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Other Peripheral

Mediators: 5hydroxytryptamine and


Purines

5-HT; serotonin and purines are


mediators at two
mediator/neurotransmitter systems p
The two systems act in both the
periphery and the central nervous
system (CNS).

5-HYDROXYTRYPTAMINE
5-HT occurs in the GI tract, blood platelets
and the CNS.
In the CNS, it is found especially in the
midbrain raphe nucleus, and it is
implicated in the control of appetite, sleep,
vomiting and mood and
Also 5-HT is thought to be involved in the
descending control of pain inputs
In the periphery, it is concerned with
microvascular control and influences the
sensitivity of pain fibres.

Substantial amounts of 5-HT are also found


in platelets, where it has an important role
in platelet aggregation; it also serves as an
inflammatory mediator.
Most of the 5-HT in the body is, however,
found in the enterochromaffin cells in the
mucosa of the stomach and intestine, where
it has important effects on secretion and
motility.
5-HT function is abnormal in affective
disorders and anxiety and it is overproduced
by tumours of enterochromaffin cells
(carcinoid syndrome).

Synthesis, storage, release and


metabolism of 5-HT
5-HT is synthesised from dietary
tryptophan (Fig. 12.1) and is stored in
granulated vesicles, much like
noradrenaline.
5-HT neurons have specific 5-HT reuptake
transporters, which are important targets
for the selective serotonin reuptake
inhibitors (SSRIs antidepressant drugs.
Reuptake is the main mechanism for
terminating 5-HT action.

Synthesis, storage, release and


metabolism of 5-HT continued
Platelets lack tryptophan hydroxylase and
are unable to synthesise 5-HT; therefore,
they accumulate it by active uptake from the
blood (especially in the intestinal circulation
where 5-HT concentration is high)
5-HT's actions are quickly terminated by
degradation and reuptake.
Much of the 5-HT released into the
circulation by enterochromaffin cells will be
deaminated by hepatic monoamine oxidase
(MAO).

Synthesis, storage, release and


metabolism of 5-HT continued
5-HT that survives first-pass liver
metabolism is taken up by endothelial cells
in lung blood vessels and subject to further
MAO action.
Sequential metabolism by aldehyde
dehydrogenase yields the major metabolite,
5-hydroxyindoleacetic acid (5-HIAA).
5-HT neurotransmission is enhanced by
MAO inhibitors and this contributes to their
antidepressant activity.

Figure 12.1
Synthesis and
metabolism of
5-HT
.

5-HT receptors
There are seven families of 5-HT receptors
(5-HT1-7) containing at least 14 members
(seeTable 12.1)
5-HT receptor activation leads to widespread
effects sometimes in opposite directions.
Most of the receptor subtypes are found in
the brain, with overlapping distributions.
Except for the 5-HT3, ligand-gated ion
channel, 5-HT receptors, are all G-protein
coupled.

Table 12-1. The roles of 5-HT receptors


ceptor

Transduction

Effects

Clinically useful drugs

1A, 1B, 1D, 1E, 1F

Buspirone(1A agonist) for


anxiety

2A, 2B, 2C

Gq activation; phospholipase C
and A2 activation; formation of
inositol trisphosphate and
diacylglycerol

Neuronal excitation, smooth


muscle contraction (vascular,
gastrointestinal tract,
bronchiolar), platelet
aggregation (2A):
cerebrospinal fluid secretion
(2C)

Ketanserin,
methysergide (2A
antagonists) for
migraine;olanzapine,
risperidone (2A antagonists)
for schizophrenia .
(LSD's psychotomimetic
actions are due to activation of
2A receptors)

Ligand-gated cation channel

Neuronal excitation, emesis


(central and peripheral
components), effects on gut
motility and secretion

Ondansetron and granisetron


are antagonists used as antiemetics

Gs activation and stimulation of Increased peristalsis, neuronal Metoclopramide, cisapride,


excitation in central and enteric zacopride are agonists
adenylate cyclase
nervous system, intestinal
stimulating peristalsis and can
secretion
be used in heartburn

5A, 5B, 6, 7

Gs activation of adenylate
cyclase by 6 and 7; 5 not
established

Not well established

None

Migraine
The aetiology of the visual disturbances, headache
and other symptoms of migraine is still not well
established,
Both abnormal neuronal discharge and changes in
cerebral blood flow being implicated.
The increase in the urinary excretion of 5-HIAA
during a migraine attack, and the useful clinical
benefits obtained by modification of 5-HT
mechanisms point to a role for 5-HT in the
pathogenesis.
5-HT-mediated vasoconstriction may contribute to
the early visual effects and inflammatory
vasodilatation to the later effects.

Migraine continued
The beneficial effects of 5-HT 2antagonists
may relate to inhibition of the early
vasoconstriction and the effectiveness of 5HT1receptor agonists (sumatriptan and
others) to constriction of cranial blood
vessels.
Dihydroergotamine and other ergot alkaloids
have additional effects on -adrenoceptors
Sumatriptanis administered
subcutaneously for an acute attack and is
effective in up to 95% of patients

Migraine continued
Methysergide, used to prevent
migraine headaches, is a potent 5HT2antagonist.
5-HT3antagonists have also been
shown to be effective in migraines.
Other drugs used for migraine are blockers, non-steroidal antiinflammatory drugs, Ca2+channel
blockers and some antiepileptic and
antidepressant drugs.

PURINES
The purine adenosine and the purine
nucleotide ATP act as mediators and
neurotransmitters, interacting with specific
receptors in a wide range of tissues.
ATP is stored in synaptic vesicles and
released from nerves as either a primary
transmitter or a co-transmitter.
Adenosineis not stored in vesicles but
can be released by nerve endings and
other cell types

PURINES continued
Adenosine also is formed by the
breakdown of ATP in the extracellular
space by ectoATPases and other
enzymes.
Adenosine acts as a neuromodulator
rather than neurotransmitter.
It reaches high concentration in
hypoxic tissues and is an important
mediator of reactive hyperaemia.

PURINES continued
Adenosine is quickly removed from
the circulation due to rapid uptake
into cells (especially endothelial cells)
and by the action of adenosine
deaminase.
This is consistent with its role as a
local hormone.
An intravenous dose of adenosine
works only for about 10s.

Receptors for purines


For historical reasons, adenosine
receptors are referred to either as P 1or A
(adenosine) receptors and ATP/ADP
receptors as P2(Table 12.2).
Adenosine receptors are subclassified as
A1, A2A, A2Band A3.
These are G-protein-coupled receptors;
A1couples to Gior Go, to inhibit
adenylate cyclase, open K+channels or
inhibit Ca2+channels.

Receptors for purines continued


A2couples to Gsto stimulate adenylate
cyclase, A3couples to Giand Gq.
Methylxanthines are adenosine receptor
antagonists and the CNS stimulant
action of caffeine can be attributed to
inhibition of A2receptor activation.
There are subtypes also of P2receptors:
P2X(ligand-gated cation channel) and
P2Y(Gq-protein coupled).

Receptors for purines continued


Several subtypes of P2Xand
P2Yreceptors have been identified.
Receptors for adenosine and ATP are
widely distributed throughout
neurons and peripheral tissues.
P2Xreceptors are found mainly on
excitable cells (neurons and smooth
muscle).

Receptors for purines continued


P2Y1and P2Y12receptors respond
particularly to ADP and are concerned
in platelet activation/thrombosis.
Important actions of adenosine and
ATP are listed inTable 12.2.

Table 12-2. Purine mediators and receptors

Mediator

Tissue
A1

Effect
Cardiac muscle

Receptor
Mechanism
Slowed atrioventricular
A1
conduction, reduced force
of contraction, slowed
pacemaker activity

Neurons

Inhibition of transmitter
release (reduced
glutamate excitotoxicity)

A1

Inhibition of Ca2+ entry

Decreased excitability

A2

Stimulation of pain fibres


(e.g. pain of angina)

A2

Mast cells

Release of mediators
(bronchoconstriction)

A3

Platelets

Inhibition of aggregation

A2

ATP

Smooth muscle

Relaxation (blood vessels, P2Y


gut) Contraction

P2X

Depolarisation, Ca2+ entry

Endothelial cells

Endothelium-dependent
vasodilatation

P2Y

Stimulation of
phospholipase C, inhibition
of adenylate cyclase
Adenylate cyclase
activation

Nitric oxide release

Increased K+ permeability

Clinical uses of drugs acting


on purinoceptors
Adenosineis used only in the treatment of
supraventricular tachycardia .
Theophylline(a methylxanthine) is a
phosphodiesterase inhibitor used in the treatment of
asthma; it has, as a side effect, CNS stimulation, which
is at least partly due to antagonism at adenosine
receptors.
Dipyridamole(another phosphodiesterase inhibitor)
interferes with the cellular uptake of adenosine and this
contributes to its inhibition of platelet aggregation and
its vasodilator action.
An active metabolite ofclopidogrel, a P2Y12antagonist,
has antiplatelet action and is used for stroke or heart
attack.

Other peripheral mediators:


peptides and proteins
Peptides (<50 amino acid residues)
and proteins outnumber non-peptides
as mediators within the body.
In the nervous system peptides are
frequently found as co-transmitters
(e.g. neuropeptide Y with
noradrenaline).

Synthesis and storage of peptide


mediators
Peptide mediators are produced by
the splitting of precursor proteins,
synthesised in the usual manner by
mRNA coding in ribosomes, and
stored in secretory vesicles.
Precursor proteins may give rise to
several peptide mediators

Synthesis and storage of peptide


mediators continued
The particular peptides generated
from the precursor in any given
tissue depending on the tissue's
complement of peptidases (e.g.
proopiomelanocortin,Fig. 13.1).
Peptide mediators have important
actions in many systems (e.g. opioid
peptides, cytokines).

Figure 13.1Proopiomelanocortin: a
precursor protein which can be
split to give several peptides.MSH,
melanocyte-stimulating hormone.

Mechanism of action of peptide


mediators
Small peptides and chemokines
generally interact with G-proteincoupled receptors, whereas other
cytokines and growth factors work
via tyrosine kinase receptors

Pharmacokinetic aspects of peptides


In general, peptides are poorly absorbed by
oral administration and are quickly broken
down by peptidases.
Unlike other mediators, reuptake is not an
important mechanism for termination of
peptide action.
They do not readily cross the blood-brain
barrier.
Antagonists produced by amino acid
substitution are likely to have pharmacokinetic
properties similar to the native peptide.

Pharmacokinetic aspects of
peptides continued
Accordingly, drug companies seek to produce
non-peptide antagonists with improved
pharmacokinetic properties.
Relatively few non-peptide drugs interacting with
these receptors are yet available,morphine
analoguesandlosartanbeing examples.
Inhibition of peptide breakdown is another
potential strategy for drug development.
(Kelatorphan, which has analgesic actions by
slowing the breakdown of enkephalins, is an
example.)

Clinical aspects of peptides


Peptides may be administered as
replacement therapy where natural
production is impaired (e.g. insulin,
clotting factors, growth hormone)
And antibodies can be used to
combat foreign proteins (e.g.
antivenins).

Clinical aspects of peptides


continued
Recombinant methods now allow
peptides to be produced in larger
quantities by bacteria rather than
being extracted from animal tissues.
Recombinant technology has also
allowed 'human' insulin to be used
rather than animal insulins.
Selected peptides and antagonists are
listed inTable 13.1.

Table 13-1. Selected peptide


mediators and clinically useful
drugs
Mediator
Angiotensin II, III

Receptor
AT1, AT2

Bradykinin
Calcitonin generelated peptide
Neuropeptide Y
(NPY)
Somatostatin

B1, B2
CGRP receptor

Cholecystokinin

CCK1, CCK2

Agonists

Clinical uses of
agonist

Icatibant
CGRP8-7

Y1-Y5
sst1-5

OT
V1, V2

Octreotide

Insulin receptor

Liver cirrhosis

Acromegaly,
gastrointestinal
tumours
Lorglumide

Gastrointestinal
disorders (Specific
tumour treatment)

Experimental
Bosentan
Morphine, fentanyl

Analgesia

Naloxone,
naltrexone

Desmopressin,
felypressin

Induction of labour
Diabetes insipidus,
vasoconstriction

Atosiban
Experimental

Tachykinins (SP etc) NK1, NK2, NK3


Glucagon
Glucagon receptor
Insulin

Clinical uses of
antagonist
Hypertension

(Potential antiobesity)

Vasoactive intestinal VPAC1, VPAC2


peptide, VIP
CorticotrophinCRF1, CRF2
releasing factor
Endothelins
ETA, ETB
Opioid peptides,
enkephalins,
endorphins
Oxytocin
Vasopressin

Antagonists
Saralasin, losartan
(AT1selective)

Experimental
Experimental

Insulins

Hypoglycaemia,
Cardiac stimulation
Diabetes mellitus
None

Pulmonary arterial
hypertension
Opioid overdose

Preterm labour

(Potential use in
type 2 diabetes)