Serotonin.dr.asa

Dr. AMREEN SABA ATTARIYA
POST GRADUATE STUDENT
DEPT OF PHARMACOLOGY
M.R. MEDICAL COLLEGE, GULBARGA
INDIA
SEROTONIN

Outline Of Presentation
Introduction to SEROTONIN
Sources, Biosynthesis, Metabolism
Receptors in detail
Physiological & Pathophysiological roles
Drugs Acting On 5HT Receptors
Recent Advances
Summary & References
Mar 6, 2017Dr.ASA:serotonin

HISTORY
SEROTONIN -name given to vasoconstrictor substance which
appeared in serum when blood clot
Named after Latin word serumserum & Greek word tonictonic
1948– first isolation Maurice Rapport & Irvine Page*
Earlier called ENTERAMINE by VITTORIO ERSPAMER et al
Enteramine found in EC cells
In 1950 --both were shown to be 5-hydroxytryptamine
* Rapport et al

Physiologic Distribution of 5HT
10% CNS
90% GI tract
 90% ECs
 10% Neurons 5-Hydroxytryptamine

SOURCE
Venom of Wasps, Bees, scorpions
Widely distributed in invertebrates
Fruits--banana, pear, pineapple, tomato, plums, nuts

SEROTONIN is:
Neurotransmitter in CNS
Local hormone in the gut
Component of the platelet clotting process
Potent stimulant of pain and itch nerves
Central (CNS) modulator of:
Migraine
Vomiting
Mood, sleep, appetite, temperature, blood pressure

Biosynthesis and metabolism of
SEROTONIN

Serotonin Uptake
Like NA actively takes up serotonin by Serotonin
transporter - amine pump (SERT) – Na+
dependent carrier
Inhibited by SSRIs & TCAs
Stored in storage vesicles by active uptake –
Vesicular monoamine transporter (VMAT 2) –
inhibited by Reserpine

SEROTONIN TRANSPORTER[SERT]
Member of class of monoamine transporters.
Has 12 transmembrane spanning Na+-dependent
transporters
Mechanism is the transportation of Na+, Cl &
substrate intracellularly in exchange for K+ *
Location: GIT, pulmonary, peripheral
vasculature, platelets
Mar 6, 2017Dr.ASA:serotonin* Sneddon, 1973; Torres et al., 2003; Ni & Watts, 2006.

5HT REC SUBTYPES
Earlier[GADDUM &PICARELLI]
Mtype= MUSCULOTROPIC
Dtype=NEUROTROPIC
M type@ cholinergic nerve
endingscontrol release of Ach
D type @ smooth muscles
NEWER [1 to 7]
1– 1A 1B 1D
2-- 2A 2B 2C
3, 4, 5, 6, 7 Mar 6, 2017Dr.ASA:serotonin

5-HT Rec - Characters
All are GPCRs except 5-HT3
Decrease cAMP production – 5-HT1
Increase cAMP production – 5-HT4, 5-HT6, 5-HT7
Generating IP3/DAG – 5-HT2
5-HT3 – Ligand gated Na+
K+
channel – faster depolarization

5HT REC SUBTYPES

PHYSIOLOGICAL ROLE
OF 5HT

PHYSIOLOGICAL ROLE
PLATELETS
Lack Tryptophan hydroxylase cant synthesize 5HT
Take up from circulation & store
VMAT-2 mediated uptake into dense core granules
Vascular injury release 5HT 5HT binds on 2A rec on
platelets weak Platelet aggregation, augmented by Collagen
If injury reaches till smooth muscle direct release of 5HT V/s
occlusion & VC Hempostasis
5HT interaction with Endothelium release NO VD
[antgonising its own plus other local hormone action]

LOCAL INFLUENCES OF
PLATELET 5HT

PHYSIOLOGICAL ROLE
CVS
+VE IONOTROPIC, +VE CHRONOTROPIC
Contraction--splanchnic, renal, pulmonary & cerebral vasculatures
Also cause release of NO & PGs + block the release of NE from
sympatheitic nerves arterial relaxation
Other hand, amplifies the local constrictor actions of NE, AngII,
and histaminereinforce the hemostatic response to 5-HT

PHYSIOLOGICAL ROLE
CVS
Effect on BP
BEZOLD
JARISCH REFLEX
Early sharp fall
----chemoreflex.
Brief rise----
vasoconstriction
and increased CO
Prolonged fall
----arterial dilatation
& extravasation of
fluid. Mar 6, 2017Dr.ASA:serotonin

PHYSIOLOGICAL ROLE
GIT
5HT-local hormone in GITinitiation & susutainance of
intestinal peristalsis
Potent stimulator of GIT Diarrhoea
Inhibit gastric acid & pepsin, increases mucus production
ULCEROPROTECTIVE PROPERTY
Stimulates vomiting (5-HT3rec on vagal afferents &
centrally) on 5-HTrec
(Physiologically regulates GI motility and peristalsis)

5HT in GIT
Abnormally increased 5-HT is found in a range of
gastrointestinal disorders including Chemotherapy-
induced Nausea & Vomiting, Carcinoid Syndrome,
Coeliac Disease, IBD & IBS-D
IBS-D- Impaired SERTincrease in mucosal 5-HT
availability.
IBS-D -- increased 5-HT postprandially

5-HT3 rec antagonists inhibit chemotherapy-induced
nausea & diarrhoea associated with both carcinoid
syndrome & IBS.
IBS-C---impaired 5-HT response &responds to 5HT-4
agonists-PRUCALOPRIDE & 5HT-4 partial agonists-
TEGASEROD.
*Spiller R Recent advances in understanding the role of 5HT in GI motility in
functional bowel disorders: alterations in 5-HT signalling & metabolism in human
disease.Neurogastroenterol Motil. 2007 Aug;19 Suppl 2:25-31.

PHYSIOLOGICAL ROLE

PHYSIOLOGICAL ROLE
CNS
NEUROHUMORAL TRANSMISSION
5HT—released by tryptaminergic neurons
Function: Temp Regulation, Endocrine Control,
ExtraPyramidal Activity
Altered function disturbances in Sleep,
Appetite, Mood, Sexual Behaviour, Motor Activity,
Perception, Migraine

PHYSIOLOGICAL ROLE
CNS
SLEEP
5HT—control sleep-wake cycle
Depletion INSOMNIA

PHYSIOLOGICAL ROLE
CNS
BEHAVIOUR
5HT—control mood, emotion, reward, memory
Low CSF-5HIAA IMPULSIVE, VIOLENT,
SUICIDAL BEHAVIOUR
Rx= SSRI[for mental depression]
5HT rec function is altered in EATING disorders –
Anorexia Nervosa, Bulimia Nervosa

DRUGS ACTING ON 5-HT

DRUGS ACTING ON 5-HT SYSTEM
5-HT Precursor – Tryptophan in diet↑  5-HT↑
production
Inhibit synthesis: p-chlorophenylalanine (PCPA) -
irreversible
Inhibit neuronal re-uptake: Cocaine, SSRI, TCA
Inhibit storage-deplete (VMAT-2): Reserpine
Inhibit metabolism: MAO-A inhibitors
Promote release: Amphetamines

SSRIs
Fluoxetine, Fluvoxamine, Paroxetine, Sertraline,
Citalopram, Escitalopram
MOA:
Selectively block reuptake of 5HT
Increased extracellular 5HT
Increased action on postsynaptic receptors
Stimulation

 PK of SSRI:
Orally absorbed
Metabolism=liver
2D6 & 2C19
t1/2=18hrs-7d
SSRI(t1/2) DOSES
(mg/d)
Fluoxetine(2d) 10-60
Fluvoxamine(18hrs) 50-300
Paroxetine(20hrs) 10-40
Sertraline(26hrs) 50-200
Citalopram(33hrs) 10-40

AE-SSRIs
Pharmacological
Action
Adverse Effect
GIT Nausea, Vomiting, Diarrhea
Neuropsychiatry Agitation, Tremor, Insomnia
And Daytime Somnolence,
Seizures, Mania
Sexual Dysfunctions Ejaculatory Delay, Anorgasmia

SEROTONERGIC
DRUGS

SEROTONERGIC DRUGS
PARTIAL AGONIST- AZAPIRONES
AGONISTS
TRIPTANS
ERGOT & ERGOT ALKALOIDS
D-LYSERGIC ACID DIETHYLAMIDE(LSD)
ANTAGONISTS-- CYPROHEPTADINE
METHYSERGIDE
KETANSERIN
ATYPICAL ANTIPSYCHOTICS

PARTIAL AGONIST- AZAPIRONES
BUSPIRONE, GEPIRONE, IPSAPERONE
Selective partial agonists of 5HT-1A
Effective in the treatment of anxiety
Mimics antianxiety properties of BDZs but donot interact
with GABAA rec
Do not display sedative & anticonvulsant properties of
BDZs.

AGONISTS
TRIPTANS
D-LYSERGIC ACID DIETHYLAMIDE(LSD)
PROKINETICS- CISAPRIDE, MOSAPRIDE

TRIPTANS
Almotriptan, Eletriptan, Frovatriptan, Naratriptan,
Rizatriptan, Sumatriptan, Zolmitriptan
Agonist of 5-HT1D 5-HT1B
Low / no affinity for other subtypes of 5-HTrec or
for adrenergic, dopaminergic, muscarinic
cholinergic, GABAA receptors

TRIPTANS-MOA
MOA: 2 hypothesis of migraine pathophysiology
I: unknown events lead to abnormal dilation of carotid AV
anastomoses in headdiverting blood from capillary bedscerebral
ischemia & hypoxia.
Rx: Triptans constrict IC blood vessels, including AV anastomoses
& restores blood flow to brain
II: 5-HT1D & 5-HT1Bserve as presynaptic autoreceptorsmodulate
neurotransmitter release from neuronal terminals
5-HT1 agonists block the release
of proinflammatory neuropeptides

TRIPTANS-PK
SUMATRIPTAN(SC, ORAL, NASAL SPRAY)
SCpeak conc 12min,BA=97% ORAL 1-2hrs,BA14-17%
t1/2 = 1-2hrs, Metabolised by MAO-A, Excretion in urine
 ZOLMITRIPTAN(ORAL)
ORAL peak conc 1.5-2hrs, BA=40% t1/2 =2-3hrs
 NARATRIPTAN(ORAL)
ORAL peak conc 2-3hrs, BA =70% t1/2 =6hrs
 RIZATRIPTAN(ORAL)
ORAL peak conc 1-1.5hrs, BA=45%
Metabolised by MAO-A

TRIPTANS-AE
Cardiac events--coronary artery vasospasm, transient
MI,atrial & ventricular arrhythmias, MI
SC Sumatriptanirritation at the site of injection
(transient mild pain, stinging, or burning sensations).
Nasal spray Sumatriptan bitter taste.
Oralparesthesias, asthenia,fatigue,flushing, feelings of
pressure, tightness, or pain in chest,neck, & jaw;
drowsiness, dizziness, nausea, sweating.

TRIPTANS-C/I
H/o ischemic or vasospastic CAD (strokeTIA), cerebrovascular, PVD
hemiplegic or basilar migraines, other significant cardiovascular
diseases, or IBD
Uncontrolled HTN.
Naratriptan C/I-severe renal/hepatic impairment.
Rizatriptan--with caution in renal/hepatic disease but not C/I
Eletriptan C/I--hepatic disease.
Almotriptan,rizatriptan, sumatriptan, zolmitriptan are C/I in
patients who have taken MAO-I within the preceding 2 weeks
All triptans C/I--near-term prior exposure to ergot alkaloids or other
5-HT agonists Mar 6, 2017Dr.ASA:serotonin

TRIPTANS-Use in Migraine
In acute Rx of migraine (with/without aura), but not for
prophylaxis.
Begin as soon as possible after onset of a migraine attack
Oral – most convenient, but Nausea & Vomiting occurs.
SUMATRIPTAN SC=6mg(max 12mg/d), Nasal spray=5-20mg
Oral=25-100mg(max 200mg/d)
ZOLMITRIPTAN oral =1.25-2.5 mg(max10mg/d)
NARATRIPTAN oral=1-2.5 mg,should not be repeated until 4
hours after previous dose. Donot exceed 5mg/day
RIZATRIPTAN oral= 5-10 mg, max 30mg/d
Donot use concurrently with other tripans / ergot derivativesMar 6, 2017

Partial agonists/antagonists at adrenergic, dopaminergic & 5HT rec
Effects depends onagent, dosage,species, tissue, physiological &
endocrinological state, & experimental conditions.
Ergot derivative-METHYSERGIDE-2A>2C blocker—Rx of acute
migraine
Ergot for migraine should be restricted to patients having frequent,
moderate migraine / infrequent, severe migraine attacks
Ergotamine, Ergonovine, Methyl-ergonovine,
Dihydroergotamine(DHE)

ERGOTAMINE
Most effective ergot alkaloid in Migraine
MOA:
Partial agonist of 5-HT1B/1D – 1. Constriction of dilated
cranial vessels
Or, 2. by specific Constriction of carotid AV shunt
channels
3. Reduction of neurogenic inflammation
Doses: oral/SL (1mg every half an hourly) till relief – 6
mg/d
DIHYDROERGOTAMINE(DHE)
Preferred for parenteral administration

Current Status of Ergots in Migraine
Not popular anymore
Regular use is hazardous
No prophylactic value – precipitate on
discontinuation
Dull headache
Available prep=Combination with caffeine,
paracetamol etc

5HT AGONIST- LSD
D-Lysergic acid diethyl amide
Chemical precursor=lysergic acid, occurs naturally in a
fungus-that grows on wheat & rye-but is devoid of
hallucinogenic actions.
LSD has indolealkylamine moiety which interacts with 5-
HT rec
Agonist 5-HT1A marked slowing of firing in Raphe
cellbodies
Studies of 5-HT2Arec knockout mice confirm the role
for this rec in LSD hallucinogenic effects*
* Gonzalez-Maeso et al., 2007

ANTAGONISTS
CYPROHEPTADINE
METHYSERGIDE
KETANSERIN
OTHERS:ATYPICAL ANTIPSYCHOTICS
ONDANSETRON, GRANISETRON
METACHLOPRAMIDE

CYPROHEPTADINE
5-HT2Ablocking property
Weak H1 antihistaminic, anticholinergic & sedative
Famous for increasing appetite
Uses: good antipruritic – used in allergies (no 5-HT Role)
Carcinoid syndrome
Gastrectomy dumping syndrome
Priapism (caused by fluoxetine)
Appetite stimulation in children
Migraine Prophylaxis
AE: weight gain, drowsiness, dry mouth, ataxia

METHYSERGIDE
Congener of methyl-ergonovine
Related to ergot alkaloids – but without ergot like effects
Weak vasoconstrictor, oxytocic
5-HT2A/2C antagonist - also tissue specific agonistic action – also
acts on 5-HT1 receptor
Uses: Prophylaxis of Migraine & other headaches, carcinoid
syndrome, post gastrectomy dumping syndrome
ADR: Abdominal, pulmonary and endocardial FIRBOSIS
If used chronicallyRx should be interrupted for 3 weeks or
more every 6 months.

KETANSERINE
Selective 5-HT2 receptor blocker[5-HT2A > 5-HT2C]
No effects on 5-HT1, 5-HT3, or 5-HT4
Additional H1, α1 and DAergic blocking action
Antagonizes VC, platelet aggregation & airway
constriction actions of 5-HT – antihypertensive
Also in vasospastic conditions – Raynauds disease
RITANSERIN= more 2A selective

OTHER ANTAGONISTS
Clozapine: Atypical antipsychotic--5HT2A/2C
blocker – weaker dopaminergic antagonist
than typical ones – used for resistant cases of
Schizophrenia
Risperidone: 5-HT2A + D2 antagonist - similar
to clozapine – used in Schizophrenia
Ondansetron: 5-HT3 antagonist – Chemo &
radiotherapy induced vomiting

DRUG REC TYPE USE
CYPROHEPTADINE 2A ANTAGONIS
T
SEROTONIN SYNDROME
METHYSERGIDE 2A/2C ANTAGONIS
T
CARCINOID & POST-
GASTRECTOMY DUMPING
SYNDROMES.
CLOZAPINE 2A/2C ANTAGONIS
T
ANTIPSYCHOTIC
RESPERIDONE 2A ANTAGONIS
T
ANTIPSYCHOTIC
KETANSERIN 2A ANTAGONIS
T
ANTIHYPERTENSIVE

DRUG REC TYPE USE DOSE
METACLOPRAMIDE 4 AGONIST GERD
IBS
10mg TDS orally
CISAPRIDE 4 AGONIST GERD
IBS
10-20mg TDS
MOSAPRIDE 4 AGONIST GERD,
IBS
5mg TDS
ONDANSETRON 3 ANTAGONIST CINV 8mg OD orally
GRANISTERON 3 ANTAGONIST CINV 2mg orally
PALANOSETRON 3 ANTAGONIST CINV

USES
Major Depression– SSRIs like Fluoxetine, Sertraline
Obsessive compulsive disorder – SSRIs
Phobic disorders - SSRIs
PMS - SSRIs
Somatoform disorders (Hypochondriasis) - SSRIs
Post traumatic stress disorder - SSRIs
Neuropathic pain & Fibromyalgia pain
Anxiety neurosis – Azapirones(5- HT1A partial agonist)Mar 6, 2017

USES
Migraine – Triptans 5-HT 1B/1D agonist
Appetite stimulant – Cyproheptadine (5-HT2A
antagonist)
Schizophrenia – Clozapine (2A/2C antagonist)
CINV –Ondansetron (Emeset 4,8mg tabs ,2mg/ml inj in 2ml
& 4ml amps), Granisetron (Granicip 1,2mg tabs ,1mg/ml
inj in 1ml & 3ml amps) Tropisetron (5-HT 3 antagonist).
GERD – Mosaprid[Moza 2.5mg ,5mg tabs] (5-HT4
agonist )
IBS – Mosapride, Prucalopride (5-HT4 agonist)

Carcinoid Syndrome
Over 90% of the serotonin in the body is found in
enterochromaffin cells in GI tract.
Carcinoid tumor secrets serotonin and is a neoplasm of
enterochromaffin cells.
Carcinoid syndrome causes subendocardial fibroplasia and
valvular or electrical malfunction.
In patients whose tumor is not operable, a serotonin
antagonist is a useful treatment.

CARCINOID SYNDROME
Cyproheptadine is a H1 and 5-HT2blocker.
It also has antimuscarinic effects and causes sedation.
It is used in the treatment of the smooth muscle
manifestations of carcinoid tumor and in cold-induced
urticaria.

Carcinoid Syndrome
5-hydroxyindoleacetic acid (5-HIAA) is a metabolite of
serotonin.
The excretion of 5-HIAA is a measure of serotonin synthesis.
The 24-hour excretion of 5-HIAA can be used as a diagnostic
test for carcinoid tumor.
Banana contains large amounts of serotonin and must be
prohibited during such tests.

Sternbach’s criteria for serotonin
syndrome*
* Sternbach, 1991;Brown et al., 1996

Agents that have potential to induce serotonin
toxicity &
their MOA for increasing serotonin levels

RECENT ADVANCES
TANDOSPIRONE – A/k/a Metanopirone--5HT1A partial
agonist—Use--anxiolytic & antidepressant. Dose =30mg/d.
AGOMELATINE – 5HT2C antagonist & agonist at
melatonin rec. Used in depression.
NELOTANSERIN (APD-125) – selective 5HT2A inverse
agonist developed by Arena pharmaceuticals for insomnia.
PALONOSETRON (Aloxi) – approved by FDA in 2003
for IV use in preventing delayed CINV

RECENT ADVANCES
RAMOSETRON – 5HT 3 antagonist available in Japan & South
east Asian countries—used in CINV.
CILANSETRON – 5HT 3 antagonist used in IBS where diarrhoea is
the dominant symptom.
LASMIDITAN-5HT1F agonist without vasoconstriction—1F is
expresses in trigeminal nerve pathway– Rx of Migraine --mainly for
individuals with CV risk factors, CVS diseases or dissatisfied with
current therapies
Newer drugs for chronic migraine OLCEGEPANT
TELCAGEPANT

SUMMARY

References…
Sander E: 5Hydroxytryptamine and dopamine Goodman & Gilman’s The
pharmacological Basis of Therapeutics 12th
ed(335-363)
5Hydroxytryptamine :Pharmacology & Pharmacotherapeutics by R.S Satoskar,
24th
ed (333-343)
5Hydroxytryptamine,its antagonist and drug therapy: Essentials of medical
pharmacology by KD Tripathi, 7th
ed(170-181)
HL Sharma, KK Sharma. Histamine, serotonin,ergot alkoloid and bradykinin In:
HL Sharma editor. Principles of pharmacology, 2nd edn. New Delhi: Para
Publishers; 2011.
Zadeh M, et al: Serotonin: J. vet. Pharmacol. Therap. 31, 187–199, doi:
10.1111/j.1365-2885.2008.00944.x. REVIEW ARTICLE
*Spiller R Recent advances in understanding the role of 5HT in GI motility in
functional bowel disorders: alterations in 5-HT signalling & metabolism in
human disease.Neurogastroenterol Motil. 2007 Aug;19 Suppl 2:25-31.

Serotonin.dr.asa

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