A little something about Serotonin, Prostaglandins and Leukotrienes

1. AUTOCOIDS
Autos ~ Self
Akos ~ Healing
substance
Dr. Maheshi Chhaya
20th October, 2018

2. SEROTONIN, AN AMINE

3. FORMATION & DEGRADATION
p-chlorphenylalanine
(PCPA)
SSRIs
VMAT-2 inhibitors
5,6-dihydroxytyptamine

4. RECEPTORS
Then
• Musculotropic (D type) – Blocked by Dibenzyline
(phenoxybenzamine)
• Neurotropic (M type) – Blocked by MorphineNow
• Four major families
• 5-HT1
• 5HT2

5. 5HT1 RECEPTOR A, B, D, E, F
Receptor Location Function Drug Use
1A Dendritic
synapses of
raphe nuclei
Reduced firing Buspirone –
Partial
agonist
Anxiety
1D/1B Cranial blood
vessels
Constriction Sumatriptan
– selective
agonist
Migraine
1D Neurons Inhibits release
of NA, 5HT and
inflammatory
neuropeptides

6. 5HT2 RECEPTOR A, B, C
Receptor Location Function Drug Use
2A,
Post-
junctional
Vascular SM
Visceral SM
Platelets
Neurons
Vasoconstriction
Contraction
Aggregation
Activation
Ketanserin -
antagonist
Hypertension
2B Rat fundus
2C Vascular
endothelium
Choroid plexus
EDRF release,
vasodilatation
CSF formation
α-methyl 5-HT is a selective agonist

7. 5HT3 RECEPTOR
Location Function Drug Use
Somatic and
autonomic
nerve endings
Pain, itch,
coronary
chemoreflex,
visceral reflexes
Ondansetron –
antagonist
2-Methyl 5-HT
- selective
agonist
Vomiting
Myenteric nerve
endgings
Augmentation
of peristalsis,
Emesis
Area postrema,
NTS
Nausea,
vomiting

8. 5HT4-7 RECEPTOR
• Cisapride, Mosapride, Renzapride - 4
Receptor Location Function Drug Use
4 GI smooth
muscle
Peristalsis Cisapride,
Renzapride
Vomiting
4-7 Mucosa,
plexuses and
smooth
muscle of the
gut
Hippocampus
and colliculi
Augmenting
intestinal
secretion (ulcer
protective) and
peristalsis
Slow
depolarization
Clozapine Antipsychotic

9. TRIPTANS
• Selectively activate 5-HT1D/1B receptors
• Migraine: First line for those who do not respond to analgesics;
recurrences may occur.
• Sumatriptan, Rizatriptan, Naratriptan, Frovatriptan
• MOA:
• 5-HT1D/1B receptor mediated constriction of dilated cranial blood vessels,
especially the arterio-venous shunts in the carotid artery
• Reduction of 5-HT release, since autoreceptors
• Inhibition of inflammatory neuropeptide release around the affected vessels &
extravasation of plasma proteins across dural vessels

10. SUMATRIPTAN
• Relief from migraine within 2-3 hours
• Recurrence in 20-40%
• Half life – 2 hours
• Oral BA – 15%
• Doses:
• 50–100 mg oral at the onset of migraine attack, may be repeated once within 24 hours
• 6 mg s.c. , to those who cannot take the drug orally or in whom the pain develops very
rapidly
• 25 mg nasal spray, repeat once after 2 hours

11. SUMATRIPTAN
• S/E - Tightness in head and chest, paresthesias in limbs,
dizziness, weakness.
• Bradycardia, coronary vasospasm and risk of myocardial
infarction - serious, but infrequent
• Seizures, HSR – rare
• C/I – IHD, HTN, epilepsy, hepatic or renal impairment and
pregnancy
• Caution - Not to drive.

12. MIGRAINE
• Mild - Simple analgesics/NSAIDs or their combinations (±
antiemetic)
• Moderate - NSAIDs combinations/a triptan/ergot alkaloids (+
antiemetic)
• Severe
• a Triptan/ergot alkaloids (+ antiemetic) + Prophylaxis (6 months at least)
• Propranolol/other β blockers
• Amitriptyline/other tricyclic antidepressants
• Flunarizine/other Ca2+ channel blockers
• Valproate/topiramate

13. ERGOT ALKALOIDS
• Claviceps purpura
• Natural – ergometrine, ergotamine, ergotoxine
• Semisynthetic – dihydroergotamine, bromocriptine,
methysergide
• MOA: Constricts cranial blood vessels and/or carotid AV shunts.
• Reduces neurogenic inflammation and leakage of plasma from
duramater (5HT1D/1B)
• Sumatriptan and ergotamine should not be administered within
24 hours of each other.

14. ERGOTAMINE
• Early: total relief even at lower doses.
• Oral or SL, 1mg very 30 minutes, till relief, max. 6mg.
• BA better SL and rectally; Half life – 2 hours
• S/E- nausea, vomiting, background headache, precipitation of attack on
discontinuation.
• C/I - Sepsis, IHD, PVD, HTN, pregnancy, liver and kidney disease
• DHE is less hazardous and is preferred.
• Caffeine – enhances absorption, also is a cerebral vasoconstrictor

15. CYPROHEPTADINE
• Blocks 5-HT2A receptors – carcinoid and
postgastrectomy dumping syndromes;
priapism/orgasmic delay caused by 5-HT uptake
inhibitors like fluoxetine and trazodone
• H1 antihistaminic – increased appetite, sedation, anti-
allergic
• Anticholinergic, sedative properties

16. METHYSERGIDE
• Ergot derivative without ergot side effects
• 5HT1, 5-HT2A/2C antagonist
• Used in migraine prophylaxis, carcinoid and
postgastrectomy dumping syndrome
• Prolonged use - abdominal, pulmonary and
endocardial fibrosis

17. KETANSERIN
• Selective 5-HT2 (A>C) receptor blocking property
• Weak α1, H1 and dopaminergic blocking property
• Ritanserin, a congener
• Used in hypertension, Raynaud’s phenomenon

18. SEROTONIN SYNDROME
Management:
Stop the drug.
BZDs, Cyproheptadine, IV fluids
IV Esmolol, Nitroprusside

19. INTERMISSION

20. PROSTAGLANDINS, THE LIPIDS
ECOSANOIDS, derivatives of Arachidonic Acid

21. PATHWAY
COX inhibitors LOX inhibitors

22. FUNCTIONS
PGE2 PGF2 TXA2 PGI2
Blood
vessels
Dilator
Maintains patency
of DA (COX2)
Constrictor
(pulmonary)
Constrictor Dilator
Platelets Aggregation
Release
(COX1)
Anti-
aggregation
Uterus Contract
Cervical priming,
Abortion)
Contract

23. FUNCTIONS
PGE2 PGF2 TXA2 PGI2
Bronchial
Muscle
Dilator Constrictor Constrictor Dilator (mild)
GIT;
Gastro-
protective
Enhanced
propulsion,
increased water,
electrolyte, mucus
secretion,, reduced
acid secretion
Opposes PGE2
Mucosal
Vasodilatation

24. FUNCTIONS
PGE2 PGF2 TXA2 PGI2
Kidney Diuretic
Vasodilatation
Antagonizes
ADH
Renin Release
Renin
Release
Vasoconstriction Diuretic
Vasodilatation
Renin Release
CNS: neuro-
modulators
Pyrogen (COX3)
ANS: NA
release
+/- +/-
Nerve
endings
Sensitize Sensitize

25. FUNCTIONS
PGE2 PGF2
Eye Inflammation
Reduces IOT
Endocrine Ant. Pituitary hormones,
steroids, insulin; TSH like
action
Gonadotropin,
prolactin,
luteolysis
(animals)
Metabolism Antilipolytic, insulin like
action, mobilization of
bone calcium

26. DRUGS
E1 E2 F2 I2
Misoprostol,
Alprostadil
Dinoproston
e,
Gemeprost
Dinoprost,
Carboprost;
Latanoprost
Epoprostern
ol

27. SIDE EFFECTS
Nausea, vomiting, watery diarrhoea
Uterine cramps, unduly forceful uterine contractions,
vaginal bleeding
Flushing, shivering, fever, malaise, fall in BP, tachycardia,
chest pain.

28. PROSTANOID RECEPTORS
• EP – 1 TO 4
• FP
• IP
• TP

29. LEUKOTREINES
• LTB4: neutrophils;
• LTC4 and LTD4, the cysteinyl LTs: macrophages
• Receptors:
• LTB4 : BLT1 and BLT2 – chemotactic, leucocytes and spleen,
affinity 1>2
• Cysteinyl LTs : cysLT1 (bronchial and intestinal SM, D>C;
Montelukast, Zafirlukast) and cysLT2 (Leucocytes and spleen, no
preferences)

30. FUNCTIONS
LTB4 LTC4 LTD4
Inflammation Neutrophil,
Monocyte
chemotaxis
Vasodilatation
Exudation of Plasma
Eosinophil chemotaxis
Bronchus Smooth Muscle Contraction
Mucus Secretion
Intestine Smooth Muscle Contraction
Nerve Endings Sensitizing