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Dr Patrick Amoateng

Dept of Pharmacology & Toxicology UG School of Pharmacy

Introduction
Serotonin was the name given to an unknown

vasconstrictor substance found in serum after blood has clotted It was identified chemically as 5hydroxytryptamine (5-HT) in 1948 It was shown to originate from the platelets It was subsequently found in the gastrointestinal tract and central nervous system (CNS) and shown to function both as a neurotransmitter and as a local hormone in the peripheral vascular system
5-HT seems to be 'involved in everything, but

responsible for nothing', a Autacoids 2011: Serotonin Apr 19, 2012 kind of mediator-

Distribution of 5-HT
5-HT occurs in the highest concentrations in three

situations in the body. In the wall of the intestine:

About 90% of the total amount in the body is present in enterochromaffin cells, which are cells derived from the neural crest, similar to those of the adrenal medulla, that are interspersed with mucosal cells, mainly in the stomach and small intestine Some 5-HT also occurs in nerve cells of the myenteric plexus, where it functions as an excitatory neurotransmitter 5-HT is present in high concentration in platelets, which accumulate it from the plasma by an active transport system and release it when they aggregate at sites of tissue damage 5-HT is a transmitter in the CNS and is present in high concentrations in localised regions of the midbrain
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In blood:

In the CNS:

5-HT

Biosynthesis of 5-HT
issynthesizedfrom theamino acidLtryptophan pathway consisting of twoenzymes:
tryptophan

Process is metabolic

hydroxylase(TPH) & amino acid decarboxylase(DDC)

The TPH-mediated

reaction is the ratelimiting step in the pathway


Two isoforms: Apr 19, 2012
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Autacoids 2011: Serotonin

Metabolism & Degradation of 5-HT


5-HT is mainly

metabolized to5HIAA, chiefly by the liver

1) oxidation

bymonoamine oxidase( MAO ) to the corresponding aldehyde

5-HIAA excreted

by the kidneys

2) oxidation

byaldehyde dehydrogenaseto 5-HIAA (the indole


acetic acid derivative)
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Distribution, biosynthesis and degradation of 5-hydroxytryptamine (5-HT)


Structures rich in 5-HT are:
gastrointestinal tract (chromaffin cells and enteric neurons) platelets central nervous system.

Metabolism closely parallels that of noradrenaline. 5-HT is formed from dietary tryptophan, which is

converted to 5-hydroxytryptophan by tryptophan hydroxylase, then to 5-HT by a non-specific decarboxylase.


5-HT is transported into 5-HT-containing cells by a

specific transport system.


Degradation occurs mainly by monoamine oxidase,

forming 5-HIAA (5-hydroxyindoleacetic acid), which is excreted in urine.


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Overview
o GIT: increased gastrointestinal motility

o o

o o o

(direct excitation of smooth muscle and indirect action via enteric neurons) SMOOTH MUSCLES: contraction of other smooth muscle (bronchi, uterus) BLOOD VESSELS: mixture of vascular constriction (direct and via sympathetic innervation) and dilatation (endothelium dependent) PLATELETS: platelet aggregation NERVE ENDINGS: stimulation of peripheral nociceptive nerve endings CNS: excitation/inhibition of CNS neurons.
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Overview
Postulated physiological and

pathophysiological roles include:


in periphery: peristalsis, vomiting, platelet

aggregation and haemostasis, inflammatory mediator, sensitisation of nociceptors and microvascular control in CNS: many postulated functions, including control of appetite, sleep, mood, hallucinations, stereotyped behaviour, pain perception and vomiting.

Clinical conditions associated with disturbed 5-

HT function include migraine, carcinoid syndrome, mood disorders and anxiety


Autacoids 2011: Serotonin Apr 19, 2012

Gastrointestinal tract
5-HT stimulates gastrointestinal motility
partly through a direct effect on the smooth muscle cells

(5-HT2-receptors) and partly as a result of an indirect excitatory effect on enteric neurons (5-HT3- and 5-HT4-receptors)

5-HT also stimulates fluid secretion and elicits nausea and vomiting by stimulating smooth muscle and sensory nerves in the stomach (5HT3- and 5-HT4-receptors)

The peristaltic reflex, evoked by increasing the

pressure within a segment of intestine, is mediated, partly at least, by the release of 5-HT from chromaffin cells in response to the mechanical stimulus Chromaffin cells also respond to vagal stimulation Autacoids 2011: Serotonin Apr 19, 2012 by releasing 5-HT

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Blood vessels
5-HT causes vasoconstriction of both arteries and

veins, via a direct action on vascular smooth muscle cells, mediated through 5-HT2A-receptors
Activation of 5-HT1-receptors causes constriction

of large intracranial vessels, dilation of which contributes to headache


5-HT can also cause vasodilatation, partly by acting

on endothelial cells to release nitric oxide and partly by inhibiting noradrenaline release from sympathetic nerve terminals

If 5-HT is injected intravenously, the blood pressure usually first rises, owing to the constriction of large vessels, and then falls, owing to arteriolar Autacoids 2011: Serotonin Apr 19, 2012 dilatation

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Platelets
5-HT causes platelet aggregation via 5-

HT2A-receptors, and the platelets that collect in the vessel release more 5-HT If the endothelium is intact, 5-HT release from adherent platelets causes vasodilatation, which helps to sustain blood flow if it is damaged (e.g. by atherosclerosis), 5-HT causes constriction and impairs blood flow further These effects of platelet-derived 5-HT are
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Nerve endings
5-HT stimulates nociceptive (pain-mediating)

sensory nerve endings, an effect mediated mainly by 5-HT3-receptors


If injected into the skin, 5-HT causes pain; given

systemically, it elicits a variety of autonomic reflexes through stimulation of afferent fibres in the heart and lungs, which further complicate the cardiovascular response
Nettle stings contain 5-HT, amongst other things

5-HT also inhibits transmitter release from adrenergic neurons in theAutacoids 2011: Serotonin Apr 19, 2012 periphery

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Central nervous system


5-HT excites some neurons and

inhibits others It also acts presynaptically to inhibit transmitter release from nerve terminals Different receptor types and different membrane mechanisms mediate these effects
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5-HT receptors
There are seven types (5-HT1-7), with

further subtypes (A-D) of 5-HT1 and 5HT2.


All are G-protein-coupled receptors,

except 5-HT3, which is a ligand-gated cation channel 5-HT1-receptors occur mainly in CNS (all subtypes) and some blood vessels (5-HT1D subtype)
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5-HT1 Receptors..
Effects are neural inhibition and

vasoconstriction
Act by inhibiting adenylate cyclase Specific agonists include sumatriptan

(used in migraine therapy) and buspirone (used in anxiety)

Ergotamine is a partial agonist Specific antagonists include

spiperone and methiothepin


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5-HT2 Receptors
5-HT2-receptors occur in CNS and

many peripheral sites (especially blood vessels, platelets, autonomic neurons) Neuronal and smooth muscle effects are excitatory. Some blood vessels dilated as a result of nitric oxide release from endothelial cells 5-HT2-receptors acts through phospholipase C/inositol
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5-HT2 Receptors..
Specific ligands include LSD (lysergic

acid diethylamide; agonist in CNS, antagonist in periphery)


Specific antagonists are ketanserin,

methysergide and cyproheptadine

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5-HT3-Receptors
5-HT3-receptors occur in peripheral

nervous system, especially nociceptive afferent neurons and enteric neurons, and in CNS
Effects are excitatory, mediated via direct

receptor-coupled ion channels

Specific agonist is 2-methyl-5-HT Specific antagonists are ondansetron

and tropisetron
Antagonists are used mainly as antiemetic
Autacoids 2011: Serotonin Apr drugs but may also be anxiolytic 19, 2012

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5-HT4-Receptors
5-HT4-receptors occur mainly in the enteric

nervous system (also in CNS)


Effects are excitatory, causing increased gastrointestinal

motility Act by stimulating adenylate cyclase

Specific agonists include metoclopramide (used

to stimulate gastric emptying)


Little is known so far about the function and

pharmacology of 5-HT5-7-receptors
Many new receptor-selective agonists and
Autacoids 2011: Serotonin antagonists are being developed Apr 19, 2012

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Ergot alkaloids
These active substances are produced by a fungus

that infects cereal crops; it is responsible for occasional poisoning incidents. The most important compounds are:
ergotamine, dihydroergotamine, used in migraine ergometrine, used in obstetrics to prevent postpartum

haemorrhage methysergide, used to treat carcinoid syndrome, and occasionally for migraine prophylaxis bromocriptine, used in parkinsonism and endocrine disorders.

Main sites of action are 5-HT receptors, dopamine

receptors and adrenoceptors (mixed agonist, antagonist and partial agonist effects) Unwanted effects include nausea and vomiting, Autacoids 2011: vasoconstriction (ergot alkaloidsSerotonin Apr 19, 2012 are

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Drugs used for migraine (Acute attack)


Simple analgesics (e.g. aspirin,

paracetamol) can be given with metoclopramide to speed up absorption Ergotamine (5-HT1D-receptor partial agonist) Sumatriptan (5-HT1D agonist) is effective but short acting (half-life about 2 hours) Newer compounds (e.g. zolmitriptan) are claimed to be faster acting and not to cause chest pain
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Drugs used for migraine (Prophylaxis)


This is considered for patients with more than one severe attack per month Beta-adrenoceptor antagonists (e.g. propranolol, metoprolol) Pizotifen (5-HT2-receptor antagonist)
Adverse effects include weight gain,

antimuscarinic effects

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Drugs used for migraine (Prophylaxis)


Other 5-HT2-receptor antagonists
cyproheptadine: also has antihistamine

and calcium antagonist actions methysergide: rarely used because of risk of retroperitoneal fibrosis and renal failure

Tricyclic antidepressants (e.g.

amitriptyline) May be effective even though patients are not depressed


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Drugs used for migraine (Prophylaxis)


Clonidime, an 2-adrenoceptor

agonist has been used, but efficacy is doubtful. Calcium antagonists (e.g. dihydropyridines, verapamil): headache is a side-effect of these drugs but, paradoxically, may reduce frequency of migraine attacks Their mechanism of action is unknown
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