Neurotransmission and drug action in the central nervous system

  

Neuroleptics

Anton Kohút

1845 FREUD from 1933 cocaine

insulin and electric shocks

1943 Hoffmann LSD 1949 lithium treatment of psychosis 1952 chlorpromazine 1954 meprobamat 1957

benzodiazepine -

chlordiazepoxide 1958 iproniazid

(inhibítor MAO)

imipramin

(tricyclic antidepressive drug)

Actions of drugs in CNS

Nonspecific

  

Anesthetic gases and vapors, The aliphatic alcohols, Some hypnotic sedative drugs.

Specific



Act on specific receptors in CNS

Neurotransmiters in CNS

Inhibitory: GABA

Fast ( GABA ligand gated ion channels) – NMDA, Slow (G-protein coupled receptors

Excitatory: NMDA (glutamate

)

Receptors and neurotransmiters in CNS Transmiters Glutamate GABA Glycine Acetylcholine 5-HT Noradrenaline Dopamine Cholecystokinin NO Receptors NMDA, and non NMDA GABA A, GABA B Glycin nicotinic, muscarinic HT 1a-d 5-HT 2-7



1



2 ,



1-3 D 1-5 CCK A ,CCK B activation of guanylate cyclase

Serotoninergic neurotransmission

5-HT-R classification and function in CNS

5HT-R Action Agonist Antagonist 1A, B 1D 2A 3 7 neuronal inhibition, behavioural effects: sleep, feeding, anxiety, thermoregul.

vasoconstriction Buspirone, Sertindole neuronal excitation (increase in the number in suicides) neuronal excitation, vomiting, anxiety not known Ergotamine Metiotepine Sumatriptan LSD



-Metyl-5 HT LSD Ergotamine Metiotepine Ketanserine Cyproheptadine Nefazodone Ondanzetrone Granizetrone Tropizetrone Ketanserine Cyproheptadine

Biogenic monoamine hypothesis

Dopamine and Parkinsonism

Subunits of GABA receptor

GABA receptor – inhibitory

  Excitotoxicity has been implicated as a pathophysiologic mechanism in many diseases, including neurodegenerative syndromes, stroke and trauma, hyperalgesia, and epilepsy. Although the clinical applications of interrupting excitoxicity remain limited, it is hoped that better understanding of

glutamate-induced excitotoxicity will lead to the development of new approaches to treatment of these diseases.

Classification of drugs influencing CNS

1. Neuroleptic drugs ( D receptors )

antipsychotic drugs, antischizophrenic drugs 

Increase of dopaminergic activity in the brain is the cause of schizoprenia, 2. Antidepressive drugs

– antidepressans

(NA, 5 HT) Depression and bipolar disorders are pervasive mood altering ilnesses affecting energy, sleep, appetite, libido and the ability to function.

  

Depression is due to a decrease of noradrenaline and serotonine,



Mania is due to oposite changes,

3. Anxiolytic and sedative - hypnotic drugs (GABA)



Unpleasant state of tension, apprehension, or uneasiness. Disorders involving anxiety are the most common mental disturbances.

   

The role of GABA receptors, Agonists of GABA receptors – benzodiazepines a effecive in the treatment of anxiety.

4 . Psychomimetics

-psychomotor stimulants

(NA, D) 5. Psychotomimetic drugs

– halucinogenes

(5-HT) 6. Antiepileptics, antiparkinsonics

-used to treat Parkinsonism and epilepsy

(GABA, NMDA)

Neuroleptics (antipsychotics)

Chlorpromazine



The spliting of the mind

Antipsychotic drugs - neuroleptics

 - are the best treatment now available.

They do not cure schizophrenia but they have greatly improved the outlook for individual patients.

 reduce the psychotic symptoms of schizophrenia, such as hallucinations and delusions, and usually allow the patient to function more effectively and appropriately.  patients vary a great deal in the amount of drug needed to reduce symptoms without producing troublesome side effects.

Dopaminergic bases of schisophrenia and mechanism of action of neuroleptics



Schizophrenia in man is associated with dopaminergic hyperactivity ( D2 ).

number of D2 receptors increase twoo-fold in schizophrenic patients -

amphetamine

brain, , which release dopamine in can produce as the symptoms of schizophrenia in man syndrome similar

  

- all the neuroleptic drugs block dopamine receptor (brain, periphery) - there are at least twoo types of receptor: D1 and D2 - clinical efficacy correlates closely with relative ability to block D2 receptors

Classification of neuroleptics

I. Typical neuroleptics



Phenothiazines

1. with aliphatic ring: chlorpromazine, levopromazine 2. with piperidine ring: thioridazine 3. with piperazine ring: prochlorperazine, perhenazine (5 10 x more active as CHPR, antiemetic action), trifluoperazine, flufenazín  

Thioxantines:

chlorprothixen,flupentixol,

Butyrophenones: haloperidol, droperidol, II.

atypical neuroleptics Dibenzodiazepines- :

ziprasidone, and risperidone clozapine, olanzepine, quetapine,

block D1, 4 a 5-HT2 ???

–

Site of chlorpromazine action

Actions of chlorpromazine

antipsychotic actions:

- reduction of hallucinations, - reduction of spontaneous physical movement - they do not depress intelectual function of the patient - antipsychotic effect usually take several veeks to occur

extrapyramidal effects: antiemetic effects:

parkinsonian symptoms, diskynesia block of D2 receptors of the chemoreceptor triger zone of the medulla antimuscarinic effects: atropine like effect

blockade of alfa-adrenoreceptor:

orthostatic hypotension

hypothermia:

neuroleptics alter temperature-regulating mechanisms (poikilothermia)

endocrine effect:

- increase in prolactin release



Atypical neuroleptics

  

have a relatively low affinity for D2 receptor are more effective than typical antipsychotics at treating the “negative” symptoms of schizophrenia, some atypical antipsychotics also act as antagonists at 5-HT2 and D4 receptors

Therapeutic uses and side effects

Therapeutic uses

  treatment of schizophrenia: prevention of severe nausea and vomiting

other:

- neuroleptanalgesia (droperidol) - chronic pain (+ opioids)

Side effects

   

parkinsonian effects: CNS depresion:

drowsiness occurrs during the firs twoo weeks of therapy

antimuscarinic effects



endocrinne

depression of the hypothalamus > galactorhea, infertility, impotence