This chapter tries to address Section K2(iv) of the 2017 CICM Primary Syllabus, which expects the exam candidate to develop an " understand the pharmacology (including toxicology) of anti-depressant and anti-psychotic drugs". No detailed exploration of this topic has ever appeared in any of the CICM exams, and the only thing that has come close were Question 21 from the second paper of 2014 (a comparison of haloperidol and diazepam), or Question 16 from the second paper of 2021 (classification of antipsychotics, but mainly about haloperidol). As such, there is probably little reason to go into a lot of depth here in the course of revision. Class characteristics are offered here for the purpose of rapid comparison and reference, in case an SAQ or viva on this topic appears at some stage.
Class Classical antipsychotics Atypical antipsychotics Examples
Routes of administration Oral, IV, SC and IM administration Oral only in the majority of cases Absorption
- Well absorbed orally
- Generally, a large first pass effect decreases bioavailability to 10-70%
- Large volume of distribution (~10-20 L/kg)
- Most are >90% protein bound
- Most are metabolised extensively in the liver.
- Many have active metabolites
- Metabolites are renally excreted
- Most of the newer agents and some of the older have long half-lives and require once daily dosing.
Mechanism of effect
- D2 receptor blockade gives rise to the antipsychoti effect, and controls the positive symptoms of psychosis
- Serotonin receptor activity of the newer agents also manages the negative symptoms
- Sedation (antihistamine effect).
- Extrapyramidal side effects (dystonia, oculogyric crisis, laryngospasm, akathisia, rigidity, parkinsonism and tardive dyskinesia)
- Hyperprolactinaemia (dopamine blockade)
- Postural hypotension and sexual dysfunction (α-adrenergic receptor blockade)
- Anticholinergic side effects (xerostomia, urinary retention, tachycardia, constipation, blurred vision, tachycardia and delirium)
- Lowered seizure threshold
- QT interval prolongation
If one want to refer to a single resource but needs something with more legitimacy than some online blog post, "Antipsychotics" by Sadek from his Clinician's Guide to Psychopharmacology (2021) would be an excellent start. That book in general is written in a conversational style resembling The Physiology Viva, which is to say it resembles a somewhat threatening and uncomfortable conversation, where one participant keeps asking really difficult and detailed questions. "Clinical pharmacokinetics of antipsychotics" by Javaid (1994) would also be nice, except it is paywalled.
The distinction between "typical" and "atypical" antipsychotics is an entirely artificial line that was drawn for marketing purposes when clozapine became available on the market in the early 1970s. Less extrapyramidal side effects, they said. Contemporary reviews of this distinction have been unable to confirm the existence of this sharp distinction. Some "typical" antipsychotic agents have very few extrapyramidal side effects (for example, perazine), and some of the novel atypical agents (eg. risperidone) have plenty of them, making it an ineffective method of discriminating between agents.
An alternative classification is possible. Here is one from Jes Gerlach (1991), which reassembles these agents into pharmacodynamic mechanism groups:
Unfortunately, as one might have guessed from their experience with other such mechanism-based classification systems, as soon as you start putting things into categories you discover that some things span multiple categories.
For a family of drugs with so many members, the pharmacokinetic properties of them all are remarkably uniform, which makes it easy to describe and study them en masse.
Atypical antipsychotics also have a few clinically significant pharmacokinetic peculiarities, as outlined by Sheldon Prescorn (2012), and a table of these properties can be reviewed by anybody who has that kind of time.
Dopamine antagonism (specifically, the antagonism of D2 dopamine receptors in the mesolimbic system) seems to be the main mechanism of action for typical antipsychotics. At the same time, the same mechanism is responsible for the extrapyramidal side effects. The antipsychotic effect is seen when the drugs are blocking65-75% of the D2 receptors, and disappears below this narrow window (Amato et al, 2020). The idea that this receptor blockade underpins the antipsychoticness of the drug is also supported by the finding that potency of D2 blocking and receptor affinity seems to be related to the magnitude of the clinical antipsychotic effect seen for each agent. Obviously, the brain is more complex than that, and there are numerous caveats to this oversimplification, but for exam purposes it will have to do.
It is possible to discuss the side effects without separating the antipsychotic drugs into groups, because: