Pharmacology of dopaminergic, serotonergic and histaminergic systems Charles University in Prague, Third Faculty of Medicine GENERAL MEDICINE 6-YEAR MASTER‘S STUDY PROGRAMME Subject: General Pharmacology Pharmacology of dopaminergic, serotonergic and histaminergic systems Prof. M. Kršiak Department of Pharmacology, Third Faculty of Medicine Ruská 87, Prague 10, Academic year 2013-2014 http://vyuka.lf3.cuni.cz CVSE3P0012 ID9225

They are the monoamine neuromediators Serotonine (5-hydrytryptamine) Dopamine Histamine They are the monoamine neuromediators

Drugs acting via dopaminergic, serotonergic, histaminergic systems They act mostly by inhibition or stimulation of dopaminergic, serotonergic, histaminergic receptors. These receptors are mostly coupled with G-proteins („metabotropic“ receptors). Some drugs act by interfering with synthesis or elimination of dopamine or serotonine.

G-PROTEIN-COUPLED RECEPTORS („metabotropic receptors“) R.J. Lefkowitz & B.K. Kobilka 2012 Nobel prize G-PROTEIN-COUPLED RECEPTORS („metabotropic receptors“) - sites for action of about 45% of drugs - for slow synaptic transmission (seconds - minutes) examples: beta-adrenergic receptors, muscarinic receptors - „coupling“: RECEPTOR - serpentine receptors: a polypeptide chain traverses the membrane seven times G PROTEIN EFFECTOR

G-PROTEIN-COUPLED RECEPTORS („metabotropic receptors“) Katzung Fig 2-14 serpentine receptors: a polypeptide chain traverses the membrane seven times, the sites for binding ligands, G-protein Katzung BG, 2009, Fig 2-11

G-PROTEIN-COUPLED RECEPTORS („metabotropic receptors“) M. Rodbell & AG Gilman 1994 Nobel prize RECEPTOR G PROTEIN - trimer, alpha, beta, gamma subunits alpha subunit: GTPase aktivity: GDPGTP, stimulation (Gs) , inhibition (GI) of the effector ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). EFFECTOR

G-PROTEIN-COUPLED RECEPTORS („metabotropic receptors“) E.W. Sutherland Nobel Prize 1971 G-PROTEIN adenylyl cyclase  cAMP Proteinkinases 2nd messengers ENZYM EFFECTOR fosfolipase C IP3, DAG ION CHANNEL Ca++ release Activation/inhibition of cellular functions eg. contractile proteins, enzymes, transporters, ion channels, secretion …

DOPAMINERGIC SYSTEM Dopamine receptors D1-5 (type D1,5, type D2,3,4 ) Clinical potency of antipsychotics correlates with their affinity for D2 receptors Dopamine receptors D1-5 (type D1,5, type D2,3,4 ) They differ in localization (occur mostly in the CNS, post- or pre-synaptically), they differ in mechanisms of transduction (some are coupled with Gs, some with Gi, some act via adenylyl cyclase, some via phospholipase C, or via ion channels – K, Ca) Synthesis of dopamine: tyrosine → L-DOPA →dopamine → noradrenalin →adrenaline Decarboxylase: L-DOPA→dopamine Decarboxylase inhibitors in combination with levodopa → antiparkinsonics Inhibitors of DA, NA, 5-HT reuptake → antidepressants Elimination of dopamine: extracellulary(in the synaptic cleft): transport protein (reuptakes DA from synapt.cleft to the presynaptic nerve ending) COMT catechol-O-methyl transferase intracellulary: MAO monoamino oxidase COMT inhibitors→ antiparkinsonics Inhibitors of MAO (IMAO) → antidepressants

MAJOR DOPAMINERGIC PATHWAYS/SYSTEMS IN CNS Ac, nucleus accumbens; Am, amygdaloid nucleus; C, cerebellum; Hip, hippocampus; Hyp, hypothalamus; LC, locus coeruleus; P, pituitary gland; SN, substantia nigra; Sep, septum; Str, corpus striatum; VTA, ventral tegmental area; Reward system Chemoreceptor trigger zone Downloaded from: StudentConsult (on 28 October 2013 06:42 PM) © 2005 Elsevier

↓ inhibition ↑ stimulation PHARMACOLOGY OF MAJOR DOPAMINERGIC SYSTEMS IN CNS System Clinically most important drugs/ effects* Note Mesocortical, mesolimbic ↓antipsychotics→antipsychotic effect ↑ e.g.. levodopa→ psychosis Nigrostriatal ↓ antipsychotics → extrapyramidal adverse effects ↑antiparkinsonics (dopaminergic) Tuberohypophyseal ↓ antipsychotics →hyperprolactinemia ↑ e.g.bromocriptine→therapy of hyperprolactinemia Reward system (nc. accumbens) ↑addictive drugs e.g. metamphetamine, morphine, nicotine, etc. Vomiting centre Chemoreceptor trigger zone in medulla, area postrema ↓ antiemetics → inhibition of nausea, vomiting - metoclopramide, domperidon ↑ e.g. apomorphine→ vomiting ↓ inhibition ↑ stimulation * Additional neuromediator systems may participate in these effects (e.g. serotonergic, glutamatergic systems in antipsychotic effects, cholinergic system in antiparkinsonic , antiemetic effects, etc.)

Antipsychotics D1 Notes alfa1 H1 mAch 5-HT2A Notes 1st generation chlorpromazine ++ +++ + + EPS, increased prolactin, hypotension, antimuscarinic effects haloperidol + + ++ - ± As chlorpromazine but fewer antimuscarinic effects 2nd generation (atypical) clozapine Risk of agranulocytosis! Regular blood counts required. Weight gain. No EPS olanzapine Weight gain. Without risk of agranulocytosis, No EPS risperidone Weight gain. Significant risk of EPS sulpiride Increased prolactin (gynaecomastia) quetiapine Weight gain. No EPS aripiprazole +++ PA Fewer side effects [“Third generation?“- dopamine stabilizers] EPS=extrapyramidal side effects, PA = partial agonist

Correlation between the clinical potency and affinity for dopamine D2 receptors among antipsychotic drugs. Figure 45.1 Correlation between the clinical potency and affinity for dopamine D2 receptors among antipsychotic drugs. Clinical potency is expressed as the daily dose used in treating schizophrenia, and binding activity is expressed as the concentration needed to produce 50% inhibition of haloperidol binding. (From Seeman P et al. 1976 Nature 361: 717.) Downloaded from: StudentConsult (on 15 December 2012 09:54 AM) © 2005 Elsevier

DRUG TREATMENT OF PARKINSON‘S DISEASE Normal extrapyramidal system: Nigrostriatal dopaminergic neurons inhibit cholinergic neurones in striatum Parkinson‘s disease: Death of nigrostriatal dopaminergic neurons → disinhibition of cholinergic neurons The aim of pharmacotherapy is, therefore, to enhance the dopaminergic transmission and to reduce the cholinergic transmision

ANTIPARKINSONICS Dopaminergic antiparkinsonics: Levodopa (+ inhibitors of dekarboxylase in the periphery:carbidopa, benserazid) IMAO (selegiline) Agonists of dopamine (ropinirol, pramipexol) Other: amantadine, inhibitors of COMT Anticholinergic antiparkinsonics: biperiden

ANTIDOPAMINERGIC ANTIEMETICS: metoclopramide, domperidone Also gastroprokinetic effect common adverse reactions: extrapyramidal - akathisia, dystonia

SEROTO(NI)NERGIC SYSTEM Serotonin receptors 14 subtypes (!) in 7 classes (5-HT1-7) Almost all are metabotropic: They differ in localization (occur mostly in the CNS, post- or pre-synaptically), but also in the periphery. They differ in mechanisms of transduction (are coupled with various G proteins, some act via adenylyl cyclase, some via phospholipase C, or via ion channels –Ca) Only 5-HT3 receptors are ionotropic Synthesis of serotonin/5-hydroxytryptamine(5-HT): tryptofan → 5-hydroxytryptofan →5-hydroxytryptamine Reuptake inhibitors of 5-HT → SSRI and some other antidepressants Elimination of serotonin: extracellular (in synaptic cleft): transport protein (reuptakesí 5-HT back in the nerve terminal) intracelular: MAO monoamino oxidase Inhibitors of MAO (IMAO) → antidepressants

MAJOR SEROTONERGIC PATHWAYS/SYSTEMS IN CNS: Downloaded from: StudentConsult (on 28 October 2013 08:26 AM) © 2005 Elsevier

FUNCTION OF SEROTONERGIC SYSTEM IN THE BRAIN: regulation of emotion (e.g. depression, anxiety), sleep, body temperature, eating, sexual functions, pain, perception (halucinations), nausea-vomiting IN THE PERIPHERY: ↑ peristalsis in the GIT, vasoconstriction, ↑↓ BP, ↑platelet agregation

PATHOLOGY OF SEROTONERGIC SYSTEM CARCINOID: neuroendocrine tumor in the ileum, appendix or respiratory tract. Due to secretion of serotonin (and additional substances), it can produce carcinoid syndrom (flushing and diarrhea, rarely dyspnea, cardiopathy). SEROTONIN SYNDROME: excess of serotonergic activity due to serotonergic drugs and /or their combinations (antidepressants, IMAO, opioids, some antimigraine drugs). The symptoms may range from barely perceptible to fatal – agitation, confusion, shivering, sweating, diarhoea, nausea, hyperthermia, hypertension, myoclonus. Severe symptoms include extreme hyperthermia, severe increases in heart rate and blood pressure that may lead to shock.

CLINICALLY IMPORTANT DRUGS ACTING VIA SEROTONERGIC SYSTEM: TRIPTANS (5-HT1D agonists)- e.g. sumatriptan – ANTIMIGRAINE DRUGS „SETRONS“ (5-HT3 antagonists)- e.g. ondansetron – ANTIEMETICS SSRI (selective serotonin reuptake inhibitors) e.g. fluoxetin, citalopram, sertralin, effective as ANTIDEPRESSANTS and in ANXIETY DISORDERS Some other antidepressant can also inhibit reuptake of seotonin IMAO (inhibitors of MAO) – ANTIDEPRESSANTS e.g.. moclobemide SDA (serotonin dopamine antagonists)atypic antipsychotics e.g. risperidone

HISTAMINERGIC SYSTEM Histamine receptors, H1,H2, H3, (H4) All are metabotropic They occur in the brain and in the periphery Synthesis, elimination of histamine – not utilized in applied pharmacology Drugs producing release of histamine – morphine, atracurium

CLINICALLY IMPORTANT DRUGS ACTING VIA HISTAMINERGIC SYSTEM: H1 antagonists 1. generation → sedation, drowseness, e.g. promethazine, antiemetics – dimenhydrinate in motion sickness IN THE BRAIN: H1 –↑ vigility, H3 – presynaptic ↓ release of neuromediators H3 antagonist betahistine→ vasodilatation in the inner ear – antivertigo drug ( Méniere‘s disease) H1 antagonists – drugs for allergic rhinitis, urticaria - H1 antagonists 2. generation (nonsedating) - cetirizin IN THE PERIPHERY: H1 – mast cells, vasodilatation, ↑ capilar permeability, alergic reactions (itching, urticaria, allergic rhinitis), bronchokonstriction H2 – parietal cell in stomach mucose (↑ sekretion HCl) H2 antagonists – drugs for peúptic ulcer disease – ranitidin, famotidin

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