Histamine and serotonin are important autacoids that act as local hormones or mediators. Histamine is synthesized from the amino acid histidine and stored in mast cells. It binds to H1, H2, and H3 receptors and causes various effects including vasodilation, increased vascular permeability, bronchoconstriction, and gastric acid secretion. Serotonin is found primarily in enterochromaffin cells and platelets. It acts as a neurotransmitter and vasoconstrictor and is involved in platelet aggregation, nausea/vomiting, and appetite regulation. First and second generation antihistamines antagonize H1 receptors and are used for allergies, while H2 receptor antagon

1. HISTAMINE AND
SEROTONIN
By
SROTA DAWN.
M . Pharma (Pharmacology)
1

2. AUTACOID
Definition:
The term is derived from ‘GREEK’
• Autos = self
• akos = healing substance or Remedy
or
some times called Local Hormones
2

3. Classification of autacoids
A. Amine Autaciods:
1. Histamine
2. Serotonin or 5-HT
B. Eicosanoids (PGs; Thromboxane ; Leukotriens)
C. Peptides Autociods:
1) Kinins (bradykinin, kallidin)
2) Renin; Angiotensins etc
3

4. HISTAMINE
• Histamine means ‘ TISSUE AMINE ’( Histos-
tissue)
• Present in all animal tissues and in some plants
also.
• mediators of allergic and inflammatory reactions;
also involved in Gastric Acid Secretions ; and act
as Neurotransmitter & Neuromodulator.
4

5. • Histamine is presents mostly in MAST cells.
• Tissues rich is histamine are skin, gastric
mucosa, intestinal mucosa, lungs, liver and
placenta.
• Non mast cell histamine occurs in brain,
epidermis, gastric mucosa, and growing regions.
• Histamine is also present in blood, most of
body secretions, venoms, pathological fluids.
5

6. Synthesis of histamine
Histidine
Histamine
(beta imidazolylethylamine)
Decarboxylase
6

7. Metabolism of histamine
Histamine
N-methyl
transferase
n-methyl
histamine
Diamine
oxidase
Imidazole
acetic acid
7

8. Storage and Release:
Histamine is usually found in storage granules as complex
with sulphated polysaccharides, heparin and released
(locally) by:
a) Immunological Mechanism
b) Tissue injury Mast cell degranulation
c) Chemical and physical Conditions
8

9. Histamine receptors
• Histamine binds to three types of Receptors ,
namely
• H1 ,
• H2 ,
• H3 (see table 1)
9

10. Partially
selective
Antagonists
Partially
Selecetive
Agonists
Post receptor
Mechanism
DistributionReceptor sub
type
Mepyramine ,
triprolidine
2-( m-
fluorophenyl)-
histamine
↑IP3 , DAGSmooth muscle ,
endothelium ,
brain
H1
Ranitidine ,
tiotidine
Dimaprit,
impromidine ,
amthamine
↑cAMPGastric mucosa ,
Cardiac muscle ,
mast cells , brain.
H2
Thioperamide,
iodophenpropit ,.
clobenpropit
R- α-
Methylhistamine,
imetit , immepip
G protein –
coupled
Presynaptic:
brain, myentric
plexus, other
neurons
H3
10
Table no 1

11. Selected Actions of Histamine
in Humans
Heart
 H1 - decreased AV conduction
 H2 - increased chronotropy,
decreased inotropy
 H1, H2 - increased automaticity
11

12. Selected Actions of Histamine
in Humans
Vascular
 H1 – in vascular endothelium NO and PG
release  vasodilation. In coronary vessels
 vasoconstriction. Increased permeability of
post capillary venules
 H2 – in vascular cells  vasodilation
mediated by cAMP
12

13. Selected Actions of Histamine
in Humans
Lung
 H1 – bronchoconstriction, increased mucus
viscosity
 H2 - slight bronchodilation, increased mucus
secretion
 H1 - stimulation of vagal sensory nerve endings:
cough
13

14. Selected Actions of Histamine
in Humans
Gastrointestinal System
 H2 - acid, fluid and pepsin secretion
 H1 - increased intestinal motility and secretions
Cutaneous Nerve Endings
 H3 - pain and itching
14

15. Triple Response of Willis
Sub-dermal histamine injection causes:
1. Red spot (few mm) in seconds: direct vasodilation
effect , H1 receptor mediated
2. Flare (1cm beyond site): axonal reflexes, indirect
arteriolar vasodilation, and itching, H1 receptor
mediated
3. Wheal (1-2 min) same area as original spot, edema
due to increased capillary permeability, H1 receptor
mediated
15

16. Histamine-related Drugs
• Mast Cell Stabilizers (Cromolyn Na, Nedocromil –
Tilade , Albuterol)
• H1 Receptor Antagonists (1st and 2nd generation)
• H2 Receptor Antagonists (Ranitidine, Cimetidine)
• H3 Receptor Agonist and Antagonists (potential
new drugs being developed)
16

17. Histamine H1- Antagonists
• First Generation: Sedating
• Second Generation: Non sedating
17

18. First Generation Agents
Examples
• Ethanolamines: DIPHENHYDRAMINE (Benadryl)
CLEMASTINE (Tavist)
• Alkylamine: CHLORPHENIRAMINE (Chlortrimeton)
• Phenothiazine: PROMETHAZINE (Phenergan)
• Piperazines: HYDROXYZINE (Vistaril)
CYCLIZINE (Antivert)
18

19. Uses of 1st generation drugs:
• Adjunctive in anaphylaxis and other cases where histamine
release can occur (H2 antagonist, and epinephrine must
also be used in anaphylaxis)
• Anti-allergy (allergic rhinitis, allergic dermatoses, contact
dermatitis)
• Sedative/sleep aid
• To prevent motion sickness (meclizine, cyclizine)
19

20. Uses
• Antiemetic: prophylactic for motion sickness
(promethazine)
• Antivertigo (meclizine)
• Local anesthetic: (diphenhydramine)
• Antitussive (diphenhydramine)
20

21. 21
Adverse effects of 1st generation drugs
Adverse Effects:
• Sedation (Paradoxical Excitation in children)
• Dizziness
• Fatigue
• Tachy dysrhythmias in overdose - rare
• Allergic reactions with topical use
• Peripheral anti-muscarinic effects
• dry Mouth
• blurred Vision
• constipation
• urinary Retention

22. Drug interactions
Drug interactions:
• Additive with classical antimuscarinics
• Potentiate CNS depressants
• opioids
• sedatives
• general and narcotic analgesics
• alcohol
22

23. Pharmacokinetics of 1st
generation drugs
• Well absorbed from the GI-tract
• Widely distributed
• Cross BBB
• Placental transfer
• Hepatic transformation, renal elimination of the
metabolites (induce hepatic microsomal
enzymes)
23

24. Examples
• CETIRIZINE (Zyrtec)
• FEXOFENADINE (Allegra)
• LORATADINE (Claritin)
• DESLORATADINE (Clarinex- FDA Approved In 2002)
• LORATADINE (Claritin Hives Relief - FDA Approved In
2004)
• AZELASTIN (Intranasal Spray)
• Anti-allergy
Second Generation Agents
24

25. Serotonin
Definition and Location:
• it is a neurotransmitter found in enterochromaffin
cells in GIT (90%) , and in plateletes and in raphe
nuclei of brain stem.
25

26. 26

27. Pharmacological actions of
Serotonin
• CVS:
1) Blood vessels:
Potent and direct contractions on smooth muscle (via 5-
HT2 ) EXCEPT : Skeletal Muscles and Heart blood
vessels.
• Note : 5- HT can give rise to triple action:
Decrease BP due to chemoreceptor response
then increase BP due to Vasoconstriction (5- HT2), then
decrease B.P due to skeletal muscle V.D
2) Platelet: Increase platelet aggregation via 5-HT2
27

28. GIT:
1) increase contraction of smooth muscle (via
5- HT4 stimulated the release of ACH).
2) Nausea and vomiting (via 5-HT3)
Respiration :
5-HT may produce weak bronchoconstriction.
CNS:
very important.(Appetite; depression and
mania; Pain; reduce Anxiety; Schizophrenia).
28

29. Clinical use of serotonergic
agonists
1) Buspirone: 5-HT1A agonist used as anxiolytic
agent.
2) Sumatriptan: 5-HT1D agonist for migraine
(Treatment and prophylactic).
29

30. 3) Metoclopromide (Plasil): 5-HT4 agonist as prokinetic
agent
for Rx of gastroesophagial reflex.
And also used for N/V via 5-HT3 antagonistic action.
4) Dexfenfuramine: Acts by stim. Release and inhib.
Reuptake of serotonin.
Used as anorexic agent.
30
Clinical use of serotonergic
agonists

31. Clinical use of antagonists
1) Ondansetron & Granisetron: 5-HT3 antagonists
Common
used for Rx of N/V induced by cytotoxic
(chemotherapy) drugs.
2) Cyproheptadine: Both H1, 5-HT1,2 and
cholinergic antagonist
used for Rx carcinoid tumor (significant increases
in serotonin) and to increase appetite..
31

32. Clinical use of antagonists
3) Ketanserin: 5-HT2/1c antagonist and α1-
adrenergic blocker.
(used as antihypertensive agent)
4) Methysergide: This is an ergot alkaloid acts as
5-HT1,2
antagonist used for Rx of migraine.
32

33. Reading
Goodman and Gilman
11th edition
Chapter 24
33

34. 34