Structures rich in 5-HT GIT (chromaffin cells and enteric neurons) platelets CNS
BIOGENIC AMINES SEROTONIN
Actions Neurotransmitter in the CNSPrecursor of melatoninInduces sleep, Intestinal motilityInvolved in Temperature regulationAffects mood and behavior (humans)Deficiency causes depressionHemostasis : 5-HT2 receptors → aggregation of platelets and vasoconstrictionCarcinoid syndrome (tumor of serotonin producing cells) large amounts released leading to diarrhea, bronchoconstriction and edemaClinical 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)5-Hydroxytryptamine = 5HT = Serotonin
hydroxylase decarboxylaseTryptophan ———-—5 - Hydroxytryptophan ——— 5HT enzyme enzymeIt 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.
Synthesis
Serotonin
By MAO enzymeMelatonin
In pineal body in C.N.S.
5-hydroxyindole acetic acid(5HIAA)
Pharmacokinetics
Not effective orallyDoes not pass B.B.BMetabolism: ↑ in carcinoid tumor & reserpine therapy ↓ in patients treated with MAO inhibitors.
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
Serotonin receptors:
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). Serotonin
Actions:
• Act as a chemical transmitter in brain May be involved in regulation of: Importance of serotonin:
Depression, anxiety Body temperature Mood Appetite Blood pressure control Pain perception Migraine headache.
Synthesis & storage in enterochromaffin cells(90%)It may be involved in peristaltic reflex,and carcinoid syndrome. Importance of serotonin:
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 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
Antagonists of 5-HT2-receptors are used: for prophylaxis of migraine
- cyproheptadine - iprazochrome - methysergide - pizotifen1.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):
Serotonin (5-HT) antagonists
Serotonin
It antagonizes, H1, serotonin and muscarinic receptors
Stimulates the appetite.
Sedation and atropine like action are adverse effects
Ketanserin: 1. It blocks 5-HT2→VD. &↓ platelet aggregation2. It blocks ά1 receptors →VD.3.Useful in hypertension and PVDClozapine: 5HT2A/2C antagonist: for schizophrenia.
5-HT3-receptors Located in enteric neurons and in CNS. Effects are excitatory, causing GI motility and vomiting.
Dolasetron Granisetron Ondansetron Tropisetron
Antagonists of 5-HT3- receptors are very powerful antiemetics:*
The natural alkaloids are of two types: Peptide alkaloids: Ergotamine Bromocriptine Ergotoxin Amine alkaloids: ergometrine lysergic acid diethylamide (LSD) Methysergide
Ergot Alkalbids
Poorly absorbed orally (caffeine ↑ oral absorption), delayed onset and prolonged duration, metabolized in liver and excreted in urine. It is cumulative Ergot Alkalbids
1.Ergotamine
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. Ergot Alkalbids
Actions:
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.
Uses
Acute attack of migraine headache
* Peripheral vascular diseases. * Coronary heart diseases. * Hypertension. * Pregnancy. * Liver and kidney diseases.
Ergot Alkalbids
Adverse effects
Nausea and vomiting, anginal pain, tingling and numbness, gangrene and abortion.
Contraindications:
produces more V.D. than ergotoxine, and it is used in cerebral ischaemia and peripheral vascular disease..
Ergot Alkalbids
1.Ergotoxine
As ergotamine but with vasodilator effect
Dihydroergotoxine (hydergin)
While dihydrogotoxin is more V.D. than ergotoxin used in cerebral ischemia.
So dihydroergotamine is V.C. used in acute migraine
• 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. Ergot Alkalbids
1.Ergometrine
(ergonovine)
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 Ergot Alkalbids
Uses
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.