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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).