5-HT Pharmacology - drdhriti


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A PowerPoint Presentation on Serotonergic Drugs suitable for UG MBBS level Medical Students

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  • Serotonin is a biogenic amine. Examples of amines include – amino acid, biogenic amines and trimethylemine and anniline
  • 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.
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  • Chemoreflex - serotonin can also elicit reflex bradycardia by activation of 5-HT3 receptors on
    chemoreceptor nerve endings.
  • 5-HT Pharmacology - drdhriti

    1. 1. Serotonin orSerotonin or 5-Hydroxytryptamine and its5-Hydroxytryptamine and its antagonistsantagonists Dr. D. K. Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong
    2. 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. 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. 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. 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. 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. 7. Refer to - Biosynthesis ofRefer to - Biosynthesis of CatecholaminesCatecholamines Phenylalanine PH Rate limiting Enzyme 5-HT, alpha Methyldopamine α-methyl-p-tyrosine
    8. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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
    20. 20. 5-HT5-HT antagonistsantagonists
    21. 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. 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. 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. 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. 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. 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. 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. 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. 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. 30. Learn …Learn … Actions and Pathophysiological Roles of 5-HT 5-HT antagonists Cyproheptadine Ergots - etgotamine
    31. 31. Thank youThank you
    32. 32. Migraine TherapyMigraine Therapy
    33. 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. 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. 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. 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. 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. 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. 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. 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. 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. 42. Thank you