hundreds of specific signalling chemicals to carry out their own signalling function and this provides an opportunity to use drugs to mimic or block the effects that those endogenous signalling chemicals would produce. By employing drugs with chemical structures similar to those of endogenous chemicals, we gain an opportunity to ‘operate the levers’ of the human machine. Not surprisingly, therefore, the vast majority of the drugs used act by altering the function of one of these key pieces of signalling and transport machinery:
Receptors
Enzymes
Ion channels
Transport molecules
Drugs used as therapeutic agents act by manipulating physiological mechanisms, which reinforces the importance of having an understanding of human physiological responses as the basis for understanding pharmacology. Without a sound knowledge and understanding of how physiological systems respond, it is impossible to make sense of how drugs will interact with those systems.
Receptors as sites of drug action
An opioid drug such as morphine acts by binding to the receptors for endogenous opioids and, by activation of those receptors, produces similar actions to those generated by the endogenous opioids, including analgesia and a range of other effects. Similarly, bronchodilator drugs such as terbutaline and salbutamol, used during an episode of acute asthma, produce their bronchodilator effect by activating adrenergic beta receptors on the airways. These receptors would be activated physiologically by adrenaline and noradrenaline secreted during the fight or flight response, and the binding of adrenaline or noradrenaline to the beta receptors in the airways would produce a dilation of the airways, allowing a more rapid ventilation of the lungs. A drug which is able to produce this effect without producing the rest of the fight or flight response is a very useful therapeutic agent during an episode of acute asthma (Figure 1.1).
Enzymes as sites of drug action
Enzymes are the large proteins that catalyse the thousands of biochemical reactions that maintain physiological function. An enzyme carries out the catalysis (speeding up) of a particular reaction by binding the reacting molecules and making it ‘easier’ for the reaction to occur (Figure 1.2). Drugs which have enzymes as their targets tend to be inhibitors of those enzymes, preventing the normal reacting substances from binding with the enzyme for catalysis.
Drugs such as non‐steroidal anti‐inflammatory drugs (NSAIDs), the prototype of which is aspirin, act by inhibiting the enzyme cyclo‐oxygenase, which is responsible for speeding up the reaction producing a range of important signalling molecules known as prostaglandins. It is the reduced level of prostaglandins as a result of blockade of cyclo‐oxygenase that produces the range of effects associated with NSAIDs. Another example of a widely used class of drugs which act by blocking an enzyme is the statin class, including atorvastatin and fluvastatin. These drugs lower cholesterol levels by inhibiting the enzyme HMG‐CoA reductase, responsible for the production of cholesterol in living cells.
Ion channels
Ion channels represent the only means for ions to cross cell membranes, and all cells contain multiple species of ion channel in their membranes. These channels can be gated in a number of ways, and drugs which can bind to specific channels can alter cellular activity profoundly by altering the passage of ions across the membrane, thereby altering the cell’s membrane potential. Most drugs that act in this way block ion channels rather than open them.
The local anaesthetic lidocaine, for example, acts by binding to and inhibiting voltage‐gated sodium channels in neuronal cell membranes, preventing the generation of action potentials by the affected neurons. Sensory neurons detecting touch, pressure and pain stimuli therefore become less responsive to those stimuli, resulting in anaesthesia.
The benzodiazepine class of drugs, including agents such as midazolam and diazepam, act by binding to a chloride ion channel in neuronal membranes.
Figure 1.1 Drugs which act at receptors. (a) A cell has receptors for a specific signalling compound (e.g. a neurotransmitter or hormone) located on the cell membrane. (b) The endogenous signalling molecule binds to its receptors, fitting the receptor perfectly. (c) The binding triggers a series of actions inside the cell. These actions would be the normal response to that signalling compound. (d) If the molecular structure of a drug is sufficiently similar to that of the endogenous signalling compound, the drug will also be able to bind to the receptor and produce the same actions in the cell. This drug would be known as an agonist at this receptor. (e) If a drug has a molecular structure vaguely similar to that of the endogenous signalling compound, it may still be able to bind to the receptor, but not fit it perfectly enough to produce the same actions in the cell. This drug could prevent the endogenous signalling compound (and the agonist) getting to the receptor, thereby blocking their actions. This drug would be known as an antagonist at the receptor.
Figure 1.2 Enzymes operate by binding reacting substances (a) and accelerating their reaction – in this case the reaction is a combination of two molecules (b), then releasing the product from the enzyme’s binding site (c). A drug which can also bind to this site can prevent the catalytic function of the enzyme, thereby reducing the level of product (d).
This channel is opened normally by the inhibitory neurotransmitter GABA (gamma‐aminobutyric acid). Opening a chloride channel in the membrane allows the influx of negatively charged chloride ions to the cell, which hyperpolarises the cell, making it less likely to produce action potentials. The benzodiazepine class of drugs also act at this ion channel, albeit at a different site to GABA, but when they bind, they enhance the inhibitory actions of GABA, and add to the hyperpolarisation of neurons and the resulting nervous system depressant effect (Figure 1.3).
Transport molecules
The large, complex proteins responsible for active transport of substances across cell membranes represent another valuable drug target for manipulation of physiological function.
There are active transporters or pumps in all cell membranes for sodium, potassium and calcium ions, and these are activated when those ions have to be transported across the cell membrane against their concentration gradient, i.e. from a lower to a higher concentration of ions. Ions can move through open ion channels if they are travelling down their concentration gradient, but will need active ‘pumping’ if they are to move the other way.
Figure 1.3 Benzodiazepines act by binding to a chloride channel. (a) The inhibitory neurotransmitter GABA has its receptor on the ligand‐gated chloride ion channel in neurons. The channel also has a binding site for drugs of the benzodiazepine class. (b) Binding of GABA to its receptor opens the channel, allowing chloride ions to flow into the neuron and hyperpolarise the membrane, inhibiting further neuronal activity. (c) Binding of a benzodiazepine to its site will, in the