Serotonin

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• Serotonin
• ( 5- hydroxy tryptamine 5HT )

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• Serotonin ( 5- hydroxy tryptamine 5HT )
• Locations
• - Gut enterochromaffin cells ( 90 )
• - CNS ( Raphe nucleus, hypothalamic limbic
  system, pituitary gland, pineal gland ?
  melatonin, role as a neurotransmitter )
• - Platelets ( scavengers )

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• Synthesis
• Trp
  l a . a
• Hydroxylase
  Decarboxylase
• 
  
• Trp 5-OH Trp
  5-HT
• l a.a methylation
• Dec.
• Tryptamine CH3 tryptamine (
  hallucinogen )

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• Serotonin synthesis inhibitors
• p chlorophenylalanin
• irreversible Trp hydroxylase
  inhibitor
• Methyl dopa
• a.a decarboxylase inhibitor

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• Serotonin metabolism excretion
• Occurs wherever serotonin is present. Major
  sites of metabolism the lungs, liver, and brain.
  Major site of excretion is the kidneys.
• 
  Ald.
• MAO
  Dehydrogenase
• 
  
• 5-HT ? 5-OH indoleacetyldehyde ?5-OH indole
  acetic acid ( 5-HIAA )

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• MAO inhibitors
• Pargyline, Tranylcyprmine
• Another pathway to serotonin occurs in the pineal
  gland
• 5-HT N-acetyl
  Hydroxy-o-methyl
• transferase
  transferase
• 5-HT N-acetyl 5-HT
  melatonin

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• Serotonin receptors
• 5 7 different receptors 3 well defined
• - 5-HT1 in CNS mediate synaptic inhibition
• mechanism ?cAMP, ? K
  conductance
• in periphery mediate excitatory
  inhibitory effects in various smooth muscles

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• - 5-HT2 mediate synaptic excitation in CNS and
  smooth muscle contraction ( gut, bronchi, blood
  vessels ) or dilatation of some blood vessels
• Mechanism ?cAMP ? K conductance ? IP3
• - 5-HT3 mainly present in CNS particularly in
  the CTZ and vomiting center ( stimulation ?
  vomiting )

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• General effects
• Serotonin physiologic effects
• Regulation of many aspects of behavior
  e.g sleep, pain perception, depression, sexual
  activity, aggressivenessetc
• Hypothalamic pituitary function
• ? ACTH GH PRL release
• ? LH FSH TSH release

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• Serotonin pharmacological effects
• - Blood vessels
• Arteries ? constriction
• Veins ? constriction
• Skeletal muscles ? dilatation
• - B.P ? ? ? (overall effect ? B.P)
• - Heart ? Ht rate and contractility
• - Small intestine ? motility ? diarrhea

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• - Stomach ? acid secretion ? mucus production
• - Bronchospasm
• - ? platelet aggregation
• - ? catecholamine release

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• Clinical pharmacology
• Serotonin agonists
• - Dexfenfluramine
• ? serotonin release, inhibits serotonin
  uptake and stimulates serotonin receptors
• Use appetite suppressant (withdrawn by
  FDA in USA due to high risk of CV events)
• - Somatriptan
• 5-HT1 agonist mainly used in migraine
• Given orally, S.C, intranasally
• Major side effects Chest pain (
  coronary artery disease )

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• - Buspirone
• 5-HT1 agonist used in cases of anxiety
• - Cisapride
• 5-HT4 agonist and has
  parasympathomimetic effect ( GIT motility) used
  in gastroesophygeal reflux (withdrawn from USA
  because it leads to long QT syndrome)
• - Ergot alkaloids (Ergotamine)
• Have partial 5-HT receptor agonistic
  activity

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• Serotonin reuptake inhibitors
• Mainly used in the management of
  depression
• Selective
• Fluoxetine, Sertraline, Fluvoxamine
• Nonselective
• TCAs

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• Inhibitors of serotonin release
• Octreotide, Lanreotide ( synthetic
  somatostatin -like drugs )
• Mainly used in the management of
  Carcinoid syndrome and intractable diarrhea

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• Carcinoid syndrome
• Serotonin producing tumor
• Manifestations
• - Diarrhea
• - Cutaneous flushing
• - Bronchoconstriction
• - Pellagra (niacinvitamin B3 deficiency)
• Management
• Serotonin release inhibitors (octreotide)
  and antagonists

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• Serotonin antagonists
• - Ergot alkaloids
• LSD (Lysergic acid diethylamide),
  Methysergide
• Use Carcinoid syndrome migraine
• - Cyproheptadine
• Antiserotonin and antihistamine effects
• Use Allergic reactions, Carcinoid
  syndrome, Cushings syndrome

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• - Ketanserin
• Antiserotonin a adrenoreceptor
  blocking effects
• - Phenothiazines
• Have a adrenergic blocking activity and
  partial
• serotonin antagonistic effects
• - 5-HT3 antagonists
• Ondansetron, Granisetron, Tropisetron
• Highly effective in the management of
  
• anticancerous induced nausea and
  vomiting
• Effective orally, I.V, I.V infusion