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5-Hydroxytryptamine, its
Antagonists and Drug Therapy
of Migraine
Dr. Anubhuti Khare
Asst. Prof.
Dept. of Pharmacology
5-HYDROXYTRYPTAMINE
(5-HT, Serotonin)
• 90% of body’s content of 5-HT- intestines
(enterochromaffin cells)
• Rest- platelets and brain
• Also found- wasp, and scorpion sting; widely
distributed in invertebrates and plants
(banana, pear, pineapple, tomato, stinging
nettle, cowhage).
SYNTHESIS, STORAGE AND
DESTRUCTION
SEROTONERGIC (5-HT) RECEPTORS
Pharmacological actions
• 1. CVS
• In intact animals- coronary chemoreflex (Bezold Jarisch
reflex) through action on vagal afferent nerve endings in the coronary
bed: bradycardia, hypotension and apnoea
• BP: a triphasic response (i.v. injection of 5-HT in animals)
• • Early sharp fall in BP—due to coronary chemoreflex.
• • Brief rise in BP—due to vasoconstriction and increased cardiac output.
• • Prolonged fall in BP—due to arteriolar dilatation and extravasation of
fluid.
• 2. Visceral smooth muscles
– GI- Peristalsis is increased & diarrhoea
– Constricts bronchi
• 3. Glands
– Inhibits gastric secretion (both acid and pepsin), but increases mucus
production
– ulcer protective property
• 4. Nerve endings and adrenal medulla
– Afferent nerve endings- tingling, pricking sensation, pain.
– Visceral afferents- respiratory & cardiovascular reflexes, nausea & vomiting.
– Adrenal medulla- release CAs
• 5. Respiration
– A brief stimulation of respiration & hyperventilation
– Large doses -transient apnoea
• 6. Platelets
– change in shape of platelets; weak aggregator
• 7. CNS
– poor entry across BBB
– serves as a transmitter, primarily inhibitory
– Direct injection in the brain- sleepiness, changes in body temperature, hunger
and a variety of behavioural effects
PATHOPHYSIOLOGICAL ROLES
• Neurotransmitter
• Precursor of melatonin
• Neuroendocrine function
• Nausea and vomiting
• Migraine
• Haemostasis
• Raynaud’s phenomenon
• Variant angina
• Hypertension
• Intestinal motility
• Carcinoid syndrome
• Use
• Due to widespread and variable actions, 5-HT has no therapeutic use.
DRUGS AFFECTING 5-HT SYSTEM
• Tryptophan
5-HT precursor
• p-Chlorophenylalanine (PCPA) inhibits tryptophan
hydroxylase (rate limiting step)
Synthesis inhibitor
• TCAs
• SSRIs
Uptake inhibitor
• Reserpine- inhibits VMAT-2
• Fenfluramine- release causing depletion
Storage inhibitor
• Nonselective MAO inhibitor(tranylcypromine)
• selective MAO-A inhibitor (clorgyline)
Degradation inhibitor
• 5, 6 dihydroxytryptamine selectively destroys 5-HT
neurones.
Neuronal degeneration
• D-Lysergic acid diethyl amide
(LSD)- nonselective 5-HT
agonist; hallucinogenic
• Azapirones (buspirone,
gepirone ,ipsapirone)-
antianxiety drugs. PA 5-HT1A
receptors
• Sumatriptan and other
triptans - selective 5-
HT1D/1B agonists; T/t of
MIGRAINE
• Cisapride Renzapride -
prokinetic drugs; selective 5-
HT4 agonist.
5-HT
receptor
agonists
5-HT ANTAGONISTS
• Cyproheptadine
– Blocks 5-HT2A receptors :controlling intestinal manifestations of
carcinoid & postgastrectomy dumping syndromes and antagonize priapism/
orgasmic delay caused fluoxetine & trazodone
– additional H1 antihistaminic, anticholinergic and sedative
properties :antipruritic, increases appetite & has been used in children and
poor eaters to promote weight gain.
• Methysergide
– antagonizes 5-HT action on vascular & visceral smooth
muscles
– 5-HT2A/2C antagonist
– Not used- abdominal, pulmonary & endocardial fibrosis
• Ketanserin
– 5-HT2 antagonist
– Opposes 5-HT induced vasoconstriction, platelet aggregation &
contraction of airway smooth muscle
– additional weak α1, H1 and dopaminergic blocking activities.
– Ritanserin- relatively more selective 5-HT2A antagonist
• Clozapine
– atypical antipsychotic - resistant cases of schizophrenia
– 5-HT2A/2C antagonist; inverse agonist at 5-HT2A/2C receptors
• Risperidone, olanzapine and quetiapine
– 5-HT2A + D2 antagonist
– Atypical antipsychotics
• Ondansetron, Granisetron and Tropisetron
– 5-HT3 antagonists
– Control anticancer & radiotherapy induced N& V
ERGOT ALKALOIDS
• Ergot is a fungus Claviceps purpurea which grows
on rye, millet and some other grains
• Epidemics of ergot poisoning (ergotism), due to
consumption of contaminated grains
• Natural ergot alkaloids
– (a) Amine alkaloid - Ergometrine (Ergonovine):
oxytocic
– (b) Amino acid alkaloids- Ergotamine, Ergotoxine :
emetic, vasoconstrictor & α adrenergic blocker/PA;
migraine
• Other semisynthetic derivatives
– (a)Dihydroergotamine (DHE), Dihydroergotoxine
(Codergocrine): antiadrenergic, cerebroactive- t/t of
dementia
– (b)2-Bromo-α-ergocryptine (Bromocriptine): D2
agonist (antiparkinsonian), inhibit prolactin release,
emetic
– (c)Methysergide: mainly anti 5-HT
• Adverse effects
• Nausea, vomiting, abdominal pain, muscle
cramps, weakness, paresthesias, coronary and
other vascular spasm, chest pain (due to coronary
vasoconstriction)
Selective 5-HT1D/1B agonists
(Triptans)
• Currently, first line drugs for patients who fail to respond to
analgesics [sumatriptan, riza., frova., nara., zolmi.]
• MOA
– 5-HT1D/1B receptor mediated constriction of dilated cranial blood
vessels (in AV shunts in the carotid artery)
– 5-HT1D/1B are presynaptic autoreceptors: triptans reduce 5-HT
release at these blood vessels
– inhibit inflammatory neuropeptide release around the affected vessels
as well as extravasation of plasma proteins across dural vessels
– suppress neurogenic inflammation of cranial vessels
• All triptans: significant pharmacokinetic differences
• Sumatriptan- lowest BA; absorbed rapidly and completely after s.c.
injection; intranasal spray
• Naratriptan & Frovatriptan- longer t½; fewer headache recurrences;
slow in affording initial pain relief.
• Side effects-
– Tightness in head & chest, feeling of heat & other paresthesias
in limbs, dizziness, weakness
– Slight rise in BP; bradycardia, coronary vasospasm & risk of MI-
rare but serious
• Contraindications:
– Ischaemic heart disease, hypertension, epilepsy, hepatic or renal
impairment & pregnancy ; cautioned not to drive.
• Sumatriptan and ergotamine should not be administered
within 24 hours of each other.
• Interaction with 5-HT reuptake inhibitors, MAO inhibitors &
lithium
MIGRAINE
• Pulsating headache
• usually restricted to one side
• attacks lasting 4–48 hours
• often associated with nausea, vomiting,
sensitivity to light and sound, flashes of light,
vertigo, loose motions and other symptoms
• Two major types
– —migraine with aura (classical migraine)
– —migraine without aura (common migraine)
• Pathogenesis
– Vascular theory
– Neurogenic theory
• Mild migraine
– fewer than one attack per month
– lasts upto 8 hours
– does not incapacitate the individual
– Drug therapy - Simple analgesics/NSAIDs or their
combinations (± antiemetic)
– Paracetamol, aspirin, ibuprofen, naproxen, diclofenac
either alone or combined with paracetamol/codeine/
diazepam or another sedative/diphenhydramine or
another antihistaminic/caffeine
• Moderate migraine
– One or more attacks per month
– lasts for 6–24 hours
– Throbbing headache more intense, nausea/vomiting & other
features more prominent
– Patient is functionally impaired
– Drug therapy- NSAIDs combinations/a triptan/ ergot alkaloids
(+ antiemetic)
– Prophylactic therapy advised: attacks more frequent than 2–3
per month
• Severe migraine
– 2–3 or more attacks per month of
– lasts 12–48 hours
– severe throbbing headache, vertigo, vomiting and other
symptoms
– Pt. grossly incapacitated during the attack
– Drug therapy- a Triptan/ergot alkaloids (+ antiemetic)
+ Prophylaxis
PROPHYLAXIS OF MIGRAINE
• (i) β-Adrenergic blockers- Propranolol
• (ii) Tricyclic antidepressants- Amitriptyline
• (iii) Calcium channel blockers- Verapamil
– Flunarizine- cerebro-selective CCB, also inhibits Na+ channels
• (iv)Anticonvulsants - Valproic acid, gabapentin, topiramate
• (v) CGRP antagonist- monoclonal antibody Erenumab (s.c. once a
month)
• Q. Serotonin can be synthesized from:
– a) Tryptophan
– b) Tyrosine
– c) Dopa
– d) Epinephrine
• Q. Drug which blocks both H1 & 5HT2 receptor:
– a) Phenoxybenzamine
– b) Cyprohepatidine
– c) Ritanserin
– d) Ondansetron
• Q. After taking some drug for acute attack of
migraine, a patient developed nausea & vomiting.
He also developed tingling & numbness in the tip
of the finger that also turned blue. Which of the
following is the most likely drug implicated in
causing the above findings?
– a) Dihydroergotamine
– b) Sumatriptan
– c) Aspirin
– d) Butorphanol

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5-HT Antagonists and Triptans in Migraine Therapy

  • 1. 5-Hydroxytryptamine, its Antagonists and Drug Therapy of Migraine Dr. Anubhuti Khare Asst. Prof. Dept. of Pharmacology
  • 2. 5-HYDROXYTRYPTAMINE (5-HT, Serotonin) • 90% of body’s content of 5-HT- intestines (enterochromaffin cells) • Rest- platelets and brain • Also found- wasp, and scorpion sting; widely distributed in invertebrates and plants (banana, pear, pineapple, tomato, stinging nettle, cowhage).
  • 4.
  • 6.
  • 7. Pharmacological actions • 1. CVS • In intact animals- coronary chemoreflex (Bezold Jarisch reflex) through action on vagal afferent nerve endings in the coronary bed: bradycardia, hypotension and apnoea • BP: a triphasic response (i.v. injection of 5-HT in animals) • • Early sharp fall in BP—due to coronary chemoreflex. • • Brief rise in BP—due to vasoconstriction and increased cardiac output. • • Prolonged fall in BP—due to arteriolar dilatation and extravasation of fluid.
  • 8. • 2. Visceral smooth muscles – GI- Peristalsis is increased & diarrhoea – Constricts bronchi • 3. Glands – Inhibits gastric secretion (both acid and pepsin), but increases mucus production – ulcer protective property • 4. Nerve endings and adrenal medulla – Afferent nerve endings- tingling, pricking sensation, pain. – Visceral afferents- respiratory & cardiovascular reflexes, nausea & vomiting. – Adrenal medulla- release CAs • 5. Respiration – A brief stimulation of respiration & hyperventilation – Large doses -transient apnoea • 6. Platelets – change in shape of platelets; weak aggregator • 7. CNS – poor entry across BBB – serves as a transmitter, primarily inhibitory – Direct injection in the brain- sleepiness, changes in body temperature, hunger and a variety of behavioural effects
  • 9. PATHOPHYSIOLOGICAL ROLES • Neurotransmitter • Precursor of melatonin • Neuroendocrine function • Nausea and vomiting • Migraine • Haemostasis • Raynaud’s phenomenon • Variant angina • Hypertension • Intestinal motility • Carcinoid syndrome • Use • Due to widespread and variable actions, 5-HT has no therapeutic use.
  • 10. DRUGS AFFECTING 5-HT SYSTEM • Tryptophan 5-HT precursor • p-Chlorophenylalanine (PCPA) inhibits tryptophan hydroxylase (rate limiting step) Synthesis inhibitor • TCAs • SSRIs Uptake inhibitor • Reserpine- inhibits VMAT-2 • Fenfluramine- release causing depletion Storage inhibitor • Nonselective MAO inhibitor(tranylcypromine) • selective MAO-A inhibitor (clorgyline) Degradation inhibitor • 5, 6 dihydroxytryptamine selectively destroys 5-HT neurones. Neuronal degeneration
  • 11. • D-Lysergic acid diethyl amide (LSD)- nonselective 5-HT agonist; hallucinogenic • Azapirones (buspirone, gepirone ,ipsapirone)- antianxiety drugs. PA 5-HT1A receptors • Sumatriptan and other triptans - selective 5- HT1D/1B agonists; T/t of MIGRAINE • Cisapride Renzapride - prokinetic drugs; selective 5- HT4 agonist. 5-HT receptor agonists
  • 12. 5-HT ANTAGONISTS • Cyproheptadine – Blocks 5-HT2A receptors :controlling intestinal manifestations of carcinoid & postgastrectomy dumping syndromes and antagonize priapism/ orgasmic delay caused fluoxetine & trazodone – additional H1 antihistaminic, anticholinergic and sedative properties :antipruritic, increases appetite & has been used in children and poor eaters to promote weight gain. • Methysergide – antagonizes 5-HT action on vascular & visceral smooth muscles – 5-HT2A/2C antagonist – Not used- abdominal, pulmonary & endocardial fibrosis
  • 13. • Ketanserin – 5-HT2 antagonist – Opposes 5-HT induced vasoconstriction, platelet aggregation & contraction of airway smooth muscle – additional weak α1, H1 and dopaminergic blocking activities. – Ritanserin- relatively more selective 5-HT2A antagonist • Clozapine – atypical antipsychotic - resistant cases of schizophrenia – 5-HT2A/2C antagonist; inverse agonist at 5-HT2A/2C receptors • Risperidone, olanzapine and quetiapine – 5-HT2A + D2 antagonist – Atypical antipsychotics • Ondansetron, Granisetron and Tropisetron – 5-HT3 antagonists – Control anticancer & radiotherapy induced N& V
  • 14. ERGOT ALKALOIDS • Ergot is a fungus Claviceps purpurea which grows on rye, millet and some other grains • Epidemics of ergot poisoning (ergotism), due to consumption of contaminated grains • Natural ergot alkaloids – (a) Amine alkaloid - Ergometrine (Ergonovine): oxytocic – (b) Amino acid alkaloids- Ergotamine, Ergotoxine : emetic, vasoconstrictor & α adrenergic blocker/PA; migraine
  • 15. • Other semisynthetic derivatives – (a)Dihydroergotamine (DHE), Dihydroergotoxine (Codergocrine): antiadrenergic, cerebroactive- t/t of dementia – (b)2-Bromo-α-ergocryptine (Bromocriptine): D2 agonist (antiparkinsonian), inhibit prolactin release, emetic – (c)Methysergide: mainly anti 5-HT • Adverse effects • Nausea, vomiting, abdominal pain, muscle cramps, weakness, paresthesias, coronary and other vascular spasm, chest pain (due to coronary vasoconstriction)
  • 16. Selective 5-HT1D/1B agonists (Triptans) • Currently, first line drugs for patients who fail to respond to analgesics [sumatriptan, riza., frova., nara., zolmi.] • MOA – 5-HT1D/1B receptor mediated constriction of dilated cranial blood vessels (in AV shunts in the carotid artery) – 5-HT1D/1B are presynaptic autoreceptors: triptans reduce 5-HT release at these blood vessels – inhibit inflammatory neuropeptide release around the affected vessels as well as extravasation of plasma proteins across dural vessels – suppress neurogenic inflammation of cranial vessels • All triptans: significant pharmacokinetic differences
  • 17. • Sumatriptan- lowest BA; absorbed rapidly and completely after s.c. injection; intranasal spray • Naratriptan & Frovatriptan- longer t½; fewer headache recurrences; slow in affording initial pain relief. • Side effects- – Tightness in head & chest, feeling of heat & other paresthesias in limbs, dizziness, weakness – Slight rise in BP; bradycardia, coronary vasospasm & risk of MI- rare but serious • Contraindications: – Ischaemic heart disease, hypertension, epilepsy, hepatic or renal impairment & pregnancy ; cautioned not to drive. • Sumatriptan and ergotamine should not be administered within 24 hours of each other. • Interaction with 5-HT reuptake inhibitors, MAO inhibitors & lithium
  • 18. MIGRAINE • Pulsating headache • usually restricted to one side • attacks lasting 4–48 hours • often associated with nausea, vomiting, sensitivity to light and sound, flashes of light, vertigo, loose motions and other symptoms • Two major types – —migraine with aura (classical migraine) – —migraine without aura (common migraine)
  • 19. • Pathogenesis – Vascular theory – Neurogenic theory • Mild migraine – fewer than one attack per month – lasts upto 8 hours – does not incapacitate the individual – Drug therapy - Simple analgesics/NSAIDs or their combinations (± antiemetic) – Paracetamol, aspirin, ibuprofen, naproxen, diclofenac either alone or combined with paracetamol/codeine/ diazepam or another sedative/diphenhydramine or another antihistaminic/caffeine
  • 20. • Moderate migraine – One or more attacks per month – lasts for 6–24 hours – Throbbing headache more intense, nausea/vomiting & other features more prominent – Patient is functionally impaired – Drug therapy- NSAIDs combinations/a triptan/ ergot alkaloids (+ antiemetic) – Prophylactic therapy advised: attacks more frequent than 2–3 per month • Severe migraine – 2–3 or more attacks per month of – lasts 12–48 hours – severe throbbing headache, vertigo, vomiting and other symptoms – Pt. grossly incapacitated during the attack – Drug therapy- a Triptan/ergot alkaloids (+ antiemetic) + Prophylaxis
  • 21. PROPHYLAXIS OF MIGRAINE • (i) β-Adrenergic blockers- Propranolol • (ii) Tricyclic antidepressants- Amitriptyline • (iii) Calcium channel blockers- Verapamil – Flunarizine- cerebro-selective CCB, also inhibits Na+ channels • (iv)Anticonvulsants - Valproic acid, gabapentin, topiramate • (v) CGRP antagonist- monoclonal antibody Erenumab (s.c. once a month)
  • 22. • Q. Serotonin can be synthesized from: – a) Tryptophan – b) Tyrosine – c) Dopa – d) Epinephrine • Q. Drug which blocks both H1 & 5HT2 receptor: – a) Phenoxybenzamine – b) Cyprohepatidine – c) Ritanserin – d) Ondansetron
  • 23. • Q. After taking some drug for acute attack of migraine, a patient developed nausea & vomiting. He also developed tingling & numbness in the tip of the finger that also turned blue. Which of the following is the most likely drug implicated in causing the above findings? – a) Dihydroergotamine – b) Sumatriptan – c) Aspirin – d) Butorphanol