Chapter 18 Psychopharmacologic Drugs

1. Chapter 18 Psychopharmacologic Drugs • Antipsychotic Agents • Antimanic drugs • Antidepressant drugs • Classification of drugs

2. mechanism of action of antipsychotics • Blockade of the dopamine receptors in the mesolimbic and mesocortical areas in the brain. • Blocking of the serotonin receptors: clozapine(氯氮平) • The mechanism of the main adverse effects is blackade of the dopamine receptors in the tuberoinfundibular结节漏斗 nigrostriatal 黑质纹状体areas.

3. Several important dopaminergic pathway • Several important dopaminergic pathway are now recognized in the brain. • (1)The first pathway the one most closely related to behavior is the mesolimbic-mesocortical pathway. • (2)Nigrostriatalpathway, involving in the coordination of voluntary自主 movement. • (3)tuberoinfundibularpathway. • The antipsychotic agents block D2 receptors stereoselectively, for the most part,and their binding affinity is very strongly correlated with clinical antipsychotic potency.

4. Antipsychotic Agents Typical Antipsychotic drugs : PhenothiazinesChlorpromazine(氯丙嗪） Atypical Antipsychotic drugs : Clozapine and risperidone Sulpiride Classification of Antipsychotic Agents

5. Antipsychotic Agents Chlorpromazine(氯丙嗪） [Pharmacological effects] • Chlorpromazine can block a number of receptors. These receptors include dopamine(DA) and alpha- adrenoceptor, muscarinic, H1 histaminic receptors(DA , α, M , H1 receptors) • Of these receptors, the dopamine receptor effects quickly became the major focus of interest. • Chlorpromazine proved to have a wide variety of central nervous system,autonomic,and endocrine effects.

6. Chlorpromazine [Pharmacological Effects] 1.Sedative and anti-antianxiety effects Antipsychotic drugs possess calming effect and lower spontaneous physical movement. 2.Effects on Conditioned response Antipsychotic drugs selectively inhibit the ability of animals to make a conditioned avoidance response.

7. Chlorpromazine [Pharmacological Effects] 3.General psychophysiological effects After given drugs,psychotic patients initially may become somewhat slow in response to external stimuli and drowsiness,and then the patients become less agitated,aggressive and impulsive behavior diminishes, and gradually,symptoms of hallucinations幻觉,delusions错觉,and incoherent thinking 妄想tent to disappear.

8. Chlorpromazine [Pharmacological Effects] 4.Effects on chemoreceptor trigger zone (CTZ) • Chlorpromazine can block apomorphine-induced vomiting. This action is due to dopamine receptor blockade, both centrally(in the chemoreceptor trigger zone of the medulla) and peripherally(on receptors in the stomach). However, large doses of chlorpromazine may depress the vomiting center directly. 5.Effects on body-temperature regulation • The chlorpromazine depress temperature-regulating mechanisms. It may produce hypothermia or hyperthermia, depending on the environmental temperature.

9. Chlorpromazine [Pharmacological Effects] 6.Effects autonomic nervous system Chlorpromazine can block alpha-receptor, converting a pressor of epinephrine. Otherwise, chlorpromazine can depresses vasomotor- stabiling center and dilates directly blood vessels. In addition,chlorpromazine also block the muscarinic actions of acetylcholine.

10. Chlorpromazine [Pharmacological Effects] 7.Effects on endocrine system More prolactin releasing induces lactation; Inhibiting corticotropin-releasing hormone(CRH) release which results in decreased release of glucocorticoids;also impairing glucose tolerance and insulin release. 8.Potentiation of other central depressive agents Antipsychotic drugs potentate the effects of sedatives, analgesics, antipyretic-analgesics and general anesthetics.

11. Chlorpromazine Therapeutic Uses • 1.Treatment of Schizophrenia（精神分裂症） • 2.Prevention of nausea and vomiting caused by drugs and radiation sickness. • 3.Hibernation therapy冬眠疗法 chlorpromazine + promethazine（异丙嗪） + pethidine （哌替啶）

12. Chlorpromazine [Adverse Reactions] • 1.Extrapyramidal Reactions锥体外系反应: • (1)Parkinson’s syndrome; • (2)Akathisia(静坐不能); • (3) Dystonic reactions (肌张力障碍)； • These acute extrapyramidal reaction can be treated with antimuscarinic drugs, artane. • (4)Tardive dyskinesia（迟发性运动障碍） • It has been proposed that it is caused by a relative cholinergic deficiency secondary to supersensitivity of dopamine receptors.

13. Chlorpromazine [Adverse Reactions] • 2.Behavioral effects • include toxic psychosis • 3. Adverse effects on autonomic nerve system • Orthostatic hypotention体位性低血压 • Dry mouth • Tachycardia • Blurred vision 视力模糊

14. Drugs used disorders Antidepressant • Nonspecific reuptake inhibitors(NE,5-HT,DA) • imipramine （米帕明）Tricyclic Antidepressants • Selective serotonin-reuptake inhibitors (5-HT) • fluoxetine (氟西汀) • Mono-amine oxidase(MAO) inhibitors • Atypical antidepressants • Mirtazapine increases the concentration of 5-HT and NE in the nerve ending by blocking the presynaptic negative feedback receptors.

15. Imipramine （米帕明） [Pharmacological Effects] • Tricyclics antidepressants block the amine (norepinephrine or serotonin) reuptake pumps. Such an action presumably permits a longer sojourn逗留 of neurotransmitter at the receptor site. (The pathogenesis of depression- the Amine-Hypothesis)

16. [Clinical Uses] • 1. The major indication for these drug is to treat depression. • 2. Enuresis遗尿 • 3. Anxiety and phobia恐怖

17. Adverse effects of Tricyclics antidepressants Sedation Sleepiness,additive effects with other sedative drugs Sympathomimetic Tremor, insomnia Antimuscarinic Blurred vision, constipation, urinary hesitancy. Cardiovascular Orthostatic hypotension,conduction defects, arrhythmias Neurological Seizures Endocrine Weight gain.

18. Antimanic Drugs Lithium salts 锂盐 • This drug may decrease norepinephrine and dopamine release. These effects might be relevant to its antimanic action. • Lithium salt counteracts mood changes without producing sedation. • Phenothiazines have calming and depressant effects which are useful in controlling all kinds of mania ,but do not normalizing behavior.