 Tissue and organ systems:

o Cardiovascular: serotonin

 Smooth muscle-- direct effects: contraction, 5-HT2 receptors

 Serotonin: vasoconstriction except:
 skeletal muscle vasculature } vasodilation
 heart } vascular endothelial cell-dependent vasodilation
 Serotonin: reflex bradycardia (5-HT3 activation of
chemoreceptor nerve endings)
 Serotonin-induced vasoconstriction: strong effects on pulmonary
and renal vasculature
 Venoconstriction with subsequent increased capillary filling
causes flushing following serotonin administration
 Serotonin: small direct positive inotropic and chronotropic
cardiac effects
  Subendocardial fibroplasia associated with prolonged elevation
of serotonin in the blood (e.g. in carcinoid syndrome) -- may
result in myocardial space forelectrical or valve malfunction.
 Serotonin: induces platelet aggregation by activation of platelet
surface 5-HT2 receptors.

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o Gastrointestinal tract: serotonin

 Serotonin:contraction of gastrointestinal smooth muscle

 increased tone, increased peristalsis

  5-HT2 receptor mediated:
 direct effect on smooth muscle receptors
 stimulation of enteric ganglia cells
  Serotonin: -- activation of 5-HT4 receptor
 increased acetylcholine release (increased
motility, prokinetic)
  Example:   Serotonin over production (carcinoid
tumor) -- severe diarrhea

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o Nervous System:
 Serotonin: stimulates itch and pain sensory nerve endings.

 Serotonin:activates chemosensitive nerve endings in coronary

vessels
 5-HT3 receptor activation on these chemosensitive vagal nerve
endings:causes chemoreceptor reflex {Bezold-Jarisch reflex}
 Reflex response: significant negative chronotropic
(bradycardic response) with hypotension:
 bradycardia -- vagal mediated (blocked by
atropine)
 Other agents that activate chemoreceptor reflex
include:
1. nicotinic cholinergic receptor agonists
2. some cardiac glycosides
   5-HT3 receptor activation in the gastrointestinal tract and in the
medullary vomiting center: vomiting reflex:
 This system is important in vomiting caused by
chemotherapeutic (anticancer) drugs

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 Clinical Pharmacology:
o Serotonin Agonists

Buspirone (BuSpar)-- 5-HT1A agonist: Sumatriptan (Imitrex): 5-HT1D agonist:

nonbenzodiazepine anxiolytic acute migraine and cluster headaches
 Sumatriptan: (Imitrex)

o Relief of migraine symptoms for most patients

o Efficacy greater than or equal to other drug treatments

(including parenteral agents or oral ergot alkaloids)
o Multiple dosing may be required (headache lasts longer than
 single dose duration)
o  Adverse Effects: Sumatriptan

   generally mild
   altered sensations (tingling, warmth, etc.)
   dizziness
   muscle weakness
   neck pain
   Chest pain (frequency: 5%)
o  Contraindications:

 in patients with ischemic heart disease

 in patients with Prinzmetal's angina (variant angina)

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o Serotonin Antagonists

Cyproheptadine
Ketanserin Ritanserin
(Periactin)
Ondansetron Granisetron
Tropisetron Dolasetron
(Zofran) (Kytril)
 Cyproheptadine (Periactin)
o Overview

 blocks serotonergic and histaminergic affects on smooth muscle

 no effect on histamine-stimulated gastric secretion
  significant antimuscarinic effects
  sedation
o Clinical Use: cyproheptadine

 Major Use: cyproheptadine

   reduces smooth muscle effects of  carcinoid tumor
   reduces postgastrectomy dumping syndrome
  Ketanserin
o Overview

 blocks 5-HT1c and 5-HT2 receptors (no activity another 5 HT or

H1 histamine receptors
 blocks a1 adrenergic receptors
 blocks platelet 5-HT2 receptors (inhibits serotonin-mediated
platelet aggregation)
 effective antihypertensive drug (probably acting through
a1 adrenergic receptors
 Ritanserin
o Blocks 5-HT2 receptors (no alpha blocking properties)

o May alter platelet function

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 Ondansetron (Zofran)
o 5-HT3 receptor blocker

 minimal effects on dopamine, histamine, adrenergic or

cholinergic receptor activity
o very effective for prevention of nausea and vomiting caused by
chemotherapy or surgery. -- major role in management of severe nausea
and vomiting due to anticancer drugs
o Clinical Use:

 Dosage: 4-8 mg IV (administered over 2-5 minutes just before

anesthesia induction)
 Highly effective in reducing postoperative nausea/vomiting
incidence -- particularly in susceptible patient groups:
 ambulatory gynecologic surgery
 middle ear surgery
 Oral or IV reduces incidence of postoperative vomiting and
preadolescent children undergoing:
 ambulatory surgery, e.g. tonsillectomy, strabismus
surgery
  Ondansetron (Zofran): effective both for prophylaxis and
treatment of postoperative nausea/vomiting
 decreases incidents & intensity of postoperative nausea
& vomiting -- but does not totally eliminate this problem
 Major advance: reduced side effects compared to
previously used antiemetic drugs such as:
o phenothiazines, antihistamines, butyrophenones

 Propofol (Diprivan) for induction and maintenance of anesthesia

may be as effective as ondansetron (Zofran) in
reducing/preventing postoperative nausea & vomiting
o  Side Effects:

 Surgical patients:
 3% increased liver transaminase enzyme levels
 3% headache
 No sedation, hypotension, dysphoria, extrapyramidal reactions --
side effects associated with other antiemetic drugs

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 Tropisetron:
o 5-HT3 receptor blocker

o Effective in managing symptoms induced by carcinoid syndrome-- also

some gastrokinetic characteristics
o Effective in preventing chemotherapy/radio therapy-induced emesis

o Effective in preventing postoperative nausea/vomiting when

administered before general anesthetic induction

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 Granisetron (Kytril)
o More selective 5-HT3 receptor blocker compared to ondansetron

o Clinical Use:

 Effective in the chemotherapy-induced emesis prevention

 Effective in preventing postoperative nausea/vomiting
 o Elimination half-life: nine hours, compared to about three hours for
ondansetron: suggesting less frequent dosing with granisetron.
o Significantly higher cost-- could limit clinical use

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 Dolasetron:
o Highly potent/selective 5-HT3 receptor blocker

o Clinical Use:

 Effective in preventing chemotherapy-induced nausea/vomiting

 Effective in reducing likelihood of postoperative nausea &
vomiting
 Antiemetic effect due to long-acting, active metabolite
(hydrodolasetron; elimination half-life = approximately 8 hours)

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Serotonin
  Chemistry: serotonin
o Widely distributed indoleethylamine formed from L-tryptophan:

 hydroxylation of the indole ring

 decarboxylation
 hydroxylation at C-5: rate-limiting step
 inhibited by p-chlorophenylalanine (PCPA, fenclonine)
o Following synthesis:

 storage or
 rapid inactivation-- oxidation (monoamine oxidase, MAO)
 Pineal gland: serotonin -- precursor for melatonin (melanocyte-
stimulating hormone)

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o Storage:
  Most serotonin (> 90%):enterochromaffin cells -- GI tract
 Blood: platelets (active carrier-mediated transport system
{similar to nerve endings})
 CNS locations:serotonin
 raphe nuclei (brain stem)
 localization of neuronal cell bodies that:
A. synthesize
B. store
C. release
 CNS serotonin involvement:
 mood
 sleep
 appetite
 temperature regulation
 pain perception
 blood-pressure regulation
 vomiting
o Degradation:

 Catabolism: monoamine oxidase -- product: 5-

hydroxyindoleacetaldehyde
 5-hydroxyindoleacetaldehyde: further oxidation
catalyzed aldehyde dehydrogenase
 amount of 5-hydroxyindoleacetic acid (5-HIAA)
excreted is a measure of serotonin synthesis.
 excessive serotonin synthesis may be helpful as a
diagnostic test for certain tumors (e.g. carcinoid)

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 Pharmacodynamics -- Mechanisms of Actions

o Effects mediated through serotonin receptors:
  At least seven major 5 HT subtypes identified
 most: G protein coupled
 at least one: ligand-gated channel

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Some Serotonin Receptor Subtypes

Coupling mechanism;
Receptor subtype Distribution
comments

cAMP, potassium
Raphe nuclei,
5-HT1A channels:partially
hippocampus
selective agonist:  8-OH-
DPAT

cAMP,partially
5-HT1D(a,b) brain selective agonist: 
sumatriptan (Imitrex)
receptor:Na-K ion
channel: partially
area postrema, sensory selective antagonists 
5-HT3
and enteric nerves ondansetron (Zofran),
ggranisetron (Kytril),
tropisetron

cAMP; partially
5-HT4 CNS, ,smooth muscle
selective agonists: 
metoclopramide (Reglan)
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