Serotonin PDF

L9 Dr. Alaa AL- Sheek Mashhad Serotonin It is an important neurotransmitter, a local hormone in the gut regulates its motility (about 90% of body's content of 5-HT is localized in the intestines), a component of the platelet cl...

L9 Dr. Alaa AL- Sheek Mashhad Serotonin It is an important neurotransmitter, a local hormone in the gut regulates its motility (about 90% of body's content of 5-HT is localized in the intestines), a component of the platelet clotting process, and is thought to play a role in migraine headache. Serotonin is also one of the mediators of the signs and symptoms of carcinoid syndrome. It is formed in biologic systems from the amino acid L-tryptophan. After synthesis, the free amine is stored or is rapidly inactivated by monoamine oxidase and stored serotonin can be depleted by reserpine Tissue and organ system effects: 1-Nervous system: Its role as a neurotransmitter, precursor of melatonin in the pineal gland and in the vomiting center. 1 It is a potent stimulant of pain and itching sensory nerve endings and is a powerful activator of chemosensitive endings located in the coronary vascular bed. 2-Respiratory system: Serotonin has a small direct stimulant effect. 3-Cardiovascular system: Serotonin directly causes the contraction of vascular smooth muscle (arteries and veins) mainly through 5-HT2 receptors. Platelet aggregation also enhanced by same receptor. 4-GIT: it increases tone and facilitating peristalsis. 5-Skeletal muscle Serotonin syndrome: when MAO inhibitors are given with serotonin agonists, especially antidepressants of the selective serotonin reuptake inhibitor, hyperthermia resulting from excessive muscle contraction. Serotonin Agonists: Buspirone: is a 5-HT1A agonist, an effective non-benzodiazepine anxiolytic. Cisapride: a 5-HT4 agonist, was used in the treatment of gastro-esophageal reflux and motility disorders. 2 Tegaserod, a newer 5-HT4 partial agonist, is used for irritable bowel syndrome with constipation. Sumatriptan and its congeners are agonists effective in the treatment of acute migraine and cluster headache attacks Migraine headache and 5-HT1D/1B agonists 3 The 5-HT1D/1B agonists (triptans) are used almost exclusively in migraine headache includes: 4 All are well absorbed orally with t ½ 2-5 hours. 5 Adverse effects are mild and include altered sensations (tingling, warmth, etc), chest pain, dizziness, muscle weakness, and neck pain. Serotonin antagonists: Phenoxybenzamine: has a long-lasting blocking action at 5-HT2 receptors. Cyproheptadine: it has potent H1-receptor-blocking as well as 5-HT2-blocking actions. Also has significant anti-muscarinic effects and causes sedation. 6 The major clinical applications are in the treatment of the smooth muscle manifestations of carcinoid tumor and in cold-induced urticaria. Ketanserin: blocks 5-HT1c and 5-HT2 receptors this drug potently blocks vascular α1 adrenoceptors. The drug blocks 5-HT2 receptors on platelets and antagonizes platelet aggregation promoted by serotonin. Ritanserin: another 5-HT2 antagonist has little or no α-blocking action. It has been reported to alter bleeding time and to reduce thromboxane formation. Ondansetron and Tropisetron: It is the prototypical 5-HT3 antagonist. Used for prevention of nausea and vomiting associated with surgery and cancer chemotherapy. 7  The ergot alkaloids Ergot alkaloids are produced by Claviceps purpurea, a fungus that infects grasses and grains. They affect adrenoceptors, dopamine receptors and 5HT receptors. The ergot alkaloids are variably absorbed from the GIT. The oral dose of ergotamine is about ten times larger than the intramuscular dose which can be improved by co-administration with caffeine. Natural ergot alkaloids are divided into: Amine alkaloid: Ergometrine (Ergonovine) which is oxytocic 8  Amino acid alkaloids: Ergotamine Ergotoxine: They are vasoconstrictor and adrenergic blocker. 9 Semisynthetic derivatives Dihydroergotamine (DHE) Dihydroergotoxine: antiadrenergic. Bromocriptine: is a dopaminergic agonist Methysergide: it is mainly anti 5-HT2. Organ system effects 10 1-CNS: Alkaloids are powerful hallucinogens e.g. Lysergic acid. Ergotism (ergot poisoning): the most dramatic effects of poisoning are dementia with florid hallucinations; prolonged vasospasm, which may result in gangrene; and stimulation of uterine smooth muscle, which in pregnancy may result in abortion. Bromocriptine, cabergoline, quitagloide, and pergolide directly suppress prolactin secretion. 2-Vascular smooth muscle: it constricts blood vessels in prolonged manner. 11 3-Uterine smooth muscle: ergot alkaloids have a stimulant action of on the uterus. Ergonovine is more selective than other ergot alkaloids in affecting the uterus. Clinical uses of ergot alkaloids: Migraine: Ergotamine can also be quite effective when given during the prodrome of an acute attack. It is available for oral, sublingual, rectal suppository, and inhaler use. It is often combined with caffeine. It can cause prolong vasospasm. Dihydroergotamine, 0.5-1 mg intravenously, is favored by some clinicians for treatment of intractable migraine. Hyperprolactinemia Bromocriptine is extremely effective in reducing the high levels of prolactin that result from pituitary tumors and has even been associated with regression of the tumor in some cases. The usual dosage of bromocriptine is 2.5 mg two or three times daily. It might induce serious postpartum cardiovascular toxicity. Cabergoline is similar to Bromocriptine but more potent. Postpartum hemorrhage Ergonovine maleate, 0.2 mg usually given intramuscularly. 12 It is usually effective within 1-5 min and is less toxic than other ergot derivatives. It is given at the time of delivery of the placenta or immediately afterward if bleeding is significant. Senile cerebral insufficiency Dihydroergotoxine has been promoted for relief of senility and more recently for the treatment of Alzheimer's dementia. 13