Clinical

pharmacology

Medicine
on CD-ROM
Clinical Pharmacology: The Basics
D Nicholas Bateman is Reader in Clinical Pharmacology and Consultant Physician at
the Royal Infirmary, Edinburgh, UK, and Director of the Scottish Poisons Information
Bureau. He qualified from Guy’s Hospital, London, and trained at the Royal
Postgraduate Medical School, London and in Newcastle upon Tyne. His research
interests are pharmaco-epidemiology, clinical toxicology and poisons information
systems.

James S McLay is Senior Lecturer in the Department of Medicine and Therapeutics at

the University of Aberdeen, UK. His research interests include the immunological and
growth regulatory functions of the natriuretic peptides and receptors.

Clinical pharmacology encompasses an understanding of how drugs work and their

appropriate use in humans.

Pharmacodynamics
The measurement of the effects of drugs on humans (or, in basic pharmacology,
an organ system) is termed ‘pharmacodynamics’. This term encompasses both
mechanism of action and end-point (e.g. heart rate, blood pressure).

Receptors
The actions of most drugs are mediated by the binding and interaction of drug
molecules with specific molecular substances or macromolecules located on the
cell surface; these are termed ‘receptors’. Some receptor sites are intracellular (e.g.
steroid). The drug–receptor interaction leads to a molecular change in the receptor,
which triggers a chain of events leading to a response. Receptors tend to be highly
specific, interacting with a limited number of structurally related molecules. For some
drugs, the receptor is nonspecific in terms of cell function (e.g. an alkalating agent that
cross-binds molecules within DNA).

Agonists and antagonists

Agonists are drugs that activate a receptor response. Antagonists are drugs that block
receptor response. Examples of such receptor systems include:
• adrenergic (agonist – salbutamol, antagonist – atenolol)
• dopaminergic (agonist – dopamine, antagonist – haloperidol)
• cholinergic (agonist – bethanecol, antagonist – atropine).

Potency
The magnitude of the effect following a drug–receptor interaction usually depends on
the dose of drug given; this relationship is commonly expressed in the form of a dose–
response curve. Onset of response occurs at a threshold dose. For different drugs with
similar actions, use of a dose–response curve allows comparison of:
• potency (the amount of drug necessary to achieve a certain effect
• ED50 (the dose that produces a 50% response, see below)
• efficacy (the maximum possible effect of a drug).
The relative potency of different drugs may be assessed using ED50. Potency has little
clinical relevance, however, because a drug that is more potent than another may also
produce more dose-related adverse effects.

Therapeutic index
The therapeutic index (therapeutic ratio) is the ratio between the toxic dose and the
therapeutic dose of a drug. The closer this ratio is to 1, the more difficult the drug is
to use in clinical practice. The therapeutic index for digoxin, for example, is very low,
whereas that for amoxicillin is extremely high.
Medical use of drugs with a narrow therapeutic index has lead to the concept of
therapeutic drug monitoring, in which the plasma concentration of drug is measured
and the dose adjusted to achieve a desired therapeutic drug concentration (see below).

LD50
In the past, toxicology studies in animals involved measurement of the dose of drug
required to kill acutely. The single dose required to kill 50% of a population is called the
LD50. This is not a helpful measure in clinical practice, however, and other measures of
toxicity are now generally applied, particularly because of animal welfare concerns.
ED50
When a drug is given to an animal or human, it has an effect and elicits a measurable
response such as increased intracellular calcium level, reduced blood pressure or
reduced heart rate. A dose–response curve is created by plotting the response on the y
axis and the dose of drug on the x axis. The dose at which the response is 50% of the
maximal effect is termed the ED50.

Pharmacokinetics and drug metabolism

The term ‘pharmacokinetics’ refers to the rate and manner in which drugs are
absorbed, distributed, metabolized and eliminated within and from the body. Knowledge
of drug pharmacokinetics clarifies the relationships between dose, dose frequency,
intensity of pharmacological effects, disease and adverse events.

Absorption and bioavailability

Orally administered drugs must be absorbed from the gut (usually in the upper small
bowel, where the surface area is greatest). Not all of an orally administered dose
may enter the systemic circulation because of insufficient absorption, or because of
metabolism in the gut wall or liver before the drug enters the systemic circu-lation.
This metabolism is termed ‘first-pass metabolism’ (see page 16). The amount of drug
entering the systemic circulation as a proportion of that administered is termed the
‘bioavailability’. Bioavailability can be calculated by comparing areas under the plasma
concentration curves for the same dose given orally and intravenously; it is expressed
as a percentage.
It is possible to avoid first-pass metabolism by giving drugs by other routes; for
example, sublingual or dermal administration may occasionally be appropriate for
nitrates. Alternatively, the oral dose can be increased appropriately.

Distribution
To allow simple mathematical modelling of the uptake and distribution of drugs in
humans, the body is regarded as a single fluid-filled compartment.
The simplest situation is a drug given intravenously that is distributed throughout the
body via the bloodstream.
• Following intravenous injection, the drug passes through the lungs and heart, and
then to dependent organs.
• Organs and tissues with the greatest blood supply (e.g. brain, kidneys, liver) are
exposed to a greater amount of drug than those with a low blood supply.
• The drug equilibrates with these tissues according to blood supply and relative
water (hydrophilic) or lipid (lipophilic) solu-bility. As a ‘rule of thumb’, the more lipophilic
the drug, the more of it enters lipid-rich tissues; the less lipophilic the drug, the more
remains in the plasma.
The period during which a drug is distributed through body tissues is termed the
‘distribution phase’.

Apparent volume of distribution (Vd)

Vd is a theoretical volume into which a dose of drug appears to have been dissolved.
It is determined by measuring the plasma concentration during the distribution phase
before elimination has occurred (Vd = D/C, where D is the total amount of drug in the
body and C is the concentration of drug in the plasma). In practice, Vd is determined
from a plot of plasma concentration vs time.
• Drugs that are highly fat soluble or are taken up rapidly by certain tissues are
removed from the circulation quickly and have a low plasma concentration. As a
result, Vd is high – possibly greater than the volume of the patient (e.g. the volume of
distribution of tricyclic antidepressants and phenothiazine antipsychotics is several
thousand litres).
• For drugs that are not water soluble, Vd is low, and more closely similar to plasma
volume (e.g. that of ethanol is about two-thirds of body weight).

Elimination
Drugs are eliminated from the body by various processes, of which the most important
are renal, biliary and (for volatile compounds such as anaesthetics) respiratory.
Phase I and phase II metabolism: before elimination can occur, lipid-soluble drugs
must be converted into more water-soluble compounds by processes known as phase
I and phase II enzymatic metabolism. The most important drug-metabolizing enzymes
are three families of the cytochrome P450 superfamily of haem protein enzyme
isoforms (CYP1A2, CYP2D6 and CYP3A4). These enzymes are responsible for the
metabolism of a wide variety of drugs.
• In phase I metabolism, reactive groups are introduced into the drug molecule by
oxidation, reduction or hydrolysis.
• In phase II metabolism, these groups undergo conjugation, usually in the liver with
glucuronide or sulphate.

Elimination in liver disease: drug-metabolizing enzymes are present in many body

tissues, including plasma, but are most active in the liver. Drug metabolism may
therefore be impaired in patients with liver disease.
Elimination in renal disease: drug excretion is often reduced in patients with renal
impairment; this is particularly important for drugs that are excreted unchanged or have
active metabolites. An example is codeine; this is metabolized to form morphine, which
is further metabolized to a 6-glucuronide compound. Accumulation of this compound
can occur in renal failure, leading to excess sedation and respiratory depression.

Effects of other drugs: the activity of drug-metabolizing enzymes in the liver may be
increased (induced) or reduced (inhibited) by external factors. Changes in metabolism
are particularly important for drugs with a low therapeutic index (e.g. warfarin,
theophylline, phenytoin). Common examples of compounds that inhibit and induce drug
metabolism are shown in Figure 1.

Commonly used drugs and environmental factors that induce or inhibit

drug metabolism

Enzyme-inducing agents
• Carbamazepine
• Phenobarbitone
• Phenytoin
• Rifampicin
• Chronic ethanol consumption
• Smoking
• Barbecued meat
• St John’s wort

Enzyme-inhibiting agents
• Cimetidine
• Ciprofloxacin
• Co-trimoxazole
• Erythromycin
• Ketoconazole
• Grapefruit juice

Drugs with which these agents commonly interact

• Carbamazepine
• Ciclosporin
• Phenytoin
• Theophylline
• Erythromycin
• Warfarin
• Low-dose oral contraceptives
All of these drugs have relatively narrow therapeutic ranges
1

First-order kinetics: in general, the rate at which drugs are metabolized and
eliminated from the body is fixed and is proportional to the dose of drug administered.
Such drugs are said to obey first-order kinetics. An effective measure of the rate of
elimination of such drugs is the plasma half-life (t½, see below); drugs are considered to
be completely eliminated after about five half-lives.
Zero-order kinetics: occasionally, enzyme metabolism is saturable; that is, the body
is unable to eliminate more than a certain amount of drug over a fixed period of time.
Drugs such as phenytoin and alcohol are said to obey zero-order (saturation) kinetics.
Unlike drugs obeying first-order kinetics (for which doubling the dose effectively
doubles the plasma concentration), even a small increase in the dose of these drugs
produces a disproportionately large increase in plasma concentration, precipi-tating
toxicity.

Elimination rate constant: the pharmacokinetics of drugs within patients can be

further understood by determining the elimination rate constant (K). The simplest
method to calculate K is from a natural logarithm plot of the plasma concentration–time
curve, which is a straight line.
Drug elimination can also be measured in terms of clearance (in a manner
analogous to creatinine clearance) by the volume of plasma cleared of drug per unit
time.

Half-life: a simpler means of understanding and using these eli-mination parameters,

and of facilitating patient care, is to express the information in terms of t½. This is
defined as the time taken for the plasma concentration of a drug to decrease to 50%
of the original value; it can be readily calculated from the equation t½ = 0.693/K. Thus,
if the plasma concentration of a drug decreases from 8 mmol/litre to 4 mmol/litre in 4
hours, the elimination t½ of that drug is 4 hours.
t½ is clinically important because it enables determination of:
• dosing frequency
• the time elapsed before a steady-state plasma concentration is reached following
repeat dosing (four to five half-lives)
• whether use of a loading dose is appropriate.
However, it is important to remember that many drugs exhibit a pharmacological action
that is longer than the elimination t½.

Pharmacogenetics
Several drug-metabolizing enzymes are subject to genetic variation in activity, and this
can lead to large differences in the rate of drug clearance from the plasma, unexpected
prolongation of t½ and increased adverse effects. Pharmacogenetic variations
are relatively common and may vary significantly between races. Examples are
debrisoquine, metoprolol and isoniazid. ‘Slow metabolizers’ are more likely to develop
adverse effects such as peripheral neuro-pathy with isoniazid. In Western countries,
slow metabolizers of drugs such as debrisoquine and metoprolol comprise about 8% of
the population.

Therapeutic drug monitoring

Therapeutic drug monitoring may be required for some drugs with a low therapeutic
index in which the relationship between dose and plasma concentration is not easily
calculated but for which the plasma level/biological effect is well documented. Usually,
this process involves measuring the trough level of the drug (i.e. the level immediately
before the next dose is administered). Dosing interval and t½ affect the amount of drug
in the body at any one time, and knowledge of these factors enables implementation of
logical dosing regimens.
• A drug such as digoxin with a t½ of 36 hours can be given once per day.
• Theophylline has a short t½ and is therefore difficult to use in conventional tablets.
The pharmacokinetics of short-t½ drugs may be altered by pharmaceutical means,
usually by administering the drug in a slow-release formulation. However, there are few
drugs for which this is necessary.

Drug interactions
Interactions between drugs may result in changes in their pharmacokinetics
(pharmacokinetic interaction) or an increase or decrease in their biological effect
(pharmacodynamic interaction).

Pharmacokinetic interactions
Pharmacokinetic interactions most commonly involve changes in metabolism in
the liver (enzyme inhibition) or excretion by the kidneys. Rarely, protein-binding
displacement causes a change in distribution.
Pharmacodynamic interactions
In pharmacodynamic interactions, different drugs act at different receptor systems to
produce, most commonly, an increased biological effect.
A useful pharmacodynamic interaction is the antihypertensive effect of concurrently
administered β-blocker and calcium channel antagonist used in hypertensive
patients. This interaction may be detrimental, however, when the same drugs result in
inappropriate hypotension in patients treated for angina.

Adverse drug reactions

Adverse drug reactions (ADRs) are commonly divided into the following types:
• A – predictable (e.g. bradycardia caused by β-adrenoceptor antagonists)
• B – bizarre
• C – chronic effects occurring only after prolonged treatment (e.g. iatrogenic
Cushing’s syndrome caused by corticosteroids)
• D – delayed effects occurring many years after treatment, or in the children of treated
patients (e.g. second malignancies in patients treated with alkylating agents)
• E – end-of-treatment effects, which occur when drugs are stopped suddenly (e.g.
myocardial infarction following acute withdrawal of β-adrenoceptor antagonists)
Types A and B ADRs are the principal groups.

Type A ADRs
Type A ADRs are common. They are caused by an augmented pharmacological effect,
are dose dependent and are seldom fatal. They often arise as a result of altered drug
pharmacokinetics caused by disease or concurrent drug therapy.

Type B ADRs
Type B ADRs are uncommon. They are unrelated to drug pharmacology and unrelated
to dose. They are unpredictable and often fatal. Such reactions often involve
anaphylactoid-type reactions.

Pharmacovigilance
Pharmacovigilance is the branch of pharmaco-epidemiology that concentrates on the
detection of ADRs. ADRs often mimic common disease states, and uncommon ADRs
may be difficult to detect unless they are severe or are temporally related to a specific
medication. In the UK, there are three types of pharmaco-vigilance study.
• The Yellow Card reporting system is a spontaneous-reporting alerting system
that may also be used as a hypothesis-generating process. It relies on health-care
professionals reporting any adverse event that they suspect may be caused by a
medication. There is no requirement for proof.
• Prescription Event Monitoring is a systematic cohort approach that may also act
as an hypothesis-generating and testing process. It is typified by the Green Form in
the UK, and is based on the monitoring of dispensed prescriptions for new drugs via a
central agency.
• The third technique involves hypothesis testing, when previous data have suggested
that a drug may be responsible for a particular adverse event. Hypothesis testing
usually involves case-control studies. Randomized clinical studies and cohort studies
are usually less efficient, because large numbers of patients are required to detect rare
events.

Delivery systems
For most drugs, there is a direct relationship between pharmaco-logical response and
concentration at the receptor; thus, to be biologically active, the drug must gain access
to the systemic circulation. Plasma drug concentration depends on both drug kinetics
and the design of the drug delivery system.

Oral administration
The most commonly used delivery systems involve absorption of drug from
the gastrointestinal tract following buccal, sublingual, rectal or, most often, oral
administration. Commonly encountered oral forms include:
• solutions
• suspensions
• capsules
• tablets
• coated tablets
• modified-release tablets.
The time taken for the drug to appear in the systemic circulation following oral
administration increases in an approximately similar order.

Tablets are the most common delivery system. They have advantages of convenience
and accuracy of dose.
Coated tablets – it is possible to alter the delivery and apparent kinetics of drugs by
changing the dissolution characteristics of tablets. Thus, a tablet may be enteric-coated
to prevent breakdown in the stomach, ensuring that it remains intact until it reaches the
small bowel. This approach is commonly used to protect drugs that are destroyed by
gastric acid (e.g. omeprazole).
Modified-release tablets – the excipients of tablets may be modified to improve
drug delivery by controlling the rate, amount and duration of drug release over a 24-
hour period. This approach is used for drugs with a short t½, which require frequent
dosing to maintain therapeutic levels (e.g. theophylline, verapamil, nifedipine).
Pro-drugs – a similar effect may be achieved by using a pro-drug. Pro-drugs are
inactive compounds that are activated by biological fluids or metabolizing enzymes
following administration (e.g. enalapril is converted to its active form enalaprilat).

Intravenous administration
Intravenous administration is most commonly used when rapid onset of action and
careful control of plasma levels are required. Drugs may be given as a:
• bolus injection
• slow infusion
• continuous infusion.

Slow infusion is used when excessively high transient plasma levels are undesirable
(e.g. phenytoin).

Continuous infusion is used when the drug has a short t½ or when its therapeutic
index is narrow and sustained controlled blood levels are required.

Clinical trials
Clinical trials are discussed elsewhere.

Compliance
If a drug is to achieve the desired therapeutic effect, it is necessary for the patient to be
compliant (concordant) with medical therapy. Compliance with therapy is defined as the
extent to which patients follow the course of treatment. Factors believed to be important
in ensuring patient compliance include the complexity of the therapeutic regimen, and
patients’ understanding of their disease and the need for and benefits of treatment. 

FURTHER READING
Mucklow J C, Waller D G. Graduate Therapeutics. A Primer for MRCP and Specialist
Training. Oxford: Butterworth-Heinemann, 2001.
Page C, Curtis M, Sutter M et al. Integrated Pharmacology. 2nd ed. St Louis: Mosby,
2002.
Waller D G, Renwick A G, Hillier K. Medical Pharmacology and Therapeutics.
Philadelphia: Saunders, 2001.
Practice points

• The pharmacodynamic effect of a drug is its effect on a measurable physiological

parameter such as heart rate, blood pressure or acid secretion into the stomach
• Pharmacokinetics describe the rate and manner in which drugs are absorbed,
distributed, metabolized and eliminated within and from the body
• Following oral administration, it takes about five half-lives for plasma drug levels to
reach a steady state
• It takes about five half-lives for a drug to be completely eliminated from the body
once administration has stopped
• Drug–drug interactions are common and predictable, and may arise as a result of
increased pharmacodynamic effect
• Drug–drug interactions involving kinetic changes usually result from effects on drug-
metabolizing enzymes in the liver; they are often serious when drugs with a narrow
therapeutic index are involved
• ADRs are common, and most often arise as a result of altered pharmacokinetics in
disease states such as renal impairment
• Pharmacovigilance is the branch of pharmaco-epidemiology that concentrates on the
detection of ADRs
• Compliance (concordance) is a measure of the extent to which a patient population
complies with a therapeutic medical regimen

Copyright © 2003 The Medicine Publishing Company Ltd

Receptor Functions
Simon R J Maxwell is Senior Lecturer in Clinical Pharmacology at the University
of Edinburgh and Honorary Consultant Physician at the Western General Hospital,
Edinburgh, UK. His research interests include the vascular biology of atherosclerosis
and endothelial function, and the role of oxidative stress and antioxidants.

David J Webb is Christison Professor of Therapeutics and Clinical Pharmacology at

the University of Edinburgh and Honorary Consultant Physician at the Western General
Hospital, Edinburgh, UK. His research interests include endothelial function and
atherogenesis.

All clinicians should have an understanding of receptor mechanisms for the following
reasons.
• Many drugs commonly used in modern practice act on receptors.
• Safe drug use requires an understanding of receptor pharmacology.
• Some common diseases involve changes in receptor numbers or coupling of
receptor stimulation to response.
• Future advances in pharmacology and therapeutics are likely to develop from the
discovery of further receptors and molecular modelling of drugs to interact with them.

Definitions
Receptors and ligands
Receptors are proteins situated in the cell membrane or at an intracellular site that
specifically recognize and bind molecules termed ‘ligands’. The ligand may be a
neurotransmitter, a hormone, a drug or a growth factor. This interaction initiates a
conformational change in the receptor protein that eventually transmits a signal into the
cell (Figure 1). The resulting intracellular signal is usually a self-amplifying cascade of
biochemical events that ‘couples’ receptor–ligand interaction to a biological response
such as contraction or secretion.
There are four principal types of receptor.
• Channel-linked receptors are usually coupled directly to an ion channel. An example
is the nicotinic acetylcholine receptor.
• G-protein-coupled receptors are all coupled to intracellular effector mechanisms via
a family of closely related ‘G-proteins’ that participate in signal transduction by coupling
receptor binding to intracellular enzyme activation or the opening of an ion channel.
Examples include the muscarinic cholinergic receptor, adrenoreceptors and opioid
receptors.
• Kinase-linked receptors are linked directly to an intracellular protein kinase that
triggers a cascade of phosphorylation reactions. Examples include receptors for insulin
and various growth factors.
• Receptors regulating gene transcription are located intracellularly and are also
known as ‘nuclear receptors’. They include receptors for steroids and thyroid hormone.
Although the term ‘receptor’ is usually restricted to proteins whose only function is to
bind a ligand, it is sometimes used more widely in pharmacology to include functional
targets such as ion channels and enzymes (Figure 2). For example, voltage-sensitive
sodium channels in excitable tissues might be considered as the ‘receptor’ for local
anaesthetics, and the enzyme xanthine oxidase the ‘receptor’ for allopurinol. In the
case of mechanoreceptors, intracellular signals are generated by mechanical forces
rather than specific ligands.
Receptor types are usually defined according to their most potent endogenous
agonist (e.g. adrenergic, serotoninergic – Figure 2). Receptor subtypes can then be
further defined by their relative response to different agonists and antagonists. Although
many different kinds of receptor have now been described, relatively few signalling
systems have been discovered; thus, there must be ‘cross-talk’ between receptors (e.g.
β-adrenergic, histamine H2, dopamine, opioid and γ-amino-butyric acid type B receptors
are all linked to modulation of cAMP levels).

Agonists and antagonists

• An agonist can be defined as a ligand, the binding of which to a receptor protein
produces a conformational change necessary to initiate a signal that is coupled to a
biological response. When all available receptors are occupied, a maximal response is
produced.
 Receptor mechanisms

Free agonist

Extracellular
Receptor binding

Cell membrane
G-protein
G-protein Adenylate
cyclase Signal transduction
Intracellular Phospholipase C

Secondary messenger
ATP cAMP Phosphatidylinositol Inositol
biphosphate triphosphate

Protein kinase A Ca2+ release from storage

Signal amplification

Protein phosphorylation Ca2+-regulated systems

Response Response Biological effect

The interaction of a ligand with a receptor protein induces a conformational change that eventually initiates an intracellular signal. The signalling mechanism may
include direct opening of an ion channel or production of a secondary messenger via interaction of the receptor with G-proteins (e.g. cAMP, inositol triphosphate).
The signal is amplified intracellularly, coupling the receptor–ligand interaction to a biological response.

Receptors and coupling mechanisms

Receptor type Coupling mechanism Examples of ligands
• Receptor-controlled Entry/exit of ions Nicotinic acetylcholine
ion channels → Depolarization or hyperpolarization γ-aminobutyric acid

• G-protein receptors Receptor protein associated with a G-protein which may: Muscarinic acetylcholine
Activate an enzyme producing a ‘secondary messenger’ β-adrenergic
Adenylate cyclase → cAMP Dopamine
Phospholipase C → inositol triphosphate, diacylglycerol Serotonin
Activate an ion channel Opioids

• Receptor-controlled Initiate protein phosphorylation (e.g. tyrosine kinase, Insulin

enzymes guanylate cyclase) Atrial natriuretic peptide

• Intracellular receptors Stimulate mRNA synthesis in the cell nucleus, leading Steroid hormones
to protein synthesis Thyroid hormones
Vitamin D

2
 • An antagonist is a ligand that binds to a receptor but does not produce the
conformational change that initiates an intracellular signal. Occupation of the receptor
by an antagonist prevents the binding of any other ligand and so ‘antagonizes’ the
biological response to the agonist.
• Some ligands have properties intermediate between agonists and antagonists and
are known as ‘partial agonists’. They are unable to produce a maximal signalling effect
even when all available receptors are occupied. However, partial agonists also block
receptor sites that could potentially be occupied by the full agonist and this competition
for receptors means that, in some circumstances, partial agonists may also appear to
antagonize the effect of full agonists (see below).
• Some ligands produce an effect opposite to that of the full agonist when they bind to
a receptor; they are termed ‘inverse agonists’. For these to be identified, the relevant
receptor must exhibit endogenous activation in the absence of ligand binding.

Dose–response curves
An understanding of receptor pharmacology requires a basic knowledge of the
dose–response curve relating the concentration of an agonist to the biological effect
it produces (Figure 3). A sigmoid curve is obtained when the percentage of maximum
effect (e.g. decrease in blood pressure, reduction in gastric acid secretion) is plotted
against the logarithm (base 10) of the concentration of the agonist. This representation
is useful because it visually expands the region over which the drug response changes
most rapidly with concentration. It is evident that increased concentration of agonist
produces an increased effect, but only over a relatively narrow concentration range
– further increases in concentration beyond this range produce little extra effect. The
maximum response on this curve is termed ‘Emax’ and the concentration of agonist that
produces 50% maximum effect (Emax/2) is the EC50.

Dose–response curves
100 Full agonist
Response (% maximum)

50 Partial agonist

EC50
0
10–9 10–8 10–7 10–6 10–5

Concentration of agonist (log scale)

The biological effect (% maximum response) and the concentration of a full

agonist are plotted on a logarithmic scale. An equipotent partial agonist has
a lower efficacy than a full agonist – it cannot achieve the maximum
response even when all available receptors are occupied. EC50 is the
concentration of agonist that produces 50% maximum effect.

Increasing drug potency

100
Response (% maximum)

50

0
10–9 10–8 10–7 10–6 10–5

Concentration of agonist (log scale)

Dose–response curves for four full agonist drugs of different

potencies but equal efficacy. 3
 Although it is generally true that the biological effect elicited by an agonist is
proportional to the fraction of receptors occupied, the relationship is often not simple
because of the phenomenon of ‘spare receptors’. It has been observed in many
receptor systems that full agonists can elicit the maximum effect without occupying all
available receptors. This apparent excess of receptors allows a full response to occur
at lower ligand concentrations than would otherwise be required.
Most drugs used in practice are administered in doses that give concentrations close
to the top of the dose–response curve. This ensures that most patients respond to the
drug without the need for a specific dose–response curve for each individual. However,
it is possible, in many cases, to achieve the desired therapeutic response at a lower
dose. This is important because drug side-effects are often dose-related in a similar
manner. The aim of the prescriber is to provide drugs at doses that provide maximum
therapeutic efficacy with minimum side-effects, and this principle guides the licensed
dose range. For most drugs, the ratio between these two doses (therapeutic index) is
high, but there are notable exceptions (e.g. digoxin, theophylline).

Efficacy of an agonist is the extent to which it can produce the maximum response
possible when all available receptors are occupied. Full agonists have high efficacy
and can produce the maximum response of which a tissue is capable. Partial agonists
have a lower efficacy – they can achieve only sub-maximum responses even when
all receptor sites are occupied. The dose–response curve for a partial agonist is
usually flatter than that of a full agonist and reaches a lower maximum (Figure 3). The
term ‘therapeutic efficacy’ is used by clinical pharmacologists to compare drugs that
produce different therapeutic effects on a biological system despite having maximum
pharmacological efficacy at their target receptor (e.g. thiazide diuretics have a lower
therapeutic efficacy than loop diuretics).

Potency of an agonist is measured by the amount (weight) required to produce a given

level of effect. More potent drugs produce biological effects at lower doses (i.e. they
have a lower EC50). It is important to note that a less potent drug may have an efficacy
similar to that of a more potent one; the difference in potency can be overcome by
giving the less potent drug in higher doses. A common example is the inhibition of acid
secretion produced by ranitidine and cimetidine at H2-receptors.
Although differences in relative potency can be overcome by a change in dose, it
should be remembered that the adverse effects of drugs are often dose-related. If
these occur by a mechanism other than receptor–ligand interaction, potency may be
relevant because only the more potent drug will be active at concentrations that avoid
unwanted side-effects. The potency of a drug is related to its affinity for the receptor
– that is, how readily the drug–receptor complex is formed.
Receptor–ligand interactions
Affinity
The affinity of a ligand for its receptor can be conveniently assessed by the
concentration of ligand required to produce 50% maximum binding. Affinity is a function
of both the rate of association and the rate of dissociation of the ligand–receptor
complex; the former depends on the ‘goodness of fit’ at a molecular level, whereas
the latter depends on how tightly the ligand is bound. Systems requiring rapid, fine
modulation (e.g. nerve synapses) cannot have agonists with a high receptor affinity
because these would produce unnecessarily prolonged responses. During stimulation,
agonist concentration near the receptor must be relatively high, but the agonist is then
cleared rapidly by active transport. In contrast, growth factors are often peptides with a
very high affinity for their receptors, and achieve their effects at concentrations that are
difficult to detect in vivo.

Receptor antagonism
Most natural and synthetic ligands are reversible and eventually dissociate from
their receptor when the ligand concentration is reduced. This fact enables biological
responses to be modulated and allows competitive interaction between agonists and
antagonists for access to the receptor. Thus, the effect of a reversible competitive
antagonist can always be overcome by giving the agonist at a sufficiently high
concentration (i.e. it is surmountable). Some antagonists are irreversible and do not
dissociate from the receptor. Such irreversible antagonists produce indefinite receptor
blockade and are less desirable as therapeutic agents. However, there are notable
exceptions. Phenoxybenzamine, the irreversible α-antagonist, is valuable when
preparing for surgery in patients with phaeochromocytoma, in whom unpredictable
bursts of agonist activity would be life-threatening. Commonly used irreversible
inhibitors of functional enzymes include aspirin and omeprazole. The pharmacological
effects of irreversible antagonists disappear only when new receptors or enzyme are
synthesized. This explains the benefits of aspirin taken intermittently as prophylaxis
against cardiovascular events.
The relative receptor occupancy of agonists and antagonists depends on their
individual concentrations and affinity for the receptor. When an antagonist is introduced
into the receptor–agonist model, the dose–response curve for the full agonist is shifted
to the right (Figure 4). This occurs because the agonist is now competing for receptor
occupation with the antagonist and, for a given percentage of receptor occupation (and
hence biological response), a higher agonist concentration is required. The effect of
competitive antagonists can be overcome with sufficiently high doses of agonist.
When a partial agonist is introduced in the presence of a full agonist, the biological
response depends on the availability of full agonist and unoccupied receptors.
When the receptors are not fully occupied, the partial agonist can be bound without
displacing the full agonist, leading to augmentation of the biological response. When
the available receptors are completely occupied by full agonist, the presence of partial
agonist competing for receptor sites tends to diminish the response. Therefore, at
concentrations at which drugs are present in excess of receptors, the dose–response
curve for the full agonist is shifted to the right (Figure 4).
This fact may have important clinical consequences. The partial β1-adrenoceptor
agonist xamoterol can stimulate cardiac contractility in healthy individuals at rest, but
in patients with severe heart failure it may antagonize the response to the full agonist
adrenaline (epinephrine) and reduce contractility. Similarly, the partial opioid agonist
nalorphine may appear to antagonize the analgesic effect of morphine. Partial agonists
have some advantages as therapeutic agents – though they are unable to achieve the
same maximum effect as the full agonist, they are less likely to produce limiting toxic
side-effects at the top of their dose–response curve (e.g. the partial opioid receptor
agonist buprenorphine does not cause as much respiratory depression as morphine
when it is used as an analgesic).

Changes in receptor responsiveness

In the short term, most receptor-mediated responses are altered by changing the local
concentration of agonist around the receptors. It is now recognized that, in the longer
term, changes are possible in the response of the tissue to a given concentration of
agonist, and can be attributed to altered receptor function. These changes (loosely
termed ‘up-regulation’ and ‘down-regulation’) may involve alterations in the number
of receptors on the cell surface or in the coupling of receptor occupation to the
intracellular response. Down-regulation is usually seen in response to chronic receptor
overstimulation as a result of long-term administration of a drug (exogenous agonist)
or a disease process (endogenous agonist). In some cases, this can occur quickly,
leading to the phenomenon of ‘tachyphylaxis’, in which repeated administration of
a drug is associated with rapidly diminishing efficacy. This phenomenon is typical
of drugs that stimulate release of neurotransmitters from nerve terminals, which
leads to rapid depletion of stores. The term ‘tolerance’ is used to describe a more
gradual decrease in responsiveness to a drug. Tolerance may be related to down-
regulation of receptors, but may also result from altered drug metabolism and
induction of physiological compensatory mechanisms. The tolerance that develops to
organic nitrates is probably related to both. A further example in which physiological
compensation reduces drug effect is the activation of the renin–angiotensin system that
occurs in response to thiazide diuretic treatment in hypertension.
There are many clinically relevant examples of altered receptor responsiveness.
• In Parkinson’s disease, the term ‘on–off phenomenon’ is used to describe the rapid
swing from mobility to immobility that occurs some hours after administration of L-
dopa. It has been attributed to down-regulation of dopaminergic receptors in the brain
following prolonged L-dopa treatment, which renders the extrapyramidal pathways
unusually sensitive to the decreasing concentration of dopamine.
• In patients with phaeochromocytoma with high endogenous catecholamine
concentrations, receptor numbers are down-regulated, leading to a relative insensitivity
to catecholamines.
• In autonomic neuropathy, receptor up-regulation renders the cardiovascular system
hypersensitive, and exaggerated responses to catecholamines may occur.
• In patients with prostate cancer, gonadotrophin-releasing hormone given
 Receptor–ligand interactions
Increasing antagonist concentration

100
Response (% maximum)

10–7M 10–6M 10–5M

50

0
10–9 10–8 10–7 10–6 10–5 10–4

Concentration of agonist (log scale)

In the presence of an antagonist, the dose–response curve of the full agonist

is shifted to the right because the full agonist competes for receptor
binding. The higher the concentration of antagonist, the greater the shift.

100 Full agonist

Full agonist
and partial
Response (% maximum)

agonist

50
Partial agonist

0
10–9 10–8 10–7 10–6 10–5

Concentration of agonist (log scale)

In the presence of a partial agonist, the dose–response curve of the full

agonist is shifted to the right. 4

continuously paradoxically inhibits gonadotrophin release in contrast to the normal

pulsatile secretion.
An alternative example of receptor up-regulation is the use of 3-hydroxy-3-
methylglutaryl co-enzyme A inhibitors to lower plasma cholesterol concentration. These
drugs inhibit the rate-limiting enzyme in the synthesis of cholesterol in hepatocytes,
promoting increased synthesis and expression of receptors for low-density lipoprotein
(LDL) particles. As a consequence, the rate of uptake of cholesterol-laden LDL particles
from the circulation is increased and the plasma cholesterol concentration is reduced.
Sometimes, receptor responses are regulated by changes in the coupling of receptor
occupation to intracellular signalling. Chronic β-adrenoceptor blockade potentiates the
response of the adenylate cyclase–cAMP system and consequently up-regulates the
response to other receptors that are linked to it.

Selectivity
Receptors are usually subtyped on the basis of their selectivity for agonists or
antagonists. Agonist selectivity is determined by the ratio of EC50 at the two receptor
subtypes. In the case of β-adrenoceptors, the concentration of norepinephrine
(noradrenaline) required to cause bronchodilatation (β2) is ten times higher than that
required to cause tachycardia (β1); therefore, the selectivity of norepinephrine for β1-
receptors with respect to β2-receptors is 10.
 Antagonist selectivity is measured as the relative shift of the agonist dose–response
curves achieved by a single dose of antagonist affecting responses mediated
through the two receptors. For example, if the non-selective β-adrenoceptor agonist
isoprenaline was used in the situation above, the concentration of atenolol achieved in
the bloodstream after administration of a 50 mg dose would shift the dose–response
curve at the bronchus by only 10% of that at the heart, giving a selectivity for β1-
receptors of 10. Thus, a ten times greater concentration of atenolol is required to
produce a shift in the agonist response curve for the lung equal to that for the heart.
It must be remembered that selectivity for a receptor subtype is only a relative
concept and does not equate with specificity. Drugs with selectivity for one receptor
subtype can produce a maximum effect at other subtypes if a sufficient quantity is given.
This is particularly important when the beneficial effects are activated by one receptor
subtype and the unwanted effects by another. For example, atenolol is considered a
β -selective adrenoreceptor antagonist but has some effects at β2-receptors, and is
1
therefore absolutely contraindicated in asthmatic patients in whom any reduction in
β2-mediated bronchodilatation may be dangerous. Selectivity is useful in clinical practice
only when the ratio of the impact of the drug at the two receptor sites is 100 or more.
When selectivity is lower, it is difficult to predict drug doses that will exploit the difference
in subtype activity. Selectivity is most likely to be achieved at the lowest effective dose.

The future
Advances in molecular biology have enabled cloning and sequencing of receptor
proteins. With recombinant synthetic technology providing sufficient quantities of
receptor protein, it is now possible to screen novel ligands rapidly without whole-
animal or organ experiments. These studies have uncovered a much higher degree
of variability within each receptor family than could have been predicted from
pharmacological experiments. From these data, it is becoming possible to design
ligands with higher selectivity for individual receptor subtypes.
Large-scale DNA sequencing has identified many DNA sequences with a distant
relationship to the G-protein-coupled receptor superfamily. The sequence homology
is usually insufficient to assign these ‘orphan’ receptors to a particular subfamily.
However, cloning and expression of orphan receptors in cells and screening for
functional responses is likely to lead to the discovery of many novel receptor ligands.


Assaying receptor binding

Assays for receptors are designed to detect binding sites, not all of which are
coupled to a signal. Most assays use radiolabelled ligand and measure the amount
of radioactivity bound to cell membranes, whole cells or tissue sections fixed to a
microscope slide. Nonspecific binding can be assessed by displacing the radiolabelled
ligand by addition of large quantities of unlabelled ligand. This procedure exploits
a fundamental property of receptor binding – that it is saturable, unlike nonspecific
binding. Mathematical manipulation of the data allows the number of receptors and
their affinities to be calculated; however, these calculations are often inaccurate when
high-affinity and low-affinity binding sites are present, and it is preferable to use a
reiterative computer program to analyse the raw data.
In receptor autoradiography, images are obtained by exposing sections of
radiographic film after incubation and washing steps. Various image analysis programs
allow colour-coded pictures to be obtained after subtraction of the nonspecific image
from the total binding. This technique gives anatomical information that is particularly
useful in establishing the likely site of action of a neurohumoral factor within a tissue.

FURTHER READING
Black J V, Stanley N P. Inverse Agonists Exposed. Nature 1995; 374: 214–15.
Broach J R, Thorner J. High-throughput Screening for Drug Discovery. Nature 1996;
384: 14–16.
Colquhoun D. Binding, Gating, Affinity and Efficacy. Br J Pharmacol 1998; 125: 923–47.
Gudermann T, Kalkbrenner F, Schulz C. Diversity and Selectivity of Receptor–G Protein
Signalling. Ann Rev Pharmacol Toxicol 1996; 36: 429–59.
Lefkowitz R J. G-proteins in Medicine. N Engl J Med 1995; 332: 186.
Lerner M R. Tools for Investigating Functional Interactions between Ligands and G-
protein Coupled Receptors. Trends Neurosci 1994; 17: 142–6.
Libert F, Vassart G, Parmentier M. Current Developments in G-protein-coupled
Receptors. Curr Opin Cell Biol 1991; 8: 218–23.
Mangelsdorf D J, Thummel C, Beato M et al. The Nuclear Receptor Superfamily: The
Second Decade. Cell 1995; 83: 835–9.
Rang H P, Dale M M, Ritter J M. Pharmacology. Edinburgh: Churchill-Livingstone,
1995.
Ross E M, Kenakin T P. Pharmacodynamics: Mechanisms of Drug Action and the
Relationship between Drug Concentration and Effect. In: Hardman J G, Limbird
L E, Gillman A G, eds. Goodman and Gillman’s The Pharmacological Basis of
Therapeutics. New York: McGraw-Hill, 2001: 31–44.
Wilson S, Bergsma D J, Chambers J K et al. Orphan G-protein-coupled Receptors: The
Next Generation of Drug Targets? Br J Pharmacol 1998; 125: 1387–92.

Copyright © 2003 The Medicine Publishing Company Ltd

Pharmacokinetics for the Prescriber
Howard L McLeod is Associate Professor of Medicine in the Department of Medicine
at Washington University, St Louis, USA. He trained in Seattle, Memphis, Philadelphia
and Glasgow, UK, and was senior lecturer in medicine at the University of Aberdeen.
His research interests include the clinical pharmacology of anticancer drugs, the
molecular basis of polymorphic drug metabolism, and the evaluation of cellular targets
for chemotherapy within human tumours.

Pharmacokinetics is a tool for describing the movement of drugs through the body
over time, and deals with the processes of absorption from the site of administration,
distribution throughout the body, metabolism or conjugation of the drug, and elimination
from the body. Pharmacokinetics can be thought of as what the patient does to the drug
(whereas pharmacodynamics is what the drug does to the patient). An understanding of
pharmacokinetics should help the clinician to:
• appreciate how dosing regimens are devised
• tailor a dosing regimen to the individual requirements of the patient (e.g. in renal
failure)
• determine what may be wrong when a patient fails to respond to treatment
• determine why a drug has caused toxicity
• elucidate the mechanisms of drug interactions.
Clinical pharmacokinetics is particularly valuable with drugs for which the margin between
therapeutic and toxic concentrations is narrow. The pharmacokinetic profile of a drug
should not be considered in isolation; its pharmacodynamic effects must also be taken
into account.

Elimination half-life
The half-life (t½) of a drug is the time taken for the circulating concentration of the drug
to decrease by 50%. A concentration–time curve (Figure 1) can be constructed by
administering the drug intravenously and removing blood for assay at frequent intervals.
With most drugs, the curve is a straight line when the concentration (vertical axis) is
expressed on a logarithmic scale, enabling t½ to be determined easily.
Knowledge of t½ is useful as a guide to:
• the time required for drug elimination (Figure 2)
• the rate of accumulation during repeated dosing (when a drug is given repeatedly, the
plasma concentration increases with each dose, Figure 3).
However, the rate at which plasma concentration increases reaches a plateau (steady
state) when the amount eliminated in a dosing interval is equal to the dose. t½ is the
only variable that determines the time required to reach steady state during repeated
dosing. More than 90% of the steady-state concentration is achieved after 4–5 half-lives.
Lignocaine, for example, has a t½ of about 1 hour; because 4 hours is too long to wait for
a clinical effect to occur, an intravenous loading dose is given, followed by a maintenance
infusion.

Volume of distribution
Volume of distribution (Vd) is a measure of how widely a drug is distributed in body tissues.
It is commonly expressed as the ratio of the total dose administered by bolus injection to
the peak plasma concentration; for example, if a dose of gentamicin is 100 mg and the
peak concentration is 5 mg/litre, Vd is 20 litres.
The concept of Vd is notional; it does not relate to any particular compartment of the
body. However, it is useful in determining how extensively a drug is distributed. The Vd
of ciclosporin, for example, is 100 litres; it is widely distributed to most body tissues.
Knowledge of Vd is also relevant to dosing regimens – when Vd changes, the loading dose
must be changed.

Clearance
The clearance of a drug, not t½, is the best measure of the rate at which it is eliminated
from the body. t½ is affected by both clearance and Vd, whereas clearance is independent
of Vd.
Clearance is calculated by dividing the dose by the area under the plasma
concentration–time curve, either after a single dose or during a dosing interval at steady
 Log-linear plot of a concentration–time curve following
an intravenous dose

C(o)
100

50
Drug concentration (mg/litre)

10

1.0

t1/2

0.1
Time

The elimination half-life (t1/2) is the time taken for the drug concentration to
fall by 50%. C(o) is the extrapolated concentration at the time of injection.
1

Relationship between half-life and drug elimination for a drug with a half-
life of 6 hours

Number of Time Plasma Original

half-lives (hours) concentration concentration
(µg/ml) eliminated (%)
0 0 100 0
1 6 50 50
2 12 25 75
3 18 12.5 87.5
4 24 6.25 93.75
5 30 3.125 96.875
6 36 1.56 98.44
7 42 0.78 99.22
8 48 0.39 99.61

2
state (Figure 3). Total body clearance is a composite of all available relative elimination
(e.g. hepatic metabolism plus renal excretion). Clearance is expressed as the volume
of plasma cleared of drug per unit time (e.g. ml/minute, as for creatinine clearance).
When calculating clearance after oral administration, an adjustment must be made for
incomplete bioavailability. Clearance, Vd and t½ are mathematically interrelated and can
be calculated from each other as well as directly from the concentration–time curve (t½ =
0.693 x Vd/clearance).

Absorption
Although absorption can occur throughout the gastrointestinal tract, drugs are absorbed
predominantly in the upper small bowel because of its large surface area. Other medications
are influenced by cellular transporters (Lin & Yamazaki). Lipid-soluble drugs are absorbed
rapidly by passive diffusion. Absorption of water-soluble drugs is slower and may be
incomplete. Most lipid-soluble drugs reach peak plasma concentrations 30–60 minutes after
ingestion, but absorption can be slowed by a heavy meal or by other therapeutic agents that
reduce the rate of gastic emptying (e.g. opiates, tricyclic antidepressants, antihistamines,
 Plasma drug concentration during repeated dosing

Doses
Peak
Plasma drug concentration

Trough

Mean steady-state
concentration

0 1 2 3 4 5 6
Time (number of half-lives)

Without a loading dose, the blue areas are equal in size

3

anticholinergics). Reduced absorption rate is important only if the pharmacological effect

sought depends on attaining a high peak concentration (e.g. antibiotics, analgesics).
Hence, patients with severe migraine and gastric stasis may not obtain pain relief from
oral aspirin or paracetamol unless gastric emptying is accelerated. In most drugs at steady
state, extent of absorption is more important than rate.

Effect of food
Generally, absorption of lipid-soluble drugs is increased in the presence of food, though
the clinical impact is small because these drugs are well absorbed (Schmidt & Dalhoff).
Water-soluble drugs are best taken on an empty stomach, at least 1 hour before a meal
with a full glass of water. If the drug is likely to produce gastrointestinal irritation (e.g.
anti-inflammatory agents), it should be taken with food whatever its solubility.

First-pass metabolism
If a drug is inactivated in the gastrointestinal tract or metabolized in the gut wall or liver
before it enters the systemic circulation, the amount reaching the site of action is reduced
(Figure 4). This effect is called ‘first-pass’ metabolism or the ‘first-pass’ effect, and usually
results from metabolism in the liver. Propranolol is metabolized to an inactive compound;
this explains the 20-fold difference between the effective intravenous and oral doses.
Grapefruit juice can inhibit enzymes in the duodenum, leading to increased bio-availability
of drugs such as felodipine, terfenadine and ciclosporin; in several cases, this interaction
has been fatal. It is sometimes possible to bypass the liver using routes of administration
other than oral; for example, glyceryl trinitrate may be given sublingually, buccally or
transdermally, and other drugs (e.g. morphine) may be given rectally.
Other biological factors may influence the degree of absorption. The P-glycoprotein
efflux pump protein is located in many tissues, including the duodenum, and acts as a
barrier to the absorption of many drugs, including ciclosporin. It functions by pumping
drug out of intestinal enterocytes, back into the bowel lumen.

Protein binding
Once a drug reaches the systemic circulation, it may be bound to circulating proteins,
usually albumin (basic drugs such as propranolol and disopyramide bind largely to globulins
and acute-phase reactants such as α1 acid glycoprotein). Most drugs must be unbound
(free) to have a pharmacological effect. Protein binding is clinically important with only
a few drugs, of which the most important are phenytoin and warfarin; three criteria must
be met:
• high protein binding (if the drug is < 90% bound to plasma proteins, changes in protein
binding have little impact on the amount of unbound drug in circulation – i.e. the drug
 Drug metabolism during first and subsequent passes through the gastrointestinal tract and liver

Extensive inactivation in the liver Enhanced efflux from

Oxidation, conjugation during the first pass enterocytes by
(e.g. propranolol, morphine) P-glycoprotein

Liver Inactivation in the gut

lumen (e.g. insulin)
Drug Gut

Portal vein
Metabolites
Inactivation in the gut
wall (e.g. tyramine)
Biliary tract

Deconjugation and
reabsorption
Enterohepatic recirculation (e.g. oestrogens)
(e.g. oestrogens, warfarin)

that is available for distribution to the site of action)

• low Vd (if the distribution of the drug to the tissues is large, even total displacement of
the drug from protein-binding sites would be ‘mopped-up’ by the wide distribution to
the tissues)
• a change in binding (the action of a drug changes only when the protein binding
changes).
Factors that alter protein binding include hypoalbuminaemia (albumin < 25 g/litre), last-
trimester pregnancy (partly as a result of hypoalbuminaemia), renal failure (in which the
affinity of proteins for drugs appears to be altered) and displacement by other drugs. The
change in protein binding is likely to be sudden only when displacement by other drugs
has occurred. In the other cases, the changes are gradual and alone would not alter the
effects of drugs because the compensatory increase in the rate of clearance from the
body prevents the build-up of a high concentration of bound drug in the plasma. However,
these effects alter the relationship between the total plasma concentration of a drug and
its unbound concentration.
Drug metabolism
Most drugs are lipid soluble and must be biotransformed to more water-soluble products
before excretion in bile and/or urine. Inactivation of a drug is the most common effect
of metabolism. The principal site of drug metabolism is the liver; other organs (e.g. gut,
lung, kidney) can metabolize drugs to some extent. The metabolism of many substances
occurs in two phases – oxidation (I) and conjugation (II) (Figure 5).
A few pro-drugs (e.g. ciclosporin, enalapril, levodopa, cyclo-phosphamide, sulindac)
have no biological activity and require metabolic activation.

Oxidation
The enzymes responsible for oxidation and similar phase I reactions (mono-oxygenases,
mixed function oxidases) are located in the hepatic endoplasmic reticulum and are
collectively termed ‘cytochrome P450’. Phase I reactions may produce inert compounds,
but many oxidated metabolites have biological activity and occasionally a toxic moiety
(e.g. from paracetamol overdose) or a carcinogenic moiety (e.g. from cigarette smoke)
is formed. Products of phase I reactions may be excreted directly or further metabolized
by conjugation. The activities of phase I enzymes can be increased (induced) by enzyme
inducers (phenobarbitone, phenytoin, carbamazepine); this is the basis of some important
drug interactions.
 Drug metabolism

Molecular weight < 300 Kidney

Liver Urine
Oxidation Glucuronide
Phase I enzymes Dealkylation Phase II enzymes Sulphate
Drug Reduction Glutathione Conjugates
Hydrolysis N-acetyl
Bile

Molecular weight > 300 Gallbladder

Phase I enzymes catalyse the modification of existing functional groups in drug molecules (oxidation reactions)
Conjugating enzymes (phase II) facilitate the addition of endogenous molecules such as sulphate, glucuronic acid and glutathione

Conjugation
In the process of conjugation, an endogenous group (e.g. glucuronic acid, sulphate)
is added to the parent drug or to its oxidated metabolite. Almost all conjugates are
inert; a notable exception is morphine 6-glucuronide. Larger molecules are excreted in
the bile, and those with a molecular weight below 300 in the urine. Some metabolites
are deconjugated by bacterial flora in the gut lumen and the parent drug can then be
reabsorbed. Enterohepatic cycling occurs with some benzodiazepines and the oestrogenic
components of the oral contraceptive pill. Interruption of this recycling has been suggested
as a basis of the possible interaction of oral contraceptives with some antibiotics.

Factors affecting metabolism

Individuals have their own complement of enzymes with overlapping substrate specificities.
These enzymes are genetically controlled, but they are also affected by factors such as
age, nutritional status, disease, smoking (tobacco and marijuana), alcohol consumption
and concomitant drugs (Fuhr).

Age: drug metabolism is impaired in premature babies. Infants and young adults eliminate
drugs more rapidly than adults. Hepatic mono-oxygenase activity decreases gradually into
old age, but conjugation enzymes appear to be better maintained in the elderly.

Liver disease
Oxidation reactions are less efficient in the presence of severe liver disease and in
malnourished patients. Conjugation mechanisms are often preserved, however, even
in hepatic cirrhosis. Dose adjustment in patients with liver disease is crude, because
impairment of hepatic function relates poorly to changes in biochemical liver function
tests.

Pharmacogenetics
Drug metabolism that varies on a genetic basis is often called polymorphic drug metabolism
because multiple clinical groups with unique patterns of elimination have been identified
(Evans & McLeod). Early studies with isoniazid identified slow and fast acetylators in
whom the drug has different pharmacological and toxic effects. Slow acetylators have
a greater hypotensive response to hydralazine and increased susceptibility to lupus-like
syndrome.
In the UK, about 8% of individuals are unable to 4-hydroxylate debrisoquine (poor
metabolizers) and consequently exhibit an exaggerated hypotensive response to this
drug (which is now little used). Impaired metabolism of other drugs (e.g. nortriptyline,
perhexiline, metoprolol) is linked to this defect. This enzyme is also responsible for
activating codeine to morphine, and poor metabolizers do not experience pain relief after
administration of codeine. Many of these drugs are metabolized by several enzymes;
thus, the pharmacological response of poor metabolizers may not differ markedly from
that in normal individuals. However, poor metabolizers may produce a different metabolite
profile and may be at a greater risk of toxic effects with these agents.
For many polymorphic enzymes, the prevalence of poor metabolizers varies between
ethnic groups; for example, slow acetylators constitute 22% of Inuits, 91% of Egyptians
and 45% of the UK population. The molecular basis has been determined for many poor
metabolizer phenotypes, and DNA-based tests using polymerase chain reaction analysis
are available at research centres.
More recently, evidence has emerged for a clinically important influence of genetic
polymorphism on cellular transporters and cellular targets of drug therapy. Initial studies
have focused on therapy for HIV, cancer, depression and epilepsy, but transport and target
pharmacogenetics are likely to be important in many areas of medicine.

Excretion
Drugs are principally excreted via the kidneys. Some drugs are also excreted via the bile,
and a few have other routes of elimination. Rifampicin, for example, is excreted in tears
and sweat, and may cause these to turn orange; patients should be warned about this,
to avoid unnecessary alarm.
Alcohol is partly eliminated via the lungs, giving the breath a distinct odour.

Renal excretion
Drugs are handled by the kidneys in three main ways.
• All drugs are filtered at the glomerulus.
• Some are actively secreted in the proximal tubule.
• Some are passively reabsorbed in the distal tubule.
Some drugs may undergo all three processes.
Active secretion increases the rate of renal clearance of drugs and passive reabsorption
reduces it; renal clearance is therefore equal to the sum of the rates of elimination by
filtration and secretion minus the rate of reabsorption. Only drug molecules that are not
protein bound in the plasma can be filtered; the clearance of drug by filtration is therefore
equal to the unbound fraction multiplied by the glomerular filtration rate.
The renal tubular system can actively secrete drugs. Separate transport systems exist for
acids (e.g. penicillins, cephalosporins) and bases (e.g. amiloride, ethambutol). Competition
occurs between drugs utilizing these systems. Probenecid increases circulating levels
of penicillins and cephalosporins and potentiates methotrexate toxicity by reducing their
tubular secretion. Cimetidine can also have a role in blocking tubular secretion.

In patients with renal impairment, doses of drugs that are usually excreted at least 50%
unchanged by the kidneys should be reduced; these drugs include digoxin, aminoglycoside
antibiotics, lithium, procainamide, methotrexate, cisplatin, carboplatin, trimethoprim and
methyldopa. Reduction in both the frequency of administration and individual doses may
be required (e.g. for aminoglycoside antibiotics, peak and trough plasma concentrations
both relate to toxicity); in these situations, therapeutic drug monitoring is often used to
tailor the dose.

Biliary excretion
Drugs are also excreted by hepatocytes into the bile, usually in conjugated form. Metabolites
with a molecular weight of more than 300 are likely to follow this route. Biliary excretion
provides a back-up pathway when renal function is impaired. Reabsorption of biliary
excreted drugs may lead to an enterohepatic cycle, which can prolong their action (e.g.
some benzodiazapines). Recycling of warfarin and digitoxin can be interrupted by resins
(e.g. cholestyramine), which bind them and thereby increase the rate of elimination.

Therapeutic drug monitoring

Measurement of drug concentrations in human plasma, serum and whole blood is a useful
tool for guiding the safe and effective use of many medications (Van Heeswijk). Therapeutic
drug monitoring is applied to various therapeutic classes of agents that:
• have a high degree of pharmacokinetic variability in the relevant patient population
• exhibit a relationship between blood concentration and toxic or therapeutic effect
• have a narrow therapeutic index
• are detectable by a rapid, accurate and reproducible assay.
At present, the indications for therapeutic drug monitoring focus on the prevention of
severe or life-threatening toxicity (e.g. acute renal failure from gentamicin, CNS toxicity
from phenytoin). There is a therapeutic basis for its use with most drugs, but it is prevention
of toxicity that makes the analysis cost-effective and justifiable in the current economic
environment.
Most commonly monitored medications are antibiotics, including aminoglycosides and
vancomycin. Anti-epileptics (phenytoin, carbamazepine, valproic acid, phenobarbitone),
lithium, digoxin, ciclosporin and theophylline are also commonly monitored. Plasma or serum
is the matrix of choice for most medications, but with some drugs (e.g. ciclosporin) whole
blood is used to give a better indication of cellular accumulation. Trough concentrations
(immediately before the next dose) are associated with toxicity in many medications. Peak
concentrations (usually obtained 1 hour after bolus injection or oral administration) predict
efficacy for some antibiotics. 

REFERENCES
Evans W E, McLeod H L. Pharmacogenomics – Drug Disposition, Drug Targets, and
Side Effects. N Engl J Med 2003; 348: 538–49.
Fuhr U. Induction of Drug Metabolizing Enzymes: Pharmacokinetic and Toxicological
Consequences in Humans. Clin Pharmacokinet 2000; 38(6): 493–504.
Lin J H, Yamazaki M. Role of P-glycoprotein in Pharmacokinetics: Clinical Implications.
Clin Pharmacokinet 2003; 42(1): 59–98.
Schmidt L E, Dalhoff K. Food–Drug Interactions. Drugs 2002; 62(10): 1481–502.
Van Heeswijk R P. Critical Issues in Therapeutic Drug Monitoring of Antiretroviral
Drugs. Ther Drug Monit 2002: 24(3): 323–31.

FURTHER READING
Clark B, Smith D A. An Introduction to Pharmacokinetics. Oxford: Blackwell Scientific,
1986.
Derendorf H, Hochhaus G. Handbook of Pharmacokinetic/Pharmacodynamic
Correlation. Oxford: CRC Press, 1995.
Rowland M, Tozer T N. Clinical Pharmacokinetics: Concepts and Applications. 3rd ed.
Philadelphia: Lea & Febiger, 1995.

Copyright © 2003 The Medicine Publishing Company Ltd

Drug Metabolism
Gabrielle M Hawksworth is Professor of Molecular Toxicology in the Departments of
Medicine and Therapeutics and Biomedical Sciences at the University of Aberdeen, UK.

Most pharmacologically active drugs are lipophilic and are metabolized to some extent.
To be excreted from the body, lipophilic drugs must be metabolized to water-soluble
products, which are not readily reabsorbed by the kidney. In some cases (pro-drugs,
e.g. azathioprine, enalapril, L-dopa, zidovudine, cyclophosphamide), metabolism
is required for therapeutic effect. For most, however, metabolism leads to loss of
therapeutic effect. In some drugs (e.g. paracetamol), metabolism may result in toxicity if
the detoxifying pathways are saturated at high drug doses.
The cytochrome P450 isoforms and other enzymes involved in major metabolic
routes will have been determined for newly licensed drugs, and adverse drug
interactions caused by altered metabolism are thus less likely to occur. For existing
drugs, however, knowledge of the routes of metabolism is essential. Despite the
abundance of papers in the medical literature, predictable adverse metabolic drug
interactions continue to occur.

Drug-metabolizing enzymes in humans

Drug metabolism is usually divided into two phases – phase I involves drug oxidation
and phase II involves conjugation of drugs with endogenous compounds. The liver
is the principal organ involved in drug metabolism; most of phase I metabolism is
catalysed by the mixed-function oxidase system, of which cytochrome P450 is the main
component. P450-dependent metabolism in the liver is the major source of differences
between individuals in response to drugs and is responsible for several adverse drug
interactions.
Terfenadine–ketoconazole is the most well known P450-related interaction. It
was first described in 1990, in a patient on the recommended prescribed dose of
terfenadine in addition to cefaclor, ketoconazole and medroxyprogesterone. She
developed symptomatic torsade de pointes, and excessive levels of parent terfenadine
and proportionately reduced levels of metabolite were found in her serum, suggesting
inhibition of terfenadine metabolism. Subsequently, this interaction was shown to
be predictable – terfenadine is metabolized by an isoform of P450 that is selectively
inhibited by ketoconazole. Other compounds (e.g. a constituent of grapefruit juice)
also inhibit this isoform. These findings led to the issue of warnings with terfenadine,
and subsequently to withdrawal of the drug; the active metabolite fexofenadine, which
has antihistamine activity, is now prescribed instead. Regulatory bodies (e.g. the UK
Committee on Safety of Medicines, the US Food and Drug Administration) now require
information on which isoforms of cytochrome P450 are involved in the metabolism of
drugs submitted for registration.
Isoforms of P450 – P450 is a large superfamily of proteins, synthesis of which is
controlled by a superfamily of genes. Isoforms of the families CYP1, CYP2 and CYP3
are responsible for drug metabolism. Within these families, six isoforms (CYP1A2,
CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4) are involved in the metabolism
of a large proportion of drugs in humans; CYP3A4 is responsible for most P450-
mediated metabolism. These isoforms show selectivity for different drugs; some
commonly used drugs are metabolized mainly by one or two P450 isoforms (Figure 1).
CYP3A4 can metabolize a wide variety of chemically heterogeneous drugs, whereas
the substrate requirements for metabolism by other P450s is more restricted.

First-pass metabolism
Metabolism of some drugs is markedly dependent on the route of administration. Drugs
administered orally gain access to the systemic circulation via the hepatic portal vein;
thus, the entire absorbed dose is exposed first to the intestinal wall and then to the
liver. Extensive first-pass metabolism occurs when a high proportion of the parent drug
is removed in this first pass through the liver; low bioavailability and marked between-
individual variation in blood concentrations of drug result. This may be avoided
by administering the drug sublingually (e.g. glyceryl trinitrate). In other cases (e.g.
lignocaine, propranolol), response to therapy may be highly variable, with problems in
clinical use.
 Drug substrates, inhibitors and inducers of the major human cytochrome P450 isoforms

P450 isoform Substrate Inhibitor Inducer

CYP1A2 Caffeine, imipramine, paracetamol, R-warfarin, Fluvoxamine Charcoal-broiled beef
verapamil, estradiol, theophylline Furafylline Cigarette smoke
Omeprazole

CYP2A6 Coumarin, nicotine, testosterone Barbiturates

Dexamethasone

CYP2B6 Cyclophosphamide, testosterone, mianserin Orphenadrine

CYP2C8 Carbamazepine, taxol

CYP2C9 Diazepam, diclofenac, ibuprofen, phenytoin Sulphaphenazole

Piroxican, S-warfarin Sulphinpyrazone

CYP2C19 Diazepam, hexobarbital, imipramine, lansoprazole

Omeprazole, proguanil, propranolol

CYP2D6 Amitriptyline, clomipramine, codeine

Desipramine
Flecainide, fluoxetine, imipramine, Quinidine
metoprolol, mexiletene
Mianserin, nortriptyline, paroxetine, propafenone,
propranolol, timolol, trifluperidol

CYP2E1 Caffeine, dapsone Ethanol

Enflurane, ethanol, halothane, theophylline Disulfiram Isoniazid

CYP3A4 Alfentanil, amiodarone, carbemazepine Clotrimazole, Carbemazepine

Cyclophosphamide, ciclosporin, dapsone, digitoxin gestodene , Dexamethasone
Itraconazole,
ketoconazole,
miconazole
Diltiazem, diazepam, erythyromycin, ethinylestradiol Omeprazole
Etoposide, imipramine, lansoprazol Phenobarbital
Lignocaine, losartan, lovastatin, simvastatin, Phenytoin
atorvastatin, midazolam, nifedipine
Omeprazole, quinidine, retinoic acid Rifampicin
Saquinavir, efavirenz, nevirapine, tacrolimus,
taxol, terfenadine
Theophylline, triazolam, verapamil, R-warfarin

1
Induction/inhibition of metabolism
Induction is a process by which enzyme activity is enhanced as a result of
increased enzyme synthesis. P450 isoforms show selectivity of induction (e.g.
rifampicin selectively induces CYP3A4). A practical consequence of enzyme induction
is that, when two or more drugs are given simultaneously, the inducer accelerates
the metabolism of the other drugs. Both licensed drugs and herbal medicines (e.g. St
John’s wort) have been shown to have clinically significant interactions.
Inhibition – several drugs (e.g. methotrexate, angiotensin-converting enzyme
inhibitors, non-steroidal anti-inflammatory drugs) exert their therapeutic effect
by enzyme inhibition. However, inhibition of drug metabolism by a concurrently
administered drug can lead to drug accumulation and toxicity. Some inhibitors are
selective for P450 isoforms (e.g. ketoconazole), whereas others (e.g. cimetidine) inhibit
all cytochrome P450-mediated metabolism. Inhibition of metabolism can also occur
when two concurrently administered drugs are substrates for the same isoform of a
drug-metabolizing enzyme.
Several of these interactions have been described for statins and antiviral drugs that
are substrates for CYP3A4.
Genetic polymorphisms
Genetic polymorphisms lead to between-individual variation in drug response; the
population is divided into ‘poor metabolizers’ and ‘extensive metabolizers’, in whom
the standard dose of a drug may lead to higher-than-normal blood concentrations
or apparent non-response, respectively. Several P450 isoforms (notably CYP2D6,
CYP2E1, CYP2C19 and CYP3A5) are expressed polymorphically in humans; this
may be important therapeutically when the drug metabolized by these isoforms has a
relatively narrow therapeutic window. Ethnic differences are seen in the incidence of
polymorphisms. A polymorphism of thiopurine methyl transferase that occurs in about
10% of Caucasian populations affects treatment with azathioprine and mercaptopurine.
It is possible to genotype patients for the known polymorphisms of cytochrome P450
and other drug-metabolizing enzymes, and hence predict phenotype; this could be
used to individualize therapy, but it is unlikely to occur in clinical practice. 

Further Reading
Bolego C, Baetta R, Bellosta S et al. Safety Considerations for Statins. Curr Opin
Lipidol 2002; 13: 637–44.
Dresser G K, Bailey D G. A Basic and Conceptual and Practical Overview of
Interactions with Highly Prescribed Drugs. Can J Clin Pharmacol 2002; 9: 191–8.
Garattini S. Drug Metabolism: From Experiments to Regulatory Aspects. Drug Metab
Rev 1997; 29(3): 853–86.
Ma M K, Woo M H, McLeod H L. Genetic Basis of Drug Metabolism. Am J Health Syst
Pharm 2002; 59: 2061–9.
Murphy P A. St John’s Wort and Oral Contraceptives: Reasons for Concern? J
Midwifery Womens Health 2002; 47: 447–50.
Rogers J F, Nafziger A N, Bertino J S. Pharmacogenetics affects Dosing, Efficacy and
Toxicity of Cytochrome-P450 Metabolized Drugs. Am J Med 2002; 113: 746–50.

Practice points
• Be aware of the major routes of metabolism of drugs prescribed
• Be aware of metabolic interactions in patients taking two or more drugs
• With complex drug regimens (e.g. transplant patients), leave dose adjustment in drug
therapy to specialist centres

Copyright © 2003 The Medicine Publishing Company Ltd

 Practical Prescribing
D John Reynolds is Consultant Physician and Clinical Pharmacologist at Oxford
Radcliffe Hospitals NHS Trust, Oxford, UK, and Honorary Senior Clinical Lecturer in
the University of Oxford.

Until recently in the UK, prescribing of drugs to patients was the sole responsibility of
doctors and dentists, but that is changing as other health-care professionals are given
statutory powers to prescribe. The process of prescribing is surprisingly complex and is
underpinned by several principles that all prescribers must understand. To highlight the
more important steps involved, this contribution considers a simple scenario of the type
that is seen in general practice thousands of times every day.

The consultation
Mrs G is a 78-year-old woman who has noticed that, over the last year, she has
developed pain in both knees when she walks. The right is worse than the left, and
occasionally she has mild swelling in that knee.
Establishing the diagnosis – before any decisions about treatment are made,
the doctor must establish what condition the patient has and what other conditions
and factors may be relevant. On examination, you find that Mrs G has moderate
osteoarthritis, but before you reach for your prescription pad you must establish more
information.
Patient expectations – what does Mrs G want from the consultation? Is she
sufficiently troubled by pain to want active treatment, or does she simply want
reassurance that her problem is caused by ‘wear and tear’ and is nothing more
serious? Many patients are satisfied just to know what is wrong, and may initially decide
against active treatment once they are reassured.
If Mrs G wants treatment, how does she feel about taking tablets? Would exercise
or physiotherapy be more appropriate and acceptable? Is she realistically able to lose
weight to reduce the burden on her joints? It is all too easy to end the consultation by
prescribing a drug without exploring other ways of managing the problem.
What else has the patient tried? – remember to ask whether the patient has used
any over-the-counter medicines to alleviate the symptoms. Ask directly about herbal
and traditional remedies. Patients often fail to mention treatments of which they think
the doctor might not approve. It transpires that Mrs G has tried a friend’s glucosamine
tablets, with some benefit.
How severe is the problem? – do not assume that, by coming to see you, Mrs G
has decided that her problem needs drug treatment. You must determine how severe
the pain is and how much it restricts her daily activities. Remember that, with symptoms
such as pain, the severity is what the patient tells you it is – not what you judge it to be.
Is Mrs G’s pain an acute flare-up or a chronic problem? For how long is any treatment
likely to be necessary?

What are the risks and benefits of drug treatment?

To make a balanced judgement about risks and potential benefits, you need further
information about the individual patient.
Co-morbidity – are there any features that might render the patient more
susceptible to drug side-effects (Figure 1)? You learn that Mrs G has a history of heart
failure secondary to hypertension. Her symptoms are well controlled. She suffered a
duodenal ulcer 25 years ago, but has never required admission to hospital.

Factors that predispose to adverse drug reactions

• Age – adverse reactions are more common in the elderly and the very young
• Gender – women are at greater risk
• Race – pharmacogenetic variations result in many adverse drug reactions and
interactions
• History of allergy or previous adverse drug reaction
• Renal impairment
• Hepatic impairment
• Heart failure
• Nutritional status
• Multiple drug therapy – predisposes to drug interactions

1
 Other medications – what other medications is Mrs G taking? The potential for
drug interactions is significant, though the most serious usually involve drugs for which
the margin between therapeutic and toxic effects is narrow (e.g. warfarin, theophylline,
digoxin, anticonvulsants). If you are in any doubt or are unfamiliar with a drug, get
further information. The British National Formulary contains an excellent appendix on
drug interactions. Mrs G is taking furosemide, 40 mg once daily, lisinopril, 20 mg once
daily, and atenolol, 25 mg once daily.
Patient’s previous experience – many patients express a preference for drugs
that have helped them in previous, similar circumstances, and have no faith in others
that were not effective (“paracetamol doesn’t work for me, doctor”). What has Mrs G
preferred to use for analgesia in the past?
Drug allergies and intolerances – always ask whether the patient is allergic to
or intolerant of any medicines. Mrs G should be asked specifically about previous
exposure to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), if you are
considering these for her arthritis. She reports that she felt light-headed when she took
codeine phosphate for recent back pain.

Choosing the right drug

If you and Mrs G agree that drug treatment is indicated, you must make several
decisions based on what you know about the patient, her condition and the drugs
available. In effect, you are calculating a benefit:harm ratio, for which you need to judge
the evidence in each of the following areas.
• How serious is the condition?
• How effective are the drugs available?
• What are the side-effects of the drugs available, including their incidence and
severity?
• Are there any ways in which this patient might differ significantly from the population
studied in published trials?
Choosing the most appropriate class of drug – Mrs G suffers pain and needs
an analgesic agent. The main classes of drugs to consider are aspirin and the
NSAIDs, paracetamol, and paracetamol combined with a minor opioid. The NSAIDs
can be further subdivided into non-selective and COX-2-selective agents. There is
good evidence that NSAIDs are more effective for the relief of acute pain than both
paracetamol alone and paracetamol-combination drugs, but in chronic pain the
evidence is less clear. The main difference between these drugs is their associated
side-effects.
• Paracetamol is well tolerated and has no major common interactions with other
drugs, with the notable exception of warfarin. (Although paracetamol is commonly
perceived as a safe drug to use with warfarin, it is clear that, when taken chronically,
it augments the anticoagulant effect, often requiring warfarin dose adjustment.) The
principal problem with paracetamol is that it must be taken four times daily for maximal
effect.
• Aspirin and the NSAIDs have significant side-effects including upper gastrointestinal
haemorrhage and perforation, which may be fatal. The excess risk of death in
patients taking a non-selective NSAID for 2 months or longer is about 1/2000, but is
substantially higher in certain groups. In the UK, about 2000 patients per year die from
haemorrhage or perforation as a direct result of NSAID use. Mrs G is in a high-risk
group because she is over 65 years of age and has a history of peptic ulcer disease. In
addition, her heart disease means that she is at high risk of a less favourable outcome
if she develops bleeding or perforation.
• COX-2-selective NSAIDs were developed in response to these problems with
NSAIDs, and in the short term at least are associated with significantly fewer upper
gastrointestinal side-effects. In 2002, the UK National Institute for Clinical Excellence
(NICE) recommended use of COX-2-selective NSAIDs in patients at high risk of
bleeding or perforation. However, NSAIDs may also impair renal function and can
exacerbate heart failure, and recent evidence suggests that significant episodes of
NSAID-related renal and heart failure may be more common than upper gastrointestinal
bleeding and perforation. COX-2-selective agents are not free from these effects, and
their use may be inadvisable even in the high-risk groups defined by NICE. Mrs G has
heart failure and use of an NSAID is therefore best avoided.
• Paracetamol with a minor opioid (e.g. codeine, dextropropoxyphene) is less effective
than NSAIDs in acute pain, but when used chronically the plasma concentration of
the opioid rises and the efficacy increases. Caution is required in the elderly, however,
because opioid drugs may cause unsteadiness, confusion and drowsiness. They also
tend to cause constipation.
 If Mrs G is happy to take a drug three or four times each day, paracetamol seems
the safest initial treatment; NSAIDs are the least attractive. If paracetamol proves
insufficient, it is probably better to change to paracetamol combined with a minor opioid
than to an NSAID, though care will be needed because Mrs G has been intolerant of
codeine in the past. If an NSAID is used, a COX-2-selective drug is likely to be safer,
but careful monitoring will be needed to ensure that Mrs G does not develop renal
impairment or worsening heart failure.
Choosing a specific drug – the specific agent to advise must now be chosen.
Most prescribers familiarize themselves with only one or two drugs from each class of
agents.
Dose – in general, the dose prescribed should be in line with that recommended
in the product licence. It is a good ‘rule of thumb’ to start any new drug at the lowest
dose available and titrate upwards depending on efficacy and side-effects. In certain
situations, dose adjustments must be made to avoid side-effects. Particular care is
needed in patients with hepatic and/or renal impairment, in the elderly and in children.
Route of administration (Figure 2) – most drugs are taken orally as tablets, but
alternative approaches are sometimes required. Mrs G could consider use of a topical
NSAID instead of oral paracetamol. This would reduce the risks of treatment, but
probably at the expense of lower efficacy and greater cost.
Duration of therapy – Mrs G’s treatment is likely to be required long term, but drugs
are often given for a specific duration. Always set a stop date, or make an early review
appointment for appropriate monitoring and re-evaluation. Mrs G should be given no
more than 1 month’s supply of treatment initially.

Routes of administration of drugs

Route Examples Rationale

Gastrointestinal tract
• Buccal, sublingual Glyceryl trinitrate Rapid absorption, and to avoid first-pass metabolism
• Oral Most agents Ease of use; must be lipid soluble to ensure reliable absorption
• Rectal Metronidazole Good absorption as an alternative to oral route if patient
cannot swallow (e.g. postoperative)
By injection
• Subcutaneous Morphine Swift onset of action
• Intradermal
• Intramuscular Prochlorperazine As an alternative to intravenous injection or for depot
preparations
• Intravenous Cefuroxime For drugs unreliably absorbed orally and/or when high plasma
concentrations needed rapidly
• Intrathecal Methotrexate For local effect avoiding systemic toxicity
• Intracavity

Topical (skin, eye, ear, nose, inhaled) – given for local effect, and to avoid systemic toxicity; can also use
drugs with low systemic bioavailablity

Monitoring drug therapy

Benefits – it is easy to start a drug and then assume that the problem has been
solved, particularly in asymptomatic conditions such as moderate hypertension and
hyperlipidaemia. However, the true end-point of stroke or heart disease may not
become apparent for years, and it is therefore essential to monitor a measurable
surrogate end-point (e.g. blood pressure, cholesterol concentration) to ensure that the
drug is achieving the desired effect.
Mrs G can monitor her treatment by assessing the degree of pain she suffers or
whether there is any functional improvement (e.g. in the distance she can walk). If
she is uncertain of any benefit, she should be encouraged to discontinue therapy and
determine whether her symptoms worsen. There is no point in Mrs G taking a drug from
which she derives no benefit, yet patients are often prescribed multiple drugs for no
clear continuing indication.
 Side-effects – all prescribers must ensure that they minimize potential adverse
effects and monitor for them when appropriate. Mrs G has impaired left ventricular
function secondary to hypertension and is taking three drugs. The safest option for
her pain relief is paracetamol, with which significant adverse effects are very unlikely.
If paracetamol proves inadequate and an NSAID is considered, however, there are
several potential problems for which both Mrs G and her prescriber must be vigilant.
She should be warned about the potential for fluid retention and worsening heart
failure, so that if she becomes more breathless or develops oedema she can seek help
promptly. Before prescribing an NSAID in this situation, it would be prudent to check
Mrs G’s renal function and electrolytes, and to repeat the blood tests after 2 weeks.

Prescribing in special situations

The pharmacokinetics and pharmacodynamics of many drugs are significantly affected
by pathophysiological changes in renal failure and liver diease, and by the physiological
changes of pregnancy. Use of drugs in pregnancy and in lactating mothers carries
specific risks for the developing fetus and newborn child. Always refer to a reference
text before using any drug with which you are not entirely familiar in any such setting.

Cost and cost-effectiveness

Doctors have a legal obligation to provide the treatments that their patients need,
but they are obliged to do so within available financial resources. NICE is a source
of guidance for the NHS, based on clinical effectiveness and cost-effectiveness. In
addition, most Primary Care Trusts and Hospital Trusts provide local clinicians with up-
to-date information to guide them in choosing medicines. The most expensive medicine
may be the one that the patient does not take, and involving patients in informed
decision-making and subsequent monitoring is central to good prescribing. 

FURTHER READING
British National Formulary. London: British Medical Association, Royal Pharmaceutical
Society of Great Britain.
Firth J D, Reynolds D J M. Scientific Background to Medicine 2. Oxford: Blackwell
Science, 2001.
Grahame-Smith D G, Aronson J K. Oxford Textbook of Clinical Pharmacology and
Drug Therapy. 3rd ed. Oxford: Oxford University Press, 2002.
National Institute for Clinical Excellence. www.nice.org.uk

Copyright © 2003 The Medicine Publishing Company Ltd

Adverse Drug Reactions
R E Ferner is Consultant Physician at City Hospital, Birmingham, UK, Honorary Senior
Lecturer in Clinical Pharmacology at the University of Birmingham, and Director of the
West Midlands Centre for Adverse Drug Reaction Reporting.

What’s new ?

• Thioridazine, cisapride and droperidol have been identified as causes of QT

prolongation and torsade de pointes
• Antiretroviral protease inhibitors (e.g. indinavir, ritonavir, saquinavir) are associated
with a ‘metabolic syndrome’ of abnormal fat distribution and diabetes
• Serotonin syndrome can be caused by selective serotonin re-uptake inhibitors,
particularly in combination with other drugs (e.g. pethidine, tramadol)

Adverse drug reactions (ADRs) are important but often difficult to diagnose. They
should be considered in the differential diagnosis of a wide range of conditions.
Detecting and reporting ADRs makes prescribing safer and more likely to achieve its
aims.

Definitions
Adverse drug reaction is ‘a response to a drug that is noxious and unintended and
which occurs in doses normally used for the treatment, prophylaxis, or diagnosis of
disease, or the modification of physiological function’ (WHO).
Adverse drug event is any adverse event that occurs while a patient is taking a
given drug. It is not necessary to determine whether the event was a response to the
drug.
Side-effect is any effect caused by a drug other than the intended therapeutic effect,
whether beneficial, neutral or harmful. The term is sometimes taken to be synonymous
with ‘adverse drug reaction’, and is sometimes used to describe ‘minor’ and predictable
ADRs (e.g. constipation with opiates).

Epidemiology
ADRs affect about 7% of medical in-patients; one-half of reactions occur before
admission. One study suggested that, in the USA, more than 100,000 patients per year
die from ADRs.

Mechanisms
The mechanisms of many ADRs are unknown. Known mechanisms are predominantly
pharmacological or immunological.

Pharmacological ADRs
Direct effects – pharmacological ADRs are sometimes an inevitable consequence
of the therapeutic action of the drug. An example is the occurrence of hypoglycaemia
with insulin; a patient’s usual dose can provoke hypoglycaemia if his or her food intake
is reduced or exercise increased, or if the absorption of insulin is increased by, for
example, an increase in blood flow. Vasodilatation from artificial tanning devices can
lead to ‘sun-bed hypoglycaemia’.
Collateral effects – adverse pharmacological consequences of drug treatment
can arise when a drug exerts its therapeutic action at a receptor or locus that is also
present elsewhere. For example, β-adrenoceptor antagonists given after myocardial
infarction act on the heart to reduce heart rate and the risks of arrhythmia, but also
act on β-adrenoceptors in peripheral arteries and can consequently worsen peripheral
vascular disease. ‘Collateral damage’ from broad-spectrum antibacterial agents
(particularly cephalo-sporins and clindamycin) can alter the bowel flora and increase
the risk of overgrowth by toxigenic Clostridium difficile; as a result, the patient develops
pseudomembranous colitis.
Many drugs act at more than one receptor type. For example, the therapeutic effect
of tricyclic antidepressants results from stimulation of monoaminergic pathways by a
reduction in monoamine re-uptake, but the drugs also have antimuscarinic activity.
 This is responsible for adverse effects such as dry mouth, constipation and retention
of urine. Advances in molecular biology have revealed the existence of many more
receptor subtypes than previously imagined, so more specific drugs may become
available in the future.

Immunological ADRs are grouped into the four classical types of Gell and Coombs.
Important examples are listed in Figure 1. Anaphylactoid reactions are caused
by inflammatory mediators released in response to pharmacological rather than
immunological stimuli, and can appear similar to anaphylactic reactions. Iodinated
contrast media, acetylcysteine infusion and modified gelatin plasma expanders can all
cause anaphylactoid reactions. Angiotensin-converting enzyme (ACE) is responsible
for degradation of the inflammatory mediator bradykinin, and it is thought that ACE
inhibitors predispose patients to angioedema by inhibiting bradykinin breakdown.

Adverse drug reactions with an immunological basis

Immunological reaction Examples

Type I – immediate hypersensitivity Anaphylaxis and urticaria with penicillins
(e.g. interaction between drug and native
protein produces a new, antigenic molecule)

Type II – cytotoxic antibody Haemolysis with methyldopa

Drug alters a membrane-bound protein; Thrombocytopenia with quinine
cytotoxic antibodies bind to the altered protein
and complement-mediated cell lysis occurs

Type III – immune complex Serum sickness with horse-derived antitetanus

Persistent foreign protein molecules cause serum and snake antivenins
antibody synthesis; immune complexes are
formed and damage tissues

Type IV – delayed hypersensitivity Erythema nodosum with sulphonamides

Delayed cell-mediated reactions Stevens–Johnson syndrome with carbamazepine
Phenytoin hypersensitivity

Susceptibility
Individuals can be susceptible to rare ADRs because of a genetic abnormality that
alters either their handling of the drug or their physiological response to it.

Abnormal drug metabolism: drug metabolism is important for two reasons.

• The effects of a drug are related to the amount present at the site of action, so
changes that alter the rate of metabolism also alter the extent and duration of effects
and adverse effects.
• The route of metabolism can influence the toxicity of a compound, by affecting the
production of potentially harmful metabolites.
Cytochrome P450 system – the most important drug metabolic enzymes are
the hepatic microsomal oxidases (the cytochrome P450 system). About sixty such
enzymes are known; the most important cytochrome P450s for drug metabolism
are CYP2D6 and CYP3A4. The ‘poor-metabolizer’ phenotype CYP2D6 is present
in about 8% of the population in the UK, in about 1% of Arabs and in 30% of Hong
Kong Chinese. Poor metabolizers exhibit reduced rates of metabolism of debrisoquine
(an obsolete antihypertensive), metoprolol, propranolol, haloperidol, amitriptyline,
nortriptyline, flecainide and propafenone. CYP3A4 is the major enzyme responsible
for the metabolism of nifedipine, amiodarone and carbamazepine. Poor metabolizers
can suffer adverse effects as a result of the increased concentration of the drug, or
the increased duration of exposure. With drugs such as carbamazepine, impaired
metabolism increases the concentration of toxic metabolites and the poor-metabolizer
phenotype may be associated with reactions such as hepatitis or Stevens–Johnson
syndrome, which are related to metabolite concentrations.
 Abnormal responses to drugs
Glucose-6-phosphate dehydrogenase (G6PD) deficiency – genetically abnormal
responses to drugs include X-linked deficiency of G6PD. This enzyme is responsible for
the oxidation of glucose-6-phosphate to the corresponding gluconolactone, generating
reduced NADPH in the process. NADPH protects RBCs from oxidative damage, and
in G6PD-deficient individuals, drugs that are oxidizing agents can cause haemolysis,
which can be fatal. More than 200 genotypes of the enzyme have been described;
the phenotype varies from a small increase in susceptibility to exquisite sensitivity to
oxidizing agents. Examples of relevant drugs are listed in Figure 2.

Some drugs that can cause haemolysis in patients with reduced glucose-
6-phosphate dehydrogenase activity
Antimalarials and related drugs
• Chloroquine (‘acceptable in acute malaria’ – British National Formulary)
• Quinine (‘acceptable in acute malaria’ – British National Formulary)
• Quinidine
• Primaquine
• Dapsone

Sulphonamides
• Co-trimoxazole
• Sulfamethoxazole
• Sulfasalazine

Other antibacterials
• Nitrofurantoin
• Ciprofloxacin
• Ofloxacin
• Other quinolones
• Nalidixic acid

Vitamins
• Vitamin C (ascorbic acid)
• Vitamin K as menadiol sodium phosphate

Analgesics and local anaesthetics

• Aspirin
• Paracetamol
• Benzocaine

Others
• Isosorbide dinitrate
• Methylene blue dye

Porphyria – acute intermittent porphyria is an autosomal dominant disorder

characterized by recurrent attacks of abdominal pain, neurological disturbance and
excessive amounts of δ-aminolevulinic acid and porphobilinogen in the urine. It is often
provoked by drug therapy. An extensive list of drugs that can precipitate the painful and
life-threatening crises is given in the British National Formulary.

Other factors: susceptibility to ADRs is also a function of age, sex, coexistent disease
and co-ingestion of other drugs, all of which can affect both the pharmacokinetics and
pharmacodynamics of drugs.

Detection and diagnosis

When an adverse event occurs during or after drug treatment, it may be a result of the
drug, or of the disease for which the drug was taken, or it may have another, unrelated
cause. In the simplest case, the reaction is closely linked to the drug in time, and the
problem resolves when the drug is stopped (‘de-challenge’) and re-emerges when
 the drug is restarted (‘re-challenge’); this seldom occurs in practice. Some reactions
(e.g. teratogenesis) occur long after exposure, some (including fatal reactions) are
irreversible, and some occur only when there is a conjunction of a particular set of
circumstances and do not recur at re-challenge. It is helpful to know whether the event
is likely to occur with the underlying disease, whether it has previously been reported
with the drug in question, and, if not, whether it might be predicted from what is known
of the drug’s structure and mode of action.
It is impossible to establish the large randomized trials that would be needed to
explore all likely and relevant adverse effects. Their detection depends heavily on
spontaneous reporting (e.g. the UK Yellow Card scheme), stimulated post-marketing
surveillance (e.g. the Drug Safety Research Unit’s Green Card scheme) and case-
control studies of the proportion exposed and unexposed to the drug in groups with and
without the condition.

Common and important syndromes induced by drugs

CNS: acute toxic confusion is a common clinical problem that is manifest as
disorientation, hallucinations and altered consciousness. The risk of acute toxic
confusion (‘delirium’) is greater in patients who already have cognitive impairment,
notably the elderly and those with incipient hepatic encephalopathy. It can occur
as a consequence of drug administration, and as part of the withdrawal syndromes
for ethanol, benzodiazepines and other sedative drugs. With ethanol, symptoms of
psychomotor agitation, tremor, sympathetic activation, hallucination and seizure are
manifest within 1 or 2 days of cessation of drinking. Major causes of drug-induced
acute toxic confusion are listed in Figure 3.

Some drugs that can cause acute toxic confusion

Administration
• Anticholinergic drugs, including tricyclic antidepressants, oxybutynin and tolterodine
• Antiparkinsonian agents, including those containing L-dopa, and dopamine agonists
• Cannabis and nabilone
• Corticosteroids in supraphysiological doses (‘steroid psychosis’)
• Digoxin
• Histamine H2-antagonists and proton pump inhibitors
• Opioids, including dihydrocodeine, pentazocine and tramadol
• Stimulant drugs of abuse, including amfetamines, cocaine and ecstasy

Withdrawal
• Barbiturates
• Benzodiazepines
• Ethanol

Respiratory system
Asthma – drugs can cause both acute and chronic respiratory disease. Asthma
induced by β-adrenoceptor antagonists remains a concern, and these drugs should not
be used in patients with moderate or severe airways obstruction. The benefits after MI
may outweigh the risks in patients with mild asthmatic symptoms. Aspirin for secondary
prevention of cardiovascular disease and non-steroidal anti-inflammatory drugs
(NSAIDs) for analgesia may worsen asthma. About 10% of asthmatic patients develop
bronchospasm after challenge with aspirin, but most such patients know that they are
susceptible. It is therefore necessary to ask whether the patient is ‘allergic’ to aspirin or
similar drugs, but not to withhold treatment for those with asthma who lack a history of
aspirin or NSAID sensitivity.
Pulmonary fibrosis is classically associated with cytotoxic agents (particularly
busulfan and bleomycin) and the antibacterial agent nitrofurantoin. Lung disease
develops in about 5% of patients treated with the anti-arrhythmic amiodarone; this
drug can cause early hypersensitivity pneumonitis, and a more chronic fibrotic reaction
associated with dense nodules in the lung periphery that is thought to result from
deposition of iodine from the drug in clusters of pulmonary macrophages (Figure 4).
Some patients (particularly those in whom pneumonitis predominates) recover with
 4 High-resolution CT scan of
the thorax in a patient who
suffered increasing shortness of
breath while taking amiodarone,
200 mg daily, to suppress
ventricular tachycardia. There
is widespread interstitial fibrosis
(‘honeycomb lung’).
corticosteroids, but amiodarone-induced pulmonary fibrosis can be fatal.
There is increasing recognition of pulmonary fibrosis associated with ergot alkaloids
and derivatives, including bromocriptine and pergolide, and with methotrexate.

Gastrointestinal tract
NSAIDs – drugs that non-selectively inhibit prostaglandin synthesis increase the rate
of peptic ulcer bleeding and complications in treated patients. Ibuprofen in standard
doses is less likely to cause peptic ulcer disease than diclofenac or naproxen, but these
are substantially safer than azapropazone or piroxicam.
Selective cyclo-oxygenase 2 (COX-2) inhibitors have been developed in an
attempt to reduce the incidence of ulcer complications while maintaining analgesic
efficacy. A randomized controlled trial in patients with rheumatoid disease suggested
that use of rofecoxib rather than naproxen reduces bleeding or perforation by about
1 event per 100 patient-years of treatment, but patients were given no anti-ulcer
prophylaxis. In a later trial, patients who had already suffered a gastrointestinal
haemorrhage fared no better with celecoxib than with diclofenac plus omeprazole.
COX-2 inhibitors lack the antiplatelet effects of non-selective inhibitors, and overall
serious adverse events may be greater in patients denied the cardiovascular benefits.

Cardiovascular system: torsade de pointes is a broad-complex tachycardia in which

the QRS axis changes sinusoidally from 0° to 180° to 360° (Figure 5). It is often drug-
induced, and is more common in women and in patients with hypomagnesaemia or
hypokalaemia. The arrhythmia is prefigured by prolongation of the QT-interval on
resting ECG, which represents an abnormality of repolarization. Torsade de pointes
occurs with many drugs, including the conventional anti-arrhythmics disopyramide
and quinidine. Sotalol (a β-adrenoceptor antagonist with class 3 anti-arrhythmic
actions) and amiodarone are also potential causes. Phenothiazines, butyrophenones
and some tricyclic antidepressants carry a risk of torsade de pointes; droperidol is
no longer marketed, and use of thioridazine has recently been restricted because
the risks are greater than with similar drugs. The risk is also greater with the non-
sedating antihistamines astemizole and terfenadine (a pro-drug of the active
metabolite fexofenadine) and the prokinetic agent cisapride. Diuretic agents that cause
hypokalaemia or hypo-magnesaemia can cause secondary torsade de pointes.

Bone marrow: bone marrow suppression or aplasia, agranulocytosis and aplastic

anaemia are important adverse effects of several commonly used treatments, and
drugs are an important cause of the syndrome. Patients can present with mouth
ulceration or neutropenic sepsis in agranulocytosis, petechiae or haemorrhage from
thrombocytopenia, or anaemia.
Common or important causes include clozapine, carbimazole and other antithyroid
drugs, carbamazepine, sulphonamides and cytotoxic agents.

Endocrine: drugs can alter glucose homeostasis by effects on insulin secretion,

insulin action and hepatic glucose production. The antiprotozoal agent pentamidine,
used to treat Pneumocystis carinii pneumonia, is toxic to pancreatic β-cells and
can cause hypoglycaemia by stimulating release of preformed insulin, followed by
hyperglycaemia as a consequence of impaired insulin production. Thiazides (including
the antihypertensive diazoxide) and the growth hormone analogue somatostatin
inhibit insulin secretion and increase blood glucose concentration; quinine and
sulfamethoxazole (in co-trimoxazole) stimulate insulin secretion and reduce blood
glucose concentration. Glucocorticoids inhibit post-receptor signalling and cause insulin
resistance.
 Torsade de pointes

Torsade de pointes is a broad-complex tachycardia in which the QRS axis varies sinusoidally. Drugs that can cause torsade de pointes include phenothiazines,
cisapride, some selective histamine H2-antagonists and drugs causing hypomagnesaemia.

5
A syndrome of subcutaneous fat wasting in the face, limbs and buttocks associated
with abdominal visceral obesity, dyslipid-aemia and insulin resistance has been
described in patients with HIV infection treated with protease inhibitors such as
indinavir, ritonavir and saquinavir. The protease inhibitors may reduce the effective
concentration of sterol regulatory element-binding protein-1c (a key regulator of
lipoprotein metabolism), thereby causing this ‘metabolic syndrome,’ which leads to
diabetes mellitus and premature cardiovascular disease.

Neuropsychiatric function
Serotonin syndrome was first described in experimental animals that developed
hyperpyrexia, myoclonus and autonomic dysfunction when given toxic doses of L-
tryptophan, a precursor of serotonin. It was subsequently recognized in patients treated
with drugs that enhance serotoninergic activity in the brain (Figure 6). Diagnostic
features in response to a serotoninergic agent include:
• changes in cognition or behaviour (e.g. agitation, confusion)
• autonomic disturbances, manifest as fever, sweating or diarrhoea
• neuromuscular dysfunction (e.g. tremor, myoclonus).
Other causes must be excluded. Serotonin syndrome usually occurs soon after
serotoninergic treatment is instituted or increased.

Some causes of serotonin syndrome

• Increased serotonin -tryptophan
L

synthesis
• Reduced serotonin Monoamine oxidase inhibitors
metabolism type A and B
• Increased serotonin Ecstasy, cocaine
release
• Reduced serotonin Selective serotonin re-uptake
re-uptake inhibitors, tricyclic antidepressants,
mirtazepine, nefazodone, venlafaxine,
tramadol, pethidine (meperidine)
• Serotonin receptor Buspirone
agonists
• Dopaminergic agents -dopa, bromocriptine
L

Neuroleptic malignant syndrome is associated with dopamine antagonists such as

haloperidol and chlorpromazine, and tends to occur over days or weeks of treatment.
It is associated with rigidity and extrapyramidal signs in addition to the features of
serotonin syndrome. 
FURTHER READING
Bombardier C, Laine L, Reicin A et al. Comparison of Upper Gastrointestinal Toxicity of
Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis. VIGOR Study Group. N
Engl J Med 2000; 343: 1520–8.
British National Formulary. London: British Medical Association, Royal Pharmaceutical
Society of Great Britain.
(www.bnf.org)
Chan F K, Hung L C, Suen B Y et al. Celecoxib versus Diclofenac and Omeprazole in
Reducing the Risk of Recurrent Ulcer Bleeding in Patients with Arthritis. N Engl J Med
2002; 347: 2104–10.
Davies D M, Ferner R E, de Glanville H. Davies’s Textbook of Adverse Drug Reactions.
5th ed. London: Chapman & Hall, 1998.
Dukes M N G, Aronson J K. Meyler’s Side Effects of Drugs. 14th ed. Amsterdam:
Elsevier, 2000.
Evans W E, McLeod H L. Pharmacogenomics – Drug Disposition, Drug Targets, and
Side Effects. N Engl J Med 2003; 348: 538–49.
(www.pneumotox.com/index.html)
Lo J C, Mulligan K, Tai V et al. ‘Buffalo Hump’ in Men with HIV-1 Infection. Lancet 1998;
351: 867–70.

Copyright © 2003 The Medicine Publishing Company Ltd

Drug Development and Regulation
Duncan Richards is Clinical Lecturer in the Department of Clinical Pharmacology at
the University of Oxford, UK. He qualified from the University of Oxford, and trained in
London and Oxford. His research interests include development of novel techniques to
assess pharmacodynamic activity in early-phase clinical trials.

What’s new ?

• The UK Medicines Control Agency and Medical Devices Agency have merged to
form the Medicines and Healthcare products Regulatory Agency
• The European Clinical Trials Directive will have a significant impact on the conduct of
clinical trials in the UK
• Molecular biology techniques are changing the way in which drugs are developed
• Many new drugs (e.g. monoclonal antibodies) cannot be developed according to
the traditional scheme, and are creating new challenges for drug developers and
regulators

Who develops drugs?

To many, the phrase ‘drug development’ conjures an image of large, multinational
pharmaceutical companies conducting phase III therapeutic trials involving several
thousand patients. Although pharmaceutical companies are the force behind the most
commonly prescribed new drugs in Western countries, there are se-veral other key
stakeholders in the process. Universities and other research establishments are often
the source of original research from which ideas for new therapies emerge. In the
past, ‘blue-sky’ research and the applied techniques required for drug development
were segregated, but this is changing. Increasingly, the drug development process is
managed by a partnership between pro-fessional researchers and professional drug
developers (usually the pharmaceutical industry).
Some drugs are not commercially attractive because the disease they treat is very
rare or, more commonly, because the disease is prevalent only in countries unable to
afford the high cost of new drugs. In countries where annual health-care spending is
about $1 per capita, use of a drug costing $30 per month is impossible. There are two
principal approaches to this problem.
• In the orphan drug programme, a government (usually the US Government acting
through the Food and Drug Administration) subsidizes the cost of drug development
undertaken by a commercial company. This has been most effective in rare diseases.
• The problem of developing inexpensive treatments for developing countries is
less easily solved. There are several programmes sponsored by governments and
international agencies such as the WHO. Drug development in these circumstances is
difficult because of limited infrastructures for clinical assessment and data capture, and
the complexities of international politics.

Drug discovery
Plants and animals: substances extracted from plants and ani-mals remain among
the most potent and widely used drugs (e.g. morphine from the opium poppy, digitalis
from the foxglove, curare from the bark of a South American tree – Figure 1). Raw
extracts from plants and animals often contain a cocktail of active ingredients. Early
drug development focused on identifying the most important ingredients and purifying
them. It is usually easier to predict the effects of a drug, both beneficial and adverse,
when dealing with a single molecule rather than a complex mixture. For example, a
series of experiments on dogs showed that removal of the pancreas rendered them
diabetic. Further work identified and purified insulin from the pancreas, and the first
insulin extracted in this manner was given to a boy with diabetes in 1922.
Drug development from animals and plants is continuing by two means:
• investigation of traditional remedies, seeking evidence of a drug effect
• screening of extracts against batteries of biological and genomic test
systems, seeking a drug action (e.g. paclitaxel, the first of the taxane class of
chemotherapeutic drugs, was originally extracted from the bark of the Pacific yew,
Taxus brevifolia – Figure 1).
 O

O O
OH
O O

N O
O O H O
X CH
3 OH H
H3C H
H3C H3C HO O O
O H3C
HO O O O H OH
O O O
HO HO HO
H
Paclitaxel O

Digoxin X = OH
Digitoxin X = H

The bark of the Pacific yew (Taxus brevifolia) is the

The foxglove (Digitalis purpurea) is the original source of paclitaxel. (By courtesy of Natural
source of the cardiac glycoside digitoxin. Resources Canada, Canadian Forest Service.)
(Source: Bodleian Library, Oxford.)

1
Molecules extracted from plants and animals are often large and complex, and are
therefore difficult to manufacture. Obtaining an adequate supply is often a limiting factor
in early drug development; for example, 2000 mature yew trees would be required to
produce 1 kg of paclitaxel if the drug were produced by extraction.

Empirical chemistry and applied pharmacology have been a fertile source of

drug development. If the active components of a molecule can be identified, a simpler
molecule with similar pharmacological properties can be designed. The molecule may
then be further modified to improve, for example, its receptor specificity or how well
it is absorbed. This is a laborious process involving synthesis of a range of related
compounds, purification, and testing in a pharmacological model (e.g. an isolated
muscle preparation).
The new technique of combinatorial chemistry enables relatively rapid production
of a wide range of related chemical structures. The rate-limiting factor is now the
development of suitable systems in which to test the compounds.

Physiology: improvements in understanding of physiology and pathophysiology over

the last 75 years have led to important drug discoveries. For example, identification of
the pivotal role of dopamine in Parkinson’s disease has driven drug development in that
field (Figure 2).

Rational drug design: a wide range of technologies is available for drug design. If a
target has been characterized, its properties can be investigated using computers that
can predict the structure of the binding site of a receptor in three dimensions from its
amino acid sequence. Using this information, the sorts of molecules that will bind with
greatest affinity to that site can be inferred.
 Pharmacology and physiology in the treatment of Parkinson’s disease

Pharmacology Physiology Clinical effect

1950s – dopamine identified

Therapeutic effect
as a neurotransmitter

Administration of a precursor of 1960s – dopamine is deficient

dopamine (L-dopa) to patients in the brains of patients
with Parkinson’s disease with Parkinson’s disease

Dopa-decarboxylase inhibitors Adverse effects from peripheral

that do not enter the brain actions of dopamine

Contribution of acetylcholine Combination medicines –

Antimuscarinic drugs to basal ganglia function co-beneldopa and co-careldopa

1990s – catechol-o-methyl transferase Recognition of other pathways

inhibitors of dopamine metabolism

2
Large pharmaceutical companies now have many thousands of molecules available
to test against potential targets. The rate-limiting factor is the generation of potential
and validated targets. Information from the human genome project suggests that only a
few traditional transmembrane receptors remain to be identified. New drugs will have to
target other molecules such as enzymes and second-messenger molecules. These are
more challenging targets because they are likely to have many actions and are found in
many cells of the body.

Pharmacogenomics: genomic technologies could potentially identify patients who are

most likely to respond to new drugs and those most at risk from adverse effects, but
such individually tailored treatment remains a distant goal. Genes that influence the
disease process may not be suitable drug targets. The process of identification of gene
products and their pattern of expression and influence on disease biology is protracted
and rewards are not guaranteed.
Molecular biological techniques are achieving more immediate benefits. Human
epidermal growth factor receptor 2 (HER2) is over-expressed in one-third of breast
cancers. Trastusuzmab is a monoclonal antibody directed against these receptors and
is effective only in women who over-express HER2. Identification of HER2 status using
molecular techniques is now helping to direct treatment appropriately.

Traditional phases of drug development

Drug development is a long process, commonly taking 12–15 years from discovery to
licence. A further 3–5 years may be required to determine the drug’s optimal clinical
role. The nature and amount of information required for licensing is well established
for chem-ical compounds aimed at specific receptors. The traditional model shown in
Figure 3 is divided into distinct phases. One of the greatest challenges facing regulatory
authorities and drug developers is defining what must be known about new drugs (e.g.
growth factors, antibodies) that do not fit neatly into this scheme.

Preclinical toxicology and pharmacology: every potential new drug must undergo a
period of testing before it can be given to humans. Traditionally, this involves toxicology
studies in rodent and non-rodent species to broadly determine the maximum tolerated
dose (following single and multiple administration) and likely areas of toxicity. Other
studies include effects on fertility and reproduction, teratogenicity, mutagenicity and
 Traditional phases of drug development

Permission to proceed
from regulatory authority

Drug Preclinical Submission

discovery testing Phase I Phase II Phase III for approval Phase IV

Pharmacological Evaluate Evaluate Evaluate Evaluation of Post-marketing

evaluation and safety and safety and effectiveness in safety and studies
toxicology pharmaco- pharmaco- selected efficacy by
kinetics in kinetics in population regulatory New
humans target authority indications
population Evaluate safety
in longer-term Evaluation of New
May include use quality of formulations
some manufactured
evaluation of product
therapeutic
drug action

20–80 100–300 1000–3000 2000–10,000

healthy patient patient patient
volunteers volunteers volunteers volunteers

Compound patent for 17 years 12 years in development 5 years exclusive marketing

4 years 1 year 2 years 4 years 1 year

5000 compounds 5 compounds enter trials 1 compound approved

This is a general guide only; the nature of the stages can vary considerably according to the drug under development

carcinogenicity. However, information from animals can be of only limited relevance to

humans. Large numbers of animals are required for preclinical toxicology testing, and
considerable efforts are made to find other models that will yield useful information.
These models (e.g. cultured human cell lines) may be more relevant when investigating
drug pharmacology, but whole-body models are still required to examine how a drug is
absorbed and where it goes in the body.

Phase I: a risk greater than minimal is not acceptable in a healthy volunteer study. The
purpose of preclinical testing is to pro-vide sufficient information to allow administration
to humans. A ‘first time in man’ (FTIM) study is usually designed to assess the safety
and tolerability of a single dose of the new drug, linked to pharmacokinetic data. The
starting dose is usually one-hundredth to one-tenth of a measure of pharmacological
or biological acti-vity in the most relevant animal species, from which the dose is
increased. The number of volunteers is small and they are monitored closely. When
appropriate, other early studies examine the safety and tolerability of the drug after
multiple dosing, and the effects of food and other drugs. The principal purpose of these
studies is to establish safety, but they also provide the first opportunity to study markers
of drug action in humans.
A problem with the traditional approach to clinical trials of new drugs is they are
conducted only in men, because of concerns about teratogenicity. There is now a move
towards including many more women in all clinical studies, not just those for diseases
such as breast cancer.

Phase II trials are concerned with assessment of the safety and tolerability of the
new drug in the target patient population. Correct selection of the study population is
 important – the tolerability of a new drug for Alzheimer’s disease may differ between
20-year-olds and patients aged 60–70 years.
Some drugs (e.g. cytotoxic drugs) cannot safely be given to healthy volunteers, and
the information about the drug that is usually collected from healthy volunteers in phase
I must be collected in phase II studies. Many of these studies are in vulnerable groups
(e.g. those with cancer), and it is important that these patients understand that they are
unlikely to derive any personal benefit from these studies. Phase II trials may evaluate
some measure of therapeutic action, but their principal purpose is to define the dose or
dose range to be used in phase III.

Phase III studies are those with which health-care professionals are most familiar.
They are usually large scale and expensive (each costing many millions of pounds).
Assessment of safety is a key part of these studies, but they are also the first
opportunity to determine whether the drug has beneficial clinical effects in a patient
population. Careful patient selection is essential, but limits the applicability of the
findings of these studies.
The results of phase III trials usually form the basis of marketing and advertising
information. It should be remembered that the patients involved were selected to show
the maximum effect of the drug, and doctors should consider whether the findings of
these studies apply to patients in their clinic.
A large phase III clinical trial may involve several hundred investigators and
several thousand patients. There are strict, legally enforceable rules regarding the
responsibilities of investigators in clinical trials (Figure 4), and clinicians should not enrol
patients into clinical trials unless they are able to comply with these rules.

Responsibilities of investigators and other staff according to Good Clinical Practice

The designated Investigator (usually a senior member of staff) is bound to ensure that the conduct
of the trial is compliant with Good Clinical Practice at that site. Space does not permit inclusion of
the complete guidelines, but if you are asked to help with the conduct of a clinical trial, consider the
following points.
• Before the start of the trial, an independent ethics committee must have approved the protocol
and associated documents. Check that this permission has been received before you enrol a
patient.
• The Investigator should maintain a list of appropriately qualified persons to whom he or she
has delegated significant trial-related duties. You should not undertake significant duties (e.g.
enrolment of patients) unless your name is on that list.
• The Investigator should ensure that all individuals assisting with the trial are adequately informed
about the protocol, the investigational product and their trial-related duties. Do not enrol patients
into trials if you are not familiar with the investigational drug or protocol. You cannot obtain
informed consent from a patient if you are not familiar with the trial yourself.
• Follow the protocol precisely. Do not deviate from the protocol unless there is immediate danger
to the patient. If you have to make a permanent change to the protocol, the sponsor and the
ethics committee must approve this.
• Take care to complete the case record form. Missing or inaccurate data may invalidate the trial,
exposing patients to risk without any benefit from the increase in knowledge. If you have to alter
the case record form, strike it out with a single line and sign and date the change.
• There are special rules regarding rapid reporting of serious adverse events during clinical trials
to the regulatory authorities. If your patient suffers an adverse event, contact the sponsor quickly
and file a report, regardless of whether you think it was related to the drug.
4

Phase IV trials are undertaken after a drug has been given some form of approval
for use by the appropriate regulatory body. They are usually of larger scale than
phase III trials. A drug may have only one licensed indication, such as a β-blocker for
hypertension, but a commercial company may sponsor other trials to evaluate its use in
myocardial infarction and heart failure. The licensing authority may consider these trials
and, if the results are accepted, extend the licence to cover these indications. A phase
IV trial may be required for a new formulation of a drug (e.g. a fast-melt sublingual
tablet).
Commercial companies are often wary of trials comparing their drug with a
competitor, fearing that their drug will be found inferior. Such trials may be sponsored
by non-commercial organ-izations (e.g. UK Medical Research Council, Wellcome
Trust).

What is a product licence?

To sell a medicine in any country, the sponsor must convince the licensing authority
of that country (see below) that it is safe, effective and manufactured to a satisfactory
quality. This does not mean that the licensing authority or the sponsor know everything
about that medicine. New drugs have been given to, at most, only a few thousand
individuals before they are granted a licence. Rare adverse effects, even serious ones,
are often not recognized before a licence is issued. In the British National Formulary,
new drugs are identified by a black triangle; clinicians should report any adverse effects
in patients given these drugs, even if minor and regardless of whether they think the
drug was responsible. Do not assume that the licensing authority and manufacturer are
already aware of effects observed.
To obtain a licence, a new drug must be effective for its indication; it does not have to
be better than alternatives, nor does it have to be cost-effective. It may take years and
several phase IV trials before the place of a new drug is established. Initially, a new drug
should be used only by specialists familiar with the alternatives; as its role becomes
established, wider use may be appropriate.
Medicines are granted a licence for a given indication only. A company cannot
promote a drug for indications for which it does not have a licence. Physicians may use
approved drugs outside their licence, and in many cases this is appropriate. However,
it is good medical practice to use drugs for their licensed indications. Widespread use
outside the licence does not encourage commercial sponsors to evaluate the drug’s use
in robust clinical trials.

Licensing new medicines

In the UK, the licensing of drugs is based on the Medicines Act (1968), which provides
a comprehensive system of licensing affecting the manufacture, sale, supply and
importation of medicinal products. The Medicines and Healthcare products Regulatory
Agency (MHRA) (formerly the Medicines Control Agency) is an executive agency of
the Department of Health and is responsible for implementation of the provisions of the
Act. The MHRA is supported by seven specialist advisory bodies (Figure 5). Licences
to manufacture, market, distribute, sell and supply medicinal products are granted by
Ministers (‘the Licensing Authority’), who are responsible to Parliament. In practical
terms, the licensing authority is the MHRA. Working with the Committee on Safety of
Medicines (CSM), it assesses the safety, efficacy and quality of each product (Figure
6).
Until recently, companies had to apply for licences in each country separately, and
the standard and nature of information required varied considerably between licensing
authorities. In 1995, a new European Community (EC) system for the author-ization of
medicinal products came into operation. Its purpose was to allow medicines marketed
in one EC country to be made available in the same manner, and subject to the same
conditions, in other EC countries. The EC licensing system uses the experience of the
individual Member States’ authorization through a system of mutual recognition. In
addition, there is a centralized system for authorization. The European Agency for the
Evaluation of Medicinal Products has been established to provide additional support
and to coordinate Member States’ work. EC decisions agreed under the new system
are binding on Member States.

Post-marketing evaluation and surveillance

In addition to licensing new medicines, the MHRA is responsible for:
• monitoring medicines and acting on safety concerns after they have been placed on
the market
• checking standards of pharmaceutical manufacture and wholesaling
• enforcing requirements
• medicines control policy.
The CSM evaluates concerns about the safety of medicines. Acting through the MHRA,
it can enforce the suspension or withdrawal of a licence. The bulletin Current Problems
in Pharmacovigilance is produced four times per year and sent to all doctors, dentists,
pharmacists and coroners in the UK. It alerts them to problems with medicines and
provides advice on their safe use.
 Bodies created as a result of the Medicines Act (1968) and their roles

Executive agency Advisory body Terms of reference

Medicines Commission Advises the Health and Agriculture Ministers of the UK

‘on matters relating to the execution of this Act or the exercise
of any powers conferred by it, or otherwise relating to
medicinal products, where either the Commission consider it
expedient, or they are requested by the Minister or Ministers in
question to do so’.

Committee on Safety of Medicines
• Provides advice to the Licensing Authority on whether new
products (new active substances) submitted to the MHRA
should be granted a marketing authorization. These
responsibilities require close collaboration with the MHRA’s
Licensing Division.
• Monitors the safety of marketed medicines, in close
association with the MHRA’s Post-Licensing Division, to
ensure that medicines meet acceptable standards of safety
and efficacy.

British Pharmacopoeia Commission Responsible for preparing new editions of the British
Pharmacopoeia and the British Pharmacopoeia (Veterinary)
and for keeping them up to date. (These are different from the
British National Formulary, which is a joint publication of the
British Medical Association and the Royal Pharmaceutical
Society of Great Britain. The Department of Health is
represented on the Joint Formulary Committee that produces
the British National Formulary.)
Medicines
and Healthcare products
Regulatory Agency
(MHRA) Veterinary Products Committee • Gives advice on safety, quality and efficacy relating to the
veterinary use of any substance or article (not instruments,
apparatuses or appliances) to which any provision of the
Medicines Act is applicable.
• Promotes collection of information on suspected adverse
reactions for the purpose of giving such advice.

Advisory Board on the Registration
of Homoeopathic Products
Gives advice on safety and quality relating to any homeopathic
medicinal product for human use for which a certificate of
registration could be granted, and any homeopathic veterinary
product that satisfies the conditions in Article 7 of the
Veterinary Homoeopathics Directive (92/74/EEC).

Independent Review Panel for Advertising
• Considers written representations from pharmaceutical
companies regarding the conformity of their advertising and
promotional material with the Regulations.
• Advises Health Ministers on the conformity of advertising
and promotional material with the Regulations before a final
decision is made by Health Ministers.

Independent Review Panel on the
Classification of Borderline Products
• Considers written and oral representations from companies
against a provisional determination by the MHRA, on behalf
of the Licensing Authority, that a product is a medicinal
product.
• Advises the Licensing Authority whether the MHRA’s
provisional determination should be confirmed.

European Clinical Trials Directive

The European Clinical Trials Directive (2001/20/EC) has implications for every health-
care professional involved in clinical re-search. It was agreed in February 2001, and
the UK is currently preparing to transpose it into domestic law. The scope of the
legislation is wide and every clinical trial involving medicinal products will be covered.
The Directive sets standards for pro-tecting clinical trial subjects, establishes ethics
committees on a legal basis, provides legal status for certain procedures, establishes
 Framework for the licensing of new medicinal products in the UK

European legislation UK Parliament Secretary of State

Department of Health

Executive agency

European Agency for the Medicines and Healthcare Committee on Safety of Medicines
Evaluation of Medicinal Products products Regulatory Agency

UK licence

Centralized authorization procedure

and mutual recognition

standards for the manufacture, import and labelling of investi-gational medicinal

products, and provides for quality assurance of clinical trials.
The Directive does not distinguish between commercial and non-commercial clinical
trials, and there is considerable concern that non-commercial academic research will
be hampered by its requirements. In addition, the definition of a medicinal product can
be wide; for example, vitamins given for therapeutic use could be included. A small
clinical investigation could require full submission to the licensing authority, similar to
that required for a new potential commercial product. It remains to be seen how the
individual Member States interpret the provisions of the Directive, but the potential
effect on academic research is great. 

FURTHER READING
Committee on Safety of Medicines. www.mhra.gov.uk/aboutagency/regframework/csm/
csmhome.htm
(Advice on reporting suspected adverse events and information on current problems
in pharmacovigilance.)
Declaration of Helsinki as amended by the World Medical Association. www.wma.net
(The Declaration of Helsinki is a statement of ethical principles guiding physicians
and other participants in medical research involving human subjects.)
Grahame-Smith D G, Aronson J K. Oxford Textbook of Clinical Pharmacology and
Drug Therapy. Oxford: Oxford University Press, 2002.
(Includes an overview of the phases of drug development.)
International Conference on Harmonization. Guidelines for Good Clinical Practice.
www.ich.org/
Medicines and Healthcare products Regulatory Agency. www.mhra.gov.uk
(Background information on the structure and function of the MCA, with contact
details and application forms for those wishing to conduct clinical trials.)
Research on Healthy Volunteers. A Report of the Royal College of Physicians. J R Coll
Physicians Lond 1986; 20: 243–57.
(Guidelines on the conduct of studies involving healthy volunteers.)

Copyright © 2003 The Medicine Publishing Company Ltd

How to Appraise Clinical Trials
Y K Loke is Lecturer in Pharmacology at the University of Oxford, UK. He qualified
from the University of London, and trained in clinical pharmacology and general
medicine in Oxford. His research interest is systematic review of adverse drug
reactions.

What’s new ?

• Organizations such as the UK National Institute for Clinical Excellence use trial data
to support decisions on the usefulness and cost-effectiveness of drugs
• Several important components of the assessment of trial validity have now been
defined
• In view of the current profusion of trial results, doctors must be able to judge for
themselves how relevant the findings are to their practice

In evidence-based medicine, trial data are of paramount importance when choosing

appropriate treatments for patients. Doctors rely on clinical trials to direct, or change,
their practice; thus, the ability to appraise a trial report critically is a useful skill. It is
important that the evaluation of a trial goes beyond a cursory look at the abstract and
results sections (as most busy clinicians are prone to do).
Critical assessment of a trial begins at the design phase, long before the first patient
is recruited into the study. It is necessary to ask the following questions, both at this
point and later.
• What is the trial for? Are there clear therapeutic questions that must be addressed?
• Can the design and conduct of the trial reliably answer those questions?
These issues are of particular interest to pharmaceutical phy-sicians, research ethics
committees, funding bodies and regulatory authorities. They are also useful starting
points for clinicians, in assessing the relevance or value of the trial’s findings. Doctors
should consider the following points, in particular.
• What do these results mean for me, and for my patients?
• What influence, if any, should the findings have on medical practice?
Individual clinicians must judge whether the trial data are of any relevance to
the patients they treat in ‘real-life’ practice. At a higher level, medicines advisory
committees, including the UK National Institute for Clinical Excellence, use trial
results as essential supporting evidence when deciding on the usefulness and cost-
effectiveness of drugs in the national health setting.
Bearing in mind the above, readers of trial reports should systematically evaluate the
following areas:
• design and conduct of the trial
• applicability of trial findings to clinical practice.

Design and conduct of controlled clinical trials

Most pharmacological treatments are now tested in controlled clinical trials before they
are licensed for use. The essence of a controlled trial is that, to assess the effects of
therapy, two or more patient groups with similar characteristics are exposed to different
treatments. Such trials can be considered as scientific experiments on humans and
should therefore be conducted according to rigorous methodological standards.
As in any experiment, the scientific integrity of the study, and the reliability of the
results, can be undermined by the presence of bias. In simple terms, bias is any
process (conscious or un-conscious) that causes results to systematically deviate
from the true values. There are several important areas in which bias may occur in a
controlled clinical trial:
• selection of patients
• delivery of the treatments that are being evaluated
• assessment of treatment outcomes
• loss of patients to follow-up.
Readers should therefore pay special attention to these aspects of trial reports and
should check that the trialists have minimized the possibility of bias.
Selection of patients
Ideally, the patient groups under comparison in a controlled clinical trial should have
identical characteristics and differ only with respect to the treatment arms to which they
belong. To achieve such a balance, each trial participant must have an equal chance
of being assigned to any one of the treatment groups. This is achieved through the
process of random allocation – neither the doctor nor the patient knows, or has any
influence on, the treatment group to which the patient is allocated.
There are two important steps in ensuring that the randomization process is
adequate:
• generating a truly random sequence, often using a computer or random number
tables (failing this, drawing numbers from a hat or flipping a coin must suffice)
• ensuring that neither the trialists nor the patients can determine the sequence, to
prevent them influencing the treatment allocation process (can be achieved by using
a remote telephone randomization centre, or simply with sealed, opaque envelopes).
Most trial reports now list the baseline characteristics of the patients in their treatment
groups, and it is worth checking that the groups are indeed similar. There are many
studies in which inadequate randomization techniques led to an imbalance, in-cluding
the following.
• Women in a labour ward were asked to choose whether they wanted to use a birthing
pool instead of the conventional delivery room. However, the birthing pool group
thereby contained more women of higher socioeconomic status who were interested
in this innovative method. It was impossible to tell whether the better health of the
babies in that group resulted from use of the birthing pool or from their mothers’ higher
socioeconomic status.
• Patients were openly enrolled into treatment groups depending on the day of
admission. However, those admitted on a Sunday, for example, could have differed
from those referred on a weekday, and this could lead to an imbalance in the groups.
Furthermore, the trialist or the patient could choose his or her preferred treatment by
arranging hospital admission for a specific day; for example, frail patients may have
preferred what appeared to be the ‘gentler’ treatment arm.

Delivery of the treatments under comparison

Ideally, patients in each group should be managed in exactly the same manner, the only
difference being the therapeutic agents under evaluation. This may not always be the
case, however, and readers should check the trial report.
• In one study, an experimental drug was administered in the coronary care unit,
whereas patients in the conventional therapy arm were cared for on general medical
wards. Improved outcomes in the experimental group may have been a consequence of
closer supervision in coronary care, rather than the drug treatment.
• Patients in a study of a new endoscopic device were treated by a consultant who
had undergone special training in the technique. Meanwhile, other patients in the trial
underwent the conventional procedure performed by a registrar.

Measuring treatment outcomes

Bias may not be a problem when measuring ‘hard’ outcomes such as numbers of
patients dead or alive at the end of the trial. However, it may occur with outcomes
that are subject to human interpretation such as deciding the cause of death, reading
an echocardiogram or assessing symptomatic change. In a trial of the benefit of
compression stockings in the prevention of travel-related thrombosis, calf vein clots
were monitored by ultrasonographers who knew which patients had used stockings.
These technicians may have believed that patients without stockings were at higher
thrombotic risk, leading to more thorough scanning of these individuals and highlighting
of borderline abnormalities.
Blinding or masking of treatments has been introduced to remove this type of bias.
In double-blind studies, neither the trialist nor the participant knows which treatment
regimen is given. It is worth checking that blinding of treatment is feasible, however; for
example, the reader should be sceptical about blinding in a study comparing a rectally
administered drug with another drug that must be given through a central venous
catheter.

Loss of patients to follow-up

There are many reasons why patients leave trials. Some develop adverse effects;
others give up because they feel no better on the trial treatment. The results of trials
may be misleading if these drop-outs are not accounted for (Figure 1). This is because
Hypothetical example of a new anti-obesity drug being
evaluated in 1000 patients

1000 obese patients start new drug

n = 1000

450 patients drop out after 2 months because they

experienced no beneficial effect on their weight

n = 550

200 experience adverse effects and decide not to

continue

n = 350

Remaining 350 are happy taking the drug and feel

that it is effective in helping them lose weight

Final mean weight loss is based on the 350

patients who complete the trial

Conclusion: the new drug is both effective and

well tolerated
1

the remaining patients are not representative of those who originally started on
treatment. To remove this type of bias, ‘intention-to-treat’ analysis is undertaken. All
randomized patients are included in the analysis, regardless of whether they completed
the trial. If such analysis is impossible, the trial should report the numbers who left and
the reasons why.
Some trials use a ‘run-in’ period, in which all eligible patients are briefly treated with
the study drug before the randomization phase. In one study, for example, 10,500
patients were initially given ramipril, 2.5 mg, but 1000 of these were subsequently
excluded from formal participation in the trial for various reasons including non-
compliance, adverse effects and deteriorating serum biochemistry. Doctors must be
cautious when interpreting adverse effects data from trials that use a run-in phase.
Many medical journals now use a standardized reporting structure for randomized
controlled trials, with a flowchart (Figure 2) that provides a quick, simple means of
assessing the trial’s design and conduct.

Are trial findings relevant to the patients in everyday clinical practice?

For busy clinicians, this is perhaps the most important question to answer when reading
a trial report. A trial may be a paragon of scientific integrity, but the patients may have
been so highly selected, and the therapy so expensive and complex, that no hospital
could hope to deliver such care in real-life practice. When deciding whether the study
findings have any validity outside the trial setting, it is helpful to consider the following:
• nature of the patients selected to participate
• treatment regimens
• health-care setting
• type and definition of outcome measures.

Selection of participants
The entry and exclusion criteria for clinical trials are often set in such a manner that
they select participants who will fare well and exclude those at substantial risk of
CONSORT flowchart showing the details that are required in a randomized
controlled trial

Assessed for eligibility (n = …)

Excluded (n = …)
• Did not meet inclusion
criteria (n = …)
Enrolment • Refused to participate
(n = …)
• Other reasons (n = …)

Randomized (n = …)

Allocated to intervention (n = …) Allocated to intervention (n = …)

• Received allocated intervention • Received allocated intervention
Allocation (n = …) (n = …)
• Did not receive allocated • Did not receive allocated
intervention (give reasons) (n = …) intervention (give reasons) (n = …)

Lost to follow-up (give reasons) Lost to follow-up (give reasons)

Follow-up (n = …) (n = …)
Discontinued intervention Discontinued intervention
(give reasons) (n = …) (give reasons) (n = …)

Analysed (n = …) Analysed (n = …)
Analysis • Excluded from analysis • Excluded from analysis
(give reasons) (n = …) (give reasons) (n = …)

adverse effects. For example, a trial of warfarin in atrial fibrillation excluded patients
aged over 70 years and those judged unlikely to be compliant. Stricter entry criteria may
create a better scientific experiment, but the trial’s participants may be unrepresentative
of patients in the community. Can doctors safely extrapolate the findings of such a trial
to clinical practice, in which most patients with atrial fibrillation are over 70 years of age
and in which the benefit:harm ratio is likely to be significantly different?
Before recommending a new treatment, it is important to check that the trials were
performed in relevant groups and, if not, to consider carefully how patients may differ
from those in the trials in response to treatment.

Treatment regimens in the trial

The dose or route of administration of drugs used in clinical trials may differ from that
in clinical practice. For example, patients in trials of cholesterol-lowering agents are
given near-maximum doses (pravastatin, 40 mg, or simvastatin, 40–80 mg), to make
the benefit of treatment as clear as possible. In real-life medicine, however, it is unclear
whether the doctor should continue with dose-titration according to response or simply
adhere to the trial protocol. This is an important area that must be considered when
appraising a trial report. It can also create difficulty in the assessment of the cost-
effectiveness of treatment.

Health-care settings and provision

Clinical trials are often conducted in well-staffed and highly equipped academic
centres. Special arrangements are usually made for follow-up, and trial participants
are monitored closely. It is therefore unsurprising that patients in trials often experience
better outcomes, even when allocated to the control arm. In practice, the monitoring
or expertise required to achieve the trial results may not be readily available outside
specialist referral centres. For example, trial data show that thrombolysis is beneficial
 in patients with echocardiographically detectable right ventricular dysfunction following
acute pulmonary embolism, but it is unlikely to be widely used in clinical practice
because few, if any, centres can offer immediate echocardiography in the emergency
department. The model of care in trials warrants close scrutiny to determine whether it
is viable outside research settings.

Selection of outcome measures

There are two issues involved when considering outcome measures.
Surrogate outcome measures are often used in clinical trials, but may or may not
accurately reflect true benefit.
• Two antihypertensive agents may reduce blood pressure (a surrogate outcome)
by equal amounts, but in practice one may be better at reducing the risk of adverse
cardiac events (the clinical outcome of interest).
• Drugs such as donepezil, given for dementia, may improve the ADAS-Cog score by a
few points, but what do these extra points mean for quality of life?
• A trial of nicorandil in ischaemic heart disease showed significant benefit in a
composite outcome measure (cardiac death, non-fatal myocardial infarction and
unplanned admission with angina). However, no significant benefit was found when
cardiac death and myocardial infarction were analysed in isolation. The main advantage
of this drug, if used in clinical practice, may therefore be in terms of admission to
hospital rather than serious myocardial infarction.
These examples demonstrate the value of scrutinizing end-points carefully to
determine whether the purported benefits are important clinical outcomes.
Relative risk and odds ratios – trials often present their data in terms of relative risk
(RR) or odds ratios (OR). However, clinicians and patients find it easier to understand
and work with measures of absolute benefit such as the number needed to treat (NNT)
and absolute risk reduction. The NNT is the estimated number of patients who must
be given the therapeutic agent for a given period of time, to achieve one additional
beneficial outcome. It is a measure of how much effort is needed to yield a useful end-
point. These measures of absolute benefit change with the underlying baseline risk of
the patient, though the relative risk often remains constant (Figure 3). It is worth reading
beyond superficially impressive RR or OR figures, and converting these into meaningful
absolute measures such as NNT. 

Examples of how the same relative risk can yield different numbers needed to treat
(NNTs) depending on the baseline risk in the patient, based on the hypothetical drug X,
which produces a ‘huge’ relative reduction of 40% in the risk of stroke

Baseline annual stroke risk Annual stroke risk Absolute reduction in NNT per year1
in a population of patients with drug X stroke risk with drug X
1% 0.6% 0.4% 250
5% 3.0% 2.0% 50
20% 12% 8.0% 13
1
NNT = 1/absolute risk reduction

FURTHER READING
Cook R J, Sackett D L. The Number Needed to Treat: A Clinically Useful Measure of
Treatment Effect. BMJ 1995; 310: 452–4.
(An important guide to interpreting trial data in a clinically relevant manner.)
Juni P, Altman D G, Egger M. Systematic Reviews in Health Care: Assessing the
Quality of Controlled Clinical Trials. BMJ 2001; 323: 42–6.
(A useful article describing the quality indicators by which a trial can be assessed.)
Moher D, Schulz K F, Altman D G. The CONSORT Statement: Revised
Recommendations for Improving the Quality of Reports of Parallel Group Randomized
Trials. BMC Med Res Methodol 2001; 1: 2.
www.biomedcentral.com/1471-2288/1/2
(Widely adopted guidelines on how to report trial data in a structured manner.)
Practice points
• Treatment decisions should be guided by evidence obtained from clinical trials
• The reliability of trial results should be evaluated by looking for potential sources of
bias in the design and conduct of the trial
• The relevance of trial results to everyday clinical practice should be considered
before making treatment decisions

Copyright © 2003 The Medicine Publishing Company Ltd