Serotonin or 5hydroxytryptamine

1
Serotonin or 5-hydroxytryptamine

• Widely distributed amine (animals plants)
• In humans, present in GI enterochromaffin cells
  (90), platelets and brain.
• Synthesized from tryptophan (in diet) in two
  steps.
• Platelets do not synthesize but take up from
  blood (active uptake process in platelets and
  nerve terminals).
• Cell storage in granules similar to
  catecholamines.

2
(Rate limiting)
OH
COOH
COOH
Tryptophan hydroxylase
C
C
NH2
NH2
N
N
In diet. Active CNS transport
Tryptophan
5-Hydroxytryptophan
5-OH Tryptophan decarboxylase
C
COOH
OH
H
N
Aldehyde dehydrogenase
C
NH2
MAO
5-Hydroxy Indole Acetic Acid
N
5-OH Indole Acetaldehyde
5-Hydroxytryptamine
3
Synthesis and Metabolism

• Competition at the level of brain and neuronal
  uptake
• Rate limiting enzyme not saturated usually
• No end-product negative feedback
• 5-OHTr decarboxylase same as DOPA decarboxylase
• 5-OHIAA actively extruded from CNS
  (probenecid-sensitive) and excreted in urine.

4
Interference with the system

• Inhibit uptake into CNS (other AAs)
• Inhibit synthesis p-chlorophenylalanine
  (irreversible)
• Inhibit neuronal re-uptake cocaine, SSRA (e.g.
  fluoxetine), TCA (e.g. imipramine)
• Inhibit storage-deplete reserpine
• Inhibit metabolism MAO inhibitors
• Promote release p-chloroamphetamine - then
  depletes (e.g. fenfluramine to ? appetite)

Non-selective
5
Serotonin Receptors

• At least 15 types and subtypes
• Multiple transduction mechanisms
• 5HT-1A role in anxiety/depression
• 5HT-1D role in migraine
• 5HT-2 role in CNS various behaviors, and in
  cardiovascular system
• 5-HT3 role in nausea and vomiting esp. due to
  Chemotherapy.

6
Endogenous Function

• Central neurotransmitter
• Precursor of melatonin
• GI tract uncertain motility?
• In carcinoid tumors large amounts released
  leading to diarrhea, bronchoconstriction and
  edema
• Platelets 5-HT2 receptors ? aggregation and
  vasoconstriction

7
Serotonin Pharmacological Effects

• Respiratory system bronchoconstriction if
  asthmatic stimulation of aortic and carotid
  chemoreceptors ? ? RR and minute vol.
• GI tract small intestine very sensitive to
  serotonin ? intense rhythmic contractions due to
  direct and indirect (ganglia in wall) effects.
• Also stimulates vomiting (5-HT3 receptors on
  vagal afferents and centrally).

8
Serotonin Pharmacological Effects -2

• Cardiovascular system Multiple direct and
  indirect effects
• Direct vasoconstriction (large arteries) and
  indirect vasodilation (NO and PGI2 mediated)
• Heart direct inotropic and chronotropic effects
• Reflex mechanisms due to change in BP
• Stimulation of sensory nerve endings in
  baroreceptors and in vagal afferents in coronary
  circulation (Bezold Jarrisch reflex) ?
  bradycardia and hypotension

9
Serotonin in the Central Nervous System

• Pain perception
• Sleep/Wakefulness
• Various behaviors normal/abnormal depression,
  schizophrenia, obsessive compulsive behavior,
  etc.
• Neuroendocrine regulation controls hypothalamic
  cells involved in release of several anterior
  pituitary hormones.

10
Migraine

• Clinical Presentations
• Often accompanied by brief aura (visual scotomas,
  hemianopia)
• Severe, throbbing, usually unilateral headache
  (few hours to a few days in duration)
• Migraine Pathophysiology
•  Vasomotor mechanism -- inferred from
• increased temporal artery pulsation magnitude
• pain relief (by ergotamine) occurs with decreased
  artery pulsations
• Migraine attack associated with (based on
  histological studies)
• sterile neurogenic perivascular edema
• inflammation (clinically effective antimigraine
  medication reduce perivascular inflammation)

11
Migraine Drug Treatment

• Ergotamine best results when drug administered
  prior to the attack (prodromal phase) -- less
  effective as attack progresses
• combined with caffeine better absorption
• potentially severe long-lasting Vasoconstriction.
  
• Dihydroergotamine (IV administration mainly) may
  be appropriate for intractable migraine
• Nonsteroidal antiinflammatory drugs (NSAIDs)
• Sumatriptan alternative to ergotamine for acute
  migraine treatment not recommended for patients
  with coronary vascular disease risk.
• formulations subcutaneous injection, oral, nasal
  spray
• selective serotonin-receptor agonist (short
  duration of action)
• probably more effective than ergotamine for
  management of acute migraine attacks (relief 10
  to 15 minutes following nasal spray)

12
Migraine Prophylaxis

•  Methysergide
• effective in about 60 of patients
• NOT effective in treating an active migraine
  attack or even preventing an impending attack.
• Methysergide toxicity retroperitoneal
  fibroplasia, subendocardial fibrosis. Recommend
  3-4 week drug holiday every six months
•  Propranolol - Most common for continuous
  prophylaxis
• best established drug for migraine attack
  prevention.
•  Amitriptyline (TCA)
• most frequently used among the tricyclic
  antidepressants
•  Valproic acid (Antiepileptic)
• effective in decreasing migraine frequency.
•  Nonsteroidal antiinflammatory drugs (NSAIDs)
• used for attack prevention and aborting acute
  attack

13
Serotonin in Migraine

• Neurogenic vs. Vascular theories
• Several drugs that modulate the serotonin system
  are effective in migraine
• Cyproheptadine/methysergide - prophylaxis
• Sumatriptan, ergotamine - acute
• MAO inhibitors and TCA both
• Caffeine (? cAMP?)
• Reserpine worsens migraine

14
PAIN
Unknown Trigger
Activation
antidromic
Cortex
Orthodromic conduction
Thalamus
Trigeminal neuron
Blood Vessel
autonomic
nausea
Mast cell
Inhibitory receptor (5-HT1D)
Trigem. Nucleus caudalis
15
Serotonin Agonists

• Sumatriptan 5-HT1D agonist contraindicated in
  patients with angina
• Fluoxetine Selective serotonin uptake inhibitors
  for depression and other indications
• Buspirone 5-HT1A agonist for anxiety
• Cisapride 5-HT4 agonist to ? GI motility and
  decrease G-E reflux (Removed from US market due
  to fatal arrhythmias)
• LSD 5HT1A hallucinogen
• Ergot alkaloids 5-HT1 and 2 and other receptors

16
Serotonin Antagonists

• Methysergide and Cyproheptadine. 5HT2
  antagonists. In carcinoid, migraine.
• Ketanserin 5HT2 and Alpha antagonist used as
  antihypertensive.
• Ondansetron 5-HT3 antagonist for chemotherapy
  induced nausea and vomiting
• Clozapine 5HT2A/2C antagonist for schizophrenia.