AUTOCOIDS –

Serotonin and Anti-serotonins

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DR. SABYATA GAUTAM

(M. PHARM, PH.D)

Dr. Sabyata Gautam

Outline
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 Introduction
 Serotonin Receptors
 Pharmacological actions
 Serotonin receptor agonist
 Migraine & use of serotonin agonists in migraine
 Serotonin antagonist drugs

Dr. Sabyata Gautam

 SEROTONIN
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Serotonin or 5-HT (5-hydroxytryptamine) is the

vasoconstrictor substance which appeared in serum
when blood clotted.

In 1950’s “Enteramine” or serotonin was found in the

smooth muscle contracting substance present in entero-
chromaffin cells of gut mucosa.

About 90% of body’s content of 5-HT is localized in the

intestines; most of the rest is in platelets and brain.
Dr. Sabyata Gautam
Dr. Sabyata Gautam 4
 Serotonin receptors
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Serotonergic (5-HT) receptors:

Four families of 5-HT receptors (5-HT1, 5-HT2, 5-HT3, 5-HT4)

comprising of 14 receptor subtypes have been recognized.

Play role in several diseases

Depression – changes in serotonin concentration in the brain

Migraine – potent constrictor of cerebral blood vessels

Dr. Sabyata Gautam

 Five subtypes (HT1A, B, D, E, and F) have been identified. It is present in
5-HT1 raphe nuclei of brain stem and hippocampus.

Three sub-types (5-HT 2 A, B, C, D-type) are present and located in

5-HT2 vascular and visceral smooth muscle, platelets and cerebral neurons.

It rapidly depolarizes nerve endings by opening the cation channel located

within it. It mediates the reflex effect at nerve endings in myenteric plexus
5-HT3 and also in area postrema and nucleus tractus solitarious (NTS) in brain stem
causing nausea and vomiting.

Present in mucosa, plexus and smooth muscle of gut causing intestinal

secretion and peristalsis. It causes hyperpolarization by decreasing K+
5-HT4
conductance in brain.
Cisapride and renzapride are selective 5-HT 4 agonists.

Dr. Sabyata Gautam 6

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 The recently cloned 5-HT5, 5-HT6 and 5-HT7

receptors are closely related to the 5-HT4 receptor.

 These are mainly located in specific brain areas, but

their functional role is not known.

Dr. Sabyata Gautam

 Pharmacological actions
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1. CVS: The net action is complex. Larger arteries and veins are
characteristically constricted. It dilates small arterioles and
constricts venules: capillary pressure rises and fluid escapes
(prolonged fall in BP).

2. Smooth muscles: It is potent stimulator of g.i.t, increasing

peristalsis. It constricts bronchi, but is less potent than
histamine. Action on other smooth muscles is inconsistent.

3. Glands: It inhibits gastric secretion (both acid and pepsin), but

increases mucus production. So, it has ulcer protective property.
Effect on other glandular secretions is not significant.
Dr. Sabyata Gautam
Pharmacological actions…
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4. Nerve endings and adrenal medulla: Afferent nerve endings are activated 
tingling & pricking sensation, pain. Depolarization of visceral afferents causes
nausea & vomiting. It is less potent than histamine in releasing CAs from
adrenal medulla.
5. Respiration: A brief stimulation of respiration and hyperventilation occurs; but
large doses can cause transient apnea.
6. Platelets: It causes change in shape of platelets and is a weak aggregator through
5-HT2A receptors.
7. CNS: Injected i.v, 5-HT does not produce central effects because it poorly crosses
BBB. However, it serves as a inhibitory transmitter. Direct injection in the brain
produces sleep, change in body temperature, hunger and variety of behavioral
effects.

Dr. Sabyata Gautam

 Depolarization
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Dr. Sabyata Gautam

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Serotonin agonists Serotonin

antagonists
Cisapride 5HT4
Sumitriptan 5HT1 Cyproheptadine (anti
Buspirone 5HT1 histamine) 5HT1
Odansetron 5HT3
Metaclopramine 5HT3
Ketanserin 5HT1+2
Ritanserin 5HT2

Dr. Sabyata Gautam

 Serotonin Receptor Agonists
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Direct-acting 5-HT-receptor agonists have widely different

chemical structures, as well as diverse pharmacological properties.
This diversity is not surprising in light of the number of 5-HT-
receptor subtypes. 5-HT1A receptor-selective agonists have helped
elucidate the functions of this receptor in the brain & have resulted
in a 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 was first in a series of new serotonin-receptor
agonists available for treatment of acute migraine attacks.
Dr. Sabyata Gautam
 Clinical actions of SEROTONIN AGONISTS
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Neurotransmission: Cells containing 5-HT are present in the raphe

nuclei of brainstem and few other sites. Compounds such as
fluoxetine and other SSRIs, modulate serotonergic transmission by
blocking reuptake of the transmitter, and so prescribed for the
management of depression.
Intestinal motility: It regulates peristalsis and local reflexes in the
gut. Cisapride, a 5-HT4 agonist, was used in the treatment of gastro-
esophageal reflux and motility disorders.
Sleep regulation: 5-HT is probably involved in sleep, temperature
regulation, thought and mood (imbalance may result in affective
disorders and schizophrenia). It is precursor of melatonin in pineal
gland.
Dr. Sabyata Gautam
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Side-effects: tingling and warmth sensation, dizziness, muscle

weakness, neck pain, chest discomfort (1-5%) probably due to
ability of these drugs to cause coronary vasospasm.

Contraindication: Coronary artery disease and in patients with

angina. Naratriptan and eletriptan are contraindicated in patients
with severe hepatic or renal impairment; frovatriptan in patients
with peripheral vascular diseases; and zolmitriptan in patients with
Wolff-Parkinson-White syndrome.

Dr. Sabyata Gautam

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Dr. Sabyata Gautam

 Migraine
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 Migraine headache afflicts 10% - 20% of the population, producing a

morbidity estimated at 64 million missed workdays per year in the
US. Although migraine is a specific neurological syndrome, the
manifestations vary widely.

 Aura may begin as long as 24 hrs before the onset of pain. 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 1-2 a year to 1-4 per month.

Dr. Sabyata Gautam

 USE OF 5-HT-RECEPTOR AGONISTS IN MIGRAINE
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 In migraine, there is vasodilatation of cranial blood vessels with

release of substance P, accompanied by nausea, vomiting,
photophobia, phonopobia, and aura.

 The efficacy of anti-migraine drugs varies with the absence or

presence of aura, duration of the headache, its severity and
intensity, and as yet undefined environmental and genetic factors
(Deleu et al., 1998).

 A rather vague and inconsistent pathophysiological characteristic

of migraine is vasoconstriction followed by vasodilation.

Dr. Sabyata Gautam

 Triptans…
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MOA: Hypothesis implicates the capacity of 5-HT1B/1D receptors

to cause constriction of intracranial blood vessels including arterio-
venous anastomoses.

According to a prominent pathophysiological model, unknown

events lead to the abnormal dilation of carotid arteriovenous
anastomoses in the head (mainly cranial skin & ears). Around 80%
of carotid arterial blood flow has been reported to be “shunted” due
to anastomoses  diverting blood from the capillaries  cerebral
ischemia and hypoxia  headache
So, an effective anti-migraine agent would close the shunts and restore blood
flow as well as block the release of pro-inflammatory neuropeptides.

Dr. Sabyata Gautam

 Triptans…
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 5-HT1-Receptor Agonists: the Triptans, Sumatriptan,

zolmitriptan, rizatriptan have led to significant progress in
preclinical and clinical research on migraine. 5-HT is said to
initiate the vasoconstrictor phase  ↓ neurogenic inflammation
of the affected blood vessels.

Methysergide and pizotifen (5-HT antagonist) are effective

prophylactics and sumatriptan (5-HT1D agonist) can control an
attack. However, the role of 5-HT in this condition is not precisely
known.

Dr. Sabyata Gautam

 Sumatriptan
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 Sumatriptan and the other triptans are selective agonists for 5-HT1D and 5-
HT1B receptors. They probably function as pre-synaptic receptors and mediate
vasoconstriction  prevent migraine attacks. MOA: a. Block release of
vasodilator neuropeptides (Substance P, Calcitonin gene-related peptide) b.
Selective constriction of intracranial blood vessels.

 The efficacy of triptan 5-HT1 agonists in migraine is equal to or greater than

that of other acute drug treatments, e.g., parenteral, oral, or rectal ergot
alkaloids.

 Oral Bioavailability: Around 14%. T1/2 : 2hrs. Metabolism: Liver

Dr. Sabyata Gautam

 Other triptans…
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 Zolmitriptan reaches its peak plasma concentration 1.5-2 hrs

after oral administration. Oral Bioavailability: 40%. It is
metabolized to an active N-desmethyl metabolite, which has
several fold higher affinity for 5-HT1B and 5-HT1D receptors than
does the parent drug.

 Rizatriptan: Bioavailability = 45% and reaches peak plasma levels

within 1-1.5 hours. Metabolism: oxidative deamination.

 Plasma protein-binding of the triptans ranges from about 14%

(sumatriptan and rizatriptan) to 30% (naratriptan).
Dr. Sabyata Gautam
Drug Routes Time to Single Dose Max. Half-
(mg) Dose/d Life
Onset (h)
(mg) (h)

Almotriptan Oral 2.6 6.25–12.5 25 3.3

Eletriptan Oral 2 20–40 80 4

Frovatriptan Oral 3 2.5 7.5 27

Naratriptan Oral 2 1–2.5 5 5.5

Rizatriptan Oral 1–2.5 5–10 30 2

Sumatriptan Oral, nasal, 1.5 (0.2 for 25–100 (PO) 200 2

subcutaneous subcutaneous)
Zolmitriptan Oral, nasal 1.5–3 1.25–2.5 10 2.8

Dr. Sabyata Gautam 22

 ERGOT ALKALOIDS
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The active principles of ergot were isolated and identified in the

early 20th century. It is the product of a fungus (Claviceps
purpurea) that grows on rye and other grains.

These alkaloids affect adrenoceptors, dopamine receptors, 5-HT

receptors, and perhaps other receptor. Ergotamine is drug of choice/
highly specific for migraine which can be given by oral, rectal,
nasal, sublingual route.

It is partial agonists at serotonin receptors (esp. 5-HT1A and 5-

HT1D); & agonist/ partial agonist at dopamine receptors. Its
vasoconstriction effect is long-lasting and cumulative.
Dr. Sabyata Gautam
ERGOT ALKALOIDS…
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 Pkt’s: Low oral bioavailability due to extensive first-pass

metabolism. Bioavailability (sublingual) = less than 1%.
Bioavailability of rectal suppositories is greater. Metabolism:
liver (various pathways). Excretion: 90% of the metabolites are
excreted in the bile.

 t1/2: 2hrs, but vasoconstriction that lasts for 24hrs or longer. Di-
hydroergotamine is eliminated more rapidly than ergotamine,
presumably due to its rapid hepatic clearance.

Dr. Sabyata Gautam

ERGOT ALKALOIDS…
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 Dose for ergotamine tartrate = 2mg sublingually, which can be

repeated at 30 mins intervals if necessary, total dose = 6mg in a
24 hrs or 10mg a week.

 Dihydroergotamine mesylate inj. can be given i.v, s.c, or i.m.

The recommended dose is 1 mg, which can be repeated after 1
hour if necessary. Total dose: 2mg (i.v) or 3mg (s.c or i.m) in
24hrs or 6mg in a wk. Nasal spray i.e 0.5 mg (one spray) in each
nostril, repeated after 15 mins for a total dose of 2 mg (4 sprays).

 Side-effects: Nausea and vomiting, Leg weakness and muscle

pains, numbness and tingling of fingers and toes.
Dr. Sabyata Gautam
 SEROTONIN ANTAGONISTS
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The actions of serotonin, like those of histamine, can be

antagonized in several ways. A wide variety of drugs with actions at
other receptors (adrenoceptors, H1-histamine receptors, etc.) are
also serotonin receptor-blocking agents.

Such antagonism is clearly desirable in those rare patients who have

carcinoid tumor and may also be valuable in certain other
conditions.

Serotonin synthesis can be inhibited by p-chlorophenylalanine and

p-chloroamphetamine. However, these agents are too toxic for
general use.
Dr. Sabyata Gautam
Drugs Action/ Uses Dose Side-effects
Phenoxybenzamine It has a long-lasting blocking action 10mg initial, Nasal congestion,
at 5-HT2 & α-blockers. 20-40mg in dizziness,
Uses: high b.p and divided doses stomach upset,
pheochromocytoma. sexual
dysfunction
Cyproheptadine It has potent H1, 5-HT2A-blocking & 12–16 mg/d tid drowsiness, dry
anti-muscarinic effects. Causes or qid mouth,
sedation. confusion, ataxia
Uses: carcinoid tumor, urticaria. and weight gain

Ketanserin It blocks 5-HT1c, 5-HT2 & α1 1-2mg/kg/day. Mild dizziness,

receptors. It blocks vasoconstriction, Bioavailability tiredness, nausea
platelet aggregation and contraction : 50% due to and dry mouth
of guinea pig ileum. first pass
metabolism.

Ondansetron It is the selective 5-HT3 antagonist. 8mg i.v. Blurred vision,

Uses: Nausea and vomiting infusion, decrease heart
associated with chemotherapy. 15min-30mins rate, anxiety
Oral bioavailability: 60-70%. t½: 3hr. before chemo-
therapy.
Dr. Sabyata Gautam 27
Dr. Sabyata Gautam 28
 thanks
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Dr. Sabyata Gautam