Neyroleptikl ə r. Neyroleptikl ə in tarixind ə n 1950-ci il – Charpentier- aminazinin sintez 1951-ci il – Laborit – aminazinin “süni hibernasiya” yaratması

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


• 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.


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


• 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 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.


1) Phenothiazines

ChlorpromazineThioridazine Fluphenazine

Trifluopromazine Piperacetazine Perfenazine

Mesoridazine Acetophenazine

Carphenazine

Prochlorperazine

Trifluoperazine

• Aliphatic Piperidine Piperazine*

* Most likely to cause extrapyramidal effects.


[Drug dose]

Eff

ect

Piperazine

Aliphatic

Piperidine


2) Thioxanthines

Thiothixene

Chlorprothixene

Closely related to phenothiazines


3) Butyrophenones

Haloperidol

Droperidol*

*Not marketed in the USA


[Drug dose]

Eff

ect

Phenothiazine d.

Thioxanthene d.

Butyrophenone d.


• Newer drugs have higher affinities for D1, 5-HT or -AR receptors.

• NE, GABA, Glycine and Glutamate have also been implicated in schizophrenia.


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


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


Pimozide

Molindone

Loxapine

Clozapine

Olanzapine

Qetiapine

Risperidone

Sertindole

Ziprasidone

Olindone

Newer Drugs


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


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


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


Some antipsychotics have effects at muscarinic acetylcholine receptors:

• dry mouth

• blurred vision

• urinary retention

• constipation

Clozapine

Chlorpromazine

Thioridazine


Some antipsychotics have effects at adrenergic receptors:

• orthostatic hypotension

Chlorpromazine

Thioridazine

Some antipsychotics have effects at H1-histaminergic receptors:

• sedation

Risperidone

Haloperidol


Blockade of D2 receptors in lactotrophs in breast increase prolactin concentration and may produce breast engorgement and galactorrhea.


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.



• 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.



Treatment Vigorous treatment with antiparkinsonian drugs is

recommended as soon as possible.

Muscle relaxants such as diazepam, dantrolene or bromocriptine may be helpful.


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).

Documents

Neyroleptikl ə r. Neyroleptikl ə in tarixind ə n 1950-ci il – Charpentier- aminazinin sintez 1951-ci il – Laborit – aminazinin “süni hibernasiya” yaratması