Neurotransmission and drug action
in the central nervous system


Neuroleptics

Anton Kohút
1845 FREUD cocaine
from 1933 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 hypnoticsedative drugs.
Specific

Act on specific
receptors in CNS
Neurotransmiters in CNS
Fast (ligand gated ion
Inhibitory:
GABA
Excitatory:
NMDA (glutamate)
channels) – NMDA,
GABA
Slow (G-protein coupled
receptors
Receptors and neurotransmiters in CNS
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
Serotoninergic neurotransmission
5-HT-R classification and function in CNS
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
LSD
Ketanserine
Cyproheptadine
(increase in the number in
suicides)
Nefazodone
3
neuronal excitation,
vomiting, anxiety
-Metyl-5HT
Ondanzetrone
Granizetrone
Tropizetrone
7
not known
LSD
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, 5HT)
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, 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
Classification of neuroleptics
I. Typical neuroleptics
 Phenothiazines
1. with aliphatic ring: chlorpromazine, levopromazine
2. with piperidine ring: thioridazine
3. with piperazine ring: prochlorperazine, perhenazine (510 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 ??? –
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: 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




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
Side effects
treatment of
schizophrenia:
 prevention of severe
nausea and vomiting
other:
- neuroleptanalgesia
(droperidol)


- chronic pain (+ opioids)




parkinsonian effects:
CNS depresion:
drowsiness occurrs during
the firs twoo weeks of
therapy
antimuscarinic effects
endocrinne
depression of the
hypothalamus >
galactorhea, infertility,
impotence