Transcript Chemical transmission and drug action in the central nervous
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