Serotonin (5-Hydroxytryptamine)(5-HT)

- Serotonin or 5-hydroxytryptamine ( 5 -HT ) is a monoamine neurotransmitter , a local hormone in the gut , a component of the platelet clotting process , and is play role in migraine headache and several other clinical condition .

Bio synthesis	- Serotonin is formed by decarboxylation of the amino acid L-tryptophan .
Storage	- Once formed , serotonin is either stored or rapidly inactivation. - Serotonin is found in:   1.       Enterochromaffin - Like ( ECL ) cells :      - Approximately 90 % of the human body's total serotonin is located in the        enterochromaffin-Like ( ECL ) cells in the gut , which regulate intestinal        movements. 2.       Blood :      - Serotonin is found in platelet , which cause vasoconstriction and helps in blood        clotting . 3.       Brain :      - Brain serotonergic neurons are involved in numerous function such as        regulation of mood , sleep , appetite , temperature , blood pressure and        vomiting . Serotonin also appears to be involve in clinical conditions such as        depression , anxiety and migraine.
Inactivation	- Serotonin is metabolized by MAO à give intermediate product ,    5-Hydroxyindoleacetaldehyde à is further oxidized by aldehyde dehydrogenase to      à 5-Hydroxyindoleacetic acid ( 5-HIAA ) .  5-HIAA à normal level 2-7 mg / day in urine . Increase 5-HIAA level in patient with carcinoid tumors .
Notes	- Melatonin Hormone : Serotonin is also a precursor of Melatonin in the pineal gland.      - Melatonin responsible for regulate circadian ( biological clock ).      - Melatonin production inhibited by the light and increase in night.      - Melatonin stimulates immune system and suppress cancer cell.      - Melatonin used in sleep and mood disorders , cancer prevention , body weight        reduction, and other uses. - Serotonin Rich Foods : Serotonin naturally exists in kiwi fruit , bananas , pineapples , tomatoes and plums .
MOA	- The action of serotonin are mediated through a remarkably large number of cell   membrane receptors. - Seven families of 5-HT receptor subtypes, all of this are coupled with G protein coupled receptors , except one (5-HT3) is a member of nicotinic / GABA , family of Na+/K+ channels proteins .

 

Pharmaco- dynamics	Nervous system	·         Brain : - Serotonin is present in a variety of sites in the brain. - It is responsible for mood, appetite, sleep, cognition, sensory   perception, motor activity, temperature regulation, sexual   behavior and hormone secretion. ·         Nerve ending : - Like Histamine , Serotonin is a potent stimulant of pain and itch   sensory nerve ending. ·         Peripheral Nervous System : 5-HT3 play important role in GIT & vomiting center. 5-HT4 play important role in enteric nervous system.
	Lung	- Serotonin has a small direct stimulant of bronchial smooth muscle in   normal humans ( 5-HT2A) . - Serotonin may also cause hyperventilation as a result of   chemoreceptor ( Bezold-jarisch ) reflex or bronchial sensory nerve   ending stimulation .
	CVS	- Serotonin directly causesà  contraction of vascular smooth muscle   (VC) (5-HT2A) . - Serotonin is a powerful VC except in skeletal muscle and the heart,   where it dilates blood vessels . - Platelet aggregation activated by 5-HT2A . - Activation of 5-HT3 receptor on these afferent vagal nerve endings   is associated with chemoreceptor reflex à bradycardia, hypotension   and decrease cardiac output .   Triphasic blood pressure response of serotonin - Injection of serotonin in experimental animal cause :      1: Decrease HR, CO and BP due to chemoreceptor response. 2: Increase in BP due to VC. 3: Decrease in BP due to VD in skeletal muscle blood vessels.
	GIT	- Serotonin is a powerful stimulant of GI smooth muscle à Increase   tone and facilitate peristalsis (5-HT2) . - Activation of 5-HT4 receptor in the enteric nervous system à   increase ACh release à Motility enhancing (Prokinetic effect) .
Serotonin Syndrome	Serotonin Syndrome : is a condition associated skeletal muscle contraction and precipitated when MAO inhibitors are given with serotonin agents especially antidepressant of selective serotonin reuptake inhibitors ( SSRIs ):(see CNS chapter). -          Main symptoms: Hypertension, agitation, mental confusion, hyperthermia,                                       diarrhea, tremors and muscle rigidity.

 

 

 

Serotonin Agonists
Buspirone (Buspar®)
- Buspirone is a selective 5-HT1A agonist , which is an antianxiety agent (non benzodiazepine). - It is primarily used to treat generalized anxiety disorder (GAD) (short-term anxiety). - Contraindication: should not be used with patient taking MAOIs may cause serotonin syndrome. - Most common side effects : dizziness , nausea , headache , nervousness , and excitement . - Usual adult dose :   - Initial dose : 5 mg 3 times a day.                                          - Maintenance dose : 20 to 60 mg/day in divided doses.                                          - Maximum dose : 60 mg per day.
Sumatriptan ( Imigran®)	Zolmitriptan ( Zomig®)	Rizatriptan (Maxalt®)
Naratriptan ( Amerge®)	Eletriptan (Relpax®)	Almotriptan (Axert®)
Frovatriptan (Frova®)
[ Triptans family ]  - Sumatriptan, Zolmitriptan  , Rizatriptan , Naratriptan, Eletriptan, Almotriptan, and Frovatriptan are    selective agonists for 5-HT1B and 5-HT1D receptors . - Triptans are a family of Tryptamine-based drugs , introduced in the 1990s for the treatment of   migraines and cluster headaches. - Triptans are first-line therapies for moderate to severe migraine , or mild to moderate migraine that   has not responded to adequate doses of simple analgesics . - All of these agents available in oral preparation , Sumatriptan available in nasal , SC and rectal   preparation , Zolmitriptan available in nasal preparation . Mechanism of action : Triptans are selective agonists for 5-HT1B and 5-HT1D receptors: 1) Inhibit the release of vasodilating peptides ( especially calcitonin gene-related peptide ; CGRP ). 2) Vasoconstriction effect on intracranial blood vessels .   - Contraindication : should not be used in patients at risk for coronary artery disease due to it may   cause coronary artery vasospasm . - Serotonin syndrome may reported during co/administration of Triptans with SSRIS , MAOIs , or other   antidepressant drugs (TCAs) .
Tegaserod (Zelmac®)
- Tegaserod is a 5-HT4 partial agonist in the enteric nervous system in the GIT, which stimulates GI   motility. - It is used for the treatment of irritable bowel syndrome with constipation (IBS-C). - It is removed from the market in 2007 due to FDA concerns about possible increased risks of heart   attack or stroke.
Cisapride (Propulsid®)
- Cisapride is a gastroprokinetic agent (enhance GI motility) , It acts directly as a serotonin 5-HT4   receptor agonist and indirectly as a parasympathomimetic (increase ACh release). - It is used for the treatment of gastroesophageal reflux disease (GERD) . - It is no longer available (voluntary withdrawal) due to its side effect ; long QT interval ( arrhythmia ) .
Mosapride (Fluxopride®)
- Mosapride is a gastroprokinetic agent , It acts directly as a serotonin 5-HT4 receptor agonist and   indirectly as a parasympathomimetic (increase ACh release). - It is used for the treatment of gastritis , gastro-esophageal reflux disease (GERD), functional dyspepsia and irritable bowel syndrome . - It is available in some countries ( e.g. Egypt ) , Now no data available to insure QT prolongation . - Drug interaction : LMEIS ( e.g. Erythromycin ) may cause à QT interval prolongation .

 

Serotonin Antagonists
- A wide variety of drugs with action at other receptors also have serotonin receptor blocking    effects . - Phenoxybenzamine is a non-selective, irreversible α-blocker, it also has long-lasting blocking   action at 5-HT2A receptor, and it is useful in the treatment of carcinoid tumor. - Cyproheptadine is a first-generation antihistamine with 5-HT2-blocking actions, in addition   to antihistamine uses , it also used in the management of moderate to severe cases of   serotonin syndrome and carcinoid tumor , it also used as appetite stimulant and migraine   prophylaxis .
Pizotifen or Pizotyline (Sandomigran®) (Mosegor®)
- Pizotifen is 5-HT2A and 5HT2c receptors antagonist, It also has some activity as an antihistamine as   well as some anticholinergic activity. - It is used for prevention of vascular headache including migraine and cluster headache . - It is off-label used as appetite stimulant. - Most common side effects: sedation, dry mouth, drowsiness and weight gain.
Ketanserin (Sufrexal®)
- Ketanserin is a 5-HT2 receptor antagonist on smooth muscle and platelet (antagonise platelet aggregation), it also block α-receptor, it used as antihypertensive - Topical Ketanserin gel was effective and safe in the primary nonsurgical treatment of anal fissure.
Ondansetron (Zofran®)	Granisetron (Kytril®)		Tropisetron (Navoban®)
- Ondansetron, Granisetron, Tropisetron are 5-HT3 receptor antagonist , used to prevent nausea and   vomiting caused by cancer chemotherapy, radiation therapy, surgery, or postoperative. - Ondansetron and Granisetron are off-label used to treat morning sickness and hyperemesis in   pregnancy (category B). - Ondansetron and Granisetron are used safely in children . - Most common side effects; may cause QT interval prolongation, increase the risk in patients taking   other medicines that prolong the QT interval.
Alosetron (Lotronex®)		Cilansetron (Calmactin®)
- Alosetron and Cilansetron are 5-HT3 receptor antagonist used for the management of severe irritable   bowel syndrome with diarrhea (IBS-D). - Alosetron used only in women , but Cilansetron effective in men as well as women. - Most common side effects of Alosetron is serious ( life-threatening) complications of constipation  e.g. ischemic colitis may lead to obstruction, (Alosetron was withdrawn from market , but it is become  available again). - Most common side effects of Cilansetron is constipation with less or self - limited serious complications .

 

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