Serotonin PDF

Newman Osafo, BPharm, PhD. Department of Pharmacology, FPPS, CoHS, KNUST [email protected] § 5-HT synthesis involves the rate limiting enzyme, tryptophan hydroxylase and is mainly degraded by the action of monoamine oxidases. § 5-HT is best known as a neurotransmitter in the brain, but...

Newman Osafo, BPharm, PhD. Department of Pharmacology, FPPS, CoHS, KNUST [email protected] § 5-HT synthesis involves the rate limiting enzyme, tryptophan hydroxylase and is mainly degraded by the action of monoamine oxidases. § 5-HT is best known as a neurotransmitter in the brain, but about 95% of it is synthesized, stored and released by enterochromaffin cells in the intestinal mucosa. 2 § 5-HT signaling may modulate the peripheral immune system § Different immune cells can generate, store, respond to and/or transport serotonin § Immune cells, including T cells, macrophages, mast cells, dendritic cells and platelets have one or more of these capacities. 3 § In monocytes/macrophages, serotonin modulates cytokine secretion. § Serotonin can also suppress the release of TNF-α and IL-1β by activating serotonin receptors (5-HT2A) § Neutrophil recruitment and T-cell activation can both be mediated by serotonin. 4 § Serotonin can affect food intake via activation of the anorexigenic melanocortin system involving 5-HT2c receptors § It also inhibits the orexigenic NPYergic system § Reduction of brain serotonin by reducing availability of its precursor tryptophan has been shown to be beneficial in the treatment in anorexia during cancer. 5 § Receptors of the CTZ that have been identified to induce emesis include opioid µ, κ, D2, NK-1 and 5-HT3. § Ondansetron and Granisetron are a selective serotonin antagonist, used for treating chemotherapy-induced nausea and vomiting. § Binds to the serotonin receptors located on the vagal neurons lining the gastrointestinal tract, and block signaling to the vomiting center in the brain 6 § The 5-HT receptors occur on other neurons in the ENS, where they can be stimulatory (5-HT3 and 5-HT4) § The availability of serotonergic prokinetic drugs has in recent years been restricted because of serious adverse cardiac events § Prucalopride is a specific 5-HT4R agonist that facilitates cholinergic neurotransmission. § Used in chronic idiopathic constipation § It acts throughout the length of the intestine, increasing oral-cecal transit and colonic transit without affecting gastric emptying. 7 § Cisapride is a 5-HT4 agonist that stimulates adenylyl cyclase activity in neurons. It also has weak 5-HT3 antagonistic properties and may directly stimulate smooth muscle. § Withdrawn due to the potential to induce serious and occasionally fatal cardiac arrhythmias. 8 § Recurrent unilateral headache which may be accompanied by GI and visual disorders § More prevalent in females than males with a ratio of 3:1 § Complex neurovascular disorder marked by vasodilation of intracranial and extracerebral vessels § Involves stimulation of surrounding trigeminal sensory nervous pain pathway that results in headache 9 § CGRP is released via activation of the trigeminovascular system § There is also markedly decreased levels of 5-HT in migraineurs § Serotonin principally acts on serotonin receptors in the trigeminovascular system to lower levels of key molecules such as CGRP § The interplay of the levels of these peptides gives the nociceptive information to the central neurons in the brain stem that in turn relay the pain signals 10 § Levels of serotonin and CGRP are affected by physiological hormonal intervention. § A fluctuation in estrogen decreases serotonin by affecting its metabolism which can bring on migraine 11 § Out of the 7 receptor types, 5-HT1, 5-HT2 and 5-HT3 are identified to be responsible for migraine § 5-HT receptors may have different roles in migraine. § 5-HT on 5-HT1 subtypes may prevent migraine whiles the opposite outcome is seen in 5-HT2 subtypes. 12 § Lysergic acid diethylamide (LSD), methysergide § They bind to multiple 5-HT receptors § Methysergide has antagonist activity on 5-HT2B to selectively decrease carotid blood flow by constricting arteriovenous anastomoses providing migraine prophylaxis. Also blocks 5- HT2A and 5-HT2C in its antimigraine action. 13 § Triptans Sumatriptan, zolmitriptan, rizatriptan, frovatriptan § Have fewer side effects than the ergot derivatives § Potent cranial vasoconstrictor with neural antimigraine activity. § Are selectively agonist on 5-HT1B/1D receptor § Vascular complications due to vasoconstriction 14 § Ditans Lasmiditan § A serotonin receptor agonist which binds to 5-HT1F receptor subtype. § Possesses fewer side effects than triptans possibly due to its lack of activity on 5-HT1D and 5-HT1B receptor subtypes. Devoid of vascular complications. § Drug causes CNS depression resulting in dizziness and sedation. 15 § Molecules that act as agonist/antagonist of 5-HT receptors in trigeminovascular system are used in migraine management. § CGRP receptor antagonist § Currently, CGRP receptor antagonists such as Rimegepant and ubrogepant are used as antimigraine therapy. § Selectively block CGRP receptor without the vasoconstrictive effect § Monoclonal antibodies targeting CGRP or its receptors: Eptinezumab, galcanezumab, erenumab. 16