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Antipsychotic drugs _AKA Neuroleptics_ antischizophrenics and


									                       Antipsychotic drugs
                 (AKA Neuroleptics, antischizophrenics and major tranquillisers)

Main categories – Typical/classical antipsychotics – e.g. chlorpromazine,
       - Atypical antipsychotics e.g. risperidone, clozapine.
       - Difference is that classicals (developed pre-1980) have pretty similar
           properties, whereas the atypical drugs are more diverse, have less tendency to
           cause unwanted motor side effects and/or have an effect on the negative
           symptoms as well as the positives.

Mechanism of action
  o All are antagonists at dopamine D2 receptors, but most also block other
    monoamine receptors, especially 5HT2. Antipsychotic potency generally runs
    parallel to activity on D2- receptors, but other activities may determine side-effect
  o Anti-psychotics take days to weeks to work, suggesting that secondary effects,
    such as increased D2 receptor numbers in the limbic system, may be more
    important that the direct effect of D2 receptor block.

Behavioral effects
  o Produces a state of apathy and reduced initiative.
  o The patients normally show fewer emotions, respond slowly to external stimuli
    and tend to become drowsy.
  o The patients are easily aroused and have no loss of intellectual function.
  o Aggressive tendencies are strongly inhibited.
  o Many antipsychotics also show antiemetic activity, reflecting antagonisms at
    dopamine receptors.

Unwanted effects
Antipsychotic-induced motor disturbances
  o Two main kinds seen, which are collectively termed the extrapyramidal side-
      effects, which result directly or indirectly from D2-receptor blockade. Atypical
      antipsychotics show less tendency to cause these effects.
          o Acute dystonia – involuntary movements (muscle spasm, protruding
              tongue, torticollis etc) and often a Parkinson-type syndrome. Occur in
              first few weeks, often declining in time, and are reversible upon Rx
              cessation. Effect consistent with blocking dopaminergic nigrostriatal
              pathway, and thus is less often seen with atypical antipsychotics that target
              the mesolimbic/mesocortical pathway.
          o Tardive dyskinesia – involuntary movements of face, tongue, trunk and
              limbs, appearing after months to years of Rx in 20-40% of Pts on classical
              antipsychotics. Side-effect is disabling and often irreversible, and often
              gets worse when Rx stops. Associated with proliferation of dopamine
              receptors (possibly presynaptic) in the corpus striatum.
Endocrine effects
  o Increases prolactin release leading to breast swelling, pain and lactation in both
Other side-effects
  o Dry mouth, blurred vision, hypotension etc result from blockade of other
      receptors, such as α-adrenoceptors and muscarinic ACh receptors.
  o Sedation and weight gain are also common.
  o Leucopenia and agranulocytosis are rare but potentially fatal and occur in the first
      few weeks.
  o Antipsychotic malignant syndrome – rare but serious, and is similar to malignant
      hyperthermia syndrome seen with certain anaesthetics. Muscle rigidity is
      accompanied by rapid rise in body temp and mental confusion. Usually
      reversible, but is fatal in 10-20% of cases.

Clinical efficacy
  o Effective in controlling symptoms of acute schizophrenia, when large doses may
     be needed.
  o Long term Rx is often effective in preventing recurrence of attacks, and enables
     most Pts to live normal lives
  o Generally not effective in controlling the negative symptoms, though newer drugs
     are claimed to relieve these symptoms
  o Approximately 40% of chronic schizophrenic Pts are poorly controlled by
     antipsychotic drugs.
  o There are negligible differences in efficacy between different antipsychotic drugs,
     though side effects differ significantly.

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