Antipsychotics

Antipsychotics are drugs used for the management of psychoses and thought disorders. They have a complicated mechanism of action with effects on multiple receptors:

  • Central dopamine (typically D2, but varies with agent) antagonism
    Responsible for the antipsychotic properties
  • 5-HT2 antagonism
  • Other receptors which are quantitatively less important:
    • H1 antagonism
    • α1 antagonism
    • Muscarinic ACh antagonism

Based on their affinity to various receptors, they are (loosely) classified as either:

  • Typical or 1st generation antipsychotics
    Higher affinity for D2 receptors (subsequently less blockade of 5-HT2), causing a greater effect on 'positive' symptoms' and a greater incidence of extrapyramidal side effects
  • Atypical or 2nd generation, which typically have fewer motor effects
    Have greater effect on negative symptoms.

Common Features of Antipsychotics

Property Drug
Uses Behavioural emergencies, schizophrenia/psychosis
CVS QT prolongation
CNS Apathy, ↓ initiative, ↓ response to external stimuli, ↓ aggression. No loss of intellectual function.
Endocrine ↑ Prolactin (typicals)
Haeme Leukopenia and agranulocytosis (predominantly clozapine, but can be all)
Metabolic Weight gain, diabetes, hypercholesterolaemia (all atypical > typical)
Other Toxicities Neuroleptic malignant syndrome, EPSE

Neuroleptic Malignant Syndrome

Antipsychotic Malignant Syndrome is rare and presents similarly to MH, with a rapid rise in body temperature and confusion. It has a high mortality (up to 20%).

Extra-Pyramidal Side Effects

Motor disturbances from antipsychotic use are termed EPSEs, and are divided into two main types:

  • Acute Dystonic Reactions are involuntary movements and parkinsonian symptoms. They are:

    • More common with typical agents
    • Decline with ongoing use
    • Reversible with cessation of the agent
  • Tardive dyskinesia is similar to ADR, except:

    • Involuntary movements are more pronounced and disabling
    • It occurs with long term use (10-20 years)
    • They are irreversible, and worsen when therapy is stopped

Comparison of Antipsychotics

Property Haloperidol Olanzapine Clozapine
Class Typical Atypical Atypical ("3rd gen")
Uses Behavioural Emergencies Behavioural Emergencies, Psychosis/Schizophrenia Treatment resistant schizophrenia
Presentation Tablets, syrup, clear solution for injection at 5mg.ml-1 Tablets, solution for injection Yellow tablet
Route of Administration PO/IM/IV PO/IM PO
Dosing 1-5mg IV, 2-30mg IM, 1-15mg PO IM 5-10mg, PO 5-20mg Must be prescribed by a psychiatrist
Absorption 50% PO bioavailability 60% PO bioavailability Rapid absorption
Distribution 92% protein bound 93% protein bound, VD ~14L.kg-1 VD 2L.kg-1
Metabolism Hepatic to largely inactive metabolites Hepatic to inactive metabolites May obey zero-order kinetics at the upper limit of the dose range
Elimination Renal of metabolites Renal of inactive metabolites Renal of active drug (~25%) and inactive metabolites
CVS Hypotension Myocarditis (potentially fatal)
CNS Seziures
GIT Antiemetic Hepatitis
Haeme Agranulocytosis, thromboembolic disease

References

Rang and Dale Smith, Scarth, Sasada Critical Care Drugs Manual http://lifeinthefastlane.com/book/critical-care-drugs/ https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=8248 https://www.ncbi.nlm.nih.gov/pubmed/8453823

Last updated 2017-02-15

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