Neurotransmission and drug action in the central nervous system

1. Neurotransmission and drug action in the central nervous system • Neuroleptics • Anton Kohút

2. 1845FREUD cocaine from 1933insulin and electric shocks 1943Hoffmann LSD • lithium treatment of psychosis 1952chlorpromazine 1954meprobamat 1957benzodiazepine - chlordiazepoxide 1958iproniazid (inhibítor MAO) imipramin(tricyclic antidepressive drug)

3. Nonspecific Anesthetic gases and vapors, The aliphatic alcohols, Some hypnotic-sedative drugs. Specific Act on specific receptors in CNS Actions of drugs in CNS

4. Inhibitory: GABA Excitatory: NMDA (glutamate) Fast (ligand gated ion channels) – NMDA, GABA Slow (G-protein coupled receptors Neurotransmiters in CNS

6. Transmiters Receptors Glutamate NMDA, and non NMDA GABA GABAA,GABAB Glycine Glycin Acetylcholine nicotinic, muscarinic 5-HT HT1a-d 5-HT 2-7 Noradrenaline 1 2 ,1-3 Dopamine D1-5 Cholecystokinin CCKA ,CCKB NO activation of guanylate cyclase Receptors and neurotransmiters in CNS

7. Serotoninergic neurotransmission

8. 5HT-R Action Agonist Antagonist 1A, B neuronal inhibition, behavioural effects: sleep, feeding, anxiety, thermoregul. Buspirone, Sertindole Ergotamine Metiotepine 1D vasoconstriction Sumatriptan Ergotamine Metiotepine 2A neuronal excitation (increase in the number in suicides) LSD Ketanserine Cyproheptadine Nefazodone 3 neuronal excitation, vomiting, anxiety -Metyl-5-HT Ondanzetrone Granizetrone Tropizetrone 7 not known LSD Ketanserine Cyproheptadine 5-HT-R classification and function in CNS

9. Biogenic monoamine hypothesis

10. Dopamine and Parkinsonism

11. Subunits of GABA receptor

12. GABA receptor – inhibitory

15. 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.

19. 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,

20. 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)

21. Neuroleptics (antipsychotics)Chlorpromazine

22. The spliting of the mind

26. 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.

27. Schizophrenia in man is associated with dopaminergic hyperactivity (D2). - number of D2 receptors increase twoo-fold in schizophrenic patients - amphetamine, which release dopamine in brain, can produce in man syndrome similar as the symptoms of schizophrenia - 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 Dopaminergic bases of schisophrenia and mechanism of action of neuroleptics

28. 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- : clozapine, olanzepine, quetapine, ziprasidone, and risperidone - block D1, 4 a 5-HT2 ??? –

31. Site of chlorpromazine action

33. 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: parkinsonian symptoms, diskynesia antiemetic effects: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

34. 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

35. 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 Therapeutic uses and side effects