Defining a Drug’s Strength. What is Potency? What is Intrinsic Activity?

There are numerous ways to define how strong a drug is, but from a pharmacological perspective there are two major axis: Binding Affinity and Intrinsic Activity.

For a given receptor and a given set of intended subjective effects, a drug would have a certain level of binding affinity and a certain level of intrinsic activity. These two are not necessarily correlated. Both would impact the subjective strength of the drug and also the objective efficacy of the compound in its ability to activate certain signaling pathways. However, how these two factors work are quite different and have a very different impact on the strength of a compound.

Ligands binding to receptors

See this relevant blog article for a review on how compounds bind to receptors: https://www.drugnerd.net/blog/pharmacodynamics-basics-what-the-hell-is-an-agonist-or-antagonist-25gz7

Binding Affinity:

As discussed in the previous blog entry, Binding Affinity refers to how readily a compound would bind to a given receptor. Drugs with stronger binding affinity require far fewer molecules of the drug in order to achieve a certain level of saturation.

Relationship between binding affinity and % of receptors that the ligand would bind to for a given concentration

Source: https://en.wikipedia.org/wiki/File:Agonists_v2.png 

Example:

Let’s use some hypotheticals. Assume there’s two drugs being evaluated: Drug A and Drug B. Both are primarily intended to bind to the Gaba A receptor, however drug A has a stronger binding affinity at Gaba A receptor than drug B.

Binding affinities are usually expressed as Ki (inhibition constant), which specifies how much concentration of a given compound is needed to saturate about 50% of a patient’s specific receptors (in this case Gaba A).

Assume Drug A has a 10x lower Ki value than Drug B. This means it requires 10x less of drug A to bind to 50% of your gaba A receptors than it would for drug B.

Let’s say that it takes on average about 100mg of drug A to roughly saturate 50% of all CNS Gaba A receptors. This would mean that it would require about 10x more (1000mg) of drug B to achieve the same result, due to it having a 10x higher Ki value.

In essence, binding affinity has a strong correlation with the “potency” of a drug, aka how high a dose of the drug is needed for intended effects. A high potency drug requires a smaller amount of the compound than a lower potency drug would.

In Actuality:

In reality, it is not quite as simple. Many other complex factors such as route of administration, pharmacokinetic (how the drug is metabolized and mobilized around the body), state and quantity of metabolic enzymes, etc could all have a massive impact on the potency of a compound. Although this means that simply looking at the binding affinity is not enough to figure out an accurate dosage of a drug, it is still a great place to start when evaluating the estimated potency of a compound.

For example, LSD has a Ki of 2.9nM at the psychedelic 5ht2a receptor.

Meanwhile, DMT has a Ki of 237nM at the 5ht2a receptor. This represents a 81.7x higher Ki for DMT, implying that an average dose of DMT would be about 81.7x higher than that of LSD.

In practice, an average dose of LSD is 100µg while an average dose of DMT is 30mg, representing a 300x higher dosage rather than the expected ~82x dosage.

Factors such as the difference in route of administration (sublingual for LSD vs smoked for DMT) and the bioavailability of the two compounds (how readily the compound gets absorbed into the body and crosses the blood-brain-barrier to reach where it needs to be) could be contributing to this vast difference between actual dosages and expected dosages based purely on binding affinity.

A DMT pipe

Intrinsic Activity:

Binding affinity tells us only half the story: It shows how readily a compound can bind to a receptor, which also tells us how large an amount of the compound must be ingested for it to bind to a sufficient number of receptors.

However, this shows nothing about what actually happens once the compound has binded to those receptors. For that we need to look at intrinsic activity. We discuss this concept in detail in this previous article: https://www.drugnerd.net/blog/pharmacodynamics-basics-what-the-hell-is-an-agonist-or-antagonist-25gz7

To summarize here: A ligand can do one of various things after it has bound to a receptor. Here’s a list of a few basic options (the total list of possibilities is much larger and the previously linked article goes more in detail)

1) Full-Agonist: Binds to the receptor and then activates it with roughly the same strength as your endogenous ligand (the body’s built in compound that’s meant to attach to that receptor)

2) Partial-Agonist: Binds to the receptor and then activates it with less strength than the endogenous ligand.

3) Antagonist: Binds to the receptor but then does not activate it at all. This essentially silences the receptor for as long as the compound is bound to it.

Seeing these 3 basic possibilities (there are a ton more!), we notice that just because a compound can bind to a receptor, doesn’t necessarily mean it will activate it strongly.

This means that there are extremely high potency drugs that have very high binding affinity (and very low Ki values) for a given receptor, while still only being a partial agonist. These drugs generally would be very high potency (requiring low dosages for an effect), but the effects cap out in intensity after a certain dosage, with this “ceiling effect” being at a level much lower than what a full agonist can achieve. So a high potency partial agonist would feel like a very “strong” drug at lower dosages since only a tiny amount is needed to reach the desired effect, but eventually ceillings out once you take more, and it will now feel “weak” since other compounds (even lower potency ones) that are full agonists could reach a much higher intensity of effect.

Chart showing that a partial agonist “caps out” at a lower “ceiling effect” than a full agonist, regardless of dosage

Source: https://commons.wikimedia.org/wiki/File:Agonist_2.png

Example:

Drug A has a Ki of 10nM

Drug B has a Ki of 100nM

Drug A is a partial agonist

Drug B is a full agonist

Ignoring pharmacokinetics, metabolism, and other complex factors, this would imply:

When attempting to achieve a low intensity experience from the two drugs:

Drug B requires about 100mg to achieve a weak high, while Drug A only needs 10mg to achieve a similar result. Drug A seems like the “stronger” drug here.

When attempting to achieve a high intensity experience from the two drugs:

Once you take more than 50mg of Drug A, any more you take feels mostly about the same and no longer increases the intensity of the experience. You take 100mg of Drug A but it feels the same as 50mg and only gives you a medium intensity experience.

Meanwhile, 1000mg of Drug B achieves a massive intensity experience that no amount of Drug A could possibly match due Drug A’s lower intrinsic activity.

So in this scenario, Drug B, despite being less potent (requiring higher dosages) seems like the stronger drug since even an infinite amount of Drug A would not be able to achieve a high as intense as that of a high dose of Drug B.

Note: Despite Drug A capping out at 50mg and a higher dose not increasing the subjective experience, increasing the dosages of partial agonists beyond their ceiling dose still has some potentially useful effects. In the case where both Drug A and Drug B are administered simultaneously, a higher dose of Drug A can serve to outcompete Drug B for binding at the receptor. Since Drug A is only a partial agonist, once it has kicked out a Drug B molecule from a receptor, that receptor would suddenly be activated less than before. This means a high enough dose of Drug A can act as a muting effect (almost similar to an antagonist) on Drug B, due to it binding more readily, but producing a lower intrinsic activity.

Implications

A conflation of these two separate measurements can frequently lead to misunderstandings of a drug’s strength. One common example is Buprenorphine, which has a lot of myths and misinformation around its potency / effectiveness / strength.

Buprenorphine

Buprenorphine is a high potency opioid that is only a partial agonist at the mu-opioid receptor (MOR). Buprenorphine has extremely high binding affinity for the MOR and has a potency of about 40-70 times that of morphine. However, since Buprenorphine is only a partial agonist, its effects cap out at a much lower ceiling than morphine is able to achieve. It is exactly this effect that causes buprenorphine to be safer in an overdose.

By being a high potency but low intrinsic activity Opioid, Buprenorphine can also act as a weak “antidote” for an overdose of an opioid full agonist. For example, if excessive morphine is taken, a high dose of Buprenorphine would lead to the Buprenorphine molecules outcompeting the morphine molecules (due to the large enough dose taken combined with a higher binding affinity), replacing full agonist morphine molecules with partial agonist Buprenorphine molecules. Since these MORs that just had their morphines replaced by Buprenorphine are now only being partially activated, the overall intensity of the opioid experience is significantly reduced.

Morphine and Buprenorphine playing Musical Chairs

In this Musical Chairs analogy, the compound with a higher binding affinity essentially has longer legs / can run faster and has an easier time outcompeting the other compound in finding a chair in time.

Image generated by Dalle 3 (ChatGPT 4.0), that’s why the text on the pill bottles are messed up. Just pretend you don't notice it pls.

This effect, of course, is not nearly as powerful as that of a full antagonist, and Buprenorphine is not a replacement for Naloxone in the case of an acute Opioid Overdose.

Note: The excessively high binding affinities of Fentanyl when compared to Naloxone, is actually the reason why fentanyl overdoses usually require a much higher dose of Naloxone to reverse than overdoses of less potent opioids such as Heroin or Morphine.