1
Introduction: Basic Concepts

Learning objectives

This chapter was written for those unfamiliar with certain aspects of pharmacology and chemistry, including physical chemistry, and for those who feel a little revision would be helpful. By the end of the chapter the reader should be able to:

• use the Henderson-Hasselbalch equation to calculate the ionization of weak acids and bases
• plot concentration-time data to determine first-order and zero-order rate constants
• explain the effect of ionization on the partitioning of weak electrolytes between buffers and octanol.

1.1 Introduction

Pharmacology can be divided into two major areas, pharmacodynamics (PD) - the study of what a drug does to the body - and pharmacokinetics (PK) - the study of what the body does to the drug; hardly rigorous definitions but they suffice. Drug disposition is a collective term used to describe drug absorption, distribution, metabolism and excretion whilst pharmacokinetics is the study of the rates of these processes. By subjecting the observed changes, for example in plasma concentrations as a function of time, to mathematical equations (models) pharmacokinetic parameters such as elimination half-life (t½), volume of distribution (V) and plasma clearance (CL) can be derived. Pharmacokinetic modelling is important for the:

• selection of the right drug for pharmaceutical development
• evaluation of drug delivery systems
• design of drug dosage regimens
• appropriate choice and use of drugs in the clinic.

A detailed knowledge of mathematics is not required to understand pharmacokinetics and it is certainly not necessary to be able to differentiate or integrate complex equations. The few examples in this book are standard differentials or integrals that can be quickly learnt if they are not known already. To understand the equations in this book requires little more than a basic knowledge of algebra, laws of indices and logarithms, a brief explanation of which can be found in Appendix 1. Furthermore, the astute reader will quickly realize that, although seemingly different, many equations take the same form, making learning easier. For example, drug binding to macromolecules, whether they be receptors, plasma proteins, transporters or enzymes, can be described using the same basic equation. Similarly, the equation describing the time course of formation and excretion of a drug metabolite is very much like that describing the plasma concentrations during the absorption and elimination of a drug.

The role of pharmacokinetics is illustrated in Figure 1.1. There is an optimum range of concentrations over which a drug has beneficial effects, but little or no toxicity - this range is the therapeutic range, sometimes referred to as the therapeutic window. There is a threshold concentration below which the drug in ineffective and a higher threshold above which adverse effects become problematic. If a single dose of a drug, for example aspirin taken to relieve a headache, is consumed, the concentration in the plasma will rise until the aspirin becomes effective. After a period of time the processes which remove aspirin from the body will reduce the concentration until the drug is no longer effective (Figure 1.1, curve (a)). The short duration of action may be fine for treating a headache but if the aspirin is to treat rheumatoid arthritis a much longer duration of action is required. Simply increasing the size of the dose is not the answer because eventually the plasma concentrations will enter the toxic region (Figure 1.1, curve (b)). However, by giving the aspirin as smaller divided doses at regular intervals the plasma concentrations can be maintained within the therapeutic window (Figure 1.1, curve (c)). The three curves depicted in Figure 1.1 were produced using relatively simple pharmacokinetic equations which will be explained later.

Figure 1.1 Typical concentration-time curves after oral administration of a drug: (a) single dose of drug; (b) a single dose twice the size of the previous one; (c) the same drug given as divided doses. The dose and frequency of dosing for (c) were calculated to ensure the concentrations remained in the therapeutic window.

1.2 Drugs and drug nomenclature

A drug is a substance that is taken, or administered, to produce an effect, usually a desirable one. These effects are assessed as physiological, biochemical or behavioural changes. There are two major groups of chemicals studied and used as drugs. First, there is a group of pharmacologically interesting endogenous substances, for example epinephrine, insulin and oxytocin. Second, there are the non-endogenous or 'foreign' chemicals (xenobiotics), which are mostly products of the laboratories of the pharmaceutical industry. Early medicines, some of which have been used for at least 5000 years, relied heavily on a variety of mixtures prepared from botanical and inorganic materials. Amongst the plant materials, the alkaloids, morphine from opium, cocaine from coca leaves and atropine from the deadly nightshade (belladonna) are still used today. Insulin, once obtained from pigs (porcine insulin), is more usually genetically engineered using a laboratory strain of Escherichia coli bacteria to produce human insulin. A few inorganic chemicals are used as drugs, including lithium carbonate (Li2CO3) and sodium hydrogen carbonate (sodium bicarbonate, NaHCO3).

1.2.1 Drug nomenclature

Wherever possible specific drug examples are given throughout this book, but unfortunately drug names can lead to confusion. Generally a drug will have at least three names: a full chemical name, a proprietary name, i.e. a trade name registered to a pharmaceutical company, and a non-proprietary name (INN) and/or an approved or adopted name. Names that may be encountered include the British Approved Name (BAN), the European Pharmacopoeia (EuP) name, the United States Adopted Name (USAN), the United States Pharmacopoeia (USP) name and the Japanese Approved Name (JAN). The World Health Organization (WHO) is introducing a system of recommended INNs and it is hoped that this will became the norm for naming drugs, replacing alternative systems (http://www.who.int/medicines/services/inn/innguidance/en/, accessed 17 February 2016). For example, lidocaine is classed as a rINN, USAN and JAN, replacing the name lignocaine that was once a BAN. Generally, the alternatives obviously refer to the same drug, e.g. ciclosporin, cyclosporin and cyclosporine. There are some notable exceptions, for example pethidine is known as meperidine in the US and paracetamol as acetaminophen. Even a simple molecule like paracetamol may have several chemical names but the number of proprietary names or products containing paracetamol is even greater, including Panadol, Calpol, Tylenol and Anadin Extra. It is therefore necessary to use an unequivocal approved name whenever possible, but alternative names and spellings are likely to be encountered, some examples of which are given in Table 1.1. Useful sites for checking, names, synonyms, chemical properties and the like include http://chem.sis.nlm.nih.gov/chemidplus/and www.chemicalize.org/ (accessed 17 February 2016).

Table 1.1 Differences in rINN and USAN nomenclature

* Chiefly previous BAN entries.

1.3 Law of mass action

The reversible binding of drugs to macromolecules such as receptors and plasma...