The relationship between the concentration of the drug to which tissues are exposed and the response that is achieved can be plotted on a dose–response curve. When the relation between drug dose (x-axis) and drug response (y-axis) is plotted on a base 10 logarithmic scale, this produces a sigmoidal dose–response curve (Fig. 1.3). Progressive increases in the drug dose (which for most drugs is proportional to the plasma drug concentration) produce increasing response, but this occurs over a relatively narrow part of the overall concentration range; further increases in drug dose beyond this range produce little extra effect. The clinical implication of this relationship is that simply increasing drug dose may not result in any further beneficial effects for patients and may cause adverse effects.

‘Therapeutic efficacy’ is a term used to describe the maximum response of drugs that produce the same therapeutic effects on the body but do so via different pharmacological mechanisms (e.g. loop diuretics have greater therapeutic efficacy than thiazide diuretics).

The adverse effects of drugs are usually dose-related in a similar way to the beneficial effects although the dose–response curve for these adverse effects is normally shifted to the right (see Fig. 1.3). The ED₅₀ points for each curve indicate that the ratio between the doses that have similar proportionate effects on the two outcomes is 100/0.1=1000. This ratio is known as the ‘therapeutic index’. In reality, drugs have multiple potential adverse effects but the concept of therapeutic index is usually reserved for those requiring dose reduction or discontinuation. For most drugs, the therapeutic index is greater than 100 but there are some notable exceptions with therapeutic indices less than 10, which are in common use (e.g. digoxin, warfarin, insulin, phenytoin, opioids). The challenge for prescribers is to titrate doses carefully to establish the dose for individual patients that maximizes benefits but avoids adverse effects.

Desensitization and withdrawal

Desensitization refers to the situation where the response to a drug diminishes when it is given continuously or repeatedly. The response may be restored by increasing the dose of the drug but, in some cases, the tissues may become completely refractory.

‘Tachyphylaxis’ describes desensitization that occurs very rapidly, sometimes due to depletion of chemicals that may be necessary for drug action (e.g. a stored neurotransmitter).

‘Tolerance’ describes a more gradual loss of response to a drug that occurs over days or weeks, which may be due to changes in receptor numbers or the development of counter-regulatory physiological changes that offset the actions of the drug (e.g. activation of the sympathetic and renin–angiotensin systems in response to diuretic therapy).

When desensitization arises because of chemical, hormonal and physiological changes that offset the actions of a drug, discontinuation may allow these changes to cause rebound ‘withdrawal effects’. Examples of drugs associated with desensitization and withdrawal effects are shown in Table 1.2.

Absorption is the process by which drug molecules gain access to the bloodstream from the site of drug administration. The rate and extent of drug absorption depend on the route of administration (see Fig. 1.4). The ‘enteral’ routes of absorption are those that involve administration via the gastrointestinal tract:

The ‘parenteral’ routes of administration avoid absorption via the gastrointestinal tract:

Other common routes of administration include:

Excretion is the process by which drugs and their metabolites are removed from the body. They may leave in the urine, bile, faeces or expired air. Renal excretion is the main route of elimination for low-molecular-weight drugs and their metabolites are sufficiently water soluble to avoid reabsorption from the renal tubule. For some drugs, active secretion from capillaries into the proximal tubule, rather than glomerular filtration, is the predominant mechanism of excretion (e.g. methotrexate, penicillin). Faecal excretion is the preferred route of elimination for larger molecular-weight drugs, including those that are excreted in the bile after conjugation with glucuronide in the liver, and any drugs that are not absorbed. Some drugs or metabolites that are excreted in the bile are sufficiently lipid soluble to be reabsorbed through the gut wall and return to the liver via the portal vein (see Fig. 1.4). This recycling is known as the ‘entero-hepatic circulation’ and can significantly prolong the residence of drugs in the body. ‘Clearance’ is the term used to describe the volume of plasma that is completely cleared of drug per unit time (expressed as mL/min) and is usually the result of either hepatic metabolism or renal excretion, or a combination of both.

For most drugs, elimination is a high capacity process that does not become saturated even at high dosage. Within this range, the rate of elimination is proportional to the amount of drug in the body (i.e. the higher the drug concentration the faster the rate of elimination). This results in so-called ‘first-order kinetics’ where a constant fraction of the drug remaining in the body is eliminated in a given time and the decline in concentration over time is exponential (Fig. 1.5). The importance of this relationship to prescribers is that it means the effect of increasing doses on plasma concentration is predictable–a doubled dose leads to a doubled concentration at all time points. Half-life (t_½) is the time taken for the plasma concentration of a drug eliminated by first-order metabolism to halve. For a few drugs in common use (e.g. phenytoin, alcohol) elimination capacity is exceeded (saturated) within the therapeutic range of dosage resulting in ‘zero-order (saturable) kinetics’, where a constant amount of the drug remaining in the body is eliminated in a given time. If the rate of administration exceeds the maximum rate of elimination the drug will accumulate progressively leading to serious toxicity.

For most drugs, it is necessary to maintain therapeutic effect beyond the first dose, often for several days (e.g. antibiotics) or even for months or years (e.g. antihypertensives, lipid-lowering drugs). This requires prescribers to plan a regimen of repeated doses, indicating the size of each individual dose, the frequency of dose administration and the overall duration of treatment. When doses are repeated, the drug will progressively accumulate in the body and its eventual plasma concentration will be considerably higher than that after a single dose (Fig. 1.6). Accumulation will continue until a ‘steady state’ is reached because the rate of elimination has increased to equal the rate of administration. It takes five half-lives to achieve a plasma concentration that is 97% of the steady state level (irrespective of the dosing interval). This is important for prescribers because it means that the effects of a new prescription, or dose titration, for a drug with a long half-life (e.g. digoxin–36 hours) may not be known for a few days. In these circumstances, the target plasma concentration can be achieved safely before five half-lives have elapsed by giving an initial ‘loading dose’ that is much larger than the maintenance dose, and equivalent to the amount of drug required in the body at steady state (Fig. 1.6). This achieves a peak plasma concentration close to the plateau concentration, which can then be maintained by successive maintenance doses.

The steady state achieved by regular drug administration actually involves fluctuations in drug concentration between peaks just after administration and troughs just prior to the next administration. Recommended dosing regimens are chosen to keep the troughs in the effective range while the peaks are not high enough to cause adverse effects. The dose interval is a compromise between convenience for the patient and a constant level of drug exposure. More frequent administration (25 mg four times daily) achieves a smoother plasma concentration profile than 100 mg once daily but is much more difficult to sustain. For drugs with short half-lives that would need frequent administration, a solution is the use of ‘modified-release’ formulations. These allow drugs to be more slowly absorbed from the gastrointestinal tract and provide a smoother plasma concentration profile, which is especially important for drugs with a low therapeutic index (e.g. levodopa).

 Pharmacodynamic variation arises when an equivalent drug concentration results in a different response because of varying receptor number and structure, receptor-coupling mechanisms and physiological changes in target organs resulting from differences in genetics, age and health. For example, the beneficial natriuresis produced by the loop diuretic furosemide is often significantly reduced at a given dose in patients with renal impairment while confusion caused by opioid analgesics is more likely in the elderly

 Pharmacokinetic variation arises when the drug concentrations achieved by equivalent doses vary and is a much more important cause of the inter-individual variation in drug responses encountered in clinical practice

 Pharmacogenetic variation arises because of genetic polymorphisms that influence both the pharmacodynamic response and pharmacokinetic handling of drugs. The impact of genetics on the response to specific drugs (‘pharmacogenetics’) is gradually being uncovered and will eventually enable prescribers to identify in advance the good responders and those who will suffer adverse effects. This move towards ‘personalized medicine’, based on genetic testing, has the potential to improve the benefit–risk ratio of the drugs that we already have but also to improve the chances of drug discovery (many drugs are lost in development because they cause an unacceptable rate of adverse effects in average unselected patient groups).