Chapter 19 Pharmacodynamics

How drugs elicit a physiological effect

Proteins play an integral role in controlling body functions through their roles as:

The chemical composition of protein molecules allows for great variation in three-dimensional structure, creating sites which, generally speaking, will interact only with specific molecules that are able to fit into the particular site (see Figure 11.5, p. 84). Most drugs act by interfering with this process at the molecular level, fitting into sites intended for the original protein molecule.

The ‘Lock and Key’ Hypothesis

The simplest way to consider the action of a chemical on an enzyme or receptor is the concept of the ‘lock and key.’ A bond is made with the enzyme or receptor (Figure 19.1). If the protein is an enzyme, a chemical reaction will take place; if it is a receptor, it might trigger a chemical reaction or start a chain of events leading to a physiological response.

Figure 19.1 The ‘lock and key’ mechanism.

This is a very simplistic explanation and there might be a certain moulding of the site to the substrate or ligand, as the protein structure is not completely immobile, but generally speaking the ‘lock and key’ mechanism is a reasonable concept.

Enzymes

• Enzymes are proteins that catalyse chemical reactions: in other words, enzymes affect the rate of a reaction but they themselves remain unchanged at the end of the reaction.

• Molecules (substrates) attach to the enzyme that converts them to something else.

• Most reactions in cells require enzymes to take place at a reasonable speed: left to their own devices, without the assistance of enzymes, reactions would take place far too slowly.

• The enzyme reaction site is fairly specific (see Figure 11.5, p. 84), which is why metabolic pathways are associated with specific enzymes.

• The efficiency with which enzymes catalyse a reaction depends on how many of them are available, as a reaction will be limited by the number of sites provided by the enzymes (capacity limited). When no more binding sites are left, the reaction has reached its optimum level.

• Enzyme activity can be affected by molecules other than substrates, which can slow down or stop a reaction. These molecules are called inhibitors. Poisons and drugs are often enzyme inhibitors.

Enzyme Inhibition

Most enzyme receptor sites are not completely specific (there is some structural leeway given the number of combinations possible and the mobility of the protein) and a relatively similarly shaped molecule might be able to achieve a ‘close fit’. This creates competition for molecules of a similar shape and the original molecule might find itself unable to find a binding site because it is already occupied. Many drugs are designed to take advantage of this phenomenon.

The various ways in which enzyme function can be affected are not dissimilar to the ways receptor function can be affected. These principles are worth bearing in mind when looking at chemicals that act directly on receptor sites.

• Competitive Inhibition

• Competitive inhibition [Figure 19.2(i)] is reversible: another molecule competes with the normal substrate and takes its place in the site.

• However, when the normal substrate concentration exceeds that of the competing molecule, the situation is more favourable and the normal substrate replaces the competing molecule.

• While the competing molecule is in place it blocks the normal action of the enzyme.

• Competitive inhibition can be reversed by increasing the substrate concentration.

• Non-competitive Inhibition

• Non-competitive inhibition [Figure 19.2(ii)] is reversible.

• The inhibitor, which is not a substrate, attaches itself to another part of the enzyme, thereby changing the overall shape of the site for the normal substrate so that it does not fit as well as before, which slows or prevents the reaction taking place.

• This type of inhibition decreases the turnover rate of an enzyme rather than interfering with the amount of substrate binding to the enzyme. The reaction is slowed rather than stopped. Non-competitive inhibition, therefore, cannot be increased by increasing the substrate.

Figure 19.2 Competitive (i), non-competitive (ii) and irreversible (iii) inhibition.

• Irreversible Inhibition

• The inhibitor becomes covalently linked or bound to the enzyme so tightly that is very difficult to detach it from the enzyme [Figure 19.2(iii); see Chapter 3 ‘Bonds found in biological chemistry’, p. 13].

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