Pharmacology of antipsychotics

This chapter tries to address Section K2(iv) of the 2023 CICM Primary Syllabus, which expects the exam candidate to develop an " understand the pharmacology 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


  • Chlorpromazine
  • Prochlorperazine


  • Haloperidol
  • Droperidol
  • Olanzapine
  • Quetiapine
  • Risperidone
  • Aripiprazole
Routes of administration Oral, IV, SC and IM administration Oral only in the majority of cases
  • Well absorbed orally
  • Generally, a large first pass effect decreases bioavailability to 10-70%
  • Large volume of distribution (~10-20 L/kg)
Protein binding
  • 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. 

Chemical classes of antipsychotics

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. 

  • Typical antipsychotics
    • Phenothiazines (chlorpromazine)
    • Butyrophenones (haloperidol, droperidol)
  • Atypical antipsychotics
    • Phenylpiperaxines  (aripiprazole)
    • Dibenzodiazepine (clozapine, quetiapine)
    • Thienobenzodiazepines (olanzapine) 
    • Benzisothiazoles and benzisoxazoles (risperidone, lurasidone)

An alternative classification is possible. Here is one from Jes Gerlach (1991), which reassembles these agents into pharmacodynamic mechanism groups:

  • Selective D2 receptor antagonists:
    • Sulpiride
    • Remoxipride
    • Raclopride
  • Partial D2 receptor agonists:
    • Terguride
    • Roxindole
  • Serotonergic agents:
    • Buspirone
  • Glutamate agonists:
    • Milacemide​​​​​​​
  • Multi-receptor blockers (D2 plus others):
    • Serotonin + D2 antagonists:​​​​​​​
      • Risperidone
    • Serotonin + D2 + α1 antagonists:​​​​​​​
      • ​​​​​​​Amperozide
      • Sertindole
    • Serotonin + D1 + D2 + α1 antagonists:
      • ​​​​​​​Clozapine
      • Savoxepine

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.

  • Administration and absorption is similar for both groups, with the older typical agents being somewhat more versatile. They are usually available in IV and IM formulations, whereas the newer agents are usually only oral. Both groups have various conveniently long-acting versions which can sit happily in a deltoid or a buttock as a depot, slowly dissociating into the bloodstream over weeks.
  • Bioavailability is pretty variable, but most of these drugs are subject to a significant first pass effect. The range is from 10% to 70%. 
  • Protein-binding is predictably high, just like it is with the antidepressants. Most agents are 90-99% protein bound (for example, haloperidol is92% protein-bound)
  • Distribution is vast, as these highly lipophilic protein-loving drugs tend to accumulate in tissues. For haloperidol, for example, the volume of distribution is 18L/kg.
  • Elimination is invariably by hepatic mechanisms, with inactive metabolites escaping via the urine. The number of possible metabolites for each drug is vast, and many have independent CNS activity (though not all of them are predictably D2 antagonists like the parent molecule). For example, risperidone is metabolised into a metabolite so active and so long-lived that it became a marketable drug all on its own (paliperidone).

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. 


Mechanism of antipsychotic action

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.

Mechanisms of side effects:

It is possible to discuss the side effects without separating the antipsychotic drugs into groups, because:

  • Atypical antipsychotics tend to still have side effects which are similar to typical ones, just not as often and with lesser severity
  • Atypical antipsychotics, when seen in the ICU, are often seen in the context of overdose, in which case the concentration is high enough for their "typical" side to come out.


  • Sedation: this effect is not always undesirable, and in fact often in the ICU these drugs are used for this specific purpose. It originates from the antihistamine effects.
  • Extrapyramidal side effects are the consequences of blocking striatal D2 receptors:
    • Dystonia: involuntary muscle spasm involving usually facial muscles (tongue, neck,  eyes, etc) which can happen on the very first day of treatment. Hideously, it can involve the larynx. 
    • Oculogyric crisis is the extreme version of this, which classically also involves an arched back and eyes which have rolled back inside their sockets.
    • Akathisia, a sort of motor restlessness, often occurs within the first week of treatment
    • Rigidity and parkinsonism typically takes months to develop
    • Tardive dyskinesia is only seen with prolonged treatment
  • Hyperprolactinaemia: Dopamine is a normal regulator of prolactin secretion, and dopamine receptor block in the tuberoinfundibular tract leads to the suppression of this regulation. With the breaks disabled, the pituitary gland pumps out gallons of prolactin. Galactorrhea and breast enlargement occurs in women, and gynecomastia in men.
  • Postural hypotension and sexual dysfunction are both the gifts of α-adrenergic receptor blockade. In overdose, the block can be sufficiently deep to produce significant vasodilation and hypotension.
  • Anticholinergic side effects (xerostomia, urinary retention, tachycardia, constipation, blurred vision, tachycardia and delirium) 
  • Lowered seizure threshold: All antipsychotics do this to some extent, but some do it more than others. It appears the oldest of the drugs have some of the greatest risk of seizures. Sadek (2021) claims that chlorpromazine and thioridazine are the most epileptogenic, but there is no reference to back it up.
  • QT interval prolongation occurs because antipsychotics block the delayed rectifier currents (Ik), which are responsible for Phase 3 of the action potential. According to Zareba & Lin (2003), this is also something that appears to be common to all of them, with a distribution ranging from minor effects (aripiprazole, olanzapine, haloperidol) to significant effects (amisulpride, thioridazine). The upshot is an increase in the risk of sudden cardiac death (from polymorphic VT) which is 2-3 times higher among chronic schizophrenia patients when compared to the rest of the population.


Fischer-Barnicol, David, et al. "Typical and atypical antipsychotics–The misleading dichotomy." Neuropsychobiology 57.1-2 (2008): 80-87.

Sadek, Joseph. "Antipsychotics." Clinician’s Guide to Psychopharmacology. Springer, Cham, 2021. 113-145.

Zareba, Wojciech, and David A. Lin. "Antipsychotic drugs and QT interval prolongation." Psychiatric quarterly 74.3 (2003): 291-306.

Collins, Nathan, and Jeffrey Sager. "Acute laryngeal dystonia: drug-induced respiratory failure related to antipsychotic medications." Journal of Neurology & Neuromedicine 3.1 (2018).

Amato, Davide, et al. "A dopaminergic mechanism of antipsychotic drug efficacy, failure, and failure reversal: the role of the dopamine transporter." Molecular psychiatry 25.9 (2020): 2101-2118.

Gerlach, Jes. "New antipsychotics: classification, efficacy, and adverse effects." Schizophrenia bulletin 17.2 (1991): 289-309.

Javaid, J. I. "Clinical pharmacokinetics of antipsychotics." Journal of clinical pharmacology 34.4 (1994): 286-295.

Preskorn, Sheldon H. "Clinically important differences in the pharmacokinetics of the ten newer “atypical” antipsychotics: part 1." Journal of Psychiatric Practice® 18.3 (2012): 199-204.