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antipsychotics

anti-psychotic medications

introduction:

  • reserpine & chlorpromazine (Largactil) were the 1st drugs used in schizophrenia, but their use has been superseded by newer drugs.
  • like tricyclic antidepressants, in general, major tranquillisers have similar P/K characteristics:
    • significant 1st pass metabolism
    • lipid-soluble, highly protein bound with large volumes of distribution
    • extensively metabolised with little excreted by kidneys unchanged.
  • patients with schizophrenia tend to have a higher incidence of diabetes & this is compounded by the increased risk when taking aliphatic phenothiazines or dibenzodiazepines. High risk patients for diabetes should be considered for risperidone or the high potency conventional antipsychotics such as the piperazines.
    • 1.63 odds ratio of developing diabetes if < 40yrs old and 4.3 for all pts (cw. 4.97 for chlorpromazine group & 1.02 for risperidone)
  • the newer “atypical antipsychotics” primarily are aimed at reducing the extrapyramidal effects of the phenothiazines:
    • clozapine was the 1st atypical agent which was discovered in the 1950's and 1st used in therapy in the 1970's but fell out of favour due to 1-2% risk of agranulocytosis, although given approval by the FDA in 1990
    • during the 1990's, olanzapine, quetiapine, and risperidone were introduced.
    • ziprasidone and aripiprazole were introduced in the early 2000's - ziprasidone was listed on PBS for Rx of acute mania in BPD in April 2009.
    • paliperidone, was approved by the FDA in late 2006
    • brexpiprazole (Rexulti) approved by FDA in 2015, and was listed on Aust. PBS in late 2017 for Rx of schizophrenia, with the advantage of less weight gain or diabetic effects

atypical antipsychotics

  • precise mechanism of action is unclear and varies between agents.
  • some researchers believe that D2 receptor antagonism, coupled with 5-HT2A receptor antagonism, is responsible for the “atypicality” of atypical anti-psychotics
  • others believe that fast dissociation (a fast Koff) from the D2 receptor, allowing for better transmission of normal physiological dopamine surges, better explains the pharmacological evidence
  • most are given once daily without food with notable EXCEPTION of ziprasidone
  • most will cause somnolescence, dizziness, nausea, and potentially extrapyramidal symptoms such as akathisia and tardive dyskinesia (although less likely than with phenothiazines)

indole derivatives

  • risperidone (Risperdal):
    • one of the most commonly prescribed atypical agents for maintenance Rx
    • approved by FDA in 1993.
  • ziprasidone (Zeldox):
    • listed on PBS in 2009 for Mx of acute mania
    • prolongs QTc thus avoid if patient at risk of prolonged QTc including patients with acute cardiac disease or on other drugs which may prolong QTc, or at risk of hypokalaemia.
    • an antagonist at the D2, 5HT2A and 5HT1D-receptors and as an agonist at the 5HT1A-receptor
    • inhibits synaptic reuptake of serotonin and noradrenaline
    • antagonism of histamine H1-receptors may explain the somnolence observed with this drug
    • antagonism of adrenergic alpha1-receptors may explain the orthostatic hypotension observed with this drug
    • antagonism of dopamine D2 receptors may cause hyperprolactinaemia
    • it has been proposed that this drug's efficacy in schizophrenia is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism
    • unlike most other atypical agents, it must be given bd with food (usual dose 40mg bd to max. 80mg bd) as its absorption is significantly reduced without food
    • tends to cause less weight gain or lipid changes than other atypical agents and perhaps less risk of type II diabetes mellitus.
    • 11% of patients with short-term use develop extrapyramidal symptoms which may be higher rate than with other atypicals.
    • marketed as Zeldox in 20mg, 40mg, 60mg & 80mg capsules.

dibenzodiazepines:

    • the 1st atypical agent which was discovered in the 1950's and 1st used in therapy in the 1970's
    • fell out of favour due to 1-2% risk of agranulocytosis
    • risk of cardiomyopathy
  • quetiapine (Seroquel):
    • mainly used for maintenance Rx but is listed on PBS listed for Mx of acute mania of BPD as well as adjunctive Rx in maintenance Rx.
    • may cause prolonged QTc and risk of torsade de pointes VT in therapeutic doses (particularly if used with other medications which may prolong QTc) and in over-dosage
  • olanzapine (Zyprexa):
    • currently the most commonly prescribed atypical agent for acute Mx in the ED
    • depot injection (Zyprexa Relprevv) introduced in 2009 for deep IM injection every 2 or 4 weeks.
    • not currently PBS listed for Mx of acute mania of BPD.
  • asenapine (Saphris):
    • introduced in Australia on PBS in 2011 as sublingual wafers in 5mg and 10mg wafers
    • similar efficacy and advere effect profile to olanzapine

benzamides

  • eg. remoxipride
  • D2 & D3 antagonism

diphenylbutylpiperidines

  • eg. pimozide

dihydroindolones

  • eg. molindone

dibenzoxazepines

  • eg. loxapine

older antipsychotic medications

phenothiazines

thioxanthenes

  • slightly less potent than phenothiazines
  • eg. thiothixene

butyrophenones

other medications used to treat psychoses

  • aripiprazole
    • D2 and 5HT1A partial agonist; 5HT2A antagonist 
    • introduced 2003; once daily dosing
    • may increase neurotransmission if dopamine concentration is low & decrease it if the level is high & thus may reduce both the positive & negative symptoms of schizophrenia
    • less somnolence and extrapyramidal symptoms than haloperidol but more nausea & dizziness and as it acts as alpha1 antagonist, may cause orthostatic hypotension
  • amisulpride
    • not approved in US.
  • lithium
antipsychotics.txt · Last modified: 2017/10/01 22:52 (external edit)