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Neurohumoral Transmission in central nervous system

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Neurotransmisson in CNS

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Neurohumoral Transmission in central nervous system

  1. 1. NEUROHUMORAL TRANSMISSION IN CENTRAL NERVOUS SYSTEM Prepared by: Sonal Vijay Pande M.PHARM,1ST YEAR Department :Pharmacology SSR College of Pharmacy ,Silvaasa 1
  2. 2. Overview  Brain  Spinal cord  The basic processes of synaptic transmission in the CNS  Process of neurotransmitter action  Action potential  Types of neurotransmitter 2
  3. 3. BRAIN 3
  4. 4. SPINAL CORD 4
  5. 5. The basic processes of synaptic transmission in the CNS 4 processes occur in relation to nerve transmission in CNS: 1)Neurotransmitters – Neurotransmitters are chemical messengers that transmit signals from a neuron to a target cell across a synapse. They are synthesized in presynaptic and are released into synaptic cleft to rapidly stimulate or inhibit postsynaptic neurons fast neurotransmitters operate through ligand-gated ion channels, slow neurotransmitters operate through G-protein-coupled receptors 5
  6. 6. 2)Neuromodulators – are released by neurons and astrocytes to produce slower pre-or postsynaptic responses (eg. Carbon dioxide, locally released adenosine, some purines, peptides, prostaglandins, arachidonic acid metabolites and Nitric oxide) 3)Neuromediators – are second messengers that play crucial role in elicitation of postsynaptic responses produced by neurotransmitters (eg. cAMP, cGMP and inositol phosphate) 4)Neurotropic factors – are mainly released by CNS neurons, astrocytes and microglia and act longer than neuromodulators to regulate the growth and morphology of neurons and control long-term changes in brain (synaptic plasticity, remodeling, phenotype characteristics) mainly by affecting gene transcription by acting through tyrosine kinase-linked receptors (eg. Cytokines, chemokines, growth factors.) 6
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  8. 8. ACTION POTENTIAL THE CHANGE IN ELECTRICAL POTENTIAL ASSOCIATED WITH THE PASSAGE OF AN IMPULSE ALONG THE MEMBRANE OF A MUSCLE CELL OR NERVE CELL. 8
  9. 9. • Resting Potential • Sodium and potassium channels are closed. Na+ rush into the cell; K+ are concentrated inside the cell. Potential difference: -85 mV. • Depolarization • Sodium channels open in response to a stimulus. Na+ rush into the cell according to the dictates of diffusion. Final potential difference +30 mV. • Repolarization • Na+ channels close and K+ channels open. K+ rush out of the cell according to the dictates of diffusion. Potential difference: slightly below -85 mV. • Hyperpolarization is a change in a cell's membrane potential that makes it more negative. It is the opposite of a depolarization. It inhibits action potentials by increasing the stimulus required to move the membrane potential to the action potential threshold. 9 • Resting Conditions Re-established • Na+ and K+ channels are closed. Sodium-potassium exchange pump moves Na+ out and K+ in. Resting potential difference: -85 mV. •
  10. 10. WHEN A NEUROTRANSMITTER BINDS: THE POSTSYNAPTIC POTENTIAL • Voltage change at receptor site – postsynaptic potential (PSP) • Changes the probability of the postsynaptic neuron firing • Positive voltage shift – excitatory PSP (decreases the negativity of the inside of the neuron with respect to the outside) • Negative voltage shift – inhibitory PSP (increases the negativity of the inside of the neuron) 10
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  12. 12. DOPAMINE 12  OVERVIEW  Introduction  Synthesis  Metabolism and reuptake  Dopamine receptors  Dopaminergic pathways  Drug related to dopamine system  Disease and its treatment  Pharmacological effect
  13. 13. DOPAMINE • It is the most important of the biogenic amine neurotransmitters in CNS • Dopamine appears to be an inhibitory neurotransmitter • Dopamine belongs to the family of catecholamines. Hormones, Epinephrine and Norepinephrine (other catecholamines) are derived from Dopamine • Plays an important role in the regulation of motor functions, initiation of behavioural patterns and modulation of visceral functions Dopamine is particularly important in relation to neuropharmacology (Parkinson's disease, schizophrenia – hyperdopaminergic state, attention deficit disorder, substance abuse, endocrine disorders, fatigue, concentration difficulty, low motivation (anhedonia)) • several classes of drugs, notably the antipsychotics, interfere with dopaminergic transmission 13
  14. 14. DOPAMINE SYNTEHESIS • The first step in the catecholamine synthesis is the hydroxylation of the tyrosine and the formation of L-DOPA. This reaction is catalysed by tyrosine hydroxylase. L-DOPA is converted into dopamine by the enzyme DOPA decarboxylase. • • Dopaminergic neurons lack dopamine β- hydroxylase, and thus do not produce noradrenaline. 14
  15. 15. DOPAMINE METABOLISM AND REUPTAKE 15
  16. 16. 16 Dopamine is broken down into inactive metabolites by: monoamine oxidase (MAO-A and MAO-B), catechol-O-methyl transferase (COMT) and aldehyde dehydrogenase (ALDH) acting in sequence -different breakdown pathways exist The main product is homovanillic acid (HVA- excreted in the urine) -the two primary metabolic routes that convert dopamine into HVA are: Dopamine → DOPAL → DOPAC (4-hydroxyphenylacetic acid) → HVA – catalyzed by MAO, ALDH, and COMT respectively Dopamine → 3-Methoxytyramine → HVA – catalyzed by COMT and MAO+ALDH respectively After the postsynaptic effects dopamine can be absorbed back into the presynaptic cell, via reuptake mediated either by the dopamine transporter or by the plasma membrane monoamine transporter - dopamine can either be broken down by a monoamine oxidase or repackaged into vesicles by vesicular monoamine transporter and released again
  17. 17. DOPAMINE METABOLISM 17
  18. 18. MAO Synaptic vesicular monoamine transporter expression: Exists as two isoenzymes, A and B, with an apparent molecular mass of 60–63 kDa each. The two MAO genes,each comprised of 15 exons, are located on the X-chromosome and appear to have been derived from the same ancestral gene. They differ in substrate specificity as well as selectivity for inhibitors. MAO-A is more highly expressed in catecholaminergic neurons, whereas MAO-B is more abundant in serotonergic and histaminergic neurons and in glial cells. Deamination of dopamine by MAO produces dihydroxyphenylacetic acid (DOPAC). Determination of the ratio of DOPAC/dopamine concentrations serves as a good method for estimating rapid changes in neuronal activity. COMT O-Methylation by COMT is primarily responsible for inactivation of circulating catecholamines. Consecutive conversion of dopamine by MAO and COMT yields homovanillic acid. The enzyme introduces a methyl group to the catecholamine, which is donated by S-adenosyl methionine (SAM). COMT is an intracellular enzyme located in the postsynaptic neuron. Any compound having a catechol structure, like catecholestrogens and catechol- containing flavonoids, are substrates of COMT. 18
  19. 19. DOPAMINE RECEPTORS Metabotropic G-protein coupled receptors • D1 – like family: – Includes subtypes D1 and D5 – Activation is coupled to Gs ; activates adenylyl cylcase which leads to increase in concentration of cAMP • D2 – like family: – Includes D2 , D3 and D4 – Activation is coupled to Gi ; inhibits adenylyl cyclase leading to decrease in concentration of Camp – Also open K channels & closes Ca influx 19
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  22. 22. 22
  23. 23. DOPAMINE PATHWAYS & FUNCTION • 1. Mesostriatal (or nigrostriatal) pathway: 75% of the dopamine in brain,consist of cell bodies in the substantia nigra whose axon terminate in the corpus straitum,this fibers run in the medial forebrain bundle along with oth monoamine containing fibres ;this is the pathway that degenerates in Parkinson disease. Involve coordination of movment • . 2. Tuberohypophyseal system: is a group of short neurons running from the ventral hypothalamus to the median eminence and pituitary gland (red arrows). Regulate secretions of prolactin pituitary gland and involved maternal behavior • , 23
  24. 24. 24 3. Mesolimbic pathway: The third pathway projects from the ventral tegmentum to the mesolimbic forebrainespecially the nucleus accumbens and the amygdaloid nucleus. Associated with pleasure ,reward and goal directed behavior. 4. Mesocortical pathway: whose cell bodies also lie in the VTA and which project via the medial forebrain bundle to the frontal cortex (solid blue arrows).involve motivational and emotional responses.
  25. 25. 25
  26. 26. DRUGS MODIFYING DOPAMINERGIC TRANSMISSON 26
  27. 27. 27
  28. 28. DOPAMINE RELATED DISEASES • Parkinson's Disease -When striatum dopamine is depleted to 20% of the original level, symptoms of Parkinson's Disease appear. • Treatment: Levodopa, Dopamine Receptor Agonists, Monoamine Oxidase Inhibitors (MAOIs) Catechol- O- Methyltransferase (COMT) inhibitors, Amantidine • Schizophrenia-Schizophrenia is thought to be due to an overstimulation of D2 receptors • chlorpromazine: D2 antagonist, alleviate the symptoms, • amphetamine: increases D2 stimulation, can induce psychotic symptoms resembling schizophrenia • Vomiting Dopaminergic neurons can cause nausea and vomiting: all dopamine receptor agonists (e.g. bromocriptine ) and drugs that increase dopamine release (e.g. levodopa) cause nausea and vomiting as side effects • Dopamine antagonists (e.g. phenothiazines , metoclopramide) have antiemetic activity (D2 receptors occur in the area of the medulla (chemoreceptor trigger zone) associated with 28
  29. 29. 29 • Other motor disorders:  Huntington’s disease Huntington disease is a progressive brain disorder that causes uncontrolled movements, emotional problems, and loss of thinking ability (cognition). the most common form of this disorder, usually appears in a person's thirties or forties Targeting both DA and glutamate receptor dysfunction could be the best strategy to treat HD symptoms.  Tourette's syndrome Tourette syndrome (TS) and obsessive-compulsive disorder (OCD) both are neuropsychiatric disorders associated with abnormalities in dopamineneurotransmission Treatment Self-care Relaxation techniques Therapies Cognitive behavioral therapy and Exposure and response prevention Medications Antipsychotic Specialists Child and Adolescent Psychiatrist, Neurologist, Psychiatrist, and Paediatrician
  30. 30. PARKINSON’S DISEASE 30  Substantial loss of Dopamine in the striatum (70 – 80%)  Loss of dopamine neurons in other systems also (mesolimbic, mesocortical and hypothalamic system)  Treatment strategy Increasing dopamine levels nerve grafting with dopamine containing cells and deep brain stimulation
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  34. 34. 34 SCHIZOPHRENIA  Defective dopamine neurotransmission relative excess of central dopaminergic activity  An increase in DA function in the mesolimbic system and a decreased function in the mesocortical DA systems(D1 predominates)  Behaviour similar to the behavioral effects of psychostimulants
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  37. 37. PHARMACOLOGICAL EFFECT 37
  38. 38. 38  ROLE OF DOPAMINE PROLACTIN SECRETION  Inhibits secretion of prolactin by acting on D2 receptors.  Treatment of hyperprolactinemia Ergot derivatives : bromocriptine, cabergoline, pergolide. Non ergot : QuinagolideCabergoline – 0.25(max 1) mg orally twice a week Quinagolide – 0.2 -0.6 mg orally per day longer t1/2 , better toleratted than ergot derivative Bromocriptine 2.5 mg OD/BD upto 15 days
  39. 39. 39  ROLE OF DOPAMINE IN RENAL SYSTEM  At low dose (0.5 to 3 micg /kg /min ):- Selectively activates dopamine specific receptors in the renal and splanchnic circulation.  Increase blood flow in these region.  Increase GFR.  Increase in urinary Na excretion  HEART AND VASCULATURE  At low concentrations, circulating DA primarily stimulates vascular D1 receptors, causing vasodilation and reducing cardiac afterload.  DA is able to activate adrenergic receptors to further increase cardiac contractility.  The net result is a decrease in blood pressure and an increase in cardiac contractili
  40. 40. 40 Goodman and Gilman’s The Pharmacological Basis of Therapeutics 12th edi; chap 15,16,22: 932-964 Bertram Katzung ; Basic and clinical pharmacology ; Drug ofabuse ;553-568 ;12th edition 2012. HL Sharma and KK;Antipsychotics ;2ndedition;chap 33; 532-542. Rang H.P.and Dale M.M;Antipsychotics;7th edition; 39,45,49; 557
  41. 41.  OVERVIEW DISTRIBUTION HISTAMINE PATHWAY SYNTHESIS STORAGEAND RELEASE HISTAMINE RECEPTOR MECHANISM OF ACTION PHARMACOLOGICAL EFFECTS USES H1 & H2 ANTAGONIST 41 Histamine
  42. 42. HISTAMINE • Histamine is hydrophilic molecule consisting of an imidazole ring 42 • Histamine is involved in inflammatory and anaphylactic reactions • Sinus problems, hay fever, bronchial asthma, hives, eczema, contact dermatitis, food allergies and reactions to drugs are all allergic reactions associated with the release of histamine and other autocoids, such as serotonin, leukotrienes, and prostaglandins.
  43. 43. DISTRIBUTION 43 • Almost all mammalian tissues contain histamine • Widely distributed in skin, GIT mucosa, lungs, brain, CSF and bone marrow. • It is also a component of some venoms, sting secretion, bacteria and plants . • The mast cell is the predominant storage site for histamine in most tissues • The concentration of histamine is particularly high in tissues that contain large numbers of mast cells, such as skin, bronchial tree mucosa, and intestinal mucosa.
  44. 44. HISTAMINE PATHWAY IN BRAIN 44 All of the neurons that are synthesizing histamine are present in a part of the brain called the tuberomammillarynucleus; that is actually a part of the hypothalamus. There are only about 64,000 of these neurons in the brain. These neurons innervate the cortex, the pituitary, the thalamic nuclei, the amygdala, hippocampus, spinal cord, and the cerebellum. Histamine activates neurons by stimulating specific receptors that have been molecularly cloned. What that means is that molecular biologists have identified the DNA sequence that codes for the proteins.
  45. 45. SYNTHESIS STORAGE AND RELEASE 45
  46. 46. SYNTHESIS STORAGE AND RELEASE 46 • Formed by the decarboxylation of the amino acid histidine by the enzyme L-histidine decarboxylase • The chief site of histamine storage in most tissues is the mast cell; in the blood, it is the basophil. • Metabolised to N-methylhistamine by histamine- Nmethyltransferase and Imidazoleacetic acid by the nonspecific enzyme diamine oxidase (DAO) • These metabolites have little or no activity and are excreted in the urine.
  47. 47. 4 7 Mechanism of antigen-antibody reaction induced release of histamine from mast cell In sensitized atopic individual, specific reaginic (IgE) antibody is produced and gets bound to Fc epsilon receptor I (FcεRI) on the surface of mast cells. On challenge, the antigen bridges IgE molecules resulting in transmembrane activation of a tyrosine- protein kinase (t-Pr-K) which phosphorylates and activates phospholipaseCγ. Phosphatidyl inositol bisphosphate (PIP2) is hydrolysed and inositol trisphosphate (IP3) is generated which triggers intracellular release of Ca2+. The Ca2+ ions induce fusion of granule membrane with plasma membrane of the mast cell resulting in exocytotic release of granule contents. In the granule, positively charged histamine (Hist+) is held complexed with negatively charged protein (Prot–) and heparin (Hep–) molecules. Cationic exchange with extracellular Na+ (and Ca2+) sets histamine free to act on the target cells. Histamine release
  48. 48. HISTAMINE RELEASE 1 IMMUNOLOGICAL RELEASE • Histamine is released from mast cells by exocytosis during inflammatory or allergic reaction • Cell fixed IgE antibodies interact with antigen • Mast cells if sensitized by surface IgE antibodies,degranulate and rapidly relese many active compounds including histamine when exposed to specific anitgen • THE IMMEDIATE ALLERGIC REATION TYPE 1 48
  49. 49. 2 NON IMMNUNE MECHANISM :MECHANICAL OR CHEMICAL RELEASE ANY PHYSICAL OR CHEMICAL AGENT THAT INJURIES TISSUE SKIN ,MUCOSA ARE SENSITIVE TO INJURY AND WIL CAUSE IMMEDIATE RELEASE OF HISTAMINE FROM MAST CELLS . 3 DRUGS OR OTHER FORGEIN COMPUNDS: POLYMERS LIKE DEXTRAN, POLYVINYL PYRROLIDONE (PVP). SOME BASIC DRUGS—TUBOCURARINE, MORPHINE, ATROPINE, PENTAMIDINE, POLYMYXIN B, VANCOMYCIN AND EVEN SOME ANTIHISTAMINICS DIRECTLY RELEASE HISTAMINE WITHOUT AN IMMUNOLOGICAL REACTION. SURFACE ACTING AGENTS LIKE TWEEN 80, COMPOUND 48/80 ETC. THE PRIMARY ACTION OF THESE SUBSTANCES IS RELEASE OF HISTAMINE FROM MAST CELLS, THEREFORE THEY ARE CALLED ‘HISTAMINE LIBERATORS’ 49
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  52. 52. RELEASE AND FUNCTION IT IS RELEASED FROM STORAGE GRANULES AS A RESULT OF THE INTERACTION OF ANTIGEN WITH IMMUNOGLOBULIN E ANTIBODIES ON THE MAST CELL SURFACE • HISTAMINE PLAYS A CENTRAL ROLE IN IMMEDIATE HYPERSENSITIVITY AND ALLERGIC RESPONSES. • THE ACTIONS OF HISTAMINE ON BRONCHIAL SMOOTH AND BLOOD VESSELS ACCOUNT FOR MANY OF THE SYMPTOMS OF THE ALLERGIC RESPONSE . • IN ADDITION, CERTAIN CLINICALLY USEFUL DRUGS CAN ACT DIRECTLY ON MAST CELLS TO RELEASE HISTAMINE, THEREBY EXPLAINING SOME OF THEIR UNTOWARD EFFECTS. • HISTAMINE HAS A MA JOR ROLE IN THE REGULATION OF GASTRIC ACID SECRETION AND ALSO MODULATES NEUROTRANSMITTER RELEASE 52
  53. 53. HISTAMINE RECEPTOR Histamine acts on three types of receptor,all of which are Gprotein coupled receptor and occur in most brain regions. H1 receptor are mainly located at the postsynaptically and cause excitation H2 and H3 receptors are inhibitory ,respectivly post and presyanptic H3 receptor being inhibitory “AUTORECEPTOR”on histamine relesing neurons. 53
  54. 54. HISTAMINE RECEPTOR 54
  55. 55. MECHANISM OF ACTION 55
  56. 56. MECHANISM OF ACTION HISTAMINE MEDITATES ITS EFFECT BY INTERACTING WITH PROTEIN COUPLED HISTAMINE RECEPTORS H1,H2,H3 AND H4 TYPES 56 Inositol triphosphate and diacylglycerol Enzyme :phoospholipase C and protein kinase C CAMP ENZYME :adenylate cyclase C and protein kinase A
  57. 57. PATHOPHYSIOLOGICAL ROLES 57 Histamine has dominant physiological role in mediating secretion of HCl in the stomach Nonmast cell histamine occurs in gastric mucosa, possibly in cells called ‘histaminocytes’ situated close to the parietal cells. This histamine has high turnover rate. It is released locally under the influence of all stimuli that evoke gastric secretion (feeding, vagal stimulation, cholinergic drugs and gastrin) and activates the proton pump (H+K+ ATPase) through H2 receptors. H2 blockers not only suppress acid secretion induced by histamine but also markedly diminish that in response to ACh and gastrin Gastric secretion
  58. 58. 58 Allergic phenomena Mediation of hypersensitivity reactions was the first role ascribed to histamine. It is an important, but only one of the mediators of such phenomena. Released from mast cells following AG : AB reaction on their surface (involving IgE type of reaginic antibodies;) in immediate type of hypersensitivity reactions, histamine is causative in urticaria, angioedema, bronchoconstriction and anaphylactic shock.
  59. 59. 59 As transmitter Histamine is believed to be the afferent transmitter which initiates the sensation of itch and pain at sensory nerve endings. Nonmast cell histamine occurs in brain, especially hypothalamus and midbrain. It is involved in maintaining wakefulness; H1 antihistaminics owe their sedative action to blockade of this function. In the brain H1 agonism suppresses appetite Histamine also appears to participate as a transmitter regulating body temperature, cardiovascular function, thirst,
  60. 60. 6 0 Inflammation Histamine is a mediator of vasodilatation and other changes that occur during inflammation. Tissue growth and repair Because growing and regenerating tissues contain high concentrations of histamine, it has been suggested to play an essential role in the process of growth and repair.
  61. 61. PHARMACOLOGICAL EFFECT 61 Histamine receptors are GPCRs • H1 receptors: mediate effects on smooth muscle leading to vasodilatation, increased vascular permeability, and contraction of nonvascular smooth muscle. • H2 receptors: mediate histamine stimulation of gastric acid secretion and may be involved in cardiac stimulation. • H3 receptors: feedback inhibitors in CNS, gastrointestinal tract, lung, heart.
  62. 62. 62 Bloodvessels : Histamine causes marked dilatation of smaller blood vessels, including arterioles, capillaries and venules. On s.c. injection Larger arteries and veins are constricted by histamine: mediated by H1 receptor on vascular smooth muscle. Histamine also causes increased capillary permeability due to separation of endothelial cells → exudation of plasma. This is primarily a H1 response. Injected intradermally, it elicits the triple response consisting of: Red spot: due to intense capillary dilatation. Wheal: due to exudation of fluid from capillaries and venules. Flare: i.e. redness in the surrounding area due to arteriolar dilatation mediated by axon reflex.
  63. 63. 63 Heart Direct effects of histamine on in situ heart are not prominent, but the isolated heart, especially of guinea pig, is stimulated—rate as well as force of contraction is increased. These are primarily H2 responses but a H1 mediated negative dromotropic (slowing of A-V conduction) effect has also been demonstrated. Glands: Histamine causes marked increase in gastric secretion—primarily of acid but also of pepsin .This is a direct action exerted on parietal cells through H2 receptors and is mediated by increased cAMP generation, which in turn activates the membrane proton pump (H+ K+ ATPase). Histamine can increase other secretions also, but the effect is hardly discernable
  64. 64. 64 . Sensory nerve endings occurs when histamine is injected i.v. or intracutaneously. Higher concentrations injected more deeply cause pain. These are reflections of the capacity of histamine to stimulate nerve endings. CNS Histamine does not penetrate bloodbrain barrier—no central effects are seen on i.v. injection. However, intracerebroventricular administration produces rise in BP, cardiac stimulation, behavioural arousal, hypothermia, vomiting and ADH release. These effects are mediated through both H1 and H2 receptors.
  65. 65. 65 1.Cardiovascular system. a. Triple effect on terminal vasculature (itching & pain): – reddening at injection site due to vasodilation – wheal or disk of edema within 1 to 2 min – a large, bright crimson flare or halo surrounding the wheal b. IV Histamine: fall in blood pressure, cutaneous flushing, over the face and upper trunk, rise in skin temperature, intense headache. 2. Smooth muscle of bronchioles; contraction of nonvascular smooth muscle. 3. Exocrine glands: potent stimulation of gastric secretion (HCl & pepsin), salivary and lacrimal gland secretion, catecholamines secretion. 4. Peripheral Nervous system: itching and pain
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  67. 67. Histamine clinical use Practical applications of histamine are limited to uses as a diagnostic agent. Histamine (histamine phosphate) is used to assess nonspecific bronchial hyperreactivity in asthmatics and as a positive control injection during allergy skin testing USES 67 •
  68. 68. DISEASE HISTAMINE INTOLERANCE • When histamine level is too high ,histamine intolerance occures • Symptoms:headache,high BP,anxiety,dizzeness,irregular heart rate • Why it occurs? • Enzyme diamine oxidase is responsible for the breakdown of histmaine. • If there is a deficency of diamine oxidase this intolerance occures 68
  69. 69. H1 ANTAGONIST 69 H1-antihistamines are clinically used in the treatment of histamine-mediated allergic conditions. These indications may include •Allergic rhinitis •Allergic conjunctivitis •Allergic dermatological conditions (contact dermatitis) •Rhinorrhea (Runny nose) •Urticaria •Angioedema •Diarrhea •Pruritus (atopic dermatitis, insect bites) •Anaphylactic or anaphylactoid reactions—adjunct only •Nausea and vomiting •Sedation (first-generation H1-antihistamine Other common adverse effects in first-generation H1-antihistamines include dizziness, tinnitus, blurred vision, euphoria, uncoordination, anxiety, increased appetite leading to weight gain, insomnia, tremor, nausea and vomiting, constipation, diarrhea, dry mouth, and dry cough. Infrequent adverse effects include urinary retention, palpitations, hypotension, headache, hallucination, and psychosis.[4]
  70. 70. • Second generation advantages • No anticolinergic side effect • Minimum sedation as donot cross BBB 70
  71. 71. PHARMACOKINETIC 71 • Absorption: Antihistaminics (H1 receptor antagonists) are well absorbed from oral and parenteral routes • Distribution: widely in the body and enter brain. Newer compounds penetrate the brain poorly. • Metabolism: In liver • Excretion: In urine
  72. 72. •Famotidine (Pepcid AC, Pepcid Oral) •Cimetidine (Tagamet, Tagamet HB) •Ranitidine (Zantac, Zantac 75, Zantac Efferdose, Zantac injection, and Zantac Syrup) •Nizatidine Capsules (Axid AR, Axid Capsules, Nizatidine Capsules) H2 BLOCKERS• H2 blocker is use in peptic ulcer ,gastroeshophagal reflux disease ,dyspepsiea 72 Side Effects Side effects from H2 blockers are rare. •Famotidine. The most common side effect is headache. •Cimetidine. Side effects are rare. But diarrhea, dizziness, rashes, headaches, and gynecomastia may occur. •Ranitidine. The most common side effect is headache. •Nizatidine. Side effects are rare.
  73. 73. 73 Serotonin • Synthesis,storage and release • Serotonin pathway • Pharmacological effect • 5-hydroxytryptamine receptors • 5-hydroxytryptamine receptor agonists • 5-hydroxytryptamine receptor antagonists
  74. 74. SEROTONIN 74 In humans 10% of serotonin (5-hydroxytryptamine, or 5HT) occurs primarily in the platelets and brain. • Serotonin was the name given to the vasoconstrictor substance which appeared in the serum when blood clotted and Enteramine to the smooth muscle contracting substance present in enterochromaffin cells of gut mucosa • .
  75. 75. SEROTONIN PATHWAY 75
  76. 76. SEROTONIN SYNTHESIS STORAGE AND RELEASE 76 • Tryptophan is initially hydroxylated to form 5-hydroxytryptophan, decarboxylation of the latter compound results in the formation of serotonin • Serotonin is initially oxidatively deaminated to form 5- hydroxyindoleacetaldehyde, and rapidly oxidized to the major metabolite 5- hydroxyindoleacetic acid and excreted in the urine
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  78. 78. 78 Serotoninpathways-the most of the serotonin in the brain is in the brainstem,specifically in the raphe nuclei These neurons control muscle activity considerable amounts are present in areas of the hypothalamus, the limbic system Regulate memory and mood in frontal cortex - regulate cognition and memory and the pituitary gland
  79. 79. 5HT RECEPTORS 79 5HT1 • 5HT2 5HT3 • 5HT4 5HT5 • 5HT6 5HT7
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  81. 81. 81 Seven families of 5-HT receptors (5-HT1 , 5-HT2 , 5-HT3 , 5-HT4, 5-HT5 , 5-HT6 , 5-HT7 ) All 5-HT receptors are G protein coupled receptors, except 5- HT3 which is a Ligand gated ion channel, its activation elicits fast depolarization. Function through: 5-HT1 : decreasing cAMP production 5-HT2 : produce IP3/DAG 5-HT4,7 : increasing cAMP production
  82. 82. 82 5-HT1 receptors Occur mainly in the brain The 5-HT1A subtype is particularly important in the brain, in relation to mood and behaviour. The 5-HT1D subtype, which is expressed in cerebral blood vessels, is important in migraine and is the target for Sumatriptan 5-HT2 receptors Particularly important in the periphery Stimulate IP3 /DAG formation The 5-HT2A subtype is functionally the most important, mediates smooth muscle contraction and platelet aggregation 5-HT3 receptors Occur mainly in the PNS, particularly on nociceptive sensory neurons and autonomic and enteric neurons, 5-HT3 receptors also occur in the brain, particularly in the area postrema, a region of the medulla involved in the vomiting reflex
  83. 83. 83 5-HT4 receptors Occur in the brain, as well as in peripheral organs such as the GIT, bladder and heart. Their main physiological role appears to be in the GIT where they produce neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis 5HT5 receptor Two genes have been identified that give rise to 5-ht5a and 5- ht5b proteins with structures consistent with GPCRs although in humans the 5-ht5b gene is a pseudogene since a stop codon has evolved that would, if expressed, result in a truncated protein devoid of key functional moieties of the receptor. The predicted protein sequences display less than 38% amino acid sequence identity to other 5-HT GPCRs, thus clearly distinguishing the 5-ht5a protein from other 5-HT receptors.
  84. 84. 5HT6 RECEPTOR The 5-HT6 receptor is a GPCR that couples via Gs to increase cAMP producti although additional transduction pathways have been proposed. The recepto structurally differentiated from the other 5-HT receptors with less than 34% acid sequence identity. 84 5HT7 RECEPTOR The 5-HT7 receptor is a GPCR that couples via Gs to increase cAMP production with some other transduction pathways also implicated in receptor function (e.g. ERK, Galpha12/RhoA/Cdc42). The structure displays less than 39% amino acid sequence identity to other 5-HT receptors. Several splice variants have been described.
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  86. 86. SEROTONIN SYNDROME • Serotonin syndrome occurs when you take medications that cause high levels of the chemical serotonin to accumulate in your body. Signs and symptoms include: • Agitation or restlessness,Confusion,Rapid heart rate and high blood pressure,Dilated pupils,Loss of muscle coordination ,Muscle rigidity,Heavy sweating,Diarrhea,Headache,Shivering,Goose bumps 86
  87. 87. DRUGS 87 These drugs and supplements include: Selective serotonin reuptake inhibitors (SSRIs), antidepressants such as citalopram (Celexa), fluoxetine (Prozac, Sarafem), fluvoxamine, paroxetine (Paxil) and sertraline (Zoloft) Serotonin and norepinephrine reuptake inhibitors (SNRIs), antidepressants such as trazodone, duloxetine (Cymbalta) and venlafaxine (Effexor) Bupropion (Wellbutrin, Zyban), an antidepressant and tobacco- addiction medication Tricyclic antidepressants, such as amitriptyline and nortriptyline (Pamelor) Monoamine oxidase inhibitors (MAOIs), antidepressants such as isocarboxazid (Marplan) and phenelzine (Nardil) Anti-migraine medications such as triptans (Axert, Amerge, Imitrex), carbamazepine (Tegretol) and valproic acid (Depakene)
  88. 88. 88 Pain medications such as opioid pain medications including codeine (Tylenol with codeine), fentanyl (Duragesic), hydrocodone meperidine (Demerol), oxycodone (Oxycontin, Percocet, Percodan) and tramadol (Ultram). Lithium (Lithobid), a mood stabilizer Illicit drugs, including LSD, Ecstasy, cocaine and amphetamines Herbal supplements, including St. John's wort, ginseng and nutmeg Over-the-counter cough and cold medications containing dextromethorphan (Delsym, Mucinex DM, others) Anti-nausea medications such as granisetron, metoclopramide (Reglan), droperidol (Inapsine) and ondansetron (Zofran) Linezolid (Zyvox), an antibiotic Ritonavir (Norvir), an anti-retroviral medication used to treat HIV/AIDS
  89. 89. OBSESSIVE COMPLUSIVE DISORDER • It is an anxiety disorder chareterised by unresonable thoughts and fear. • Level of serotonin is reduced. • Drugs: • Anxiolytics • Antidepressents • SSRI 89
  90. 90. DEPRESSION • Depression is the most common of all affective disoreders(disoreder of mood,disturbuance of thoughts)ranges from mild to severe. • Depression is cause by deficit of monoamine transmitter in certain areas in brain. 90
  91. 91. 91
  92. 92. 5 HT AGONIST 92 Selective 5-HT1A agonists : 8-hydroxy-2-(di-npropylamino) tetralin (8-OH DPAT) highly selective agonist but not used clinically Buspirone, Gepirone, Ipasapirone : potent 5- HT1A agonists used in treating anxiety. Given orally at a dosage of 15 mg/day the drug is rapidly absorbed half- life of about 2.5 hours The mean peak plasma concentration (Cmax) is approximately 2.5 μg/L, and the time to reach the peak is under 1 hour, however it takes days or weeks to produce its effect. The absolute bioavailability of buspirone is approximately 4%. Side effects: Mainly nausea, dizziness, headache, restlessness but no sedation or loss of coordination
  93. 93. 93 5-HT1D receptor Sumatriptan, used for treating migraine Pharmacokinetics: Administered subcutaneously, orally, and intranasally. Orally, single dose of 25, 50, or 100 mg, if patient has a partial response to the initial dose, a single additional dose may be taken after 2 h up to a max of 200 mg/day Subcutaneous 6 mg initially. May repeat once after 1 h (max, 6 mg 5-HT4 receptor agonists Metoclopramide which stimulate coordinated peristaltic activity (prokinetic action), are used for treating gastrointestinal disorders, increase motility Pharmacokinetics: Given orally at a dose of 5-10 mg, is rapidly and well absorbed, bioavailability is 80% ± 15.5%, plasma half life or 4-5 h and peak plasma
  94. 94. 94 Side effects : Fatigue, motor restlessness, spasmodic torticollis, occulogyric crisis, also can cause galactorrhoea and disorders of menstruation. Contraindications : Metoclopramide should not be used whenever stimulation of gastrointestinal motility might be dangerous, e.g., in the presence of gastrointestinal hemorrhage, mechanical obstruction, or perforation
  95. 95. 5HT ANTAGONIST 5-HT2 RECEPTOR ANTAGONISTS : CYPROHEPTADINE: PRIMARILY BLOCKS 5-HT2A RECEPTOR, USED IN CONTROLLING THE SYMPTOMS OF CARCINOID TUMORS. METHYSERGIDE & DIHYDROERGOTAMINE: USED MAINLY FOR MIGRAINE PROPHYLAXIS. KETANSERIN: 5HT2 (BLOCKADE OF 5HT2A IS STRONGER THAN OF 5HT2C) AND Α1 ANTAGONIST, USED AS ANTIHYPERTENSIVE. CLOZAPINE: PARTIAL ANTAGONIST AT 5-HT2A/2C RECEPTOR, RISPERIDONE: IS A COMBINED 5-HT2A + DOPAMINE D2 ANTAGONIST 95
  96. 96. 96 Side effects : Clozapine is usually used only in patients that have not responded to other anti-psychotic treatments due to its danger of causing agranulocytosis. Common side effects include extreme constipation, nighttime drooling, muscle stiffness, sedation, tremors, hyperglycemia, and weight gain . The risk of developing extrapyramidal symptoms such as tardive dyskinesia is below that of typical antipsychotics
  97. 97. 97 HT3 receptor antagonists : Ondansetron, Granisetron, Tropisetron: These agents have an important place in treating emesis linked with chemotherapy. Long duration of action. Can be administered as a single dose prior to chemotherapy. Are extensively metabolized in the liver. Elimination is through the urine. Common side effect is headache. 5-HT mixed agonist and antagonist : Lysergic acid diethylamide (LSD) Is a potent hallucinogen, activates 5-HT1A, 5-HT2A/2C, 5-HT5-7, also antagonizes 5-HT2A receptors in the ileum.
  98. 98. 98 • Other related drugs : SSRI : specifically inhibit serotonin reuptake, have 300-3000 fold selectivity, drug of choice in treating depression. Example : Fluoxetine, citalopram, fluvoxamine, paroxetine, sertraline, Indication : Depression, obsessive compulsive disorder, panic disorder, generalized anxiety and bulimia nervosa. Pharmacokinetics : All the SSRIs are well absorbed after oral administration. All have large volume of distribution. Plasma half lives range between 16-36 h but Fluoxetine have a half life of 50 h. Fluoxetine and paroxetine are inhibitors of enzyme CYP2D6. Excretion is primarily through the kidneys, except Paroxetine and Sertraline undergo 35% fecal excretion, 50% renal excretion. Dosage should be adjusted downward in hepatic impairment
  99. 99. 99 Adverse effects : Nausea, vomiting, diarrhea, Headache, restlessness, fatigue, sleep disturbances. Should be used cautiously in children and teenagers, 1 out of 50 children become suicidal as a result of SSRI treatment,
  100. 100. THANK YOU 10 0

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