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PDA Block 2 > Serotonin > Flashcards

Serotonin Flashcards

1
Q

How is serotonin synthesized?

A
  • From essential amino acid tryptophan
  • 5-Hydroxytryptophan formed by tryptophan hydroxylase — rate limiting step.
    • Except in the CNS ⇒ low tryptophan levels
    • Requires O2 and a reduced pteridine cofactor
  • Synthesized in most all tissues that contain it
    • Except blood platelets
    • Converted to melatonin in the pineal gland
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2
Q

Metabolism:

A
  • Converted by monoamine oxidase & aldehyde dehydrogenase ⇒ 5- hydroxyindole acetic acid
    • ​May also be reduced to an alcohol
  • Neuronal action terminated primarily by high affinity active reuptake mechanism (SERT) ⇒ intraneuronal conversion to 5- hydroxyindoleacetic acid
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3
Q

Distribution:
Enterochromaffin cells of GI mucosa

A

largest store in body - 90%

  • Synthesis and storage take place
  • Slow spontaneous release - turnover 1 day
  • May be part of “enteric nervous system”
    • small fraction of GI serotonin is in neurons
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4
Q

Distribution:

Blood platelets

A

8%

  • no synthesis takes place in platelets
    • uptake, storage and release
  • site for removal of serotonin from plasma
    • may be involved in clotting
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5
Q

Distribution:

CNS

A

midbrain raphe nuclei - 2%:

  • project to hypothalamus, neostriatum, limbic forebrain, neocortex, medulla and spinal cord
  • synthesis, storage and release occur
  • **rapid turnover < **less than 4 hours
    • affected by many psychoactive drugs
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6
Q

Receptors:

A

At least 13 subtypes:

  • Most are GPCRs
    • Except 5HT3
  1. 5-HT1(A-E) - inhibition of adenylate cyclase.
    • 5- HT1A also opens K+ channel
  2. 5-HT2(A-C) - PI hydrolysis
  3. 5-HT3 - ligand-gated Cation channel
  4. 5-HT4 - 7 - activation of adenylate cyclase or unknown
  5. Auto-receptors – decrease serotonin release – 1A and 1D like
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7
Q

5-HT1 family:

A
  1. 5-HT1A
    • Gi Inhibition of adenylate cyclase
    • Gi Opening of K+ channel
    • Go Closing of Ca2+ channel
  2. 5-HT1B, 5-HT1D, 5-HT1E
    • Gi Inhibition of adenylate cyclase
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8
Q

5-HT2 family:

A

5-HT2A, 5-HT2B, 5-HT2C :

  • Gq
  • Phosphoinositide hydrolysis
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9
Q

Other serotonin recpetor subtypes:

A
  • 5-HT4, 5-HT5A, 5-HT6,5-HT7:
    • Gs
    • Activation of adenylate cyclase
  • 5-HT5B
    • Unknown coupling mech.
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10
Q

What is the major difference with HT3 receptors?

A
  • Ligand-gated ion channels
    • ​not GPCRs
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11
Q

What are the pharmacological actions of serotonin in the GI system?

A
  • Site of synthesis and storage
    • ​neuronal & non-neuronal
  • Slow release
    • turnover rate = 1 day
  • Contraction of G.I. smooth muscle:
    • esophagus, stomach and intestine
    • increases tone, peristalsis, and diarrhea
  • Emesis
    • ​induced by 5-HT3 receptors in brain and G.I. tract
  • Carcinoid syndrome – serotonin secreting tumors
    • also bradykinin
    • treated with serotonin antagonists or octreotide a somatostatin analog
    • can cause severe diarrhea and asthma
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12
Q

What are the pharmacological actions of serotonin in the cardiovascular system?

A

Vasoconstriction or vasodilation:

  • Potent vasoconstriction in large arteries and veins in most vascular beds
    • especially pulmonary and renal vessels (5-HT2)
    • also cranial blood vessels (5-HT1D)
  • Vasodilation
    • coronary arteries, arterioles
    • skeletal muscle and cutaneous blood vessels
  • Bezold-Jarisch reflex: chemoreceptors in coronary vasculature
    • powerful activator of afferent vagal nerve endings
    • response is bradycardia, hypotension and hypoventilation
  • Platelet aggregation
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13
Q

What are the pharmacological actions of serotonin in the CNS?

A

Cell bodies in midbrain raphe nuclei:

  1. Sensory perception - LSD
  2. Sleep – Slow wave deep sleep
    • not REM sleep
  3. Temperature regulation
  4. Neuroendocrine regulation
    • release of ACTH, GH, prolactin, TSH, FSH and LH
  5. Learning and memory – particularly short-term.
  6. Pain perception – spinal and brain sites.
  7. Drug abuse
  8. Emesis – 5-HT3 receptors
  9. Mental Illness
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14
Q

Descrbe how serotonin is involved in mental illness:

A
  1. Affective disorders
    • SSRIs & SNRIs
  2. Schizophrenia
    • atypical antipsychotics
  3. Obsessive-compulsive disorder
    • SSRIs
  4. Anxiety disorders – 5-HT1A receptors
  5. Aggressive behavior
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15
Q

Serotonin Agonists (4):

A
  1. Lysergic Acid Diethylamide
  2. Buspirone (BuSpar®)
  3. Sumatriptan (Imitrex®)
  4. Tegaserod
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16
Q

Lysergic Acid Diethylamide (LSD):

A
  • potent hallucinogen (~1μg/kg)
  • Full or partial agonist at 5-HT2 receptors
  • Other drugs with similar action include psilocybin, mescaline and dimethyltryptamine (DMT)
17
Q

Buspirone (BuSpar®):

A
  • partial agonist at 5-HT1A receptors
  • used as antianxiety agent
18
Q

Sumatriptan (Imitrex®):

A

agonist at 5-HT1D receptor

  • used in the treatment of migraine headaches
    • ​stops existing headache
  • side effects: nausea and vomiting, angina, dizziness and flushing
19
Q

Tegaserod:

A
  • 5-HT4 partial agonist used to treat irritable bowel syndrome with constipation in women
  • stimulates G.I. motility
20
Q

Indirect agonists (2):

A
  1. Fluoxetine (Prozac®)
  2. Phenelzine
21
Q

Fluoxetine (Prozac®):

A

Serotonin specific reuptake inhibitors (SSRIs)

  • blocks the active reuptake of serotonin into neurons
  • increases amount of serotonin at synapse
  • used in treatment of affective disorders, obsessive compulsive disorders, panic attacks, etc.
  • side effects: sexual dysfunction, nausea
  • Other SSRIs include sertraline, paroxetine, fluvoxamine and citalopram
22
Q

Phenelzine:

A

Monoamine oxidase inhibitors

  • block metabolism of serotonin, NE and DA
  • used in treatment of depression and narcolepsy
  • Side effects: food induced hypertensive crisis
23
Q

Serotonin antagonists (3):

A
  • Cyproheptadine
  • Ondansetron (Zofran® / Zofran® ODT)
  • Alosetron
24
Q

Cyproheptadine:

A
  • 5-HT2 receptor antagonist
    • also histamine H1 antagonist
  • treatment: skin allergies & carcinoid
    • particularly pruritus and urticaria
25
Q

Ondansetron (Zofran® / Zofran® ODT):

A
  • 5-HT3 receptor antagonists
  • very effective in treatment of chemotherapy- induced nausea and vomiting
    • acts both at G.I. and brain receptors
  • I.V. and oral forms available
26
Q

Alosetron:

A
  • Selective 5-HT3 antagonist
  • Treats women with diarrhea-predominant IBS who have failed to respond to conventional therapy
  • Can produce severe GI adverse effects
    • restricted prescribing program must be followed

PDA Block 2 (15 decks)

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