Antipsychotics- Pharmacology

DA hypothesis

Drugs which release DA in the brain (e.g. amphetamine) or D2 receptor antagonists (apomorphine) produce a psychotic state in man and make schizophrenic patients worse.  DA receptor antagonists are used to treat the symptoms of SZD.  Therefore it is presumed that there is an overactivity of the DA pathways in SZD.

Dopamine receptor subtypes

  • D1 receptor family- stimulate cAMP.  D1 is found in striatal, limbic and cortical pathways, D5 just in striatal and limbic pathways.
  • D2 receptor family- inhibit cAMP.  D2 is found in striatal, limbic and cortical pathways, D3 in the limbic and cerebellar pathways and D4 in the limbic and cortical pathways.

Different antipsychotics have a different potency for D2 blockade:

Classical (Typical) Antipsychotics

The important two are chlorpromazine and haloperidol.

  • Chlorpromazine is a Group 1 Typical (1st gen) and it is a highly effectinve D1 and D2 blocker.  It also blocks some 5HT, ACh, histamine and alpha adrenergic receptors.  This means that it can often cause pronounced sedation, moderate antimuscarinice effects and moderate extrapyramidal side effects.
  • Haloperidol is a Group 3 typical and is more selective for DA receptors so has a better side effect profile, although EPSEs are still a concern.  It can also cause a rise in prolactin levels.

Atypical Antipsychotics

These are effectively the same class of drug but have a different pharmacological profile and do not have as many side effect.

  • Clozapine
    • Mainly D1 and D4 blockade (in comparison with D2 blockade) so little EPSE risk.
    • Lots of anticholinergic and antimuscarinic side-effect.
    • It is the only drug that seems to treat the suicidal tendency in patients with SZD.
  • Olanzapine
    • Receptor antagonism: 5-HT(2a) = H1 = M1 > 5-HT(2c) > D2 > alpha 1 > D1
    • Low risk of EPSEs or prolactin SE but side effects include sedation, weight gain, dizziness, dry mouth, constipation and possible glucose dysregulation (reversible diabetes).
  • Quetiapine
    • Receptor antagonism: H1 > a1 > 5-HT(2) > alpha 2 > D2
    • Same risks as olanzapine
  • Respiradone
    • Receptor antagonism: 5-HT(2) > D2 = alpha 1 & 2.  NB Little to no histamine, D1 and 5-HT(1) affinity.
    • Can cause EPSEs and prolactin side effects.

Neuroleptic Malignant Syndrome

This is a condition commonly caused by an adverse reaction to antipsychotic (neuroleptic) drugs- notably the classical ones, although the atypicals can cause this too.  It is characterised by the following features (FALTER):-

  • Fever
  • Autonomic instability
  • Leukocytosis
  • Tremor
  • Elevated enzymes (elevated Creatinine Kinase)
  • Muscle rigidity

Management is to withdraw the antipsychotic immediately. Bromocriptineis thought to help (opposite effect to antipsychotic) but removal of the neuroleptic treatment is vital.


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