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 (typical antipsychotics) |
| 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 | Seizures | ||
| 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