2. HISTORY
In 1935, Vittorio Erspamer showed that an extract
from enterochromaffin cells made intestines contract.
Two years later, Erspamer was able to show that it was a
previously unknown amine, which he named enteramine.
In 1948, Maurice M. Rapport, Arda Green, and Irvine Page of the
Cleveland Clinic discovered a vasoconstrictor substance in blood
serum and named it SEROTONIN.
5-HT was synthesised in 1951 .
In 1957,Gaddum & Picarelli proposed 2 distinct 5-HT receptor
subtypes-M & D receptors.
In 1979, Peroutka & Snyder provided evidence for 2 distinct
recognition sites for 5-HT.
3. ANATOMY
• The neurons of the raphe nuclei are the principal source of 5-HT
release in the brain.
• The raphe nuclei are neurons grouped into 9 pairs and
distributed along the entire length of the brainstem, centered
around the reticular formation.
• Axons from the neurons of the raphe nuclei form a
neurotransmitter system, reaching almost every part of the
CNS.
• Axons of neurons in the lower raphe nuclei terminate in the
cerebellum and spinal cord, while the axons of the higher nuclei
spread out in the entire brain.
11. Hydroxylation at C5 is rate limiting step ,can be blocked by p-
chlorophenylalanine & p-chloroamphetamine.
5-HT is concentrated in synaptic vesicles by a vesicle associated
transporter (VAT) that is blocked by reserpine.
Serotonin or 5-Hydroxytryptamine (5-HT) is a monoamine
neurotransmitter.
Biochemically derived from tryptophan, serotonin is primarily
found in the
• Enterochromaffin cells in Gastrointestinal tract (˃ 90 %)
• Platelets
• Central nervous system (CNS)
12. TERMINATION
• Serotonergic action is terminated primarily via uptake of 5-HT
from the synapse.
• This is accomplished through the specific monoamine
transporter for 5-HT, SERT, on the presynaptic neuron.
• Another monoamine transporter known as PMAT has been
regarded to be important in the clearance of Serotonin.
13. 5-ht RECEPTORS
• The 5-HT receptors are the receptors for serotonin.
• They are located on the cell membrane of nerve cells and
mediate the effects of serotonin as the endogenous ligand .
• All 5-HT receptors (except 5-HT3) are G protein-coupled, seven
transmembrane (or heptahelical) receptors that activate an
intracellular second messenger cascade.
14.
15.
16.
17. SEROTONIN RECEPTORS
Family Type Mechanism Potential
5-HT1 G-protein coupled.
Decreasing cellular levels
of cAMP.
Inhibitory
5-HT2 G-protein coupled.
Increasing cellular levels
of IP3 and DAG.
Excitatory
5-HT3
Ligand-
gated Na+ and K+ cation
channel.
Depolarizing plasma
membrane.
Excitatory
5-HT4 G-protein coupled.
Increasing cellular levels
of cAMP.
Excitatory
5-HT5 G-protein coupled.
Decreasing cellular levels
of cAMP.
Inhibitory
5-HT6 G-protein coupled.
Increasing cellular levels
of cAMP.
Excitatory
5-HT7 G-protein coupled.
Increasing cellular levels
of cAMP.
Excitatory
18.
19. 5- HT 1 RECEPTOR
• G protein coupled receptor acts by ↓ cAMP
• It is of 6 types
• 5-HT 1A & 5-HT 1B are autoreceptors
• 5-HT 1A –Localized in raphe nuclei & hippocampus
Selective agonist- 8-OH DPAT
Selective antagonist- WAY100635
• 5- HT 1B - Localized in Substantia niagra, globus pallidus ,basal
ganglia
Selective agonist- Sumatriptan, CP93129
20. • 5-HT 1D – Localized in brain
5-HT 1B/1D cause constriction of cranial blood vesssels.
Selective agonist- Sumatriptan
It also cause inhibition of NA release from sympathetic nerve endings
& inflammatory neuropeptides from nerve endings in cranial blood
vessels
• 5-HT 1E – Localized in cortex, putamen
• 5-HT 1F- Localized in cortex , hippocampus
Selective agonist- LY334370
• 5-HT 1P- Localized in enteric nervous system
Selective agonist- 5-Hydroxyindalpine
Selective antagonist - Renzapride
21. 5- HT 2 RECEPTOR
• It is a G protein coupled receptor acts by ↑IP3/DAG
• Earlier designated as D type.
• It is of 3 types.
• 5-HT 2A -Most widely expressed, localized in platelets, vascular
& visceral smooth muscle, cerebral cortex.
Mediates most of the direct actions of 5-HT like
vasoconstriction, intestinal, uterine & bronchial contraction,
platelet aggregation & activation of cerebral neurons.
Selective agonist – α-methyl-5-HT
Selective antagonist – Ketanserin
• 5-HT 2B – Localized in stomach fundus
Selective agonist- α-methyl-5-HT
Selective antagonist – SB204741
22. • 5- HT 2C – Localized in choroid plexus, hippocampus, substantia
niagra. It elicits vasodilatation through EDRF release.
Selective agonist- α-methyl-5-HT
Selective antagonist – Mesulergine
• 5- HT 3 receptor- It is a Na+ - K+ ion channel
Localized in area postrema, sensory & enteric nerves
Mediates indirect & reflex effects of 5-HT at :
a) Somatic & autonomic nerve endings- pain, itch ,coronary
chemoreflex (bradycardia, ↓BP due to withdrawal of sympathetic
tone, respiratory stimulation or apnea elicited by stimulation of
receptors in coronary bed).
b) Nerve endings in myenteric plexus- ↑ peristalsis, emetic reflex
c) Area postrema & NTS in brain stem- nausea, vomiting
23. Selective agonist – 2-methyl-5-HT,
Selective antagonist – Granisetron, Ondansetron ,Tropisetron
• 5- HT 4 receptor-
It is a G protein coupled receptor acts by ↑ cAMP
Localized in hippocampus & colliculi (↓ K conductance), smooth
muscle of gut (↑ intestinal secretion & peristalsis)
Selective agonist- 5-methoxytryptamine, Renzapride
• 5-HT 5 receptor
It is a G protein coupled receptor acts by ↓ cAMP
Localized in hippocampus
It is of 2 types-5-HT 5A & 5-HT 5B
24. • 5-HT 6 receptor
It is a G protein coupled receptor acts by ↑ cAMP
Localized in striatum
• 5-HT 7 receptor
It is a G protein coupled receptor acts by ↑ cAMP
Localized in hypothalamus, intestine.
25. ACTIONS
1. CVS- Arteries are constricted (by action on smooth muscle) &
dilated (through EDRF release) by direct action of 5-HT
depending on vascular bed & basal tone.
It releases Adr from adrenal medulla
In microcirculation, it dilates arterioles & constricts venules
capillary pressure ↑ & fluid escapes
In intact animals, bradycardia seen due to activation of coronary
chemoreflex (Bezold Jarisch refex) through action on vagal
afferent nerve endings in coronary bed evoking bradycardia,
hypotension & apnoea.
26. BP – triphasic response is classically seen on iv injection
Early sharp fall in BP-due to coronary chemo reflex
Brief rise in BP- due to vasoconstriction & ↑ CO
Prolonged fall in BP- due to arteriolar vasodilatation &
extravasation of fluid.
2.Smooth Muscle-
GIT- ↑ peristalsis & diarrhoea (also due to ↑ secretion)
Bronchi- It constricts bronchi but is less potent than histamine.
27. 3. Glands – It inhibits gastric secretion (acid & pepsin) but ↑
mucus production ulcer protective property
4.Nerve endings & Adrenal medulla- Activation of afferent nerve
endings- tingling & pricking sensation, pain
5.Respiration- Brief stimulation of respiration & hyperventilation.
Large doses can cause transient apnea (coronary chemoreflex).
6.Platelets- It causes changes in shape of platelets & is a weak
aggregator (5-HT 2A receptor)
7.CNS-Direct injection in brain causes sleepiness, change in body
temperature, hunger & behavioural effects.
28. PATHOPHYSIOLOGICAL ROLES
1. Neurotransmitter- It is a neurotransmitter in brain & is
involved in sleep, temperature regulation, thought, cognitive
function, behaviour & mood(imbalance causes affective
disorders & schizophrenia), vomiting & pain perception
2. Precursor of melatonin in pineal gland- regulates biological
clock & maintain circadian rhythm.
3. Neuro-endocrine function- Hypothalamic neurons that control
release of anterior pituitary hormones are probably regulated
by serotonergic mechanism.
29.
30. 4.Nausea & vomiting- especially evoked by cytotoxic drugs or
radiotherapy is mediated by release of 5-HT (5-HT 3 receptors
in gut ,area postrema & NTS)
5.Migraine – It initiates vasoconstrictor phase of migraine &
participates in neurogenic inflammation of cranial blood vessels.
6.Haemostasis – It causes platelet aggregation & clot formation at
site of injury to blood vessel & also promotes retraction of
injured vessel.
7.Raynaud’s phenomenon- 5-HT release from platelets may trigger
acute vasospastic episodes of larger arteries. Ketanserin (5-HT 2
antagonist) is used as a prophylactic.
31. 8. Hypertension - ↑ responsiveness to 5-HT & ↓ uptake &
clearance by platelets seen in hypertensives. Ketanserin has
anti-hypertensive property
9.Intestinal motility- Enterochromaffin cells & 5-HT containing
neurons regulate peristalsis & local reflexes in gut(activated by
intestinal distension).
10.Carcinoid tumours-They produce massive amounts of 5-HT.
Bowel hypermotility & bronchoconstriction in carcinoid is due
to 5-HT.
Pellagra may occur due to diversion of tryptophan for
synthesizing 5-HT.
32. DRUGS AFFECTING 5-HT SYSTEM
1. 5-HT Precursor- Tryptophan increases brain 5-HT
& produces behavioural effects.
2. Synthesis lnhibitor- p-Chlorophenylalanine (PCPA)
selectively inhibits tryptophan hydroxylase (rate limiting
step) & ↓5-HT level in tissues. It is not used clinically due to
high toxicity.
3. Uptake Inhibitor – TCAs inhibit 5-HT & NA uptake. Fluoxetine &
Sertraline are selective serotonin reuptake inhibitors(SSRI).
33.
34. 4.Storage Inhibitor –Reserpine blocks 5-HT (as well as NA) uptake
in storage granules & cause depletion. Fenfluramine selectively
releases 5-HT & has anorectic property.
5. Degradation Inhibitor – Nonselective MAO inhibitor
(Tranylcypromine) & Selective MAO inhibitor (Clorgyline)
↑ 5-HT content by inhibiting degradation.
6. Neuronal Degeneration- 5,6 dihydroxytryptamine selectively
destroys 5-HT neurons.
35.
36. 5-HT AGONISTS
1. D-Lysergic acid diethyl amide (LSD)- It is a potent hallucinogen.
It activates 5-HT 1A on raphe cell bodies, 5-HT 2A/2C
(responsible for hallucinogenic effect) & 5-HT 5-7 in brain.
2. Azapirones – They include Buspirone, Gepirone & Ipsapirone.
It is a new class of anti-anxiety drugs which do not cause
sedation. They act as partial agonist of 5-HT 1A receptors in
brain.
3. 8-Hydroxydipropylamino tetraline (8-OH DPAT) – It is a highly
selective 5- HT 1A agonist used as an experimental tool.
37. 4. Triptans like Sumatriptan, Zolmitriptan,Naratriptan,Rizatriptan-
selective 5-HT 1B/1D agonist, constrict cerebral blood vessels &
is the most effective treatment of migraine attacks.
5.Cisapride,Mosapride -5-HT 4 agonist. It increases GI motility & is
used in GERD, irritable bowel syndrome.
Renzapride & Prucalopride is also 5- HT 4 agonist.
38. 5-HT ANTAGONISTS
1. Cyproheptadine – It blocks 5-HT 2A receptors & also has H1
anti-histaminic, anticholinergic & sedative properties.
It is used to ↑ appetite in children & poor eaters to promote
weight gain.
Used to control intestinal manifestations of carcinoid & post-
gastrectomy dumping syndromes.
Also in antagonizing priapism/orgasmic delay caused by 5-HT
uptake inhibitors (Fluoxetine & Trazadone).
Used in allergic conditions.
Side effects- drowsiness, dry mouth, confusion, ataxia, weight
gain.
39. 2.Methysergide – It antagonizes actions of 5-HT on smooth
muscles including that of blood vessels.
Potent 5-HT 2A/2C antagonist
Used in migraine prophylaxis, carcinoid & post-gastrectomy
dumping syndromes.
Side effects- abdominal, pulmonary & endocardial fibrosis on
prolonged use.
3. Ketanserin- It is selective 5-HT 2 antagonist (5-HT 2A> 5-HT2C).
It blocks 5-HT induced vasoconstriction, platelet aggregation &
contraction of airway smooth muscle.
It also has α1, H1 & dopaminergic blocking activity.
It is used as an effective anti-hypertensive (α1 blockade)
Ritanserin is a more selective 5-HT 2A congener of Ketanserin.
40. 4. Clozapine - It is an atypical antipsychotic which blocks
dopamine & 5-HT 2A/2C receptors. It is also an inverse agonist
at cerebral 5-HT 2A/2C receptors so used in resistant
schizophrenia.
5. Risperidone – This atypical antipsychotic is 5-HT 2A & D2
antagonist like Clozapine.
It is used in schizophrenia.
6. Ondansetron – It is selective 5-HT 3 antagonist.
It is used in controlling nausea & vomiting due to anticancer
drugs & radiotherapy.
Granisetron & Tropisetron are other selective 5-HT 3
antagonists.
41. CLINICAL PHARMACOLOGY OF 5-HT
• Serotonin has no clinical application as a drug.
• However, its receptor agonism & antagonism has many
clinical implications.
• Serotonin is closely related with behaviour, mood & is
therefore important in many neuropsychiatric diseases and
their symptomatology.
• It also has a role in many other clinical conditions.
46. What is Migraine?
• A debilitating neurobiological headache disorder
• Affects 18% of women & 6% of men
• Decreases with age
• Two categories
– 80% = common migraine
– 20% = classic migraine (w/ aura)
47. MIGRAINE
• It is a disorder characterized by pulsating headache, usually
restricted to one side, which comes in attacks lasting 4-48 hrs &
is often associated with nausea, vomiting, sensitivity to light &
sound, flashes of light, vertigo, loose motions & other
symptoms.
• It is of 2 types
a) Migraine with aura (classical migraine) – headache is
preceded by visual or neurological symptoms.
b) Migraine without aura (common migraine)
• 5-HT appears to play a pivotal role in this disorder.
48. Causes of Migraine
• Increased excitability of CNS
• Meningeal blood vessel dilation
• Activation of perivascular sensory trigeminal nerves
• Pain impulses
• Vasoactive neuropeptides contain:
– substance P
– calcitonin gene-related peptide (CGRP)
– neurokinin A
• combination of increased pain sensitivity, tissue and vessel swelling,
and inflammation
49. MIGRAINE - PATHOPHYSIOLOGY
VASCULAR THEORY
• Intracerebral blood vessel vasoconstriction – aura
• Intracranial/Extra cranial blood vessel vasodilatation – headache
SEROTONIN THEORY
• Decreased serotonin levels linked to migraine
• Specific serotonin receptors found in blood vessels of brain
• Neurovascular process, in which neural events result in
activation of blood vessels, which in turn results in pain and
further nerve activation
52. History of Treatment
• Herbal brews and folk practices
• 1200 BC: Egyptians – clay crocodile & magic herbs
• 10th century AD: Arabian physicians – garlic or hot iron to
incision at temple
• Mid-1600’s AD: Dr. Thomas Willis – enemas, blood letting,
leeches, and natural products
• 1870’s: cold bandage on head, quiet room, and sleep
53. DRUG THERAPY OF MIGRAINE
1. Mild Migraine – Cases having <1 attack/month of throbbing
but tolerable headache lasting upto 8 hrs which does not
incapacitate the individual. Drugs used include-
a. Analgesics - Paracetamol (0.5-1 gm) or aspirin (300-600mg) 4-
6 hourly.
b. NSAIDs – Drugs like Ibuprofen (400-800 mg 8 hourly) ,
Naproxen (500mg followed by 250mg 8 hourly) , Diclofenac
(50mg 8 hourly), Mephenamic acid (500mg 8 hourly) either
alone or combined with Paracetamol/ Codeine/ Diazepam/
Diphenhydramine / Caffeine.
c. Antiemetics – Metoclopramide (10mg oral/im) is commonly
used. Domperidone (10-20mg oral) & Prochlorperazine (10-25
mg oral/im) are also effective.
54. 2. Moderate Migraine – It is when throbbing headache is more
intense, lasts for 6-24 hours, nausea/vomiting & other features
are prominent & patient is functionally impaired. 1 or more
attacks /month occur. Treatment includes-
a) NSAIDs or their combinations
b) Ergot alkaloids – Ergotamine (1mg oral at half hr interval till
relief is obtained or a total of 6mg is given). Caffeine 100mg is
taken with ergotamine.
c) Sumatriptan – 50-100mg oral at onset of migraine, repeated
once within 24 hrs if required. It is the only triptan available for
parenteral use. Dose – 6mg sc
Rizatriptan is more potent, has higher bioavailability with fast
onset of action. Dose – 10mg, repeat once after 2 hr if
required.
d) Antiemetics
55. 3. Severe Migraine – Patients suffer 2-3 or more attacks/month of
severe throbbing headache lasts 12-48 hours, accompanied by
vertigo, vomiting & other symptoms, the patient is grossly
incapacitated during attack. Treatment includes-
a) Ergot alkaloids
b) Sumatriptan
c) Antiemetics
Prophylactic regime lasting 6 months is recommended.
56. PROPHYLAXIS OF MIGRAINE
1. β adrenergic blockers – Propranolol 40mg BD, may be
increased upto 160mg BD
2. TCAs – Amitriptylline 25-50mg HS. It is better suited for
patients who also suffer from depression.
3. Calcium channel blockers – Verapamil is useful. Flunarizine 10-
20 mg OD is more effective.
4. Anticonvulsants – Valproic acid 400-1200mg/day &
Gabapentin 300-1200 mg/day. Topiramate 25 mg OD is also
useful.
5. 5-HT antagonists – Methysergide & Cyproheptadine may be
helpful but seldom used now.
57. RECENT ADVANCES
• Tandospirone – Also known as Metanopirone. It is a 5-HT
1A partial agonist. It is used in China & Japan as an
anxiolytic & antidepressant. Dose – 30mg/day.
• Agomelatine – 5-HT 2C antagonist & agonist at melatonin
receptor. Used in depression.
• Nelotanserin (APD-125) – selective 5-HT 2A inverse agonist
developed by Arena pharmaceuticals for treatment of
insomnia.
• Palonosetron (Aloxi) – approved by FDA in 2003 for iv use
in preventing delayed chemotherapy induced nausea &
vomiting. Oral formulation approved in 2008 for acute
chemotherapy induced nausea & vomiting.
58. CONTD…
• Ramosetron – 5-HT 3 antagonist available in Japan & South
east Asian countries used in chemotherapy induced nausea
& vomiting.
• Cilansetron – 5-HT 3 antagonist used in Irritable Bowel
Syndrome (IBS) where diarrhoea is the dominant symptom.
