Pharmacology concerns the study of how drugs affect the function of host tissues or combat infectious organisms. In most cases, drugs bind selectively to target molecules within the body, usually proteins but other macromolecules as well. The main drug targets are receptors, enzymes, ion channels, transporters (carriers) and DNA. There are few instances (e.g. osmotic purgatives and antacids) of drugs acting without binding to a specific target.
It is generally desirable that a drug should have a higher affinity for its target than for other binding sites. First, it ensures that the drug’s free concentration (and hence action) is not reduced by nonproductive binding to the much greater number of nontarget molecules in the body. Second, lower doses can be used, which automatically reduces the risks of unwanted actions at other sites that may cause toxicological side effects. Chapter 4 deals specifically with the consequences of drug binding to these targets. The rest of this chapter will deal predominantly with the principles of receptor pharmacology.
Receptors as Drug Targets
Receptors are protein macromolecules – on or in cells – that act as recognition sites for endogenous ligands such as neurotransmitters, hormones, inflammatory/immunological mediators, etc. Many drugs used in medicine make use of these receptors. The effect of a drug may be to produce the same response as the endogenous ligand or to prevent the action of an endogenous (or exogenous) ligand. A drug (or endogenous chemical) that binds to a receptor and activates the cell’s response is termed an agonist . A drug that reduces or inhibits the action of an agonist is termed an antagonist , and therefore has no biological activity per se.
Receptors are perhaps the most common ‘target’ for a drug, and understanding the interactions between drugs and receptors is a fundamental tenet of pharmacology. Proteins (receptors) are not rigid structures, but due to their inherent kinetic energy, will vibrate, or shimmer, to induce slight variations in shape, such that a receptor will alternate between periods of ‘inactive’ and ‘active’ conformations. Within the vicinity of the receptor, several drug molecules will surround the space. Through random motion, during time, occasionally some of those molecules will collide with the ‘active pocket’ of the receptor when it is in the active conformation. This active pocket is commonly known as the orthosteric binding site ( Fig. 3.1 ). Thus when an agonist fits in the active pocket, the receptor is held in the active conformation for a period of time until the agonist is displaced, and this leads to biochemical processes occurring.
The action of an inflammatory mediator, histamine, on bronchial smooth muscle can be taken as an example. There are two aspects to this action:
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The agonist–receptor (drug–receptor) interaction
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The agonist-induced (drug-induced) response
The action of histamine could be measured at various levels: molecular, cellular, tissue and system. With the drug–receptor interaction, we will be dealing with the concepts of affinity , occupancy and selectivity . With the drug-induced response, we will meet the concepts of efficacy and potency :
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Affinity : The ability of a drug to bind to a receptor.
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Occupancy : The proportion of receptors to which a drug is bound.
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Selectivity : Relative affinity or activity of a drug between different receptor types. Largely replaced the concept of specificity, since it is improbable that any drug is specific for a particular receptor.
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Efficacy : The ability of an agonist to elicit a response following binding.
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Potency : A measure of the concentration of a drug (agonist or antagonist) at which it is effective.
The agonist–receptor (drug–receptor) interaction
In Fig. 3.2 as an example of a tissue, the smooth muscle surface (which can be stimulated by histamine) is represented by the blue curved segment. The receptors (shown as cups) are representative of the total number of receptors on the muscle (R tot ). The histamine molecules are represented by the grey circles. When the muscle is exposed to a concentration of histamine [A] and allowed to come to a dynamic equilibrium, where the drug occupation of a number of receptors (AR) at any point is steady. We now need to consider the relationship between [A] and the occupancy of the receptors [AR]/[R tot ].
Drug–receptor interaction is usually freely reversible and can be represented by the following equation:
The Law of Mass Action (the rate of the reaction is proportional to the product of the concentrations of the reactants) can be applied to the reaction. At equilibrium the forward and reverse rates are equal, i.e.:
k+1[A][R]=k1[AR]
[A][R][AR]=k1k+1=KA
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