Schizophrenia Antipsychotics

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giddyupp
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33787
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Schizophrenia Antipsychotics
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2011-01-13 13:15:57
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Schizophrenia Antipsychotics PHPR521
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Schizophrenia Antipsychotics
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  1. What are the Characteristic symptoms of a schizophrenic?
    • Hallucinations
    • Delusions
    • Disorganized Speech
    • Grossly disorganized or catatonic behavior
    • Negative symptoms
  2. What is the fx of the Nigrostriatal tract in schizophrenia?
    • Route:
    • Substantia nigra to Caudate nucleus and Putamen

    • Function:
    • Extrapyramidal system
    • Movement

    • DA Antagonist Effect:
    • Movement disorders
    • Tardive dyskinesia
    • Pseudo-Parkinsonism
  3. What is the fx of the Mesolimbic tract in schizophrenia?
    Excess DA = positive Schiz symptoms

    • Route:
    • Midbrain ventral tegmentum (A10 area) to Limbic areas

    • Function:
    • Arousal, memory, stimulus processing, motivation, emotional content

    • DA Antagonist Effect:
    • Relief of psychosis
  4. What is the fx of the Mesocortical tract in schizophrenia?
    Insuffient DA = negative Schiz symptoms

    • Route:
    • Midbrain ventral tegmentum (A10 area) to Frontal and Prefrontal Cortex

    • Function:
    • Cognition, communication, social function, response to stress

    • DA Antagonist Effects:
    • Relief of psychosis
    • Akathisia
  5. What is the fx of the Tuberoinfundibular tract in schizophrenia?
    • Route:
    • Hypothalamus to Pituitary

    • Function:
    • Regulate prolactin release

    • DA Antagonist Effect:
    • Increased prolactin concentrations
  6. What drugs are used to treat schizophrenia?
    • 1st generation antipsychotics (FGAs or neuroleptics)
    • 2nd generation antipsychotics (SGAs or atypicals)
  7. Which FGAs (neuroleptics)are used to treat schizophrenia?
    • chlorpromazine (Thorazine)
    • thioridazine (Mellaril)
    • mesoridazine (Serentil)
    • haloperidol (Haldol)
    • perphenazine (Trilafon)
    • fluphenazine (Prolixin)
    • loxapine (Loxitane)
    • trifluoperazine (Stelazine)
    • thiothixene (Navane)
    • molindone (Moban)
  8. What are the advantages of FGAs (neuroleptics)?
    • cheap
    • effective for positive sx (perphenazine was 2nd best in CATIE trial)
  9. What are the disadvantages of FGAs (neuroleptics)?
    • MANY SE!
    • failure to change insight or judgment
    • lack of efficacy in 20-30% of pts
    • may worsen negative sx
    • DI with drugs that affect gastric pH
  10. What are the side effects of FGAs (neuroleptics)?
    • EPSE
    • prolactin elevation
    • sexual dysfx
    • anticholinergic effects
    • sedation
    • wt gain
    • dizziness
    • OH
  11. Which SGAs (atypicals) are used to treat schizophrenia?
    • clozapine (Clozaril)
    • risperidone (Risperdal)
    • paliperidone (Invega)
    • olanzapine (Zyprexa)
    • quetiapine (Seroquel)
    • ziprasidone (Geodon)
    • iloperidone (Fanapt)
    • asenapine (Saphris)
    • aripiprazole (Abilify)
  12. How do most of the SGAs (atypicals) work?
    • serotonin-dopamine antagonism (SDA
    • more 5-HT2 than D2
    • increased DA release:
    • improved neg sx (MC tract)
    • less EPSE (NS tract)
  13. What is the only drug succussfully used to treat pts refractory to FGAs?
    clozapine (Clozaril)
  14. Which SGAs are better than FGAs for depressive-type sx seen in schizophrenia?
    • aripiprazole (Abilify)
    • quetiapine (seroquel)
  15. Which antipsychotic is cheapest of all APs (FGA and SGA)?
    resperidone (Risperdal) (generic)
  16. Which SGA is the only one that may not need to be titrated to an effective dose?
    asenapine (Saphris)
  17. How are the SGAs associated with metabolic problems (ranking)?
    • up to 100lbs/y
    • 10-20lbs in a few months
    • clz, olz > risp, quet >ase > zip, ari
  18. What are the advantages of clozapine (Clozaril)?
    • the only AP effective for tx refractory Schizophrenics
    • the only AP FDA approved to reduce risk of recurrent suicidal behavior
  19. What are the disadvantages of clozapine (Clozaril)?
    • Agranulocytosis (reason to d/c)
    • Seizures (if cont'd tx needed, add VPA and keep < 900 mg/d)
    • Most metabolic problems (wt gain)
    • 2D6 substrate (Fluoxetine, Paroxetine)
    • sialorrhea
    • sedation
  20. What are the advantages of risperidone (Risperdal, Risperdal Consta, Risperdal M-TAB)?
    • First-line agent
    • many dosage forms
    • most potent D2 blocker SGA (good for very psychotic pt)
    • FDA approved for schiz and bi-polar in children and adolescents
    • cheapest AP available
  21. What are the disadvantages of risperidone (Risperdal, Risperdal Consta, Risperdal M-TAB)?
    • Most potent D2 blockade SGA (more EPSE, dose dependent)
    • Most Prolactin elevation
    • 2D6 substrate (Fluoxetine, Paroxetine)
  22. Paliperidone (Invega, Invega Sustenna)
    9-OH metabolite of Risperidone

    • Same SE as Risperidone, maybe more Prolactin elevation
    • OROS extended-release (Invega)

    Extended release injectable = 1/mo dosing (Invega Sustenna)
  23. What are the advantages of Olanzapine (Zyprexa, Zyprexa Relprevv, Zyprexa Zydis)?
    • Relatively free of drug interactions (best in CATIE trial)
    • long-acting injectable dosing q 2-4wks (Zyprexa Relprevv)
    • oral disentegrating tablet (Zyprexa Zydis)
  24. What are the disadvantages of Olanzapine (Zyprexa, Zyprexa Relprevv, Zyprexa Zydis)?
    • Most expensive of any AP $$$$
    • Most metabolic problems
    • Most wt gain
    • Dose-dependent EPSE above 20mg
    • 3h observation req'd after Relprevv injection for delirium/sedation or coma
  25. What are the advantages of Quetiapine (Seroquel)?
    • Very low risk of EPSE
    • Very good....if it works
    • well tolerated by many pts
    • seems to help depressive sx
  26. What are the disadvantages of Quetipine (Seroquel)?
    • Second most expensive $$$$
    • Some don't think it works (CATIE trial)
    • Must titrate slowly
    • Somnolence
    • 3A4 substrate
  27. What are the advantages of Ziprasidone (Geodon)?
    • LITTLE TO NO WT GAIN OR METABOLIC EFFECTS@!
    • somewhat novel MOA - SDA, but also modest reuptake inhibition of 5-HT and NE
    • available as a short-acting injection
    • giving w/ food doubles bioavailability
  28. What are the disadvantages of Ziprasidone (Geodon)?
    • Most QTc prolongation - no Antiarrhythmics, Antihistamines, Moxifloxacin, Sparfloxacin Erythromycin Ketoconazole, Thioridazine, Pimozide, Methadone, possibly TCA's
    • w/ or w/o food needs to be consistent
  29. What are the risk factors for QT prolongation?
    • Known heart disease
    • History of Syncope
    • Family hx of sudden death at < 40yo
    • Congenital long QT syndrome
  30. What are the advantages of Iloperidone (Fanapt)?
    • low EPSE
    • little effect on lipids
    • little effect on prolactin
  31. What are the disadvantages of Iloperidone (Fanapt)?
    • Most potent Alpha blocker - slow dose titration required to dec.
    • risk of OH
    • Numerically, if not statistically, least effective in studies
    • QTc prolongation
    • 2D6 and 3A4 interactions
  32. What are the advantages of Asenapine (Saphris)?
    • Novel MOA - Blocks 5-HT2A, 5-HT2C, and D2 receptors
    • no titration required (maybe)
    • First drug approved for Schiz and Bipolar simultaneously
    • Sublingual tablets only - no food or liquids for 10 min after dose; DON'T swallow tablet
  33. What are the advantages of Asenipine (Saphris)?
    • 2D6 substrate and inhibitor
    • Insomnia
    • Oral hypoesthesia
    • no food or liquids for 10min after dose
    • little research completed
  34. What are the advantages of Aripiprazole (Abilify)?
    • Unique pharmacology - D2 and 5-HT1A partial agonist (D2 partial is unique)
    • 5-HT2A antagonist
    • little effect on wt or metabolism
    • may DECREASE prolactin (d/t partial agonism of DA)
    • Less sedating
    • Approved for adjunct tx of tx-resistant depression
    • approved for adolescents
  35. What are the disadvantages of Aripiprazole (Abilify)?
    • Akathisia
    • Nausea
    • Dizziness
    • OH
  36. Which SGAs cause agranulocytosis?
    clozapine (Clozaril)
  37. Which SGAs cause the most EPSE?
    • risperidone (Risperdal)
    • olanzapine (Zyprexa)
  38. Which SGA causes the most prolactin increase?
    risperidone (Risperdal)
  39. What SGAs causes the most wt gain?
    • Olanzapine (Zyprexa)
    • Clozapine (Clozaril)
  40. Which SGAs cause the most metabolic problems?
    • Clozapine (Clozaril)
    • Olanzapine (Zyprexa)
  41. Which SGA causes the most nausea?
    Aripiprazole (Abilify)
  42. Which SGA causes akathisia?
    Aripiprazole (Abilify)
  43. Which SGA causes the most dizziness?
    Aripiprazole (Abilify)
  44. Which SGA causes the most OH?
    Aripiprazole (Abilify)
  45. Which SGA causes the most somnolence?
    Quetiapine (Seroquel)
  46. What are the optimal doses of SGAs?
    • risperidone (Risperdal) - 3-6mg/d
    • asenipine (Saphris) - 5mg/d
    • olanzapine (Zyprexa) - 10-20mg/d qd
    • iloperidone (Fanapt) - 12-24mg/d
    • aripiprazole (Abilify) - 15mg/d
    • ziprasidone (Geodon) - 120-160mg/d
    • clozapine (Clozaril) - 300-60 mg/d
    • quetiapine (Seroquel) - 300-600mg/d
  47. Schizophrenia Symptom clusters
    • Positive:
    • Bizarre behavior, Delusions, Loose associations, Hallucinations, Disorganized thinking, Conceptual disorganization

    • Negative:
    • Blunted affect, Alogia, Poverty of speech, Anhedonia, Withdrawal, Avolition

    • Cognitive:
    • Impaired attention, working memory and/or executive function
  48. What are the symptoms of Neuroleptic Malignant Syndrome (NMS)?
    • Autonomic dysfunction:
    • tachycardia, HTN, tachypnea, diaphoresis, dysrrhythmias, sialorrhea, incontinence, normal or decreased bowel sounds

    • Altered mental status:
    • confusion, delirium, lethargy, stupor, coma, fluctuating levels of consciousness (LOC)

    • Muscular Rigidity:
    • lead pipe rigidity, akinesia, bradykinesia, bradyreflexia, tremor, myoclonus, chorea, opisthotones, cogwheeling

    • Hyperthermia:
    • T >38.5 (often higher than 41.1
  49. NMS lab findings
    • leukocytosis
    • increased transaminases
    • increased CK
    • metabolic acidosis
    • hyper/hyponatremia
    • myoglobinuria
    • mild coagulopathies
  50. NMS complications
    • rhabdomyolysis
    • renal failure
    • aspiration pneumonia
    • pulmonary embolism
    • adult respiratory distress syndrome (ARDS)
    • disseminated intravasular coagulation (DIC)
    • seizures
    • MI
  51. Symptoms of Serotonin Syndrome
    • Mental status changes:
    • agitation, delilrium, hypervigilance, pressured speech, exaggerated startle response

    • Autonomic hyperactivity:
    • tachycardia, shivering, diaphoresis, mydriasis, diarrhea, HTN

    • Neuromuscular abnormalities:
    • hyper-reflexia, myoclonus, peripheral hypertonicity, repetetive head rotation, tremor, rigidity

    • Other:
    • hyperthermia, hyperactive bowel sounds
  52. Serotonin Syndrome lab findings
    • metabolic acidosis
    • rhabdomyolysis
    • increased transaminases
    • increased creatinine
  53. Complications of Serotonin Syndrome
    • seizures
    • renal failure
    • disseminated intravascular coagulation (DIC)
  54. What symptoms are unique between NMS and Serotonin Syndrome?
    • NMS:
    • lead-pipe rigidity in all muscle groups, bradyreflexia, stupor, time to develop = 1-3 days

    • SS:
    • rigidity predominantly in lower extremities, hyperreflexia, agitation, mydriasis, hyperactive bowel sounds, clonus, time to develop = <12h
  55. Define serotonin syndrome
    a predictable consequence of excess serotonergic agonism of central and peripheral serotonergic receptors
  56. What is the most favored hypothesis for NMS?
    sudden and profound central dopaminergic blockade
  57. How is NMS managed?
    • d/c APs
    • d/c any anticholinergics
    • dopamine agonists (bromocriptine, amantadine)
    • dantrolene (direct-acting skeletal muscle relaxant)
    • benzodiazepines
    • aggessive cooling
    • antipyretics
    • fluid and electrolyte repletion
    • appropriate tx of potential complications
  58. How is serotonin syndrome managed?
    • d/c serotonergic drugs
    • supportive care
    • benzodiazepines to control agitation
    • 5-HT2A antagonists – cyproheptadine, atypical antipsychotics, chlorpromazine pressors for BP control
    • vecuronium to decrease muscle activity
  59. What role do the following drugs play in NMS?
    • BZD - decrease muscular rigidity = decrease heat
    • Chlorpromazine - can be the cause
    • Anticholinergics - DO NOT USE!!!!
    • antipyretics - decrease temp
    • Bromocriptine - DA agonist = decrease temp by increase DA production
    • Dantrolene - muscle relaxant = decrease temp
    • Amantadine - DA agonist = decrease temp by increase DA production
  60. What role do the following drugs play in serotonin syndrome?
    • BZD - control agitation = decrease heat
    • Cyproheptadine - 5-HT2a antagonism
    • SGAs - 5-HT2a antagonism
    • Chlorpromazine - 5-HT antagonism
    • Anticholinergics - DO NOT USE !!!!
    • Vecuronium - paralysis to decrease excessive muscle movement = decrease temp
    • Succinylcholine - DO NOT USE!!!!
    • antipyretics - NONE
    • Propranolol - DO NOT USE could cause hypotension and mask tachycardia
    • Bromocriptine - DO NOT USE/ could cause ss
  61. How should AP tx be reinstituted after a case of NMS?
    • 2 week minimum washout after full resolution of NMS
    • reduction of risk factors
    • resume with informed consent
    • close observation
    • low dose, low potency agent
    • slow, cautious titration to full effectiveness
  62. What are the risk factors for NMS?
    • high initial dose of AP
    • rapid upward titration
    • change to higher potency
    • use of long-acting depot injectable neuroleptics
    • high ambiet temps
    • dehydration
    • concommittant illness
    • AIDS-related dementia
    • head trauma
    • general debilitation
    • organic brain disease
  63. What are the risk factors for serotonin syndrome?
    • Use of serotonergic drugs
    • Use of combinations of drugs that lead to increased serotonin

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