Drug Action and Receptor | Pharmacodynamics

After reading this article you will learn about:- 1. Definition of Drug Action and Receptors 2. Theories for Relationship Between Drug-Receptor Interaction.

Definition of Drug Action and Receptors:

The term “drug action” is used to describe the method by which the drug influences a cell and the term ‘Drug effect or response’ is a sequel to this action. Modification of physiological function or a biochemical process induced by a drug generally results from interaction between the drug and a macromolecular component of the organism (tissue) called as receptor.

A “receptor” is defined as that component of a cell or organism that interacts with a drug and initiates the chain of biochemical events leading to the drugs observed effects. The receptors are usually protein molecules, which undergo a change in conformational status whenever acted upon by a drug, thereby inducing changes in systems within the cell.

The existence of receptors was inferred from the experimental observation of Paul Ehrlich and J.N. Langley at the end of nineteenth century. They were impressed by the chemical and physiologic specificity of drug effects.

Ehrlich noted that certain synthetic organic agents had characteristic anti-parasitic effects while other agents did not, although their chemical structures differed only slightly.

Langley noted the ability of the South American arrow poison, curare, to inhibit the contraction of skeletal muscles caused by nicotine; however, the tissue remained responsive to direct electrical stimulation. They also studied the mutual antagonism of pilocarpine and atropine on the salivary secretion in the cat.

In order to produce a pharmacological response, the drug molecules must get very close to the receptor molecules of the cell. This necessitates a non-uniform distribution of the drug molecules within the body or tissue meaning that drug molecules must be bound to particular constituent of cells and tissues in order to produce an effect.

Ehrlich summed it up in his phrase ‘corpora non agunt nisi fixata’ (A drug will not work unless it is bound). But quite a number of drugs disobey/escape this dictum and act without being bound to any tissue constituent e.g., osmotic diuretics, osmotic purgatives, antacids, heavy metal chelating agents, etc.

The receptor theory is as important and basic to pharmacology as the atomic theory is to physical sciences. The drug-receptor interaction implies a mutual molding of drug and receptor like a lock and its matching key.

The drug receptor interaction is usually reversible; it obeys the law of mass action and usually involves ionic bonds, hydrogen bonds, and van der Waals forces. In situation of irreversible interaction, the drugs have exceedingly long persistence and duration of action in the body.

Radio ligand binding studies have shown that the receptor numbers do not remain constant but change according to circumstances. When tissues are continuously exposed to an agonist, the number of receptors decrease (down-regulation) and this may be a cause of tachyphylaxis i.e., loss of efficacy with frequently repeated doses.

Prolonged contact with an antagonist leads to formation of new receptors (up-regulation). These conditions sometimes invite pharmacological idiosyncrasies.

Theories for Relationship Between Drug-Receptor Interaction:

There are two theories for relationship between drug-receptor interaction and response generated, as follows:

1. Occupation Theory of Drug Action:

It was propounded by A.J. Clark and proposed that the extent to which a tissue responds depends on the proportion of its receptor population which has become occupied by a drug and the maximal response is reached when the total number of receptors are occupied.

He presumed that each occupied receptor delivered a constant unit of response and that this individual occupancy stimuli summated in mathematical fashion to give a linearly proportional response.

However, one difficulty was in the case of partial agonists, which is unable to elicit a maximal response as much as that of a full agonist even after full receptor occupancy. Stephenson modified this theory to incorporate this difficulty and invoked the concept of efficacy.

A drug of high efficacy elicits a maximal response after occupying only a small proportion of the receptor population and leave a number of spare receptors.

In contrast a drug of lower efficacy has to occupy a greater proportion of receptors to elicit a maximal response. The partial agonist still fails to induce a maximal response even when all the receptors are occupied because its efficacy is too low to allow a maximal response. However, still the theory cannot explain the phenomenon of tachphylaxis.

2. Rate Theory of Drug Action:

It was introduced by W.D.M. Paton at the end of 1950’s when occupation theory failed to justify different drug actions. The theory considered that occupation alone was of no importance to the action of agonists, instead it is the act of making a drug and receptor associate which donates a unit of stimulus to the cells.

The greater the number of associations made per unit time the greater is the stimulus provided. For a response to be maintained, the complex has to break and be re-made. The more rapidly the complex dissociates, the more rapidly can new associations take place.

Each association between a drug molecule and a receptor provides one quantum of stimulation. Thus for an agonist it is the rate of dissociation which determines potency and this is constant for each drug (dissociation constant-K_d).

The antagonist according to this hypothesis, makes complexes rapidly but dissociates relatively slowly.

Recent Theories:

While the occupation theory envisaged a static relationship between drug molecules and receptors. The rate theory had a more dynamic view of this relationship, by way of complexation and regeneration of receptors. More recent observations have carried this dynamic view further, and a more complex model of drug-receptor interactions have been proposed.

Common to all receptor theories, is the postulate that an agonistic drug combines with a site on a receptor and the receptor becomes activated, so triggering a response from the cell. When the drug leaves, the receptor returns to the non-activated (inactive or resting) state and this is essential for further response cycles.

On the same receptor is also present an allosteric site adjacent to the active site, at which an antagonist may bind, and either obscure or distort the active site so that the agonist can no longer complex with the receptor.

Based on studies of the action of acetylcholine on nicotinic receptors of neuromuscular junction, an alternative theory of two-state model has been proposed in this model, it is envisaged that the receptor can exist in two states ‘resting’ (R) and ‘activated’ R* either of which can bind a drug molecule. Normally when no ligand/ drug is present, the equilibrium favours the resting state.

In the presence of agonist the conformation of the binding site changes to activated form and increases its affinity for the agonist. Removal of agonist allows the binding site to revert to the resting state. An antangonist has a higher affinity for the receptors in resting state, thereby stabilizing a high proportion of receptors in the resting state, for which an agonist has low affinity.

In contrast, a partial agonist is able to stabilize receptors in an intermediate, i.e., partially activated state in which tissue response reveals evidence of both stimulation and inhibition. The two-state model can also explain for the phenomenon of inverse agonists, which occurs with benzodiazepines.

It is postulated that these receptors for benzodiazepines, in the absence of any ligand, are distributed more-or-less equally between the two states, so the equilibrium can be shifted in either direction, producing opposite effects. Evidence has been produced in support of the claim that changes in receptor populations are produced by factors other than drugs, e.g., electrolyte concentration, temperature etc..