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MCW - Pharmacology > Block 2_1 - Serotonin > Flashcards

Block 2_1 - Serotonin Flashcards

1
Q

Outline Steps in Serotonin Synthesis

  • note rate limiting step, cofactors
A
  1. Tryptophan (essential amino acid)

Tryptophan Hydroxylase (rate limiting step)

  1. 5-hydroxytryptophan

L-aromatic amino acid decarboxylase (with pyridoxine cofactor)

  1. Serotonin (5-hydroxytryptamine)
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2
Q

How is serotonin synthesis different in the brain/CNS? Cofactors?

A

Tryptophan hydroxylase is not the rate limiting step because of low tryptophan levels (i.e. tryptophan concentration limits synthesis in the brain) - Requires O2 and reduced pteridine cofactor

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3
Q

Serotonin is converted to what in the pineal gland?

A

Melatonin (5-methoxy-N-acetyltryptamine)

Serotonin –a–> N-Acetyl Serotonin –b–> Melatonin

a) 5 HT N-acetylase
b) 5-hydroxy indole O-methyl transferase

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4
Q

Name 2 ways Serotonin is metabolized (and terminated)

A
  1. Converted by monoamine oxidase (MAO) and aldehyde dehydrogenase to 5-hydroxyindole acetic acid
  2. Neuronal action terminated primarily by high affinity active reuptake mechanism - serotonin transporter (SERT) - then intraneuronal conversion to 5-hydroxyindole acetic acid
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5
Q

Distribution of Serotonin in the body?

A

GI System - 90%

Platelets - 8%

CNS - 2%

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6
Q

Serotonin is synthesized in most tissues that contain it except _____

A

Blood Platelets

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7
Q

Distribution of Serotonin in GI Mucosa

  1. Cells?
  2. Release?
  3. May be a part of what system?
A
  1. Enterochromaffin cells
  2. Slow spontaneous release - turnover 1 day
  3. Enteric Nervous System - small fraction of GI serotonin is in neurons
    - note: synthesis and storage is both neuronal and non-neuronal
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8
Q

Distribution of Serotonin in Blood Platelets

  1. Stored where?
  2. uptake, storage and release is similar to what?
  3. T/F serves as a site for removal of serotonin from plasma and may be involved in clotting
A
  1. vesicles with ATP - similar to neurons
  2. neuronal serotonin
  3. True
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9
Q

Distribution of Serotonin in the CNS

  1. Cell bodies where?
  2. Project where?
  3. Turnover?
  4. affected by?
A
  1. midbrain raphe nuclei
  2. hypothalamus, neostriatum, limbic forebrain, neocortex, medulla, spinal cord
  3. rapid turnover, less than 4 hours
  4. many psychoactive drugs
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10
Q

Serotonin Receptor Subtype 5-HT1A, 1B, 1D, 1E

G protein - Effector Pathway?

A

5-HT1A, 1B, 1D, 1E

Gi - Inhibition of Adenylate Cyclase

5-HT1A

Gi - Opening of K+ channel

Go - closing of Ca2+ channel

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11
Q

Serotonin Receptor Subtype 5-HT<span>2A, 2B, or 2C</span>

G protein - Effector Pathway?

A
  1. Gq - Phosphoinositide Hydrolysis
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12
Q

Serotonin Receptor Subtype 5-HT<span>4, 5A, 6, or 7</span>

G protein - Effector Pathway?

A
  1. Gs - Activation of Adenylate Cyclase
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13
Q

Serotonin Receptor Subtype 5-HT<span>5B</span>

G protein - Effector Pathway?

A
  1. ? - Unknown Coupling Mechanism
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14
Q

Serotonin Receptor Subtype 5-HT<span>3</span>

G protein - Effector Pathway?

A
  1. None - Ligand-gated cation channel
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15
Q

Serotonin Autoreceptors

  1. Act similar to what?

Actions?

A
  1. 5-HT1A and 5-HT1D
  2. decrease serotonin release
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16
Q

4 systems of Serotonin action

A
  1. GI System - Enterochromaffin cells
  2. Cardiovascular System
  3. Platelets
  4. CNS
17
Q

Pharmacological Action of Serotonin on GI System (3 things)

A
  1. Causes contraction of GI Smooth muscle including esophagus, stomach and intestine
    - increasing tone, peristalsis and diarrhea
  2. Emesis (vomiting) can be induced by 5-HT3 receptors in the brain and G.I. Tract
  3. Carcinoid Syndrome - Tumors of enterochromaffin cells
  • Secrete serotonin and bradykinin
  • can cause severe diarrhea and asthma
  • Treatment
    • serotonin antagonists or
    • somatostatin analogs (octreotide) which blocks the secretion of all mediators from the carcinoid tumor
18
Q

Effects of Serotonin on Cardiovascular System (4 things)

A
  1. Potent Vasoconstriction of large arteries, veins, and most vascular beds (especially pulmonary and renal vessels)
  • Predominately Direct via
    • 5-HT2 receptors on smooth muscle cells
    • 5-HT1D in cranial blood vessels
  • Indirect
    • Amplification of α-mediated effects of catecholamines or
    • Displacement of norepinephrine from adrenergic nerves
  1. Vasodilation in coronary arteries, arterioles as well as skeletal muscle and cutaneous blood vessels
  2. Bezold-Jarisch Reflex
  • Serotonin powerfully activates chemoreceptors in coronary vasculature –> activates vagal nerve endings
  • bradycardia, hypotension, hypoventilation
  1. Platelet Aggregation - active uptake of serotonin from circulation
19
Q

Effects of Serotonin on CNS

  1. cell bodies where?
  2. Involved in … (hint: 9 + 5 things)
A
  1. Acts as Neurotransmitter - cell bodies in midbrain raphe nuclei
  2. May be involved in
  3. Sensory perception - LSD
  4. Sleep - slow wave deep sleep
  5. Temperature regulation
  6. Neuroendocrine regulation - release of ACTH, GH, prolactin, TSH, FSH, LH
  7. Learning and memory - particularly short-term
  8. Pain perception - spinal and brain sites of action
  9. Drug Abuse
  10. Emesis - 5-HT3 Receptors
  11. Mental Illness
    1. Affective disorders (SSRIs and SNRIs)
    2. Schizophrenia - atypical antipsychotics
    3. Obsessive-compulsive disorder (OCD) - SSRIs
    4. Anxiety Disorder - 5-HT1A receptor
    5. Aggressive Behavior
20
Q

Serotonin Agonists

A

Agonists

  1. Lysergic Acid Diethylamide (LSD)
  2. Buspirone
  3. Sumatriptan
  4. Tegaserod
  5. Lorcaserin

Indirect Agonists** **

6. Fluoxetine

7. Phenelzine

21
Q

Lysergic Acid Diethylamide (LSD)

  1. Action
  2. acts on what receptor
  3. specific or nonspecific
A
  1. Potent Hallucinogen
  2. Full or partial agonist at 5-HT2 receptors
  3. relatively nonspecific
22
Q

Buspirone

  1. acts on what receptor?
  2. Use
A
  1. 5-HT1A
  2. antianxiety agent
23
Q

Sumatriptan

  1. acts on what receptor?
  2. Use
  3. Side Effects
A
  1. 5-HT1D Agonist
  2. Acts on cerebral blood vessels.
    * Treatment of Migraine headaches. Stops existing ones
  3. Side Effects: nausea, vomiting, angina, dizziness, and flushing
24
Q

Tegaserod

  1. receptor?
  2. Use
A
  1. 5-HT4 partial agonist
  2. treat irritable bowel syndrome with constipation in women
    - stimulates GI Motility
    - stimulates intestinal secretion
    - releases other enteric transmitters
    note: taken off the market in 2007 due to CV effects. restored with a limited prescribing program
25
Q

Lorcaserin

  1. Receptor
  2. Use
A

New Drug used for the treatment of obesity in adults

  1. 5-HT2C receptor agonist
  2. Activation of 5-HT2C receptors in the hypothalamus activate proopiomelanocortin (POMC) production and promote weight loss through satiety
26
Q

Fluoxetine

  1. Mechanism of action
  2. Use
  3. Side Effects
A
  1. Serotonin specific reuptake inhibitor (SSRI) - blocks active reuptake of serotonin. Increases the amount of transmitter in synapse
  2. Treatment of affective disorders (mood changes), OCD, panic attacks
  3. sexual dysfunction, nausea
27
Q

Phenelzine

  1. Mechanism of Action
  2. Use
  3. Side Effects
A
  1. Monoamine Oxidase (MAO) inhibitors - block metabolism of serotonin, norepinephrine, and dopamine
    - increased synaptic serotonin
  2. Affective disorders and narcolepsy
  3. Food induced hypertensive crisis
28
Q

Serotonin Antagonists

A

1. Cyproheptadine

2. Ondansetron

3. Alosetron

29
Q

Cyproheptadine

  1. receptor
  2. Therapeutic Use
A
  1. 5-HT2 receptor antagonist
    - also histamine H1 antagonist
  2. treatment of skin allergies, particularly pruritus and urticaria
    - treatment of carcinoid (tumor from GI tract)
30
Q

Ondansetron

  1. Receptor
  2. Therapeutic Use
  3. Site of action
  4. Route of Administration
A
  1. 5-HT3 receptor antagonist
  2. treatment of chemotherapy induced nausea and vomiting
    - post-op and x-ray therapy induced nausea and vomiting
  3. Acts both at GI and brain/CNS receptors
  4. IV and oral forms available
31
Q

Atypical antipsychotic agents such as clozapine and olanzapine block ______ receptors in addition to dopamine receptors.

A

5-HT2

32
Q

Alosetron

  1. receptor
  2. Therapeutic Use
  3. Side Effects
A
  1. 5-HT3
  2. treat women with diarrhea-predominant Irritable bowel syndrome (IBS) who have failed to respond to conventional therapy
  3. can produce severe GI adverse effects. a restricted prescribing program must be followed
33
Q

Melatonin

  1. Synthesized
  2. receptors? coupled to which G protein?
  3. Therapeutic Use
A
  1. from serotonin in pineal
  2. own receptors M1, M2 - Gi associated
  3. Used to treat insomnia - follows circadian clock

MCW - Pharmacology (8 decks)

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