histamine and serotonin ppt by srota dawn
TRANSCRIPT
1
HISTAMINE AND SEROTONIN
By
SROTA DAWN.
M . Pharma (Pharmacology)
2
AUTACOID
Definition:
The term is derived from ‘GREEK’
• Autos = self
• akos = healing substance or Remedy
or
some times called Local Hormones
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
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.
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.
6
Synthesis of histamine
Histidine
Histamine(beta imidazolylethylamine)
Decarboxylase
7
Metabolism of histamine
Histamine
N-methyl transferase
n-methyl histamine
Diamine oxidase
Imidazole acetic acid
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
9
Histamine receptors
• Histamine binds to three types of Receptors , namely
• H1 ,
• H2 ,
• H3 (see table 1)
10
Partially selective Antagonists
Partially Selecetive Agonists
Post receptor Mechanism
Distribution Receptor sub type
Mepyramine , triprolidine
2-( m-fluorophenyl)-histamine
↑IP3 , DAG Smooth muscle , endothelium , brain
H1
Ranitidine , tiotidine
Dimaprit, impromidine , amthamine
↑cAMP Gastric 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
Table no 1
11
Selected Actions of Histamine in Humans
Heart
H1 - decreased AV conduction
H2 - increased chronotropy,
decreased inotropy
H1, H2 - increased automaticity
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
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
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
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
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)
17
Histamine H1- Antagonists
• First Generation: Sedating
• Second Generation: Non sedating
18
First Generation Agents
Examples
• Ethanolamines: DIPHENHYDRAMINE (Benadryl) CLEMASTINE (Tavist)
• Alkylamine: CHLORPHENIRAMINE (Chlortrimeton)
• Phenothiazine: PROMETHAZINE (Phenergan)
• Piperazines: HYDROXYZINE (Vistaril)
CYCLIZINE (Antivert)
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)
20
Uses
• Antiemetic: prophylactic for motion sickness (promethazine)
• Antivertigo (meclizine)
• Local anesthetic: (diphenhydramine)
• Antitussive (diphenhydramine)
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
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)
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
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.
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
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).
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).
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.
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..
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.
33
Reading
Goodman and Gilman11th editionChapter 24
34
THANK YOU