5-HT Pharmacology - drdhriti
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Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter synthesized from tryptophan. It is present mainly in the gastrointestinal tract and blood platelets, with some in the central nervous system. Serotonin acts through multiple receptor subtypes and has diverse physiological effects including regulation of mood, appetite, sleep, and cardiovascular and gastrointestinal functions. Antagonists of serotonin receptors are used to treat conditions like migraine, hypertension, nausea/vomiting, and carcinoid syndrome. Common antagonists include cyproheptadine, ketanserin, ondansetron, and ergot alkaloids.
5-HT Pharmacology - drdhriti
- 1. Serotonin orSerotonin or 5-Hydroxytryptamine and its5-Hydroxytryptamine and its antagonistsantagonists Dr. D. K. Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong
- 2. What is Serotonin?What is Serotonin? Vasoconstrictor - Serotonin and Enteramine Serotonin or 5-Hydroxytryptamine (5-HT) is a monoamine neurotransmitter, biochemically derived from tryptophan Feelings of well-being Present in Intestine (90%) along with platelets and brain (10%) ◦ 90% in EC cells and 10% in neurones of different plexuses Stored in granules like catecholamine Also present in plants and insects ◦ Plants like tomato, banana & pineapple ◦ Lower animals - mollusks, arthropods, snake and bee venom/sting
- 3. Physiologic Distribution of SerotoninPhysiologic Distribution of Serotonin (5-Hydroxytryptamine (5-HT)(5-Hydroxytryptamine (5-HT) 10% CNS 90% GI tract 90% ECs 10% Neurons 5-Hydroxytryptamine 5
- 4. Synthesis, Metabolism and DestructionSynthesis, Metabolism and Destruction Dietary tryptophan ◦ converted to 5–hydroxy– tryptophan by tryptophan hydroxylase ◦ then to 5-HT by a non–specific decarboxylase Degradation ◦ mainly monoamine oxidase (MAO–A > MAO–B) ◦ 5–hydroxyls Indole acetic acid (5-HIAA) in urine
- 5. N C N C NH2 COOH COOH NH2 OH N C NH2 OH H Tryptophan 5-Hydroxytryptophan 5-Hydroxytryptamine N C COOH 5-OH Indole Acetaldehyde 5-Hydroxy Indole Acetic Acid Tryptophan hydroxylase 5-OH Tryptophan decarboxylase M AO Aldehyde dehydrogenase (Rate limiting) In diet. Active CNS transport Dietary
- 6. Serotonin UptakeSerotonin Uptake Non-specific Decarboxylase produces 5-HT (also CA) Amine pump (SERT) actively takes up Serotononin (like CA) in serotonergic nerve endings – Na+ dependent carrier …. Inhibited by SSRIs and TCAs Platelets do not synthesize 5-HT (deficiency of tryptophan hydroxylase) -– but actively takes up by SERT – during intestinal passage Stored in storage vesicles by active uptake (like CAs) – Vesicular monoamine transporter (VMAT 2) – inhibited by Reserpine Degrading enzyme MAO is common for both MAO
- 7. Refer to - Biosynthesis ofRefer to - Biosynthesis of CatecholaminesCatecholamines Phenylalanine PH Rate limiting Enzyme 5-HT, alpha Methyldopamine α-methyl-p-tyrosine
- 8. 5-HT5-HT ReceptorsReceptors Classically - Musculotropic (D type) and Neurotropic (M type) – blockade by Dibenzylline (Phenoxybenzamine) and Morphine respectively Methysergide and cyproheptadine are classical blockers – blocks D-type only Radiological binding studies – molecular characterization and cloning …. FOUR FAMILIES - 5-HT1, 5-HT2, 5-HT3 and 5-HT4-7 All are GPCRs except 5-HT3 (5-HT3 is a ligand gated Na+ channel) ◦ All are cAMP ………. except 5-HT2 (IP3-DAG) ◦ 5-HT1 inhibits cAMP and 5-HT4, 5-HT6 and 5- HT7 increases cAMP
- 9. 5-HT15-HT1 –– ReceptorsReceptors Five Subtypes – A, B, D, E and F All acts as autoreceptors Gi/G0 subtypes (inhibits adenylyl cyclase) - inhibit firing of neurones or release of 5-HT ◦ Also, activation of K+ channel and inhibits Ca++ channel 5-HT1A – Brainstem (Raphe nuclei) and hippocampus (antidepressant – Buspirone - partial agonist) 5-HT1D – Basal ganglia and substancia nigra (dopeminergic) 5-HT1B/1D – Cranial Blood Vessels (for constriction – sumatriptan – selective agonist)
- 10. 5-HT5-HT22 Mainly 3 subtypes (5-HT2A, 5-HT2A and 5-HT2A) – all are Gq types – IP3/DAG ◦ 5-HT2A Widely distributed postjunctional (D-type) Located in all smooth muscles - vascular, visceral – also platelets and cerebral neurones Mediates DIRECT ACTIONS Vasoconstriction, intestinal, uterine and bronchial constrictions, platelet aggregation and activation of cerebral neurones etc. Ketanserin - specific antagonist ◦ 5-HT2c –– vasodilatation through EDRF … choroid plexus
- 11. 5-HT5-HT33 Neuronal 5-HT Receptor – depolarization of nerve endings and opening of channels (M-type) – Mediates indirect and reflex effects Somatic and ANS nerve endings – pain, itch, coronary chemoreflex ◦ Fall in BP, bradycardia, stimulation of respiration or apnoea and other visceral reflexes Myenteric plexus nerve endings: augmentation of peristalsis and emetic reflex Brain: Area postrema and NTS: nausea and vomiting Ondansetron – specific antagonist
- 12. 5-HT5-HT4-74-7 Gs-type of receptor – activates adenylyl cyclase ◦ Mucosa, plexuses and smooth muscles of gut ◦ Related to - augmentation of Intestinal secretion and peristalsis ◦ In Brain: hippocampaus area – slow depolarization of K+ channel ◦ Specific role is unknown till now ◦ Cizapride and renzapride – specific agonist of the 5- HT4 receptor ◦ 5-HT5, 5-HT6 and 5-HT7 – closely related to 5-HT4
- 13. Receptor Type Location Functions Agonists Antagonists 5-HT1 GPCR (Gi/Go) Auto-receptors in brain – prejunctional Inhibits Serotonergic activity 5-HT1A do Raphe nuclei, Hippocampus Inhibits firing of raphe nuclei Buspirone (Partial) 5-HT1D/1B do Cranial blood vessels and CNS neurons Constricts vessels and inhibits release of inhibitory neuropeptides Sumatriptan 5-HT2A GPCR (IP3/DAG) Post-junctional visceral and vascular SM Contraction, platelet aggregation, neuronal activation in brain Ketanserin 5-HT3 Ligand gated Na+ channel Somatic and ANS Nerve endings, Myenteric plexus and NTS in brain Reflex actions – peristalsis, bradycardia, hypotension, apnoea, pain etc. Ondansetron 5-HT4 GPCR (Gs) Mucosa, plexuses and SM of gut Secretion, and peristalsis Renzapride
- 14. Actions ofActions of 5-HT5-HT Potent depolarizer of Nerve endings – exerts direct as well as indirect effects Tachyphylaxis Arteries are constricted (direct) or dilated (EDRF) – depends on vascular bed and basal tone Also releases Adrenaline – affects ganglionic transmission – CVS reflexes Overall, large arteries and veins are constricted but in microcirculation arterioles dilate and veins constrict Constriction of veins – escape of fluid
- 15. Actions of 5-HT - CVSActions of 5-HT - CVS Heart: Isolated heart stimulation - direct ionotropic and chronotropic effects ◦ Intact animal Heart: Bradycardia due to stimulation coronary chemoreflex (Bezold Jarrisch reflex) – through vagaus Nerve ◦ Overall bradycardia, hypotension and apnoea Blood Pressure: Triphasic response on BP ◦ Early sharp fall: Coronary chemoreflex ◦ Brief rise in BP: vasoconstriction and increased cardiac output ◦ Prolonged fall in BP: arteriolar dilatation and extravasation of fluid (Not involved in Physiological Regulation of BP) – Preeclmpsia Ketanserin – 5-HT antagonist (5-HT2)
- 16. Actions ofActions of 5-HT5-HT -Visceral SM-Visceral SM GIT: Stimulator of GIT – direct and through entero- chromaffin cells in the mucosa main 5-HT in body ◦ ↑ GIT motility – increased peristalsis and diarrhoea Bronchi: Constricts, but less potent than histamine Glands: 5-HT inhibits gastric acid and pepsin, secretion however increase mucus production thus it has ulcer protective property Nerve endings and adrenal medulla: afferent nerve endings are activated – tingling and pricking sensation – also pain ◦ Depolarization of visceral afferents – respiratory and CVS reflexes, nausea and vomiting Respiration: brief stimulation of respiration – reflex from bronchial afferents – hyperventilation. Large dose – apnoea – coronary chemoreflex
- 17. Actions ofActions of 5-HT5-HT – contd.– contd. Platelet: 5-HT2A action – changes in shape and size of platelets – but weak aggregator CNS: Poor entry to BBB – however it’s a transmitter – INHIBITORY ◦ Direct Injection: Hunger, sleepiness, behavioural changes
- 18. Pathphysiological Roles –Pathphysiological Roles – 5-HT5-HT Neurotransmitter: Raphe nuclei, substancia nigra and other sites ….. Send serotonergic to limbic system, cortex, neostriatum and also to Spinal chord – regulates sleep, temperature regulation, thought process, cognitive, behaviour and mood, appetite, vomiting and pain perception Precursor of Melatonin: Pineal gland Neuroendocrine Function: Hypothalamic hormones to Anterior Pituitary – serotonergic (!) Nausea and Vomiting: Cytotoxic drugs and radiotherapy – receptor of gut 5HT3 Migraine: Vasoconstrictor phase of migraine – Methysergide and Sumatriptan
- 19. 5-HT5-HT Physiological Roles – contd.Physiological Roles – contd. Haemostasis: Platelet aggregation and clot formation enhancer Raynaud`s phenomenon: Vasospastic Variant angina: Coronary vasospasm or Variant angina Hypertension: Not clearly known – reduced uptake and clearance of 5-HT - Ketanserin Intestinal Motility: Regulates local reflex and peristalsis in gut Carcinoid syndrome: Massive release – hypermotility and bronchoconstriction 5-HTs – NO THERAPEUTIC USE
- 21. Antagonists of serotoninAntagonists of serotonin Ergot derivatives: Ergotamine, ergonovine and methysergide (Carcinoid) etc. Alpha-blockers: Phenoxybenzamine Antihistaminics: Cyproheptadine, cinnarizine Phenothiazines: Chlorpromazine Ketanserin: used as antihypertensive Clozapine: for schizophrenia Metoclopramide, Ondansetron and Granisetron are currently available as anti-emetic for chemotherapeutic induced nausea and vomiting (5-HT3 antagonists)
- 22. CyproheptadineCyproheptadine 5-HT2A blocking property Also H1 antihistamic, anticholinergic and sedative action Famous for increasing appetite Uses: ◦ Allergic reactions like hay fever ◦ Serotonin syndrome ◦ Carcinoid syndrome ◦ Priapism (fluoxetine) ◦ Appetite stimulation in children Adverse effects: weight gain, drowsiness, dry mouth etc.
- 23. KetanserineKetanserine Selective 5-HT2 receptor blocker – negligible 5- HT1, 5-HT3 and 5-HT4 blocker 5-HT2A > 5-HT2C Additional H1, α1 and dopaminergic blocking action Antagonizes vasoconstriction, platelet aggregation and airway constriction actions of 5-HT Used as antihypertensive agent Other drugs like – clozapine, risperidone and ondansetron will be discussed elsewhere !
- 24. Ergot Alkaloids and derivativesErgot Alkaloids and derivatives Ergot alkaloids ---- toxic effects First isolated by Dale & Barger in 1906 from fungus Claviceps purpurea ---- on rye and other grains - sclerotinium Contains – LSD, histamine, acetylcholine and tyramine etc. They have long been recognized as abortifacients and poisonings produced an intense burning sensation & gangrenous condition in the limbs as a result of persistent peripheral vasoconstriction Diverse pharmacological actions – agonist, antagonist and partial agonist of serotonin, alpha-receptor and dopaminergic receptors
- 25. Classification of ergot alkaloidsClassification of ergot alkaloids 1. Natural – Derivatives of the tetra-cyclic compounds (lysergic acid) Amine alkaloids – Ergometrine (ergonovine) - oxytotic Amino acid alkaloids - Ergotamine, Ergotoxine ... Vasoconstrictor & α - blocker 1. Semi-synthetic – Bromocriptine, Methysergide, Dihydro-ergotamine (DHE) 2. Synthetic – (non lysergic acid derivative) Metergotine
- 26. ErgometrineErgometrine Amine ergot alkaloid Partial agonist of 5-HT receptor in uterus, placenta and umbilical blood vessels and some areas in brain Weak agonist but no antagonistic effect of α receptor Moderately potent antagonist of 5-HT2 in intestine Less dopaminergic action in CTZ – no vomiting Most prominent - Uterine myometrium Will be discussed elsewhere !
- 27. ErgotamineErgotamine Amino acid alkaloid Partial agonist and antagonist of α adrenergic and 5-HT1 and 5-HT2 receptors, but no interaction with 5-HT3 or dopaminergic receptors Actions: ◦ Sustained vasoconstriction, visceral smooth muscle contraction and vasomotor centre depression ◦ Antagonizes action of NA and 5-HT in smooth muscles ◦ Overall BP effect - insignificant ◦ Potent emetic via CTZ and oxytotic ◦ Prolong use – vasoconstriction and damage endothelium
- 28. DihydroergotamineDihydroergotamine (DHE)(DHE) Hydrogenated ergotamine Less serotonergic action than ergotamine and less α - adrenergic agonist action Better blocker of α-adrenergic receptor Less vasoconstrictor and so less intimal damage Lesser oxytotic and emetic
- 29. ErgotsErgots Pharmacokinetics: Poor bioavailability – 1% - slow and incomplete absorption plus 1st pass metabolism ◦ Sublingual/rectal administration ◦ Metabolized in liver nd excreted in bile ◦ Ergotamine is sequestrated to tissues – half life – 2 Hrs ◦ Crosses BBB ADRs: Nausea, vomiting, muscle cramps, weakness, paraesthesia, coronary and other vasospasm, chest pain etc. CIs: Sepsis, IHD, Peripheral vascular disease, hypertension, liver disease and pregnancy
- 30. Learn …Learn … Actions and Pathophysiological Roles of 5-HT 5-HT antagonists Cyproheptadine Ergots - etgotamine
- 33. What is migraineWhat is migraine Severe, throbbing, pulsating headache usually unilateral headache (few hours to a few days in duration) Associated with nausea, vomiting, sensitivity to light and sound, flashes of light, loose motion and others Types: ◦ Classical with aura ◦ Without aura (common) Pathophysiology: ◦ Pulsatile dilatation of temporal or certain cranial vessels ◦ Vascular theory: initial vasoconstriction or shunting of blood through carotid arterio-venous anastomosis causing cerebral ischaemia ◦ Neurogenic theory: depression of cortical electrical activity followed by depression Migraine attack associated with (based on histological studies): sterile neurogenic perivascular edema inflammation (clinically effective antimigraine medication reduce perivascular inflammation)
- 34. Pharmacotherapy of MigrainePharmacotherapy of Migraine Three types: Mild, Moderate and Severe Mild: NSAIDS and Antiemetics (optional) Ibuprofen (400 mg 8 hrly) Paracetamol (500 mg 8 hrly) Naproxen (250 mg 8 hrly) Mefenamic acid (500 mg 8 Hrly) Diclofenac (50 mg 8 Hrly) ◦ Antiemetics: Metoclopramide (10 mg oral or IV) Domperidone (10 mg oral)
- 35. Migraine - ModerateMigraine - Moderate Intense throbbing headache lasting for 6 – 24 Hrs, nausea and vomiting and functionally impaired patient ◦ NSAIDs ◦ Antiemetics ◦ Specific drugs like ergots and others (sumatriptan)
- 36. Migraine - SevereMigraine - Severe More than 2-3 attacks per month lasting for 12 – 48 hrs, often vertigo and vomiting and patient is completely incapacitated ◦ NSAIDS cannot relieve symptoms ◦ Specific antimigraine drugs like ergot alkaloids and triptans ◦ Also prophylactic regimens
- 37. ErgotamineErgotamine Most effective ergot alkaloid MOA: ◦ Partial agonist of 5-HT1B/1D ◦ Constriction of dilated temporal vessels ◦ Constriction of carotid AV shunt channels ◦ Reduction of neurogenic inflammation and leakage of plasma in duramater Doses: oral/sublingual (1 mg every half an hourly) till relief – 6 mg/ day Kinetics: only 1% Bioavailability orally – high first pass metabolism ◦ Given by SL route and rectal ◦ Metabolized in liver and excreted in bile ◦ Sequestrated to tissues and long lastin effect ◦ Crosses BBB ADRs: Nausea, vomiting, abdominal pain, muscle cramps etc. Also chest pain, vascular spasm etc.
- 38. DHEDHE Almost equally effective as ergotamine Preferred for parenteral administration Erratic oral absorption – combined with caffeine 100 mg for enhancing oral absorption Ergo status in Migraine: ◦ Not popular anymore ◦ Regular use is hazardous ◦ No prophylactic value – precipitate on discontinuation ◦ Dull headache ◦ Combination with caffeine, paracetamol, belladona etc. are available
- 39. Selective 5-HT1B/1D agonistSelective 5-HT1B/1D agonist SumatriptanSumatriptan Selective agonist of 5-HT1B/1D receptor No interaction with other 5-HT receptors No interaction with adrenergic, dopaminergic and cholinergic receptors, GABA MOA: Blockade of 5-HT1D/1B mediated constriction dilatation of extracerebral blood vessel Constriction of arteriovenous shunt of carotid artery Inhibition of release of 5-HT and inflammatory neuropeptides around the affected vessels – supression of neurogenic inflammation Supression of impulse transmission in trigeminovascular system Kinetics: Poorly absorbed from GIT, bioavailability – 10 – 15% only Complete absorption after subcutaneous administration Metabolized by MAO-A and excreted in urine, t1/2 is 2-3 Hrs
- 40. Sumatriptan – contd.Sumatriptan – contd. Administration & Doses: ◦ Onset of acute attack ◦ Better tolerated than ergotamine ◦ 50 to 100 mg as initial dose and repeated after 24 Hrs if required ◦ Should not be given is first dose fails ◦ SC dose – 12 mg (1 ml) stat and repeated if required Adverse effects: Dose related - Tightness of chest, feeling of heat, paresthesia of limbs, dizziness and weakness (short lasting) – common with SC route ◦ Risk of MI and seizure and death Contraindications: IHD, epilepsy, hypertension, pregnancy, hepatic and renal impairment (Rizatriptan, zolmitriptan, naratriptan, almotriptan)
- 41. Prophylaxis of MigraineProphylaxis of Migraine Necessary when attacks are frequent – 2 (two) or more attacks per month Aim is to abolish attack totally Discontinue every 4 - 6 months and observe Beta-adrenergic blockers – Propranolol (40 mg BD), timolol etc. (not metoprolol or atenolol) TCAs: Amitryptylline (25 – 50 mg BD) Calcium channel blockers: Verapamil – not used now (flunnarizine – weak Ca channel blocker is effective) Anticonvulsants: Valproic acid (400 – 1200 mg/day), gabapentin (300 – 1200 mg per day) and newer topiramate (25 mg OD) – effective
- 42. Thank you
Editor's Notes
- #2: Serotonin is a biogenic amine. Examples of amines include – amino acid, biogenic amines and trimethylemine and anniline
- #4: As you all know, serotonin is a biogenic amine that is predominantly located in the gastrointestinal tracts. In fact, it has been estimated that 95% of all the serotonin in the body is in the digestive tract. 90% of this is in the enterochromaffin cells in the mucosa, 10% is in the neurons in different plexuses, which we will discuss later. About 5% of the body serotonin is in the central nervous system. Next slide, please
- #16: Chemoreflex - serotonin can also elicit reflex bradycardia by activation of 5-HT3 receptors on chemoreceptor nerve endings.