histamine

Introduction
Histamine and its synthesis
Histamine receptors and its features
Pharmacological action
Pathophysiological action
Anaphylaxis and its treatment
H1 receptor antagonist
Pharmacological actions
Therapeutic actions
Newer, nonsedative antihistaminics
H2 receptor antagonists
H3 receptor antagonist
Conclusion
References

1. Histamines and Antihistamine Seminar by: Monika 1 st year Post graduate Department of Public Health Dentistry

2. Content: Introduction Histamine and its synthesis Histamine receptors and its features Pharmacological action Pathophysiological action

3. Anaphylaxis and its treatment H1 receptor antagonist Pharmacological actions Therapeutic actions Newer, nonsedative antihistaminics H2 receptor antagonists H3 receptor antagonist Conclusion References

4. INTRODUCTION: Histamine meaning tissue amine is almost ubiquitously present. Its pharmacology was studied by DALE. It was implicated as a mediator of hypersensitivity phenomena an tissue injury reactions.

5. Tissues rich in histamine are skin,gastric and intestinal mucosa, lungs, liver and placenta. Non mast cell histamine occur in brain epidermis, gastric mucosa and growing regions.

6. Biosynthesis of histamine

7. HISTAMINE LIBERATORS: Those which release histamine mainly from the mast cells with minimal damage: Proteolytic enzymes like trypsin, certain venoms, food products like crabs, lobsters etc. Surface tension reducing substances like bile salts, anionic and cationic surfactants .

8. Those which release histamine accompanied by substantial tissue damage: Trauma due to cold and chemical, thermal or radiant energy. Antigen-antibody reactions.

9. Histamine, anaphylaxis and allergy: Histamine is an important major early mediator. Clinical anaphylaxis is used to describe a clinical state irrespective of the mechanism. It may be due to drugs, foods, plants, chemicals, latex, insect bites e.t.c .

10. Anaphylaxis may progress slowly or rapidly; it is usually rapid following parentral drugs.

11. Anaphylactic shock Anaphylactic shock is a medical emergency and needs immediate treatment of: laryngeal edema , bronchospasm and hypotension.

12. Treatment of Anaphylactic shock: Attend the airway. Administration of adrenaline: Adrenaline doses: adults: 0.5 ml of a 1:1000 solution IM or 3-5ml of a 1:10000 solution IM. Children: 0.01 ml of a 1:1000 solution per kg.

13. Administration of IV fluids: immediate administration of large quantities of fluids IV. Glucocorticoids: hydrocortisone hemisuccinate 100mg is given intravenously followed by oral prednisolone.

14. Antihistaminic drugs: inject H2 receptor antagonist IV(cimetidine 500mg or ranitidine 50 mg, over 3-5mins). Bronchodilators: IV aminophylline or nebulised salbutamol.

15. Supportive measures: these include oxygen and assisted ventilation.

16. Histamine receptors Histaminergic receptors were classified by Asch and Schild (1966) into H1 and H2 and H3 in 1983.

17. Distinctive features of histaminergic receptors. H1 H2 H3 Selective agonist 2-methyl histamine 4-methyl histamine α -methyl histamine Selective antagonist mepyramine cimetidine thioperamide Receptor type G-protein coupled G-protein coupled G-protein coupled

18. H1 H2 H3 Effector type PIP2 HYDROLYSIS get converted to IP3, release of calcium from intracellular stores. Adenyl cyclase activation- increase cAMP Restricting calcium influx, potassium channel activation.

19. H1 H2 H3 Distribution in body: Smooth muscle –contraction. Blood vessels- Endothelium- vasodilation Afferent nerve endings- stimulation Adrenal medulla- release of catecholamines Brain-transmitter Gastric glands- acid secretion Blood vessels- dilatation Heart- Atria- + ive chronotropy Ventricles-+ ive inotropy Uterus- relaxation Brain- transmitter Brain- inhibition of histamine release Lung,spleen,skin,gastric mucosa- decrease histamine release. Ileum- inhibition of acetylcholine release from myentric plexus neurones

20. Pharmacological actions : Blood vessels: It causes marked dilatation of smaller blood vessels including arterioles, capillaries and venules . Larger arteries and veins are constricted by histamine and increases capillary permeability .

21. Triple response: Histamine injected intradermally elicits triple response: Red spot: due to intense capillary dilatation. Wheal: due to exudation of fluid from capillaries and venules . Flare: arteriolar dilatation mediated by axon reflex.

22. Heart: direct effects of histamine on in situ heart are not prominent. Visceral smooth muscle: causes bronchoconstriction Glands: marked increase in gastric secretion.

23. Sensory nerve endings: itching occurs when histamine injected i.v. or intracutaneously . Adrenal medulla: release of adrenaline occurs. CNS: histamine does not penetrate blood brain barrier, no central effects are seen on injection.

24. Pathophysiological action of histamine:

25. As transmitter: histamine is a afferent transmitter which initiates the sensation of itch and pain at sensory nerve endings. Non mast cell histamine act as a transmitter regulating body temperature, cardiovascular function, thirst, hormone release.

26. Inflammation: it has been implicated as a mediator of inflammation. Tissue growth and repair: growing and regenerating tissues contain high concentrations.

27. Uses: Testing of acid secreting capacity of stomach: It causes maximal stimulation of parietal cells, marked side effect occur and H1 antagonist must be given before hand . Pheochromocytoma : Histamine causes rise in BP in these patients.

28. To test neutral and vascular integrity at a local site(in leprosy, gangrene, e.t.c ), histamine will not be able to produce flare after intradermal injection in case functional nerves or arterioles are not present.

29. H1 antagonists (conventional antihistaminics ) These drugs competitively antagonise actions of histamine at the H1 receptor. They have diverse chemical structures, but majority have substituted ethylamine side chains.

30. Clinical classification, doses H1antihistaminics. Drug Dose and route Highly sedative Diphenhydramine Promethazine hydroxyzine 25-50 mg oral 25-50 mg oral 25-50 mg oral Moderately sedative Pheniramine Antazoline Trimeprazine Meclizine 25-50 mg oral,i.m 50-100mg oral, i.m 10-40 mg oral 25-50 mg oral

31. Mild sedative Chlorpheniramine 2-4 mg (0.1 mg/kg) oral, i.m Mepyramine 25-50mg, i.m Dimethidene 1mg oral Triprolidine 2.5-5mg oral Cyclizine 50 mg oral

32. Newer compounds Non sedating antiallergic terfenadine 60-180mg oral astemizole 10mg oral loratadine 10mg oral cetrizine 10mg oral antivertigo cinnarizine 25-50mg oral

33. Chemical classification: Ethanolamine derivatives: diphenhydramine and dimenhydrinate . Ethlenediamine derivative: Tripelennamine , mepyramine . Alkylamine derivative: Chlorpheniramine , acrivastine . Piperazines : Hydroxyzine, meclinizine , cinnarazine , cetrizine . Phenothiazines : Promethazine, trimeprazine Piperidines : Cyproheptadine , loratadine . Dibenzoxepines : doxepine

34. Pharmacokinetics: The classical H1 antihistaminics are well absorbed from oral and parentral routes, metabolized in the liver and excreted in urine.

35. They are widely distributed in the body and enter brain. Duration of action of most agents is 4-6 hours, except meclizine and clemastine which act for 12-24 hours.

36. Pharmacological actions: Antagonism of histamine: they effectively block histamine induced bronchoconstriction, contraction of intestinal and other smooth muscle and triple response. Release of adrenaline from adrenal medulla in response to histamine abolished.

37. Antiallergic reaction : Many manifestations of immediate hypersensitivity (type1reactions) are suppressed. Urticaria , itching and angioedema are well controlled.

38. CNS: Antihistamine produce variable degree of CNS depression. Excitement and convulsions are frequently seen at toxic doses.

39. Certain H1 antihistamines are effective in preventing motion sickness. Promethazine and few other antihistamines reduce tremor, rigidity and sialorrhoea

40. Sedation and hypnosis CNS depression is a common side effect with the majority of antihistaminic drugs in therapeutic doses and these drugs induce varying degrees of sedation, drowsiness and sleep. Sedation is beneficial in the tretment of allergic reactions.

41. Antiemetic and anti-motion sickness effects: Motion sickness, attributed commonly to vestibular disturbances is benefitted by anti- histaminics . Vomitting due to other labyrinthine disturbances also responds to anti- histaminics .

42. Antiparkinsonian effect: Central antimuscarinic actions of some anti- histaminics are useful in treating parkinsonism.

43. Autonomic nervous system : Majority of the antihistaminics exhibit muscarinic blocking activity. Certain antihistaminics such as antazoline and phenindamine exert an adrenergic blocking effect.

44. Anticholinergic action: High low minimal/absent promethazine chlorpheniramine Mepyramine diphenhydrine antazoline clemastine pheniramine hydroxyzine terfenadine cyproheptadine triprolidine astemizole dimenhydrinate cyclizine loratadine

45. Blood pressure:Most antihistaminics cause a fall in BP on i.v. injection. Uptake of NA: many of these drugs inhibit neuronal uptake of nor adrenaline .

46. Cardiovascular system: Therapeutic doses of anti- histaminics fail to effect the CVS, rapid i.v. administration may produce a quinidine like effect .

47. Local anaesthesia: Antihistaminics such as promethazine and diphenhydramine exihibit local anaesthetic activity.

48. Adverse reactions: Sedation Hypnosis Fatigue Lassitude Diplopia

49. Dry mouth Blurring of vision Bladder disturbance Nausea Vomitting Epigastric distress Hypotension Sense of tightness in chest

50. H1 receptor antihistaminic agents Drug Adult oral dose Diphenhydramine HCl 25 to 50 mg Dimenhydrinate 25 to 100mg Mepyramine maleate 50 to 100 mg Pheniramine maleate 25 to 75 mg Cinnarazine 25 mg Acrivastine 8 mg Cetirizine 10 mg

51. Therapeutic uses: Allergic disorders: The antihistaminics are beneficial in the suppression of allergic manifestations like urticaria . They are extremely effective in the treatement of seasonal hay fever.

52. The antihistaminics effectively counter the pruritus and urticaria in atopic and contact dermatitis. Combination of a phenothiazine with antihistaminic gives better results.

53. Systemic administration also controls to some extent the pain and itch due to bee or wasp stings. Pruritus: adequate treatement depends upon recognition of the local or systemic factors responsible for it.

54. For example adequate treatement of scabies would generally relieve itching in this condition. The itching in elderly patients which is due to dryness of skin is treated by moisturising of the skin

55. Itching due to inflammatory skin conditions can be relieved by a combination of a weak corticosteroid applied locally and systemically administerd antihistaminic.

56. Reaginic allergy: It is known to be familial. A period of relative immunodeficiency may precede frank development of allergies in genetically predisposed children. Infants of allergic parents kept on allergen avoidance regimen for first six months of life .

57. Allergic conjunctivitis is a common condition and causes itching. Local treatement with H1 receptor antagonists ( emedastine 0.05%, levocabastine 0.05%, mast cell stabilizers ( cromolyn sodium 4%, nedocromil sodium 2%).

58. Antihistaminics are effective in the treatement of urticaria and angioedema. Urticaria may occur as acute episodes but is considered chronic when it lasts for longer than six weeks. It may occur in a person with atopic history

59. In a few cases, an allergen (fish, seafood, nuts eggs, food additives such as citric acids preservatives and colouring agents like tartrazine ; drugs such as aspirin and other NSAIDS; vegetable gums), an offending physical agent (mechanical trauma, cold, heat), history of insect bites and stings may be identified.

60. No such factor is found in majority of chronic urticarias .

61. The treatement of choice for acute urticaria and acute angioedema is a subcutaneous injection of adrenaline( 1:1000 aqueous solution) in the dose of 0.3ml, repeated if necessary.

62. If adrenaline is contraindicated for some reason, an injection of an antihistamine(50 mg of diphenhydramine IM or IV) may be used. Antihistaminics by mouth are the drug of choice in chronic urticarias ; they are more effective when given regularly on a prophylactic basis after urticarial lesions start.

63. The newer non sedative antihistaminics are effective in chronic urticaria and do not produce lesion.

64. Mastocytosis : The rare disease is characterised by an abnormal increase in mast cells in the body leading to an increase in the production of mast cell mediators of which histamine is a prominent member.

65. This gives rise to symptoms such as pruritus, diarrhoea and anaphylaxis. Partial symptomatic relief can be obtained by a combination of H1 and H2 receptor antagonists.

66. Other uses: As hypnotics :(diphenhydramine and promethazine) As antiemetics In parkinsonism(di phenhydramine and promethazine)

67. In motion sickness and vertigo:( dimenhydrinate , promethazine and chlorotheophyllinate , piperazine antihistaminics such as meclizine) As antitussive( diphenhydramine) In drug induced acute dystonias ( diphenhydramine, promethazine)

68. As lytic cocktail: (promethazine, pethidine and chlorprimazine )

69. Newer, nonsedative antihistaminics (second generation)

70. The second generation antihistaminics may be defined as those H 1 receptor blockers marketed after 1980 which have one or more of following properties: Higher H1 selectivity: no anticholinergic side effects. Absence of CNS depressant property

71. These newer drugs have the advantage of not impairing psychomotor performance, produce no subjective effects, no sleepiness, do not potentiate alchohol or benzodiazepines.

72. Indications: Allergic rhinitis and conjunctivitis, hay fever, pollinosis - control sneezing e.t.c Urticaria , dermographism , atopic eczema. Acute allergic reactions to drugs and foods.

73. Fexofenadine: It is the active metabolite of terfenadine . It does not cross blood brain barrier, does not produce sedation or impair psychomotor performance and is free of atropinic side effects. Use: allergic rhinitis and urticaria .

74. Loratidine : Another long acting selective peripheral H1 antagonist which lacks CNS depressant effects and is fast acting. Use: urticaria , atrophic dermatitis .

75. Desloratidine : It is the major active metabolite of loratidine effective at half the dose. Non interference with psychomotor and cardiac safety are documented .

76. cetrizine It is a metabolite of hydroxyzine with marked affinity for peripheral H1 receptors, penetrates brain poorly. It inhibits release of histamine and of cytotoxic mediators from platelets as well as eosinophil chemotaxis during the secondary phase of the allergic responses

77. Use: upper respiratory allergies, pollinosis , urticaria and atopic dermatitis.

78. Uses: Allergic disorders: antihistaminics do not suppress AG:AB reaction, but block the effects of released histamine. They effectively control certain immediate type of allergies, e.g. itching, urticaria , seasonal hay fever, allergic conjunctivitis and angioedema of lips .

79. Other conditions involving histamine: anti histaminics block symptoms produced by histamine liberators afford symptomatic relief in insect bite and ivy poisoning. Common cold: may afford symptomatic relief.

80. Vertigo: cinnarizine modulates calcium fluxes and attenuates vasoconstrictor action of many endogenous substances. It inhibits vestibular sensory nuclei in the inner ear, supresses post rotatory labyrinthine reflexes.

81. It can also be used in cough, parkinsonism, acute muscle dystonia and as sedative, hypnotic and anxiolytic.

82. H2 receptor antagonist: H2 receptors are responsible for histamine induced gastric acid secretion. H2 receptors antagonists specifically block this action of histamine by competitive inhibition .

83. They also block positive chronotropic action of histamine, counter the enhanced automacity of auricles and ventricles and prevent ventricular arrythymias induced by histamine. Use : treatement of peptic ulcer.

84. H3 receptors: It is thought to be presynaptic autoreceptors that exert a tonic autoinhibitory control on histamine synthesis and release within the brain. e.g. betahistine is a weak , partial agonist at H1 and H2 receptors but behaves as a weak H3 receptor antagonist.

85. Applied aspects: Allergic manifestations to local anesthetics may range from an allergic dermatitis to typical bronchospasm to fatal systemic anaphylaxis. Allergy to local anesthetics occurs much more frequently in response to the ester local anesthetics such as procaine, propoxycaine .

86. Allergy to sodium bisulfite or metabisulfite is being reported with increasing frequency. Bisulfites are antioxidants and are commonly used in resturants wher they are sprayed on fruits and vegetables as an antioxidant to prevent discoloration.

87. Bisulfites are also used to prevent bacterial contamination of wines, beers and distilled water. A history of bisulfite allergy should alert the doctor to the possibility of this same type of response if sodium bisulfite is included in the local anesthetic catridge .

88. Clinical manifestation of allergy related to topical anesthetic application may include mild erythema, edema , and ulcerations. Acrylic resins can produce allergy most likely to occur with self cured acrylics. Denture sore mouth is a inflammatory changes of mucous membranes developing beneath the dentures.

89. Allergy testing in dental office: Skin testing is the primary means of testing for local anesthetic allergy. Intracutaneous testing involves the injection of 0.1ml of the test solution .

90. Patch test:

91. Latex sensitivity: Latex sesitivity has become a significant problem among health care professionals. The use of vinyl as a latex substitute has minimized the occurrence of allergic reactions.

92. Conclusion: They play a very important role in : patients at risk of allergy as well as among health care professionals in whom latex allergy are being reported in increasing frequency. It is therefore important for the clinicians to have proper knowledge and consider changing the method of therapeutic management with histamines.

93. References: Tripathi KD. Essentials of Medical Pharmacology. 6 th ed. New Delhi: Medical Publishers Ltd; 2002. p. 151. Satoskar R.S. Pharmacology And Pharmacotherapeutics . 18 th ed. Mumbai: Popular Prakashan ; 2003. p. 311.

94. 3) Malamed SF. Medical Emergencies in the Dental Office. 6 th ed. New Delhi: Elsevier; 2007. p.397.