adenylyl cyclase ⇒ c-AMP incr. (ie. similar to beta-adren)
  • ⇒ activ. of c-AMP depend. protein kinases:
  • ⇒ decr. gastric acid secretion from most stimuli;
• H2 antagonists:
  • eg. cimetidine, ranitidine, etc
  • see H2-type antihistamines

• ? inhib. coupling to adenylyl cyclase;
• H3 antagonists:
  • thioperamide -but potential use not established.