Understanding Chlorpromazine: Antipsychotic Drug Classification and Pharmacological Effects

2. Psychotropic drugs Liming Zhou (周黎明) Department of pharmacology

3. Classification • Antipsychotic Drugs • Antimanic drugs • Antidepressants • anxiolytics

4. Antipsychotic Drugs

5. Contents • Overview • Inreuduction of Schizophrenia • Classification of antipsychotic drugs • Chlorpromazine

6. Overview • Antischizophrenic,neuroleptic drugs • These agents are prescribed for treating schizophrenia or management of psychotic symptoms

7. Overview • What is schizophrenia ? • There appears to be a genetic component to schizophrenia. • There is also evidence for changes in brain structure.

8. Schizophrenia • schizophrenia • Clinical Manifestations • Characteristics-- perturbations affecting: • language • perception • thinking • volition • Behavior • social activity size of ventricles

9. Schizophrenia • Syndrome overview: • Typically begins in late adolescence • Insidious onset. •  Poor outcome. • Social withdrawal /perceptual distortions lead to chronic delusions （错觉）/hallucinations （幻觉）.

10. Schizophrenia • Positive Symptoms: • Conceptual disorganization • Delusions • Hallucinations

11. Schizophrenia Negative Symptoms: • Anhedonia (快感缺乏) • Decreased emotional expression • Impaired concentration • Diminished socialization

12. Classification of antipsychotic drugs • Phenenothiazines（吩噻嗪类) (Chlorpromazine) • Thioxanthenes(硫杂蒽类） (Tardan,flupenthixol) • Butyrophenones（丁酰苯类） (Haloperidol) • Atypicals )(非典型药物） (Clozapine)

13. Chlorpromazine (wintermine) • Pharmaciolgical effects • CNS effects 1.neuroleptic effect: hallucination and delusions（错觉）improvement

14. Mechanism of action Blockade dopaminergic neurotransmission -the limbic - nigrostriatal - hypothalamic system.

15. Dopamine Hypothesis: This idea was suggested by observation that drugs which reduced dopaminergic activity reduced acute symptoms/signs of psychoses. • Symptoms notably Decreased -- • agitation • anxiety • hallucinations

16. Four pathway of dopaminergic neurotransmission • 1)Mesolimbic-mesocortical pathway (one most closely related to behavior ) • 2)nigrostriatal pathway(it is involved in the coordination of voluntary movement) • 3)tuberoinfundibular pathway (inhibits prolactin secreation) • 4）medullary-periventricular pathway (the function is not clear ,may be involved eating behavior)

17. Dopamin receptor: two type, five subtype - DA1 (D1-like receptor): D1,D5 - DA2 (D2-like receptor): D2,D3, D4

18. D2 like receptors (D2, D3, D4) • Activate Gi  cAMP • Block Ca++ channels • Open K+ channels • D2: putamen(壳核）, olfactory tubercle（嗅结节） • D3: frontal cortex, medulla, midbrain • D4: ???

19. D2 receptor activation  motor activity  aggravates schizophrenia • D2 receptor blockade  alleviation of schizophrenia

20. Neuroleptic effect: blocking DA2 • Side effect (extra-pyramidal symptoms.): blocking DA2

21. Pharmalogical effects • Antiemetic effect. -This is a results of blocking DA2 receptor. -In low doses, blocking DA2 receptor in chemoreceptor trigger zone(CTZ). -In high doses, chlorpromazine may directly depress the medulla vomiting center.

22. Pharmalogical effects • Altering temperature-regulating mechanisms. • in a cold climate it decrease temperature in body • in a hot climate they can cause hyperthermia

23. Pharmalogical effects • Sympathetic and parasympathetic nervous system effect: -Blocking α-adrenergic receptor  Orthostatic hypotension. -Blocking M-receptor. Blurred vision Constipation Dry mouth Decreased sweating

24. Pharmalogical effects • Endocrine system effect • Increasing the lactogenic hormone(催乳素).Increased levels of prolactin may lead to galactorrhea （溢乳). • phenothiazines decrease FSH and ACTH. • Decreasing release and secretion of pituitary growth hormone.

25. Prolactin • FSH • ACTH • growth hormone.

26. Therapeutic uses • 1. Psychotic disorders, all kind of schizophrenia. • 2. Nausea and vomiting.(except carsickness). • 3. Decrease the temperature. • 4. Control of intractable hiccup（呃逆打嗝). • 5.Therapy gigantism(巨人症).

27. untoward effects • (1) Special side effect: Extrapyramidal symptoms • A. Parkinsonian syndrome: the patients display rigidity(僵化)and tremor • B. Acut dystonia: patients display facial grimacing (面部的歪扭,) torticollis(斜颈) • C.Akathisia (静坐不能) • D. tardive dyskinesia (迟发性运动障碍）

28. patient display sucking of the lips and other involuntary facial movement. (The dyskinesia may persist for after discontinuation of the therapy).

29. Untoward effects • (2)General side effect: • A. CNS depression • B. M-receptor blocking: The symptom of M- receptor blocking • C. Orthostatic hypotension

30. Untoward effects • (3)Inducing psychosis by drug • (4)seizure and epilepsy • (5)allergic reaction • (6)cardiovascular effect

31. Untoward effects • (7)Endocrine disorder: • Hyperprolactinemia--causes: For women:   Amenorrhea(abnormal suppression or absence of menstrual flow), galactorrhea , infertility For men: impotence  infertility,diminished libido • For children: decreasing growth.

32. Drug interaction: 1)Increasing CNS inhibition with ethanol, sedative-hypnotics, morphine. 2)Inhibiting the of L-Dopa (agonist of the doparmin-receptor). 3)Increase the dose with phentoin and carbamazepine.

33. Atypical antipsychotic drugs • Clozapine and Risperidone selectively inhibit D4 and 5-HT2-receptors. • Risperidone selectively inhibit D2 and 5-HT2-receptors. • Sulpiride selectively inhibit D2-receptors in the mesolimbic and mesocortical areas of the brain. • Sulpiride ,Clozapine and risperidone have low risk of extra-pyramidal adverse reaction.

34. Atypical antipsychotic drugs Sulpiride • Selectively inhibit D2-receptors in the mesolimbic and mesocortical areas of the brain. • Producing low extra-pyramidal adverse reaction.

35. Antimanic drug • Lithium carbonate

36. Pharmacodynamics Possible mechanisms of action: -effects on electrolyte/ion transport neurotransmitter -neurotransmitter release modulation influence on second messengers. Lithium salts how to affect second messengers?(learning by yourself)

37. Antidepressants • Overview • Classification • TCA Antidepressants

38. Overview • Depression is an alteration of mood characterized by sadness, worry, and anxiety. • The patient may suffer from losses of weight, libido, and enthusiasm.

39. Depression Clinical depression is a syndrome that may include: • Sustained mood disturbances • Impaired memory and concentration • Disturbed sleep • Reduced energy level • Reduced libido • Impaired sleep.

40. Depression • Patient complaints suggestive of depression may include: •   Pain (headaches, body aches) •  A mood of apathy, anxiety, or irritability •   Sexual complaints • low energy, excessive tiredness •  reduced capacity for enjoyment.

41. Classification of Antidepressant Drugs • Five of antidepressant • Tricyclic antidepressants (TCA) • Monoamine oxidase inhibitors (MAO) • NA reuptake inhibitors • Serotonin-specific reuptake inhibitors (SSRIs) • Serotonin and NA-specific reuptake inhibitors

42. Most antidepressants are believed to improve by increasing NT • Catecholamine • 5-HT stores

43. Tricyclic antidepressant TCAs Imipramine

44. Pharmalogic effects • CNS -In the depressed patients , an elevation of mood occur 2-3 weeks after administration begins, the latency period can be as long as 4 weeks. -The imipramine blocks the re-uptake of serotonin and NA

45. Pharmalogic effects Autonomic nervous system Blocking m-receptor

46. Pharmalogic effects Cardovascular effect: • Hypotensin (blocking α receptor) • Tachycardia

47. Mechanism of TCA: • Blocking re-uptake of neurotransmitter • Norepinephrine(NA) • Serotonin(5-HT)

50. Clinic use • 1)Therapy depression • 2)Therapy enuresis • 3)Therapy anxiety and phobic-anxiety syndromes • 4)Obsessive-compulsive neurosis companied by depression