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

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

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

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.

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.

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

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).

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.

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.

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

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

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

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

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

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®)

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

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.

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

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

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

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

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

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.

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.

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.

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.

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.