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

Downloaded from: StudentConsult (on 28 October 2013 06:42 PM)

© 2005 Elsevier

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.)

Downloaded from: StudentConsult (on 15 December 2012 09:54 AM)

© 2005 Elsevier

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

Downloaded from: StudentConsult (on 28 October 2013 08:26 AM)

© 2005 Elsevier

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: