antipsychotics, neuroleptics

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  • 1.Antipsychotics neuroleptics or major tranquilizers Hiwa K. Saaed, PhD hiwapharm@yahoo.com Hiwa.saaed@univsul.net11/29/2013FIRST-GENERATION ANTIPSYCHOTIC (low potency) Chlorpromazine Prochlorperazine Thioridazine FIRST-GENERATION ANTIPSYCHOTIC (high potency) Fluphenazine Haloperidol Pimozide Thiothixene SECOND GENERATION ANTIPSYCHOTIC Aripiprazole Asenapine Clozapine Iloperidone Lurasidone Olanzapine Quetiapine Paliperidone Risperidone Ziprasidone1

2. Learning objectives Pharmacy students should: be familiar with the symptoms & health consequences of schizophrenia be able to describe the mechanism(s) of action and adverse effects of antipsychotics11/29/20132 3. Schizophrenia The Greek translation is schizein split and phren mind which refers to a split from reality. A group of severe disorders characterized by atypical: 1. Cognition 2. Behavior 3. Emotions11/29/20133 4. Schizophrenia is a particular type of psychosis-that is, a mental disorder caused by some inherent dysfunction of the brain, possibly an overactivity of the mesolimbic dopaminergic neurons. It is characterized by:1.Positive symptoms; are those that can be regarded as an abnormality or exaggeration of normal function.2.Negative symptoms; are those that indicate a loss or decrease in function11/29/20134 5. Symptoms of Schizophrenia http://www.youtube.com/watch?v=gGnl8dqEoPQ+ve symptoms: the presence of inappropriate behaviors Delusions (false belief) Hallucinations (false perception) often in the form of voices thinking or speech disturbances bizarre behavior11/29/2013-ve symptoms: the absence of appropriate behaviors Lack of motivation social withdrawal blunted affect poverty of speech anhedonia (lack of interest in pleasurable activities)5 6. Dopamine Hypothesis of SchizophreniaThis hypothesis is suggests that excessive dopaminergic activity plays a role in the disorder: 1.many antipsychotic drugs strongly block D2 receptors in the CNS, especially in the mesolimbic-frontal system.2.Dopamine precursor or agonist, either aggravate schizophrenia or produce psychosis de novo in some patients; such as levodopa (a precursor), amphetamines (releasers of dopamine), apomorphine (a direct dopamine receptor agonist),3.Increase in brain dopamine receptor density11/29/20136 7. Dopaminergic systems: Mesolimbic-mesocortical pathway: the one most closely related to behavior (mental and emotional) Nigrostriatal pathway: it is involved in the coordination of posture and voluntary movement Tuberoinfundibular pathway: inhibit prolactin secretion Medullary-periventricular: eating behavior Incertohypothalamic: It has a role in sexual behaviour.11/29/20137 8. 11/29/20138 9. Antipsychotics (neuroleptics, antischizophrenic) Used primarily to treat schizophrenia, also effective in other psychotic disorders, such as manic states with psychotic symptoms such as grandiosity or paranoia and hallucinations, and delirium.11/29/20139 10. Antipsychotic drugs Neuroleptic drugs are not curative and do not eliminate the fundamental thinking disorder, but they often: 1. Decrease the intensity of hallucinations and delusions. 2. Permit the psychotic patient to function in a supportive environment.11/29/201310 11. Antipsychotics Decrease dopaminergic and/or serotonergic neurotransmission.Typical Classic drugs (D2) Chlorpromazine Fluphenazine Haloperidol Thioridazine trifluperazine Effective in controlling +ve symptoms11/29/2013Atypical Newer 5-HT2 Clozapine Quetiapine Risperidione Ziprasidone aripiprazole Effective in controlling -ve symptoms, More costly, less EPS 11 12. Chemical classification of antipsychotic agents: A. Phenothiazine derivatives (tricyclic+S+side chain) Divided depending on side chain: Aliphatic group: chlorpromazine oldest Piperazine group: trifluperazine, fluphenazine, terphenazine,prochlorperazine, thiethylperazine Piperidin group: thioridazine, mesoridazine11/29/201312 13. Chemical classification of antipsychotic agents: B. Thioxanthene derivatives: (thiothixene, flupenthixole) less potent than phenothiazine group. C. Butyrophenone derivatives: (haloperidol) highly potent like piperazine phenothiazine D. Miscellaneous structures: pimozide, molindone ,loxapine,clozapine, quetiapine,Risperidone sertindole, olanzapine, and zeprasidone.11/29/201313 14. Dopamine receptor-blocking activity in the brain:D1 and D5 receptors: activate adenylyl cyclase. D2, D3, and D4 receptors: inhibit adenylyl cyclase , or mediate membrane K+ channel opening leading to neuronal hyperpolarization.the clinical efficacy of the typical neuroleptic drugs correlates closely with their relative ability to block D2 receptors in the mesolimbic system of the brain. On the other hand, the atypical drug clozapine has a high affinity for the D4 receptor and 5-HT2, very low affinity to D2 which may explain its minimal ability to cause extrapyramidal side effects.11/29/201314 15. Serotonin receptor-blocking activity in the brain: Clozapine has high affinity for D1, D2, D4, 5-HT2A, muscarinic, and -adrenergic receptors. Olanzapine, Risperidone and quetiapine, blocks 5-HT2 receptors to a greater extent than it does D2 receptors. Ziprasidone an antagonist at the D2, 5-HT2A and 5-HT1D an agonist at 5-HT1A Aripiprazole is a partial agonist at D2 and 5-HT1A receptors but strong antagonist at 5-HT2A receptors.11/29/201315 16. 11/29/201316 17. pharmacological actions 1. Antipsychotic actions: Neuroleptic stage-ALL the drugs also have a calming effect reduce spontaneous physical movements, produce emotional indifference to environment. The antipsychotic effects usually take several weeks to occur, suggesting that the therapeutic effects related to secondary changes in the corticostriatal pathways. 2. Antiemetic effects Except thioridazine, MOST of the neuroleptic drugs D2receptors of the chemoreceptor trigger zone (CTZ) of the medulla.11/29/201317 18. pharmacological actions 3. Antimuscarinic effects: SOME; particularly thioridazine, chlorpromazine, clozapine, and olanzapine 4. Blockade of -adrenergic receptors: causes orthostatic hypotension and light-headedness. Other effects 5. Alter temperature-regulating mechanisms and can produce poikilothermia (body temperature varies with the environment). 6. Increases in prolactin release (block D2 receptor) 7. Sedation (H1 blockade) all except haloperidol11/29/201318 19. Antipsychotics autonomic effect11/29/201319 20. Therapeutic uses 1. Schizophrenia Rx 2. Mania (bipolar disorder): initial Rx of Mania. Atypical antipsychotic drugs are often used with Lithium. maintenance Rx of bipolar disorder Olanzapine and aripiprazole are approved.3. Prevention of severe nausea and vomiting: Most commonly prochlorperazine are useful in the treatment of drug-induced nausea, but NO nausea arising from motion sickness (scopolamine is the drug of choice).11/29/201320 21. Other uses: 4. As tranqulizers to manage agitated and disruptive behavior. 5. Treatment of chronic pain with severe anxiety in combination with opiates. 6. Hiccups: chlorpromazine 7. Antipruritus and sedation: promethazine 8. Pimozide is primarily indicated for treatment of the motor and phonic tics of tourette disorder11/29/201321 22. 1. Extrapyramidal side effects: http://www.youtube.com/watch?v=QYYx1mZDpPw http://www.youtube.com/watch?v=WAg2iLEWVh01. It is appearance is time dependent, -Early phase (reversible) Acute dystonias* occurring within few days, (*Rx by Trihexphenidyl, orphenadrine, procyclidine, or diazepam), followed by **akathisias (the inability to remain seated due to motor restlessness). #Parkinson symptoms occur a bit later on. (** Rx by propranolol, or antimuscarinic),-Late phase (irreversible) Tardive Dyskinesia: inappropriate postures of the neck, trunk, and limbs, which is irreversible, occurs with chronic treatment after months or years of treatment.11/29/201322 23. 1.Tardive Dyskinesia, TD (D2 supersensitivity phenomenon): Patients display rhythmical involuntary movements, including lateral jaw movements, and fly-catching motions of tongue. TD is postulated to result from an increased number of dopamine receptors This makes the neuron supersensitive to the actions of dopamine, and it allows the dopaminergic input to this structure to overpower the cholinergic input, causing excess movement in the patient. NB: antimuscarinic increase the severity of TD Increase the dose of neuroleptic! Attenuate temporarily 11/29/201323 24. Avoiding EP Adverse effects Using Those drugs that exhibit strong anticholinergic activity, such as thioridazine, show few EP disturbances. This contrasts with haloperidol and fluphenazine, which have low anticholinergic activity and produce EP effects. Clozapine and risperidone: these drugs have a low potential for causing EP symptoms and lower risk of Tardive Dyskinesia.11/29/201324 25. Avoiding EP adverse effects Risperidone should be included among the first-line antipsychotic drugs, whereas clozapine should be reserved for severely schizophrenic patients who are refractory to traditional therapy. Clozapine can produce bone marrow suppression and CV side effects. The risk of severe agranulocytosis necessitates frequent monitoring of WBC count.11/29/201325 26. 2.Neuroleptic malignant syndrome:this potentially fatal reaction to neuroleptic drugs is characterized by muscle rigidity, fever, stupor, unstable BP, and myoglobinemia. Treatment necessitates 1. discontinuation of the neuroleptic 2. supportive therapy, administration of: Dantrolene diazepam or bromocriptine may be helpful. 11/29/201326 27. 3.Other effects:Anticholinergic; dry mouth, urinary retention, constipation, and loss of accommodation. Thioridazine, clozapine, haloperidol (high to less) Antiadrenergic; Lowering BP and orthostatic hypotension (-blocker), ex, phaenothiazine Endocrine alteration: The neuroleptics depress the hypothalamus, causing amenorrhea, galactorrhea, infertility, and impotence. Significant weight gain &a