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Serotoninergics - drdhriti



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

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. Next slide, please
  • Chemoreflex - serotonin can also elicit reflex bradycardia by activation of 5-HT3 receptors on chemoreceptor nerve endings.

Serotoninergics - drdhriti Serotoninergics - drdhriti Presentation Transcript

  • Serotonin or 5-Hydroxytryptamine Department of Pharmacology NEIGRIHMS, Shillong
  • Contents
    • Biosynthesis, storage and metabolism of Serotonin
    • Serotonergic Receptors and their distribution
    • Actions of Serotonin and Physiological Roles 5-HT receptor antagonists
    • Migraine and its drug therapy
    • Newer drugs used in Migraine
  • What is Serotonin?
    • Serotonin and Enteramine
    • Serotonin or 5-Hydroxytryptamine (5-HT) is a monoamine neurotransmitter, biochemically derived from tryptophan
    • Feelings of well-being
    • Present in GI enterochromaffin cells (90%)
      • 90% in EC cells and 10% in neurones of different plexuses
    • 10% in platelets and brain
    • Stored in granules like catecholamine
    • Also present in plants and insects
    • It is also present in plant like tomato, banana & pineapple lower animals (mollusks, arthropods, snake and bee venom/sting)
  • Physiologic Distribution of Serotonin (5-Hydroxytryptamine (5-HT) 10% CNS
    • 90% GI tract
    • 90% EC s
    • 10% Neurons
    5-Hydroxytryptamine 5 NH 2 OH NH
  • Synthesis, 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
  • N C N C NH 2 COOH COOH NH 2 OH N C NH 2 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 MAO Aldehyde dehydrogenase (Rate limiting) In diet. Active CNS transport Dietary
  • Serotonin Uptake
    • Non-specific Decarboxylase produces 5-HT (also CA)
    • Amine pump (SERT) actively takes up Serotononin (also CA and also present in platelets) – Na+ dependent carrier
    • Stored in storage vesicles by active uptake – Vesicular monoamine transporter (VMAT 2)
      • SLC family
    • 5-HT transporter proteins - outer membrane of platelets
    • Deficiency of tryptophan hydroxylase 5-HT can’t synthesized in platelets – but actively taken up from the serotonin transporter proteins
  • Modulation of Serotonin Uptake
    • 5-HT Precursor – ↑Tryptophan in diet ↑ 5-HT production
    • Inhibit uptake into CNS (other AA’s)
    • Inhibit synthesis: p-chlorophenylalanine (PCPA) - irreversible
    • Inhibit neuronal re-uptake: Cocaine, SSRA (e.g. fluoxetine, Paroxetin), TCA (e.g. Imipramine)
    • Inhibit storage-deplete (VMAT-2): Reserpine
    • Inhibit metabolism: MAO inhibitors (MAO-A)
    • Promote release: p-chloroamphetamine - then depletes (e.g. fenfluramine, dexfenfluramine to ↓ appetite)
  • 5-HT Receptors
    • These receptors are of seven types (5-HT1, 5-HT2 ,….5-HT7)
    • 5-HT1 (A to F subtypes) and 5-HT2 have (A - D) subtypes
        • 5-HT1A 5-HT1B…. 5-HT1F
        • 5-HT2A 5-HT2B…. 5-HT2D
    • All are GPCR except 5-HT3
      • All are cAMP except 5-HT2 (IP3-DAG)
      • 5-HT3 is a ligand gated Na+ channel
    • 5-HT1 inhibits cAMP and 5-HT4, 5-HT5 and 5- HT6 increases cAMP
  • 5-HT1 - Receptors
    • All are autoreceptors and inhibit firing of neurones or release of 5-HT
    • 5-HT1A – Brainstem and hippocampus (antidepressant – Buspirone)
    • 5-HT1D – Basal ganglia and substancia nigra (dopeminergic)
    • 5-HT1B/1D – Cranial Blood Vessels (for constriction – sumatriptan - agonist)
  • 5-HT2
    • 5-HT2: Mainly 4 subtypes (5-HT2A ….... 5-HT2D)
      • Located in all smooth muscles - vascular, visceral
      • Platelets
      • Also in 5-HT2
      • Mediates direct effects of HT
        • Vasoconstriction, intestinal, uterine and bronchial constrictions
    • Ketanserin, Cyproheptadine, Methysergide are specific antagonists
  • 5-HT3
    • Peripheral
      • located exclusively on neurons and mediate neurotransmitter release - parasympathetic, sympathetic, sensory and enteric
          • cardiac inhibition/activation, pain, initiation of the vomiting reflex
    • Central
      • facilitate dopamine and 5–HT release, inhibit ACh and noradrenaline release
          • anxiety, depression, memory, tolerance and dependence
    • Ondansetron in specific antagonist
  • 5-HT4-7
    • Mucosa, plexuses and smooth muscles of Gut
      • Augmentation of Intestinal secretion and peristalsis
    • In Brain: hippocampaus area
      • Specific role is unknown till now
      • Cizapride – specific agonist of the receptor
  • Actions of 5-HT - CVS
    • Multiple direct and indirect effects:
    • Powerful vasoconstrictor except skeletal muscle and heart vessels 5-HT2 mediated)
    • Overall, large arteries and veins are constricted but in microcirculation arterioles dilate
    • Constriction of veins – escape of fluid
    • Heart: direct ionotropic and chronotropic effects
    • Reflex action (5-HT3 mediated) in chemoreceptor nerve endings: Bradycardia and hypotension due to stimulation of sensory nerve endings in baro-receptors, chemo-receptors and in vagal afferents in coronary circulation (Bezold Jarrisch reflex)
    • 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)
  • Actions of 5-HT - GIT
    • Entero-chromaffin cells in the mucosa main 5-HT in body
    • ↑ GIT motility
      • partly through direct effect on the smooth muscle cells (5-HT2 receptor)
      • partly as a result of indirect excitatory effect on enteric neurons (5-HT3 & 4 receptors)
    • Also stimulates vomiting (5-HT3 receptors on vagal afferents and centrally) on 5-HT receptors
    • 5-HT inhibit gastric acid and pepsin, secretion however increase mucus production thus it has ulcer protective property
    • (Physiologically regulates GI motility and peristalsis)
  • Actions of 5-HT – contd.
    • Respiration:
      • Bronchoconstriction of smooth muscles of Bronchi and reflex stimulation (bronchial afferents) of Respiration and hyperventiltion
      • Boronchoconstriction is of lesser magnitude than histamine
    • Platelets:
      • Responsible physiologically for Haemostasis by promoting platelet aggregation and clot formation, thereby preventing leakage
      • Works in conjunction with collagen and other mediators
      • Exogenous 5-HT also changes shape of platelets in injury and promote aggregation (via 5-HT2A)
  • Actions of 5-HT – Nervous System
    • Neurotransmitter in serotonergic neuron (raphe nuclei, pons & medulla)
    • These neurons mainly regulate appetite, mood, sleep body temperature, thought, pain perception, vomiting & behaviors (normal and abnormal )
    • 5-HT poorly cross blood brain barrier however direct injection in brain produces sleepiness, change in body temperature, vomition & appetite
    • Serotonin stimulates adrenal gland (autonomic ganglia) for release catecholamine but lesser than histamine
    • Also activates afferent nerve endings – tingling, pricking and pain sensations
    • 5-HT is Melatonin precursor in pineal body – biological clock
  • Actions of 5-HT - Others
    • Migraine:
      • Responsible for causation of migraine
      • Both antagonist and agonist of 5-HT re used in migraine treatment
    • Carcinoid tumor:
      • Produces massive 5-HT
      • Increased bowel motility and bronchoconstriction
      • Pellagra – due to diversion of tryptophan for 5-HT synthesis
  • 5-HT antagonists
  • Antagonists of serotonin
    • Ergot derivatives: Ergotamine, ergonovine and methysergide (Carcinoid) etc.
    • Alpha-blockers like phenoxybenzamine
    • Antihistaminics: Cyproheptadine, cinnarizine
    • Phenothiazines like 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)
  • Cyproheptadine
    • 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.
  • Ketanserine
    • Selective 5-HT2 receptor blocker
    • Additional H1, α 1 and dopaminergic blocking action
    • Negligible action on other 5-HT receptors
    • 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 !
  • Ergot Alkaloids and derivatives
    • Ergot alkaloids ---- toxic effects
    • First isolated by Dale & Barger in 1906 from fungus Claviceps purpurea ---- on rye and other grains
    • 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
  • Classification of ergot alkaloids
    • Natural – Derivatives of the tetra-cyclic compounds (lysergic acid)
      • Amine alkaloids – Ergometrine (ergonovine)
      • Amino acid alkaloids - Ergotamine , Ergotoxine
    • Semi-synthetic – Bromocriptine, Methysergide, Dihydro-ergotamine (DHE)
    • Synthetic – (non lysergic acid derivative) Metergotine
  • Ergometrine
    • Amine ergot alkaloid
    • Partial agonist of 5-HT receptor in uterus, placenta and umbilical blood vessels
    • No antagonistic effect of alpha-receptor
    • Moderately potent antagonist of 5-HT2 in intestine
    • Less dopaminergic action in CTZ – no vomiting
    • Uterine myometrium
    • Will be discussed elsewhere !
  • Ergotamine
    • Amino acid alkaloid
    • Partial agonist of alpha 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
      • Potent emetic via CTZ and oxytotic
      • Prolong use – vasoconstriction and damage endothelium
  • Dihydroergotamine (DHE)
    • Hydrogenated ergotamine
    • Less serotonergic action than ergotamine and alpha-adrenergic action
    • Better blocker of alpha adrenergic receptor
    • Less vasoconstrictor and so less intimal damage
    • Lesser oxytotic and emetic
  • Migraine Therapy
  • What 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)
  • Pharmacotherapy 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)
  • Migraine - 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)
  • Migraine - 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
  • Ergotamine
    • 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.
  • DHE
    • 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
  • Selective 5-HT1B/1D agonist Sumatriptan
    • 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
  • 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)
  • Prophylaxis 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
  • Thank you