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By

Pharm. Sheku S. Mansaray


B.Pharm (Hons), M.Sc., MPCPharm., MPSSL
Course Outcome
 At the end of this course, the students should understand
serotonin with respect to the following:
 Its source and Chemistry
 Synthesis and metabolism
 Distribution and function of its various receptors
 Principles of its pharmacokinetic and pharmacodynamic
properties
 Its pharmacological actions/pathophysiological roles
INTRODUCTION
 Serotonin was the name given to the vasoconstrictor substance
which appeared in the serum when blood clotted and
Enteramine to the smooth muscle contracting substance present
in enterochromaffin cells of gut mucosa.
 In the early 1950s both were shown to be 5-hydroxytryptamine
(5-HT).
INTRODUCTION CONT.
 5-Hydroxytryptamine (5-HT, serotonin):
 Is a regulator of smooth muscle in the cardiovascular system and
the gastrointestinal tract
 An enhancer of platelet aggregation and
 A neurotransmitter in the central nervous system (CNS).
 It is found in high concentrations in:
 Enterochromaffin cells throughout the gastrointestinal tract
 Storage granules in platelets, and broadly throughout the CNS.
Source and Chemistry
 5-HT is widely distributed in the animal and plant kingdoms
 It occurs in animals such as the tunicates, mollusks, arthropods,
and coelenterates
 It is also found in fruits, nuts, venoms (including those of the
common stinging nettle and of wasps and scorpions).
Source and Chemistry Cont.
 Numerous synthetic or naturally occurring congeners of 5-
HT have pharmacological activity.
 Many of the N- and O-methylated indoleamines, such as
N,N-dimethyltryptamine, are hallucinogens.
Synthesis and Metabolism
 Dietary tryptophan is the source of serotonin.
 Enzymes and cofactors necessary for serotonin synthesis are
present in both the enterochromaffin cells of the gastrointestinal
tract and neurons in the brain.
 Tryptophan is initially hydroxylated to form 5-
hydroxytryptophan by the enzyme tryptophan hydroxylase.
Synthesis and Metabolism Cont.
 Decarboxylation of the latter compound by the action of L-
amino acid decarboxylase results in the formation of serotonin.
 The enzymes responsible for the metabolism of serotonin are
present in all of the cells containing this amine and in the liver.
 It is initially oxidatively deaminated by the enzyme monoamine
oxidase (MAO) to form 5-hydroxyindoleacetaldehyde
Synthesis and Metabolism Cont.
 This compound is subsequently rapidly oxidized by a ubiquitous
enzyme, aldehyde dehydrogenase to the major metabolite 5-
hydroxyindoleacetic acid, which is excreted in the urine.
 Other minor pathways of metabolism of 5-HT include: sulfation
and O- or N-methylation.
 The latter reaction could lead to the formation of an endogenous
psychotropic substance, 5-hydroxy-N,N-dimethyltryptamine
Synthesis and Metabolism Cont.
NOTE
 Much of the serotonin released in the brain at synapses is
taken back into the initial neuron by an active reuptake
mechanism to be released again.
Serotonin (5-HT) synthesis

tryptophan 5-HTP
hydroxylase decarboxylase

tryptophan 5-HTP 5-HT


(Rate limiting)
COOH OH COOH
Tryptophan
hydroxylase
C NH2 C NH2

N N
In diet. Active
Tryptophan CNS transport 5-Hydroxytryptophan

5-OH Tryptophan
decarboxylase
C COOH
OH H
N

C NH2
5-Hydroxy Indole N
Acetic Acid 5-OH Indole
Acetaldehyde 5-Hydroxytryptamine
SEROTONERGIC (5-HT) RECEPTORS
 Gaddum and Picarelli (1957) classified 5-HT receptors into
musculotropic (D type) and neurotropic (M type) on the
basis of pharmacological criteria.
 Subsequently 5-HT receptors were differentiated by their
high or low affinity for [3H] 5-HT in radio ligand binding
studies.
 However, the present system of classifying 5-HT receptors is
based on molecular characterization and cloning of the
receptor cDNAs.
Serotonin Receptors; Distribution and Function
 At least fifteen (15) distinct mammalian receptor types and
subtypes for serotonin have been established.
 They are characterized as 5-HT1, 5-HT2, . . . 5-HT7 subsets.
 There are at least five subtypes of the 5-HT1 subset and three
receptor subtypes for the 5-HT2 subset.
Serotonin Receptors; Distribution and
Function Cont.
 All 5-HT receptors (except 5-HT3) are G protein coupled
receptors which function through decreasing (5-HT1) or
increasing (5-HT4, 5-HT6, cAMP production or by generating
IP3/DAG (5-HT2) as second messengers.
 The 5-HT3 is a ligand gated cation (Na+,K+) channel which on
activation elicits fast depolarization.
Serotonin Receptors; Distribution and
Function Cont.
 5–HT1
 7 trans–membrane domains
 G protein linked
 cAMP dependant
 anxiolytic and antidepressant
 subtypes
 5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F
Serotonin Receptors; Distribution and
Function Cont.
 5–HT1A
 limbic system
 regulation of emotions
 neocortex
 hypothalamus
 substantia gelatinosa
 proprioception
 5–HT1B (rat)
Serotonin Receptors; Distribution and
Function Cont.
 5–HT1D
 autoreceptors
 inhibitory feedback
 heteroreceptors
 modulate release
 acetylcholine

 glutamate

 anti–migraine effect of sumatriptan


Serotonin Receptors; Distribution and Function
Cont.
 5–HT1E
 ? functional role
 5–HT1F
 ? functional role
 distribution includes CNS, uterus, mesentery
 inhibit cAMP
 high affinity
 sumatriptan, methysergide
Serotonin Receptors; Distribution and Function
Cont.
5-HT2 Receptors
There are 3 subtypes (5–HT2A, 5–HT2B, 5–HT2C) of 5-HT2
receptor; all are coupled to phospholipase C and function
through generation of IP,/DAG.
5-HT2A receptor also inhibits K+ channels resulting is slow
depolarization of neurones.
Serotonin Receptors; Distribution and
Function Cont.
 5–HT2A
 Periphery
 contraction of vascular/non–vascular smooth muscle
 platelet aggregation
 increased capillary permeability
 modulation of the release of other neurotransmitters and hormones
 ACh, adrenaline, dopamine, excitatory amino acids, vasopressin
Serotonin Receptors; Distribution and
Function Cont.
 5–HT2A
 CNS
 motor behaviour
 head twitch
 wet dog shakes
 sleep regulation
 nociception
 neuroexcitation
Serotonin Receptors; Distribution and
Function Cont.
 5–HT2B (rat): It mediates contraction of rat gastric fundus
 5-HT2c receptor is located on vascular endothelium where it
can elicits vasodilatation through EDRF release.
 The choroid plexus also expresses large number of 5-HT2c
receptors.
Serotonin Receptors; Distribution and
Function Cont.
 5-HT3 Receptor: This is the neuronal 5-HT receptor which
rapidly depolarizes nerve endings by opening the cation channel
located within it and corresponds to the original M type
receptor.
 It mediates the indirect and reflex effects of 5-HT at:
 Somatic and autonomic nerve endings →pain, itch, coronary
chemoreflex (bradycardia, fall in BP due to withdrawal of
sympathetic tone, respiratory stimulation or apnoea elicited by
stimulation of receptors in the coronary bed), other visceral
reflexes.
Serotonin Receptors; Distribution and
Function Cont.
 Nerve endings in myenteric plexus →augmentation of
peristalsis, emetic reflex.
 Area postrema and nucleus tractus solitarious in brainstem
→nausea, vomiting.
Serotonin Receptors; Distribution and
Function Cont.
5-HT,4-7 Receptors:
 The 5-HT4 receptor has been demonstrated in the mucosa,
plexuses and smooth muscle of the gut, which is probably
involved in augmenting intestinal secretion and peristalsis.
 It is also located in brain, especially hippocampus and the
colliculi where it causes slow depolarization by decreasing K+
conductance.
Pharmacological Effects
 CVS:
1. Arteries are constricted (by action on smooth muscle) as well as
dilated (through EDRF release) by direct action of 5-HT,
depending on the vascular bed and the basal tone.
 In addition, 5-HT releases Adr from adrenal medulla, affects
ganglionic transmission and evokes cardiovascular reflexes.
 In the microcirculation 5-HT dilates arterioles and constricts
venules thereby causing capillary pressure to rise and escape of
fluid.
Pharmacological Effects Cont.
 Note : 5- HT can give rise to triple action:
Decrease BP due to chemoreceptor response followed by
increase BP due to Vasoconstriction (5-HT2), then decrease B.P
due to skeletal muscle V.D
Stimulation of sensory nerve endings in baroreceptors and in
vagal afferents in coronary circulation (Bezold Jarrisch reflex)
→ bradycardia and hypotension

Platelet:
 5-HT causes changes in shape of platelets and is a weak
aggregator through 5-HT2A receptors.
Pharmacological Effects Cont.
Respiratory system:
 A brief stimulation of respiration (mostly reflex from
bronchial afferents) and hyperventilation are the usual
response, but large doses can cause transient apnoea
through coronary chemoreflex.
Pharmacological Effects Cont.
Smooth muscles:
 5-HT is a potent stimulator of the GIT, both by direct
action as well as through enteric plexuses. Peristalsis is
increased and diarrhoea can occur (also due to increased
secretion).
 It constricts bronchi, less potent than histamine.
 Action on other smooth muscles in man are feeble and
inconsistent.
Pharmacological Effects Cont.
Glands:
 5-HT inhibits gastric secretion (both acid and pepsin), but
increases mucus production. It thus has ulcer protective
property.
Pharmacological Effects Cont.
CNS:
 Injected i.v., 5-HT does not produce central effects
because it poorly crosses blood brain barrier.
 However, it serves as a transmitter, primarily inhibitory.
 Direct injection in the brain produces sleepiness, changes
in body temperature, hunger and a variety of behavioural
effects.
PATHOPHYSIOLOGICAL ROLES
Neurotransmitter:
 5-HT is a confirmed neurotransmitter in the brain
 Cells containing 5-HT are present in the raphe nuclei of
brainstem, substantia nigra and few other sites
 5-HT is believed to be involved sleep, temperature regulation,
thought, cognitive function, behaviour and mood
 Imbalance of 5-HT result in affective disorders and
schizophrenia, vomiting and pain perception.
PATHOPHYSIOLOGICAL ROLES CONT.
Neuroendocrine function:
 The hypothalamic neurones that control release of anterior
pituitary hormones are probably regulated by serotonergic
mechanism.
Nausea and vomiting:
 Especially that evoked by cytotoxic drugs or radiotherapy is
mediated by release of 5-HT and its action on 5-HT3 receptors in
the gut, area postrema and nucleus tractus solitarious.
PATHOPHYSIOLOGICAL ROLES CONT.
Migraine:
 5-HT is said to initiate the vasoconstrictor phase of migraine
and to participate in neurogenic inflammation of the affected
blood vessels.
Haemostasis:
 Platelets release 5-HT during aggregation at the site of injury
to blood vessel. Acting in concert with collagen and other
mediators, 5-HT accelerates platelet aggregation and clot
formation. Thus, it serves to amplify the response. Also, its
contractile action appears to promote retraction of the injured
vessel. Both the above actions contribute to haemostasis.
PATHOPHYSIOLOGICAL ROLES CONT
Raynaud's phenomenon:
 Release of 5-HT from platelets may trigger acute vasospastic
episodes of larger arteries.
Variant angina:
 Along with thromboxane A2, 5-HT released from platelets has
been implicated in causing coronary spasm and variant angina.
PATHOPHYSIOLOGICAL ROLES CONT
Hypertension:
 Increased responsiveness to 5-HT as well as its reduced uptake
and clearance by platelets has been demonstrated in
hypertensive patients.
Intestinal motility:
 Enterochromaffin cells and 5-HT containing neurones may
regulate peristalsis and local reflexes in the gut. This system
appears to be activated by intestinal distension and vagal
efferent activity.
Serotonin (5-HT) Receptor Agonists
 Direct-acting 5-HT-receptor agonists possess widely different
chemical structures, as well as diverse pharmacological
properties.
 5-HT1A receptor-selective agonists consist of new class of anti-
anxiety drugs including buspirone , gepirone, and ipsapirone.
 5-HT1D receptor-selective agonists, such as sumatriptan, have
unique properties that result in constriction of intracranial blood
vessels.
 Sumatriptan is part of a series of new serotonin-receptor agonists
available for treatment of acute migraine attacks.
Serotonin (5-HT) Receptor Agonists Cont.
 Other such agents approved for the acute treatment of migraine
include zolmitriptan, naratriptan, and rizatriptan, all of which
are selective for 5-HT1D and 5-HT1B receptors.
 A number of 5-HT4 receptor-selective agonists have been
developed or are being developed for the treatment of disorders
of the GI tract.
5-HT-Receptor Agonists and Migraine
 Migraine headache affects 10% to 20% of the population,
producing a morbidity estimated at 64 million missed workdays
per year in the United States.
 It is a specific neurological syndrome, with varying
manifestations.
 The principal types are:
 Migraine without aura (common migraine) is a severe,
unilateral, pulsating headache that typically lasts from 2 to 72
hours.
 These headaches are often aggravated by physical activity and
are accompanied by nausea, vomiting, photophobia
(hypersensitivity to light), and phonophobia (hypersensitivity to
sound).
5-HT-Receptor Agonists and Migraine Cont.
 Migraine with aura (classic migraine); the headache is
preceded by neurologic symptoms called auras, which
can be visual, sensory, and/or cause speech or motor
disturbances.
which includes:
 Migraine with typical aura
 Migraine with prolonged aura
 Migraine without headache and
 Migraine with acute-onset aura.
Pathophysiology of Migraine
 One pathophysiological model of migraine, includes unknown
events that lead to the abnormal dilation of carotid arteriovenous
anastomoses in the head.
 Following this dilation, as much as 80% of carotid arterial blood
flow has been reported to be "shunted "via these anastomoses,
located mainly in the cranial skin and ears, diverting blood from
the capillary beds and thereby producing cerebral ischemia and
hypoxia.
 Therefore, based on this model, an effective antimigraine agent
would close the shunts and restore blood flow to the brain.
Pathophysiology of Migraine Cont.
 Drugs such as ergotamine, dihydroergotamine, and
sumatriptan share the capacity to produce this vascular
effect with a pharmacological specificity on 5-HT1B- and
5-HT1D-receptor subtypes.
Clinical Presentations
 It often begins with premonitory aura (usually last for 24 hours
before the onset of pain) and often is accompanied by
photophobia, hyperacusis, polyuria, diarrhea, and disturbances
of mood and appetite.
 A migraine attack may last for hours or days and be followed
by prolonged pain-free intervals.
 The frequency of migraine attacks is extremely variable, but
usually ranges from 1 to 2 a year to 1 to 4 per month.
5-HT1-Receptor Agonists: the Triptans
 The selective pharmacological effects of the “triptans”, at 5-
HT1 receptors have led to insights into the pathophysiology of
migraine.
These drugs include:
 Sumatriptan
 Zolmitriptan
 Naratriptan
 Rizatriptan
NOTE: Their ability to decrease, rather than exacerbate, the
nausea and vomiting of migraine is an important advance in the
treatment of the condition.
Pharmacological Properties
 The pharmacological effects of the triptans appear to be limited
to the 5-HT1 family of receptors, providing evidence that this
receptor subclass plays an important role in the acute relief of a
migraine attack.
 The triptans selective for 5-HT1D and 5-HT1B receptors and
have a low or no affinity for other subtypes of 5-HT receptors.
 The triptans are essentially inactive at α1 and α2 adrenergic, β
adrenergic, dopaminergic, muscarinic cholinergic, and
benzodiazepine receptors.
Mechanism of Action
 Two hypotheses have been proposed to explain the efficacy of 5-
HT1B/1D-receptor agonists in migraine:
 One hypothesis implicates the capacity of these receptors to
cause constriction of intracranial blood vessels including
arteriovenous anastomoses.

 An alternative hypothesis is based on the observation that both 5-


HT1B and 5-HT1D receptors serve as presynaptic autoreceptors,
modulating neurotransmitter release from neuronal terminals
Mechanism of Action Cont.

 5-HT1 agonists may block the release of proinflammatory


neuropeptides at the level of the nerve terminal in the
perivascular space.

 The ability of potent 5-HT1-receptor agonists to inhibit


endogenous neurotransmitter release in the perivascular
space could account for their efficacy in the acute
treatment of migraine.
Pharmacokinetics of the ‘Triptans’
 When given SCly, sumatriptan reaches its peak plasma
concentration in approximately 12 minutes.
 Following oral administration, peak plasma concentrations occur
within 1 to 2 hours.
 Bioavailability following the subcutaneous route of
administration is approximately 97%; after oral administration or
nasal spray, bioavailability is only 14% to 17%.
 The elimination half-life is approximately 1 to 2 hours.
 Sumatriptan is metabolized predominantly by MAO-A, and its
metabolites are excreted in the urine.
Pharmacokinetics of the ‘Triptans’ Cont.
 Zolmitriptan reaches its peak plasma concentration 1.5 to 2 hours
after oral administration.
 Its bioavailability is about 40% following oral ingestion.
 Zolmitriptan is converted to an active N-desmethyl metabolite,
which has several fold higher affinity for 5-HT1B and 5-HT1D
receptors than does the parent drug.
 Both the metabolite and the parent drug have half-lives of 2 to 3
hours.
Pharmacokinetics of the ‘Triptans’ Cont.
 Naratriptan, administered orally, reaches its peak plasma
concentration in 2 to 3 hours and has an absolute bioavailability
of about 70%.
 It is the longest acting of the triptans, having a half-life of about
6 hours.
 Fifty percent of an administered dose of naratriptan is excreted
unchanged in the urine, and about 30% is excreted as products of
oxidation by CYPs.
Pharmacokinetics of the ‘Triptans’ Cont.
 Rizatriptan has an oral bioavailability of about 45% and reaches
peak plasma levels within 1 to 1.5 hours after oral ingestion of
the drug.
 The principal route of metabolism of rizatriptan is via oxidative
deamination by MAO-A.
 Plasma protein-binding of the triptans ranges from about 14%
(sumatriptan and rizatriptan) to 30% (naratriptan).
Use in Treatment of Migraine
 The triptans are effective in the acute treatment of migraine
(with or without aura)
 They are not intended for use in prophylaxis of migraine.
N/B:
 Treatment with these agents should begin as soon as possible
after onset of a migraine attack.
 Oral dosage forms of the triptans are the most convenient to
use, but they may not be practical in patients experiencing
migraine-associated nausea and vomiting.
Adverse Effects
 Rare but serious cardiac events have been associated with the
administration of 5-HT1 agonists including:
 Coronary artery vasospasm
 Transient myocardial ischemia
 Atrial and ventricular arrhythmias
 Myocardial infarction
 Most patients report transient mild pain, stinging, or burning
sensations at the site of injection.
Adverse Effects
 The most common side effect of sumatriptan nasal spray is a
bitter taste.
N/B: Orally administered triptans can cause:
 Paresthesias
 Asthenia and fatigue
 Flushing
 Feelings of pressure
 Tightness, or pain in the chest, neck, and jaw
 drowsiness
 dizziness
 Nausea
 sweating.
Contraindications
 Patients who have a history of ischemic or vasospastic coronary
artery disease, cerebrovascular or peripheral vascular disease
uncontrolled hypertension
 Naratriptan is contraindicated in patients with severe renal or
hepatic impairment.
 Sumatriptan, rizatriptan, and zolmitriptan are contraindicated in
patients who are taking monoamine oxidase inhibitors.
 Precaution: Rizatriptan should be used with caution in patients
with renal or hepatic disease
Other Serotonin (5-HT) Receptor Agonists
1. Buspirone: 5-HT1A agonist used as anxiolytic agent.

2. Metoclopromide: 5-HT4 agonist as prokinetic agent


(for Rx of gastroesophagial reflex). How does it work? And
also used for N/V via 5-HT3 antagonistic action.

3. Dexfenfuramine: Acts by stim. release and inhib.


Reuptake of serotonin.
Used as anorexic agent.
5-HT-Receptor Antagonists
 The 5-HT receptor antagonists vary widely in their properties
 The ergot alkaloids and related compounds tend to be nonspecific
5-HT-receptor antagonists
 However, a few ergot derivatives such as metergoline bind
preferentially to members of the 5-HT2-receptor family.
5-HT-Receptor Antagonists Cont.
 A number of selective antagonists for 5-HT2A/2C and 5-
HT3 receptors are currently available.
 Ketanserin is the prototypic 5-HT2A-receptor antagonist
Other members include:
 Ondansetron
 Granisetron
 Dolasetron
 Cyproheptadine
 Methysergide
Ketanserin
 Ketanserin potently blocks 5-HT2A receptors, less potently
blocks 5-HT2C receptors, and has no significant effect on 5-
HT3 or 5-HT4 receptors or any members of the 5-HT1-receptor
family.
 It also has high affinity for α-adrenergic receptors and
histamine H1 receptors
Ketanserin Cont.
 Chemical relatives of ketanserin such as ritanserin a more
selective 5-HT2A-receptor antagonists with low affinity for a1
adrenergic receptors.
 Ritanserin, as well as most other 5-HT2A-receptor
antagonists, also potently antagonize 5-HT2C receptors.
Ketanserin Cont.
 Its oral bioavailability is about 50%, and its plasma half-
life is 12 to 25 hours.
 The primary mechanism of inactivation is hepatic
metabolism.
Ketanserin Cont.
 Ketanserin lowers blood pressure in patients with hypertension,
causing a reduction comparable to that seen with β-adrenergic-
receptor antagonists or diuretics.
 This effect likely relates to its blockade of α1 adrenergic
receptors, not its blockade of 5-HT2A receptors.
 Ketanserin inhibits 5-HT-induced platelet aggregation, but it does
not greatly reduce the capacity of other agents to cause
aggregation.
Methysergide
 Methysergide (1-methyl-d-lysergic acid butanolamide) is a
congener of methylergonovine
 It blocks 5-HT2A and 5-HT2C receptors, but appears to have
partial agonist activity in some preparations.
Methysergide Cont.
 Methysergide inhibits the vasoconstrictor and pressor effects of
5-HT.
 It has been found to both block and mimic the central effects of
5-HT.
 It is not selective (it also interacts with 5-HT1 receptors) but its
therapeutic effects appear primarily to reflect blockade of 5-HT2
receptors
 It has only weak vasoconstrictor and oxytocic activity.
Methysergide Cont.
 Methysergide has been used for the prophylactic treatment of
migraine and other vascular headaches, including Horton's
syndrome.
 The protective effect takes 1 to 2 days to develop and disappears
slowly when treatment is terminated.
 This might be due to the accumulation of an active metabolite
of methysergide, methylergometrine, which is more potent than
the parent drug.
Methysergide Cont.
 Methysergide also has been used to combat diarrhea and
malabsorption in patients with carcinoid tumors
 It is also beneficial in postgastrectomy dumping syndrome
Side Effects
Common side effects include:
 Gastrointestinal disturbances (heartburn, diarrhea, cramps,
nausea, and vomiting)
 Symptoms related to vasospasm-induced ischemia (numbness
and tingling of extremities, pain in the extremities, and low back
and abdominal pain).
Side Effects Cont.
 Effects attributable to central actions include: unsteadiness,
drowsiness, weakness, lightheadedness, nervousness, insomnia,
confusion, excitement, hallucinations, and even frank psychotic
episodes.
 A potentially serious complication is inflammatory fibrosis
(retroperitoneal fibrosis, pleuropulmonary fibrosis, and
coronary and endocardial fibrosis).
Cyproheptadine
 The structure of cyproheptadine resembles that of the
phenothiazine, histamine H1-receptor antagonists
 It is an effective H1-receptor antagonist.
 It also has a prominent 5-HT blocking activity on smooth muscle
by virtue of its binding to 5-HT2A receptors.
 In addition, it has a weak anticholinergic activity and possesses
mild CNS depressant properties.
Cyproheptadine Cont.
 Cyproheptadine shares the properties and uses of other H1-
receptor antagonists.
 It is effective in controlling skin allergies, particularly the
accompanying pruritus.
 N/B: Cyproheptadine can be used to counteract the sexual side
effects of selective 5-HT-reuptake inhibitors such as fluoxetine
and sertraline
Cyproheptadine Cont.
 The 5-HT blocking actions of cyproheptadine explain its value in
the postgastrectomy dumping syndrome, intestinal hypermotility
of carcinoid, and migraine prophylaxis
Side Effects
 These include those common to other H1-receptor
antagonists, such as drowsiness, weight gain and increased
growth.
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