Histamine is a physiologically active amine found in plant and animal tissues that is released during allergic reactions. It stimulates gastric secretion and causes blood vessel dilation and constriction of airways. Antihistamines work by blocking histamine receptors to reduce the symptoms of allergy conditions like rhinitis, hives, and anaphylaxis. First generation antihistamines are more sedating due to crossing the blood-brain barrier, while second generation antihistamines have fewer side effects by primarily blocking peripheral histamine receptors. Drug interactions can increase the risk of arrhythmias, so antihistamines should be used cautiously with CYP3A4 inhibitors like ketoconazole and ery

1. HISTAMINE AND
ANTIHISTAMINES

2. 1910-1911
Henry Dale and Patrick
Laidlaw identified and
described the
properties of histamine
(from: histos = tissue,
with an amine
constituent).

3. ◾ Is a physiologically active amine, C5H9N3, found in
plant and animal tissue and released from mast cells
as part of an allergic reaction in humans.
-It stimulates gastric secretion and
-causes dilation of capillaries,
-constriction of bronchial smooth muscle, and
-decreased blood pressure.
Imidazoline
ring and
amine gp

4. ◾ Formed from the amino acid Histadine in a
decarboxylation reaction with the enzyme histadine
decarboxylase
◾ Occurs primarily in mast cells and basophils

5. ◾ Signal involved in local
immune response, also a
neurotransmitter
◾ synthesized by the
decarboxylation of histidine
◾ Either stored or quickly
inactivated by histamine-N-
methyltransferase and
diamine oxidase
◾ Release of histamine from
mast cells is stimulated by IgE
antibodies which respond to
foreign antigens in the body

6. Type Location Function
H1 histamine receptor
(H1 &H2- intra dermal
injection- can cause
tripple reaction)
•Smooth muscle-
spasmodic
contractions of ileum,
uterus, diarrhoea
•Exocrine glands-
pancreas, salivary,
lacrimal
• Endothelium
• CNS tissue
vasodilation
Bronchoconstriction
bronchial smooth
muscle contraction
separation of
endothelial cells
(responsible for hives),
and pain and itching
due to insect stings;
the primary receptors
involved in allergic
rhinitis symptoms and
motion sickness;
sleep regulation.

7. Type Location Function
2
H histamine receptor
Located on parietal
cells
Primarily stimulate
gastric acid secretion
3
H histamine receptor
Found on central
nervous system and to
a lesser extent
peripheral nervous
system tissue
Decreased
neurotransmitter
release: histamine,
acetylcholine,
norepinephrine,
serotonin
4
H histamine receptor
Found primarily in the
basophils and in the
bone marrow. It is also
intestine, spleen, and
colon.
Plays a role in
found on thymus, small chemotaxis.

8. ◾ Early phase reaction:
occurs within minutes
of exposure to an
allergen and lasts for
30-90 minutes
◾ Late phase reaction:
begins 4-8 hours later
and can last for several
days, often leading to
chronic inflammatory
disease

9. ◾ Morphine, D-tuboocurarine,
◾ Trimethophan, Polymyxin-b,
◾ Succinyl Choline, Hydralazine,
◾ Dextran, Polyvinyl Pyrolidine(pvp),
◾ Ditergents, Substance P,
◾ Bradykinin, Radiocontrast Media

10. ◾ -β-2agonist-Adrenaline, Ephedrine, Isoproterenol
◾ Mast cell stabilizers-Disodium Chromoglycate,
Ketotifen
◾ Negetive feedback control

12. ◾ Mild/cutaneous
◾ Mild to moderate
◾ Severe/anaphylactic
◾ erythema, urticaria, and/or
itching
◾ skin reactions, tachycardia,
dysrhythmias, moderate
hypotension, mild respiratory
distress
◾ severe hypotension,
ventricular fibrillations,
cardiac arrest,
bronchospasm, respiratory
arrest

13. ◾ A histamine antagonist (commonly called an
antihistamine) is a pharmaceutical drug that
◾  inhibits the action of histamine by either blocking
its attachment to histamine receptors, or
◾  inhibiting the enzymatic activity of histidine
decarboxylase which catalyzes the transformation of
histidine into histamine

14. 1st Generation:
◾ Highly Sedative-dimenhydrinate, Diphenhydramine,
Doxylamine, Hydroxyzine, Promethazine
◾ Moderately Sedative-clemastine, Pyrilamine,
Cyproheptadine, Pheniramine,
◾ Mild Sedative-chlorpheniramine, Triprolidine,
Cyclizine, Betahistine
2nd Generation:
◾ Terfenadine, Astemizole, Cetirizine, Loratadine,
Mizolastine, Fexofenadine, Levocetrizine, Ebastine

15. Receptor type Agonist Antagonist
H1 Histaprodifen , Triprolidine
Chlorpheniramine
H2 Dimaprit,Amthapine Nizatidine,Ranitidine
Famotidine
H3 R-α-methyl histamine
Imetit
Iodophenpropit
Clobenpropit
Thioperamide
H4 Imetit,
Clozapine
Thioperamide

16. PK, lower drug-drug
interactions
Receptor affinity and
selectivity, efficacy
Safety, lower
cardiotoxicity
◾ General trend: improve tolerability and safety (less
to no sedation; reduce the cholinergic effects)
Targeted Molecules
for improvement
Type of Improvement
Loratadine
Hydroxyzine
Terfenadine
Astemizole
Objective
Class
Piperidine
Piperazine
Piperidine
Piperidine
Levocetirizine
Active metabolite Isomer Purification
Desloratadine
Cetirizine
Fexofenadine
No possible improvement
not even designed as an antihistamine; discovered
during research of calcium channel-blocking agents

17. 0.2
0
0.4
0.6
0.8
1
1.4
1.2
Number
of
viable
cells
(absorbance)
withdrawn from the
market due to
cardiotoxicity
A SET OF AHS TESTED FOR TOXICITY (INHIBITION OF CELLULAR PROLIFERATION) BY THE MTS
ASSAY (SUSSMAN NL ET AL. CELL NOTES, ISSUE 3, 2002: 7-10). ALL DRUGS TESTED IN
QUADRUPLICATE AT 80M AND ALL ASSAYS PERFORMED AT 72 HRS.
Still on the market

18. • Allergic rhinitis (common cold)
• Allergic conjunctivitis (pink eye)
• Allergic dermatological conditions
• Urticaria (hives)
• Angioedema (swelling of the skin)
• Pruritis (atopic dermatitis, insect bites)
• Anaphylactic reactions (severe allergies)

19. ◾ First Generation Drugs:
 Anticholinergic CNS interactions
 Gastrointestinal reactions
 Common side effects: sedation, dizziness, tinnitus,
blurred vision, euphoria, lack of coordination,
anxiety, insomnia, tremor, nausea and vomiting,
constipation, diarrhea, dry mouth, and dry cough,
 thrombocytopenia , neutropenia , aplastic anemia
 Associated with the first generation H1-
antihistamines and due to their lack of selectivity
for the H1 receptor and anti-cholinergic activity.
Side effects are due to CNS depression(by crossing
BBB)

20. ◾ Second Generation Drugs:
 Common side effects: drowsiness, fatigue,
headache, nausea and dry mouth
Newer second generation H1-antihistamines are
more selective for the peripheral histamine
receptors and have far less side effects(doesn’t
cross BBB) (drowsiness, fatigue, headache, nausea
and dry mouth)

21. ◾ Ketoconazole , Erythromycin
Inhibit CYP3A4 microsomal enzymes can lead to
elevated plasma levels of antihistaminesleading to
life threatening arrhythmiastorsades-de-pointes
Astemizole and terfenadine –no longer used

22. THANKYOU
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