Receptor theory

To explain the concept of drug action with respect to: receptor theory

To define and explain dose-effect relationships of drugs, including dose-response curves with reference to: therapeutic index, potency and efficacy, competitive and non-competitive antagonists, partial agonists, mixed agonist-antagonists and inverse agonists

To explain the Law of Mass Action and describe affinity and dissociation constants

A receptor is a component of a cell which interacts with a drug and initiates a sequence of events leading to an observed change in function.

• Existence of receptors is inferred from the response of tissues to drugs, genome sequencing, and molecular biology.
• A drug binds to a receptor forming a receptor-drug complex, which initiates a cascade of events to exert a pharmacological effect.

Dissociation Constants

Interaction between a receptor and a drug is based upon the law of mass action, which states the rate of a chemical reaction is proportional to the masses of reacting substances. This can be expressed as:
$[Drug] + [Receptor] \Leftrightarrow [Drug-Receptor]$

The ratio of the rate constant for the forwards reaction (K_association) and the backwards reaction (K_dissociation) is the dissociation constant. This is the concentration of drug when 50% of receptors are occupied:

$K_D = {[D][R] \over [D-R]}$

A low K_D value indicates that a lower concentration of drug is required to occupy 50% of the receptor, indicating that the drug has a high affinity for the receptor.

Physiological factors which affect the dissociation constant are determined by the Arrhenius equation:

$k = Ae^{-E_A \over RT}$, where:

• $A$ is a constant
• $T$ is temperature in kelvin
• $E_A$ is the activation energy required, which may be lowered by a catalyst
• $R$ is the gas constant

Properties of Drugs

Key properties of drugs include:

• Potency
  The amount of drug required to have an effect.
  • Given by the (typically the E_D50)
  • This relates to Bowman's principle, which states that the least potent anaesthetic agents have the quickest onset
    This is because they are administered in higher doses (as they are less potent, more is required to get an effect), which results in a high concentration gradient and a rapid distribution into tissues.

• Efficacy
  The maximal effect that a drug can generate.

• Intrinsic activity
  The size of effect a drug has when bound, which is graded from 0 to 1.
  • This is also known as activity

Drug-Receptor Interactions

Drugs can be classified by the way they interact with receptors into:

• Agonists
  • Partial agonists
  • Inverse agonists
• Antagonists
  • Indirect antagonists
• Allosteric Modulators
• Mixed Agonist-Antagonists

Agonists

An agonist will generate a maximal response at the receptor site. An agonist has high affinity and an activity of 1. Agonists can be compared by:

• Relative potency implies that if two agonists are equally efficacious, a smaller dose of one is required to get an effect
• Relative efficacy implies that the maximal effect of one agonist is greater than the other

Partial agonist

A partial agonist generates a submaximal response at the receptor. A partial agonist has a high affinity and an activity between 0 and 1. A partial agonist can act as an effective antagonist in the presence of a full agonist, as it will prevent maximal binding at a receptor, even with a high agonist concentration.

Inverse agonist

A drug which has a negative activity (between 0 and -1) producing the opposite response (compared to the endogenous agonist) at receptor.

• Occurs due to loss of constitutive activity at that receptor

Antagonist

An antagonist produces no response at the receptor site, and prevents other ligands binding. Antagonists have high affinity and an activity of 0.

Antagonists with these properties are also known as direct antagonists, which can be either:

• Competitive antagonists
  Displace other ligands from a binding site. Competitive antagonists can be:
  • Reversible
    The effect can be overridden by increasing the dose of agonist.
  • Irreversible
    Drug cannot be overridden by increasing dose of agonist. Dose-response curve appears similar to that of the non-competitive antagonist.
• Non-competitive antagonists
  Create a conformational change in the receptor. They cannot be overridden by increasing the dose of agonist.

Indirect Antagonist

Indirect antagonists reduce the clinical effect of a drug, but do so via means other than receptor interaction. They include:

• Chemical antagonists
  Where the drug binds directly to another. Examples include protamine and heparin, and sugammadex and rocuronium.
• Physiologic antagonists
  A countering effect is produced by agonism of other pathways.

Allosteric Modulator

A drug which binds to an allosteric site on the receptor and produces conformational change that alters the affinity of the receptor for the endogenous agonist.

Allosteric modulators can be:

• Positive
  Increases affinity for endogenous agonist.
  • e.g. Benzodiazepines are positive allosteric modulators at the GABA_A receptor
• Negative
  Decreases affinity for endogenous agonist.

Mixed Agonist-Antagonist

A drug which has different effects on different receptors.

References

1. Pinnock C, Lin T, Smith T. Fundamentals of Anaesthesia. 2nd Ed. Cambridge Universiy Press. 2003.
2. Encyclopaedia Britannica. Available at: https://www.britannica.com/science/law-of-mass-action
3. Petkov V. Essential Pharmacology For The ANZCA Primary Examination. Vesselin Petkov. 2012.