I will introduce the most basic and fundamental concepts of pharmacology. If this is too much then don’t worry, you’re forgiven. I think its necessary to at least have the basics written down on here so that I can refer back to the post if need be. Or perhaps whilst reading this you will discover a new passion for drug kinetics. (I am glad modesty doesn’t get in the way of my pipetting).

A drug is a chemical agent used in the diagnosis, treatment, or prevention of disease. In most cases, drugs are molecules that elicit response by binding to receptors. Receptors are proteins that act as gatekeepers: they respond to external stimuli (signals) outside of the cell, transmit the signal to the cell, and cause a change in cellular behaviour. Receptors enable organisms to adapt to constantly changing environments, both internally-changing environments in close proximity to the cell and to external signals arising from outside the body. Endogenous molecules (found in the body) that elicit responses via the activation of receptors include hormones, ions, cytokines, growth factors and neurotransmitters. Molecules that bind receptors are termed ligands.

The idea of defined receptor molecules for drugs (or poisons) was proposed by Paul Ehrlich (1854-1915), who developed salvarsan, the treatment against syphilis. This was the first drug targeted against a specific pathogen.

In drug research and development, compounds are generally developed to bind to receptors. They are developed either to elicit a response, often mimicking an endogenous compound; or they are developed such that they bind to a receptor but do not elicit a response. The overall concept behind drug development is to understand normal cellular functioning and delineate the steps that go wrong under pathological conditions. The aim is to then develop ligands that target specific proteins along the chain of events to alter the successive steps. For example, this could result in an upregulation of a certain protein or the inhibition of a protein, inhibiting its actions.

But of course this is an oversimplified model – ligands do not just bind in a binary fashion (bound or not bound; effect or no effect). There are multiple binding sites and ligands vary in affinity, efficacy and potency (see below). Primary ligands can be displaced by secondary ligands that may bind receptor binding sites with higher affinity. The variables are numerous and pharmacometrics is a broad discipline that utilises models of biological systems and mathematics to describe, explain and predict the relationships of variables within these systems. This includes pharmacokinetics, pharmacodynamics, and understanding the pathology of disease.

Pharmacokinetics: the study of the fate of substances administered externally to a living organism. Broadly speaking this includes understanding the absorption, distribution, metabolism and elimination of a drug (shortened to ADME).

Pharmacodynamics: the study of the biochemical/physiological effects of drugs on an organism, its mechanism of action and the relationship between drug concentration and effect. In simplified terms, pharmacokinetics is the study of what the body does to the drug and pharmacodynamics is the study of the effect of the drug on the body.

Dose-response curves

A dose-response curve is a simple X-Y graph describing the relationship between  concentration of a drug and effect (fraction bound or the functional response elicited on the cell, tissue or organism). Dose-response curves are integral to pharmacometrics to describe relationships within biological systems.

Compounds that bind receptors can be described in terms of affinity (i.e. the ability of a drug to bind to a receptor), potency (i.e. how much of the drug is needed to produce a desired effect), and efficacy (i.e. max response achievable from a drug). For example, morphine is a highly potent drug and evokes a larger response at low concentration compared to ibuprofen, a drug of lower potency that will evoke a small response at low concentration. In Figure 1, Drug A has a higher potency as a lower concentration of drug A than drug B is needed to produce a desired response.

Figure 1: Dose-response curve

The efficacy describes the relationship between receptor occupancy and the ability to initiate a response; i.e. it refers to the relative ability of the drug-receptor complex to produce a maximum functional response. This is not to be confused with affinity, which describes only the ability of the drug to bind the receptor. Potency is proportional to both efficacy and affinity.

Classification of drugs

Drugs are classified by how they interact with receptors. The 3 primary classifications are (full) agonists, partial agonists, and antagonists. Agonists are chemicals that bind to receptors and elicit a response. Partial agonists bind to the receptor but with partial efficacy (i.e. reduced maximum functional response relative to the full agonist). Inverse agonists bind to the receptor and elicit a response opposite to that of the agonist. Antagonists bind to the receptor but do not provoke a response; instead, they block or dampen agonist-mediated activation. Refer to Figures 2 and 3 for a schematic representation of the different types of drugs.

Figure 2: Responses induced by different types of drugs

Figure 3: efficacy of different types of drugs relative to endogenous agonist

For the curious:
- Pharmacodynamics
- Introducing dose-response curves
- A Short Introduction to Pharmacokinetics