Which of the following statements best describes the role of a drug that acts as an agonist?

Key points

Ligand-gated ion channels and G-protein-coupled receptors are important in anaesthesia.

Agonists bind to receptors to produce a functional response.

Agonists can be full, partial or inverse.

Antagonists reverse the effects of agonists.

Antagonists can be competitive or non-competitive.

Receptors

A receptor can be defined loosely as ‘a molecule that recognizes specifically a second small molecule whose binding brings about the regulation of a cellular process…in the unbound state a receptor is functionally silent’. This definition states that a receptor binds specifically a particular ligand (e.g. bombesin binds to bombesin receptors and not vanilloid receptors) but in reality selectivity is a more accurate definition as in some cases high concentrations of ligands will bind to multiple receptor types. The caveat that in the unbound state a receptor is silent holds true in most cases (particularly those encountered with current clinically useful drug-receptors) but an exception can be used to explain inverse agonism.

Receptors can be subdivided into four main classes: ligand-gated ion channels, tyrosine kinase-coupled, intracellular steroid and G-protein-coupled (GPCR). Basic characteristics of these receptors along with some drugs that interact with each type are shown in Table 2.

Table 2

Basic receptor characteristics

The nicotinic acetylcholine receptor should be a familiar member of the ligand-gated ion channel family to all anaesthetists as this is the site of action for neuromuscular blocking agents. The receptor (as is characteristic of this family) is composed of multiple subunits that come together to form an aqueous pore through which (not only) Na+ ions flow. Binding of acetylcholine opens the pore allowing Na+ influx to produce a depolarization. Other examples of this family include the GABAA receptor (a major target for anaesthetic action) whose activation allows Cl− influx to produce membrane hyperpolarization and reduced central transmission.

Tyrosine kinase-coupled and steroid receptors are of little direct anaesthetic relevance and will not be considered further in this article. Anaesthetic steroids (e.g. alphaxalone) do not produce anaesthesia via the steroid receptor; they potentiate the actions of GABAA at the GABAA receptor. GPCRs are an important class encompassing some of the major systems used/manipulated clinically in the anaesthetic setting. These include adrenergic, muscarinic and opioid receptors. Activation of a GPCR allows interaction with a G-protein, which is composed of α, β and γ subunits. Activated Gα subunits then interact with an effector molecule to produce a second messenger, which then brings about a cellular response (Table 3). Activated Gα subunits can also interact with ion channels to modulate ion conductance.

Table 3

Some examples of receptor–G-protein interaction (not comprehensive)

Drug–receptor interaction

As noted above, drug receptor interaction can generally be defined as specific, dose-related and saturable. These characteristics of a drug at a receptor are described by KD and ED50 and can be obtained from ligand binding and dose–response curves.

The equilibrium dissociation constant KD

The equilibrium dissociation constant KD is loosely defined as the concentration of a radioligand that occupies half of a particular receptor population. The concentration used here is the in vitro concentration; clinically the mass (dose) of drug given to a patient is more commonly used (see below). KD is determined experimentally and is a measure of the affinity of a drug for a receptor. More simply, the strength of the ligand–receptor interaction. To determine KD, a fixed mass of membranes (with receptor) are incubated with increasing concentrations of a radioligand until saturation occurs. At saturation, Bmax is determined (maximum receptor number) and half of this is used to determine KD (Fig. 1). High affinity binding occurs at low drug concentrations; conversely, low affinity binding occurs at high drug concentration. If a ligand has affinity it does not necessarily mean that it will produce a response. For example, an antagonist that displays high affinity does not produce a response in its own right.

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Saturation binding experiment. As the concentration of radiolabel increases the amount bound increases until saturation (Bmax). At half Bmax the KD is extrapolated. This rectangular hyperbola is often converted to a semi-logarithmic plot from which more accurate estimates can be obtained. In this example the KD is estimated at 1 nM (1 × 10−9 M) or as a pKD (−log10KD) of 9.

Agonists and ED50

An agonist is a drug that binds to a receptor and produces a functional response. Examples include morphine (μ-opioid receptor) and clonidine (α2-adrenoceptor). The ability to produce a response is termed efficacy (or intrinsic activity); this varies with the type of response measured. This article will consider whole animal response as much as possible. The dose range over which a response is produced is termed potency. Potency of a particular agonist can be defined from the dose–response curve (Fig. 2) as the dose of drug that produces 50% of the maximum response (ED50); the maximum response itself is a crude measure of efficacy.

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Dose–response curve illustrating the characteristics of agonists. Full and equipotent partial and high potency partial agonists are shown. Potency is the dose range over which a response is produced and described by ED50. In this example, the ED50 for the full and equipotent partial agonist (point 1 on the graph) is 300 ng and for the high potency partial agonist (point 2 on the graph) is 10 ng. Efficacy or the ability to produce a response for the partial agonist is lower than for the full agonist. In this example the rank order of efficacy is full > high potency partial > equipotent partial.

It is important to remember that potency and efficacy are different concepts and cannot be interchanged. If an agonist has high efficacy, it does not necessarily mean that it will display high potency and vice versa. An agonist that produces the maximum response capable in that system is termed a full agonist and anything producing a lower response is a partial agonist. These principles are illustrated in Figure 2. The full agonist is shown in closed squares. In this example, the efficacy is 100% and potency (ED50) is 300 ng [midway between 100 ng (10−7 g) and 1 mg (10−6 g) on a log scale]. In filled circles is an equipotent (same ED50) partial agonist of lower efficacy (maximum response ∼40%). However, in the open circles a low efficacy high potency (ED50 = 10 ng) partial agonist is shown. Again, note that in this example, potency and efficacy are not interchangeable.

How do potency and efficacy relate to affinity? As noted previously, just because a ligand has affinity it does not necessarily mean that it will have efficacy; for example, a simple antagonist will have affinity but an efficacy of zero. Clearly, for an agonist the ability to bind to a receptor will determine the ability to produce a response and to some extent the size of that response. However, the two are seldom linked in a linear fashion and depend on what response is measured. Therefore, no firm definitions can be given. An additional and important characteristic of partial agonists is that they can reverse the effects of full agonists. For example, a hypothetical patient given buprenorphine (partial μ-agonist) would require higher doses of morphine to produce the same degree of analgesia as morphine alone (i.e. buprenorphine will antagonize the effects of morphine at the μ-receptor). However, when the effects of buprenorphine wane, morphine-induced analgesia and respiratory depression will become more evident.

Relationship between receptor occupation and response–receptor reserves

If a simple receptor occupancy curve for a full agonist is plotted on the same axes as a dose–response curve, the functional response often lies to the left of the occupancy curve. The implication of this is that at low receptor occupancy a full response can be produced. It is often the case that only 5–10% occupancy is needed to produce a full response indicating that ∼90% of receptors are not needed to elicit a maximum response and hence form the receptor reserve. For a partial agonist, remember that the maximum response is reduced compared with the full agonist such that even at 100% occupancy a full response (similar to the full agonist) cannot be produced. Spare receptors are not pooled or hidden; they are simply surplus to requirements.

Antagonists

Neutral antagonists block the effect of an agonist. There are two types of antagonism: competitive (reversible, surmountable) and non-competitive (irreversible, insurmountable). For example, naloxone is a competitive antagonists at all opioid receptors and ketamine is a non-competitive antagonist at the NMDA-glutamate receptor.

The action of a competitive antagonist can be overcome by increasing the dose of the agonist (i.e. the block is surmountable). Both the agonist and antagonist bind to the same site on the receptor. The effect that this has on the dose–response curve of an agonist is to shift it to the right. As the response is surmountable, the maximum response remains unchanged (Fig. 3). The degree of rightward shift is related to the affinity of the antagonist and the dose used. The higher the dose, the more agonist needed to overcome the response. The higher the affinity of the antagonist, the greater the shift (remember affinity is the strength of antagonist–receptor interaction and more agonist is needed to interrupt this interaction). Conversely, if the degree of shift is known, then the affinity of the antagonist can be estimated.

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Dose–response curve illustrating the characteristics of antagonists. A competitive antagonist shifts the agonist dose response curve to the right with no change in the apparent maximum response obtained. The non-competitive or irreversible antagonist depresses the maximum response.

The actions of a non-competitive antagonist cannot be overcome by increasing the dose of agonist (Fig. 3). This is because the agonist and antagonist binding sites are different; hence, the agonist will not displace the antagonist molecule (e.g. ketamine binds in the NMDA receptor channel pore but the agonist, glutamate, binds to the extracellular surface of the receptor). Graphically, the actions of an irreversible antagonist are the same as those for a non-competitive antagonist but the explanation is different; for the irreversible antagonist the binding site may be the same as the agonist but as it is irreversible (often chemically linked) it cannot be displaced and hence cannot be overcome.

Mixed agonists–antagonists

Where subtypes of receptors occur, it is possible that a single ligand can have agonist and antagonist properties (i.e. mixed pharmacology). Some of the best illustrations of this occur in opioid receptors of which there are three classical subtypes: μ, δ and κ. For example, pentazocine is an antagonist at μ and an agonist at δ/κ opioid receptors.

Inverse agonists

In the receptor definition above it was stated that ‘in the unbound state a receptor is functionally silent’ and this is true in most cases. However, some receptor systems display constitutive activity, either experimentally as a result of over expression or as a result of mutation. These receptors are active in the absence of agonist. An inverse agonist would inhibit this constitutive activity and, as such, is said to display negative efficacy. Figure 4 illustrates this principle where a conventional agonist, a competitive antagonist and an inverse agonist are displayed. The actions of both the agonist and inverse agonist can be reversed by a competitive antagonist as described above. The clinical significance of inverse agonism remains to be explored but inverse agonism has been reported for several systems including benzodiazepine and cannabinoid receptors.

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Dose–response curve illustrating the characteristics of an inverse agonist. In this example a negative efficacy of ∼50% is shown. An agonist and antagonist are included for comparison.

Key references

Aitkenhead AR, Rowbotham DJ, Smith G. Textbook of Anaesthesia, 4th Edn. London: Churchill–Livingstone,

Calvey TN, Williams NE. Principles and Practice of Pharmacology for Anaesthetists, 3rd Edn. Oxford: Blackwell Scientific Publications,

Kenakin T. Pharmacologic Analysis of Drug–Receptor Interaction. Philadelphia: Lippincott-Raven,

Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology, 5th Edn. London: Churchill–Livingstone,

Pharmacology - General