Kharkiv National Medical University Department of Pharmacology and

Kharkiv National Medical University Department of Pharmacology and Medical Prescription Assistant, Ph. D. Gordiychuk Daria Psychotropic agents.

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

Introduction n The term psychosis refers to a variety of disorders characterized by one or more following symptoms: 1) 2) 3) 4) 5) 6) mental of the 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;

PSYCHOTROPIC DRUGS Drugs with depressive type of action 1. 2. 3. 4. Neuroleptics (antipsychotics) Tranquilizers (anxiolytics) Sedative drugs Normotymics (tymoleptics, tymoanaleptics) Drugs with stimulative action 1. 2. 3. 4. Antidepressants Psychomotor stimulants Nootropic drugs Drugs which increase general tone (adaptogens) Psychotomimetics (psychodysleptics) 1. 2. LSD Cannabis sativa L.

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

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

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

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

Neurochemical theories of psychosis n n 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.

Neurochemical theories cont. I. n n 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.

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

The Serotonin Hypothesis of Schizophrenia II. n n The Serotonin theory of schizophrenia It has been found that 5 -HT 2 A-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 -HT 2 A-receptors modulate the release of dopamine, norepinephrine, glutamate, GABA and acetylcholine in the cortex, limbic region, and striatum. 12

Neurochemical theories III. The Glutamate theory of schizophrenia n 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; n n Hypofunction of NMDA receptors, located on GABAergic interneurons contributed to schizophrenia.

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

Antipsychotic Agents n n 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!!!

Antipsychotic Agents n n 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.

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 mesocortical tract, 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.

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!!!

Five DA receptors have been described, consisting of two separate families – the D 1 - and D 2 -like groups: (1) The D 1 -receptor is coded by a gene on chromosome 5, increases c. AMP by activation of adenylyl cyclase, and is located mainly in the putamen, nucleus accumbens, and olfactory tubercle. The second member of this family is D 5. It is coded by a gene on chromosome 4, also increases c. AMP, and is found in the hippocampus and hypothalamus. The therapeutic potency of the most antipsychotic drugs correlates strongly with their D 2 -affinity.

(2) The D 2 -receptor family includes D 2, D 3 and D 4 receptors. D 2 -receptors is coded on chromosome 11, decreases c. AMP (by inhibition of adenylyl cyclase), and inhibits calcium channels but opens potassium channels. It is found both pre- and postsynaptically on neurons in the caudateputamen, nucleus accumbens, and olfactory tubercle. A second member of this family, the D 3 -receptor, also coded by a gene on chromosome 11, is thought to decrease c. AMP and is located in the frontal cortex, medulla, and midbrain. The D 4 -receptor also decreases c. AMP.

Distribution and characteristics of DA receptors in the central nervous system

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

Classification of neuroleptics (cont. ) II. Atypical neuroleptics n n n Clozapine Olanzapine Remazopride Risperidone Ziprasidone

Mechanisms of action of neuroleptics Antipsychotic effect of TYPICAL neuroleptics is realized via blockade of dopamine receptors, mainly D 2 receptors of the mesolimbic and mesocortical pathways. n Antipsychotic effect of ATYPICAL neuroleptics is realized via blockade of serotoninergic (5 HT 2), relatively selective D 4 receptors and α 1 - adrenoceptors. n

Pharmacodynamic of neuroleptics 1. CNS: In normal individuals antipsychotics 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.

Pharmacodynamic of neuroleptics cont. The thermoregulatory centre is turned off, rendering the patient poikilothermic (body temperature 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).

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. Anticholinergic property of neuroleptics is weak. The phenothiazines have weak H 1 -antihistaminic and anti-5 -HT actions as well. Promethazine has strong sedative, and H 1 -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.

Psychiatric INDICATIONS of neuroleptics 1. Schizophrenia is 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

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.

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 !!!

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.

Nonpsychiatric indications (1) Most older antipsychotics, with the exception of thioridazine, have a strong ANTIEMETIC EFFECT. This action is due to D 2 -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 considerable H 1 -receptor-blocking action and used for (2) relief of pruritus or, in the case of promethazine, as (3) preoperative sedatives. The butyrophenone droperidol is used in combination with an opioid, fentanyl, in neurolept-anaesthesia (-analgesia).

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 druginduced 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.

Adverse reactions of neuroleptics cont. - Neurologic effects: 1. 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.

Adverse reactions of neuroleptics cont. b)Tardive dyskinesia - persistent involuntary movements of mouth, tongue or face. Autonomic nervous system side effects Antimuscarinic (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.

Adverse reactions of neuroleptics cont. Ocular complications Deposits 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

Adverse reactions of neuroleptics cont. Metabolic and endocrine side effects Weight 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 reactions Agranulocytosis, cholestatic jaundice, and skin eruptions occur rarely with the high-potency antipsychotic drugs currently used.

Adverse reactions of neuroleptics cont. Neuroleptic malignant syndrome This 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

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 drugs is 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.

ANXIOLYTICS (tranquilizers)

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

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

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

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

A model of the GABAA receptorchloride ion channel macromol ecular complex

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 Anxiolytic effect have all BDZs: relaxant, and anticonvulsant (antiepileptic) Alprazolam, Bromazepam (Lexotan – tab. 3 effects. mg), Chlordiazepoxide, Diazepam, Lorazepam,

CNS action and classification (medical use) of BDZs cont. Hypnotic (euhypnotic) effect: Bromazepam, Flurazepam, Flunitrazepam Nitrazepam, Midazolam, Triazolam, etc. Anticonvulsive (antiepileptic) BDZs: Clonazepam, Clorazepate,

Pharmacokinetics of BDZs: BDZs are effective after administration by mouth but enter the circulation at very different rates that are reflected in the speed of onset of action, e. g. alprazolam is rapid, oxazepam is slow. The liver metabolizes them, usually to inactive metabolites, but some compounds produce active metabolites with long t 1/2 which greatly extends drug action, e. g. chlordiazepoxide, clorazepate, and diazepam.

Biotransformation of benzodiazepines

Medical uses of tranquilizers Anxiolytic action Treatment of neurosis, accompanied by fear, anxiety, exertion, increased irritability, insomnia; n In case of headache and heart pain of neurotic origin, so called organic neurosis; n In case of abstinence in alcohol and drugs addicts; n In case of diencephalons crisis (sybazon). Tranquilizers do not diminish productive symptoms of psychosis! n

Medical uses of tranquilizers cont. n Hypnotic action – they cause sleep, which is very close to physiological one according to its parameters: Nitrazepam Phenazepam Diazepam Chlozepid n Depression of CNS – for atharalgesia: Sybazon Midazolam

Medical uses of tranquilizers cont. Anti-seizure and myorelaxing action (depression of CNS structures, braking polysynaptic spinal reflexes) sybazon, fenazepam n n In a case of seizures of any etiology (epileptic status, tetanus, poisoning with seizure causing poisons) sybazon is introduced intravenously (intramuscularly) – 2 -4 ml of 0, 5 % solution repeatedly (maximal daily dose – 14 ml); To eliminate muscle tension in a case of radiculitis, arthritis, myositis, bursitis.

Seizures (tetanus) drug of a first choice - Sibazon

SIDE EFFECT OF TRANQUILIZERS n Psychological and physical addiction; Prophylaxis: 1. Duration of treatment course should not be more than 2 months; 2. Repeated course – not earlier than after 3 weeks break. Sleepiness, reeling walk, retarded reactions; n tranquilizers should not be administered in ambulatories to people whose professions are connected with quick reactions Paradox reaction of excitation, insomnia; Dizziness, decreasing of libido, disturbances of menstrual cycle; n Uncontrolled urination, defecation, ataxia, dysartria; n Acute poisoning in case of overdosing. n n

FLUMAZENIL (ANEXAT) ANTAGONIST OF BDZs receptors

NB!!! Combination of tranquilizers with alcohol-containing drinks is absolutely contraindicated (pathological alcohol intoxication)

Azapirones Buspirone is a selective partial agonsist of presynaptic 5 -HT 1 A-receptors. By stimulating these receptors it reduces activity of dorsal raphe 5 -HT-ergic neurons. Buspirone relieves mild to moderate generalized anxiety, but is ineffective in severe cases (panic reactions and obsessive compulsive disorder). Sedative H 1 -blockers Hydroxyzine is an H 1 -blocker with sedative, antiemetic, antimuscarinic, and spasmolytic effects. It is effective in pruritus, and urticaria.

LITHIUM salts LITHIUM CARBONATE

INDICATIONS FOR ADMINISTRATION OF LITHIUM DRUGS n Prophylaxis and treatment of endogen (affective) psychosis: maniac-depressive, schizo-affective, organic affective n Prophylaxis and treatment of affective disturbances in patients with epilepsy, chronic alcoholism, in psychopaths

Method of lithium drugs administration It is administered orally; n Treatment concentration of lithium in blood – 0, 6 -0, 8 mmol/l (not more than 1, 5 -1, 6 mmol/l); n The effect develops after few days – 5 -6 months; n Small width of therapeutic action (treatment with lithium drugs needs the same attentiveness from the doctor as treatment with insulin). n

Acute poisoning with lithium drugs It develops if the concentration is over 1, 5 -2 mmol/l Development of constant nausea and tremor during treatment with lithium means that the dose should be decreased SYMPTOMS OF POISONING n Nausea, vomiting, diarrhea n Tremor, general muscular weakness, twitching muscles n Noise in the ears, unclear vision, somnolence, dysartria n Changes of handwriting: massive, bold n Local neurological symptoms, meningism n Oliguria n Changes in ECG, arrhythmia, decreasing of BP n Sopor, coma n Death – from hypostatic pneumonia

Treatment of intoxication with lithium drugs n n n n A lot of drinking, 10% solution of sodium chloride (till 300 ml/day), 5% solution of sodium hydrocarbonate (till 300 ml/day) intravenously; Mannit, urea (saluretics are contraindicated!); Pyracetam, vinpocetin; Prophylaxis of pneumonia – antibiotics; Control of water-electrolyte balance, acid-base balance; Symptomatic therapy, for example, in case of seizures – sybazon; Haemodialysis if necessary.

Prophylaxis of intoxication with lithium drugs Salt in day ration should not be limited n A lot of drinking n Do not indicate saluretics, sweatstimulating drugs n Heavy physical work or other situations, accompanied by considerable sweating should be avoided n

SEDATIVE drugs

SEDATIVE DRUGS classification n Bromides: Na-bromide, K-bromide Drugs of plant origin: Valeriana, dog nettle, melissa, passiflora etc. Combined agents: Valocormidum, Corvalolum etc. !!!They do not cause addiction, somnolence, myorelaxation, ataxia!!!

Valeriana

MEDICAL USES OF SEDATIVE DRUGS Neurosis n Stress n Neurasthenia n Hysteria n Increased irritability n Insomnia n Primary stages of essential hypertension n

Bromism (brom acute poisoning) Cause – accumulation of bromide ions in organism in case of their prolonged administration as a result of material accumulation; n Symptoms: rhinitis, cough, conjunctivitis, skin rash, general weakness, memory disorders; n Treatment: sodium chloride (10 -20 g / day), a lot of drinking (3 -5 l / day), regular and frequent cleaning of skin and digestive tract. n

Thank your for attention!!!