PHARMACOLOGY

AUTACOIDS (SEROTONIN)
Esmarliza K. Tacud-Luzon, M.D.
10/19/2020
Lecture #5

OUTLINE
I. Serotonin
a. Synthesis, storage and metabolism
b. Physiological roles of serotonin
c. Mechanism of action ofn serotonin
d. Pharmacologic effects of serotonin
i. CVS
ii. Respiratory
iii. Nervous
iv. GIT
v. Skelatal muscle and eye
e. Serotonin Syndrome
f. Clinical Use
g. Serotonin Agonist
h. Serotonin Antagonist
i. Clinical Use

REFERENCES
 Doc Luzon;s PPT
 Katzung’s Basic and Clinical Pharmacology Figure 1. Synthesis of serotonin from L-tryptophan

Legends:   In the blood, serotonin is found in platelet which concentrate

the amine via serotonin transporter mechanism (SERT) similar to
REMEMBER Previous Trans Clinical
Lecturer Book serotonergic nerve endings
(Exams) Trans Com Correlation
  Once transported into the platelet or nerve ending, 5-HT is
      concentrated in vesicles by a vesicle-associated transporter
(VAT) that is blocked by reserpine
From the Subject Head / Trans Group / Review of Concepts  Serotonion is metabolized via monoamine oxidase (MAO) to
produce 5-hydroxyindoleacetaldehyde and further oxidized by
aldehyde dehydrogenase to produce 5-hydroxyindoleacetic
I. SEROTONIN (5-HYDROXYTRYPTAMINE)
acid (excreted in the urine 3-10mg/day)
 One of the most important autacoid. Has many physiologic roles  The excretion of 5-hydroxyindoleacetic acid increases in the
and serotonin agonists and antagonists have many clinical following conditions:
applications  Carcinoid syndrome
 Widely distributed in plants and animal tissues.  Using some old anti-hypertensive drugs (reserpine)
 In human about 90% of total body serotonin present in  Ingetion of banana
enterochromaffin tissues, 8% in platelets and 2% CNS.
PHYSIOLOGICAL ROLES OF SEROTONIN
  Important neurotransmitter
 It acts as a neurotransmitter in the brain
  Local hormone in the gut  Regulation of temperature
  Component of platelet clotting process  Pain perception
  Play a role in migraine headache  In pathogenesis of migraines
 In pathogeneis of depression
  Also plays a role in carcinoid syndrome
 In pathogenesis of anxiety
 Neoplasm of enterochromaffin cells
 Involved in intestinal motility
SYNTHESIS, STORAGE & METABOLISM
 Control of vomiting
  Synthesized from the amino acid L-tryptophan by  Control of appetite
hydroxylation (tryptophan hydroxylase-1) of indole ring  Pathogenesis lof carcinoid syndrome
followed by decarboxylation (aromatic L-amino acid MECHANISM OF ACTION OF SEROTONIN
decarboxylase) of the amino acid
 Serotonin exerts its action by binding to 7 subtypes of receptor.
 5-HT1 - GPCR
 5-HT2 - GPCR
 5-HT3 - Ligand-gated ion channel
 5-HT4 - GPCR
 5-HT5 - GPCR
 5-HT6 - GPCR
 5-HT7 – GPCR

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 The second messenger of G-protein coupled receptors is either Skeletal Muscle and Eye
cylic AMP or IP3 and DAG   5-HT2 receptors are present on skeletal muscle
 NOTE: Different serotonin receptors and their locations can be membranes but theoir physiologic role is not well understood.
found in the appendix (Figure 1) Plays a role in pathologic condition such as serotonin
PHARMACOLOGIC EFFECTS OF SEROTONIN syndrome.
Cardiovascular system   5-HT2A reduces intraocular pressure (animal models)
 Heart  Can be blocked by ketanserin and similar 5-HT2 antagonists.
 Smalldirect (+) chronotropic and inotropic effect with no
clinical significance Uterus
 Blood Vessels  Large dose of serotonin impairs placental blood supply
  Powerful vasoconstrictor via 5-HT2 receptor except in  and may lead to fetal distress
skeletal muscle and heart (vasodilation)
 Triphasic blood pressure response SEROTONIN SYNDROME
 Early depressor phase due to decrease heart rate and  It is related to the interactions of serotonin reuptake inhibitors or
cardiac output due to chemoreceptor reflex with monoamine oxidase inhbitors (MAOIs) or interaction with
 Presser effect due to increase TPR and cardiac output serotonin agonists and MAOIs
 Late depressor phase which is related to to vasodilation  Clinical emergency with high mortality rate
in skeletal muscle.  Characterized by:
  Platelet  Hyperthermia
 Stimulate aggregation via 5-HT2 receptor   Due to excessive skeletal muscle contractions
 Rigidity
Respiratory System   Due to action on skeletal mucle
 Small direct stimulant effect on bronchial smooth muscle via 5-  Myoclonus
HT2A receptor.  Mental changes
 Produces hyperventilation due to stimulation of bronchial  Tachycardia
sensory nerve endings
 Treatment is supportive
  Facilitates Ach release from bronchial vagal nerve endings CLINICAL USE
  In carcinoid syndrome  Serotonin has no clinical applications
 Episodes of bronchoconstriction is due to elevated  Clinical conditions in which 5-HT plays a role:
serotonin.  Migraine
 Carcinoid syndrome
Nervous System
 Stimulation of sensory nerve endings leads to pain and itching SEROTONIN AGONIST
  Precursor of melatonin in pineal gland   Serotonin has no clinical applications as a drug. However,

  Participate in vomiting reflex via 5-HT3 receptor in the GIT several receptor subtype-selective agonists have proved to be
of value
and in the vomiting center in the medulla
 Buspirone
 Important in vomiting caused by cancer chemotheraphy
 acts on 5-HT1A receptor
drugs
 It is an anxiolytic drug ( non benzodiazepines non
  Activation of 5-HT3 receptor on the afferent vagal nerve barbiturates anxiolytic)
endings is associated with chemoreceptor reflex (Bezold-   it addresses your cns depression
Harish reflex)
 Dexfenfluramine
 Reflex response consist of marked bradycardia and
 suppresses appetite and used to ↓ body weight
hypotension
 Sumatriptan, Amlotriptan, Eletriptan, Naratriptan,
 Bradycardia caused by vagal outflow to the heart
Rizatriptan, Zolmitryptan
 Hypotension is due to decrease CO as a result of
 they act on 5-HT1B and D receptors and used in treatment
bradycardia
of acute migraine
Gastrointestinal Tract  Cisapride
 it is used in the management of reflux esophagitis but now
 Powerful stimulant of GIT smooth muscle, increasing tone and rarely used because it causes serious ventricular
facilitating peristalsis via direct action on 5-HT2 receptor arrhytmias
  Activation of 5-HT4 receptor in ENS causes increase Ach  it acts on 5-HT4 receptor
release thereby facilitating motility-enhancing effect of serotonin  other 5-HT4 receptor agonist are
agonists such as cisapride.  Tageserol and Metaclopromide
  In carcinoid tumor
 Overproduction of serotonin causes severe diarrhea
Other Serotonin Agonist
 Sumatriptan
  Serotonin has little general inhibitory effect on GIT
 a receptor agonist
secretions.
 it is a 5-HT1D agonist

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   all serotonin agonist that ends in -triptan is used for acute  they are, however non-selective, and act laso on targets,
migrane such as alpha-adrenoceptos and histamine receptors
 Effective in the treatment of acute migraine and cluster  Dihydroergotamine and methysergide belong to the ergot
headache attacks – an observation that supports the family and are used mainly for migraine prophylaxis
association of 5-HT abnormalities with these headache  Ketotifen is sometimes used to treat asthma but the role of 5-
syndromes HT receptors in this condition is unclear
 it is available for oral, nasal, or parenteral administration  Other 5-HT2 antagonists are used to control the symptoms of
carcinoid tumours
Serotonin re-uptake inhibitors
 Used for treatment of depression 5-HT Antagonists
 Dexfenfluramine  Ketanserin
 a reuptake inhibitor with other effects, was used exclusively  5-HT2 and alpha-adrenoceptor blocker
for appetite-reducing effect. while effective as an  Phenoxybenzamine
anorexiant, it is toxic:  alpha-adrenoceptor blocker
 cardiac disease in patients and neurological damage in  Cyproheptadine
animals were reported  H1-blocker are also good 5-HT2 blockers
 Ondansetron
SEROTONIN ANTAGONIST  5-HT3 blocker
 Cyproheptadine (periactin)
  so if serotonin is used to decreased the appetite, CLINICAL USE
Cyproheptadine will stimulate the appetite  Used in the treatment of carcinoid tumor, a neoplasm that
 it is H1 and 5-HT2 blocker, used mainly as appetite secrete large amount of 5-HT (and peptides) and causes
stimulant diarrhea, bronchoconstriction, flushin
  The actions of cyproheptadine are predictable from its  Ondansetron is extremely useful in the control of post-
operative vomiting associated with cancer chemotherapy
H1 histamine and 5-HT receptor affinities. It prevents the
smooth muscle effects of both amines but has no effect on
Toxicity
the gastric secretion stimulated by histamine. It also has
significant antimuscarinic effects and causes sedation  Adverse effects of Ketanserin are those of alpha blockade and
 other uses include: H1 blockade
 Allergic rhinitis, cold urticaria, prophylaxis of migraine, in  The toxicity of Ondansetron include diarrhea and headache
Dumping syndrome after gasterectomy and in carcinoid
syndrome
 Ketanserin
 it is 5-HT2 and α-blocker
 it was used in the treatment of hypertension
  The mechanism involved in ketanserin’s hypotensive
action probably involves α1 adrenoceptor blockade more
than 5-HT2 receptor blockade
 Ritanserin
 it is 5-HT2 blocker and has no α-blocking effect
  It has been reported to alter bleeding time and to reduce
thromboxane formation, presumably by altering platelet
function
 Ondansetron, Granisetron, Tropisetron and Alosetron
 Acts on 5-HT3 receptor as antagonists and used mainly in
cytotoxic induced nausea and vomiting
 Ergot Alkaloids
  actually they have a different classification
 they are produced by fungus that infects grain
 can act on the following receptors:
 a – Serotonin receptor
 b – α adrenoceptor
 c – Dopamine receptor
 Ergots act as agonist, partial agonist or antagonist

5-HT RECEPTOR ANTAGONISTS

 5-HT2-receptor antagonist
 (e.g. dyhdroergotamine, methysrgide, cyproheptadine,
kentanserin, ketotifen, pizotifen)
 these classical 5-HT anatagonists act mainly on the 5-HT2-
receptors.

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 APPENDIX

Figure 1. Serotonin Receptor Subtypes

Figure 2. Pharmakokinetics of Triptans (5-HT1D or 5-HT1B Agonists) (Most popular are sumatriptan and zolmitriptan)

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