Transcript Neyroleptiklər

Neyroleptiklər
Neyroleptikləin tarixindən
1950-ci il – Charpentieraminazinin sintez
1951-ci il – Laborit – aminazinin
“süni hibernasiya” yaratması
1952-ci il – Delay və Deniker –
aminazinin psixozlarda tədbiqi
1958-ci il – Janssen –
haloperidolun tədbiqi
Neyroleptiklərin
təsnifatı
Fenotiazinlər
Tioksantenlər
Butirofenonlər
İndollar
Benzomidlər
Dibenziarinlər
Benzoksazollar
Fenotiazinlər
Alifatik
Piperidin
Piperazin
Aminazin
Tizersin
Teralen
Neuleptil
Sonapaks
Majeptil
Stelazin
Etaperazin
Butirofenonlər
Haloperidol
Trisedil
Droperidol
Difenil-butirofenonlar
Pimozid
Fluspirilen
(imap)
Orap
Semap
Tioksantenlər
Alifatik
Xlorprotiksen
Piperazin
Klopiksol
Flupentiksol
Neyroleptiklərin kliniki təsiri
xüsusiyyətləri
Preparat
Sedativ neyroleptiklər
Aminazin (Xlorpomazin)
Tizersin (levomepazin)
Xlorprotiksen
Klopiksol (zuklopentiksol)
Neuleptil (perisiazin)
Sonapaks (tioridazin)
Teralen (alimemazin)
Tiaprid (tiapidal)
Antipsixotik neyroleptkilər
Majeptil (tioproperizin)
Sedativ təsir
Ümumi
antipsixotik
təsir
Məqsədyö
nlü
antipsixoti
k təsir
Neyroleptiklərin kənar
təsirləri və fəsadları
Qeyri nevroloji
Nevroloji
Ümumi sedativ təsir
Distonik təsir
Ortostatik hipotenziya
Parkinsonobənzər təsir
Periferik antixolinergik təsir
Akatiziya
Mərkəzi antixolinergik təsir
Diskineziya
Ürək-damar sisteminə təsir
Epileptogen
Hematoloji təsir
Bəd növlü neyroleptik sindrom
Hepatoloji təsir
Endokrin siteminə təsir
Oftalmoloji təsir
Dermatoloji təsir
Bədən çəkisinin artası
Qəfil ölüm
Antipsychotic/Neuroleptics
OLDER DRUGS
Three major groups :
1) Phenothiazines
2) Thioxanthines
3) Butyrophenones
Antipsychotics/Neuroleptics
Tyrosine
Tyrosine
Dopamine Synapse
L-DOPA
DA
dopamine
receptor
antagonist
D2
• Old antiphsychotics
/neuroleptics are D2
dopamine receptor
antagonists. Although
they are also effective
antagonists at ACh, 5HT, NE receptors.
Antipsychotics/Neuroleptics
•
It appears that the specific interaction of
antipsychotic drugs with D2 receptors is important
to their therapeutic action.
•
The affinities of most older “classical” agents for
the D2 receptors correlate with their clinical
potencies as antipsychotics.
Antipsychotic/Neuroleptics
[3H]Haloperidol binding
IC50 (mol/L)
Correlations between therapeutic potency and
affinity for binding D2 receptors.
promazine
chlorpromazine
clozapine
thiothixene
haloperidol
spiroperidole
Clinical dose of drug [mg d-1]
Antipsychotics/Neuroleptics
•
Both D1 and D2 receptors are found in high
concentrations in the striatum and the nucleus accumbens.
•
Clozapine has a higher affinity for the D4 receptors than
for D2.
•
Recently it has been found that most antipsychotic drugs
may also bind D3 receptors (therefore, they are nonselective).
Antipsychotics/Neuroleptics
•
Antipsychotics produce catalepsy (reduce motor activity).
–
•
BLOCKADE OF DOPAMINE RECPTORS IN BASAL GANGLIA.
Antipsychotics reverse hyperkinetic behaviors (increased
locomotion and stereotyped behavior).
–
•
BLOCKADE OF DOPAMINE RECPTORS IN LIMBIC AREAS.
Antipsychotics prevent the dopamine inhibition of prolactin
release from pituitary.
–
BLOCKADE OF DOPAMINE RECEPTORS IN PITUITARY.
 hyperprolactinemia
Pharmacokinetics
Absorption and Distribution
• Most antipsychotics are readily but incompletely
absorbed.
• Significant first-pass metabolism.
• Bioavailability is 25-65%.
• Most are highly lipid soluble.
• Most are highly protein bound (92-98%).
• High volumes of distribution (>7 L/Kg).
• Slow elimination.
**Duration of action longer than expected, metabolites are present and
relapse occurs, weeks after discontinuation of drug.**
Pharmacokinetics
Metabolism
• Most antipsychotics are almost completely metabolized.
• Most have active metabolites, although not important in
therapeutic effect, with one exception. The metabolite of
thioridazine, mesoridazine, is more potent than the parent
compound and accounts for most of the therapeutic
effect.
Pharmacokinetics
Excretion
• Antipsychotics are almost completely metabolized and
thus, very little is eliminated unchanged.
• Elimination half-lives are 10-24 hrs.
Antipsychotic/Neuroleptics
1)
Phenothiazines
• Aliphatic
Piperidine
Piperazine*
Chlorpromazine Thioridazine
Fluphenazine
Trifluopromazine Piperacetazine
Perfenazine
Mesoridazine
Acetophenazine
Carphenazine
Prochlorperazine
Trifluoperazine
* Most likely to cause
extrapyramidal effects.
Antipsychotic/Neuroleptics
Piperazine
Piperidine
Effect
Aliphatic
[Drug dose]
Antipsychotic/Neuroleptics
2) Thioxanthines
Thiothixene
Chlorprothixene
Closely related to phenothiazines
Antipsychotic/Neuroleptics
3) Butyrophenones
Haloperidol
Droperidol*
*Not marketed in the USA
Antipsychotic/Neuroleptics
Butyrophenone d.
Phenothiazine d.
Effect
Thioxanthene d.
[Drug dose]
Antipsychotics/Neuroleptics
•
Newer drugs have higher affinities for D1, 5-HT
or -AR receptors.
•
NE, GABA, Glycine and Glutamate have also
been implicated in schizophrenia.
Antipsychotics/Neuroleptics
The acute effects of antipsychotics do not explain why their
therapeutic effects are not evident until 4-8 weeks of
treatment.
Blockade of D2 receptors

Short term/Compensatory effects:

Firing rate and activity of nigrostriatal and mesolimbic
DA neurons.
Antipsychotics/Neuroleptics
Presynaptic Effects
Blockade of D2 receptors

Compensatory Effects

Firing rate and activity of nigrostriatal and mesolimbic DA neurons.

DA synthesis, DA metabolism, DA release.
Postsynaptic Effects
Depolarization Blockade
Inactivation of nigrostriatal and mesolimbic DA neurons.
Antipsychotic/Neuroleptics
Newer Drugs
Pimozide
Molindone
Loxapine
Clozapine
Olanzapine
Qetiapine
Risperidone
Sertindole
Antipsychotic/Neuroleptics
Drug
Clinical
Ex. Py.
Potency
toxicity
Chlorpromaz. Low
Haloperidol
High
Thiothixene
High
Clozapine
Medium
Ziprasidone
Medium
Risperidone
High
Olanzapine
High
Sertindole
High
Medium
Very High
Medium
Very low
Very Low
Low
Very Low
Very Low
Sedation
Hypote.
Medium
Very High
Medium
Low
Low
Low
Medium
Very low
High
Low
Medium
Medium
Very low
Low
Very low
Very Low
Antipsychotic/Neuroleptics
Chlorpromazine: 1 = 5-HT2 = D2 > D1 > M > 2
Haloperidol: D2 > D1 = D4 > 1 > 5-HT2 >H1>M = 2
Clozapine: D4 = 1 > 5-HT2 = M > D2 = D1 = 2 ; H1
Quetiapine: 5-HT2 = D2 = 1 = 2 ; H1
Risperidone: 5-HT2 >> 1 > H1 > D2 > 2 >> D1
Sertindole: 5-HT2 > D2 = 1
Antipsychotic/Neuroleptics
Clinical Problems with antipsychotic drugs
include:
1)
Failure to control negative effect
2)
Significant toxicity
a)
b)
c)
d)
e)
3)
Parkinson-like symptoms
Tardive Dyskinesia (10-30%)
Autonomic effects
Endocrine effects
Cardiac effects
Poor Concentration
The Nigro-Striatal Pathway
DA
neuron
Striatum
ACh
neuron
+
Substantia
Nigra
GABA
- neuron
-
Inhibition
of
Motor Activity
-
GABA
neuron
Antipsychotic/Neuroleptics

Some antipsychotics have effects at muscarinic
acetylcholine receptors:
•
dry mouth
•
blurred vision
•
urinary retention
•
constipation
Clozapine
Chlorpromazine
Antipsychotic/Neuroleptics
Some antipsychotics have effects at adrenergic
receptors:

•
orthostatic hypotension
Chlorpromazine
Thioridazine

Some antipsychotics have effects at H1-histaminergic
receptors:
•
sedation
Risperidone
Antipsychotic/Neuroleptics

Blockade of D2 receptors in lactotrophs in
breast increase prolactin concentration and
may produce breast engorgement and
galactorrhea.
Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
Is a rare but serious side effect of neuroleptic
(antipsychotic) therapy that can be lethal. It can arise
at any time in the course of treatment and shows no
predilection for age, duration of treatment,
antipsychotic medication, or dose.
Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
•
Occurs in pts. hypersensitive to the Ex.Py. effects of
antipsychotics.
•
Due to excessively rapid blockade of postsynaptic
dopamine receptors.
•
The syndrome begins with marked muscle rigidity.
•
If sweating is impaired, a fever may ensue. The stress
leukocytosis and high fever associated with this syndrome
may be mistaken for an infection.
•
Autonomic instability with altered blood pressure and heart
rate is another midbrain manifestation.
•
Creatine kinase isozymes are usually elevated, reflecting
Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
Treatment
Vigorous treatment with antiparkinsonian drugs is
recommended as soon as possible.
Muscle relaxants such as diazepam, dantrolene or
bromocriptine may be helpful.
Antipsychotic/Neuroleptics
Drug Interactions
•
•
•
•
•
Additive effects with sedatives.
Additive effects with anticholinergics.
Additive effects with antihistaminergics.
Additive effects with -AR blocking drugs.
Additive effects with drugs with quinidine-like
action (thioridazine).