Receptor theory of drug action

This chapter answers parts from Section C(ii)  of the 2017 CICM Primary Syllabus, which asks the exam candidate to "explain the concept of drug action with respect to receptor theory".  Nobody has ever been asked about this in the exams or vivas; nor is it ever likely to emerge as a dominant topic of a future SAQ. The subject matter is sufficiently esoteric and remote from clinical reality that even the CICM examiners are unlikely to view it as a fair discriminator of good trainees from bad. The concept of receptor theory is so well-entrenched and foundational that most trainees of modern medicine cannot conceive of a universe without it.

Because of this reliance and over-familiarity, any question about receptor theory will come as an unexpected and thought provoking challenge. You do not want a though-provoking challenge in the exam. In order to protect trainees from such an eventuality, this chapter offers a brief overview of the major issues, as well as a short summary to memorise and regurgitate.

In summary:

• Drugs interact with receptors  to produce a change in the state of the receptor, which is then translated into a physiological effect.
• This molecular interaction with the receptor can be modeled mathematically and obeys the Law of Mass Action.
• The binding of drug and receptor determines the quantitative relationship between dose and effect.
• Mutual affinity of drugs and receptors determines the selectivity of drug effects
• Competition of mutually exclusive molecules for the same receptors explains agonist, partial agonist and antagonist drug activity
• Occupancy theory rests  on the concept that the proportion of occupied receptors is related to the effect of the drug (eg. for full agonists and a linear relationship, 100% occupancy = 100% effect)
• The Operational Model extends occupancy theory by introducing a constant (τ) as a measure of agonist efficacy, which incorporates both tissue responsiveness and drug efficacy
• The Two State Model permits the possibility of "baseline activity" (i.e. receptor activation in the absence of an agonist) and therefore allows the existence of "inverse agonists" which suppress baseline receptor activity. It also redefines efficacy as the increased affinity of the agonist for active (vs. inactive) states of the receptor. It is most suited to describing the activity of gated channels.
• The Ternary Model incorporates the post-receptor amplification of signal due to intracellular second messenger systems; i.e. situations where minimal levels of receptor occupancy may produce maximal levels of drug effect. It is most suited to describing the behaviour of transmembrane signalling systems such as G-protein coupled receptors.

The best peer-reviewed literature references for this topic is probably either the 2004 article or the 2008 article by Terry Kenakin. Both are unfortunately paywalled. The other is a 2006 article by  H.P. Rang (half of Rang & Dale) which is free because the British Journal of Pharmacology doesn't need your money. 

Receptor theory

How to define this fundamental concept? Everybody has had a go. Miller's Pharmacology and Statistics defines a receptor as "a component of a cell that interacts selectively with an extracellular compound to initiate a cascade of biochemical events that culminate in the observed effects of the compound." For the purposes of having a firm official definition, we can turn to a 2003 review of pharmacological nomenclature, which describes a receptor as:

"A cellular macromolecule, or an assembly of macromolecules, that is concerned directly and specifically in chemical signaling between and within cells"

The main points to describe receptor theory are:

• Drugs interact with receptors in a reversible manner to produce a change in the state of the receptor
• This interaction can be modeled mathematically and follows the Law of Mass Action
• The binding of drug and receptor determines the quantitative relationship between dose and effect.
• Mutual affinity of drugs and receptors determines the selectivity of drug effects
• Competition of mutually exclusive molecules for the same receptors explains agonist, partial agonist and antagonist drug activity

Generally speaking, the confirmation of this idea is credited to Alfred Joseph Clark who published his seminal work (Mode of action of drugs on cells) in 1934. Clark and J.H Gaddum were the first to produce the classic graph of the hyperbolic dose-response curve (in that historical case, the curve represented the response of frog myocardia to acetylcholine). "The concentration-action curve of acetylcholine expresses an adsorption process", Clark wrote.  "Adsorption" in this case was used to describe binding to some sort of surface receptors.

Clark and Gaddum were also able to demonstrate the classical "right shift" of the curve with the administration of an antagonist, which further confirmed that the foundations of their theory were correct: the drug effects were produced by the binding of two mutually exclusive compounds at the same population of sites. Unfortunately neither author were able to pursue this further; the concept of drug antagonism and the occupation theory of drug-receptor interaction was developed about then years later by Schild (1947).

Occupancy theory of drug-receptor interaction

Quoting from Kenakian (2008), "receptor occupancy theory describes the quantitative relationships between drug concentrations and the responses that result from the interaction of those drugs with receptors". This theory also describes the behaviour of agonists and antagonist.

 For instance, observe the interaction of agonist A with receptor R, to create the drug/receptor complex AR:  

The equilibrium association constant k_a is the ratio of occupied receptor concentration to the product of agonist concentration and unoccupied receptor concentration. It is the association constant, not to be confused with the dissociation constant k_A.

Let us assume that only occupied receptors produce a response. Then, the magnitude of the response can be expressed as a fraction of occupied receptors. Occupy 50% of the receptors, get 50% of the response. Thus:

So, if the concentration of unoccupied receptors can be expressed as [R] = [AR]/([A] × k_a), the above equation can be rewritten as  

To substitute k_A for k_a is useful because it has units of concentration: it is also the concentration of agonist that occupies half of the available receptor population. 

Evolution of occupancy theory

There were several distinct evolutionary steps in the development of occupancy theory, each of which modified the concept to explain the differences between the model and the observed results of experiments. To borrow a graph from Kenakin (2008): 

Clark's occupancy theory (1934) described the relationship between dose and response as a linear relationship, making the assumption that the maximal response to the drug is equal to the maximal tissue response. This theory is most suited to describe the behaviour of full agonists.

Ariens modification of the occupancy theory (1954) describes a situation where the maximal drug response is not equal to the maximal tissue response (i.e. it permits the existence of partial agonist drugs). This was done by using the modifier α, "intrinsic activity". A full agonist has an α-value of 1.0; if a drug only produces 50% of the maximal tissue response it is a partial agonist with an α-value of 0.5. 

Stephensen's modification of the occupancy theory (1956) added the concepts of stimulus and efficacy. The agonist drug stimulates the system and produces a response; and there may be a non-linear relationship between the two. The tissue response to receptor activation could therefore be dissociated completely from the binding of agonist to receptor. This concept of intrinsic efficacy (ε) was defined as the unit stimulus per occupied receptor. Total efficacy (e) is therefore defined as ε × [R_t]. This is discussed in greater detail in the chapter on potency and efficacy.

Operational model

The occupancy model as described above has several limitations:

• R, the receptor molecules, in reality are not static and have a tendency to undergo conformational changes and various functional alterations which change their affinity for their agonists
• Efficacy (e) is a dimensionless constant which does not correlate to any molecular mechanisms

 The operational model was an answer to these limitations, developed by Black and Leff (1983). It has become the standard approach used for pharmacodynamic models. The major modification of occupancy theory was the introduction of τ - "transducer ratio", a constant which quantifies both the efficacy of the agonist and the tissue response to receptor stimulation. This τ value defines the operational efficacy for an agonist. When τ is large the drug is a full agonist; when τ is low it is a partial agonist. With a very small τ value the operational model describes competitive antagonism.

Two-state model

The two-state model incorporates some acknowledgement of the fact that receptor molecules undergo structural and functional changes, and may have different affinities for drugs (and different pharmacodynamic responses) in their different states. It was first used by Katz and Thesleff (1957) to describe the effect of suxamethonium on acetylcholine-gated ion channels at the motor endplate. This model also introduced (L), an allosteric constant which is defined as the ratio of active to inactive receptors. This model permits a baseline level of receptor activation, i.e. receptor activity in the absence of an agonist drug. This concept then gives rise to the possibility of inverse agonists: drugs which affect L by suppressing baseline receptor activity.

Ternary complex model

This model attempts to incorporate post-receptor signaling into the concept of drug response, which is vaguely related to (ε) from the occupancy model. It was first described by DeLean et al (1980) as a way of describing the effect of increasing G-protein concentration on the response to β-receptor activation. The model permits different scales of response amplification which follows the activation of receptors; more G-protein would mean more response to the activation of fewer receptors and therefore a greater apparent efficacy of the drug. The extended ternary complex model also incorporates the concept of baseline activity, allowing some G-proteins to be active in the absence of any agonist.