Pharmacology of dopaminergic, serotonergic and histaminergic
systems
Prof. M. Kršiak
Department of Pharmacology, Third Faculty of Medicine
Ruská 87, Prague 10,
Subject: General Pharmacology
Charles University in Prague, Third Faculty of Medicine
Academic year 2013-2014
GENERAL MEDICINE 6-YEAR MASTER‘S STUDY PROGRAMME
http://vyuka.lf3.cuni.cz
CVSE3P0012 ID9225
Dopamine Serotonine (5-
hydrytryptamine)
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.
- 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“)
R.J. Lefkowitz & B.K. Kobilka 2012 Nobel prize
G-PROTEIN-COUPLED RECEPTORS(„metabotropic receptors“)
Katzung Fig 2-14
Katzung BG, 2009, Fig 2-11
serpentine receptors: a polypeptide chain traverses the membrane seven times, the sites for binding ligands, G-protein
G-PROTEIN-COUPLED RECEPTORS(„metabotropic receptors“)
RECEPTOR
G PROTEIN - trimer, alpha, beta, gamma subunits alpha subunit: GTPase aktivity: GDPGTP,
stimulation (Gs) , inhibition (GI) of the effector
EFFECTOR
M. Rodbell & AG Gilman 1994 Nobel prize
ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP).
EFFECTOR
ENZYM
adenylyl cyclase cAMP
fosfolipase C IP3, DAG
Pro
tein
kina
ses
G-PROTEIN-COUPLED RECEPTORS(„metabotropic receptors“)
G-PROTEIN
RECEPTOR
Ca++ release
2nd messengers
Activation/inhibition of cellular functionseg. contractile proteins, enzymes, transporters,
ion channels, secretion …
ION CHANNEL
E.W. Sutherland Nobel Prize 1971
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
Elimination of dopamine:extracellulary(in the synaptic cleft):
transport protein (reuptakes DA from synapt.cleft to the presynaptic nerve ending)
COMT catechol-O-methyl transferaseintracellulary: MAO monoamino oxidase
DOPAMINERGIC SYSTEMClinical potency of antipsychotics correlates with their
affinity for D2 receptors
Decarboxylase inhibitors in combination with levodopa → antiparkinsonics
COMT inhibitors→ antiparkinsonics
Inhibitors of MAO (IMAO) → antidepressants
Inhibitors of DA, NA, 5-HT reuptake → antidepressants
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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
MAJOR DOPAMINERGIC PATHWAYS/SYSTEMS IN CNS
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 D2 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
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.)
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Correlation between the clinical potency and affinity for dopamine D2 receptors among antipsychotic drugs.
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
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
ANTIPARKINSONICS
ANTIDOPAMINERGIC ANTIEMETICS:
metoclopramide, domperidone
Also gastroprokinetic effect
common adverse reactions: extrapyramidal - akathisia, dystonia
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
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
Reuptake inhibitors of 5-HT → SSRI and some other antidepressants
SEROTO(NI)NERGIC SYSTEM
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MAJOR SEROTONERGIC PATHWAYS/SYSTEMS IN CNS:
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
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.
PATHOLOGY OF SEROTONERGIC SYSTEM
CLINICALLY IMPORTANT DRUGS ACTING VIA SEROTONERGIC SYSTEM:
TRIPTANS (5-HT1D agonists)- e.g. sumatriptan – ANTIMIGRAINE DRUGS
SSRI (selective serotonin reuptake inhibitors) e.g. fluoxetin, citalopram, sertralin,
effective as ANTIDEPRESSANTS and in ANXIETY DISORDERSSome other antidepressant can also inhibit reuptake of seotonin
IMAO (inhibitors of MAO) – ANTIDEPRESSANTS e.g.. moclobemide
„SETRONS“ (5-HT3 antagonists)- e.g. ondansetron – ANTIEMETICS
SDA (serotonin dopamine antagonists)atypic antipsychotics e.g. risperidone
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
HISTAMINERGIC SYSTEM
Drugs producing release of histamine – morphine, atracurium
IN THE BRAIN:H1 –↑ vigility, H3 – presynaptic ↓ release of neuromediators
H1 antagonists 1. generation → sedation, drowseness, e.g. promethazine, antiemetics – dimenhydrinate in motion sickness
IN THE PERIPHERY:
H1 – mast cells, vasodilatation, ↑ capilar permeability, alergic reactions (itching, urticaria, allergic rhinitis), bronchokonstriction
H2 – parietal cell in stomach mucose (↑ sekretion HCl)
H1 antagonists – drugs for allergic rhinitis, urticaria - H1 antagonists 2. generation (nonsedating) - cetirizin
H2 antagonists – drugs for peúptic ulcer disease – ranitidin, famotidin
H3 antagonist betahistine→ vasodilatation in the inner ear – antivertigo drug ( Méniere‘s disease)
CLINICALLY IMPORTANT DRUGS ACTING VIA HISTAMINERGIC SYSTEM: