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Dr. Womble

Antipsychotics. Dr. Womble. Psychosis. Psychosis is defined as a state in which a person’s mental capacity to recognize reality, communicate, and relate to others is impaired, thus interfering with the capacity to deal with life’s normal everyday demands

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Dr. Womble

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  1. Antipsychotics Dr. Womble

  2. Psychosis • Psychosis is defined as a state in which a person’s mental capacity to recognize reality, communicate, and relate to others is impaired, thus interfering with the capacity to deal with life’s normal everyday demands • most common mental disorder in which psychotic sx may be present is schizophrenia.

  3. Schizophrenia • a general term for a mental disorder characterized by • delusions, loosening of associations, decrease speech content, auditory hallucinations, disturbed sense of self, and withdrawal from the external world. • Onset early adulthood prior to normal function

  4. Antipsychotics (Neuroleptics) • Referred to as antischizophrenic, antipsychotic or major tranquilizers • Typical properties due to dopamine receptor antagonism • 1950’s, first generation, D2 • High EPS • Atypical properties due to Serotonin and DA receptor antagonism • Second generation • Not curative, does not eliminate thinking disorder, but allow patient to function in supportive environment • Pathogenesis of schizophrenia is unknown

  5. Schizophrenia • Characterized by delusions, hallucinations (hearing voices), thinking and speech disturbances • Often affected during adolescence, strong genetic component • Characterized by 2 components; • breakdown of personality • loss of contact with reality • Antianxiety agents not useful for psychotic disorders • Considered neurodevelopmental disorder • Structural and functional changes present in utero

  6. Schizophrenia • Positive symptoms - symptoms that most individuals do not normally experience but are present in schizophrenia. • Delusions, auditory hallucinations, thought disorder, regarded as manifestations of psychosis • Negative symptoms - symptoms that reflect the loss or absence of normal traits or abilities. • Blunted affect and emotion, poverty of speech, inability to experience pleasure, lack of desire to form relationships, and lack of motivation

  7. Schizophrenia Etiology • Serotonin Hypothesis • 5-HT stimulation responsible for hallucinations • Atypical antipsychotics - MOA • Dopamine Hypothesis • Firtst NT based MOA, no longer considered to cover all aspects of schizophrenia • Important in uderstanding pos./neg. symptoms • Glutamate Hypothesis • Hypofunction of NMDAr - decreased GABAergic inhibitory activity

  8. Antipsychotics • Reserpine and chlorpromazine were first drugs used for schizophrenia / psychosis • Divided into five major classifications based on structure. Side chains have significant effect on potencies • 1. Phenothiazines • 2. Benzisoxazoles • 3. Dibenzodiazepines • 4. Butyrophenones • 5. Thioxanthenes • Management of psychotic disorder can be determined by familiarity of effects drugs in each class

  9. Typical Antipsychotics(1. Phenothiazine) • 3 subclasses • 1. Aliphatic – least potent • Chlorpromazine –intermediate extrapyramidal side effects and intermediate anticholinergic action, high incidence of sedative action • 2. Piperazine – most potent, selective and effective, increased incidence of Tardivedyskinesia • Fluphenazine (Prolixin) • Prochlorperazine (Compazine) • Perphenazine (Trilafon) • 3. Piperidine – least potent, lower incidence of extrapyramidal side effects, high incidence of anticholinergic action • Thioridazine (Mellaril) • Mesoridazine (Serentil)

  10. Action of Phenothiazine • CNS – reduces anxiety, response to external stimuli, intelligence is not diminished, reflexes not suppressed, mild sedation • Limbic system Da receptors involved in mood/feeling • 5 subclasses of DA receptors (D1-D5) • D1/5 activate, D2/3 inhibit adenylcyclase • D2 involved in psychotic disorders • Blockade of D2 receptor is antipsychotic action • Autonomic effects – antimuscarinic action (piperidines – strongest, piperizines – weakest) urinary retention, ortho hypo, dry mouth, sedation, inh of GI smooth muscle - constipation • Alpha-antagonist – ortho hypo, poikilothermia, inc. prolactin release • Basal Ganglia – blockade of D1 or D2 results in EPS • Cardiovascular – depressed by antipsychotics – hypotension • Chemoreceptor trigger zone (CTZ) - (anti-emetic action) • Hypothalmus – DA receptors inhibit release of prolactin, phenothiazines block DA receptors - stimulate release of prolactin – hormonal side effects • Misc. – no physical dependence, mild CNS depressant (toxic dose), decrease seizure threshold

  11. Side effects of Phenothiazine • Side effects • Orthostatic hypotension – due to alpha blockade, dose/effect response • Extrapyramidal Syndrome – increased cholinergic activity (Piperazine – highest, Piperidines – lowest) • Parkinson-like Syndrome • Akathesia – uncontrollable restlessness, distress, anxiety • TardiveDyskinesia – develops late in antipsychotic therapy, usually at high doses x 6 months, rhythmic motions of head, face and shoulders, may be irreversible • Do not use DA or Levo-Dopa, use diphenhydramine (Benadryl), benztropine (Cogentin) or trihexephenidyl (Artane).

  12. Therapeutic use of Phenothiazines • Tx psychotic disorders • Schizophrenia, senile dementia, extreme paranoia, manic phase of manic depressive syndrome, • Anti-emetics – radiation toxicity, anticancer meds, opioids, gastroenteritis • Phenothiazines control • positive symptoms – Hallucinations, delusions, hostility, hyperactivity • Not negative symptoms – social withdrawal, lack of expression, decrease in speech patterns

  13. Dopamine Pathways • Nigrostriatal • Mesocortical– Mesolimbic • Tuberoinfundibular • Incertohypothalamic Douglas L. Geenens, D.O. 2000

  14. Dopamine PathwaysNigrostriatal • Projects from the substantianiagrato the basal ganglia • part of extrapyramidalsystem • Thus side effects are called “extrapyramidal” • Chronic blockade can cause • Potentially irreversible movement disorder • “TardiveDyskinesia Douglas L. Geenens, D.O. 2000

  15. Dopamine PathwaysNigrostriatal • Controls movements • Types of movement disorders caused by this pathway include: • Akathisia • Dystonia • Tremor, rigidity, bradykinesia • Drug-induced Parkinsonism Douglas L. Geenens, D.O. 2000

  16. Dopamine PathwaysMesolimbic - Mesocortical • Blockade may help reduce negative symptoms of schizophrenia • May be involved in the cognitive side effects of antipsychotics “mind dulling” Douglas L. Geenens, D.O. 2000

  17. Dopamine PathwaysTuberoinfundibular • DA released at this site regulates the secretion of prolactin from the anterior pituitary gland. • Blockade produces galactorrhea • Dopamine=PIF Douglas L. Geenens, D.O. 2000

  18. Dopamine PathwaysIncertohypothalamic • Connects the hypothalamus and the limbic system • Regulates sexual desire Douglas L. Geenens, D.O. 2000

  19. Classes of Antipsychotics 1. Phenothiazines 2. Benzisoxazoles 3. Butyrophenones 4. Thioxanthenes 5. Dibenzodiazepines

  20. Atypical Antipsychotics • In the last decade new "atypical" antipsychotics have been introduced, >effective, <s/e • typical antipsychotics appear to be equally effective for helping reduce the positive symptoms like hallucinations and delusions • but may be better than the older medications at relieving the negative symptoms of the illness, such as withdrawal, thinking problems, and lack of energy.

  21. Mechanism of Action of Atypical Antipsychotics • Blockade of DA (D1 and D4) and / or 5-HT receptors. Many also block cholinergic, adrenergic, and histamine receptors – variety of side effects (low D2) • DA receptor antagonism in brain (typical and atypical antipsychotics) • Neuroleptics are antagonized by agents that increase DA concentration (L-dopa and amphetamines) • Serotonin receptor antagonism in brain (atypical)

  22. NEUROBIOLOGY OF CLOZAPINE Here you can see that Clozapine will not bind to any Dopamine receptor, it is selective, it has an affinity for the D4 receptor subtype.

  23. Atypical Antipsychotics • Low or no EPS • 5-HT2A antagonist • Control both positive and neg. symptoms • Aripiprazole (Abilify),Risperidone (Risperdal), Clozapine (Clozaril), Olanzapine (Zyprexa), Quetiapine (Seroquel), and Ziprasidone (Geodon).

  24. Atypical Antipsychotics(second generation) • Clozapine (prototype) • Little to no EPS, high incidence of agranulocytosis (regular CBC’s), High incidence of siezures • Olanzapine (Zyprexa) • Sedation, weight gain, no agranulocytosis, low incidence of siezures • Quetiapine (Seroquel) • Sedation, low incidence of all side effects

  25. Action of Atypical Antipsychotics • Antipsychotic – reduce hallucinations, agitation, require several weeks to occur • EPS – Parkinsonian symptoms, akathisia, tardivedyskinesia.(clozapine, risperidone show low incidence) • Antiemetic – D2 receptor antagonist in CMZ of medulla (except thioridazine) • Antimuscarinic – blurred vision,dry mouth, sedation, confusion, inhibition of GI and urinary smooth muscle – constipation, urinary retention. (all esp. thioridazine and chlorpromazine) • α-blockade – orthostatic hypotension, lightheadedness, alter temperature regulating mechanisms, block D2 receptors in pituitary – prolactin release

  26. Therapeutic application of antiemetic agents • Vertigo – meclizine, dimenhydrinate • Motion sickness – scoopolamine, promethazine • Cancer chemo – droperidol, haloperidol, metoclopramide, prochloperazine • Radiation therapy – thiethylperazine, domperidone

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