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A particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking disturbance
- schizophrenia
- 1% of population
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Support for the Dopamine Hypothesis for Schizophrenia
- many antipsychotics block postsynaptic D2 receptors in the CNS
- drugs that increase DA activity aggrivate schiz. or induce psychosis
- increased DA receptors in schizophrenics
- successful treatment results in a change in DA metabolites excreted
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Theories against the Dopamine Hypothesis for Schizophrenia
- current antipsychotics are partially effective or ineffective
- Phencyclidine (NMDA receptor antagonist) induces schiz. more than DA agonsist
- Atypical anti psychotics are effective in schiz. but are not potent DA blockers
- DA blockade is fast, but antipsychotics take weeks to work
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Serotonin Hypothesis for schizophrenia
- Hallucinogens are 5-HT agonists
- Clozapine and quetiapine are inverse agonists of 5-HT2A
- 5-HT2A/C regulate DA and NMDA neurotransmission
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Support for Glutamate hypothesis for schizophrenia
phencyclidine (NMDA receptor antagonist) induces schizophrenia
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4 classes of antipsychotics
- phenothiazines
- thioxanthenes
- butyrophenones
- atypical antipsychotics
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Characteristics of Phenothiazines
- Tricyclic structure
- alliphatic
- piperidine
- piperazine
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Aliphatic phenothiazines
- chlorpromazine
- triflupromazine
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Piperidine phenothiazines
- less potent
- less extrapyrimidal and sedative effects
- weight gain
- thioridazine
- mesoridazine
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Piperazine phenothiazines
- potent in low doses
- least sedative/hypotension
- more severe extrapyrimidal effects
- fluphenazine
- trifluoperazine
- perphenazine
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Thioxanthines
- less potent than phenothiazine analogs
- aliphatic thioxanthenes
- piperazine thioxanthenes
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Butyrophenones
- Haloperidol
- more potent with fewer autonomic effects
- more sever extrapyramidal effects
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Antipsychotic effects
- suppression of conditioned responses
- haloperidol and piperazines are most potent
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Increased dopamine activity in the mesolimbic and mesocortical areas is proposed to
cause psychosis related abnormal behaviors
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Antipsychotic drugs tend to...
block dopamine receptors within ranges that suppress psychotic behaviors
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Mesolimbic-mesocortical pathway
- substantia nigra to limbic system and neocortex
- behavioral control
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Nigrostriatal pathway
voluntary movement coordination
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Tuberoinfundibular pathway
neuroendocrine regulation
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Incertohypothalamic pathway
- amygdala
- behavioral regulation
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CNS side effects and toxicity of antipsychotics
- depression and sedation
- decreased seizure threshold
- depression of chemoreceptor trigger zone
- extrapyramidal symptoms
- tardive dyskinesia
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Antipsychotics that are most potent depression and sedation causers
aliphatics
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antipsychotics responsible for decreased seizure threshold
aliphatics
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antipsychotics that depress chemoreceptor trigger zone
thioridazine
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antipsychotics that result in extrapyramidal symptoms
- piperazines
- butyrophenones
- due to DA receptor blockade in basal ganglia
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Cause of Tardive dyskinesia
- DA receptor supersensitivity in basal ganglia
- relative cholinergic deficiency
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Extrapyramidal symptoms
- PD syndrome
- Akathisia
- Acute dystonia
- catatonia, hyperthermia
- neuroleptic malignant syndrome
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Treatment for PD syndrome
muscarinic drugs or amantadine
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strong subjective feeling sof distress and discomfort, compulsion for constant movement
akathisia
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Treatment of akathisia
- dose reduction of antipsychotics
- anti-pd drugs
- sedative antihistamines with anticholinergic properties
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treatment for acute dystonia
anticholinergic anti-PD drugs
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antipsychotics which may cause catatonia or hyperthermia
chlopromazine or clozapine
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Neuronal connections in PD
dopaminergic neurons misfunction from substantia nigra to corpus striatum
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4 characteristics of tardiv dyskinesia
- more pronounced in older patients with abrupt withdrawl of antipsychotics
- less prominant with thioridazine (piperidine phenoxanthines) and clozapine
- sterotyped involuntary movements
- symptoms are untreatable and may persist indefinitely
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Management of tardive dyskinesia
- discontinue or reduce dose of antipsychotic
- switch to a newer atypical antipsychotic
- eliminate all drugs with anticholinergic action such as anti-pd drugs and TCAs
- use diazepam
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Peripheral side effects of antipsychotics
- hyperprolactinemia and amenorrhea
- altered body temperature regulation
- alpha adrenergic blockade
- anticholinergic action
- hypersensitivity/weight gain
- agranulocytosis
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Hyperprolactinemia and amenorrhea
- inhibition of prolactin secretion by DA
- increased conversion of androgen to estrogen
- false positive pregnancy tests
- infertility or impotence
- dose reduction or use aripiprazole
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Alpha adrenergic blockade
- aliphatic phenothiazines
- orthostatic hypotension/faintness
- palpitations
- nasal stuffiness
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Anticholinergic action
- thioridazine or tricyclic structure
- dry mouth
- blurred vision
- urinary retention
- constipation
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Agranulocytosis
- 1-2% of patient taking clozapine
- increased blood cell counts
- weekly blood counts for first 6 weeks then every 3 weeks
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weight gain
common with clozapine or olanzapine
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Absorption of Antipsychotics
- unpredictable after oral administration
- IM increases bioavailability
- highly lipophilic and protein bound
- long duration of action
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Liver metabolism of antipsychotics
- significant first pass metabolism
- oxidation by CYP and conjugation
- metoabolites excreted in urin and bile
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Mesoridazine
- active metabolite of thioridazine
- more potent antipsychotic effect
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Drug interactions of antipsychotics with CNS depressants
- Anticholinergic effects
- potentiates sedatives, analgesics, alcohol, hypnotics and antihistamines
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Neuroleptic drugs inhibit...
action of dopaminergic agonists and levodopa
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antipsychotic drugs with anti-hypertensive agents
- blocks antihypertensive effects of guanethidine
- alpha adrenergic blocking action
- postural hypotension
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antipsychotics with digoxin
thioridazine and ziprasidone may partially nullify the ionotropic effect of digoxin
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Therapeutic uses of antipsychotics
- psychosis, mania, severe agitation schizophrenia
- delusional paranoia
- antinauseant
- hiccough and pruritis
- tourette's syndrome
- huntington's disease
- anesthesia
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used for treatment of delusional paranoid state
fluphenazine
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mechanism of anti-nausiants
block DA receptors centrally and peripherally
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Drugs used as anti nauseants
- prochlorperazine
- benzquinamide
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used for pruritus
trimeprazine
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used for huntington's disease
haloperidol
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drugs used for anesthesia
butyrophenone droperidol with fentanyl to provide neuroleptanesthesia
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New antipsychotic drugs
- clozapine
- olanzapine
- quetipine
- risperidone
- aripiprazole
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Clozapine
- high seratonin potency
- potent anti-cholinergic
- limited D2 receptor blockade
- fatal agranulocytosis
- used for older patients with dementia
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Olanzapine
- most tolerable atypical antipsychotic
- not for older adult patients with dementia
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qutiapine
most prescribed
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risperidone
- similar to clozapine
- more potent DA antagonism
- less side effects (anticholinergic and sedative effects)
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aripiprazole
- low weight gain
- long half life
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