1. HISTAMINE
&
ANTIHISTAMINICS
Dr.Vijay bhushanam

2. HISTAMINE (Introduction)
• First Autacoid to be discovered. (Greek: autos=self;
akos=cure)
• Synthesized in 1907
• Isolated and demonstrated to be a natural
constituent of mammalian tissues (1927); hence the
name Histos=Tissue
• H1 was discovered in1966
• H2 in1972
• H3 in1987
• H4 in 2001

3. HISTAMINE (Introduction)
• Sinus problems, hay fever, bronchial asthma, hives,
eczema, contact dermatitis, food allergies and reactions
to drugs are all allergic reactions associated with the
release of histamine and other autocoids, such as
serotonin, leukotrienes, and prostaglandins.
• Histamine is involved in inflammatory and anaphylactic
reactions.
• Histamine also acts as a neurotransmitter in the central
nervous system (CNS).

4. HISTAMINE (Chemistry)
• Histamine is a hydrophilic molecule consisting of
• An imidazole ring and
• An amino group connected by two methylene groups.

5. HISTAMINE (Distribution)
• Almost all mammalian tissues contain histamine.
• Widely distributed in skin, GIT mucosa, lungs, brain, CSF
and bone marrow.
• It is also a component of some venoms, sting secretion,
bacteria and plants.
• The mast cell is the predominant storage site for histamine
in most tissues
• The concentration of histamine is particularly high in
tissues that contain large numbers of mast cells, such as
skin, bronchial tree mucosa, and intestinal mucosa.

6. HISTAMINE (Synthesis, Storage,
and Metabolism)
• Formed by the decarboxylation of the amino acid histidine
by the enzyme L-histidine decarboxylase
• The chief site of histamine storage in most tissues is the
mast cell; in the blood, it is the basophil.
• Metabolised to N-methylhistamine by histamine-N-
methyltransferase and Imidazoleacetic acid by the
nonspecific enzyme diamine oxidase (DAO)
• These metabolites have little or no activity and are
excreted in the urine.

7. HISTAMINE (Release and functions)
• It is released from storage granules as a result of the
interaction of antigen with immunoglobulin E (IgE)
antibodies on the mast cell surface,
• Histamine plays a central role in immediate hypersensitivity
and allergic responses.
• The actions of histamine on bronchial smooth muscle and
blood vessels account for many of the symptoms of the
allergic response.
• In addition, certain clinically useful drugs can act directly on
mast cells to release histamine, thereby explaining some of
their untoward effects.
• Histamine has a major role in the regulation of gastric acid
secretion and also modulates neurotransmitter release

8. HISTAMINE (Pharmacological Effects)
• Histamine receptors are GPCRs
• H1 receptors: mediate effects on smooth muscle leading to
vasodilatation, increased vascular permeability, and
contraction of nonvascular smooth muscle.
• H2 receptors: mediate histamine stimulation of gastric acid
secretion and may be involved in cardiac stimulation.
• H3 receptors: feedback inhibitors in CNS, gastrointestinal
tract, lung, heart.

9. HISTAMINE (Receptors)

10. HISTAMINE (Pharmacological Effects)
1. Cardiovascular system.
a. Triple effect on terminal vasculature (itching & pain):
– reddening at injection site due to vasodilation
– wheal or disk of edema within 1 to 2 min
– a large, bright crimson flare or halo surrounding the wheal
b. IV Histamine: fall in blood pressure, cutaneous flushing, over the
face and upper trunk, rise in skin temperature, intense headache.
2. Smooth muscle of bronchioles; contraction of nonvascular smooth
muscle.
3. Exocrine glands: potent stimulation of gastric secretion (HCl & pepsin),
salivary and lacrimal gland secretion, catecholamines secretion.
4. Peripheral Nervous system: itching and pain

11. HISTAMINE (Pharmacological Effects)
• Exocrine Glands
• Gastric glands
• Salivary glands
• Sweat glands Secretion
• Pancreas
• Bronchial glands
• Lacrimal glands

12. HISTAMINE (Pharmacological Effects)
• Arterioles,
• Capillaries
• Venules
• Vasodilation
• Increased
permeability(edema)
• Systemic hypotension

13. HISTAMINE (Pharmacological Effects)
• Vascular Smooth Muscles
• Bronchial tree
• GIT
• Uterus
• Contraction

14. HISTAMINE (Clinical Uses)
• Practical applications of histamine are limited to uses as
a diagnostic agent.
• Histamine (histamine phosphate) is used to assess
nonspecific bronchial hyperreactivity in asthmatics and
as a positive control injection during allergy skin testing.

15. H1-RECEPTOR ANTAGONISTS
(Conventional Antihistaminics)
1. First generation Antihistaminics
Highly sedative: Diphenhydramine, Dimenhydrinate,
Promethazine, Hydroxyzine
Moderately sedative: Pheniramine,Cyproheptadine,
Meclizine, Buclizine, Cinnarazine
Mild sedative: Chlorpheniramine, Dexchlorpheniramine,
Dimethindene, Triprolidine, Mebhydroline, Cyclizine,
Clemastine
2. Second generation Antihistaminics: Fexofenadine,
Loratadine, Desloratadine, Cetrizine, Levocetrizine,
Azelastine, Mizolastine, Ebastine, Rupatadine

16. Antihistaminics
(Pharmacokinetics)
• Absorption: Antihistaminics (H1 receptor antagonists) are
well absorbed from oral and parenteral routes
• Distribution: widely in the body and enter brain. Newer
compounds penetrate the brain poorly.
• Metabolism: In liver
• Excretion: In urine

17. Antihistaminics
(Pharmacological actions)
• Smooth Muscle: Inhibit most of the effects of histamine
on smooth muscles, especially the constriction of
respiratory smooth muscle
• Capillary Permeability. H1 antagonists strongly block the
increased capillary permeability and formation of oedema
and wheal brought about by histamine.
• Flare and Itch. The flare component of the triple
response and the itching caused by intradermal injection
of histamine are two different manifestations of the action
of histamine on nerve endings. H1 antagonists suppress
both.

18. Antihistaminics
(Pharmacological actions)
• Immediate Hypersensitivity Reactions (Anaphylaxis
and Allergy): Oedema formation and itch are effectively
suppressed. Other effects, such as hypotension, are less
well antagonized. Bronchoconstriction is reduced little, if
at all.
• Central Nervous System:
• The first-generation H1 antagonists can both stimulate
and depress the CNS.
– Stimulation  Restless, nervous, sleeplessness & convulsions
– Central depression  Diminished alertness, slowed reaction
times, and somnolence are common manifestations.
• The second-generation ("nonsedating") H1 antagonists do
not cross the blood-brain barrier appreciably.

19. Antihistaminics
(Pharmacological actions)
• Anticholinergic action: Many H1 blockers in addition antagonize
muscarinic actions of Ach.
1. High Anticholinergic action: Promethazine, Diphenhydramine,
Dimenhydrinate, Pheniramine, Cyproheptadine
2. Low Anticholinergic action: Chlorpheniramine, Hydroxyzine,
Triprolidine, Cyclizine
3. Minimal/No Anticholinergic action:Fexofenadine, Astemizole,
Loratadine, Cetrizine, Mizolastine
• Local anesthetics: some drugs like Pheniramine have strong
membrane stabilizing property. But not used clinically.
• BP: Most antihistaminics cause a fall in BP on IV injection.

20. Antihistaminics
(Side effects and toxicity)
• Side effects are frequent but mild.
• Sedation, diminished alertness and concentration, light
headedness, motor incordination, fatigue and tendency o fall
asleep.
• Second generation antihistaminics are largely free of CNS
effects.
• Anticholinergic propertiesDryness of mouth, alteration of
bowel movement, urinary hesitancy and blurring of vision
• Epigastric distress and headache.
• Acute overdose causes excitation, tremors, hallucinations,
muscular incordination, convulsions, flushing,
hypotension,death.

21. Antihistaminics
Comparison between 1st generation and 2nd generation
• 2nd generation antihistaminics have
• Higher H1 selectivity; hence no anticholinergic side
effects
• Absence of CNS depressant property; Less/No sedation
• Additional anti-allergic properties apart from histamine
blockade; some inhibit late phase allergic reaction by
acting on leukotrienes or by antiplatelet activating factor.

22. Antihistaminics
(Uses)
• Allergic disorders,
• Other conditions involving histamine: Insect bite, Ivy
poisoning etc.
• Pruritides
• Common cold
• Motion sickness
• Vertigo
• Pre anesthetic medication
• Cough
• Parkinsonism
• Acute muscle dystonias
• As sedative, hypnotic, anxiolytic

23. H2 and H3Receptor Antagonists
• H2 antihistaminics: Cimetidine, Ranitidine,
Famotidine, Roxatidine
• Primarily used in peptic ulcer and other gastric
hypersecretory states
• H3 antihistaminics: Thioperamide
• No clinical utility.

24. THANK YOU