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HISTAMINE AND
SEROTONIN
By
SROTA DAWN.
M . Pharma (Pharmacology)
1
AUTACOID
Definition:
The term is derived from ‘GREEK’
• Autos = self
• akos = healing substance or Remedy
or
some times ca...
Classification of autacoids
A. Amine Autaciods:
1. Histamine
2. Serotonin or 5-HT
B. Eicosanoids (PGs; Thromboxane ; Leuko...
HISTAMINE
• Histamine means ‘ TISSUE AMINE ’( Histos-
tissue)
• Present in all animal tissues and in some plants
also.
• m...
• Histamine is presents mostly in MAST cells.
• Tissues rich is histamine are skin, gastric
mucosa, intestinal mucosa, lun...
Synthesis of histamine
Histidine
Histamine
(beta imidazolylethylamine)
Decarboxylase
6
Metabolism of histamine
Histamine
N-methyl
transferase
n-methyl
histamine
Diamine
oxidase
Imidazole
acetic acid
7
Storage and Release:
Histamine is usually found in storage granules as complex
with sulphated polysaccharides, heparin and...
Histamine receptors
• Histamine binds to three types of Receptors ,
namely
• H1 ,
• H2 ,
• H3 (see table 1)
9
Partially
selective
Antagonists
Partially
Selecetive
Agonists
Post receptor
Mechanism
DistributionReceptor sub
type
Mepyra...
Selected Actions of Histamine
in Humans
Heart
 H1 - decreased AV conduction
 H2 - increased chronotropy,
decreased inotr...
Selected Actions of Histamine
in Humans
Vascular
 H1 – in vascular endothelium NO and PG
release  vasodilation. In coro...
Selected Actions of Histamine
in Humans
Lung
 H1 – bronchoconstriction, increased mucus
viscosity
 H2 - slight bronchodi...
Selected Actions of Histamine
in Humans
Gastrointestinal System
 H2 - acid, fluid and pepsin secretion
 H1 - increased i...
Triple Response of Willis
Sub-dermal histamine injection causes:
1. Red spot (few mm) in seconds: direct vasodilation
effe...
Histamine-related Drugs
• Mast Cell Stabilizers (Cromolyn Na, Nedocromil –
Tilade , Albuterol)
• H1 Receptor Antagonists (...
Histamine H1- Antagonists
• First Generation: Sedating
• Second Generation: Non sedating
17
First Generation Agents
Examples
• Ethanolamines: DIPHENHYDRAMINE (Benadryl)
CLEMASTINE (Tavist)
• Alkylamine: CHLORPHENIR...
Uses of 1st generation drugs:
• Adjunctive in anaphylaxis and other cases where histamine
release can occur (H2 antagonist...
Uses
• Antiemetic: prophylactic for motion sickness
(promethazine)
• Antivertigo (meclizine)
• Local anesthetic: (diphenhy...
21
Adverse effects of 1st generation drugs
Adverse Effects:
• Sedation (Paradoxical Excitation in children)
• Dizziness
• ...
Drug interactions
Drug interactions:
• Additive with classical antimuscarinics
• Potentiate CNS depressants
• opioids
• se...
Pharmacokinetics of 1st
generation drugs
• Well absorbed from the GI-tract
• Widely distributed
• Cross BBB
• Placental tr...
Examples
• CETIRIZINE (Zyrtec)
• FEXOFENADINE (Allegra)
• LORATADINE (Claritin)
• DESLORATADINE (Clarinex- FDA Approved In...
Serotonin
Definition and Location:
• it is a neurotransmitter found in enterochromaffin
cells in GIT (90%) , and in platel...
26
Pharmacological actions of
Serotonin
• CVS:
1) Blood vessels:
Potent and direct contractions on smooth muscle (via 5-
HT2 ...
GIT:
1) increase contraction of smooth muscle (via
5- HT4 stimulated the release of ACH).
2) Nausea and vomiting (via 5-HT...
Clinical use of serotonergic
agonists
1) Buspirone: 5-HT1A agonist used as anxiolytic
agent.
2) Sumatriptan: 5-HT1D agonis...
3) Metoclopromide (Plasil): 5-HT4 agonist as prokinetic
agent
for Rx of gastroesophagial reflex.
And also used for N/V via...
Clinical use of antagonists
1) Ondansetron & Granisetron: 5-HT3 antagonists
Common
used for Rx of N/V induced by cytotoxic...
Clinical use of antagonists
3) Ketanserin: 5-HT2/1c antagonist and α1-
adrenergic blocker.
(used as antihypertensive agent...
Reading
Goodman and Gilman
11th edition
Chapter 24
33
34
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  1. 1. HISTAMINE AND SEROTONIN By SROTA DAWN. M . Pharma (Pharmacology) 1
  2. 2. AUTACOID Definition: The term is derived from ‘GREEK’ • Autos = self • akos = healing substance or Remedy or some times called Local Hormones 2
  3. 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. 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. 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. 6. Synthesis of histamine Histidine Histamine (beta imidazolylethylamine) Decarboxylase 6
  7. 7. Metabolism of histamine Histamine N-methyl transferase n-methyl histamine Diamine oxidase Imidazole acetic acid 7
  8. 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. 9. Histamine receptors • Histamine binds to three types of Receptors , namely • H1 , • H2 , • H3 (see table 1) 9
  10. 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. 11. Selected Actions of Histamine in Humans Heart  H1 - decreased AV conduction  H2 - increased chronotropy, decreased inotropy  H1, H2 - increased automaticity 11
  12. 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. 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. 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. 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. 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. 17. Histamine H1- Antagonists • First Generation: Sedating • Second Generation: Non sedating 17
  18. 18. First Generation Agents Examples • Ethanolamines: DIPHENHYDRAMINE (Benadryl) CLEMASTINE (Tavist) • Alkylamine: CHLORPHENIRAMINE (Chlortrimeton) • Phenothiazine: PROMETHAZINE (Phenergan) • Piperazines: HYDROXYZINE (Vistaril) CYCLIZINE (Antivert) 18
  19. 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. 20. Uses • Antiemetic: prophylactic for motion sickness (promethazine) • Antivertigo (meclizine) • Local anesthetic: (diphenhydramine) • Antitussive (diphenhydramine) 20
  21. 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. 22. Drug interactions Drug interactions: • Additive with classical antimuscarinics • Potentiate CNS depressants • opioids • sedatives • general and narcotic analgesics • alcohol 22
  23. 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. 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. 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. 26
  27. 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. 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. 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. 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. 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. 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. 33. Reading Goodman and Gilman 11th edition Chapter 24 33
  34. 34. 34
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