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 Clinical
Lecturer Book Trans Com serotonergic nerve endings
(Exams) Trans 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
I. SEROTONIN (5-HYDROXYTRYPTAMINE) aldehyde dehydrogenase to produce 5-hydroxyindoleacetic
acid (excreted in the urine 3-10mg/day)
1. One of the most important autacoid. Has many
 The excretion of 5-hydroxyindoleacetic acid increases in the
physiologic roles and serotonin agonists and antagonists
following conditions:
have many clinical applications
2. Widely distributed in plants and animal tissues.  Carcinoid syndrome
3. In human about 90% of total body serotonin present in  Using some old anti-hypertensive drugs (reserpine)
enterochromaffin tissues, 8% in platelets and 2% CNS.  Ingetion of banana
4.  Important neurotransmitter PHYSIOLOGICAL ROLES OF SEROTONIN
5.  Local hormone in the gut 9. It acts as a neurotransmitter in the brain
10. Regulation of temperature
6.  Component of platelet clotting process 11. Pain perception
7.  Play a role in migraine headache 12. In pathogenesis of migraines
8.  Also plays a role in carcinoid syndrome 13. In pathogeneis of depression
14. In pathogenesis of anxiety
1. Neoplasm of enterochromaffin cells
15. Involved in intestinal motility
SYNTHESIS, STORAGE & METABOLISM
16. Control of vomiting
  Synthesized from the amino acid L-tryptophan by
17. Control of appetite
hydroxylation (tryptophan hydroxylase-1) of indole ring 18. Pathogenesis lof carcinoid syndrome
followed by decarboxylation (aromatic L-amino acid MECHANISM OF ACTION OF SEROTONIN
decarboxylase) of the amino acid
19. Serotonin exerts its action by binding to 7 subtypes of
receptor.
1. 5-HT1 - GPCR
2. 5-HT2 - GPCR
3. 5-HT3 - Ligand-gated ion channel
4. 5-HT4 - GPCR
5. 5-HT5 - GPCR
6. 5-HT6 - GPCR
7. 5-HT7 – GPCR

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 20. The second messenger of G-protein coupled receptors is 1. Overproduction of serotonin causes severe
either cylic AMP or IP3 and DAG diarrhea
21. NOTE: Different serotonin receptors and their locations 36.  Serotonin has little general inhibitory effect on GIT
can be found in the appendix (Figure 1) secretions.
PHARMACOLOGIC EFFECTS OF SEROTONIN
Cardiovascular system Skeletal Muscle and Eye
22. Heart 37.  5-HT2 receptors are present on skeletal muscle
1. Smalldirect (+) chronotropic and inotropic effect with
membranes but theoir physiologic role is not well
no clinical significance
understood. Plays a role in pathologic condition such as
23. Blood Vessels
serotonin syndrome.
1.  Powerful vasoconstrictor via 5-HT2 receptor
38.  5-HT2A reduces intraocular pressure (animal models)
except in skeletal muscle and heart (vasodilation)
1. Can be blocked by ketanserin and similar 5-HT 2
2. Triphasic blood pressure response
antagonists.
1. Early depressor phase due to decrease heart
rate and cardiac output due to chemoreceptor
Uterus
reflex
 Large dose of serotonin impairs placental blood supply
2. Presser effect due to increase TPR and
 and may lead to fetal distress
cardiac output
3. Late depressor phase which is related to to
SEROTONIN SYNDROME
vasodilation in skeletal muscle. 39. It is related to the interactions of serotonin reuptake
24.  Platelet inhibitors or with monoamine oxidase inhbitors (MAOIs)
1. Stimulate aggregation via 5-HT2 receptor or interaction with serotonin agonists and MAOIs
40. Clinical emergency with high mortality rate
Respiratory System 41. Characterized by:
25. Small direct stimulant effect on bronchial smooth muscle 1. Hyperthermia
via 5-HT2A receptor. 1.  Due to excessive skeletal muscle
26. Produces hyperventilation due to stimulation of bronchial
contractions
sensory nerve endings
2. Rigidity
27.  Facilitates Ach release from bronchial vagal nerve 1.  Due to action on skeletal mucle
endings 3. Myoclonus
28.  In carcinoid syndrome 4. Mental changes
1. Episodes of bronchoconstriction is due to elevated 5. Tachycardia
serotonin. 42. Treatment is supportive
CLINICAL USE
Nervous System 43. Serotonin has no clinical applications
29. Stimulation of sensory nerve endings leads to pain and 44. Clinical conditions in which 5-HT plays a role:
itching 1. Migraine
30.  Precursor of melatonin in pineal gland 2. Carcinoid syndrome

31.  Participate in vomiting reflex via 5-HT3 receptor in

SEROTONIN AGONIST
the GIT and in the vomiting center in the medulla
1. Important in vomiting caused by cancer
45.  Serotonin has no clinical applications as a drug.
However, several receptor subtype-selective agonists
chemotheraphy drugs
have proved to be of value
32.  Activation of 5-HT3 receptor on the afferent vagal 46. Buspirone
nerve endings is associated with chemoreceptor reflex 1. acts on 5-HT1A receptor
(Bezold-Harish reflex) 2. It is an anxiolytic drug ( non benzodiazepines non
1. Reflex response consist of marked bradycardia and barbiturates anxiolytic)
hypotension
3.  it addresses your cns depression
1. Bradycardia caused by vagal outflow to the
47. Dexfenfluramine
heart
1. suppresses appetite and used to ↓ body weight
2. Hypotension is due to decrease CO as a result
48. Sumatriptan, Amlotriptan, Eletriptan, Naratriptan,
of bradycardia
Rizatriptan, Zolmitryptan
1. they act on 5-HT1B and D receptors and used in
Gastrointestinal Tract
treatment of acute migraine
33. Powerful stimulant of GIT smooth muscle, increasing 49. Cisapride
tone and facilitating peristalsis via direct action on 5-HT 2 1. it is used in the management of reflux esophagitis
receptor but now rarely used because it causes serious
34.  Activation of 5-HT4 receptor in ENS causes increase ventricular arrhytmias
Ach release thereby facilitating motility-enhancing effect 2. it acts on 5-HT4 receptor
of serotonin agonists such as cisapride. 3. other 5-HT4 receptor agonist are
35.  In carcinoid tumor 1. Tageserol and Metaclopromide

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Other Serotonin Agonist 5-HT RECEPTOR ANTAGONISTS
 Sumatriptan 56. 5-HT2-receptor antagonist
 a receptor agonist 1. (e.g. dyhdroergotamine, methysrgide,
 it is a 5-HT1D agonist cyproheptadine, kentanserin, ketotifen,
  all serotonin agonist that ends in -triptan is used for acute pizotifen)
2. these classical 5-HT anatagonists act mainly on the
migrane
5-HT2-receptors.
 Effective in the treatment of acute migraine and cluster
3. they are, however non-selective, and act laso on
headache attacks – an observation that supports the
targets, such as alpha-adrenoceptos and
association of 5-HT abnormalities with these headache
histamine receptors
syndromes
57. Dihydroergotamine and methysergide belong to the
 it is available for oral, nasal, or parenteral administration
ergot family and are used mainly for migraine prophylaxis
58. Ketotifen is sometimes used to treat asthma but the role
Serotonin re-uptake inhibitors
of 5-HT receptors in this condition is unclear
 Used for treatment of depression
59. Other 5-HT2 antagonists are used to control the
 Dexfenfluramine
symptoms of carcinoid tumours
 a reuptake inhibitor with other effects, was used exclusively
for appetite-reducing effect. while effective as an 5-HT Antagonists
anorexiant, it is toxic: 60. Ketanserin
 cardiac disease in patients and neurological damage in 1. 5-HT2 and alpha-adrenoceptor blocker
animals were reported 61. Phenoxybenzamine
1. alpha-adrenoceptor blocker
SEROTONIN ANTAGONIST 62. Cyproheptadine
50. Cyproheptadine (periactin) 1. H1-blocker are also good 5-HT2 blockers
51.  so if serotonin is used to decreased the appetite, 63. Ondansetron
Cyproheptadine will stimulate the appetite 1. 5-HT3 blocker
1. it is H1 and 5-HT2 blocker, used mainly as appetite
stimulant CLINICAL USE
2.  The actions of cyproheptadine are predictable 64. Used in the treatment of carcinoid tumor, a neoplasm
from its H1 histamine and 5-HT receptor affinities. It that secrete large amount of 5-HT (and peptides) and
prevents the smooth muscle effects of both amines causes diarrhea, bronchoconstriction, flushin
but has no effect on the gastric secretion stimulated 65. Ondansetron is extremely useful in the control of post-
by histamine. It also has significant antimuscarinic operative vomiting associated with cancer
effects and causes sedation chemotherapy
3. other uses include:
1. Allergic rhinitis, cold urticaria, prophylaxis of Toxicity
migraine, in Dumping syndrome after 66. Adverse effects of Ketanserin are those of alpha
gasterectomy and in carcinoid syndrome blockade and H1 blockade
52. Ketanserin 67. The toxicity of Ondansetron include diarrhea and
1. it is 5-HT2 and α-blocker headache
2. it was used in the treatment of hypertension
3.  The mechanism involved in ketanserin’s
hypotensive action probably involves α1
adrenoceptor blockade more than 5-HT2 receptor
blockade
53. Ritanserin
1. it is 5-HT2 blocker and has no α-blocking effect
2.  It has been reported to alter bleeding time and
to reduce thromboxane formation, presumably by
altering platelet function
54. Ondansetron, Granisetron, Tropisetron and
Alosetron
1. Acts on 5-HT3 receptor as antagonists and used
mainly in cytotoxic induced nausea and vomiting
55. Ergot Alkaloids
1.  actually they have a different classification
2. they are produced by fungus that infects grain
3. can act on the following receptors:
1. a – Serotonin receptor
2. b – α adrenoceptor
3. c – Dopamine receptor
4. Ergots act as agonist, partial agonist or antagonist

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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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