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Pharmacology Section 10 Neuroleptic Drugs. Marta Jóźwiak-Bębenista Department of Pharmacology Medical University of Lodz

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Presentation on theme: "Pharmacology Section 10 Neuroleptic Drugs. Marta Jóźwiak-Bębenista Department of Pharmacology Medical University of Lodz"— Presentation transcript:

1 Pharmacology Section 10 Neuroleptic Drugs. Marta Jóźwiak-Bębenista Department of Pharmacology Medical University of Lodz

2 Neuroleptic Drugs = antischizophrenic drugs, antipsychotic drugs or major tranquilizers

3 Schizophrenia

4 What is the difference? PSYCHOSIS Psychosis is a thought disorder characterized by disturbances of reality and perception, impaired cognitive functioning, and inappropriate or diminished affect (mood). Psychosis denotes many mental disorders. SCHIZOPHRENIA Schizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking disturbance.

5 Schizophrenia Schizophrenia is characterized by profound disruption in cognition and emotion, affecting the most fundamental human attributes: language, thought, perception, affect, and sense of self Schizophrenia is characterized by profound disruption in cognition and emotion, affecting the most fundamental human attributes: language, thought, perception, affect, and sense of self

6 Prevalence of schizophrenia 1.1% population over the age of % population over the age of mln people worldwide suffer from schizophrenia 51 mln people worldwide suffer from schizophrenia 12 million people in China (a rough estimate based on the population) 8.7 million people in India (a rough estimate based on the population) 2.2 million people in USA 285,000 people in Australia Over 280,000 people in Canada Over 250,000 diagnosed cases in Britain

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8 Etiology of Schizophrenia Idiopathic Biological Correlates 1) Genetic Factors 2) Neurodevelopmental abnormalities. 3) Environmental stressors.

9 The risk of getting schizophrenia

10 Dopamine Theory of Schizophrenia Many lines of evidence point to the aberrant increased activity of the dopaminergic system as being critical in the symptomatology of schizophrenia. Many lines of evidence point to the aberrant increased activity of the dopaminergic system as being critical in the symptomatology of schizophrenia.

11 Dopaminergic system There are 4 major pathways for the dopaminergic system in the brain: The mesolimbic pathway The mesolimbic pathway from substantia nigra to limbic system, functions of memory, emotion, arousal, and pleasure The mesocortical pathway The mesocortical pathway from substantia nigra to neocortex, cognition, social behavior, planning, problem solving, motivation, and reinforcement in learning The nigrostriatal pathway The nigrostriatal pathway from the substantia nigra to the striatum, coordination of involuntary movement from the substantia nigra to the striatum, coordination of involuntary movement The tuberoinfundibular pathway The tuberoinfundibular pathway from the hypothalamus to the pituitary gland, secretion of certain hormones (prolactin) from the hypothalamus to the pituitary gland, secretion of certain hormones (prolactin)

12 THE DOPAMINERGIC SYSTEM

13 Catecholamines Tyrosine  Tyrosine hydroxylase L-Dopa  Dopa decarboxylase Dopamine (DA)  Dopamine  hydroxylase Norepinephrine (NE) (Noradrenaline) Phenylethanolamine-  -N-methyltransferase  -N-methyltransferase Epinephrine (EPI) (Adrenaline)

14 Dopamine Synapse DA L-DOPA Tyrosine

15 Dopamine receptors D 1, D 5 dopamine receptors -  cAMP by activation of adenylyl cyclase D 1, D 5 dopamine receptors -  cAMP by activation of adenylyl cyclase D 1 – putamen, nucleus acumbens D 5 – hypothalamus, hippocampus D 2, D 3, D 4 dopamine receptors -  cAMP by inhibition of adenylyl cyclase, inhibits Ca 2+ channels and open K + channels D 2, D 3, D 4 dopamine receptors -  cAMP by inhibition of adenylyl cyclase, inhibits Ca 2+ channels and open K + channels D 2 – caudate–putamen, nucleus acumbens D 3 – frontal cortex, medulla, midbrain There are at least five subtypes of receptors:

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17 The dopamine hypothesis (1): Most antipsychotic drugs strongly block postsynaptic D2 receptors in the CNS (meso- limbic system) Most antipsychotic drugs strongly block postsynaptic D2 receptors in the CNS (meso- limbic system) Drugs that increase dopaminergic activity aggravate schizophrenia and produce psychosis de novo Drugs that increase dopaminergic activity aggravate schizophrenia and produce psychosis de novo Increased dopamine receptor density has been found post mortem in brains of schizophrenics Increased dopamine receptor density has been found post mortem in brains of schizophrenics

18 The dopamine hypothesis (2): PET has shown increased dopamine receptor density in schizophrenics PET has shown increased dopamine receptor density in schizophrenics Successful treatment of schizophrenics changes the amount of homovanilinic acid – metabolite of dopamine in cerebrospinal fluid, plasma and urine. Successful treatment of schizophrenics changes the amount of homovanilinic acid – metabolite of dopamine in cerebrospinal fluid, plasma and urine.

19 SCHIZOPHRENIA Dysfunction of DA- ergic system: Hyperactivity of DA system ( mesolimbic pathway) Hypo-activity in frontal cortex ( mesocortical pathway) Dysfunction of 5- HT, GABA and glutamate –ergic systems

20 Onset of schizophrenia Onset - early adulthood, between the ages of 15 and 25. Onset - early adulthood, between the ages of 15 and 25. Men tend to develop schizophrenia slightly earlier (16 – 25 years old) than women (25 – 30 years old). Men tend to develop schizophrenia slightly earlier (16 – 25 years old) than women (25 – 30 years old). The average age of onset is 18 in men and 25 in women The average age of onset is 18 in men and 25 in women

21 The Course of Schizophrenia

22 Early intervention and early use of new medications lead to better medical outcomes for the individual Early intervention and early use of new medications lead to better medical outcomes for the individual The earlier someone with schizophrenia is diagnosed and stabilized on treatment, the better the long-term prognosis for their illness The earlier someone with schizophrenia is diagnosed and stabilized on treatment, the better the long-term prognosis for their illness Teen suicide is a growing problem and teens with schizophrenia have approximately a 50% risk of attempted suicide Teen suicide is a growing problem and teens with schizophrenia have approximately a 50% risk of attempted suicide Anti-psychotic medications are the generally recommended treatment for schizophrenia !!! Anti-psychotic medications are the generally recommended treatment for schizophrenia !!! If medication for schizophrenia is discontinued, the relapse rate is about 80 percent within 2 years. With continued drug treatment, only about 40 percent of recovered patients will suffer relapses. If medication for schizophrenia is discontinued, the relapse rate is about 80 percent within 2 years. With continued drug treatment, only about 40 percent of recovered patients will suffer relapses.

23 Outcomes of schizophrenia After 30 years of diagnosed schizophrenia 25% Completely Recover 25% Completely Recover 35% Much Improved, relatively independent 35% Much Improved, relatively independent 15% Improved, but require extensive support network 15% Improved, but require extensive support network 10% Hospitalized, unimproved 10% Hospitalized, unimproved 15% Dead (Mostly Suicide) 15% Dead (Mostly Suicide)

24 Symptoms of schizophrenia (1): Positive Positive appear to reflect an excess or distortion of normal functions: * delusions (paranoid, reference, somatic, delusions of grandeur) * halucinations (visual, auditory, tactile, olfactory, gustatory) * disorganized speech = „word salad” *disorganized or catatonic behavior Negative Negative appear to reflect a diminution or loss of normal functions: * lack of emotion* low energy * affective flattening * low motivation *inappropriate social skills * alogia

25 The terms "positive" and "negative" may be confusing. They should not be interperated as "good" and "bad" symptoms.

26 Symptoms of schizophrenia (2): Cognitive Cognitive disorganized thinking disorganized thinking slow thinking slow thinking difficulty in understanding difficulty in understanding poor concentration poor concentration poor memory poor memory difficulty with expressing thoughts difficulty with expressing thoughts difficulty with integrating thoughts, feelings and behavior difficulty with integrating thoughts, feelings and behavior

27 Symptoms of schizophrenia (3): Disorganized symptoms (?) Disorganized symptoms (?) * thought disorder * confusion * disorientation * memory problems Disorganized symptoms may reflect an underlying dysfunction common to several psychotic disorders, rather than being unique to schizophrenia.

28 Schizophrenia Active phase Hallucinations and delusions are prominent symptoms Residual phase

29 U.S. diagnostic criteria for schizophrenia (1) A. Characteristic symptoms: ≥2 during a 1- month period : A. Characteristic symptoms: ≥2 during a 1- month period :delusionshalucinations disorganized speech disorganized behavior negative symptoms

30 U.S. diagnostic criteria for schizophrenia (2) Only one Criterion A symptom is required if delusions are bizarre or hallucinations consist of a voice keeping up a running commentary on the person’s behavior or thoughts, or two or more voices conversing with each other. Only one Criterion A symptom is required if delusions are bizarre or hallucinations consist of a voice keeping up a running commentary on the person’s behavior or thoughts, or two or more voices conversing with each other.

31 U.S. diagnostic criteria for schizophrenia (3) B. Social/occupational dysfunction B. Social/occupational dysfunctionwork interpersonal relations self-care C. Duration C. Duration continuous signs of the disturbance persist for at least 6 months, including 1 month of symptoms from Criterion A and prodromal symptoms)

32 U.S. diagnostic criteria for schizophrenia (4) D. Schizoaffective and mood disorder exclusion D. Schizoaffective and mood disorder exclusion no major depressive, manic or mixed episodes have occurred with the active-phase symptoms E. Substance/general medical condition exclusion E. Substance/general medical condition exclusion F. Relationship to a pervasive developmental disorder F. Relationship to a pervasive developmental disorder

33 Types of schizophrenia Paranoid schizophrenia Paranoid schizophrenia Disorganized schizophrenia (hebephrenic) Disorganized schizophrenia (hebephrenic) Catatonic schizophrenia Catatonic schizophrenia Residual schizophrenia Residual schizophrenia Schizoaffective disorder Schizoaffective disorder Undifferentiated schizophrenia Undifferentiated schizophrenia

34 Neuroleptic drugs ANTI-PSYCHOTIC DRUGS TYPICAL NEUROLEPTICS ATYPICAL NEUROLEPTICS PHENOTHIAZINES THIOXANTHENES BUTYRO- PHENONES BENZISOXAZOLES DIBENZO- DIAZEPINES

35 Phenothiazines Chlorpromazine Chlorpromazine Fluphenazine Fluphenazine Prochlorperazine Prochlorperazine Promethazine Promethazine Thioridazine Thioridazine

36 Other groups of typical neuroleptics Thioxanthene ThioxantheneThiothixene Butyrophenone ButyrophenoneHaloperidol

37 Typical neuroleptics – mechanism of action

38 Mechanisms of Action of Antipsychotics conventional antipsychotics  D2 receptor blockade of postsynaptic in the mesolimbic pathway atypical antipsychotics  D2 receptor blockade of postsynaptic in the mesolimbic pathway to reduce positive symptoms;  enhanced dopamine release and 5-HT 2A receptor blockade in the mesocortical pathway to reduce negative symptoms;  other receptor-binding properties may contribute to efficacy in treating cognitive symptoms, aggressive symptoms and depression in schizophrenia

39 Atypical neuroleptics Benzisoxazoles BenzisoxazolesRisperidonZiprasidon Dibenodiazepines DibenodiazepinesClozapineQuetiapineOlanzapine

40 Atypical neuroleptics - mechanism of action

41 What is the clinical difference between older and newer drugs? New antipsychotic drugs has been shown to be more effective than older ones for treating negative symptoms New antipsychotic drugs has been shown to be more effective than older ones for treating negative symptoms

42 Actions of neuroleptic drugs (1) Dopamine receptor Dopamine receptor all, particularly: haloperidol, fluphenazine, thiothixene Muscarinic receptor Muscarinic receptor thioridazine, chlorpromazine  - Adrenergic receptor  - Adrenergic receptorchlorpromazine Serotonin receptor Serotonin receptor risperidone, clozapine H1 - Histamine receptor H1 - Histamine receptor promethazine, chlorpromazine

43 Actions of neuroleptic drugs (2) Antipsychotic actions: Antipsychotic actions: reduce the halucinations reduce spontaneous physical movement Occur after 4 – 6 weeks of treatment Extrapyramidal effects: Extrapyramidal effects: Parkinsonian symptoms akathisia tardive dyskinesia

44 Actions of neuroleptic drugs (3) Antiemetic effect (exept thioridazine) Antiemetic effect (exept thioridazine) Antimuscarinic effect: Antimuscarinic effect: blurred vision, dry mouth, sedation, confusion, inhibition of GI and urinary smooth muscle Other effects: Other effects: hypotension, lightheadness

45 Neuroleptic drugs are not curative and do not eliminate the fundamental thinking disorder, but often do permit the psychotic patient to function in a supportive environment Neuroleptic drugs are not curative and do not eliminate the fundamental thinking disorder, but often do permit the psychotic patient to function in a supportive environment

46 Therapeutic uses Schizophrenia Schizophrenia Other psychosis Other psychosis Schizoaffective disorders Schizoaffective disorders Delirium Delirium Prevention of severe nausea and vomiting (vertigo, motion sickness, cancer chemo- and radiotherapy) Prevention of severe nausea and vomiting (vertigo, motion sickness, cancer chemo- and radiotherapy) Tranquilizers Tranquilizers In combination with narcotic analgesics for treatment of chronic pain with severe anxiety In combination with narcotic analgesics for treatment of chronic pain with severe anxiety Intractable hiccups Intractable hiccups

47 Pharmacokinetics Neuroleptics are absorbed after oral administration Neuroleptics are absorbed after oral administration Pass through blood – brain barrier Pass through blood – brain barrier Bind well to plasma proteins, highly lipid-soluble Bind well to plasma proteins, highly lipid-soluble Are metabolized in liver by P-450 system Are metabolized in liver by P-450 system

48 Adverse effects (1) Acute Acute dystonia Medium- term Akathisia Parkinsonism Chronic Tardive dyskinesia Tardive dystonia Neurologic effects due to D2 receptor blockade Neurologic effects due to D2 receptor blockade

49 Acute dystonia Fixed muscle postures with spasm: clenched jaw muscles protruding tongue opisthotonos torticollis oculogyric crisis (mouth open, head back, eyes staring upwards)  In the beginning of treatment  Common in young males  Treatment with anticholinergic drugs (procyclidine 5-10mg or benztropine i.m or i.v)

50 Akathisia motor restlessness affect lower limb very distressing to the patient Treatment – reduction of the drug dose.

51 Parkinsonism induced by blockade of D2 receptors in the striatum !!! appear after a few days to weeks Treatment: anticholinergic drugs (e.g procyclidine) reduction of dose switching to an atypical antipsychotic

52 Tardive dyskinesia Tardive dyskinesia orofacial dyskinesia -lip smacking and tongue rotating. Tardive dystonia Tardive dystonia specific movements of the head, neck and trunk. There is no effective treatment !!! They are irreversible. Appear after months to years of drug treatment Clozapine and Risperidone have a low potential for causing extrapyramidal symptoms and lower risk of tardive dyskinesia

53 Adverse effects (2): Anticholinergic effects due to muscarinic blockade: Anticholinergic effects due to muscarinic blockade: loss of accomodation, dry mouth, blurred vision, constipation, urinary retention Ortostatic hypotension due to  -adrenergic blockade Ortostatic hypotension due to  -adrenergic blockade Neuroendocrine adverse effects due to D2 blockade in the tuberoinfundibular pathway : Neuroendocrine adverse effects due to D2 blockade in the tuberoinfundibular pathway : Amenorrhoea-galactorrhoea Amenorrhoea-galactorrhoea Infertility Infertility Impotence, Failure to ejaculate Impotence, Failure to ejaculate Drowsiness Drowsiness Weight gain, Weight gain, Urticaria, dermatitis, rashes, dermal photosensitivity Urticaria, dermatitis, rashes, dermal photosensitivity

54 Adverse effects of clozapine Bone marrow suppression Bone marrow suppression Cardiovascular side effects Cardiovascular side effects Diabetes Diabetes Adverse effects of chlopromazine Cholestatic jaundice Cholestatic jaundice

55 Neuroleptic Malignant Syndrome Precise pathophysiology unknown – deranged dopaminergic function ? Precise pathophysiology unknown – deranged dopaminergic function ? It is an idiosyncratic reaction that appears from a few days to weeks after beginning treatment, but can occur anytime. It is an idiosyncratic reaction that appears from a few days to weeks after beginning treatment, but can occur anytime. The mortality – 20% in untreated (bromocriptine – D1/D2 agonist; dantrolene – sceletal muscle relaxant; supportive treatment) The mortality – 20% in untreated (bromocriptine – D1/D2 agonist; dantrolene – sceletal muscle relaxant; supportive treatment)

56 Neuroleptic Malignant Syndrome (NMS) Hyperthermia Hyperthermia Muscle rigidity Muscle rigidity Autonomic instability Autonomic instability Fluctuating consciousness Fluctuating consciousness Mortality due to renal failure caused by rhabdomyolysis. Mortality due to renal failure caused by rhabdomyolysis.

57 Interactions of neuroleptics Additive effects: Additive effects:sedatives  - adrenoreceptor – blocking drugs anticholinergic drugs quinidine-like action (thioridazine, ziprasidone)

58 Contraindications Alcohol abuse Alcohol abuse Seizure disorders (Chlorpromazine) Seizure disorders (Chlorpromazine) Epilepsy Epilepsy Agranulocytosis (Clozapine) Agranulocytosis (Clozapine)

59 Neuroleptics overdose Rarely fatal Rarely fatal Drowsiness proceeds to coma, with intervening period of agitation Drowsiness proceeds to coma, with intervening period of agitation Increased muscular excitability may lead to convulsions Increased muscular excitability may lead to convulsions Decreased deep tendon reflexes Decreased deep tendon reflexes Ventricular tachyarrhythmias Ventricular tachyarrhythmias Gastric lavage !!! Gastric lavage !!!

60 Dosage of neuroleptic drugs Antipsychotics may be given in divided daily doses initially while effective dosage level is being sought. Antipsychotics may be given in divided daily doses initially while effective dosage level is being sought. 2 or more episodes of schizophrenia – therapy for 5 years 2 or more episodes of schizophrenia – therapy for 5 years Fluphenazine and haloperidol i.m.  slow release drugs (up to 3 weeks) Fluphenazine and haloperidol i.m.  slow release drugs (up to 3 weeks)


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