Pharmacology seminar in serotonin

1. SEROTONIN
& DRUGS ACTING ON 5-HT
RECEPTORS
1

2. CONTENT
• INTRODUCTION
• SOURCES
• SYNTHESIS , DESTRUCTION & REUPTAKE
• SEROTONERGIC RECEPTORS
• PHYSIOLOGICAL ACTIONS
• PATHOLOGICAL ROLES
• DRUGS ACTING ON 5HT RECEPTORS
2

3. INTRODUCTION
• Serotonin/ 5 hydroxytryptamine is a biogenic amine.
• Site -EC cells in the stomach & intestine (80 to 90 % )
-Platelets
-Brain
• In CNS -Neurotransmitter regulating physiological
functions.
• In periphery- autacoid involved in regulation of smooth
muscle function & platelet aggegation.
3

4. SOURCES
Leafy vegetables, banana, pineapple, walnuts , milk
eggs, chicken & salmon.
4

5. SYNTHESIS
• 5-HT is β-aminoethyl-5-hydroxyindole.
• Synthesized from the amino acid tryptophan.
5

6. DESTRUCTION
• Degraded by enzyme MAO-A & dehyrogenase.
6

7. • Actively taken up by membrane of platelets & serotonergic
nerve endings via amine pump- serotonin transporter
(SERT), a Na+ dependent carrier.
• Uptake at the vesicular membrane is by vesicular
monoamine transporter (VMAT-2)- Inhibited by Reserpine
• Cocaine, TCA & SSRI inhibit reuptake
7
REUPTAKE

8. SEROTONERGIC RECEPTORS
• Classified into musculotropic ( D type) &
neurotropic (M type) on the basis of their blockade by
phenoxybenzamine & morphine.
• Based on molecular character- four families of 5-HT
receptors (5-HT1 , 5-HT2 , 5-HT3, 5-HT4- 7)
comprising of 14 receptor subtypes .
8

9. 9
G protein coupled receptors Ligand
gated
cation
cAMP IP3/ DAG cAMP (Na-,K+)
channel
5-HT1 5-HT2 5-HT4 , 5-HT5,
5-HT6, 5-HT7
5-HT3
Coupled
with Gi/Go
protein &
inhibit
adenylyl
cyclase
Gq protein-
activate PL- C
Gs protein,
activates adenylyl
cyclase

10. 5-HT1
• Six subtypes (5-HT 1A, B,D,E,F,P)
• 5-HT-1A also activates K channels & inhibits Ca channels.
Function primarily as autoreceptors in brain- inhibit
release of 5-HT from nerve endings.
10

11. TYPE SITE DRUGS
5-HT-1A Somato dentritic synapse of Raphe nuclei
of brainstem
The antianxiety drug
buspirone acts as a partial
agonist of 5-HT 1A receptor.
Hippocampus
5-HT-1B Basal ganglia on axonal terminal, inhibit
voltage gated Ca channels in presynaptic
neuron.
5-HT-ID Regulate dopaminergic tone in substantia nigra- basal ganglia.
Inhibition
-5-HT release from forebrain serotonergic neurons.
-NA release from sympathetic nerve endings .
5-HT 1D/1B  Constriction of cranial blood vessels.
 Inhibit release of Inflammatory
neuropeptide from nerve endings in
cranial blood vessels.(5-HT 1F )
Antimigraine drug
- Sumatripran is a selective
5-HT 1D/1B agonist.
-Lasmiditan selective
5-HT 1F agonist
5-HT 1P ENS mediate their slow depolarization.
11

12. 5HT2
TYPES SITE ACTION DRUGS
5-HT 2A (D type)
 Most widely
expressed
postjunctional 5-
HT receptor
Vascular & visceral
smooth muscle
Vasoconstriction,
intestinal, uterine &
bronchial muscle
contraction
Ketanserin is a 5-
HT 2A antagonist
Clozapine (atypical
antipsychotic) has
high affinity for 5-
HT 6 & 5-HT 7,
receptors in
addition to being a
5-HT2A/2C
antagonist.
α -methyl 5-HT is
a selective agonist
Platelets Platelet aggregation
Prefrontal cortex Activation of
cerebral neurons.
5-HT2C Vascular
endothelium
Vasodilatation
through EDRF
release
Choroid plexus Regulate CSF
formation.
12

13. 5HT3/ M type receptor
• Neuronal 5-HT receptor which rapidly depolarizes
nerve endings by opening the cation channel
located within it.
• Mediates indirect & reflex effects of 5-HT at:
Site Action Drugs
Somatic &
autonomic nerve
endings
Mediating pain, itch, coronary
chemoreflex.
Ondansetron, selective
5-HT3 antagonist -
antiemetic
 2-Methyl 5-HT is a
selective 5-HT3 agonist.
Nerve endings in
myenteric plexus
Augmentation of peristalsis, emetic
reflex.
5HT release from EC cells
CTZ & NTS
(brainstem )
Inducing nausea & vomiting.
13

14. 5HT4 Receptor
SITE ACTION DRUGS
Mucosa,
Plexuses & smooth
muscle of the gut
Augmenting
intestinal
secretion &
peristalsis.
LES contraction
Cisapride &
Mosapride
selective 5-HT 4
agonists, weak
5HT3 antagonism
Metaclopramide-
5-HT4 agonists, D2
& 5HT3
antagonism
Hippocampus &
colliculi
Slow
depolarization (by
K conductance)
14

15. ACTION
1. CVS
Action on Blood vessels
Larger arteries,
veins, venules &
capillary
Constricted,
capillary pressure
rises & fluid
escapes
Direct action on
vascular smooth
muscle(5HT 2A)
Skeletal muscles,
coronary bed &
arterioles
Dilates EDRF release
(5HT2C)
15

16. 16
Action on heart- mediate coronary chemoreflex
Bradycardia , hypotension
& apnoea
Activation of
chemoreceptors in
coronary vascular bed
through action on 5HT3
receptors in vagal afferent
nerve endings

17. Action on BP- triphasic response on i.v
• Early sharp fall in BP- coronary chemoreflex.(5HT3)
• Brief rise in BP- Vasoconstriction & cardiac
output.(5HT2A)
• Prolonged fall in BP- Arteriolar dilatation in skeletal
muscles & extravasation of
fluid. (5HT2C)
17

18. 2. CNS
• Injected i.v., 5-HT does not produce central effects .
• It serves as a primarily inhibitory transmitter, mediating :
 REM Sleep- of 5 HT cause insomnia (5HT 1A)
 Aggressive behavior- of 5 HT (5HT 1B > 5HT 1A)
 Mood & emotional changes- involved in
Anxiety (5HT 1A)
Depression ( 5HT 1B , 5HT 1A)
Psychosis(5HT 2A)
18

19.  Stimulates satiety center( 5HT 2C, 5HT 1B, 5HT 6)
 Precursor of melatonin-Maintain biological clock &
circadian rhythm.
 Pain perception- receptors in nociceptive sensory
neurons, dorsal horn of spinal cord & autonomic nerve
ending. (5HT 3)
 Vomiting- CTZ, NTS(5HT 3)
 Neuroendocrine function- regulate hypothalamic
control of anterior pitutary hormones.(5HT 1A& 2HT 2/5HT 1C)
19

20. 3. Visceral smooth muscles
 Potent stimulator of g.i.t., both by direct action & via enteric
plexuses. (5HT 1P,2A,3,4 )
 Peristalsis & diarrhea .
 5-HT constricts bronchi- but is less potent than histamine.
5HT2A
4. Glands
 Inhibits gastric secretion (both acid & pepsin) 5HT3
 Mucus production- It thus has ulcer protective property.
20

21. 5. Respiratory system
 Brief stimulation of respiration (reflex from bronchial
afferents) & hyperventilation .
 Large doses injected i.v. - transient apnoea through
coronary chemoreflex. (5HT 3)
6. Platelets (5-HT 2A)
 Changes in shape of platelets-weak aggregator, no
release reaction.
21

22. 7. Nerve endings & adrenal medulla
 Afferent nerve endings are activated by 5-HT causing
tingling , pricking & pain.
 Depolarization of visceral afferents elicits respiratory
& cardiovascular reflexes, nausea & vomiting.
 Less potent than histamine in releasing CAs from
adrenal medulla.
22

23. PATHOLOGICAL ROLES
1. CNS disorders
Anxiety in 5HT Buspirone acts as a
partial agonist of 5-HT1 A
receptor
Depression Monoamines in limbic
system
SSRI, TCA
Psychosis in 5HT
-5HT 2 receptors are
involved,
- Its antagonism relives
negative symptoms of
schizophrenia
Clozapine - 5-HT2A/2C
blocker weak
dopaminergic antagonist.
Risperidone -5-HT 2A + D2
antagonist
23

24. 2.Other disorders
• Migraine-
 5 HT initiate the vasoconstrictor phase .
 Neurogenic inflammation of affected blood vessels.
• Carcinoid syndrome-
 Is a tumor of EC cells of GIT releases excess of 5HT
 Diagnostic value
24

25. • Hypertension & Preeclampsia –
 Increased responsiveness to 5-HT,
 Reduced uptake & clearance by platelets.
• Nausea & vomiting-
 Evoked by cytotoxic drugs / radiotherapy-is mediated
by release of 5-HT & its action on 5-HT3 receptors in
the gut, CTZ & NTS.
25

26. • Variant angina-
TXA2, 5-HT released from platelets -cause
coronary spasm & variant angina.
• Raynaud’s syndrome-
 Release of 5-HT from platelets -trigger acute
vasospastic episodes of larger arteries.
Ketanserin has prophylactic value.
26

27. DRUGS ACTING ON 5HT RECEPTORS
AGONIST
5HT 1A 5HT 1B/1D 5HT 1F 5HT4
Buspirone Sumatriptan
Rizatriptan
Naratriptan
Zolmitriptan
Frovatriptan
Lasmiditan Metoclopromide
Mosapride
Cisapride
Itopride
Cinitapride
27

28. ANTAGONIST
5HT 2A 5HT 2A/2C 5HT 2 5HT3
Cyproheptidine
Risperidone
Methysergide
Clozapine
Ketanserin
Ondansetron
Metoclopromide
28

29. Cyproheptadine
 MOA – Antagonises 5HT 2A, H1 & M receptors
 Uses
• Allergies, antipruritic
• appetite -used in children who are poor eaters to
promote weight gain.
• Controlling intestinal manifestations of carcinoid
• Post gastrectomy dumping syndromes
• Antagonizing priapism/ orgasmic delay caused by
5-HT uptake inhibitors like fluoxetine & trazodone
 S/E: drowsiness, dry mouth, confusion, ataxia &
weight gain 29

30. Methysergide
• Semisynthetic derivative of ergot alkaloid that do not
produce ergot like vasoconstriction / oxytocic effect
• MOA-Antagonizes 5HT2A/2C receptors of on vascular
& visceral smooth muscles
• USE- migraine prophylaxis, carcinoid &
postgastrectomy dumping syndrome
• S/E- Reversible abdominal, pulmonary &
endocardial fibrosis. 30

31. Ketanserin
• MOA-Selective 5-HT 2 receptor blocking property
with weak H 1, adrenergic & dopaminergic blocking
activity
• 5-HT induced vasoconstriction, platelet aggregation
& contraction of airway smooth muscle are
antagonized
• Use: antihypertensive, but did not gain popularity.
31

32. Ondansetron
• MOA- 5HT3 antagonism on vagal afferent in git ,
NTS& CTZ
• Pk:
 Oral bioavailability is 60- 70% due to first pass
metabolism.
 Metabolized - CYP1A2, CYP2D6 & CYP3A4.
followed by glucuronide & sulfate conjugation.
 Eliminated- urine & faeces
 t½ is 3- 5 hrs
 Duration of action is 8- 12 hrs 32

33. • Use: controlling nausea & vomiting following
 Anticancer drugs
 Radiotherapy.
 Post operative
 Drug & disease
• S/E : Headache, dizziness, mild constipation &
abdominal discomfort.
33

34. GRANISETRON
• 10 times more potent than ondansetron.
• Plasma t½ is longer (8- 12 hrs) – can be given BD the
day of chemotherapy.
• More effective during the repeat cycle of
chemotherapy.
• S/E profile is similar to ondansetron.
34

35. PALONOSETRON
• Longest acting 5-HT3 blocker having the highest
affinity for 5-HT3 receptors.
• Use: Delayed vomiting occurring between 2nd & 5th
day of chemotherapy.
• S/E:
 Headache, fatigue, dizziness, abdominal pain.
 Additive Q-T prolongation can occur when given
with moxifloxacin, erythromycin, anti-psychotics,
antidepressants, etc.
 Rapid i. v. injection -blurring of vision
35

36. RAMOSETRON
• Use:
 CINV
 PONV
 Diarrhoea predominant IBD syndrome.
36

37. Atypical antipsychotic
• Clozapine
 MOA:5-HT2A/2C blocker, H1 blockage, α adrenergic
blockage, anticholinergic & weak dopaminergic D2
antagonist.
 Use: Resistant cases of schizophrenia.
 S/E: Aganulocytosis, weight gain, hyperlipidemia,
Precipitate diabetes, seizures, sedation.
37

38. • Risperidone
 MOA: 5-HT2A + D2 antagonist, α & H1 blocker.
 Use: Ameliorates negative symptoms of
schizophrenia
 S/E: Agitation, weight gain & new onset diabetes
38

39. ERGOT ALKALOID
• Chemical substance present in fungus Claviceps purpurea /
ergot which infect & grows mainly on rye & millets in
damp condition.
• Accidental consumption of contaminated grains leading to
poisoning called ergotism/ St. Antony’s fire.
39

40. • Gangrene of fingers & toes , abortion in pregnant,
hallucination(5HT2), dementia & convulsion
• Ergot contains a host of pharmacologically active
substances- alkaloids, LSD, histamine, ACh, tyramine
and other amines, sterols, etc.
40

41. • The ergot alkaloid & related compounds have diverse
pharmacological properties.
• Act as agonists, partial agonists & antagonists on
certain subtypes of adrenergic, serotonergic &
dopaminergic receptors in a tissue specific manner.
41

42. CLASSIFICATION OF ERGOT ALKALOID
• Natural ergot alkaloids ,derivatives of lysergic acid.
(a)Amine alkaloid- Ergometrine (oxytocic)
(b) Amino acid alkaloids -Ergotamine, Ergotoxine
• Semisynthetic derivatives
(a) Dihydroergotamine ,Dihydroergotoxine
(b) Bromocriptine :dopaminergic D2 agonist
(c) Methysergide:5-HT 2A/2C antagonist
42

43. DRUGS RECEPTORS USES
5-HT α adrenergic DA
Ergotamine 5HT 1&2
partial Agonist
/Antagonist
Partial
Agonist(Blood
vessels)
Antagonist(other
sites)
- Migraine
Dihydroergota
mine
(Reduce
agonist)
enhances
blocking property
Weak
Antagonist
Ergometrine 5-HT 2
PartialAgonist(in
uterus)/Antagonist in
git.
Weak Agonist PPH
Dihydroergotox
ine
Partial
Agonist/Antagonist
Potent blocker Dementia( Ach
release)
43

44. Pharmacological action
• CNS
 Via 5HT2 receptors- hallucination
 Via D2 receptors- Reduce prolactin & Emesis
• Smooth muscles
 Vascular smooth muscle constriction – partial agonist
action on α receptors & 5HT2 receptors
44

45.  Uterine smooth muscle at term contracted due to 5HT2
agonist & α agonist action
 GI smooth muscles: Nausea & vomiting
- Gastric motility by acting on peripheral DA & 5HT receptors
-Stimulating Vomiting Center in CNS.
45

46.  Pharmacokinetics
• Oral bioavailability of amino acid ergot alkaloids &
their hydrogenated derivatives is poor (< 1 %)
• Bioavailability is higher after sublingual & rectal
administration.
• Metabolized in liver & excreted in bile.
• Ergotamine is sequestrated in tissues-produces longer
lasting actions compared to its plasma t½ of 2 hours.
• Ergot alkaloids effectively cross blood brain barrier.
50

47.  Adverse effects
• Nausea, vomiting, abdominal pain.
• Muscle cramps, weakness, paresthesias.
• Coronary & other vascular spasm, chest pain
 C/I
• Sepsis, IHD,PVD, HTN, pregnancy, liver & kidney
disease.
51

48. BUSPIRONE
• MOA: Partial agonist on 5HT 1A receptor.
Stimulates presynaptic 5 HT1A autoreceptors reducing
activity of dorsal raphe serotonergic neurons.
• Pk :
 Rapidly absorbed
 Undergo extensive first pass metabolism
 Bioavailability is <5%
 T1/2 2-3.5 hrs
 Excreted in urine & faeces
52

49. • Uses
 Generalized anxiety of mild to moderate intensity
without panic attacks.
 At higher dose augment effects of SSRI in OCD.
• S/E
 Dizziness, nausea, abdominal discomfort, headache &
light headedness
53

50. SUMATRIPTAN
• MOA: Selective 5-HT1B/1D agonists
• Action in migraine
 Constriction of dilated cranial extra cerebral blood
vessels ( arterio-venous shunt in carotid artery)
 5-HT & inflammatory neuropeptide release around
the affected vessels & extravasation of plasma protein
across dural vessel.
54

51. • Advantages over Ergotamine
 Better tolerated than ergotamine.
 Faster relief than ergotamine (2.5 hrs)
 Lesser rebound headache & background headache.
 Also able to take care of other related problems e.g.
nausea, photophobia etc.
 Available as TDP, autoinjectable, needle free
s/c injectable & powdered nasal spray
55
Sumavel Dosepro

52. • PK:
 Sumatriptan is absorbed rapidly & completely after s.c.
injection.
 Oral bioavailability averages only 15%.
 Absorption is faster after intranasal spray, but bioavailability
remains same.
 Sumatriptan is rapidly metabolized by MAO-A isoenzyme
 Excreted in urine; elimination t½ is - 2 hours.
56

53. • S/E
 Tightness in head & chest,
 Feeling of heat & other parenthesia in limbs,
 Dizziness, weakness are short lasting
 Bradycardia, coronary vasospasm and risk of MI-
serious, but infrequent
 Few sudden deaths
57

54. • C/I:
 IHD, hypertension, epilepsy, hepatic or renal
impairment and pregnancy
58

55. Rizatriptan
 This congener of sumatriptan
 More potent.
 Higher oral bioavailability.
 Faster onset of action.
59

56. Lasmiditan
• 5HT 1F receptor agonist
• Decreases release of inflammatory mediators from
nerve ending without causing vasoconstriction.
• Used: Used in acute treatment of migraine
60

57. METACLOPRAMIDE
• MOA
5-HT4 agonism
 D2 antagonism &
 at high concentration 5-HT3 antagonism
61

58. Actions
• 5-HT4 agonism in GIT
 Activation 5-HT4 receptor on primary
afferent neurones of the ENS .
 Activate the excitatory interneurone.
 Enhance ACh release from
myenteric motor neurones.
 Gastric hurrying & LES tone.
62

59. • D2 antagonism
-In GIT (Inhibiting ACh release)- blocks
 LES relaxation
 Gastric dilatation &
 Delay gastric empting
Thus act as prokinetic
-In CNS blocks
 CTZ activation- antiemetic properly.
-Other
 Extrapyramidal effects
 Hyperprolactinaemia.
63

60. • 5-HT3 antagonism at high concentration- Blocks
 Inhibitory myenteric inteneurones &
 NTS/CTZ
• PK:
 Rapidly absorbed orally
 Enters brain, crosses placenta & secreted in milk.
 Partly conjugated in liver
 Excreted in urine within 24 hours
 t½ is 3- 6 hours.
 Action lasts for 4-6 hours.
64

61. • Uses
 Antiemetic- postoperative, drug induced, migraine,
radiation sickness, prophylaxis & treatment of
vomiting induced by cisplatin.
 Gastrokinetic:
(a) In emergency general anaesthesia
(b)To relieve gastric stasis associated with
postvagotomy/ diabetic gastroparesis
 Dyspepsia & other functional g.i. disorders
 GERD
65

62. • Drug interaction
 The rate of absorption of aspirin , diazepam, digoxin
may be altered by the gastric hurrying
 By blocking DA receptors in basal ganglia, it
abolishes the therapeutic effect of levodopa.
66

63. • S/E:
 Sedation, dizziness
 Loose stools
 Muscle dystonias - in children
 Long-term use parkinsonism, galactorrhoea &
gynaecomastia.
67

64. CISAPRIDE
(Prokinetic)
 MOA:
 5-HT 4 agonism which promotes
ACh release from myenteric motor
neurones & cAMP dependent Cl -
secretion in colon.
 Weak 5-HT3 antagonism which
suppresses inhibitory transmission
in myenteric plexus.
68

65.  Actions
 LES tone
 Hasten gastric emptying
 GI motility is facilitated including colon
• S/E:
 Ventricular arrhythmias & death with CYP3A4
inhibitors
 At high concentrations- blocks delayed rectifying K
channels in heart- Q T prolongation
69

66. MOSAPRIDE
• Congener of cisapride with similar action & S/E.
• Indications:
 Diabetic gastroparesis
 Nonulcer dyspepsia
 GERD (as adjuvant to PPIs)
 Chronic constipation.
70

67. ITOPRIDE
• MOA: D2 antidopaminergic, anti cholinergic with
very weak affinity for 5HT 4 receptors with similar
indication
• Advantage
 No cardiac arrhythmia
 Metabolized by FMO-No drug interaction with
CYP3A4 inhibitors
 S/E: Abdominal pain, diarrhoea,headache,
galactotthoea & gynecomastia
71

68. CINITAPRIDE
• MOA:
 Inhibiting 5-HT2 & dopamine D2 receptors,
 Stimulating 5-HT4 receptors in the myenteric plexus.
• Uses: functional g.i. disorders like
 Non-ulcer dyspepsia
 Delayed gastric emptying
 GERD.
• S/E: Drowsiness (Driving is not advised ), diarrhea,
muscle dystonia, mental confusion & allergic
reactions.
72

69. RECENT ADVANCES
73

70. 5HT6 antagonists in symptomatic treatment
for Alzheimer's in Phase 3 CT
• Idalopirdine
• Intepirdine
• Latrepirdine
• SUVN-502
74

71. Rationale
• In alzheimer’s disease there is overexpression of
5HT6 receptor -lead to cognitive impairment .
• Blockage of the 5HT6 receptor in hippocampus,
nucleus accumbens & striatum.
• Leads to acetylcholine & glutamate GABA
-improves cognition, learning ,memory & even
improve anxiety & depression associated with the
progression of Alzheimer’s dementia.
75

72. 5HT7 agonist & antagonist in
preclinical phase
• AS-19
• LP-44
• LP-12 Agonist
• LP-211
• E-55888.
• SB-269970(Antagonist)
• Action on thermoregulation, circadian rhythm,
learning and memory ,sleep ,mood & addictive
behavior are studied.
76

73. Thank you
77

74. Questions
• What are the minor metabolisms of 5HT –
Omethyltransferase, n methyl tranferease
• Synthesis of 5HT- FROM TRIPTOPHAN
• Name biogenic amines- NA, H, 5HT, DA
• Decarboxylase-ACT on DOPA & 5hydroxytriptophan
• How does 5HT cause sleep-melatonin( MINOR
METABOLITE)
• How does ergotamine causes emesis- alkaloid in git cause
emesis
• What is serotonin syndrome- next slide
• Most commonly used serotonin drugs-Antiemetic,
prokinetic , triptans
78

75. Serotonin syndrome- 5HT
hyperfunction
• Caused by combination treatment of SSRI,SNRI,
Triptans, TCA with MAO inhibitors-excessive
serotonin
• TX: Stop drug( resolves in 1 day), systematic (
cooling BDZ)
• Features: Anxiety, AGITATION,restlessness,
tremors, HYPERACTIVITY & HYPERREFLEXIA,
hypothermia & then pyrexia, increased bowel
sounds, diarrhoea, tachycardia
• Seizures, Clonus, marked pyrexia
79

76. MIGRAINE
• Chronic neurological d/o with
Unilateral , pulsatile /throbbing headache
Lasting 4hrs-2 days
Associated with- n,v,sensitivity to ling &
sound, flashes of light, vertigo, loose
motion…etc
80

77. • Types
Classical/ with aura( visual /neurologial
symptom)
Common/ without aura
81

78. THEORY OF MIGRAINE
• vascular theory
Vascular constriction ( or shunting of blood via
carotid av anastomosis) leading to
hypoperfusion & ischemia of the cortex later f/B
vascular dilation
• Mutations of neuronal calcium channels,
leading to hypersensitivity, resulting in
migraine attacks.
82

79. Neurogenic theory
Neurogenic theory
excess activation of NMDA receptors
overactivity of excitatory neurotransmitters like
aspartate & glutamate causing neuronal excitability;
83
cortical spreading
depression
Retrograde
transmission of
impulse
release of
vasoactive peptides
substance P,
CGRP from
trigeminal neural
endings,
NO, 5HT
Neurogenic
inflamation
of affected
blood
vessal wall
Plasma leak--- Perivascular
edema
streatching
of dura—
Pain nerve
ending
stimulation

80. MILD MODERATE SEVERE
No of attacks per
month
<1 >1 2-3/<
Throbbing
headache
tolerable More intense severe
Duration 8hrs 6-24hrs 12-2days
Headache Does not
incapacitate
Functionally impair Grossly
incapacitated
Associated with N & v Vertigo, nausea
Simple
analgesic/NSAID/Co
mbination(+/-
antiemetic)
NSAID combination,
triptan/ergot
(+antiemetic)
triptan/ergot
(+antiemetic)
+ Prophylaxis
 Propranolol
 Amitrityline
 Flunarazine/CCB
 Valproate/Topira
mate
 Erenumab
84

81. SIMPLE ANALGESIC
• PARACETAMOL -0.5mg/ 1gm OR
• ASPIRIN
at onset repeated 4-6 hourly
85

82. NSAID-8th hourly
• IBUPROFEN 400-800mg
• NAPROXEN 500mg f/b 250mg
• DICLOFENAC 50mg
• MEPHANEMIC ACID 500mg
• INDOMETHACIN 50
Alone or with PCT/ Codeine/ diazepam/
diphenhydramine/other anti histaminic/caffeine
• Dispersible / effervescent tablet
86

83. antiemtic
• METACLOPRAMIDE 10mg oral/om
• Domperidone 10-20mg oral
• Prochlorperazine
87