For Medical Students

1. Ashfaq
SEROTONIN
(5-Hydroxytryptamine)

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)

8. • CVS
– B.P.
• Triphasic B.P. Response
– Dec. B.P. (5HT3 … Chemoreceptor ref.)
– Inc. B.P. ( 5HT2 …. Vasocostriction.)
– Dec. B.P. ( Vasodilation of Sk.Ms. Vessels
– Vessels
• Vasocostriction (5HT2)
• Dilation --- Sk.Ms.& Heart ( Intact Endothelium )
• Pulmonary & Renal vassels Constriction
• Veins also constrict ….. Capillary filling ….. Flush
• Prolonged B.P. ……… subendocardial fibroplasia.
– Heart
• Direct +chronotropic & Ionotropic Effect (small)
• 5-HT1A, 5-HT2, 5-HT4 ……. Development of Heart in Fetus
• 5HT2B Agonists …. Ch. Exposure …. Valvulopathy
• 5HT2B Antagonists can prevent Pulmonary hypertension

9.  GIT
 Secretions
Little effect …. Generally Inhibitory
 Motility
 Powerful Stimulant (5-HT2, & Stimulation of Ganglion cells in ENS) .
(also 5-HT1A & 5-HT7 )
Inc. Tone & Facilitate Peristalsis
 Prokinetic Effect ( 5-HT4 in ENS)
 Increse Ach. Release ….. Cisapride

10.  Skeletal Muscle
 5-HT2 Role not understood
 Serotonin Syndrome
 Hyperthermia
 Hyprtension
 Tremour
 Clonus
 Hyper reflexia
 Hyperactive Bowel Sounds …. Diarrhea
 Mydriasis
 Agitation
 Coma
 Onset in Hrs
 D/D Malignant Hyperthermia (MH) & Neuroleptic malignant
Syndrome (NMS)

11.  Eye
 5-HT2A Agonists Reduce IOP
 5-HT2 Antagonists & Ketanserin Block this action

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

16.  Acute Attack
◦ Triptans Sumatryptan
◦ Ergot Alkaloids
◦ Antidepressants
 Stimulate Presynaptic 5-HT1D/1B receptors on Trigeminal
Nerve Endings (Inhibit Rlease of Vasoactive Peptide)
 Ergot alkaloids & Triptans have VASOCONSTROCTOR
Effect
◦ Antiseizures
 Suppress Excessive firing of neurons.

17. • Others
– NSAIDS
• Paracetamol,
• Aspirin,
• Ibuprofen
– Antiemetics
• Metoclopramide I/V
– Rarely Parenteral Opioid

18.  Prophylaxis
 Propranolol, Nadolol
 Amitriptyline
 Topiramate
 Verapamil

19. Triptans
• Naratiptan Eletriptan
• Zolmitiptan Frovatriptan
• Almotriptan Rizatriptan
– All are 5HT1 agonists
– Equal in efficacy
– Greater efficacy than Other Drugs
• e.g. Oral, Parentral, Rectal, Ergot Alkaloids
– Differ Pharmacokinetically

20. Side Effects Of Triptans
• Mild
– Altered Sensations ( Tinggling, Warmth )
– Dizziness
– Muscle Weakness
– Neck Pain
– Injection Site Reaction ( if Parenral )
– Chest Pain 1 – 5%
• Duration of Action Shorter Than duration of
Headache ( should be repeated )

21. • Severe
– Risk of Coronary artery disease
– Naratriptan & Eletriptan C/I Hepatic &Renal impairment
Or Peripheral vascular Synd.
– Frovotiptan C/I in peripheral vascular disease.
– Zolmitriptan C/I in Wolff-Parkinson-White Synd.
Brand name Expensive USE Generic Sumatriptan

22.  Tetracyclic Ergoline ring
 AMINE ALKALOIDS
▪ 6-Methylergoline
▪ Lysergic acid diethylamide (LSD)
▪ Ergonovine ( Ergometrine )
 PEPTIDE ALKALOIDS
▪ Ergotamine
▪ Alpha- Ergocryptine
▪ Bromocriptine
▪ Cabergoline

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)

29. Clinical Uses
• Migraine
• Hyperprolactinemia
• Postpartum hemorrahage
• Diagnosis of variant angina
• Senile cerebral insufficiency (Alzimer’s Disease)

30. Toxicity & C/I
• GIT DISTURBANCES
• Overdosage ….
– Vasospasm (nitroprusside)
– Cardiac toxicity
• Valve damage, (Fibrotic changes)
• Ureter obstrucion (spasm) ….. Hydronephrosis
• C/I
– Obstructive vascular disease
– Pregnancy

31. Thanks