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
1st 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
a. Pharmacological actions
b. 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.

6. • 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.

7. Biosynthesis of histamine

8. 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.

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

10. 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.

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

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

13. Treatment of Anaphylactic shock:
1. Attend the airway.
2. 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.

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

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

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

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

19. 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

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

21. H1 H2 H3
Distribution
in body:
Smooth
muscle –
contraction.
Blood vessels-
Endothelium-
vasodilation
Afferent nerve
endings-
stimulation
Adrenal
medulla-
release of
catecholamine
s
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,sk
in,gastric
mucosa-
decrease
histamine
release.
Ileum-
inhibition of
acetylcholine
release from
myentric
plexus
neurones

22. 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.

23. 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.

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

26. • 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.

27. Pathophysiological action of
histamine:

29. • 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.

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

31. 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.

32. 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.

33. 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.

34. 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

35. 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

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

37. 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

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

39. • 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.

40. 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.

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

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

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

44. 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.

45. 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.

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

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

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

49. • 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.

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

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

52. Adverse reactions:
• Sedation
• Hypnosis
• Fatigue
• Lassitude
• Diplopia

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

54. 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

55. 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.

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

57. • 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.

58. • 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

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

60. • 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.

61. • 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%).

62. • 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

63. • 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.

64. • No such factor is found in majority of chronic
urticarias.

65. • 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.

66. • 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.

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

68. 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.

69. • 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.

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

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

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

73. NEWER, NONSEDATIVE
ANTIHISTAMINICS(SECOND
GENERATION)

74. • 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

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

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

77. 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.

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

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

80. 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

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

82. 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.

83. • 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.

84. • 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.

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

86. 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.

87. • 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.

88. 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.

89. 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.

90. 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.

91. 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.

92. 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.

95. 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 .

96. Patch test:

99. 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.

100. 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.

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

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