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SEROTONIN for better understanding .pptx

Serotonin (5-HT) is a monoamine neurotransmitter that has diverse functions including mood, cognition, and physiological processes. It is found widely in nature, especially in the gastrointestinal tract, blood platelets, and central nervous system. 5-HT is synthesized from tryptophan and stored in neurons and chromaffin cells. It is released and acts on several receptor subtypes to exert its effects before being reuptaken or metabolized. Key 5-HT receptors include 5-HT1 receptors which inhibit adenylate cyclase, and 5-HT2 receptors which stimulate phospholipase C. Agonists and antagonists that target these receptors are used to treat various conditions like anxiety, migraine, and hypertension.

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SEROTONIN (5-HT) GROUP 02 BPH 2.1A
INTRODUCTION  Serotonin or Hydroxytryptamine is a monoamine neurotransmitter  Its biological function is complex, touching on diverse functions including mood, cognition, learning, memory and numerous physiological processes such as vomiting and vasoconstriction.  Before identification of 5-HT it was known that when blood is allowed to clot a vasoconstrictor (tonic) substance is released from the clot into the serum  This substance was called serotonin  Independent studies established the existence of a smooth muscle stimulant in intestinal mucosa (enteramine)
Occurrence and Distribution  Widely distributed in nature  Found in plant & animal tissues  Found in venoms and stings  Play role in several diseases eg. Carcinoid syndrome (tumor of enterochromaffin cells)  Functions as a neurotransmitter and a local hormone in the peripheral vascular system
Occurance and Distribution cont… In the walls of the intestines in  Enterochromaffin cells (90% of total amount in the body)  nerve cells of myenteric plexus (where it functions as an excitatory neurotransmitter)  5-HT is released in response to mechanical and neuronal stimuli In blood: Occur in high concentrations in platelets  Platelets accummulate 5-HT from plasma by an active carrier mediated transport mechanism  Released when platelets aggregate at sites of tissue damage
Occurrence cont In the CNS Found in high concentrations in specific areas of the midbrain In the pineal gland 5-HT serves as a precursor of melatonin (a melanocyte- stimulating hormone) Excites some neurones and inhibits others
Biosynthesis & metabolism of 5-HT  Synthesized from dietary tryptophan  Formed by hydroxylation of the indole ring followed by decarboxylation of the amino acid  Hydroxylation at C5 is the rate limiting step and can be blocked by chlorophenylalanine (PCPA; fenclonine) or parachloroamphetamine.  Mechanisms of synthesis, storage, release and reuptake of 5-HT are very similar to those of NA  Many drugs affect both processes indiscriminately  5-HT is often stored in neurons and chromaffin cells as a co-transmitter together with peptide hormones such as somatostatin, substance P, VIP  Serotonin can be depleted from storage vescicles by reserpine in much the same way as catecholamines
Biosynthesis and Metabo…
Biosynthesis cont
5-HIAA  Excreted in urine  Used as an indicator of 5-HT production in the body  Used in the diagnosis of carcinoid syndrome
Uptake and termination of Serotonin  5-HT is actively taken up by an amine pump serotonin transporter (SERT), a Na+ dependent carrier, which operates at the membrane of platelets (therefore, 5-HT does not circulate in free form in plasma) and serotonergic nerve endings.  This pump is inhibited by selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).  Platelets do not synthesize 5-HT but acquire it by uptake during passage through intestinal blood vessels.
Uptake continue…  Again like CAs, 5-HT is stored within storage vesicles, and its uptake at the vesicular membrane by vesicular monoamine transporter (VMAT-2) is inhibited by reserpine, which causes depletion of CAs as well as 5- HT.  The degrading enzyme MAO is also common for both. The isoenzyme MAO-A preferentially metabolizes 5-HT
5-HT-Receptors 5-HT1-receptors  Occur mainly in the brain  Subtypes are distinguished on the basis of regional distribution and pharmacological specificity  Function as inhibitory pre-synaptic receptors  G-protein coupled & linked to inhibition of adenylate cyclase
5-HT1A -Receptors  Important in the brain  Cause neuronal inhibition  Decrease levels of cAMP  Involved in the regulation of behavior, mood, sleep, feeding, temperature, anxiety
Agonist of 5-HT1A 1. Buspirone  It is indicated for anxiety and taken orally  It is metabolized in the liver and excreted by the kidney  The elimination t1/2 of unchanged buspirone is 2 to 3 hours
Agonist cont MOA: Buspirone exerts anxiolytic activity through high affinity for serotonin 5-HT1A receptor Side effects: dizziness, drowsiness, nausea, headache, nervousness, blurred vision.  Buspirone is contraindicated to patients with epilepsy, severe renal or hepatic impairment
Agonist cont Other 5-HT1A agonist drugs are  5-carboxamidotryptamine (5-CT) which is indicated for migraine and work by causing vasodilation of carotid circulation  Subsequent structural modification of 5-CT led to the discovery of another antimigraine drug sumatriptan
Antagonist of 5-HT1A  1. Spiperone  It is dopamine antagonist that binds dopamine and serotonin (5-HT1A) receptor  Spiperone is a typical antipsychotic and research chemical  It is licensed for clinical use in Japan as a treatment of schizophrenia
Antagonist cont  2. Ergotamine  It is non selective serotonin receptors inhibitors and is partial agonist  It is taken orally or sublingual or dihydroergotamine taken parenteral  It is short acting drug and has low orally bioavailability  Indicated for use as a therapy to abort or prevent vascular headache, e.g migraine
Ergotamine cont  Also used in combination to treat uterine atony, 3rd stage of labour, uterine bleeding and postpartum hemorrhage (PPH)  Side effects: nausea, vomiting, abdominal pains, transient hypertension, diarrhea and potentially fatal are myocardial infarction (MI) and pulmonary oedema.  Contraindication: Pregnancy, 1st and 2nd stages of labour, patients with preeclampsia, eclampsia or threatened abortion
Antagonist cont  3. Methiothepin (Metitepine)  Acts as non selective antagonist of serotonin, dopamine and adrenergic receptors and has antipsychotic properties  Also methiothepin suppress human ovarian cancer cell growth by repressing mitochondrion mediated metabolism and inhibit angiogenesis in vivo.
5-HT1B -Receptors  Also CNS, causing pre-synaptic inhibition  Involved in the regulation of behavior  Agonist: 5-CT (5-Carboxamidotryptamine)  Antagonist: methiothepin.  Ergotamine is antagonist but as well as partial agonist, i.e can bind to the agonist recognition site but trigger a response that is lower than that of a full agonist.
5-HT1D -Receptors  CNS and cerebral blood vessels  Mediate cerebral vasoconstriction, regulate behavior and locomotion  Inhibit adenylate cyclase, both 5-HT1D and 5-HT1B are found on cerebral and meningeal vessels and mediate vasoconstriction  Useful for treatment of acute migraine  Cause coronary vasospasm (contraindicated in coronary artery disease and angina)
Agonist of 5-HT1D  1. Sumatriptan, Naratriptan, Rizatriptan, Zolmitriptan (act on both 5-HT1D and 5-HT1B  Are indicated in treatment of acute migraine and acute cluster headache  It is administered orally, SC injection, nasal powder and nasal sprays  It has half life of 1 to 4 hours and metabolized by liver and excreted by kidney
Sumatriptan cont  Side effects: injection site reaction, paresthesia, dizziness, warm/hot sensation, chest discomfort. Potentially fatal are cardiac arrhythmias and MI.  Contraindications: patient with history of MI or stroke, severe hepatic impairment, uncontrolled hypertension
Agonist cont  Other agonist of 5-HT1D is 5-CT  Believed to be important in migraine
Antagonists of 5-HT1D 1. Methiothepin 2. Ergotamine is also a partial agonist
Other 5-HT1-receptors  5-HT1E present in the cortex and putamen  5-HT1F present in the cortex and hippocampus (involved in long term memory formation and memory retrieval)  Inhibit adenylate cyclase  No specific agonists or antagonists yet
5-HT2-Receptors  All stimulate Phospholipase C (PLC) leading to hydrolysis of Phosphatidylinositol 4,5-biophosphate (PIP2  Stimulation increase levels of IP3 and DG  More important in the periphery than CNS  Cause neuronal excitation  Modulate behavior  Mediate platelet aggregation, smooth muscle contraction (bronchial, uterus)  Vasoconstriction/vasodilatation)
5-HT2A-Receptors  CNS, PNS, smooth muscle, platelets  In the CNS they mediate behavioral changes (e.g. Lysergic acid diethylamide, LSD-classical hallucinogen)  In the periphery they mediate smooth muscle contraction
Agonists of 5-HT2A 1. α-Methyl 5-HT α-methyl Serotonin is an agonist of serotonin (5-HT) receptors. It binds selectively to 5-HT1A, 5-HT1B, 5-HT2C, and 5-HT1D receptors over 5-HT1E This product is not for human or veterinary use.
Agonist cont  2. LSD (Lysergic acid diethylamide)  Activation of 5-HT2A receptors in the central nervous system results in an increase in body temperature (hyperthermia) and increased secretion of ACTH.  In the periphery, 5-HT2A receptors mediate the contractile responses of vascular smooth muscle, and a component of the contractile response of smooth muscle in the gut, to 5- HT.  The 5-HT2A receptor has been implicated in the hallucinogenic effects of 5-HT2 receptor agonists
LSD cont  LSD is absorbed quickly through the GIT and enters the blood stream  It is distributed throughout the body and it crosses the blood- brain barrier to reach the brain.  It is metabolized by liver and the metabolite are excreted through the urine  The half life of LSD is about 3 to 4 hours, but the hallucinogenic effects of the drug can last for up to 12 hours
LSD cont  Lysergic acid diethylamide (LSD) is a strong mood- and perception-altering hallucinogen, that can affect a person’s thoughts, feelings, and perceptions of their surroundings  Today, LSD is categorized as a Schedule I drug under the Controlled Substances Act, as it has no currently accepted medical use in the U.S. and has a high potential for abuse
Antagonists of 5-HT2A  They are non-selective;  Also act on α-adrenoceptors and histamine receptors  Cyproheptadine and pizotifen are used to control symptoms of the carcinoid syndrome  Dihydroxyergotamine is used for prophylaxis of migraine  Ketotifen: sometimes used for treatment of asthma  Ritanserin: is a more selective 5-HT2 –receptor antagonist with little or no α- adrenoceptor blocking effect  It alters bleeding time and reduce thromboxane formation by altering platelet function
1. Cyproheptadine  It primarily blocks 5-HT2A receptors and has additional H1 antihistaminic, anticholinergic and sedative properties like other antihistaminics, it has been used in allergies and is a good antipruritic, but the anti 5-HT action has no role in these conditions.  It increases appetite and has been used in children and poor eaters to promote weight gain.  The H1 antihistaminic action and an action on growth hormone secretion has been suggested to account for this.
MOA of Cyproheptadine  Cyproheptadine is a sedating antihistamine with antimuscarinic, serotonin antagonist and ca channel blocking properties. It compete with histamine for H1 receptor site on effector cells, and it also has potent 5-HT antagonist activity through 5-HT2A receptor blocking action  Cyproheptadine is well absorbed from GIT  It is mostly metabolized by the liver and the metabolite are excreted through the urine
Cyproheptadine cont  Side effects: drowsiness, dry mouth, confusion, weight gain, ataxia (poor muscle control)  Contraindication: narrow angle glaucoma, hypersensitivity, lactation, acute asthmatic attacks
2. ketotifen  It is used in treatment of allergic conjunctivitis, asthma prophylaxis,  It can be taken orally and as an eye drops  MOA: Selectively and competitively inhibits the release of mediators from cells involved in hypersensitivity reactions  Side effects: weight gain, rash, respiratory infection  Contraindication: hypersensitivity
3. Methysergide  It is chemically related to ergot alkaloids; antagonizes action of 5-HT on smooth muscles including that of blood vessels, without producing other ergot like effects: does not interact with a adrenergic or dopamine receptors.  Methysergide is a potent 5-HT2A/2C antagonist with some tissue specific agonistic actions as well; but is nonselective acts on 5-HT1 receptors also.  It is well absorbed from the GIT and reaches its peak concentration in the blood within about one hour
Methysergide cont  It is metabolized by the liver, and the metabolites are excreted through the urine  It has been used for migraine prophylaxis, carcinoid and postgastrectomy dumping syndrome.  Prolonged use has caused abdominal, pulmonary and endocardial fibrosis, because of which it has gone into disrepute.
4. Ketanserin  It has selective 5-HT2 receptor blocking  property with negligible action on 5-HT1, 5-HT3 and 5 HT4 receptors and no partial agonistic activity. Among 5-HT2 receptors, blockade of 5-HT2A is stronger than 5-HT2C blockade.  5-HT induced vasoconstriction, platelet aggregation and contraction of airway smooth muscle are antagonized.  It has additional weak alpha1, H1 and dopaminergic blocking activities.  Ketanserin is an effective antihypertensive, but a1 adrenergic blockade appears to be causative rather than 5-HT2A blockade.
Other antagonists of 5-HT2A  Pizotifen is non selective and used in treatment of headache and migraine  It is a sedating antihistamine with strong serotonin antagonist and weak antimuscarinic properties. It also antagonize the action of tryptamine  It has nausea, weight gain, increased appetite, drowsiness, dizziness, reduced libido as its side effects  Dihydroxyergotamine is also antagonist of 5-HT2A
Other antagonists cont  Risperidone This atypical antipsychotic is a combined 5-HT2A + dopamine D2 antagonist, similar to clozapine. Like the latter, it especially ameliorates negative symptoms of schizophrenia, but produces extrapyramidal side effects at only slightly higher doses  Clozapine In addition to being a dopaminergic antagonist (weaker than the typical neuroleptics), this atypical antipsychotic is a 5- HT2A/2C blocker. Clozapine may also exert inverse agonist activity at cerebral 5-HT2A/2C receptors which may account for its efficacy in resistant cases of schizophrenia
5-HT2B-Receptors  Found in Stomach fundus  Mediate contraction of the fundus  Agonist: α-Me 5-HT  Antagonist: not yet identified (SB204741)
5-HT2C-Receptors  Found in Choroid plexus, hippocampus, substantia nigra  Agonist: α-Me 5-HT, LSD  Antagonist: Methysergide
5-HT3-Receptors  Occur mainly in the PNS  Found mainly on nociceptive neurons (specialized subset of sensory neurons that mediate pains); autonomic and enteric neurones  CNS in the area postrema  5-HT exerts a strong excitatory effect on these neurons  The receptors are linked to a Na+-K+ ion channel  Do not involve 2nd messengers in signal transduction
5-HT3-Receptors cont  The physiological role of this receptor is not known  It has been postulated that excitation of vascular sensory nerve terminals by 5-HT from platelets may be involved in the pathogenesis of migraine  Selective 5-HT3-receptor antagonists are used as anti- emetics
Agonist of 5-HT3-Receptors  1. 2-methyl-5-Hydroxytruptamin (2-Me-HT)  It is a potent and selective 5-HT receptor agonist  Is shown to display anti-depressive like effects  2. m-chlorophenyl-biguanide  It binds to 5-HT3 receptors with high affinity  Its effects can be blocked by ondansetron (selective 5-HT3 antagonist)
Antagonist of 5-HT3  Ondansetron  It is the prototype of the new class of selective 5-HT3 antagonists that have shown remarkable efficacy in controlling nausea and vomiting following administration of highly emetic anticancer drugs and radiotherapy  Ondansetron is well absorbed from the GIT  It metabolized by the liver and has a half-life of about 3 to 6 hours  Ondansetron is excreted through the urine and faeces
Ondansetron cont  Side effects: headache, constipation, malaise/fatigue  Ondansetron is contraindicated in patient with profound Hypotension and hypersensitivity  Granisetron and Tropisetron are the other selective 5- HT3 antagonists.
5-HT4-Receptors  Occur in the brain, myenteric neurones, bladder and heart  Main physiological role appears to be in the GIT where they produce neuronal excitation, and mediate the effect of 5-HT in stimulating peristalsis  Enhance release of Ach  G-protein coupled and activate adenylate cyclase ( cAMP)
5-HT4-Receptors Agonists  1. Metoclopramide  Used for gastroesophageal reflux and motility disorders (nausea and vomiting, gastro-esophageal reflux disease, diabetic gastric stasis)  It can be taken orally and parenteral  It is well absorbed from GIT, and metabolized by the liver and has a half-life of 2 to 3 hours.
Metoclopramide cont  MOA: Metoclopramide enhances the motility of upper GI tract and increases gastric emptying without affecting gastric, biliary or pancreatic secretions. It increases duodenal peristalsis which decreases intestinal transit time and increases lower esophageal sphincter tone  It is also a potent central dopamine receptor antagonist may also has serotonin receptor (5-HT3) agonist properties
Metoclopramide cont  Side effects: extrapyramidal symptoms (dystonic reactions in young adults), fatigue, restlessness, sedation, headache, dizziness  Frequency SE of metoclopramide but not defined: diarrhea, galactorrhea, gynecomastia, impotence  Contraindication: GI hemorrhage, epilepsy, confirmed or suspected pheochromocytoma, concomitant use with levodopa or dopaminergic agonists
Other 5-HT receptors  5-HT5, 6, 7  All have been identified in the brain  Specific agonists and antagonists are still being developed  Clozapine is a partial agonist of both 5-HT6 and 5- HT7-receptors
Selective Serotonin re-uptake inhibitors(SSRI)  A Depression an infective symptoms characterized by intense sadness, general loss of interest in everyday aspects of life.  SSRIs believed to relieve mood disorders by increasing serotonin in the brain. Serotonin also known as 5- hydroytryptamine is a monoamine neurotransmitter but it can also act as a hormone 'where its controls moods and is responsible for happiness.  Generally depression can be treated by four groups including SSRI and Atypical antidepressant ,monamine oxidase inhibitors(MOA),Tricyclic's
Selective Serotonin re-uptake inhibitors(SSRI)  SSRIs blocks the reabsorption (reuptake) of serotonin into neurons, this means more serotonin available to improve and modulate serotonergic transmission of messages between neurons. SSRIs are called selective because they mainly affect serotonin not other neurotransmitters.  SSRIs are metabolized by the cytochrome p-450 system and fluvoxamine is potent p-450 inhibitors  They have half life of about 18 to 26 hours  SSRIs are administered orally. The use of antidepressants will make the individual harder on her/his self harder to emphasize ,harder to climax, harder to cry.
Mechanism of action SSRIs  Blocks serotonin transporter(SERT) increasing extracellular levels of serotonin within the synaptic cleft .the 5HT1A receptors also down regulates after a lag of 2-4weeks (on set of action for SSRIs resulting in serotonin flowing down the presynaptic neurons and the neurons firing.  Example of drugs of SSRIs are sertaline,paroxetine,fluvoxamine,flucoxetine,escitalopram,citalop ram,dapoxetine,voitioxetine  what do SSRIs do in the body, are group of medications that treat depression and other mental health condition the SSRIs work by raising the level of certain chemical –serotonin in the brain ,they may also help the brain process serotonin more effectively
Selective Serotonin re-uptake inhibitors(SSRI)  Side effects: vomiting ,erectile dysfunction(impotence) diarrhea, nausea, decreased libido ,nervousness.  contraindicated in combination therapy with monoamine oxidase inhibitor's because this combination result in serotonin syndrome “its characterized by hyperthermia(overheating of the body), muscle rigidity(is a muscle pain and inability to move).
Other use of some SSRIs  Some SSRI has been developed and is being promoted for delaying premature ejaculation (PE)  Example of this SSRI is Dapoxetine
Ergot Alkaloids  Active substances produced by Claviceps purpurea, a fungus infecting cereals  Responsible for episodes of poisoning when cereal containing the fungus is consumed  Symptoms: - mental disturbance  Intensely painful peripheral vasoconstriction (leading to gangrene)  Structure of ergot alkaloids is based on lysergic acid  Amine alkaloids: 6-methylergoline, lysergic acid, lysergic acid diethylamide, ergonovine(ergometrine) and Methysergide  Peptide alkaloids: ergometrine, bromocriptine and α-ergocryptine
Mechanism of Action  Act on several types of receptors  Act as agonists, partial agonists and antagonists at α-adrenoceptors, serotonin receptors (5-HT1A and 5-HT1D mainly)  Less effect on 5-HT1C, 5-HT2 and 5-HT3  Agonist or partial agonist effect on central dopamine receptors  Cause stimulation of smooth muscle  Some are relatively selective for vascular smooth muscle  Others act mainly on the uterus
Clinical uses Prophylaxis of migraine (ergotamine and dihroxyergotamine)  Methysergide also useful for prophylaxis  Hyperprolactinemia: Prolactin is an anterior pituitary hormone  Levels increase when there is a tumor of the gland  Also prolactin levels can be elevated due to use of centrally acting dopamine antagonists, especially antipsychotic drugs  Due to –ve feedback hyperprolactinemia is associated with amenorrhea and infertility in women  Also galactorrhea in both sexes  Bromocriptine is useful for reducing prolactin levels from pituitary tumors  Has been associated with regression of the tumor in some cases
 Ergometrine is used to control of postpartum hemorrhage  Diagnosis of variant angina (Ergometrine produces prompt vasoconstriction during coronary angiography to diagnose variant angina  Treatment of senile cerebral insufficiency (used for relief of insenility and Alzheimer’s dementia)
Pharmacological effects of 5-HT GIT  Increase motility and contraction of isolated strips of intestine  Effect is due to direct effect on smooth muscle  Indirect excitatory effect on enteric neurons  Chromaffin cells release 5-HT in response to mechanical and vagal stimulation
Other smooth muscles Uterus, bronchial tree  Contracted by 5-HT in many species except in humans where it occurs to a minor extent Blood vessels  Effect depends on various factors  Size of the vessel  Species  The prevailing sympathetic activity  Large vessels (arteries & veins) are usually constricted by 5-HT (sensitivity varies greatly)  It is a direct effect on vascular smooth muscle mediated by 5-HT2A-receptors  5-HT also causes vasodilatation by acting on 5-HT1-receptors, partly by releasing NO from endothelial cells and partly by inhibiting NA release from sympathetic nerve terminals
 5-HT2A is vasoconstrictor and 5-HT1 is vasodilator  When 5-HT2A receptors are blocked by ketanserin the vasodilator effect is revealed  When 5-HT is injected IV the BP usually 1st rises due to vasoconstriction of large blood vessels  It then falls due to arteriolar vasodilatation  In skeletal muscle and the heart it causes vasodilatation
Platelets  5-HT causes platelet aggregation via 5-HT2A receptors  Aggregated platelets release more 5-HT  When endothelium is intact 5-HT causes vasodilatation (sustain blood flow)  If endothelium is damaged 5-HT causes vasoconstriction and impair blood flow)  The effects of platelet-derived 5-HT are important in vascular disease
5-HT In the CNS  Found in high concentrations in specific areas of the midbrain  In the pineal gland 5-HT serves as a precursor of melatonin (a melanocyte- stimulating hormone)  Excites some neurones and inhibits others  Acts pre-synaptically to inhibit transmitter release from nerve terminals  Different receptor types & membrane mechanisms mediate these effects
5-HT in the Brain  involved in the regulation of mood, sleep, appetite, temperature  Perception of pain  Regulation of blood pressure  Vomiting  Also involved in aspects of depression, anxiety and migraine
Nerve Endings  Potent stimulant of pain & itch sensory nerve endings  Injected into the skin it causes pain  Responsible for some of the symptoms of insect and plant stings  Effect mediated by 5-HT3-receptors
Systemic effect  5-HT is a powerful activator of chemosensitive endings located in the coronary vascular bed  Activation of 5-HT3-receptors on these afferent vagal nerve endings is associated with the chemoreceptor reflex (the Bezold-Jarisch reflex)  Reflex response consists of marked bradycardia and hypotension  5-HT inhibits transmitter release from adrenergic neurons in the periphery
Effects in the Heart In the heart 5-HT Dilates coronary blood vessels
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