This quote from Miller (2004) makes it clear that the affinity of drugs for the H1 receptor does not correlate to sedation:

Although both dosage and affinity for histamine H1 receptors play a part in the sedative effect of a medication, what ultimately determines sedative effect is the amount of the drug reaching the histamine H1 receptors in the central nervous system. For example, quetiapine, which has little affinity for the histamine H1 receptors, is a less potent antipsychotic medication and requires many more milligrams to be effective than do higher-potency medications such as risperidone and ziprasidone. Because of this, quetiapine has a greater sedative effect on patients in clinical use than do risperidone and ziprasidone.

enter image description here

Is there a mathematical way to compare affinity to potency between different drugs?


1 Answer 1


There are a few important things to consider as you interpret these data.

Here potency means Chlorpromazine equivalents

When your linked review refers to potency, it is likely referring to the old concept of chlorpromazine equivalents. The table in the article cites Jibson and Tandon in a review in CNS news special report from 2001. This is not a standard peer reviewed article, and I can't access it, but it lists relative potency in mg, with chlorpromazine set at 100mg and haloperidol at 2mg:

enter image description here

This is almost certainly chlorpromazine equivalents. You can read a discussion of the limitations of this understanding of antipsychotic potency here, but these numbers are not based on a mathematically rigorous pharmacodynamic analysis. They are not consistent, especially for atypical antipsychotics, and are estimated based on clinical data of the minimum effective dose among other methods.

So, where the affinity in this article, $\frac{1}{K_D}$, has a rigorous pharmacodynamic definition, potency does not. Here it is, effectively, shorthand for how much of a drug you have to administer in order to get a therapeutic effect.

Antipsychotic drugs act at many CNS receptors

To understand exactly what Miller means when he says:

For example, quetiapine, which has little affinity for the histamine H1 receptors, is a less potent antipsychotic medication and requires many more milligrams to be effective than do higher-potency medications such as risperidone and ziprasidone.

You need to understand that $H_1$ receptors do not mediate the primary clinical target. So the lower potency of quetiapine means you have to give more of it to have a clinical effect. Because of the higher typical dose of quetiapine, even though the affinity for $H_1$ receptors is relatively low, you're going to get more binding to $H_1$ than with, e.g., risperidone, which requires a lower dose.

Take a look at the chart in the Richelson and Souder article Miller cites to see the different receptor targets for these antipsychotic drugs. enter image description here

The primary therapeutic targets (used to characterize the general clinical potency) are (probably) the $D_2$, $5HT_{1A}$, and $5HT_{2A}$ receptors. The action at the $H_1$ receptor is primarily an adverse effect. Miller is trying to say that the sedation effect does depend on affinity at $H_1$, but you also have to consider the dose required to get an effect at $D_2$ and the relevant $5HT$ receptors.

A rigorous definition of potency involves simplification

There is a rigorous definition of potency for an agonist (and also of inhibition for an antagonist, and antipsychotic drugs are antagonists). Potency is both distinct from and dependent on affinity. I'd recommend Goodman and Gillman Chapter 3, if you'd like to learn more. It's not particularly relevant to understanding this article, in part because Miller doesn't use this definition of potency, and in part because the model involves a single ligand-receptor interaction that directly mediates a desired effect. It's based on the following equation, where $LR^*$ is an activated ligand-receptor: $L + R \rightleftharpoons LR \rightleftharpoons LR^*$. Because both desired and adverse effects of antipsychotics involve actions at many different receptors even beyond those in Richelson and Souder, the simple model falls short.

  • $\begingroup$ Thank you for the response. I just saw your comment. I need to get a hold of the book to try to understand more before I assume you explanation isn't adequate. $\endgroup$
    – William
    Jul 8, 2018 at 22:20
  • $\begingroup$ @William what do you need help understanding? $\endgroup$
    – De Novo
    Jul 8, 2018 at 22:20
  • $\begingroup$ @William the basic idea here is that the article is talking about a general clinical concept of potency, and the clinical (side) effect of sedation for drugs that are given in very different doses. This is not a single receptor system, and Miller is not talking about the relationship between affinity for $H_1$ and potency at $H_1$. I've studied this a good deal, in and beyond medical school. I'm happy to help answer your questions about it if you need more help. Just ask. $\endgroup$
    – De Novo
    Jul 8, 2018 at 22:36
  • $\begingroup$ I'm trying to compare the drugs and from what I have gathered from reading your post is that there is no way to rank their sedation except with clinical trials and comparing sedation described by the patient. $\endgroup$
    – William
    Jul 11, 2018 at 7:28
  • $\begingroup$ I am asking for an equation I don't see where potency is plugged into the equation. Can you please post a Mathematical example walking though either Zyprexa or Seroquel. $\endgroup$
    – William
    Jul 11, 2018 at 8:10

You must log in to answer this question.

Not the answer you're looking for? Browse other questions tagged .