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5- Hydroxytryptamine and it’s Antagonists
Dr. Nikhilkumar S Sakle
Assistant Professor
Department of Pharmacology
Y. B. Chavan College of Pharmacy,
Aurangabad
1
5-HYDROXYTRYPTAMINE
(5-HT, Serotonin)
• 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.
2
SYNTHESIS, STORAGE AND
DESTRUCTION
3
SEROTONERGIC (5-HT) RECEPTORS
5-HT receptors
5-HT1
5-HT1A,
5-HT1B,
5-HT1C,
5-HT1D,
5-HT1E,
5-HT1F,
5-HT2
5-HT2A,
5-HT2B,
5-HT2C,
5-HT3
5-HT4
5-HT5
5-HT6
5-HT7
4
5
Agonists and antagonists
6
ACTIONS
• 1. CVS- Arteries are constricted (by action on
smooth muscle) & dilated (through EDRF release)
by direct action of 5-HT depending on vascular bed
& basal tone.
▫ It releases Adr from adrenal medulla
▫ In microcirculation, it dilates arterioles & constricts
venules capillary pressure ↑ & fluid escapes
▫ In intact animals, bradycardia seen due to activation of
coronary chemoreflex (Bezold Jarisch refex) through
action on vagal afferent nerve endings in coronary bed
evoking bradycardia, hypotension & apnoea.
7
• BP – triphasic response is classically seen on iv
injection Early sharp fall in BP-due to coronary
chemo reflex Brief rise in BP- due to
vasoconstriction & ↑ CO Prolonged fall in BP-
due to arteriolar vasodilatation & extravasation
of fluid.
• 2. Smooth Muscle-
▫ GIT- ↑ peristalsis & diarrhoea (also due to ↑
secretion) Bronchi- It constricts bronchi but is less
potent than histamine.
8
• 3. Glands – It inhibits gastric secretion (acid & pepsin)
but ↑ mucus production - ulcer protective property
• 4. Nerve endings & Adrenal medulla- Activation of
afferent nerve endings- tingling & pricking sensation,
pain
• 5. Respiration- Brief stimulation of respiration &
hyperventilation. Large doses can cause transient apnea
(coronary chemoreflex).
• 6. CNS-Direct injection in brain causes sleepiness,
change in body temperature, hunger & behavioural
effects.
• 7. Platelets- It causes changes in shape of platelets & is
a weak aggregator (5-HT 2A receptor)
9
10
PATHOPHYSIOLOGICAL ROLES
• 1. Neurotransmitter
• 2. Precursor of melatonin
• 3. Neuroendocrine function
• 4. Nausea and vomiting
• 5. Migraine
• 6. Haemostasis
• 7. Raynaud’s phenomenon
• 8. Variant angina
• 9. Hypertension
• 10. Intestinal motility
• 11. Carcinoid syndrome
11
Use
• Due to widespread and variable actions, 5-HT
has no therapeutic use.
12
DRUGS AFFECTING 5-HT SYSTEM
• 1. 5-HT precursor
• 2. Synthesis inhibitor
• 3. Uptake inhibitor
• 4. Storage inhibitor
• 5. Degradation inhibitor
• 6. Neuronal degeneration
• 7. 5-HT receptor agonists
▫ (i) D-Lysergic acid diethyl amide (LSD)—
▫ (ii) Azapirones
▫ (iii) Sumatriptan
▫ (iv) Cisapride
• 8. 5-HT receptor antagonists
13
5-HT ANTAGONISTS
• The ability to antagonize at least some actions of 5-HT is
found in many classes of drugs,
• e.g.
▫ Ergot derivatives (ergotamine, LSD, 2-bromo LSD,
methysergide),
▫ Adrenergic α blockers (phenoxybenzamine),
▫ Antihistaminics (cyproheptadine, cinnarizine),
▫ Chlorpromazine,
▫ Morphine, etc.,
• but these are nonselective and interact with several other
receptors as well.
• Many are partial agonists or antagonize certain actions
of 5-HT but mimic others.
14
• 1. Cyproheptadine:
• It primarily blocks 5-HT2A receptors and has additional H1
antihistaminic, anticholinergic and sedative properties.
• Like other antihistaminics, it has been used in allergies and is
a good antipruritic, but the anti 5-HT action has no role in
these conditions.
• It increases appetite and has been used in children
and poor eaters to promote weight gain.
• The H1 antihistaminic action and an action on growth
hormone secretion has been suggested to account for this.
• The anti 5-HT activity of cyproheptadine has been utilized in
controlling intestinal manifestations of carcinoid and
postgastrectomy dumping syndromes as well as in
antagonizing priapism/orgasmic delay caused by 5-HT uptake
inhibitors like fluoxetine and trazodone.
15
• 2. Methysergide:
• It is chemically related to ergot alkaloids; antagonizes action
of 5-HT on smooth muscles including that of blood vessels,
without producing other ergot like effects: does not interact
with α adrenergic or dopamine receptors.
• Methysergide is a potent 5-HT2A/2C antagonist with some
tissue specific agonistic actions as well; but is nonselective—
acts on 5-HT1 receptors also.
• It has been used for migraine prophylaxis, carcinoid and
postgastrectomy dumping syndrome.
• Prolonged use has caused abdominal, pulmonary and
endocardial fibrosis, because of which it has gone into
disrepute.
16
• 3. Ketanserin:
• It has selective 5-HT2 receptor blocking property with negligible
action on 5-HT1, 5-HT3 and 5 HT4 receptors and no partial
agonistic activity.
• Among 5-HT2 receptors, blockade of 5-HT2A is stronger than 5-
HT2C blockade.
• 5-HT induced vasoconstriction, platelet aggregation and contraction
of airway smooth muscle are antagonized.
• It has additional weak α1, H1 and dopaminergic blocking activities.
• Ketanserin is an effective antihypertensive, but α1 adrenergic
blockade appears to be causative rather than 5- HT2A blockade.
• Trials of Ketanserin in vasospastic conditions have shown
symptomatic improvement only in Raynaud’s disease.
17
• 4. Clozapine:
• In addition to being a dopaminergic antagonist
(weaker than the typical neuroleptics), this
atypical antipsychotic is a 5-HT2A/2C blocker.
• Clozapine may also exert inverse agonist activity
at cerebral 5-HT2A/2C receptors which may
account for its efficacy in resistant cases of
schizophrenia.
18
• 5. Risperidone
• This atypical antipsychotic is a combined 5-HT2A +
dopamine D2 antagonist, similar to clozapine.
• Like the latter, it especially ameliorates negative
symptoms of schizophrenia, but produces
extrapyramidal side effects at only slightly higher
doses.
• Other atypical antipsychotics like olanzapine and
quetiapine are also combined 5-HT and DA
antagonists, but interact with other
neurotransmitter receptors as well.
19
• 6. Ondansetron
• It is the prototype of the new class of selective 5-
HT3 antagonists that have shown remarkable
efficacy in controlling nausea and vomiting
following administration of highly emetic
anticancer drugs and radiotherapy
20
ERGOT ALKALOIDS
• Natural ergot alkaloids:
▫ (a) Amine alkaloid Ergometrine (Ergonovine):
which is oxytocic
▫ (b) Amino acid alkaloids Ergotamine, Ergotoxine
(mixture of ergocristine + ergocornine +
ergocryptine): they are vasoconstrictor and α
adrenergic blocker/ partial agonist.
• Other semisynthetic derivatives:
▫ (a)Dihydroergotamine (DHE), Dihydroergotoxine
(Codergocrine): are antiadrenergic, cerebroactive.
▫ (b) 2-Bromo-α-ergocryptine (Bromocriptine): is a
dopaminergic D2 agonist.
▫ (c) Methysergide: it is mainly anti 5-HT.
21
Actions
• Ergotamine
• It acts as a partial agonist and antagonist at α
adrenergic and all subtypes of 5-HT1 and 5-HT2 receptors,
but does not interact with 5-HT3 or dopamine receptors:
produces sustained vasoconstriction, visceral smooth muscle
contraction, vasomotor centre depression and antagonizes the
action of NA and 5-HT on smooth muscles.
• The overall effect of oral/rectal doses of ergotamine on BP is
insignificant. It is a potent emetic (through CTZ and
vomiting centre) and moderately potent oxytocic.
• At high doses CNS stimulation and paresthesias may be
experienced.
• On chronic exposure (ergot poisoning) vasoconstriction is
accompanied by damage to capillary endothelium—
thrombosis, vascular stasis and gangrene.
22
• Dihydroergotamine (DHE)
• Hydrogenation of ergotamine reduces
serotonergic and α-adrenergic agonistic actions,
but enhances α-receptor blocking property.
• Consequently DHE is a less potent
vasoconstrictor; primarily constricts capacitance
vessels and causes less intimal damage.
• It is a weaker emetic and oxytocic, but has some
antidopaminergic action as well.
23
• Dihydroergotoxine (Codergocrine)
• This hydrogenated mixture of ergotoxine
group of alkaloids is a more potent α blocker and
a very weak vasoconstrictor.
• In the brain, a variety of partial
agonistic/antagonistic actions on 5-HT receptors,
metabolic and vascular effects and enhancement
of ACh release in cerebral cortex have been
demonstrated.
• It has been promoted for treatment of dementia.
24
• Bromocriptine
• The 2 bromo derivative of ergocryptine is a
relatively selective dopamine D2 agonist on
pituitary lactotropes (inhibits prolactin
release), in striatum (anti-parkinsonian)
and in CTZ (emetic—but less than ergotamine).
• In certain brain areas weak anti-dopaminergic
action has also been shown.
• It has very weak anti 5-HT or α blocking actions
and is not an oxytocic.
25
• Ergometrine (Ergonovine)
• This amine ergot alkaloid has very weak agonistic and
practically no antagonistic action on α adrenergic
receptors: vasoconstriction is not significant.
• Partial agonistic action on 5-HT receptors has been
demonstrated in uterus, placental and umbilical blood
vessels and in certain brain areas.
• It is a moderately potent 5-HT2 antagonist in g.i.
smooth muscle and a weak dopaminergic agonist on the
pituitary lactotropes as well as CTZ; emetic potential is
low.
• The most prominent action is contraction of
myometrium; used exclusively in obstetrics.
26
Adverse effects
• Nausea, vomiting, abdominal pain, muscle
cramps, weakness, paresthesias, coronary and
other vascular spasm, chest pain (due to
coronary vasoconstriction) are the frequent side
effects.
• These drugs are contraindicated in presence of
sepsis, ischaemic heart disease, peripheral
vascular disease, hypertension, pregnancy, liver
and kidney disease.
27
DRUG THERAPY OF MIGRAINE
• MIGRAIN – pulsating headache, usually
restricted to one side, which comes in attacks
lasting 4–48 hours and is often associated with
nausea, vomiting, sensitivity to light and sound,
flashes of light, vertigo, loose motions and other
symptoms.
• Pulsatile dilatation of certain large cranial
vessels is the immediate cause of pain.
28
29
Drug therapy of Migraine
30
SPECIFIC ANTIMIGRAINE DRUGS
• Ergotamine:
• Oral/sublingual route is preferred, 1 mg is given at half
hour intervals till relief is obtained or a total of 6 mg is
given.
• Acts by constricting the dilated cranial vessels and/or
by specific constriction of carotid A-V shunt channels.
• Ergotamine and DHE have also been shown to reduce
neurogenic inflammation & These actions appear to
be mediated through partial agonism at 5-HT1D/1B
receptors in and around cranial vessels.
• Dihydroergotamine (DHE):
• Preferred for parenteral administration because injected
DHE is less hazardous.
31
Selective 5-HT1D/1B Agonists
(Triptans)
• First line drugs for patients who fail to respond
to analgesics.
• Sumatriptan:
• Rizatriptan:
• Administered at the onset of an attack of
migraine-complete/significant relief within 2–3
hours.
32
Side effects:
• Tightness in head and chest, feeling of heat and other
paresthesias in limbs, dizziness, weakness are short
lasting, but dose related side effects. These are more
common after s.c. injection, which is painful.
• Slight rise in BP occurs, but has little clinical relevance,
because sumatriptan is not a drug for regular use.
• Bradycardia, coronary vasospasm and risk of myocardial
infarction are the serious, but infrequent adverse effects.
• Few sudden deaths have been ascribed to sumatriptan.
Seizures and hypersensitivity reactions are rare.
33
Contraindications:
• Ischaemic heart disease, hypertension, epilepsy,
hepatic or renal impairment and pregnancy are
the contraindications.
• Patients should be 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 and lithium has been reported.
34
PROPHYLAXIS OF MIGRAINE
• Regular medication to reduce the frequency
and/or severity of attacks is recommended for
moderate-to-severe migraine when 2–3 or more
attacks occur per month.
▫ Propranolol/other β blockers
▫ Amitriptyline/other tricyclic antidepressants
▫ Flunarizine/other Ca2+ channel blockers
▫ Valproate/topiramate
35
(i) β-Adrenergic blockers
• Propranolol is the most commonly used drug:
reduces frequency as well as severity of attacks
in upto 70% patients.
• Effect is generally seen in 4 weeks and is
sustained during prolonged therapy.
36
(ii) Tricyclic antidepressants
• amitriptyline (25–50 mg at bed time) has been
most extensively tried, reduce migraine attacks.
• It is effective in many patients but produces
more side effects than propranolol.
37
(iii) Calcium channel blockers
• Flunarizine is a relatively weak Ca2+ channel
blocker that also inhibits Na+ channels.
• Frequency of attacks is often reduced
• It is claimed to be a cerebro-selective Ca2+
channel blocker; may benefit migraine by
reducing intracellular Ca2+ overload.
38
(iv)Anticonvulsants
• Valproic acid (400–1200 mg/day) and
gabapentin (300–1200 mg/day) have some
prophylactic effect in migraine.
• The newer drug topiramate has recently been
approved for migrain prophylaxis. A 50%
reduction in the number of attacks
39
(v) 5-HT antagonists
• The prophylactic effect of methysergide and
cyproheptadine is less impressive than β-
blockers.
• They are seldom used now for migraine.
40

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Pharmacology of 5-hydroxytryptamine and Antagonist

  • 1. 5- Hydroxytryptamine and it’s Antagonists Dr. Nikhilkumar S Sakle Assistant Professor Department of Pharmacology Y. B. Chavan College of Pharmacy, Aurangabad 1
  • 2. 5-HYDROXYTRYPTAMINE (5-HT, Serotonin) • 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. 2
  • 4. SEROTONERGIC (5-HT) RECEPTORS 5-HT receptors 5-HT1 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT1E, 5-HT1F, 5-HT2 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3 5-HT4 5-HT5 5-HT6 5-HT7 4
  • 5. 5
  • 7. ACTIONS • 1. CVS- Arteries are constricted (by action on smooth muscle) & dilated (through EDRF release) by direct action of 5-HT depending on vascular bed & basal tone. ▫ It releases Adr from adrenal medulla ▫ In microcirculation, it dilates arterioles & constricts venules capillary pressure ↑ & fluid escapes ▫ In intact animals, bradycardia seen due to activation of coronary chemoreflex (Bezold Jarisch refex) through action on vagal afferent nerve endings in coronary bed evoking bradycardia, hypotension & apnoea. 7
  • 8. • BP – triphasic response is classically seen on iv injection Early sharp fall in BP-due to coronary chemo reflex Brief rise in BP- due to vasoconstriction & ↑ CO Prolonged fall in BP- due to arteriolar vasodilatation & extravasation of fluid. • 2. Smooth Muscle- ▫ GIT- ↑ peristalsis & diarrhoea (also due to ↑ secretion) Bronchi- It constricts bronchi but is less potent than histamine. 8
  • 9. • 3. Glands – It inhibits gastric secretion (acid & pepsin) but ↑ mucus production - ulcer protective property • 4. Nerve endings & Adrenal medulla- Activation of afferent nerve endings- tingling & pricking sensation, pain • 5. Respiration- Brief stimulation of respiration & hyperventilation. Large doses can cause transient apnea (coronary chemoreflex). • 6. CNS-Direct injection in brain causes sleepiness, change in body temperature, hunger & behavioural effects. • 7. Platelets- It causes changes in shape of platelets & is a weak aggregator (5-HT 2A receptor) 9
  • 10. 10
  • 11. PATHOPHYSIOLOGICAL ROLES • 1. Neurotransmitter • 2. Precursor of melatonin • 3. Neuroendocrine function • 4. Nausea and vomiting • 5. Migraine • 6. Haemostasis • 7. Raynaud’s phenomenon • 8. Variant angina • 9. Hypertension • 10. Intestinal motility • 11. Carcinoid syndrome 11
  • 12. Use • Due to widespread and variable actions, 5-HT has no therapeutic use. 12
  • 13. DRUGS AFFECTING 5-HT SYSTEM • 1. 5-HT precursor • 2. Synthesis inhibitor • 3. Uptake inhibitor • 4. Storage inhibitor • 5. Degradation inhibitor • 6. Neuronal degeneration • 7. 5-HT receptor agonists ▫ (i) D-Lysergic acid diethyl amide (LSD)— ▫ (ii) Azapirones ▫ (iii) Sumatriptan ▫ (iv) Cisapride • 8. 5-HT receptor antagonists 13
  • 14. 5-HT ANTAGONISTS • The ability to antagonize at least some actions of 5-HT is found in many classes of drugs, • e.g. ▫ Ergot derivatives (ergotamine, LSD, 2-bromo LSD, methysergide), ▫ Adrenergic α blockers (phenoxybenzamine), ▫ Antihistaminics (cyproheptadine, cinnarizine), ▫ Chlorpromazine, ▫ Morphine, etc., • but these are nonselective and interact with several other receptors as well. • Many are partial agonists or antagonize certain actions of 5-HT but mimic others. 14
  • 15. • 1. Cyproheptadine: • It primarily blocks 5-HT2A receptors and has additional H1 antihistaminic, anticholinergic and sedative properties. • Like other antihistaminics, it has been used in allergies and is a good antipruritic, but the anti 5-HT action has no role in these conditions. • It increases appetite and has been used in children and poor eaters to promote weight gain. • The H1 antihistaminic action and an action on growth hormone secretion has been suggested to account for this. • The anti 5-HT activity of cyproheptadine has been utilized in controlling intestinal manifestations of carcinoid and postgastrectomy dumping syndromes as well as in antagonizing priapism/orgasmic delay caused by 5-HT uptake inhibitors like fluoxetine and trazodone. 15
  • 16. • 2. Methysergide: • It is chemically related to ergot alkaloids; antagonizes action of 5-HT on smooth muscles including that of blood vessels, without producing other ergot like effects: does not interact with α adrenergic or dopamine receptors. • Methysergide is a potent 5-HT2A/2C antagonist with some tissue specific agonistic actions as well; but is nonselective— acts on 5-HT1 receptors also. • It has been used for migraine prophylaxis, carcinoid and postgastrectomy dumping syndrome. • Prolonged use has caused abdominal, pulmonary and endocardial fibrosis, because of which it has gone into disrepute. 16
  • 17. • 3. Ketanserin: • It has selective 5-HT2 receptor blocking property with negligible action on 5-HT1, 5-HT3 and 5 HT4 receptors and no partial agonistic activity. • Among 5-HT2 receptors, blockade of 5-HT2A is stronger than 5- HT2C blockade. • 5-HT induced vasoconstriction, platelet aggregation and contraction of airway smooth muscle are antagonized. • It has additional weak α1, H1 and dopaminergic blocking activities. • Ketanserin is an effective antihypertensive, but α1 adrenergic blockade appears to be causative rather than 5- HT2A blockade. • Trials of Ketanserin in vasospastic conditions have shown symptomatic improvement only in Raynaud’s disease. 17
  • 18. • 4. Clozapine: • In addition to being a dopaminergic antagonist (weaker than the typical neuroleptics), this atypical antipsychotic is a 5-HT2A/2C blocker. • Clozapine may also exert inverse agonist activity at cerebral 5-HT2A/2C receptors which may account for its efficacy in resistant cases of schizophrenia. 18
  • 19. • 5. Risperidone • This atypical antipsychotic is a combined 5-HT2A + dopamine D2 antagonist, similar to clozapine. • Like the latter, it especially ameliorates negative symptoms of schizophrenia, but produces extrapyramidal side effects at only slightly higher doses. • Other atypical antipsychotics like olanzapine and quetiapine are also combined 5-HT and DA antagonists, but interact with other neurotransmitter receptors as well. 19
  • 20. • 6. Ondansetron • It is the prototype of the new class of selective 5- HT3 antagonists that have shown remarkable efficacy in controlling nausea and vomiting following administration of highly emetic anticancer drugs and radiotherapy 20
  • 21. ERGOT ALKALOIDS • Natural ergot alkaloids: ▫ (a) Amine alkaloid Ergometrine (Ergonovine): which is oxytocic ▫ (b) Amino acid alkaloids Ergotamine, Ergotoxine (mixture of ergocristine + ergocornine + ergocryptine): they are vasoconstrictor and α adrenergic blocker/ partial agonist. • Other semisynthetic derivatives: ▫ (a)Dihydroergotamine (DHE), Dihydroergotoxine (Codergocrine): are antiadrenergic, cerebroactive. ▫ (b) 2-Bromo-α-ergocryptine (Bromocriptine): is a dopaminergic D2 agonist. ▫ (c) Methysergide: it is mainly anti 5-HT. 21
  • 22. Actions • Ergotamine • It acts as a partial agonist and antagonist at α adrenergic and all subtypes of 5-HT1 and 5-HT2 receptors, but does not interact with 5-HT3 or dopamine receptors: produces sustained vasoconstriction, visceral smooth muscle contraction, vasomotor centre depression and antagonizes the action of NA and 5-HT on smooth muscles. • The overall effect of oral/rectal doses of ergotamine on BP is insignificant. It is a potent emetic (through CTZ and vomiting centre) and moderately potent oxytocic. • At high doses CNS stimulation and paresthesias may be experienced. • On chronic exposure (ergot poisoning) vasoconstriction is accompanied by damage to capillary endothelium— thrombosis, vascular stasis and gangrene. 22
  • 23. • Dihydroergotamine (DHE) • Hydrogenation of ergotamine reduces serotonergic and α-adrenergic agonistic actions, but enhances α-receptor blocking property. • Consequently DHE is a less potent vasoconstrictor; primarily constricts capacitance vessels and causes less intimal damage. • It is a weaker emetic and oxytocic, but has some antidopaminergic action as well. 23
  • 24. • Dihydroergotoxine (Codergocrine) • This hydrogenated mixture of ergotoxine group of alkaloids is a more potent α blocker and a very weak vasoconstrictor. • In the brain, a variety of partial agonistic/antagonistic actions on 5-HT receptors, metabolic and vascular effects and enhancement of ACh release in cerebral cortex have been demonstrated. • It has been promoted for treatment of dementia. 24
  • 25. • Bromocriptine • The 2 bromo derivative of ergocryptine is a relatively selective dopamine D2 agonist on pituitary lactotropes (inhibits prolactin release), in striatum (anti-parkinsonian) and in CTZ (emetic—but less than ergotamine). • In certain brain areas weak anti-dopaminergic action has also been shown. • It has very weak anti 5-HT or α blocking actions and is not an oxytocic. 25
  • 26. • Ergometrine (Ergonovine) • This amine ergot alkaloid has very weak agonistic and practically no antagonistic action on α adrenergic receptors: vasoconstriction is not significant. • Partial agonistic action on 5-HT receptors has been demonstrated in uterus, placental and umbilical blood vessels and in certain brain areas. • It is a moderately potent 5-HT2 antagonist in g.i. smooth muscle and a weak dopaminergic agonist on the pituitary lactotropes as well as CTZ; emetic potential is low. • The most prominent action is contraction of myometrium; used exclusively in obstetrics. 26
  • 27. Adverse effects • Nausea, vomiting, abdominal pain, muscle cramps, weakness, paresthesias, coronary and other vascular spasm, chest pain (due to coronary vasoconstriction) are the frequent side effects. • These drugs are contraindicated in presence of sepsis, ischaemic heart disease, peripheral vascular disease, hypertension, pregnancy, liver and kidney disease. 27
  • 28. DRUG THERAPY OF MIGRAINE • MIGRAIN – pulsating headache, usually restricted to one side, which comes in attacks lasting 4–48 hours and is often associated with nausea, vomiting, sensitivity to light and sound, flashes of light, vertigo, loose motions and other symptoms. • Pulsatile dilatation of certain large cranial vessels is the immediate cause of pain. 28
  • 29. 29
  • 30. Drug therapy of Migraine 30
  • 31. SPECIFIC ANTIMIGRAINE DRUGS • Ergotamine: • Oral/sublingual route is preferred, 1 mg is given at half hour intervals till relief is obtained or a total of 6 mg is given. • Acts by constricting the dilated cranial vessels and/or by specific constriction of carotid A-V shunt channels. • Ergotamine and DHE have also been shown to reduce neurogenic inflammation & These actions appear to be mediated through partial agonism at 5-HT1D/1B receptors in and around cranial vessels. • Dihydroergotamine (DHE): • Preferred for parenteral administration because injected DHE is less hazardous. 31
  • 32. Selective 5-HT1D/1B Agonists (Triptans) • First line drugs for patients who fail to respond to analgesics. • Sumatriptan: • Rizatriptan: • Administered at the onset of an attack of migraine-complete/significant relief within 2–3 hours. 32
  • 33. Side effects: • Tightness in head and chest, feeling of heat and other paresthesias in limbs, dizziness, weakness are short lasting, but dose related side effects. These are more common after s.c. injection, which is painful. • Slight rise in BP occurs, but has little clinical relevance, because sumatriptan is not a drug for regular use. • Bradycardia, coronary vasospasm and risk of myocardial infarction are the serious, but infrequent adverse effects. • Few sudden deaths have been ascribed to sumatriptan. Seizures and hypersensitivity reactions are rare. 33
  • 34. Contraindications: • Ischaemic heart disease, hypertension, epilepsy, hepatic or renal impairment and pregnancy are the contraindications. • Patients should be 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 and lithium has been reported. 34
  • 35. PROPHYLAXIS OF MIGRAINE • Regular medication to reduce the frequency and/or severity of attacks is recommended for moderate-to-severe migraine when 2–3 or more attacks occur per month. ▫ Propranolol/other β blockers ▫ Amitriptyline/other tricyclic antidepressants ▫ Flunarizine/other Ca2+ channel blockers ▫ Valproate/topiramate 35
  • 36. (i) β-Adrenergic blockers • Propranolol is the most commonly used drug: reduces frequency as well as severity of attacks in upto 70% patients. • Effect is generally seen in 4 weeks and is sustained during prolonged therapy. 36
  • 37. (ii) Tricyclic antidepressants • amitriptyline (25–50 mg at bed time) has been most extensively tried, reduce migraine attacks. • It is effective in many patients but produces more side effects than propranolol. 37
  • 38. (iii) Calcium channel blockers • Flunarizine is a relatively weak Ca2+ channel blocker that also inhibits Na+ channels. • Frequency of attacks is often reduced • It is claimed to be a cerebro-selective Ca2+ channel blocker; may benefit migraine by reducing intracellular Ca2+ overload. 38
  • 39. (iv)Anticonvulsants • Valproic acid (400–1200 mg/day) and gabapentin (300–1200 mg/day) have some prophylactic effect in migraine. • The newer drug topiramate has recently been approved for migrain prophylaxis. A 50% reduction in the number of attacks 39
  • 40. (v) 5-HT antagonists • The prophylactic effect of methysergide and cyproheptadine is less impressive than β- blockers. • They are seldom used now for migraine. 40