The document provides an overview of histamine and antihistamines. It discusses how histamine is synthesized and stored in mast cells and basophils. Histamine is released through immunologic and non-immunologic mechanisms to produce local inflammatory responses. It acts through four G-protein coupled receptors (H1-H4) and has effects on blood vessels, heart, lungs, gastric acid secretion, and the central nervous system. Antihistamines like diphenhydramine and cetirizine are H1 receptor antagonists used to treat allergic conditions by blocking the effects of histamine. First generation antihistamines have anticholinergic effects while second generation drugs have fewer side effects.

1. Histamine &
Antihistamines
Dr.C.Adithan

2. Overview of lecture
 Autacoids
 Histamine
Histamine receptors
Distribution, MOA, Functions
Agonists: Clinical use
 Antihistamines
 1st
Generation drugs
 2nd
Generation drugs
 Therapeutic uses
 Adverse effects

3. Autacoids
 Autos = self; akos = remedy or medicinal agent
 Local hormones
 These are produced by the tissues or endothelial
cells which after being released act locally at the
site or near the site of their release.

4. Classification
 Amines: histamine, serotonin (5-HT)
 Peptides: kinins, angiotensin
 Lipid derived: prostaglandins,
leukotrienes, thromboxanes, platelet
activating factor (PAF).
 Others: endothelium-derived relaxing
factor (NO), cytokines .

5. Sir Henry Dale
Histamine
1907: synthesised as a
curiosity by Windaus and
Vogt
1911: responsible for
anaphylaxis by Dale and
Laidlaw

6. Histamine
 Imidazole derivative, a biogenic amine
 is an endogenous substance synthesized, stored
and released in
(a) mast cells, which are abundant in the skin, GI,
and the respiratory tract,
(b) basophils in the blood, and
(c) some neurons in the CNS and peripheral NS
 It is not a drug but is important due to its physiological
and pathophysiological actions. Therefore, drugs that
inhibit its release or block its receptors have
therapeutic value.
‘histamine’ - Greek word for tissue (‘histos’)

7. Biosynthesis of histamine

8. Histamine metabolism
N-Methyl histamine Imidazoleacetic acid
N-Methyl imidazole acetic acid Imidazole acetic acid riboside
N-Methyl transferase Diamine oxidase
MAO-B
Phosphoribosyl
transferase
Histamine

9. Storage of histamine
 Mast cells
 Basophils
 Histaminocytes (stomach)
 Histaminergic neurons
Stored in secretory granules
high in skin, bronchial mucosa
and intestinal mucosa

10. Storage
 ‘Slow-turnover’ histamine is stored as
heparin-histamine complex in cytoplasmic
granules in mast cells (lungs, GIT) and
basophils.
 ‘Fast-turnover’histamine is stored in CNS
neurons, skin and ECL of stomach.
ECL: Enterochromaffin like cells,
a type of neuroendocrine cells found in the gastric glands

11. Release of ‘Slow turnover’ histamine
Allergic reaction:
Antigen combines with IgE antibodies
on the surface of mast cells or
basophils.

12. Release of histamine
 Immunologic release
Exposure of an antigen to a previously sensitized (exposed) subject can
immediately trigger allergic reactions. If sensitized by IgE antibodies
attached to their surface membranes will degranulate when exposed to
the appropriate antigen and release histamine, ATP and other
mediators
 Chemical & mechanical release due to mast cell injury

13. IgE - Mediated Releasers
 Food: eggs, peanuts, milk products, grains,
strawberries, etc
 Drugs: penicillins, sulfonamides, etc
 Venoms: fire ants, snake, bee, etc
 Foreign proteins: nonhuman insulin, serum
proteins, etc
 Enzymes: chymopapain

14.  Morphine and other opioids, i.v.
 Aspirin and other NSAIDs in some asthmatics
 Vancomycin, i.v. (Red man syndrome),
polymixin B
 Some x-ray contrast media
 Succinylcholine, d-tubocurarine, 48/80
 Anaphylotoxins: c3a, c5a
 Cold or solar urticaria
Non-immune Releasers

15. Diseases:  histamine release
 Mastocytosis (too many mast cells)
Systemic : urticaria, dermographism, pruritus,
headache, weakness, hypotension, flushing of face,
diarrhea or peptic ulceration
Cutaneous – pigmented cutaneous lesions that sting
when stroked
 Gastric carcinoid tumors (geographical flush)
 Myelogenous leukemia (basophils -chronic
pruritus)
 Insect stings
 Venoms and some sea foods

16. Drugs that inhibit histamine release
Adrenaline
Ephedrine
Isoproterenol
Mast cell stabilizers

17. Histamine receptors: H1, H2, H3 & H4, G-protein coupled
Characteristi
c
H1 H2 H3 H4
G-protein coupling Gq/11 Gs Gi/o Gi/o
Second
messenger
Ca2+,
NO, cGMP cAMP cAMP cAMP ,Ca2+
Distribution Smooth muscle,
endothelial cells,
CNS
Gastric parietal
cells, cardiac
muscle,
mast cells,
CNS
CNS:
presynaptic
Cells of
hematopoietic
origin
Representative
antagonist
chlorpheniramine ranitidine pitolisant JNJ7777120
Gq-phospholipase C activation, Ca2+
channel opening; Gs-adenylyl cyclase activation;
Gi-adenylyl cyclase inhibition ; G0- Ca2+
channel inhibition

18. Pharmacological Actions

19. Histamine- Allergic actions
 Immediate hypersensitivity and allergic response
(IgE)
 Other mediators released : PLA2, PAF, LTC4 & LTD4, kinins
Mast cells
basophils
IgE
Atopic
individuals

20. rhinitis,asthma
atopic dermatitis

21. Blood vessels:
Vasodilation (H1 & H2) in arteries (NO mediated)
tends to constrict large vessels (rodents)
Increased capillary permeability (H1)
Lowering of BP
Constricts veins extravasation of fluid & edema
Triple response of Lewis: flush, flare and wheal

22. Heart:
Force of contraction of heart
 heart rate
Slows AV conduction (arrhythmia in high doses)
Lungs
H1 – bronchoconstriction, increased mucus viscosity
H2 - slight bronchodilation, increased mucus secretion
H1 - stimulation of vagal sensory nerve endings: cough

23. Gastric acid secretion: marked increase
Direct action exerted on parietal cells through H2 receptors, mediated by
increased cAMP generation which activates membrane proton pump

24. Sensory nerve endings: Peripheral nerve
endings: Itching, pain, flare
Autonomic ganglia and adrenal medulla:
Stimulated and release of adrenaline, secondary
rise of BP

25.  Does not cross BBB
 ICV admn causes
Raise in BP
Cardiac stimulation
hypothermia
behavioural arousal
Vomiting
ADH release
 Mediated by H1 and H2 receptors
CNS

26. Pathophysiological roles:
• Cellular mediator of immediate HSR and
acute inflammatory response
• Anaphylaxis
• Seasonal allergies
• Duodenal ulcers
• Systemic mastocytosis
• Gastrinoma (Zollinger-Ellison Syndrome)

27. Uses: No therapeutic value
1.Diagnostic – nonspecific bronchial
hyperreactivity in asthmatics
2.Positive control during allergy
skin testing

28. Histamine-related Drugs
 Mast Cell Stabilizers (sodium cromoglycate, Nedocromil )
 H1 Receptor Antagonists (1st
and 2nd
generation)
 H2 Receptor Antagonists (Ranitidine, Cimetidine)
 H3 Receptor Agonist and Antagonists (potential new
drugs being developed)

29. Ist
generation
Diphenhydramine
Dimenhydranate
Promethazine
Chlorpheniramine
Meclizine
Cyclizine
Cinnarazine
Hydroxazine
IInd
generation
Cetrizine
Levo cetrizine
Fexofenidine
Loratidine
Azelastine
mezolastine
Histamine H1- Antagonists

30. 1st
gen. antihistamines
 Short to intermediate
acting
 Sedation
 Anti muscarinic
actions
2nd
gen. antihistamines
 Long acting
 Least / No sedation
 No autonomic effects

31. Pharmacological Actions

32. Pharmacological Actions
1.Antagonism of histamine:
Block: bronchoconstriction, triple response
Fall BP: low dose blocked, for high dose both H1 and H2 blocker needed
2. Antiallergic action:
 type I reaction suppressed
 Anaphylactic fall in BP: partially blocked
 Asthma in man: unaffected
3. CNS: variable effect: sedation, no sedation, restlessness, insomnia
4. Anti-cholinergic action: more in 1st generation
5. Local anaesthetic: Not used clinically
6. BP: fall only with i.v., admn and not with p.o.

33. Therapeutic uses

35.  Bronchial asthma: ineffective since
(1) Leukotrienes and PAF are more important
(2) Histamine is high in conc. Conventional dose
of antihistamine are not adequate
 Anaphylactic shock and laryngeal oedema:
Adjuvant value only. Adrenaline is essential
 Perennial vasomotor rhinitis, atopic
dermatitis, chronic urticaria: less marked
effect, combine with H2 blocker

36. First Generation Agents
Adverse Effects:
 Sedation (Paradoxical Excitation in children)
 Dizziness
 Fatigue
 Peripheral antimuscarinic effects like
 Dry Mouth
 Blurred Vision
 Constipation
 Urinary Retention

37. Drug interactions:
 Additive with classical antimuscarinics
 Potentiate CNS depressants
opioids
sedatives
general and narcotic analgesics
alcohol
First Generation Agents

38. H 2 antagonist
 Ranitidine, cimetidine, famotidine
 s/e of cimetidine: antiandrogenic
 Uses – peptic ulcer disease.

39. ACh
PGE2
Histamine
Gastrin
Adenyl
cyclase
_
+
ATP cAMP
Protein Kinase
(Activated)
Ca++
+
Ca++
Proton pump
K+
H+
Gastric acid
Parietal cell
Lumen of stomach
Antacid
Omeprazole
Ranitidine
H2M3
Misoprostol
_
_
_
+
PGE
receptor
+
+
Gastrin
receptor+
+
+

40. Thank you