neyroleptikl ə r. neyroleptikl ə in tarixind ə n 1950-ci il – charpentier- aminazinin sintez...
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Neyroleptiklər
Neyroleptikləin tarixindən
1950-ci il – Charpentier- aminazinin 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
Butirofenonlər
Tioksantenlər
İndollar
Benzoksazollar
DibenziarinlərBenzomidlər
Fenotiazinlər
Alifatik Piperidin
AminazinTizersinTeralen
NeuleptilSonapaks
MajeptilStelazin
Etaperazin
Piperazin
Butirofenonlər
HaloperidolTrisedil
Droperidol
Difenil-butirofenonlar
PimozidFluspirilen
(imap)Orap
Semap
Tioksantenlər
Alifatik Piperazin
Xlorprotiksen KlopiksolFlupentiksol
Neyroleptiklərin kliniki təsiri xüsusiyyətləri
Preparat Sedativ təsirÜmumi
antipsixotik təsir
Məqsədyönlü
antipsixotik təsir
Sedativ neyroleptiklər
Aminazin (Xlorpomazin)
Tizersin (levomepazin)
Xlorprotiksen
Klopiksol (zuklopentiksol)
Neuleptil (perisiazin)
Sonapaks (tioridazin)
Teralen (alimemazin)
Tiaprid (tiapidal)
Antipsixotik neyroleptkilər
Majeptil (tioproperizin)
Moditen (flufenazin)
Piportil (pipotazini)
Fluarksol (flupentiksol)
Topral (sultoprid)
Haloperidol
Stelazin (trifluoperazin)
Aetaperazin (perfenazin)
Neyroleptiklərin kənar təsirləri və fəsadları
Qeyri nevroloji
Ümumi sedativ təsir
Nevroloji
Ortostatik hipotenziya
Periferik antixolinergik təsir
Qəfil ölümBədən çəkisinin artası
Dermatoloji təsir
Oftalmoloji təsir
Endokrin siteminə təsir
Hepatoloji təsir
Hematoloji təsir
Ürək-damar sisteminə təsir
Mərkəzi antixolinergik təsir
Distonik təsir
Parkinsonobənzər təsir
Akatiziya
Bəd növlü neyroleptik sindrom
Epileptogen
Diskineziya
Antipsychotic/Neuroleptics
Three major groups :
1) Phenothiazines
2) Thioxanthines
3) Butyrophenones
OLDER DRUGS
Antipsychotics/Neuroleptics
• Old antiphsychotics /neuroleptics are D2 dopamine receptor antagonists. Although they are also effective antagonists at ACh, 5-HT, NE receptors.
Dopamine Synapse
DA
L-DOPA
Tyrosine
Tyrosine
dopaminereceptorantagonist
D2
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
Correlations between therapeutic potency and affinity for binding D2 receptors.
[3 H]H
alop
erid
ol b
indi
ngIC
50 (
mol
/L)
Clinical dose of drug [mg d-1]
haloperidol
clozapinethiothixene
chlorpromazinepromazine
spiroperidole
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 non-selective).
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
ChlorpromazineThioridazine Fluphenazine
Trifluopromazine Piperacetazine Perfenazine
Mesoridazine Acetophenazine
Carphenazine
Prochlorperazine
Trifluoperazine
• Aliphatic Piperidine Piperazine*
* Most likely to cause extrapyramidal effects.
Antipsychotic/Neuroleptics
[Drug dose]
Eff
ect
Piperazine
Aliphatic
Piperidine
Antipsychotic/Neuroleptics
2) Thioxanthines
Thiothixene
Chlorprothixene
Closely related to phenothiazines
Antipsychotic/Neuroleptics
3) Butyrophenones
Haloperidol
Droperidol*
*Not marketed in the USA
Antipsychotic/Neuroleptics
[Drug dose]
Eff
ect
Phenothiazine d.
Thioxanthene d.
Butyrophenone d.
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.
DA synthesis, DA metabolism, DA release
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.
Receptor Supersensitivity
Antipsychotic/Neuroleptics
Pimozide
Molindone
Loxapine
Clozapine
Olanzapine
Qetiapine
Risperidone
Sertindole
Ziprasidone
Olindone
Newer Drugs
Antipsychotic/Neuroleptics
Clinical Ex. Py.
Drug Potency toxicity Sedation Hypote.
Chlorpromaz. Low Medium Medium HighHaloperidol High Very High Very High LowThiothixene High Medium Medium MediumClozapine Medium Very low Low MediumZiprasidone Medium Very Low Low Very lowRisperidone High Low Low LowOlanzapine High Very Low Medium Very lowSertindole High Very 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) Parkinson-like symptoms
b) Tardive Dyskinesia (10-30%)
c) Autonomic effects
d) Endocrine effects
e) Cardiac effects
3) Poor Concentration
The Nigro-Striatal Pathway
Inhibitionof
Motor Activity
DAneuron ACh
neuron
GABAneuron
GABAneuron
Substantia Nigra
+
-
-
-
-
Striatum
Antipsychotic/Neuroleptics
Some antipsychotics have effects at muscarinic acetylcholine receptors:
• dry mouth
• blurred vision
• urinary retention
• constipation
Clozapine
Chlorpromazine
Thioridazine
Antipsychotic/Neuroleptics
Some antipsychotics have effects at adrenergic receptors:
• orthostatic hypotension
Chlorpromazine
Thioridazine
Some antipsychotics have effects at H1-histaminergic receptors:
• sedation
Risperidone
Haloperidol
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 muscle damage.
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).
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