This document discusses the pharmacology of serotonin (5-HT). It begins by describing the historical identification of 5-HT and its role as a neurotransmitter and hormone. It then discusses the distribution, biosynthesis, metabolism, and receptors of 5-HT. The major receptors discussed are 5-HT1-5HT4 receptors, and their roles in the CNS and periphery. The effects of 5-HT at different receptors, such as its effects on blood vessels, platelets, and smooth muscle are summarized. Finally, the mechanisms and uses of serotonergic drugs like SSRIs and ergot alkaloids are discussed.

1. THE PHARMACOLOGY
OF SEROTONIN (5-HT)

2. Historical background
 Before identification of 5-HT it was known
that when blood is allowed to clot a
vasoconstrictor (tonic) substance is released
from the clot into the serum
 This substance was called serotonin
 Independent studies established the
existence of a smooth muscle stimulant in
intestinal mucosa (enteramine)

3.  Serotonin was identified chemically in 1948
to be 5-HT and shown to originate from
platelets
 Synthesized in 1951; confirmed to be
similar to enteramine

4. Occurance
 Widely distributed in nature
 Found in plant & animal tissues
 Found in venoms and stings
 Play role in several diseases eg. Carcinoid
syndrome (tumor of enterochromaffin cells)
 Functions as a neurotransmitter and a local
hormone in the peripheral vascular system

5. Distribution in the body
 In the walls of the intestines in
-enterochromaffin cells (90% of total
amount in the body)
- nerve cells of myenteric plexus
(where it functions as an excitatory
neurotransmitter)
 5-HT is released in response to mechanical
and neuronal stimuli

6. In blood: Occur in high concentrations
in platelets
 Platelets accummulate 5-HT from plasma
by an active carrier mediated transport
mechanism
 Released when platelets aggregate at sites
of tissue damage

7. In the CNS
 Found in high concentrations in specific
areas of the midbrain
 In the pineal gland 5-HT serves as a
precursor of melatonin (a melanocyte-
stimulating hormone)
 Excites some neurones and inhibits
others

8. Biosynthesis & metabolism
 Synthesized from dietary tryptophan
 Formed by hydroxylation of the indole ring
followed by decarboxylation of the amino
acid
 Hydroxylation at C5 is the rate limiting step
and can be blocked by chlorophenylalanine
(PCPA; fenclonine) or
parachloroamphetamine.

9. Biosynthesis & metabolism
 Mechanisms of synthesis, storage,
release and reuptake of 5-HT are very
similar to those of NA
 Many drugs affect both processes
indiscriminately
 5-HT is often stored in neurons and
chromaffin cells as a co-transmitter
together with peptide hormones such as
somatostatin, substance P, VIP

10.  Serotonin can be depleted from storage
vescicles by reserpine in much the same
way as catecholamines.

11. Tryptophan
Tryptophan hydroxylase
5-Hydroxytryptophan
L-aromatic acid decaboxylase
5-HT
MAO (oxidative deamination)
5-hydroxyindole acetaldehyde
Aldehyde dehydrogenase (oxidation)
5-hydroxyindole Acetic acid (5-HIAA)

12. 5-HIAA
 Excreted in urine
 Used as an indicator of 5-HT production in
the body
 Used in the diagnosis of carcinoid
syndrome

13. Pharmacological effects of 5-HT
GIT
 Increase motility and contraction of isolated
strips of intestine
 Effect is due to direct effect on smooth
muscle
 Indirect excitatory effect on enteric neurons
 Chromaffin cells release 5-HT in response
to mechanical and vagal stimulation

14. Other smooth muscles
Uterus, bronchial tree
 Contracted by 5-HT in many species except
in humans where it occurs to a minor extent
Blood vessels
 Effect depends on various factors
– Size of the vessel
– Species
– The prevailing sympathetic activity

15.  Large vessels (arteries & veins) are
usually constricted by 5-HT (sensitivity
varies greatly)
 It is a direct effect on vascular smooth
muscle mediated by 5-HT2A-receptors
 5-HT also causes vasodilatation by
acting on 5-HT1-receptors, partly by
releasing NO from endothelial cells and
partly by inhibiting NA release from
sympathetic nerve terminals

16.  5-HT2A is vasoconstrictor and 5-HT1 is
vasodilator
 When 5-HT2A receptors are blocked by
ketanserin the vasodilator effect is revealed
 When 5-HT is injected i.v the BP usually 1st
rises due to vasoconstriction of large blood
vessels
 It then falls due to arteriolar vasodilatation

17.  In skeletal muscle and the heart it causes
vasodilatation

18. Platelets
 5-HT causes platelet aggregation via 5-
HT2A receptors
 Aggregated platelets release more 5-HT
 When endothelium is intact 5-HT causes
vasodilatation (sustain blood flow)
 If endothelium is damaged 5-HT causes
vasoconstriction and impair blood flow)
 The effects of platelet-derived 5-HT are
important in vascular disease

19. In the CNS
 Found in high concentrations in specific
areas of the midbrain
 In the pineal gland 5-HT serves as a
precursor of melatonin (a melanocyte-
stimulating hormone)
 Excites some neurones and inhibits
others

20.  Acts pre-synaptically to inhibit transmitter
release from nerve terminals
 Different receptor types & membrane
mechanisms mediate these effects

21. 5-HT in the brain
 involved in the regulation of mood, sleep,
appetite, temperature
 Perception of pain
 Regulation of blood pressure
 Vomiting
 Also involved in aspects of depression,
anxiety and migraine

22. Nerve endings
 Potent stimulant of pain & itch sensory
nerve endings
 Injected into the skin it causes pain
 Responsible for some of the symptoms of
insect and plant stings
 Effect mediated by 5-HT3-receptors

23. Systemic effects
 5-HT is a powerful activator of
chemosensitive endings located in the
coronary vascular bed
 Activation of 5-HT3-receptors on these
afferent vagal nerve endings is associated
with the chemoreceptor reflex (the Bezold-
Jarisch reflex)
 Reflex response consists of marked
bradycardia and hypotension

24.  5-HT inhibits transmitter release from
adrenergic neurons in the periphery

25. Effect on the heart
 Dilates coronary blood vessels

26. 5-HT-Receptors
5-HT1-receptors
 Occur mainly in the brain
 Subtypes are distinguished on the basis of
regional distribution and pharmacological
specificity
 Function as inhibitory pre-synaptic
receptors
 G-protein coupled & linked to inhibition of
adenylate cyclase

27. 5-HT1A -Receptors
 Important in the brain
 Cause neuronal inhibition
 Decrease levels of cAMP
 Involved in the regulation of behavior,
mood, sleep, feeding, temperature, anxiety
 Agonists: by 5-Carboxamidotryptamine, 8-
hydroxy-2(di n-propylamino)tetraline and
busipirone(PA)
 Antagonists: spiperone, methiothepin,
ergotamine(PA)

28.  Busipirone is a nonbenzodiazepine
anxiolytic

29. 5-HT1B -Receptors
 Also CNS, causing pre-synaptic inhibition
 Involved in the regulation of behavior
 Agonist: 5-CT
 Antagonist: methiothepin. Ergotamine is a
partial agonist

30. 5-HT1D -Receptors
 CNS and cerebral blood vessels
 Mediate cerebral vasoconstriction, regulate
behavior and locomotion
 Inhibit adenylate cyclase
 Agonists: 5-CT and sumatriptan,
naratriptan, rizatriptan, zolmitriptan (act on
both 5-HT1D and 5-HT1B

31.  both 5-HT1D and 5-HT1B are found on
cerebral and meningeal vessels and mediate
vasoconstriction
 Useful for treatment of acute migraine
 Cause coronary vasospasm (contraindicated
in coronary artery disease and angina)
 Antagonist: methiothepin. Ergotamine is a
partial agonist

32.  Believed to be important in migraine
 Sumatriptan is used to treat acute migraine
attacks
 Ergotamine is used for prophylaxis of
migraine
 Vasodilator effect by 5-HT1-receptors on
cerebral blood vessels is unusual
 in most blood vessels vasoconstriction is
mediated by 5-HT2-receptors

33. Other 5-HT1-receptors
 5-HT1E present in the cortex and putamen
 5-HT1F present in the cortex and
hippocampus
 Inhibit adenylate cyclase
 No specific agonists or antagonists yet

34. 5-HT2-Receptors
 All stimulate PLC leading to hydrolysis of
PIP2
 Stimulation increase levels of IP3 and DG
 More important in the periphery than CNS
 Cause neuronal excitation
 Modulate behavior
 Mediate platelet aggregation, smooth
muscle contraction (bronchial, uterus)
 Vasoconstriction/vasodilatation)

35. 5-HT2A-Receptors
 CNS, PNS, smooth muscle, platelets
 In the CNS they mediate behavioral
changes (eg. Lysergic acid diethylamide,
LSD)
 In the periphery they mediate smooth
muscle contraction
 Agonist: α-Me 5-HT, LSD
 Antagonists: dihydroxyergotamine,
ketanserin, cyproheptadine, ketotifen,
pizotifen(non-selective), LSD, methysergide

36.  They are non-selective;
 Also act on α-adrenoceptors and histamine
receptors
 Cyproheptadine and pizotifen are used to
control symptoms of the carcinoid
syndrome
 Dihydroxyergotamine is used for
prophylaxis of migraine
 Ketotifen: sometimes used for treatment of
asthma

37.  Ritanserin: is a more selective 5-HT2 –
receptor antagonist with little or no α-
adrenoceptor blocking effect
 It alters bleeding time and reduce
thromboxane formation by altering platelet
function

38. 5-HT2B-Receptors
 Stomach fundus
 Mediate contraction of the fundus
 Agonist: α-Me 5-HT
 Antagonist: not yet identified (SB204741)

39. 5-HT2C-Receptors
 Choroid plexus, hippocampus, substantia
nigra
 Agonist: α-Me 5-HT, LSD
 Antagonist: methysergide

40. 5-HT3-Receptors
 Occur mainly in the PNS
 Found mainly on norciceptive neurones;
autonomic and enteric neurones
 CNS in the area postrema
 5-HT exerts a strong excitatory effect on
these neurons

41.  The receptors are linked to a Na+-K+ ion
channel
 Do not involve 2nd messengers in signal
transduction
 Agonist: 2-Me-5-HT, m-chlorophenyl-
biguanide
 Antagonist: Tropisetron, ondansetron,
granisetron

42.  The physiological role of this receptor is not
known
 It has been postulated that excitation of
vascular sensory nerve terminals by 5-HT
from platelets may be involved in the
pathogenesis of migraine
 Selective 5-HT3-receptor antagonists are
used as anti-emetics

43. 5-HT4-Receptors
 Occur in the brain, myenteric neurones,
bladder and heart
 Main physiological role appears to be in the
GIT where they produce neuronal
excitation, and mediate the effect of 5-HT in
stimulating peristalysis
 Enhance release of Ach
 G-protein coupled and activate adenylate
cyclase ( cAMP)

44.  Agonists: Cisapride and metoclopramide,
renzapride
 Used for gastroesophageal reflux and
motility disorders

45. Other 5-HT receptors
 5-HT5, 6, 7
 All have been identified in the brain
 Specific agonists and antagonists are still
being developed
 Clozapine is a partial agonist of both 5-HT6
and 5-HT7-receptors

46. Serotonin re-uptake
inhibitors(SSRI)
 Modulate serotonergic transmission by
blocking reuptake of 5-HT
 Paroxetine, fluoxetine, sertraline,
citalopram, fluvoxamine
 Useful for the management of depression
and other behavioral disorders

47. Ergot alkaloids
 Active substances produced by Claviceps
purpurea, a fungus infecting cereals
 Responsible for episodes of poisoning when
cereal containing the fungus is consumed
 Symptoms: - mental disturbance
– Intensely painful peripheral vasoconstriction
(leading to gangrene)

48.  Structure of ergot alkaloids is based on
lysergic acid
 Amine alkaloids: 6-methylergoline, lysergic
acid, lysergic acid diethylamide,
ergonovine(ergometrine) and methysergide
 Peptide alkaloids: ergometrine,
bromocryptine and α-ergocryptine

49. Mechanism of action
 Act on several types of receptors
 Act as agonists, partial agonists and
antagonists at α-adrenoceptors, serotonin
receptors (5-HT1A and 5-HT1D mainly)
 Less effect on 5-HT1C, 5-HT2 and 5-HT3
 Agonist or partial agonist effect on central
dopamine receptors

50.  Cause stimulation of smooth muscle
 Some are relatively selective for vascular
smooth muscle
 Others act mainly on the uuterus

51. Ergot
alkaloi
d
-
Adreno
ceptors
Dopam
ine
Rec.
5-HT2-
receptor
s
Uterine s.
mstimulat
ion
Bromoc
ryptine
- +++ - No effect
Ergome
trine
+ + -(PA) +++
Ergota
mine
--(PA) No
effect
+ (PA) +++
LSD No
effect
+++ --
++ (in
CNS)
+
Methys
ergide
Little/n
o effect
Little/n
o effect
--- (PA) Little/no
effect

52. Clinical uses
Prophylaxis of migraine (ergotamine and
dihroxyergotamine)
 Methysergide also useful for prophylaxis
 Hyperprolactinemia: Prolactin is an anterior
pituitary hormone
 Levels increase when there is a tumor of the
gland
 Also prolactin levels can be elevated due to
use of centrally acting dopamine
antagonists, especially antipsychotic drugs

53.  Due to –ve feedback hyperprolactinemia is
associated with amenorrhea and infertility
in women
 Also galactorrhea in both sexes
 Bromocriptine is useful for reducing
prolactin levels from pituitary tumors
 Has been associated with regression of the
tumor in some cases

54.  Ergometrine is used to control of
postpartum hemorrhage
 Diagnosis of variant angina (Ergometrine
produces prompt vasoconstriction during
coronary angiography to diagnose variant
angina
 Treatment of senile cerebral insufficiency
(used for relief of insenility and
Alszheimer’s dementia)

55. THE PHARMACOLOGY OF
PURINES
 Adenosine
 ADP and ATP (purine nucleotides)

56. HISTORY
 In 1929 it was shown that when adenosine
is injected into anaesthetized animals it
causes:
– Cardiac slowing
– A fall in blood pressure
– Vasodilatation
– Inhibition of intestinal movements

57.  Now it is known that purines participate in
many physiological control mechanisms
e.g.
– Regulation of coronary blood flow &
myocardial function
– Platelet aggregation
– Neurotansmission in boith PNS and CNS

58. Adenosine
 Produced by many tissues as a by product
of ATP
 Released from neurons, glia and other cells
through membrane transport systems
 Functions as a mediator in the CNS and
periphery

59. Not a classical neurotransmitter
 No synthetic pathway
 No vesicular storage
 No Ca2+-dependent release in response to
stimulation in the brain or CNS

60. Adenosine receptors
 Effects of adenosine are mediated by A1, A2
and A3 receptors.
 These are G-protein coupled receptors
 The adenosine receptors are not sensitive to
the nucleotides AMP, ADP or ATP
 A1 and A2 receptors are antagonized by
methylxanthines

61.  Some of the pharmacological effects of the
methylxanthines are due to adenosine antagonism
 They also increase cAMP by inhibiting
phosphodiesterases
 Methylxanthines esp. analogues of theophylline
are A1/A2-receptor antagonists
 Certain theophylline analogues show greater
selectivity for adenosine receptors over
phosphodiesterase

62. Pharmacological effects of
adenosine
 ADP and adenosine function as local
regulators such that their rate of production
varies with the functional state of the tissue
 They control blood flow to tissues and
protect them from ischaemia

63.  Adenosine causes vasodilatation, including
coronary vessels (A2)
 Causes vasoconstriction in the kidneys (A1)
 Adenosine infusion causes a fall in blood
pressure
 Adenosine inhibits platelet aggregation via
A2 - receptors

64.  Blocks cardiac AV conduction (A1) and
reduction of force of contraction
 Bronchoconstriction, especially in asthmatic
patients (A1).
 Antiasthmatic effect of methylxanthines
may partly reflect A1-receptor antagonism
 Release mediators from mast cells (A3),
contributing to bronchoconstriction.

65.  Stimulates norciceptive afferent neurons,
especially in the heart (A2).
 Adenosine release in response to ischaemia
has been suggested as a mechanism of
anginal pain
 Carotid afferents are also stimulated causing
reflex hyperventilation

66.  Inhibit transmitter release at both PNS and CNS
(A1)
 In the CNS it exerts a pre- and postsynaptic
depressant action
– Reducing motor activity
– Depress respiration
– Induce sleep
– Reduce anxiety
– These effects are opposite to those of methylxanthines

67.  Neuroprotection, in cerebral ischaemia.
 Inhibition of glutamate release through A1-
receptors may be involved

68. Clinical uses
 used for the treatment of supraventricular
tachycardias
 Given i.v. it is destroyed or taken up within
seconds
 It is safer than β-adrenoceptor antagonists
or verapamil because of its short duration of
action

69.  Longer acting A1-receptor agonists with
greater receptor selectivity are available
 These could prove useful in ischaemic heart
disease, hypertension, stroke
 Selective adenosine receptor antagonists
could also have advantages over
theophylline in the treatment of asthma
 Adenosine uptake is inhibited by
dipyridamole which is used as a vasodilator
and antiplatelet

70. ATP as a neurotransmitter
 It is a co-transmitter in Nadrenergic neurons
 It is contained in synaptic vesicles of both
adrenergic and cholinergic neurons
 Accounts for many of the actions produced by
stimulation of autonomic nerves that are not due to
Ach or NA
– Eg. Relaxation of intestinal smooth muscle evoked by
sympathetic stimulation
– Contraction of the bladder produced by
parasympathetic nerves

71.  ATP is released in a ca2+-dependent
fashion, on nerve stimulation
 Exogenous ATP mimics effects of nerve
stimulation in various preparations
 It functions as a fast neurotransmitter both
in the CNS and autonomic ganglia
 Intracellular ATP controls membrane K+-
channels thus affecting vascular smooth
muscle & insulin secretion

72. ATP receptors
 ATP receptors respond to various adenine
nucleotides; prefer ATP to ADP or AMP
 Two main types P2X and P2Y each with
subclasses
 P2X receptors are ligand gated cation
channels
 P2Y are G-protein-coupled receptors, linked
mainly to PIP2 hydrolysis and Adenylate
cyclase in some cases

73.  The role of ATP as a fast neurotransmitter
involves P2X receptors
 P2X receptors are blocked by suramin and a
purine analogue, PPADS
 The other actions of ATP are linked to
various 2nd messenger systems for which no
antagonists are known

74.  Platelets express P2T receptors which
respond selectively to ADP.
 ADP causes platelet aggregation; the
opposite effect to that of adenosine
 The action of ADP on platelets is
antagonised by ATP
 ADP released from platelets and from the
vascular endothelium promotes thrombosis

75.  Drugs acting selectively on ATP and ADP
receptors have not yet been developed for
clinical purposes