A PowerPoint Presentation on Serotonergic Drugs suitable for UG MBBS level Medical Students

1. Serotonin orSerotonin or
5-Hydroxytryptamine and its5-Hydroxytryptamine and its
antagonistsantagonists
Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong

2. What is Serotonin?What is Serotonin?
 Vasoconstrictor - Serotonin and Enteramine
 Serotonin or 5-Hydroxytryptamine (5-HT) is a
monoamine neurotransmitter, biochemically derived
from tryptophan
 Feelings of well-being
 Present in Intestine (90%) along with platelets and brain
(10%)
◦ 90% in EC cells and 10% in neurones of different plexuses
 Stored in granules like catecholamine
 Also present in plants and insects
◦ Plants like tomato, banana & pineapple
◦ Lower animals - mollusks, arthropods, snake and bee
venom/sting

3. Physiologic Distribution of SerotoninPhysiologic Distribution of Serotonin
(5-Hydroxytryptamine (5-HT)(5-Hydroxytryptamine (5-HT)
10% CNS
90% GI tract
 90% ECs
 10% Neurons
5-Hydroxytryptamine
5

4. Synthesis, Metabolism and DestructionSynthesis, Metabolism and Destruction
Dietary tryptophan
◦ converted to 5–hydroxy– tryptophan by
tryptophan hydroxylase
◦ then to 5-HT by a non–specific decarboxylase
Degradation
◦ mainly monoamine oxidase (MAO–A >
MAO–B)
◦ 5–hydroxyls Indole acetic acid (5-HIAA) in
urine

5. N
C
N
C NH2
COOH COOH
NH2
OH
N
C NH2
OH H
Tryptophan 5-Hydroxytryptophan
5-Hydroxytryptamine
N
C COOH
5-OH Indole
Acetaldehyde
5-Hydroxy Indole
Acetic Acid
Tryptophan
hydroxylase
5-OH Tryptophan
decarboxylase
M
AO
Aldehyde
dehydrogenase
(Rate limiting)
In diet. Active
CNS transport
Dietary

6. Serotonin UptakeSerotonin Uptake
 Non-specific Decarboxylase
produces 5-HT (also CA)
 Amine pump (SERT) actively
takes up Serotononin (like CA)
in serotonergic nerve endings –
Na+ dependent carrier ….
Inhibited by SSRIs and TCAs
 Platelets do not synthesize 5-HT
(deficiency of tryptophan
hydroxylase) -– but actively takes
up by SERT – during intestinal
passage
 Stored in storage vesicles by
active uptake (like CAs) –
Vesicular monoamine
transporter (VMAT 2) – inhibited
by Reserpine
 Degrading enzyme MAO is
common for both MAO

7. Refer to - Biosynthesis ofRefer to - Biosynthesis of
CatecholaminesCatecholamines
Phenylalanine
PH
Rate limiting Enzyme
5-HT, alpha Methyldopamine
α-methyl-p-tyrosine

8. 5-HT5-HT
ReceptorsReceptors
 Classically - Musculotropic (D type) and Neurotropic (M type) –
blockade by Dibenzylline (Phenoxybenzamine) and Morphine
respectively
 Methysergide and cyproheptadine are classical blockers – blocks
D-type only
 Radiological binding studies – molecular characterization and
cloning ….
 FOUR FAMILIES - 5-HT1, 5-HT2, 5-HT3 and 5-HT4-7
 All are GPCRs except 5-HT3 (5-HT3 is a ligand gated Na+ channel)
◦ All are cAMP ………. except 5-HT2 (IP3-DAG)
◦ 5-HT1 inhibits cAMP and 5-HT4, 5-HT6 and 5- HT7 increases cAMP

9. 5-HT15-HT1 ––
ReceptorsReceptors
 Five Subtypes – A, B, D, E and F
 All acts as autoreceptors Gi/G0 subtypes (inhibits
adenylyl cyclase) - inhibit firing of neurones or release
of 5-HT
◦ Also, activation of K+ channel and inhibits Ca++
channel
 5-HT1A – Brainstem (Raphe nuclei) and hippocampus
(antidepressant – Buspirone - partial agonist)
 5-HT1D – Basal ganglia and substancia nigra
(dopeminergic)
 5-HT1B/1D – Cranial Blood Vessels (for constriction –
sumatriptan – selective agonist)

10. 5-HT5-HT22
Mainly 3 subtypes (5-HT2A, 5-HT2A and 5-HT2A) –
all are Gq types – IP3/DAG
◦ 5-HT2A
 Widely distributed postjunctional (D-type)
 Located in all smooth muscles - vascular, visceral – also
platelets and cerebral neurones
 Mediates DIRECT ACTIONS
 Vasoconstriction, intestinal, uterine and bronchial
constrictions, platelet aggregation and activation of cerebral
neurones etc.
 Ketanserin - specific antagonist
◦ 5-HT2c –– vasodilatation through EDRF … choroid
plexus

11. 5-HT5-HT33
 Neuronal 5-HT Receptor – depolarization of nerve
endings and opening of channels (M-type) – Mediates
indirect and reflex effects
 Somatic and ANS nerve endings – pain, itch, coronary
chemoreflex
◦ Fall in BP, bradycardia, stimulation of respiration or apnoea and
other visceral reflexes
 Myenteric plexus nerve endings: augmentation of
peristalsis and emetic reflex
 Brain: Area postrema and NTS: nausea and vomiting
 Ondansetron – specific antagonist

12. 5-HT5-HT4-74-7
Gs-type of receptor – activates adenylyl cyclase
◦ Mucosa, plexuses and smooth muscles of gut
◦ Related to - augmentation of Intestinal secretion and
peristalsis
◦ In Brain: hippocampaus area – slow depolarization of
K+ channel
◦ Specific role is unknown till now
◦ Cizapride and renzapride – specific agonist of the 5-
HT4 receptor
◦ 5-HT5, 5-HT6 and 5-HT7 – closely related to 5-HT4

13. Receptor Type Location Functions Agonists Antagonists
5-HT1 GPCR
(Gi/Go)
Auto-receptors
in brain –
prejunctional
Inhibits Serotonergic
activity
5-HT1A do Raphe nuclei,
Hippocampus
Inhibits firing of raphe
nuclei
Buspirone
(Partial)
5-HT1D/1B do Cranial blood
vessels and
CNS neurons
Constricts vessels and
inhibits release of
inhibitory neuropeptides
Sumatriptan
5-HT2A GPCR
(IP3/DAG)
Post-junctional
visceral and
vascular SM
Contraction, platelet
aggregation, neuronal
activation in brain
Ketanserin
5-HT3 Ligand
gated Na+
channel
Somatic and
ANS Nerve
endings,
Myenteric
plexus and NTS
in brain
Reflex actions –
peristalsis, bradycardia,
hypotension, apnoea, pain
etc.
Ondansetron
5-HT4 GPCR
(Gs)
Mucosa,
plexuses and
SM of gut
Secretion, and peristalsis Renzapride

14. Actions ofActions of 5-HT5-HT
 Potent depolarizer of Nerve endings – exerts direct as well as
indirect effects
 Tachyphylaxis
Arteries
are constricted (direct) or dilated (EDRF) – depends
on vascular bed and basal tone
Also releases Adrenaline – affects ganglionic
transmission – CVS reflexes
Overall, large arteries and veins are constricted but in
microcirculation arterioles dilate and veins constrict
Constriction of veins – escape of fluid

15. Actions of 5-HT - CVSActions of 5-HT - CVS
 Heart: Isolated heart stimulation - direct ionotropic and
chronotropic effects
◦ Intact animal Heart: Bradycardia due to stimulation coronary
chemoreflex (Bezold Jarrisch reflex) – through vagaus Nerve
◦ Overall bradycardia, hypotension and apnoea
 Blood Pressure: Triphasic response on BP
◦ Early sharp fall: Coronary chemoreflex
◦ Brief rise in BP: vasoconstriction and increased cardiac output
◦ Prolonged fall in BP: arteriolar dilatation and extravasation of
fluid
(Not involved in Physiological Regulation of BP) – Preeclmpsia
Ketanserin – 5-HT antagonist (5-HT2)

16. Actions ofActions of 5-HT5-HT -Visceral SM-Visceral SM
 GIT: Stimulator of GIT – direct and through entero-
chromaffin cells in the mucosa main 5-HT in body
◦ ↑ GIT motility – increased peristalsis and diarrhoea
 Bronchi: Constricts, but less potent than histamine
 Glands: 5-HT inhibits gastric acid and pepsin, secretion
however increase mucus production thus it has ulcer
protective property
 Nerve endings and adrenal medulla: afferent nerve
endings are activated – tingling and pricking sensation –
also pain
◦ Depolarization of visceral afferents – respiratory and CVS
reflexes, nausea and vomiting
 Respiration: brief stimulation of respiration – reflex
from bronchial afferents – hyperventilation. Large dose
– apnoea – coronary chemoreflex

17. Actions ofActions of 5-HT5-HT – contd.– contd.
Platelet: 5-HT2A action – changes in shape
and size of platelets – but weak
aggregator
CNS: Poor entry to BBB – however it’s a
transmitter – INHIBITORY
◦ Direct Injection: Hunger, sleepiness,
behavioural changes

18. Pathphysiological Roles –Pathphysiological Roles – 5-HT5-HT
 Neurotransmitter: Raphe nuclei, substancia nigra and other sites
….. Send serotonergic to limbic system, cortex, neostriatum and
also to Spinal chord – regulates sleep, temperature regulation,
thought process, cognitive, behaviour and mood, appetite, vomiting
and pain perception
 Precursor of Melatonin: Pineal gland
 Neuroendocrine Function: Hypothalamic hormones to
Anterior Pituitary – serotonergic (!)
 Nausea and Vomiting: Cytotoxic drugs and radiotherapy –
receptor of gut 5HT3
 Migraine: Vasoconstrictor phase of migraine – Methysergide and
Sumatriptan

19. 5-HT5-HT Physiological Roles – contd.Physiological Roles – contd.
 Haemostasis: Platelet aggregation and clot formation
enhancer
 Raynaud`s phenomenon: Vasospastic
 Variant angina: Coronary vasospasm or Variant
angina
 Hypertension: Not clearly known – reduced uptake
and clearance of 5-HT - Ketanserin
 Intestinal Motility: Regulates local reflex and
peristalsis in gut
 Carcinoid syndrome: Massive release – hypermotility
and bronchoconstriction
5-HTs – NO THERAPEUTIC USE

20. 5-HT5-HT antagonistsantagonists

21. Antagonists of serotoninAntagonists of serotonin
Ergot derivatives: Ergotamine, ergonovine and
methysergide (Carcinoid) etc.
Alpha-blockers: Phenoxybenzamine
Antihistaminics: Cyproheptadine, cinnarizine
Phenothiazines: Chlorpromazine
Ketanserin: used as antihypertensive
Clozapine: for schizophrenia
Metoclopramide, Ondansetron and Granisetron
are currently available as anti-emetic for
chemotherapeutic induced nausea and vomiting
(5-HT3 antagonists)

22. CyproheptadineCyproheptadine
 5-HT2A blocking property
 Also H1 antihistamic, anticholinergic and sedative action
 Famous for increasing appetite
 Uses:
◦ Allergic reactions like hay fever
◦ Serotonin syndrome
◦ Carcinoid syndrome
◦ Priapism (fluoxetine)
◦ Appetite stimulation in children
 Adverse effects: weight gain, drowsiness, dry mouth
etc.

23. KetanserineKetanserine
Selective 5-HT2 receptor blocker – negligible 5-
HT1, 5-HT3 and 5-HT4 blocker
5-HT2A > 5-HT2C
Additional H1, α1 and dopaminergic blocking
action
Antagonizes vasoconstriction, platelet
aggregation and airway constriction actions of
5-HT
Used as antihypertensive agent
Other drugs like – clozapine, risperidone and
ondansetron will be discussed elsewhere !

24. Ergot Alkaloids and derivativesErgot Alkaloids and derivatives
Ergot alkaloids ---- toxic effects
First isolated by Dale & Barger in 1906 from fungus Claviceps
purpurea ---- on rye and other grains - sclerotinium
Contains – LSD, histamine, acetylcholine and tyramine etc.
They have long been recognized as abortifacients and poisonings
produced an intense burning sensation & gangrenous condition
in the limbs as a result of persistent peripheral vasoconstriction
Diverse pharmacological actions – agonist, antagonist and partial
agonist of serotonin, alpha-receptor and dopaminergic receptors

25. Classification of ergot alkaloidsClassification of ergot alkaloids
1. Natural – Derivatives of the tetra-cyclic
compounds (lysergic acid)
Amine alkaloids – Ergometrine (ergonovine) -
oxytotic
Amino acid alkaloids - Ergotamine, Ergotoxine ...
Vasoconstrictor & α - blocker
1. Semi-synthetic – Bromocriptine,
Methysergide, Dihydro-ergotamine (DHE)
2. Synthetic – (non lysergic acid derivative)
Metergotine

26. ErgometrineErgometrine
Amine ergot alkaloid
Partial agonist of 5-HT receptor in uterus, placenta
and umbilical blood vessels and some areas in brain
Weak agonist but no antagonistic effect of α
receptor
Moderately potent antagonist of 5-HT2 in intestine
Less dopaminergic action in CTZ – no vomiting
Most prominent - Uterine myometrium
Will be discussed elsewhere !

27. ErgotamineErgotamine
Amino acid alkaloid
Partial agonist and antagonist of α adrenergic
and 5-HT1 and 5-HT2 receptors, but no
interaction with 5-HT3 or dopaminergic
receptors
Actions:
◦ Sustained vasoconstriction, visceral smooth muscle
contraction and vasomotor centre depression
◦ Antagonizes action of NA and 5-HT in smooth
muscles
◦ Overall BP effect - insignificant
◦ Potent emetic via CTZ and oxytotic
◦ Prolong use – vasoconstriction and damage
endothelium

28. DihydroergotamineDihydroergotamine
(DHE)(DHE)
Hydrogenated ergotamine
Less serotonergic action than ergotamine
and less α - adrenergic agonist action
Better blocker of α-adrenergic receptor
Less vasoconstrictor and so less intimal
damage
Lesser oxytotic and emetic

29. ErgotsErgots
 Pharmacokinetics: Poor bioavailability – 1% - slow
and incomplete absorption plus 1st
pass metabolism
◦ Sublingual/rectal administration
◦ Metabolized in liver nd excreted in bile
◦ Ergotamine is sequestrated to tissues – half life – 2 Hrs
◦ Crosses BBB
 ADRs: Nausea, vomiting, muscle cramps, weakness,
paraesthesia, coronary and other vasospasm, chest pain
etc.
 CIs: Sepsis, IHD, Peripheral vascular disease,
hypertension, liver disease and pregnancy

30. Learn …Learn …
Actions and Pathophysiological Roles of
5-HT
5-HT antagonists
Cyproheptadine
Ergots - etgotamine

31. Thank youThank you

32. Migraine TherapyMigraine Therapy

33. What is migraineWhat is migraine
 Severe, throbbing, pulsating headache usually unilateral headache (few
hours to a few days in duration)
 Associated with nausea, vomiting, sensitivity to light and sound, flashes of
light, loose motion and others
 Types:
◦ Classical with aura
◦ Without aura (common)
 Pathophysiology:
◦ Pulsatile dilatation of temporal or certain cranial vessels
◦ Vascular theory: initial vasoconstriction or shunting of blood through carotid
arterio-venous anastomosis causing cerebral ischaemia
◦ Neurogenic theory: depression of cortical electrical activity followed by
depression
 Migraine attack associated with (based on histological studies):
 sterile neurogenic perivascular edema
 inflammation (clinically effective antimigraine medication reduce
perivascular inflammation)

34. Pharmacotherapy of MigrainePharmacotherapy of Migraine
Three types: Mild, Moderate and Severe
Mild: NSAIDS and Antiemetics (optional)
 Ibuprofen (400 mg 8 hrly)
 Paracetamol (500 mg 8 hrly)
 Naproxen (250 mg 8 hrly)
 Mefenamic acid (500 mg 8 Hrly)
 Diclofenac (50 mg 8 Hrly)
◦ Antiemetics:
 Metoclopramide (10 mg oral or IV)
 Domperidone (10 mg oral)

35. Migraine - ModerateMigraine - Moderate
Intense throbbing headache lasting for 6
– 24 Hrs, nausea and vomiting and
functionally impaired patient
◦ NSAIDs
◦ Antiemetics
◦ Specific drugs like ergots and others
(sumatriptan)

36. Migraine - SevereMigraine - Severe
More than 2-3 attacks per month lasting
for 12 – 48 hrs, often vertigo and
vomiting and patient is completely
incapacitated
◦ NSAIDS cannot relieve symptoms
◦ Specific antimigraine drugs like ergot alkaloids
and triptans
◦ Also prophylactic regimens

37. ErgotamineErgotamine
 Most effective ergot alkaloid
 MOA:
◦ Partial agonist of 5-HT1B/1D
◦ Constriction of dilated temporal vessels
◦ Constriction of carotid AV shunt channels
◦ Reduction of neurogenic inflammation and leakage of plasma in
duramater
 Doses: oral/sublingual (1 mg every half an hourly) till relief – 6 mg/
day
 Kinetics: only 1% Bioavailability orally – high first pass metabolism
◦ Given by SL route and rectal
◦ Metabolized in liver and excreted in bile
◦ Sequestrated to tissues and long lastin effect
◦ Crosses BBB
 ADRs: Nausea, vomiting, abdominal pain, muscle cramps etc. Also
chest pain, vascular spasm etc.

38. DHEDHE
Almost equally effective as ergotamine
Preferred for parenteral administration
Erratic oral absorption – combined with
caffeine 100 mg for enhancing oral absorption
Ergo status in Migraine:
◦ Not popular anymore
◦ Regular use is hazardous
◦ No prophylactic value – precipitate on
discontinuation
◦ Dull headache
◦ Combination with caffeine, paracetamol, belladona
etc. are available

39. Selective 5-HT1B/1D agonistSelective 5-HT1B/1D agonist
SumatriptanSumatriptan
 Selective agonist of 5-HT1B/1D receptor
 No interaction with other 5-HT receptors
 No interaction with adrenergic, dopaminergic and cholinergic
receptors, GABA
MOA:
 Blockade of 5-HT1D/1B mediated constriction dilatation of
extracerebral blood vessel
 Constriction of arteriovenous shunt of carotid artery
 Inhibition of release of 5-HT and inflammatory neuropeptides
around the affected vessels – supression of neurogenic
inflammation
 Supression of impulse transmission in trigeminovascular system
Kinetics:
 Poorly absorbed from GIT, bioavailability – 10 – 15% only
 Complete absorption after subcutaneous administration
 Metabolized by MAO-A and excreted in urine, t1/2 is 2-3 Hrs

40. Sumatriptan – contd.Sumatriptan – contd.
 Administration & Doses:
◦ Onset of acute attack
◦ Better tolerated than ergotamine
◦ 50 to 100 mg as initial dose and repeated after 24 Hrs if
required
◦ Should not be given is first dose fails
◦ SC dose – 12 mg (1 ml) stat and repeated if required
 Adverse effects: Dose related - Tightness of chest,
feeling of heat, paresthesia of limbs, dizziness and
weakness (short lasting) – common with SC route
◦ Risk of MI and seizure and death
 Contraindications: IHD, epilepsy, hypertension,
pregnancy, hepatic and renal impairment
(Rizatriptan, zolmitriptan, naratriptan, almotriptan)

41. Prophylaxis of MigraineProphylaxis of Migraine
 Necessary when attacks are frequent – 2 (two) or
more attacks per month
 Aim is to abolish attack totally
 Discontinue every 4 - 6 months and observe
 Beta-adrenergic blockers – Propranolol (40 mg BD),
timolol etc. (not metoprolol or atenolol)
 TCAs: Amitryptylline (25 – 50 mg BD)
 Calcium channel blockers: Verapamil – not used now
(flunnarizine – weak Ca channel blocker is effective)
 Anticonvulsants: Valproic acid (400 – 1200 mg/day),
gabapentin (300 – 1200 mg per day) and newer
topiramate (25 mg OD) – effective

42. Thank
you