Question 21

Compare and contrast the pharmacology of haloperidol and diazepam.

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College Answer

These are both commonly used agents and a tabulated format worked well. Subheadings 
covering the “general” pharmacology approach ensured core areas were addressed. Vague terms 
such as "good" or "moderate" did not allow a detailed comparison between the agents. 
Repetition of facts between sections such as uses, pharmacodynamics, effects and adverse 
effects did not gain further marks.


Name Haloperidol Diazepam
Class Antipsychotic Sedative
Chemistry Butyrophenone Benzodiazepine
Routes of administration Oral, IV, IM, s/c Oral, IV, IM, s/c
Absorption Rapidly and completely absorbed; oral bioavailability is about 60% Rapidly and completely absorbed; oral bioavailability is about 94%
Solubility pKa 8.66; minimally water-soluble pKa 3.4; practically insoluble in water
Distribution VOD=18L/kg; 92% protein-bound VOD = 0.8-1.0L/kg;
Target receptor D2 receptors, as well as muscarinic cholinergic receptors, histamine receptors and alpha-adrenergic receptors GABA-A channel (a separate binding site from GABA)
Metabolism Hepatic metabolism into inactive metabolites Hepatic metabolism: N-demethylated by CYP3A4 and 2C19 to the active metabolite N-desmethyldiazepam, and is hydroxylated by CYP3A4 to the active metabolite temazepam.
Elimination Inactive metabolites are renally cleared Inactive glucouronides are renally excreted
Time course of action Elimination half-life of 14-36 hours Half-life of diazepam is 30-50 hours, and terminal elimination half-life of the active metabolite N-desmethyldiazepam is up to 100 hours.
Mechanism of action Antipsychotic effects are mediated mainly by the D2 antagonist effect on the dopaminergic neurons in the mesolimbic system Allosteric modulator of the GABA-A receptor: acts on GABA-A chloride channels, where it binds to a site distinct from the GABA binding site, and potentiates the effects of GABA, this increasing the chloride current and hyperpolarising the cell membrane of the neuron
Clinical effects 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
Sedation, amnesia, anticonvulsant effect, mild decrease in cerebral oxygen demand, no effect on ICP.
Respiratory response to raised CO2 is flattened, but respiratory drive is not as suppressed as it would be with opioids. Airway reflexes are depressed.
Haemodynamic effects (decreased blood pressure and heart rate) are related to its suppression of the sympathetic nervous system. These are less pronounced than those of propofol.
Single best reference for further information Tyler et al (2017) FDA PI document


Tyler, Marshall W., Josefa Zaldivar-Diez, and Stephen J. Haggarty. "Classics in chemical neuroscience: haloperidol." ACS chemical neuroscience 8.3 (2017): 444-453.

Calcaterra, Nicholas E., and James C. Barrow. "Classics in chemical neuroscience: diazepam (valium)." ACS chemical neuroscience 5.4 (2014): 253-260.