Psychotropic agents.

1. Kharkiv National Medical UniversityDepartment of Pharmacology and Medical Prescription Assistant, PhD. Gordiychuk Daria Psychotropic agents.

2. PLAN of LECTURE: • 1.Neuroleptics. • 2. Anxyolitics. • 3. Lithium salts. • 4. Sedatives.

3. Introduction • The term psychosis refers to a variety of mental disorders characterized by one or more of the following symptoms: • Diminished and distorted capacity to process information and draw logical conclusions; • Hallucinations, usually auditory or visual, but sometimes tactile or olfactory; • Delusions (false believes); • Incoherence or marked loosening of associations; • Catatonic or disorganized behavior; • Aggression or violence;

4. PSYCHOTROPIC DRUGS Drugs with depressivetype of action Neuroleptics(antipsychotics) Tranquilizers(anxiolytics) Sedative drugs Normotymics(tymoleptics, tymoanaleptics) Drugs withstimulativeaction Antidepressants Psychomotor stimulants Nootropic drugs Drugs which increase general tone (adaptogens) Psychotomimetics(psychodysleptics) LSD Cannabis sativa L.

5. Introduction cont. The psychotic disorders include: SCHIZOPHRENIA; the manic phase of BIPOLAR (manic-depressive) ILLNESS; acute idiopathic PSYCHOTIC ILLNESSES; other conditions marked by severe agitation.

6. Nature of Psychosis & Schizophrenia SCHIZOPHRENIA is a particular type of psychosis characterized mainly by a clear sensorium but a marked thinking disturbance. Because it affects young people, is often chronic and is usually highly disabling. There is a strong hereditary factor in its aetiology, and evidence suggestive of a fundamental biological disorder (neurodevelopmental disorder).

7. Schizophrenia - symptoms Positive Symptoms Hallucinations Delusions (bizarre, persecutory) Disorganized Thought Perception disturbances Inappropriate emotions Negative Symptoms Blunted emotions Anhedonia Lack of feeling Mood Symptoms Loss of motivation Social withdrawal Insight Demoralization Suicide FUNCTION Cognition New Learning Memory

8. Positive/active symptoms include thought disturbances, delusions, hallucinations. Negative/passive symptoms include social withdrawal, loss of drive, diminished affect, paucity of speech, impaired personal hygiene.

9. Neurochemical theories of psychosis Came mainly from analyzing the effects of antipsychotic and propsychotic drugs from pharmacology rather than from neurochemistry; The main neurochemical theories centre on dopamine and glutamate, although other mediators, particularly 5-HT, are also receiving attention.

10. Neurochemical theories cont. • The Dopamine theory of schizophrenia • It is based on multiple lines of evidence suggesting that excessive dopaminergic activity underlies schizophrenia; • It is still highly relevant to understanding the major dimensions of schizophrenia, such as positive and negative symptoms, cognitive impairment, and possibly depression.

11. Neurochemical theories cont. • The Dopamine theory of schizophrenia • However, the dopamine hypothesis is far from a complete explanation of all aspects of schizophrenia, especially the cognitive impairment.

12. The Serotonin Hypothesis of Schizophrenia • The Serotonin theory of schizophrenia • It has been found that 5-HT2A-receptor blockade is a key factor in the mechanism of action of the main class of atypical antipsychotic drugs such as clozapine and quetiapine; • 5-HT2A-receptors modulate the release of dopamine, norepinephrine, glutamate, GABA and acetylcholine in the cortex, limbic region, and striatum. 12

13. Neurochemical theories • The Glutamate theory of schizophrenia • Glutamate is the major excitatory neurotransmitter in the brain; • Phencyclidine and ketamine are noncompetitive inhibitors of the N-methyl-D-aspartate (NMDA) receptor can exacerbate both cognitive impairment and psychosis in patients with schizophrenia; • Hypofunction of NMDA receptors, located on GABAergic interneurons contributed to schizophrenia.

14. The effects of DA, 5-HT and NE on the brain functions

15. Antipsychotic Agents Are able to reduce psychotic symptoms in a wide variety of conditions, including schizophrenia, bipolar disorder, psychotic depression, senile psychoses, various organic psychoses, and drug-induced psychoses. They are also able to improve mood and reduce anxiety and sleep disturbances, but they are not the treatment of choice when these symptoms are the primary disturbance in nonpsychotic patients!!!

16. Antipsychotic Agents Their antipsychotic actions appear to reflect a blockade at dopamine and/or serotonin receptors; Many of these agents also block cholinergic, adrenergic, and histaminergic receptors. The undesirable side effects of these agents are often a result of actions at these other receptors.

17. Several important DA-ergic systems or pathways are now recognized in the brain: (1) The first pathway (the one most closely related to behavior) is the mesocorticaltract, which projects from cell bodies near the substantia nigra to the limbic system and neocortex. (2) The second system (the nigrostriatal tract) consists of neurons that project from the substantia nigra to the caudate and putamen; it is involved in the coordination of voluntary movement.

18. 3) The third pathway (the tuberoinfundibular tract) connects arcuate nuclei and periventricular neurons to the hypothalamus and posterior pituitary. !!!DA released by these neurons physiologically inhibits prolactin secretion!!!

19. Five DA receptors have been described, consisting of two separate families – the D1- and D2-like groups: (1) The D1-receptor is coded by a gene on chromo- some 5, increases cAMP by activation of adenylyl cyclase, and is located mainly in the putamen, nucleus accumbens, and olfactory tubercle. The second member of this family is D5. It is coded by a gene on chromosome 4, also increases cAMP, and is found in the hippocampus and hypothalamus. The therapeutic potency of the most antipsychotic drugs correlates strongly with their D2-affinity.

20. (2)The D2-receptor family includes D2, D3 and D4- receptors. D2-receptors is coded on chromosome 11, decreases cAMP (by inhibition of adenylyl cyclase), and inhibits calcium channels but opens potassium channels. It is found both pre- and postsynaptically on neurons in the caudate- putamen, nucleus accumbens, and olfactory tubercle. A second member of this family, the D3-receptor, also coded by a gene on chromosome 11, is thought to decrease cAMP and is located in the frontal cortex, medulla, and midbrain. The D4-receptoralso decreases cAMP.

21. Distribution and characteristics of DA receptors in the central nervous system

22. TYPICAL NEUROLEPTICS (D2-blockers) 1. Phenothiazines With aliphatic side chain Chlorpromazine (Aminazinum) Triflopromazine With piperidine side chain Thioridazine With piperazine side chain Trifluoperazine (Triftazinum) Fluphenazine decanoate 2. Butyrophenones Haloperidol Droperidol Trifluperidol 3. Thioxanthenes Chlorprothixene Thiothixene Flupenthixol Others: Pimozide Loxapine Classification of neuroleptics

24. Classification of neuroleptics (cont.) • Atypical neuroleptics • Clozapine • Olanzapine • Remazopride • Risperidone • Ziprasidone

25. Mechanisms of action of neuroleptics • Antipsychotic effect of TYPICAL neuroleptics is realized via blockade of dopamine receptors, mainly D2 receptors of the mesolimbic and mesocortical pathways. • Antipsychotic effect of ATYPICAL neuroleptics is realized via blockade of serotoninergic (5-HT2), relatively selective D4 receptors and α1- adrenoceptors.

26. Pharmacodynamic of neuroleptics 1. CNS: Innormal individualsantipsychotics produce neuroleptic syndrome – indifference to surroundings, deficiency of thought, psychomotor slowing, emotional quieting, reduction in initiative. In psychotic patients neuroleptics reduce irrational behaviour, agitation and aggresiveness. They control psychotic symptomatology. Disturbed thought and behaviour are gradually normalized, anxiety is relieved. Hyperactivity, hallucinations, and delusions are suppressed. NB!!! The psychosedative effect is produced immediately while the antipsychotic effect takes a week to develop. Tolerance develops only to the psychosedative effect.

27. Pharmacodynamic of neuroleptics cont. Thethermoregulatory centre is turned off, rendering the patient poikilothermic (body tem- perature falls if surroundings are cold and the contrary). The medullary, respiratory and other vital centres are not affected, except of very high doses. It is very difficult to produce coma with neuroleptics. Antiemetic effect is exerted through the CTZ ( D-ergic activity). Almost all neuroleptics, except thioridazine, have this effect. However, they are ineffective in motion sickness. Antipsychotic agents produce a state of rigidity and immobility (catalepsy).

28. Pharmacodynamic of neuroleptics cont. 2. ANS: Neuroleptics have varying degrees of α-adrenergic blocking activity and produce hypotension (primarily postural). The hypotensive effect is more marked after parenteral administration. Anticholinergicpropertyof neuroleptics is weak. The phenothiazines have weak H1-antihistaminic and anti-5-HT actions as well. Promethazine has strong sedative, and H1-antihistaminic action. 3. Endocrine system: Neuroleptics consistently increase prolactin release by blocking the inhibitory action of DA on pituitary gland. This may result in galactorrhea and gynecomastia. They reduce gonadotrophins, ACTH, GH and ADH secretion.

29. Psychiatric INDICATIONS of neuroleptics 1.Schizophreniais the primary indication for neuroleptics. Unfortunately, many patients show little response. 2.Antipsychotics are also indicated for schizoaffective disorders, which share characteristics of both schizophrenia and affective disorders. The psychotic aspects of this illness require treatment with antipsychotic drugs, which may be used with other drugs such as antidepressants, lithium, or valproates.

30. Whilst a typical antipsychotics should provide adequate treatment of positive symptoms including hallucinations and delusions in at least 60% of cases, patients are often left with unresolved negative symptoms such as apathy, flattening of affect, and alogia. Evidence suggests that clozapine and the newer atypicals have a significant advantage over typical drugs against negative symptoms.

31. Psychiatric INDICATIONS of neuroleptics The manic phase in bipolar affective disorder often requires treatment with neuroleptics (chlorpromazine, haloperidol), though lithium or valproic acid supplemented with high-potency benzodiazepines (e.g. lorazepam or clonazepam) may suffice in milder cases. !!! Recent controlled trials support the efficacy of monotherapy with atypical antipsychotics in the acute phase (up to 4 weeks) of mania, and olanzapine has been approved for this indication!!!

32. Psychiatric INDICATIONS of neuroleptics Nonmanic excited states may also be managed by antipsychotics, often in combination with benzodiazepines.Other indications for the use of antipsychotics include disturbed behavior in patients with Alzheimer's disease, and psychotic depression. Antipsychotics are not indicated for the treatment of various withdrawal syndromes, e.g. opioid withdrawal. In small doses antipsychotics have been promoted (wrongly) for the relief of anxiety associated with minor emotional disorders, but the anxiolytic agents are preferred.

33. Nonpsychiatric indications (1) Most older antipsychotics, with the exception of thioridazine, have a strong ANTIEMETIC EFFECT. This action is due to D2-RECEPTOR BLOCKADE, both centrally (in the chemoreceptor trigger zone of the medulla) and peripherally (on receptors in the stomach). Some drugs, such as prochlorperazine are promoted only as antiemetics.Phenothiazines with shorter side chains have consi- derable H1-receptor-blocking action and used for (2)relief ofpruritus or, in the case of promethazine, as (3)preoperative sedatives. The butyrophenone droperidolis used in combination with an opioid, fentanyl, in neurolept-anaesthesia (-analgesia).

34. Adverse reactions of neuroleptics: • – behavioral effects:The older typical antipsychotic drugs are unpleasant • to take. Many patients stop taking these drugs • because of the adverse effects, which may be • soften by giving small doses during the day and • the major portion at bedtime. • A “pseudodepression” that may be due to drug-induced akinesia usually responds to treatment with antiparkinsonian drugs.Other pseudodepressions may be due to higher doses; the decreasing the dose may relieve the symptoms. • Toxic-confusional states may occur • with very high doses of drugs that have • prominent antimuscarinic actions.

35. Adverse reactions of neuroleptics cont. • Neurologic effects: • Extrapyramidal reactions occurring early during • treatment with older agents include typical neuroleptics. • a)Parkinson's syndrome, akathisia (uncontrollable • restlessness), and acute dystonic reactions • (spastic retrocollis or torticollis). • NB!!! Parkinsonism can be treated, with conventional antiparkinsonian drugs of the antimuscarinic type or, in rare cases, with amantadine.

36. Adverse reactions of neuroleptics cont. b)Tardive dyskinesia- persistent involuntary movements of mouth, tongueor face. Autonomic nervous system side effectsAntimuscarinic (atropine-like) adverse effects: urinary retention, dry mouth, midriasis. Alpha-blockade: Orthostatic hypotension or impaired ejaculation should be managed by switching to drugs with less marked adrenoceptor-blocking actions.

37. Adverse reactions of neuroleptics cont. Ocular complicationsDeposits in the anterior portions of the eye (cornea and lens) are a common complication of Chlorpromazine therapy. Thioridazine is the only antipsychotic drug that causes retinal deposits, which in advanced cases may resemble retinitis pigmentosa. The deposits are usually associated with “browning” of vision. The maximum daily dose of thioridazine has been limited to 800 mg to reduce the possibility of this complication.

38. Adverse reactions of neuroleptics cont. Metabolic and endocrine side effectsWeight gain is very common, especially with clozapine and olanzapine, and requires monitoring of food intake, especially carbohydrates. Hyperglycemia may develop. Hyperprolactinemia in women results in the amenorrhea – galactorrhea syndrome and infertility; in men loss of libido, impotence, gynecomastia and infertility may result. Toxic or allergic reactionsAgranulocytosis, cholestatic jaundice, and skin eruptions occur rarely with the high-potency antipsychotic drugs currently used.

39. Adverse reactions of neuroleptics cont. Neuroleptic malignant syndromeThis life-threatening ADR occurs in patients who are extremely sensitive to the extrapyramidal effects of antipsychotics. The initial symptom is marked muscle rigidity. If sweating is impaired, as it often is during treatment with anticholinergic drugs, fever may ensue, often reaching dangerous levels. The stress leukocytosis and high fever associated with this syndrome suggest an infectious process. Autonomic instability, with altered blood pressure and pulse rate, is often present. Creatinekinase isoenzymes are usually elevated, reflecting muscle damage.

40. Adverse reactions of neuroleptics cont. • Neuroleptic malignant syndrome cont. • This syndrome is believed to result from an excessively • rapid blockade of postsynaptic DA receptors. A severe • form of extrapyramidal syndrome follows. • Early in the course, vigorous treatment of the extrapyramidal syndrome with antiparkinsonian drugsis worthwhile. • Muscle relaxants, particularly diazepam, are often • useful. Other muscle relaxants, such as dantrolene, • or DA agonists, such as bromocriptine, have been • reported to be helpful. • If fever is present, cooling by physical measures should be tried.

41. ANXIOLYTICS (tranquilizers)

42. Antianxiety drugs (anxyolitics) • Anxiolytic drugs are designed for treatment of anxiety, panic disorders and phobias. • Anxiety is unpleasant emotional state characterised by uneasiness, discomfort, fear about some defined or undefined threat.

43. 1.BENZODIAZEPINES a). Short acting Oxazepam Triazolam b). Intermediate acting Lorazepam Alprazolam Estazolam Temazepam c). Long acting Chlordiazepoxide (Chlozepidum) Clonazepam Clorazepate Diazepam (Sibazonum) Phenazepamum Medazepam (Mezapam, Rudotel) Antianxiety drugs (classification)

44. Antianxiety drugs classification cont. 2. PROPANDIOL DERIVATIVE • Meprobamate (Meprotanum) 3. DIPHENYLMETHANE DERIVATIVE • Benactyzime (Amizylum) 4. AZAPIRONES • Buspirone • Gepirone • Tofizopam (Grandaxin) 5. MISCELLANEOUS • Trimetozine (Trioxazin) • Hydroxyzine • Zolpidem

46. Mechanism of BZD action When GABA binds with the GABAA-receptor, the permeability of the central pore of the receptor to chloride ions increases (hyperpolarization) and decreasis excitability. Benzodiazepines(BDZs) enhance the effectiveness of GABA by increasing the frequency of the opening of the chloride ions. BDZs are agonists at the receptor and the FLUMAZENIL (antagonist) prevents agonists from binding at the receptor site.

47. A model of the GABAA receptor-chloride ion channel macromole- cular complex

49. CNS action and classification (medical use) of BDZs The action of all BDZs is qualitatively similar, but there are prominent differences in selectivity and time course of effect: different members of BDZs are used for different therapeutic purposes. In contrast to barbiturates BDZs exert relatively selective anxiolytic (antianxiety), hypnotic (euhypnotic), muscle relaxant, and anticonvulsant (antiepileptic) effects. • Anxiolytic effect have all BDZs: • Alprazolam, Bromazepam (Lexotan – tab. 3 mg), • Chlordiazepoxide, Diazepam, Lorazepam, • Мedazepam (daily tranquillisant), Nordiazepam,etc.

50. CNS action and classification (medical use) of BDZs cont. • Hypnotic (euhypnotic) effect: • Bromazepam, Flurazepam, Flunitrazepam • Nitrazepam, Midazolam, Triazolam, etc. • Anticonvulsive (antiepileptic) BDZs: • Clonazepam, Clorazepate, Diazepam, • Lorazepam, Nitrazepam • Central muscle relaxants: • Diazepam, Tetrazepam