Potency and efficacy

This chapter is related to one of the aims of Section C(i) from the 2017 CICM Primary Syllabus, which expects the exam candidate to "define and explain dose-effect relationships of drugs, including dose-response curves with reference to ... potency and efficacy". These are fairly fundamental concepts in pharmacodynamics, and so it is all the more puzzling that these issues have never surfaced in the CICM Part I exams, considering especially how fond of graphs the examiners are, and how well this topic lends itself to cross-table viva examination.

Because there's no explanation of this in Birkett (2009), the first priority for revision of this topic falls on “Basic and Clinical Pharmacology” by Katzung et al. The 14th (electronic) edition, in chapter 2 (Drug Receptors & pharmacodynamics, by Mark von Zastrow) contains a section called "Relationship between drug dose & clinical response". Apart from breaking the rules of responsible ampersand usage, this section is satisfactory for the purposes of exam preparation. Its content is used for the definitions below. The gold standard for all pharmacological definitions outside of the exam context is the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification (Neubig et al, 2003) and is referenced wherever the official college textbooks are inadequate.

In summary:

• Potency is the concentration (EC₅₀) or dose (ED₅₀) of a drug required to produce 50% of that drug’s maximal effect.
• Efficacy (E_max) is the maximum effect which can be expected from this drug (i.e. when this magnitude of effect is reached, increasing the dose will not produce a greater magnitude of effect)
• Intrinsic activity is the drug's maximal efficacy as a fraction of the maximal efficacy produced by a full agonist of the same type acting through the same receptors under the same conditions

Potency

According to Katzung, potency is defined as 

"... the concentration (EC₅₀) or dose (ED₅₀) of a drug required to produce 50% of that drug’s maximal effect. "

The value of a drug's potency should be stated in terms of a dose, i.e. in units of weight. Given the primacy of this source in the official literature list, one would have to assume that this is the gospel college definition for exam purposes. Other possible definitions also exist, which are both  less cumbersome and less accurate. For instance, Wikipedia defines it as "the amount required to produce an effect of given intensity", which is memorably short but very vague. If there was any official definition outside of the realms of CICM primary exam preparation, it would have to be the one from the International Union of Pharmacology nomenclature document (Neubig et al, 2003) which reads:

"[Potency is] an expression of the activity of a drug, in terms of the concentration or amount needed to produce a defined effect."

The IUP also add that it is "an imprecise term that should always be further defined" (in terms of EC₅₀, for example) and complain that the term is "sometimes, incorrectly, used to refer to the maximum effect attainable". These complaints don't make up any part of this definition, and it is not described as a definition per se, but rather as "suggested usage". 

Anyway. This probably works better with an example.

• Both Drug A and Drug B achieve the same maximum effect, i.e. they have equal efficacy.
• However, drug A achieves this effect at a lower dose.
• Thus, Drug A has higher potency than Drug B.

Relative potency is a variant  where instead of using units to describe the dose required to achieve a certain endpoint, one ends up using a ratio of equivalent doses; i.e. one might say that Drug A is 100 times more potent than Drug B because it achieves the same effect with  1/100th of the dose. 

Efficacy

Efficacy in Katzung is discussed using the term "maximal efficacy" or E_max, and no specific definition is offered (probably because this is better explained using an example). To again resort to the "suggested usage" column from Neubig et al (2003),  efficacy is 

"the concept... to express the degree to which different agonists produce varying responses, even when occupying the same proportion of receptors."

The definition is actually adapted from Stephenson (1956), at the very dawn age of receptor theory. Stephenson needed to discuss the effect of agonist drugs on the tissues:  

"Different drugs may have varying capacities to initiate a response and consequently occupy different proportions of the receptors when producing equal responses. This property will be referred to as the efficacy of the drug".

The key thing to grasp here is that a drug, when occupying the receptor, does not by default produce one standard unit of response. It may produce a complete response, or no response, or some partial response. Thus, E_max is the maximum effect which can be expected from this drug; i.e. once this magnitude of effect is achieved, giving an increasingly higher dose of the drug will not produce a an increase in the magnitude of effect.

This is obviously not something that can be measured uniformly for all drugs (what units would you use?). But, it is still possible to express this variable numerically, as a ratio of the drug's maximal efficacy to the maximal efficacy of some known potent agonist. This is referred to as intrinsic activity, which the ever-scientific International Union of Pharmacology has rebranded as the maximal agonist effect: 

"The maximal effect that an agonist, whether conventional or inverse, can elicit in a given tissue under particular experimental conditions. It is best expressed as a fraction of the effect produced by a full agonist of the same type acting through the same receptors under the same conditions."

The IUP stressed that it is only sensible to discuss maximal agonist effect within the framework of specific experimental conditions, "because maximal effects are highly dependent on the experimental conditions such as tissue used, level of receptor expression, the type of measurement used (e.g., IP3 vs. Ca²⁺, vs. contraction or secretion), and changes in signal transduction efficiency." Another important matter to note is that the term has a different meaning in the clinical context, as compared to the pharmacological laboratory. In vitro maximal efficacy might be achievable by a sufficiently high concentration of the drug, but in vivo the patient will surely be dead from the side effects. Maximal efficacy in the clinical setting is therefore the maximum extent of effect which can be achieved by reasonable people in the intact living patient. The effectiveness of the drug is again another matter entirely

Again, this is one of those things that is easier to explain with a graph. 

Here, Drug A achieves a higher maximum effect than Drug B. Drug A is therefore said to be more efficacious.

Here, both Drug A and Drug B achieve the same maximum effect, i.e. they have equal efficacy. However, Drug A achieves this effect at a lower dose (i.e  Drug A has higher potency than Drug B).

Here, both Drug A and Drug B achieve the same maximum effect, i.e. they have equal efficacy. At EC50, Drug B is more potent than drug A. Both Drug A and Drug B achieve the maximum effect (Emax) at the same dose (i.e. they have equal maximum potency). However, drug B achieves this effect with a lower dose. Drug A, however, has a a steeper dose-response curve than Drug B - a rise from EC50 to Emax is accomplished with a relatively small increase in dose.