5HT IN DETAIL

1. Dr Ankita Jire
JR
Dept of pharmacology
GMC Nagpur
12/24/2016 1Serotonin receptors: Agonists & antagonists

2.  Introduction
 Sources & Chemistry
 Synthesis
 Serotonin receptors
 Pharmacological actions of serotonin
 Pathophysiological roles
 Serotonin receptors:Agonists
 Serotonin receptors:Antagonists
 Summary
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3. Serotonin or 5-Hydroxytryptamine (5-HT)
 Biogenic monoamine
 Identified as neurotransmitter in central nervous
system (CNS) & also have prominent peripheral
actions
 Serotonin is found in
GIT
Platelets
CNS
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4.  Present in vertebrates, tunicates, molluscs,
arthropods, coelenterates, fruits & nuts
 Component of venoms of common stinging
nettle, wasps & scorpions.
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5.  5-HT [3-(β-aminoethyl)-5-hydroxyindole]
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7.  Hydroxylation at C5 by tryptophan hydroxylase-1
is rate-limiting step
 5-Hydroxyindole Acetic Acid(5-HIAA) formation
accounts for nearly 100% of metabolism of 5-HT in
brain
 5-Hydroxyindole Acetic Acid (5-HIAA) from brain
& peripheral sites of 5-HT storage & metabolism is
excreted in urine
 Larger amounts are excreted by patients with
malignant carcinoid
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8.  In 1957, Gaddum and Picarelli
 M receptors -located on parasympathetic nerve
endings, controlling release of acetylcholine
 D receptors -located on smooth muscle
5-HT receptor
M receptors
D receptos
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9.  The current classification scheme (Hoyer et al.,
1994) includes seven subfamilies of 5-HT
receptors
5HT receptors
5-HT1
5-HT1A
5-HT1B
5-HT1D
5-HT2
5-HT2A
5-HT2B
5-HT2C5-HT3
5-HT4
5-HT5
5-HT6
5-HT712/24/2016 9Serotonin receptors: Agonists & antagonists

10. 12/24/2016 10Serotonin receptors: Agonists & antagonists

11.  Five members
 Preferentially couple to G protein & inhibit
adenylyl cyclase
 5-HT1A, 5-HT1B & 5-HT1D receptor subtypes
activate K+ & inhibit Ca2+ channels
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13. Receptor 5-HT1A 5-HT1D/1B
Location Raphe nuclei of the
brainstem
Substantia nigra & basal
ganglia
Function Neuronal inhibition
Behavioural effects:
sleep, feeding, thermo-
regulation, anxiety
Contraction
CSF production
Neuronal excitation
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14.  3 subtypes
 Couple to G protein→activate phospholipase C
function through Inositol triphosphate /
Diacylglycerol
 5-HT2A inhibits K+ channels
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15. Receptor 5HT2A 5HT2B 5HT2C
Location Vascular & visceral
smooth muscles,
platelets,prefrontal
cortex
Gastric
fundus
Choroid
plexus,
hypothalamus
Function Neuronal excitation,
Smooth muscle
contraction,
Platelet aggregation,
Vasoconstriction
Contraction CSF
production,
feeding
behaviour &
mood
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16.  Ionotropic receptor, belonging to nicotinic-
acetylcholine superfamily of receptors
Location -Parasympathetic
terminals in GI tract,
including vagal &
splanchnic afferents
-CNS
Solitary tract nucleus
& in area postrema
Function Emesis
Neuronal excitation
Behavioural effects:
anxiety
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17.  Couple to G proteins activate adenylyl
cyclase increase in intracellular cyclic AMP
Location -GIT
neurons of myenteric plexus & on smooth muscle
& secretory cells
-CNS
superior & inferior colliculi
Hippocampus
Function Evoke intestinal secretion & peristaltic reflex
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18.  Closely related to 5-HT4 receptor
 Mainly located in specific brain areas but
their functional role is not known
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20. 1.CARDIOVASCULAR SYSTEM
A) Blood Pressure
i.Early sharp fall-due to coronary
chemoreflex (Bezold Jarisch Reflex)
ii.Brief rise - due to vasoconstriction &
increased cardiac output
iii. Prolonged Fall-due to dilatation of blood
vessels
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21. FALL
FALL
RISE
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22. B) Effects on Blood vessels and Hemostasis
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23. C) Heart:
+ve Inotropic, +ve Chronotropic
2. Visceral smooth muscle
GIT- ↑ peristalsis &↑ secretion
Bronchi- Bronchoconstriction
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24. 3. Glands
Inhibits gastric secretion (acid & pepsin) but ↑
mucus production ulcer protective property
4.Nerve endings
Activation of afferent nerve endings- tingling &
pricking sensation, pain
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25. 5.Respiration
Brief stimulation of respiration & hyperventilation
Large doses can cause transient apnea (coronary
chemoreflex)
6.Platelets (5-HT 2A receptor)
Causes changes in shape of platelets & is a weak
aggregator
7.CNS
Direct injection in brain causes sleepiness, change
in body temperature, hunger & behavioural
effects
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26.  Neurotransmitter
Involved in sleep, temperature regulation, thought,
cognitive function, behaviour, mood, appetite, vomiting &
pain perception
 Precursor of melatonin in pineal gland
Regulates biological clock & maintain circadian rhythm
 Neuro-endocrine function
Regulate hypothalamic neurons that control release of
anterior pituitary hormones
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27.  Nausea & vomiting
Evoked by cytotoxic drugs/radiotherapy is mediated by
release of 5-HT
 Migraine
Initiates vasoconstrictor phase of migraine & participates
in neurogenic inflammation of cranial blood vessels
 Haemostasis
Causes platelet aggregation & clot formation at site of
injury to blood vessel & also promotes retraction of
injured vessel
 Raynaud’s phenomenon
5-HT release from platelets may trigger acute
vasospastic episodes of larger arteries
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28.  Hypertension
↑ responsiveness to 5-HT & ↓ uptake & clearance by
platelets seen in hypertensives
 Intestinal motility
Enterochromaffin cells & 5-HT containing neurons
regulate peristalsis & local reflexes in gut (activated
by intestinal distension)
 Carcinoid tumours
Produce massive amounts of 5-HT leading to bowel
hypermotility & bronchoconstriction
-Pellagra due to diversion of tryptophan for
synthesizing 5-HT
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30. 1.Triptans
 Indole derivatives
 Selective 5-HT1D/1B agonists
Ex.Sumatriptan, Eletriptan, Frovatriptan ,Naratriptan,
Zolmitriptan, Rizatriptan, Almotriptan
 Mechanism of action
-5-HT1D/1B receptor mediated constriction of dilated
cranial blood vessels, especially arterio-venous shunts in
carotid artery
-Dilatation of these shunt vessels during migraine
attack is believed to divert blood flow away from
brain parenchyma
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31.  Indication
Treatment of acute attacks of moderate to severe
migraine not responding to analgesics
Sumatript
an
Frovatript
an
Rizatripta
n
Naratripta
n
Zolmitript
an
Oral
bioavail-
Ability(%)
15 25 45 70 40
T
max(Hours)
1.5-2 2-4 1-1.5 2-3 1.5-2
T ½(Hours) 2 26 2-3 6 2-3
Oral
dose(mg)
50-100 2.5 5-10 2.5 2.5
Max dose
(mg/day)
200 7.5 30 5 10
Comparative features of triptans
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32. Side effects
 Tightness in head & chest, paresthesias in limbs,
dizziness, weakness
 Bradycardia, coronary vasospasm & risk of
myocardial infarction
Contraindications
Ischaemic heart disease,
hypertension, epilepsy
Sumatriptan & Ergotamine should not be administered
within 24 hours of each other12/24/2016 32Serotonin receptors: Agonists & antagonists

33.  Donitriptan
Fewer side effects than sumatriptan but same
cardiovascular side effects
Trexima (oral tablet)
• Combination of sumatriptan succinate & naproxen
sodium
• FDA approval-T/t of acute migrain
• Designed to provide faster relief & lesser relapse
rate
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34. 2. selective 5-HT4 agonist
 Prokinetic drugs- increases gastrointestinal motility
Ex.Metoclopramide,Cisapride,Mosapride,Renzapride,
Prucalopride
5-HT4 receptor activation on primary afferent neurones
(PAN) of ENS via excitatory interneurones
Enhance ACh release from myenteric motor neurones
 Indication
-Gastroesophageal reflux disease
-Gastroparesis
-Refractory severe chronic constipation
Side effect
Blocks delayed rectifying K+ channels in heart—prolongs Q-
Tc interval & predisposes to torsades de pointes/ventricular
fibrillation
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35. 3. Azapirones
 Selective partial agonists of 5-HT1A receptors in
brain
Ex.Buspirone, gepirone & ipsapirone
 Reduces activity of dorsal raphe serotonergic
neurons
 Mimics antianxiety properties of benzodiazepines
but does not interact with GABAA receptors
 Indication
Anxiety disorders
Side effects
-Dizziness, nausea,headache, light-headedness
-Rise in BP in patients on MAO inhibitors
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36. 4. Lysergic acid
diethyl amide
(LSD)
5. 8-Hydroxy(2
N,N-
Dipropylamino)-
Tetraline
(8-OH-DPAT)
6. Lorcaserin
Receptors Nonselective 5-HT
agonist 5-HT1A,
5-HT2A/2C, 5-HT5-7
5-HT1A selective
receptor agonist
Selective 5-
HT2C agonist
Action Potent hallucinogen Anti-depressant,
anti-anxiety
Anti-Obesity
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38. 1. Selective 5-HT3 antagonists
 Ex-Ondansetron, Granisetron, Ramosetron &
Palonosetron,Alosetron
 Blocks depolarizing action of 5-HT exerted through
5-HT3 receptors on vagal afferents in g.i.t. as well
as in Nucleus Tractus Solitarius & Chemoreceptor
Trigger Zone
 Indication
-Nausea & vomiting following administration of highly
emetic anticancer drugs & radiotherapy
-Postoperative nausea
-Hyperemesis of pregnancy
-Irritable bowel syndrome
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39. Drug Chemical
nature
Receptor
interactions
T1/2 (hour) Dose (iv)
Ondansetron Carbazole
derivative
5-HT3
antagonist
3.9 0.15 mg/kg
Granisetron Indazole 5-HT3
antagonist
9-11.6 10 μg/kg
Dolasetron Indole
moiety
5-HT3
antagonist
7-9 1.8 mg/kg
Palonosetron Isoquinoline 5-HT3
antagonist:
highest
affinity
40 0.25 mg
Side effects
-Constipation or diarrhea, headache & lightheadedness
-Hypotension, bradycardia, chest pain, allergic reactions
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40. 2. 5-HT2 receptor antagonists
Ex. Trazodone & nefazodone
 Primary metabolite m-chlorphenylpiperazine (m-cpp) is
potent 5-HT2 antagonist
-α Adrenergic antagonist
 Indication
Major depression, Anxiety
 Side effects
Hepatotoxicity,sedation,postural hypotension,priapism
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41. 3.Cyproheptadine
 Primarily blocks 5-HT2A receptors
 Additional H1 antihistaminic, anticholinergic &
sedative properties
 Indication
-Intestinal manifestations of carcinoid &
postgastrectomy dumping syndromes
-migraine prophylaxis
Side effects
Drowsiness, dry mouth, confusion, ataxia, weight gain
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42. 4. Methysergide
 Congener of methylergonovine
 Potent 5-HT2A/2C antagonist
 Acts on 5-HT1 receptors also
 Indication
Migraine prophylaxis, carcinoid & postgastrectomy
dumping syndrome
Side effects
Abdominal, pulmonary & endocardial fibrosis
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43. 5.Ketanserin
 Selective 5-HT2 receptor antagonist
(5HT2A>5HT2C)
Ritanserin (more 5HT2A agonist)
 Additional weak α1, H1 & dopaminergic blocking
activities
 Antagonize 5-HT induced vasoconstriction, platelet
aggregation & contraction of airway smooth muscle
 Indication
Raynaud’s disease
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44. 6. Clozapine
 Inverse agonist at cerebral 5-HT2A/2C receptors
 Indication
Resistant cases of schizophrenia
7. Risperidone,Olanzapine & Quetiapine
 Combined 5-HT2A + dopamine D2 antagonist
 Indication
Schizophrenia
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45. 1.Synthesis inhibitor
P-Chlorophenylalanine (PCPA) selectively inhibits
tryptophan hydroxylase & reduces 5-HT level in
tissues
2. Uptake inhibitor
a)Selective serotonin reuptake inhibitors (SSRI)
b) Serotonin and noradrenaline reuptake inhibitors
(SNRIs)
c)Tricyclic antidepressants
Inhibit monoamine reuptake & interact with
muscarinic, α adrenergic, H1, 5-HT1, 5-HT2 receptors12/24/2016 45Serotonin receptors: Agonists & antagonists

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47. Drug Bioavail
ability
(%)
Plasma
T1/2
(Hours)
Active
metabolite
T1/2
(Hours)
Vd
(L/Kg)
Protein
binding(%)
Citalopram 80 33-38 - 15 80
Escitalopram 80 27-32 - 12-15 80
Fluoxetin 70 48-72 180 12-97 95
Fluvoxamine 90 14-18 14-16 25 80
Paroxetin 50 20-23 - 28-31 94
Sertraline 45 22-27 62-104 20 98
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48.  Indication
Depression, Obsessive- compulsive disorders, panic
disorder, premenstrual dysphoric disorder ,
posttaumatic stress disorder, Generalized anxiety
disorder,
 Side Effects
Insomnia, increased anxiety, irritability &
decreased libido,diarrhoea
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49.  Monoamine Oxidase Inhibitors(MAOI) enhance
effects of SSRIs due to inhibition of serotonin
metabolism
 Synergistic ↑in extracellular brain serotonin
serotonin syndrome
 Symptoms
Hyperthermia, muscle rigidity, myoclonus, tremors,
autonomic instability, confusion & irritability
coma & death
 Treatment
Stop all serotonergic drugs
Nonselective serotonin antagonists12/24/2016 49Serotonin receptors: Agonists & antagonists

50.  Inhibits uptake of both NA & 5-HT
 Ex. Venlafaxine, Duloxetine
 Indication
Depression, anxiety
 Side effects
Nausea, sweating, anxiety, dizziness, impotence
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51. 3.Storage inhibitor
 Reserpine
Blocks 5-HT & NA uptake into storage vesicles by
inhibiting VMAT-2 depletion of all monoamines
 Indication
Hypertension
Side effects
Sedation, mental depression,suicidal tendency,
extrapyramidal symptoms
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52. 4.Degradation inhibitor
Nonselective Monoamine Oxidase Inhibitors
(tranylcypromine) & Selective MAO-A inhibitor
(chlorgyline) ↑5-HT content by preventing its
degradation
5. Neuronal degeneration
5, 6 dihydroxytryptamine selectively destroys 5-HT
neurones
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53. 6. Noradrenergic & specific serotonergic antidepressant
(NaSSA) Mirtazapine
 Blocks α2 auto-receptors (on NA neurones) & hetero-receptors (on
5-HT neurones) enhancing both NA & 5-HT release
 Augmented NA further increases firing of serotonergic raphe
neurones via α1 receptors
 Selective enhancement of antidepressive 5-HT1 receptor action is
achieved by concurrent blockade of 5-HT2 & 5-HT3 receptors which
are responsible for some adverse effects of high serotonergic tone
 Indication
Mild & severe depression with insomniaSide effects
Increased appetite & weight gain
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55. Recept
or
Location Main function Signalling
system
Significant drugs
Agonists Antagonists
5-HT1A CNS(Raphe
nuclei of
brain stem)
Neuronal
inhibition
Behavioural
effects: sleep,
feeding, thermo-
regulation,
anxiety
G protein
(Gi/Go)
↓ cAMP (may
modulate
Ca2+
channels)
Buspirone
(partial
agonist)
Ergotamine
5-HT1B CNS
(Subiculum)
vascular
smooth
muscle
Presynaptic
inhibition
Behavioural
effects
Pulmonary
vasoconstriction
Triptans
5-HT1D CNS(Cranial
blood
vessels)
Cerebral
vasoconstriction
Triptans Ergotamine
(PA)
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56. Receptor Location Main function Signalling
system
Significant drugs
Agonists Antagonists
5-HT2A CNS, PNS,
smooth
muscle,
platelets
Neuronal excitation
Behavioural effects
Smooth muscle
contraction (gut,
bronchi, etc.)
Platelet
aggregation,
Vasoconstriction/va
sodilatation
G protein
(Gq/G11)
↑ IP3,
Ca2+
LSD,α
methyl
5HT
Ketanserin
Ritanserin
Cyproheptadine
Methysergide
5-HT2B Gastric
fundus
Contraction LSD,α
methyl
5HT
5-HT2C CNS
(Choroid
plexus,hypo
thalamus)
CSF production
Neuronal excitation
LSD,α
methyl
5HT
Methysergide
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57. Receptor Location Main function Signalling
system
Significant drugs
Agonists Antagonists
5-HT3 PNS, CNS Neuronal excitation
Emesis
Behavioural effects:
anxiety
Ligand-
gated
cation
channel
2-methyl
5HT
Dolesatron
Granisetron
Ondansetron
Palonosetron
Tropisetron
5-HT4 (GI tract),
CNS
Neuronal excitation
GI motility
G protein
↑cAMP
Metoclo-
Pramide,
cisapride
GR-113808
5-HT5 CNS Modulation of
exploratory
behaviour
As above - -
5-HT6 CNS,
leukocytes
Learning & memory? As above - -
5-HT7 CNS, GI
tract, blood
vessels
Thermoregulation?
Circadian rhythm?
As above - -
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58.  The pharmacological basis of therapeutics - Goodman and
gilman (12th edition)
 Basic And Clinical Pharmacology(Katzung)12th edition
 General pharmacology-Basic concepts(HL Sharma & KK
Sharma)2nd edition
 Subtypes of receptors for serotonin:Annual review of
pharmacology & toxicology 1990
 Neurotransmitters
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