1. Structures rich in 5-HT GIT (chromaffin cells and enteric neurons)
platelets
CNS
G.I.T
Platelet
C.N.S.

2. BIOGENIC AMINES SEROTONIN
Actions
Neurotransmitter in the CNS
Precursor of melatonin
Induces sleep, Intestinal motility
Involved in Temperature regulation
Affects mood and behavior (humans)
Deficiency causes depression
Hemostasis : 5-HT2 receptors → aggregation of platelets and vasoconstriction
Carcinoid syndrome (tumor of serotonin producing cells) large amounts released leading to diarrhea, bronchoconstriction and edema

3. Clinical conditions in which 5-HT plays a role include:
migraine
mood disorders (depressive illnesses)
anxiety
vomiting
carcinoid syndrome (malignant tumors of
enterochromaffin cells in intestines) 3

4. Synthesis 5-Hydroxytryptamine = 5HT = Serotonin
hydroxylase decarboxylase
Tryptophan ———-—5 - Hydroxytryptophan ——— 5HT
enzyme enzyme
It is formed in argentaffm cells in GIT (mainly) and brain.
90% of body serotonin is present in entrochromaffin cells of gut. It is stored in platelets and inside vesicles in nerve endings.

5. Pharmacokinetics Not effective orally Does not pass B.B.B
Metabolism:
Serotonin
By MAO enzyme
In pineal body in C.N.S.
5-hydroxyindole
acetic acid(5HIAA)
Melatonin
↑ in carcinoid tumor
& reserpine therapy
↓ in patients treated
with MAO inhibitors.

6. Serotonin receptors: 5HT1A,B,D,E,F. present in C.N.S.
5HT2,A,B,C. present in smooth muscles, platelets and C.N.S.
 5HT3 →. in C.N.S (CTZ)
 5HT4 in gut smooth muscles, they increase ACh release in gut.
 5HT3, 4,5,6,7 receptors are present in area postrema and in peripheral nerves

7. Serotonin
Actions:
1. Cardiovascular system :Stimulation of heart and increased platelet aggregation.
Vaso.Cons. of B.V. especially veins and V.D. of skeletal
muscle vessels and ↑capillary permeability.
2.Spasmogenic effect on smooth muscles.
3. Antidiuretic effect due to V.C. of afferent renal arterioles.
4. Ganglion stimulant action and stimulation of sensory nerve endings(pain).

8. Importance of serotonin:
C.N.S.
• Act as a chemical transmitter in brain
May be involved in regulation of:
Body temperature
Pain perception
Depression, anxiety
Mood
Appetite
Blood pressure control
Migraine headache.

9. Importance of serotonin:
G.I.T
Synthesis & storage in enterochromaffin cells(90%)
It may be involved in peristaltic reflex,
and carcinoid syndrome.
Platelet
Hemostatic by V.C. and increasing platelet aggregation.

10. 5-HT1-receptors: 5-HT1A - 5-HT1F All subtypes occur in CNS
and cause neural inhibition

11. Buspirone anxiolytic agent partial agonist of the 5-HT1A-receptors
used in anxiety

12. 5-HT1D-receptors are found in some blood vessels
They produce vasoconstriction.
pathophysiology of migraine

13. The agonist of 5-HT1D-receptors Naratriptan Rizatriptan Sumatriptan
are highly effective, but expensive,
in acute attacks of migraine:
Naratriptan
Rizatriptan
Sumatriptan
Zolmitriptan

14. Activation of 5-HT2-receptors in CNS produces excitement
in blood vessels - contraction
and platelet aggregation

15. 5-HT2-receptors are used:
Antagonists of
5-HT2-receptors are used:
for prophylaxis of migraine
- cyproheptadine
- iprazochrome
- methysergide
- pizotifen
as a peripheral vasodilator
- Naftidrofuryl (Dusodril®)

16. Serotonin (5-HT) antagonists
1.Methysergide (Deseril): It is LSD derivative, not hallucinogenic, used in prophylaxis of migraine headache and in carcinoid syndrome. It is not used for more than 3-4 months to avoid retroperitoneal, pleural and endocardial fibrosis.
2.Cyproheptadine (periactin):
It antagonizes, H1, serotonin and muscarinic receptors
Stimulates the appetite.
Sedation and atropine like action are adverse effects

18. Clozapine: 5HT2A/2C antagonist: for schizophrenia.
Ketanserin:
1. It blocks 5-HT2→VD. &↓ platelet aggregation
2. It blocks ά1 receptors →VD.
3.Useful in hypertension and PVD
Clozapine: 5HT2A/2C antagonist: for schizophrenia.

19. 5-HT3-receptors Located in enteric neurons and in CNS.
Effects are excitatory, causing
GI motility and vomiting.

20. powerful antiemetics:
Antagonists of 5-HT3-
receptors are very
powerful antiemetics:
Dolasetron
Granisetron
Ondansetron
Tropisetron 20

21. 21

22. Agonists of 5-HT4-receptors Tegaserod (Zelmac®) activates 5-HT4-
receptors in the intestine and stimulates
peristalsis and secretion.
Indication: colon irritable syndrome

23. Ergot Alkalbids The natural alkaloids are of two types:
Peptide alkaloids: Ergotamine
Bromocriptine
Ergotoxin
Amine alkaloids: ergometrine
lysergic acid diethylamide (LSD)
Methysergide

24. Ergot Alkalbids 1.Ergotamine
Poorly absorbed orally (caffeine ↑ oral absorption), delayed onset and prolonged duration, metabolized in liver and excreted in urine. It is cumulative

25. Actions: Uses Ergot Alkalbids Acute attack of migraine headache
 Partial agonist on α -receptor.
 Partial agonist on serotonin receptors.
 Contract smooth muscles of uterus (oxytocic action).
 Stimulate C.T.Z. and inhibit V.M.C. and R.C.
Uses
Acute attack of migraine headache
Due to its V.C. effect, given in first stage to prevent second stage. Better add caffeine(Cafergot). It is available for oral, sublingual, rectal, inhaler, I.M. and I.V. use.

26. Ergot Alkalbids Adverse effects
Nausea and vomiting, anginal pain, tingling and numbness, gangrene and abortion.
Contraindications:
* Peripheral vascular diseases.
* Coronary heart diseases.
* Hypertension.
* Pregnancy.
* Liver and kidney diseases.

27. So dihydroergotamine is V.C. used in acute migraine
Ergot Alkalbids
1.Ergotoxine
As ergotamine but with
vasodilator effect
Dihydroergotoxine (hydergin)
produces more V.D. than ergotoxine, and it is used in cerebral ischaemia and peripheral vascular disease..
So dihydroergotamine is V.C. used in acute migraine
While dihydrogotoxin is
more V.D. than ergotoxin used in cerebral ischemia.

28. Ergot Alkalbids 1.Ergometrine (ergonovine)
• It is completely absorbed from GIT and has a short duration.
 It has potent oxytocic action (active and rapid).
 No α -blocking effect or C.N.S. action
 Slight effect on B.V. (weak ά-agonist)
 Partial agonist on 5-HT receptors.

29. Uses Ergot Alkalbids Diagnosis of variant angina.
Prevention and treatment of postpartum hemorrhage and in subinvolution of uterus.
Methylergometrine (methergine) is more potent than ergometrine. It is used in treatment of postpartum hemorrhage
Diagnosis of variant angina.
Ergonovine (Ergometrine) produces prompt V.C. of coronary vessels in Prinzmetal's or variant angina so may be given by I.V. infusion during coronary angiography for diagnosis→ Ischemic heart changes in ECG.