2. • Substances in tissues (In response to stimulus …… Released )
Red Skin, Itch, Pain, Bronchospasm. [ autocoids ]
Histamine & SEROTONIN ( Bioactive amines )
• Vasoconstrictor released from clot.
Tonic Substance …. SEROTONIN
• SM stimulant in intestine
( ENTERAMINE )
Synthesis 5-Hydroxytryptamine (5-T)
ALL … same metabolite of
5-Hydroxytyptaphan
3. Serotonin acts as
• Neurotransmitter
• Local Hormone
• Component of platelet clotting process
• Role in migraine (Headache)
• Mediator of Signs & Symptoms of Carcinoid
syndrome ( carcinoid Tumor)
( serotonin antagonists as TREATMENT)
4. Plants, Animals,Venoms & Stings
(Red skin, Itch, Pain, Bronchospasm)
L- tryptaphan
Hydroxylation of indole ring at C 5 (Rate limiting )
[fenclonine(PSPA), p-chloramphetamine]
Decarboxylation
SEROTONIN
5. Storage by VAT (vesicle associated transporter)
Metabolism By MAOs
◦ 5-hydroxyindoleacetaldehyde
◦ 5-hydroxyindoleacetic acid ( 5-HIAA )
◦ Excretion in urine (24 hrs HIAA in Urine DIAGNOSTIC)
90% of total in Enterochromaffin cells in GIT
In Plaetlets …. Blood …. SERT (active serotonin
Transporter)
Membranes of serotonergic Nerve Endings
Cell bodies of of serotonergic neurons Raphe N.
6. Mechanism of Action( Subtype, location, G protein )
Through Specific Receptors ( 5-HT Receptors)
– 7 Sub Types ( 5-HT1 ……..5-HT3 ………..5-HT7 )
• Further sub Types
– 5-HT1 A. 5-HT1B, 5-HT1D, 5-HT1E. 5-HT1F … Gi, cAMP
– 5-HT2A. 5HT2B, 5-HT2C ………………….Gq, IP3
– 5-HT3 ….. Ion Channel
– 5-HT4 …. Gs, cAMP
– 5-HT5A,B … , cAMP
– 5-HT6,7 …Gs, cAMP
– 5-HT1P … GO . Slow EPSP …. Enteric Nervous system
• 6 are G-Protein Linked Membrane Receptors
• 1 i.e. 5-HT3 Is Ligand gated Ion Channel
( Member of nicoitinic/GABAA family of Na/K Channel Protein )
7. CNS
◦ Neurotransmitter
◦ Precursor of Melatonin
PNS
◦ Chemoreceptor reflex ( Bezold-Jarisch reflex )
◦ 5H3 receptors in coronary vasculature when
stimulated , there is bradycardia (vagal outflow) &
hypotension (decreased heart rate)
12. Therapeutic Uses
Not Clinically used
• Some 5-HT agonists are in use
– Triptans 5-HT1D/1B (Migraine)
– Ergot Alkaloids 5-HT1D/1B (Migraine)
Partial agonist
– CISAPRIDE 5-HT4 (Prokinetic, GERD)
– TEGASEROD 5-HT4 Partial agonist(IBS)
– FLUOXETINE SSRI (antidepressant)
13. Serotonin Antagonists
Synthesis Inhibitors
p-chloroampetamine, TOXIC
p-chlorophenylalanin TOXIC
Storage Inhibitors
Reserpine Symptholytic effects. High circulting Serotonin
Antagonism at RECEPTORS is desirable in Carcinoid Tumor
• 5HT2 Blockers
– Phenoxybenzamine (alpha1 Blockers)
– Cyproheptidine (Phenothiazine H1 Blocker)
– Ketanserine alpha1 Block Antagonise Platelet aggregation
– Ritanserine No alpha block Alter BT., Thrmboxane, Alter Platelet
• 5HT3 Blockers
– Ondansetron Antiemetic in Cancer Chemotherapy
14. “Classic”
“aura” nausea,Vomiting,Visual Disturbances
(Scotomas, Hemiaopia)Speech abnormalities
Severe Throbbing Unilateral Headache
“Common”
No “aura”
Headache is similar
15. Still not Understood
◦ Involves Trigeminal N. distribution to
intracranial/Extracranial arteries
◦ Temporal Artery Pulsation
◦ CGRP ( Calcitonin gene-related peptide),
powerful vasodilator
◦ Substance P
◦ Neurokinin A
- Extravasation of plasma & plasma proteins
- Mechanical stretch of PAIN NERVE ENDINGS
by this perivascular edema
23. Oral …. Invariable absorption
(Increase with Caffeine)
Amine alkaloids can be given
RECTALLY,
Buccal Cavity,
Aerosole (Bromocriptine, Cabergoline can be
given ORALLY)
I/M slow absorption, RELIABLE
METABOLISM …. Extensive … Hydroxylation
of Ring (1st step)
24. Pharmacodynamics
• Mechanism of Action
– Act on several Receptors
(Agonist, Partial agonist, Antagonist)
– Antagonist at Alpha Adrenoceptor
– Antagonist at 5HT1A, 5HT1D; Less 5HT2,3
– Agonist &Partial agnist at Dopamine Recetors in CNS
– High affinity at Presynaptic/Prejunctional Receptors
• Powerful Stimulant effect on Uterus (Gravid/Full
Term) …..Ergometrine
(5-HT2 Agonistic/Partial agonistic Effect)
25. Organ System Effect
• CNS
– Ergotism
– Hallucinogens (LSD) 5-HT2 Antagonist.
– Behavioural Effects , (LSD)
• (Prejunctional or Post junctional 5HT2 in CNS (agonist
Effect)
– Suppress prolactin
• (direct effect through D regulatory receptors
– Bromocriptine, Cabergoline, Pergolide
26. Vascular Smooth Muscle
Constriction (even in nanomolar conc.)
ProlongedVasospasm (alpha Blocker dec. it)
Phenomenon of Epineph. Reversal ( P. agonist)
P.agonist at 5HT2 vascular receptors
ACTION ON PREJUNCTIONAL NEURONAL 5-HT
RECEPTORS
INTOXICITY vascular spasm is not reversed by
alpha antagonists, serotonin antagonists or
combination of both.
27. • Uterine smooth muscle
– During pregnancy the SM is dramatically
sensitized
– Constriction/spasm (alpha1, serotonin effect)
– In very small dose INITIATE rhythmic contractions
& relaxations
ERGONOVINE more selective for Uterine SM
28. Other Smooth Muscles
- No significant effect on
bronchiolar & urinary SMs
- GIT Ms. are quite sensitive
Nausea, vomiting, diarrhea with low
dose
(Emetic centre, GIT serotonin receptors)