Serotonin ( 5- hydroxy tryptamine; 5HT ). Serotonin ( 5- hydroxy tryptamine; 5HT ) Locations: Locations: - Gut enterochromaffin cells ( 90% ) - Gut enterochromaffin.

Serotonin Serotonin

( 5- hydroxy tryptamine; ( 5- hydroxy tryptamine; 5HT )5HT )

Serotonin ( 5- hydroxy tryptamine; 5HT )Serotonin ( 5- hydroxy tryptamine; 5HT )

Locations:Locations: - - Gut enterochromaffin cells ( 90% )Gut enterochromaffin cells ( 90% )

- CNS ( Raphe nucleus, hypothalamic - CNS ( Raphe nucleus, hypothalamic –– limbic system, pituitary gland, pineal limbic system, pituitary gland, pineal gland → melatonin, role as a gland → melatonin, role as a neurotransmitter )neurotransmitter )

- Platelets ( scavengers- Platelets ( scavengers ) )

Synthesis:Synthesis: ** TrpTrp l l –– a . a a . a

HydroxylaseHydroxylase DecarboxylaseDecarboxylase

Trp 5-OH Trp Trp 5-OH Trp 5-HT5-HT

ll a.aa.a methylationmethylation DecDec.. Tryptamine Tryptamine CH CH33 –– tryptamine tryptamine

( hallucinogen )( hallucinogen )

Serotonin synthesis inhibitors:Serotonin synthesis inhibitors:

** p ** p –– chlorophenylalanin chlorophenylalanin

irreversible Trp hydroxylase irreversible Trp hydroxylase inhibitorinhibitor

** Methyl dopa** Methyl dopa

a.a decarboxylase inhibitora.a decarboxylase inhibitor

Serotonin metabolism & excretion:Serotonin metabolism & excretion:

Occurs wherever serotonin is present. Occurs wherever serotonin is present. Major sites of metabolism the lungs, liver, Major sites of metabolism the lungs, liver, and brain. Major site of excretion is the and brain. Major site of excretion is the kidneys.kidneys.

Ald. Ald.

MAO DehydrogenaseMAO Dehydrogenase

5-HT → 5-OH indoleacetyldehyde →5-OH 5-HT → 5-OH indoleacetyldehyde →5-OH indole acetic acid ( 5-HIAA )indole acetic acid ( 5-HIAA )

MAO inhibitors:MAO inhibitors:

Pargyline, TranylcyprminePargyline, Tranylcyprmine Another pathway to serotonin occurs in Another pathway to serotonin occurs in

the pineal gland:the pineal gland: 5-HT N-acetyl Hydroxy-o-methyl 5-HT N-acetyl Hydroxy-o-methyl

transferasetransferase transferasetransferase

5-HT N-acetyl 5-HT 5-HT N-acetyl 5-HT melatoninmelatonin

Serotonin receptors:Serotonin receptors:

5 – 7 different receptors 3 well defined5 – 7 different receptors 3 well defined

- 5-HT- 5-HT11 in CNS: mediate synaptic inhibition in CNS: mediate synaptic inhibition mechanism: ↓cAMP, ↑ Kmechanism: ↓cAMP, ↑ K++

conductanceconductance

in periphery: mediate excitatory & in periphery: mediate excitatory & inhibitory effects in various smooth musclesinhibitory effects in various smooth muscles

- 5-HT- 5-HT22 mediate synaptic excitation in mediate synaptic excitation in CNS and smooth muscle contraction CNS and smooth muscle contraction ( gut, bronchi, blood vessels ) or ( gut, bronchi, blood vessels ) or dilatation of some blood vesselsdilatation of some blood vessels

Mechanism: ↓cAMP; ↓ KMechanism: ↓cAMP; ↓ K++ conductance; ↑ IPconductance; ↑ IP33

- 5-HT- 5-HT33 mainly present in CNS mainly present in CNS particularly in the CTZ and vomiting particularly in the CTZ and vomiting center ( stimulation → vomiting )center ( stimulation → vomiting )

General effects:General effects: Serotonin physiologic effects:Serotonin physiologic effects:

* Regulation of many aspects of * Regulation of many aspects of behavior e.g sleep, pain perception, behavior e.g sleep, pain perception, depression, sexual activity, depression, sexual activity, aggressivenessaggressiveness……etcetc

* Hypothalamic * Hypothalamic –– pituitary function pituitary function

↑ ↑ ACTH; GH; PRL releaseACTH; GH; PRL release ↓ ↓ LH; FSH; TSH releaseLH; FSH; TSH release

Serotonin pharmacological effects:Serotonin pharmacological effects:- Blood vessels- Blood vessels Arteries → constrictionArteries → constriction Veins → constrictionVeins → constriction Skeletal muscles → dilatationSkeletal muscles → dilatation- B.P ↓ ↑ ↓ (overall effect ↑ B.P)- B.P ↓ ↑ ↓ (overall effect ↑ B.P)- Heart ↑ Ht rate and contractility- Heart ↑ Ht rate and contractility- Small intestine ↑ motility → diarrhea- Small intestine ↑ motility → diarrhea

- Stomach ↓ acid secretion ↑ mucus - Stomach ↓ acid secretion ↑ mucus productionproduction

- Bronchospasm- Bronchospasm

- ↑ platelet aggregation- ↑ platelet aggregation

- ↑ catecholamine release- ↑ catecholamine release

Clinical pharmacologyClinical pharmacology* Serotonin agonists:* Serotonin agonists: - - DexfenfluramineDexfenfluramine ↑ ↑ serotonin release, inhibits serotonin serotonin release, inhibits serotonin

uptake and stimulates serotonin receptorsuptake and stimulates serotonin receptors Use: appetite suppressant (withdrawn Use: appetite suppressant (withdrawn

by FDA in USA due to high risk of CV by FDA in USA due to high risk of CV events)events)

- - SomatriptanSomatriptan 5-HT5-HT11 agonist mainly used in migraine agonist mainly used in migraine Given orally, S.C, intranasallyGiven orally, S.C, intranasally Major side effects: Chest pain Major side effects: Chest pain

( coronary artery disease )( coronary artery disease )

- - BuspironeBuspirone

5-HT5-HT11 agonist used in cases of anxiety agonist used in cases of anxiety

- - CisaprideCisapride

5-HT5-HT44 agonist and has agonist and has parasympathomimetic effect ( GIT motility) parasympathomimetic effect ( GIT motility) used in gastroesophygeal reflux (withdrawn used in gastroesophygeal reflux (withdrawn from USA because it leads to long QT from USA because it leads to long QT syndrome)syndrome)

- Ergot alkaloids (- Ergot alkaloids (ErgotamineErgotamine))

Have partial 5-HT receptor agonistic Have partial 5-HT receptor agonistic activityactivity

Serotonin reuptake inhibitorsSerotonin reuptake inhibitors

Mainly used in the management Mainly used in the management of depressionof depression

SelectiveSelective

Fluoxetine, Sertraline, Fluoxetine, Sertraline, FluvoxamineFluvoxamine……

Nonselective Nonselective

TCATCA’’ss

Inhibitors of serotonin release:Inhibitors of serotonin release:

OctreotideOctreotide, Lanreotide ( synthetic , Lanreotide ( synthetic somatostatin somatostatin --like drugs )like drugs )

Mainly used in the management Mainly used in the management of Carcinoid syndrome and intractable of Carcinoid syndrome and intractable

diarrheadiarrhea

Carcinoid syndromeCarcinoid syndromeSerotonin producing tumorSerotonin producing tumorManifestations:Manifestations: - Diarrhea- Diarrhea - Cutaneous flushing- Cutaneous flushing - Bronchoconstriction- Bronchoconstriction

- Pellagra (niacin=vitamin B- Pellagra (niacin=vitamin B33 deficiency) deficiency)ManagementManagement Serotonin release inhibitors Serotonin release inhibitors

(octreotide) and antagonists(octreotide) and antagonists

* Serotonin antagonists* Serotonin antagonists - Ergot alkaloids- Ergot alkaloids LSD (Lysergic acid diethylamide), LSD (Lysergic acid diethylamide),

MethysergideMethysergide Use: Carcinoid syndrome; migraineUse: Carcinoid syndrome; migraine - - CyproheptadineCyproheptadine Antiserotonin and antihistamine Antiserotonin and antihistamine

effectseffects Use: Allergic reactions, Carcinoid Use: Allergic reactions, Carcinoid

syndrome, Cushingsyndrome, Cushing’’s syndromes syndrome

- Ketanserin- Ketanserin Antiserotonin + Antiserotonin + αα –– adrenoreceptor blocking adrenoreceptor blocking

effectseffects- Phenothiazines- Phenothiazines Have Have αα –– adrenergic blocking activity and adrenergic blocking activity and

partial partial serotonin antagonistic effectsserotonin antagonistic effects

- - 5-HT5-HT33 antagonists antagonists OndansetronOndansetron, Granisetron, Tropisetron, Granisetron, Tropisetron Highly effective in the management of Highly effective in the management of

anticancerous anticancerous –– induced nausea and induced nausea and

vomitingvomiting Effective orally, I.V, I.V infusionEffective orally, I.V, I.V infusion