# 02-2 Clinical therapeutics and good prescribing

# 2 Clinical therapeutics and good prescribing

Clinical therapeutics and 
good prescribing
SRJ Maxwell
Principles of clinical pharmacology 14
Pharmacodynamics 14
Pharmacokinetics 17
Inter-individual variation in drug responses 19
Adverse outcomes of drug therapy 21
Adverse drug reactions 21
Drug interactions 23
Medication errors 24
Drug regulation and management 26
Drug development and marketing 26
Managing the use of medicines 27
Prescribing in practice 28
Decision-making in prescribing 28
Prescribing in special circumstances 31
Writing prescriptions 33
Monitoring drug therapy 34


14 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
strength of the chemical bond. Some drug–receptor 
interactions are irreversible, either because the affinity is so 
strong or because the drug modifies the structure of its 
molecular target.
• Selectivity describes the propensity for a drug to bind to 
one target rather than another. Selectivity is a relative 
term, not to be confused with absolute specificity. It is 
common for drugs targeted at a particular subtype of 
receptor to exhibit some effect at other subtypes. For 
example, β-adrenoceptors can be subtyped on the basis 
of their responsiveness to the endogenous agonist 
noradrenaline (norepinephrine): the concentration of 
noradrenaline required to cause bronchodilatation (via 
β2-adrenoceptors) is ten times higher than that required to 
cause tachycardia (via β1-adrenoceptors). ‘Cardioselective’ 
β-blockers have anti-anginal effects on the heart (β1) but 
may still cause bronchospasm in the lung (β2) and are 
contraindicated for asthmatic patients.
• Agonists bind to a receptor to produce a conformational 
change that is coupled to a biological response. As 
agonist concentration increases, so does the proportion of 
receptors occupied, and hence the biological effect. Partial 
agonists activate the receptor but cannot produce a 
maximal signalling effect equivalent to that of a full agonist, 
even when all available receptors are occupied.
• Antagonists bind to a receptor but do not produce the 
conformational change that initiates an intracellular signal. 
A competitive antagonist competes with endogenous 
ligands to occupy receptor-binding sites, with the resulting 
antagonism depending on the relative affinities and 
concentrations of drug and ligand. Non-competitive 
antagonists inhibit the effect of an agonist by mechanisms 
other than direct competition for receptor binding with the 
agonist (e.g. by affecting post-receptor signalling).
Dose–response relationships
Plotting the logarithm of drug dose against drug response 
typically produces a sigmoidal dose–response curve (Fig. 2.2). 
Progressive increases in drug dose (which, for most drugs, is 
proportional to the plasma drug concentration) produce increasing 
Prescribing medicines is the major tool used by doctors to 
restore or preserve the health of patients. Medicines contain 
drugs (the specific chemical substances with pharmacological 
effects), either alone or in combination with additional drugs, in 
a formulation mixed with other ingredients. The beneficial effects 
of medicines must be weighed against their cost and potential 
adverse drug reactions and interactions. The latter two factors 
are sometimes caused by injudicious prescribing decisions 
and by prescribing errors. The modern prescriber must meet 
the challenges posed by the increasing number of drugs and 
formulations available and of indications for prescribing them, 
and the greater complexity of treatment regimens followed by 
individual patients (‘polypharmacy’, a particular challenge in the 
ageing population). The purpose of this chapter is to elaborate 
on the principles and practice that underpin good prescribing 
(Box 2.1).
Fig. 2.1 Pharmacokinetics and pharmacodynamics. 
Dosage
regimen
Plasma
concentration
Concentration at
the site of action
Pharmacological
effects
Pharmacokinetics
‘what the body does
to a drug’
Monitoring
Measure plasma drug
concentration
‘what a drug does
to the body’
Monitoring
Measure clinical
effects
Time
Concentration
Pharmacodynamics
Concentration
Effect
*These steps in particular take the patient’s views into consideration to establish 
a therapeutic partnership (shared decision-making to achieve ‘concordance’).
 2.1 Steps in good prescribing
• Make a diagnosis
• Consider factors that might influence the patient’s response to 
therapy (age, concomitant drug therapy, renal and liver function etc.)
• Establish the therapeutic goal*
• Choose the therapeutic approach*
• Choose the drug and its formulation (the ‘medicine’)
• Choose the dose, route and frequency
• Choose the duration of therapy
• Write an unambiguous prescription (or ‘medication order’)
• Inform the patient about the treatment and its likely effects
• Monitor treatment effects, both beneficial and harmful
• Review/alter the prescription
Principles of clinical pharmacology
Prescribers need to understand what the drug does to the 
body (pharmacodynamics) and what the body does to the drug 
(pharmacokinetics) (Fig. 2.1). Although this chapter is focused on 
the most common drugs, which are synthetic small molecules, 
the same principles apply to the increasingly numerous ‘biological’ 
therapies (sometimes abbreviated to ‘biologics’) now in use, 
which include peptides, proteins, enzymes and monoclonal 
antibodies (see Box 4.2, p. 65).
Pharmacodynamics
Drug targets and mechanisms of action
Modern drugs are usually discovered by screening compounds 
for activity either to stimulate or to block the function of a specific 
molecular target, which is predicted to have a beneficial effect 
in a particular disease (Box 2.2). Other drugs have useful but 
less selective chemical properties, such as chelators (e.g. for 
treatment of iron or copper overload), osmotic agents (used as 
diuretics in cerebral oedema) or general anaesthetics (that alter 
the biophysical properties of lipid membranes). The following 
characteristics of the interaction of drugs with receptors illustrate 
some of the important determinants of the effects of drugs:
• Affinity describes the propensity for a drug to bind to a 
receptor and is related to the ‘molecular fit’ and the 


Principles of clinical pharmacology • 15

Fig. 2.2 Dose–response curve. The green curve represents the beneficial effect of the drug. The maximum response on the curve is the Emax and 
the dose (or concentration) producing half this value (Emax/2) is the ED50 (or EC50). The red curve illustrates the dose–response relationship for the most 
important adverse effect of this drug. This occurs at much higher doses; the ratio between the ED50 for the adverse effect and that for the beneficial effect 
is the ‘therapeutic index’, which indicates how much margin there is for prescribers when choosing a dose that will provide beneficial effects without also 
causing this adverse effect. Adverse effects that occur at doses above the therapeutic range are normally called ‘toxic effects’, while those occurring within 
the therapeutic range are ‘side-effects’ and those below it are ‘hyper-susceptibility effects’. 
Hypersusceptibility
Side-effects






0.0001
0.001
0.01
0.1




Therapeutic index
100/0.1 = 1000
Drug dose (mg)
 Response (% of maximum)
Toxic effects
Adverse
effect
ED50 =100 mg
Beneficial
effect
ED50 =0.1 mg
Emax 
ED50
ED50
 2.2 Examples of target molecules for drugs
Drug target
Description
Examples
Receptors
Channel-linked receptors
Ligand binding controls a linked ion channel, known as ‘ligand-gated’ 
(in contrast to ‘voltage-gated’ channels that respond to changes in 
membrane potential)
Nicotinic acetylcholine receptor
GABA receptor
Sulphonylurea receptor
G-protein-coupled receptors 
(GPCRs)
Ligand binding affects one of a family of ‘G-proteins’ that mediate signal 
transduction either by activating intracellular enzymes (such as adenylate 
or guanylate cyclase, producing cyclic AMP or GMP, respectively) or by 
controlling ion channels
Muscarinic acetylcholine receptor
β-adrenoceptors
Dopamine receptors
5-Hydroxytryptamine (5-HT, 
serotonin) receptors
Opioid receptors
Kinase-linked receptors
Ligand binding activates an intracellular protein kinase that triggers a 
cascade of phosphorylation reactions
Insulin receptor
Cytokine receptors
Transcription factor receptors
Intracellular and also known as ‘nuclear receptors’; ligand binding 
promotes or inhibits gene transcription and hence synthesis of new 
proteins
Steroid receptors
Thyroid hormone receptors
Vitamin D receptors
Retinoid receptors
PPARγ and α receptors
Other targets
Voltage-gated ion channels
Mediate electrical signalling in excitable tissues (muscle and nervous 
system)
Na+ channels
Ca2+ channels
Enzymes
Catalyse biochemical reactions. Drugs interfere with binding of substrate 
to the active site or of co-factors
Cyclo-oxygenase
ACE
Xanthine oxidase
Transporter proteins
Carry ions or molecules across cell membranes
5-HT re-uptake transporter
Na+/K+ ATPase
Cytokines and other 
signalling molecules
Small proteins that are important in cell signalling (autocrine, paracrine 
and endocrine), especially affecting the immune response
Tumour necrosis factors
Interleukins
Cell surface antigens
Block the recognition of cell surface molecules that modulate cellular 
responses
Cluster of differentiation molecules 
(e.g. CD20, CD80)
(ACE = angiotensin-converting enzyme; AMP = adenosine monophosphate; ATPase = adenosine triphosphatase; GABA = γ-aminobutyric acid; GMP = guanosine 
monophosphate; PPAR = peroxisome proliferator-activated receptor)


16 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
therapeutic index is usually based on adverse effects that might 
require dose reduction or discontinuation. For most drugs, the 
therapeutic index is greater than 100 but there are some notable 
exceptions with therapeutic indices of less than 10 (e.g. digoxin, 
warfarin, insulin, phenytoin, opioids). The doses of such drugs 
have to be titrated carefully for individual patients to maximise 
benefits but avoid adverse effects.
Desensitisation and withdrawal effects
Desensitisation refers to the common situation in which the 
biological response to a drug diminishes when it is given 
continuously or repeatedly. It may be possible to restore the 
response by increasing the dose of the drug but, in some cases, 
the tissues may become completely refractory to its effect.
• Tachyphylaxis describes desensitisation that occurs very 
rapidly, sometimes with the initial dose. This rapid loss of 
response implies depletion of chemicals that may be 
necessary for the pharmacological actions of the drug (e.g. 
a stored neurotransmitter released from a nerve terminal) 
or receptor phosphorylation.
• Tolerance describes a more gradual loss of response to a 
drug that occurs over days or weeks. This slower change 
implies changes in receptor numbers or the development 
of counter-regulatory physiological changes that offset the 
actions of the drug (e.g. accumulation of salt and water in 
response to vasodilator therapy).
• Drug resistance is a term normally reserved for describing 
the loss of effectiveness of an antimicrobial (p. 116) or 
cancer chemotherapy drug.
• In addition to these pharmacodynamic causes of 
desensitisation, reduced response may be the 
consequence of lower plasma and tissue drug 
concentrations as a result of altered pharmacokinetics 
(see below).
When drugs induce chemical, hormonal and physiological 
changes that offset their actions, discontinuation may allow 
these changes to cause ‘rebound’ withdrawal effects (Box 2.3).
response but only within a relatively narrow range of dose; further 
increases in dose beyond this range produce little extra effect. 
The following characteristics of the drug response are useful in 
comparing different drugs:
• Efficacy describes the extent to which a drug can produce 
a target-specific response when all available receptors or 
binding sites are occupied (i.e. Emax on the dose–response 
curve). A full agonist can produce the maximum response 
of which the receptor is capable, while a partial agonist at 
the same receptor will have lower efficacy. Therapeutic 
efficacy describes the effect of the drug on a desired 
biological endpoint and can be used to compare drugs 
that act via different pharmacological mechanisms (e.g. 
loop diuretics induce a greater diuresis than thiazide 
diuretics and therefore have greater therapeutic efficacy).
• Potency describes the amount of drug required for a given 
response. More potent drugs produce biological effects at 
lower doses, so they have a lower ED50. A less potent 
drug can still have an equivalent efficacy if it is given in 
higher doses.
The dose–response relationship varies between patients 
because of variations in the many determinants of pharmacokinetics 
and pharmacodynamics. In clinical practice, the prescriber is 
unable to construct a dose–response curve for each individual 
patient. Therefore, most drugs are licensed for use within a 
recommended range of doses that is expected to reach close to 
the top of the dose–response curve for most patients. However, 
it is sometimes possible to achieve the desired therapeutic 
efficacy at doses towards the lower end of, or even below, the 
recommended range.
Therapeutic index
The adverse effects of drugs are often dose-related in a similar 
way to the beneficial effects, although the dose–response curve 
for these adverse effects is normally shifted to the right (Fig. 2.2). 
The ratio of the ED50 for therapeutic efficacy and for a major 
adverse effect is known as the ‘therapeutic index’. In reality, 
drugs have multiple potential adverse effects, but the concept of 
 2.3 Examples of drugs associated with withdrawal effects
Drug
Symptoms
Signs
Treatment
Alcohol
Anxiety, panic, paranoid delusions, 
visual and auditory hallucinations
Agitation, restlessness, 
delirium, tremor, tachycardia, 
ataxia, disorientation, seizures
Treat immediate withdrawal 
syndrome with benzodiazepines
Barbiturates, benzodiazepines
Similar to alcohol
Similar to alcohol
Transfer to long-acting 
benzodiazepine then gradually 
reduce dosage
Glucocorticoids
Weakness, fatigue, decreased 
appetite, weight loss, nausea, 
vomiting, diarrhoea, abdominal pain
Hypotension, hypoglycaemia
Prolonged therapy suppresses the 
hypothalamic–pituitary–adrenal axis 
and causes adrenal insufficiency 
requiring glucocorticoid replacement. 
Withdrawal should be gradual after 
prolonged therapy (p. 670)
Opioids
Rhinorrhoea, sneezing, yawning, 
lacrimation, abdominal and leg 
cramping, nausea, vomiting, diarrhoea
Dilated pupils
Transfer addicts to long-acting 
agonist methadone
Selective serotonin re-uptake 
inhibitors (SSRIs)
Dizziness, sweating, nausea, insomnia, 
tremor, delirium, nightmares
Tremor
Reduce SSRIs slowly to avoid 
withdrawal effects


Principles of clinical pharmacology • 17

Parenteral administration
These routes avoid absorption via the gastrointestinal tract and 
first-pass metabolism in the liver:
• Intravenous (IV). The IV route enables all of a dose to enter 
the systemic circulation reliably, without any concerns 
about absorption or first-pass metabolism (i.e. the dose is 
100% bioavailable), and rapidly achieve a high plasma 
concentration. It is ideal for very ill patients when a rapid, 
certain effect is critical to outcome (e.g. benzathine 
benzylpenicillin for meningococcal meningitis).
• Intramuscular (IM). IM administration is easier to achieve 
than the IV route (e.g. adrenaline (epinephrine) for acute 
anaphylaxis) but absorption is less predictable and 
depends on muscle blood flow.
• Subcutaneous (SC). The SC route is ideal for drugs that 
have to be administered parenterally because of low oral 
bioavailability, are absorbed well from subcutaneous fat, 
and might ideally be injected by patients themselves (e.g. 
insulin, heparin).
• Transdermal. A transdermal patch can enable a drug to be 
absorbed through the skin and into the circulation (e.g. 
oestrogens, nicotine, nitrates).
Other routes of administration
• Topical application of a drug involves direct administration 
to the site of action (e.g. skin, eye, ear). This has the 
advantage of achieving sufficient concentration at this site 
while minimising systemic exposure and the risk of 
adverse effects elsewhere.
• Inhaled (INH) administration allows drugs to be delivered 
directly to a target in the respiratory tree, usually the small 
airways (e.g. salbutamol, beclometasone). However, a 
significant proportion of the inhaled dose may be 
absorbed from the lung or is swallowed and can reach the 
systemic circulation. The most common mode of delivery 
is the metered-dose inhaler but its success depends on 
some degree of manual dexterity and timing (see Fig. 
17.23, p. 571). Patients who find these difficult may use a 
‘spacer’ device to improve drug delivery. A special mode 
Pharmacokinetics
Understanding ‘what the body does to the drug’ (Fig. 2.3) is 
extremely important for prescribers because this forms the basis 
on which the optimal route of administration and dose regimen 
are chosen and explains the majority of inter-individual variation 
in the response to drug therapy.
Drug absorption and routes of administration
Absorption is the process by which drug molecules gain access 
to the blood stream. The rate and extent of drug absorption 
depend on the route of administration (Fig. 2.3).
Enteral administration
These routes involve administration via the gastrointestinal 
tract:
• Oral. This is the most common route of administration 
because it is simple, convenient and readily used by 
patients to self-administer their medicines. Absorption after 
an oral dose is a complex process that depends on the 
drug being swallowed, surviving exposure to gastric acid, 
avoiding unacceptable food binding, being absorbed 
across the small bowel mucosa into the portal venous 
system, and surviving metabolism by gut wall or liver 
enzymes (‘first-pass metabolism’). As a consequence, 
absorption is frequently incomplete following oral 
administration. The term ‘bioavailability’ describes the 
proportion of the dose that reaches the systemic 
circulation intact.
• Buccal, intranasal and sublingual (SL). These routes 
have the advantage of enabling rapid absorption 
into the systemic circulation without the uncertainties 
associated with oral administration (e.g. organic nitrates 
for angina pectoris, triptans for migraine, opioid 
analgesics).
• Rectal (PR). The rectal mucosa is occasionally used 
as a site of drug administration when the oral route is 
compromised because of nausea and vomiting or 
unconsciousness (e.g. diazepam in status epilepticus).
Fig. 2.3 Pharmacokinetics summary. Most 
drugs are taken orally, are absorbed from the 
intestinal lumen and enter the portal venous 
system to be conveyed to the liver, where they may 
be subject to first-pass metabolism and/or 
excretion in bile. Active drugs then enter the 
systemic circulation, from which they may diffuse 
(or sometimes be actively transported) in and out 
of the interstitial and intracellular fluid 
compartments. Drug that remains in circulating 
plasma is subject to liver metabolism and renal 
excretion. Drugs excreted in bile may be 
reabsorbed, creating an enterohepatic circulation. 
First-pass metabolism in the liver is avoided if 
drugs are administered via the buccal or rectal 
mucosa, or parenterally (e.g. by intravenous 
injection). 
I
n
t
e
r
s
t
i
t
i
a
l
 
f
l
u
i
d
Intracellular
fluid
Kidney
Liver
Parenteral
Mouth
Stomach
Small
intestine
Large
intestine
Rectum
Buccal
Excretion
in urine
Excretion
in faeces
Portal
venous system
Intestinal wall enzymes
 Liver enzymes
Metabolism
Circulating
plasma
Rectal
Oral


18 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
Drug excretion
Excretion is the process by which drugs and their metabolites 
are removed from the body.
Renal excretion is the usual route of elimination for drugs or 
their metabolites that are of low molecular weight and sufficiently 
water-soluble to avoid reabsorption from the renal tubule. Drugs 
bound to plasma proteins are not filtered by the glomeruli. The 
pH of the urine is more acidic than that of plasma, so that 
some drugs (e.g. salicylates) become un-ionised and tend to 
of inhaled delivery is via a nebulised solution created by 
using pressurised oxygen or air to break up solutions and 
suspensions into small aerosol droplets that can be 
directly inhaled from the mouthpiece of the device.
Drug distribution
Distribution is the process by which drug molecules transfer into 
and out of the blood stream. This is influenced by the drug’s 
molecular size and lipid solubility, the extent to which it binds to 
proteins in plasma, its susceptibility to drug transporters expressed 
on cell surfaces, and its binding to its molecular target and to 
other cellular proteins (which can be irreversible). Most drugs 
diffuse passively across capillary walls down a concentration 
gradient into the interstitial fluid until the concentration of free drug 
molecules in the interstitial fluid is equal to that in the plasma. 
As drug molecules in the blood are removed by metabolism or 
excretion, the plasma concentration falls, drug molecules diffuse 
back from the tissue compartment into the blood and eventually 
all will be eliminated. Note that this reverse movement of drug 
away from the tissues will be prevented if further drug doses 
are administered and absorbed into the plasma.
Volume of distribution
The apparent volume of distribution (Vd) is the volume into which 
a drug appears to have distributed following intravenous injection. 
It is calculated from the equation
Vd
D C
=

where D is the amount of drug given and C0 is the initial plasma 
concentration (Fig. 2.4A). Drugs that are highly bound to plasma 
proteins may have a Vd below 10 L (e.g. warfarin, aspirin), while 
those that diffuse into the interstitial fluid but do not enter cells 
because they have low lipid solubility may have a Vd between 10 
and 30 L (e.g. gentamicin, amoxicillin). It is an ‘apparent’ volume 
because those drugs that are lipid-soluble and highly tissue-bound 
may have a Vd of greater than 100 L (e.g. digoxin, amitriptyline). 
Drugs with a larger Vd have longer half-lives (see below), take 
longer to reach steady state on repeated administration and are 
eliminated more slowly from the body following discontinuation.
Drug elimination
Drug metabolism
Metabolism is the process by which drugs are chemically altered 
from a lipid-soluble form suitable for absorption and distribution 
to a more water-soluble form that is necessary for excretion. 
Some drugs, known as ‘prodrugs’, are inactive in the form in 
which they are administered but are converted to an active 
metabolite in vivo.
Phase I metabolism involves oxidation, reduction or hydrolysis 
to make drug molecules suitable for phase II reactions or for 
excretion. Oxidation is by far the most common form of phase 
I reaction and chiefly involves members of the cytochrome 
P450 family of membrane-bound enzymes in the endoplasmic 
reticulum of hepatocytes.
Phase II metabolism involves combining phase I metabolites 
with an endogenous substrate to form an inactive conjugate that 
is much more water-soluble. Reactions include glucuronidation, 
sulphation, acetylation, methylation and conjugation with 
glutathione. This is necessary to enable renal excretion, because 
lipid-soluble metabolites will simply diffuse back into the body 
after glomerular filtration (p. 349).
Fig. 2.4 Drug concentrations in plasma following single and multiple 
drug dosing. A In this example of first-order kinetics following a single 
intravenous dose, the time period required for the plasma drug 
concentration to halve (half-life, t1/2) remains constant throughout the 
elimination process. B After multiple dosing, the plasma drug 
concentration rises if each dose is administered before the previous dose 
has been entirely cleared. In this example, the drug’s half-life is 30 hours, 
so that with daily dosing the peak, average and trough concentrations 
steadily increase as drug accumulates in the body (black line). Steady state 
is reached after approximately 5 half-lives, when the rate of elimination 
(the product of concentration and clearance) is equal to the rate of drug 
absorption (the product of rate of administration and bioavailability). The 
long half-life in this example means that it takes 6 days for steady state to 
be achieved and, for most of the first 3 days of treatment, plasma drug 
concentrations are below the therapeutic range. This problem can be 
overcome if a larger loading dose (red line) is used to achieve steady-state 
drug concentrations more rapidly. 
Time (hours)
A constant fraction of drug
is cleared in unit time
t1/2= 8 hours
C0
Plasma drug concentration




A
Loading
dose
Dose
Dose
Dose
Dose
Dose
Dose
Dose
Subtherapeutic
Dose interval = 24 hours
Time (days)
Plasma drug concentration






Therapeutic range
Adverse effects
t1/2= 30 hours
B


Principles of clinical pharmacology • 19

means that the effects of a new prescription, or dose titration, for 
a drug with a long half-life (e.g. digoxin – 36 hours) may not be 
known for a few days. In contrast, drugs with a very short half-life 
(e.g. dobutamine – 2 minutes) have to be given continuously by 
infusion but reach a new steady state within minutes.
For drugs with a long half-life, if it is unacceptable to wait for 
5 half-lives until concentrations within the therapeutic range are 
achieved, then an initial ‘loading dose’ can be given that is much 
larger than the maintenance dose and equivalent to the amount 
of drug required in the body at steady state. This achieves a 
peak plasma concentration close to the plateau concentration, 
which can then be maintained by successive maintenance doses.
‘Steady state’ actually involves fluctuations in drug concentrations, with peaks just after administration followed by troughs 
just prior to the next administration. The manufacturers of 
medicines recommend dosing regimens that predict that, for 
most patients, these oscillations result in troughs within the 
therapeutic range and peaks that are not high enough to cause 
adverse effects. The optimal dose interval is a compromise 
between convenience for the patient and a constant level 
of drug exposure. More frequent administration (e.g. 25 mg 
4 times daily) achieves a smoother plasma concentration profile 
than 100 mg once daily but is much more difficult for patients 
to sustain. A solution to this need for compromise in dosing 
frequency for drugs with half-lives of less than 24 hours is the 
use of ‘modified-release’ formulations. These allow drugs to 
be absorbed more slowly from the gastrointestinal tract and 
reduce the oscillation in plasma drug concentration profile, which 
is especially important for drugs with a low therapeutic index 
(e.g. levodopa).
Inter-individual variation in drug responses
Prescribers have numerous sources of guidance about how to 
use drugs appropriately (e.g. dose, route, frequency, duration) 
for many conditions. However, this advice is based on average 
dose–response data derived from observations in many individuals. 
When applying this information to an individual patient, prescribers 
must take account of inter-individual variability in response. Some 
of this variability is predictable and good prescribers are able to 
anticipate it and adjust their prescriptions accordingly to maximise 
the chances of benefit and minimise harm. Inter-individual variation 
in responses also mandates that effects of treatment should be 
monitored (p. 34).
Some inter-individual variation in drug response is accounted 
for by differences in pharmacodynamics. For example, the 
beneficial natriuresis produced by the loop diuretic furosemide 
is often significantly reduced at a given dose in patients with 
renal impairment, while delirium caused by opioid analgesics 
is more likely in the elderly. Differences in pharmacokinetics 
more commonly account for different drug responses, however. 
Examples of factors influencing the absorption, metabolism and 
excretion of drugs are shown in Box 2.4.
It is hoped that a significant proportion of the inter-individual 
variation in drug responses can be explained by studying genetic 
differences in single genes (‘pharmacogenetics’; Box 2.5) or the 
effects of multiple gene variants (‘pharmacogenomics’). The aim 
is to identify those patients most likely to benefit from specific 
treatments and those most susceptible to adverse effects. In 
this way, it may be possible to select drugs and dose regimens 
for individual patients to maximise the benefit-to-hazard ratio 
(‘personalised medicine’).
be reabsorbed. Alkalination of the urine can hasten excretion 
(e.g. after a salicylate overdose; p. 138). For some drugs, active 
secretion into the proximal tubule lumen, rather than glomerular 
filtration, is the predominant mechanism of excretion (e.g. 
methotrexate, penicillin).
Faecal excretion is the predominant route of elimination for 
drugs with high molecular weight, including those that are excreted 
in the bile after conjugation with glucuronide in the liver, and 
any drugs that are not absorbed after enteral administration. 
Molecules of drug or metabolite that are excreted in the bile 
enter the small intestine, where they may, if they are sufficiently 
lipid-soluble, be reabsorbed through the gut wall and return to 
the liver via the portal vein (see Fig. 2.3). This recycling between 
the liver, bile, gut and portal vein is known as ‘enterohepatic 
circulation’ and can significantly prolong the residence of drugs 
in the body.
Elimination kinetics
The net removal of drug from the circulation results from a 
combination of drug metabolism and excretion, and is usually 
described as ‘clearance’, i.e. the volume of plasma that is 
completely cleared of drug per unit time.
For most drugs, elimination is a high-capacity process that does 
not become saturated, even at high dosage. The rate of elimination 
is therefore directly proportional to the drug concentration because 
of the ‘law of mass action’, whereby higher drug concentrations 
will drive faster metabolic reactions and support higher renal 
filtration rates. This results in ‘first-order’ kinetics, when a constant 
fraction of the drug remaining in the circulation is eliminated 
in a given time and the decline in concentration over time is 
exponential (Fig. 2.4A). This elimination can be described by 
the drug’s half-life (t1/2), i.e. the time taken for the plasma drug 
concentration to halve, which remains constant throughout the 
period of drug elimination. The significance of this phenomenon 
for prescribers is that the effect of increasing doses on plasma 
concentration is predictable – a doubled dose leads to a doubled 
concentration at all time points.
For a few drugs in common use (e.g. phenytoin, alcohol), 
elimination capacity is exceeded (saturated) within the usual 
dose range. This is called ‘zero-order’ kinetics. Its significance 
for prescribers is that, if the rate of administration exceeds 
the maximum rate of elimination, the drug will accumulate 
progressively, leading to serious toxicity.
Repeated dose regimens
The goal of therapy is usually to maintain drug concentrations 
within the therapeutic range (see Fig. 2.2) over several days (e.g. 
antibiotics) or even for months or years (e.g. antihypertensives, 
lipid-lowering drugs, thyroid hormone replacement therapy). This 
goal is rarely achieved with single doses, so prescribers have 
to plan a regimen of repeated doses. This involves choosing 
the size of each individual dose and the frequency of dose 
administration.
As illustrated in Figure 2.4B, the time taken to reach drug 
concentrations within the therapeutic range depends on the 
half-life of the drug. Typically, with doses administered regularly, 
it takes approximately 5 half-lives to reach a ‘steady state’ in 
which the rate of drug elimination is equal to the rate of drug 
administration. This applies when starting new drugs and when 
adjusting doses of current drugs. With appropriate dose selection, 
steady-state drug concentrations will be maintained within the 
therapeutic range. This is important for prescribers because it 


20 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
 2.5 Examples of pharmacogenetic variations that influence drug response
Genetic variant
Drug affected
Clinical outcome
Pharmacokinetic
Aldehyde dehydrogenase-2 deficiency
Ethanol
Elevated blood acetaldehyde causes facial flushing and 
increased heart rate in ~50% of Japanese, Chinese and other 
Asian populations
Acetylation
Isoniazid, hydralazine, procainamide
Increased responses in slow acetylators, up to 50% of some 
populations
Oxidation (CYP2D6)
Nortriptyline
Increased risk of toxicity in poor metabolisers
Codeine
Reduced responses with slower conversion of codeine to more 
active morphine in poor metabolisers, 10% of European 
populations
Increased risk of toxicity in ultra-fast metabolisers, 3% of 
Europeans but 40% of North Africans
Oxidation (CYP2C18)
Proguanil
Reduced efficacy with slower conversion to active cycloguanil 
in poor metabolisers
Oxidation (CYP2C9)
Warfarin
Polymorphisms known to influence dosages
Oxidation (CYP2C19)
Clopidogrel
Reduced enzymatic activation results in reduced antiplatelet 
effect
Sulphoxidation
Penicillamine
Increased risk of toxicity in poor metabolisers
Human leucocyte antigen (HLA)-B*1502
Carbamazepine
Increased risk of serious dermatological reactions (e.g. 
Stevens–Johnson syndrome) for 1 in 2000 in Caucasian 
populations (much higher in some Asian countries)
Pseudocholinesterase deficiency
Suxamethonium (succinylcholine)
Decreased drug inactivation leads to prolonged paralysis and 
sometimes persistent apnoea requiring mechanical ventilation 
until the drug can be eliminated by alternate pathways; occurs 
in 1 in 1500 people
Pharmacodynamic
Glucose-6-phosphate dehydrogenase 
(G6PD) deficiency
Oxidant drugs, including antimalarials 
(e.g. chloroquine, primaquine)
Risk of haemolysis in G6PD deficiency
Acute intermittent porphyria
Enzyme-inducing drugs
Increased risk of an acute attack
SLC01B1 polymorphism
Statins
Increased risk of rhabdomyolysis
HLA-B*5701 polymorphism
Abacavir
Increased risk of skin hypersensitivity reactions
HLA-B*5801 polymorphism
Allopurinol
Increased risk of rashes in Han Chinese
HLA-B*1502 polymorphism
Carbamazepine
Increased risk of skin hypersensitivity reactions in Han Chinese
Hepatic nuclear factor 1 alpha (HNF1A) 
polymorphism
Sulphonylureas
Increased sensitivity to the blood glucose-lowering effects
Human epidermal growth factor receptor 
2 (HER2)-positive breast cancer cells
Trastuzumab
Increased sensitivity to the inhibitory effects on growth and 
division of the target cancer cells
Age
• Drug metabolism is low in the fetus and newborn, may be enhanced 
in young children, and becomes less effective with age
• Drug excretion falls with the age-related decline in renal function
Sex
• Women have a greater proportion of body fat than men, increasing the 
volume of distribution and half-life of lipid-soluble drugs
Body weight
• Obesity increases volume of distribution and half-life of lipid-soluble 
drugs
• Patients with higher lean body mass have larger body compartments 
into which drugs are distributed and may require higher doses
Liver function
• Metabolism of most drugs depends on several cytochrome P450 
enzymes that are impaired in patients with advanced liver disease
• Hypoalbuminaemia influences the distribution of drugs that are highly 
protein-bound
Kidney function
• Renal disease and the decline in renal function with ageing may lead 
to drug accumulation
Gastrointestinal function
• Small intestinal absorption of oral drugs may be delayed by reduced 
gastric motility
• Absorptive capacity of the intestinal mucosa may be reduced in 
disease (e.g. Crohn’s or coeliac disease) or after surgical resection
Food
• Food in the stomach delays gastric emptying and reduces the rate (but 
not usually the extent) of drug absorption
• Some food constituents bind to certain drugs and prevent their 
absorption
Smoking
• Tar in tobacco smoke stimulates the oxidation of certain drugs
Alcohol
• Regular alcohol consumption stimulates liver enzyme synthesis, while 
binge drinking may temporarily inhibit drug metabolism
Drugs
• Drug–drug interactions cause marked variation in pharmacokinetics 
(see Box 2.11)
 2.4 Patient-specific factors that influence pharmacokinetics


Adverse outcomes of drug therapy • 21

Adverse outcomes of drug therapy
The decision to prescribe a drug always involves a judgement 
of the balance between therapeutic benefits and risk of an 
adverse outcome. Both prescribers and patients tend to be more 
focused on the former but a truly informed decision requires 
consideration of both.
Adverse drug reactions
Some important definitions for the adverse effects of drugs are:
• Adverse event. A harmful event that occurs while a patient 
is taking a drug, irrespective of whether the drug is 
suspected of being the cause.
• Adverse drug reaction (ADR). An unwanted or harmful 
reaction that is experienced following the administration of 
a drug or combination of drugs under normal conditions of 
use and is suspected to be related to the drug. An ADR 
will usually require the drug to be discontinued or the dose 
reduced.
• Side-effect. Any effect caused by a drug other than the 
intended therapeutic effect, whether beneficial, neutral 
or harmful. The term ‘side-effect’ is often used 
interchangeably with ‘ADR’, although the former usually 
implies an ADR that occurs during exposure to normal 
therapeutic drug concentrations (e.g. vasodilator-induced 
ankle oedema).
• Hypersensitivity reaction. An ADR that occurs as a result 
of an immunological reaction and often at exposure to 
subtherapeutic drug concentrations. Some of these 
reactions are immediate and result from the interaction of 
drug antigens with immunoglobulin E (IgE) on mast cells 
and basophils, which causes a release of vasoactive 
biomolecules (e.g. penicillin-related anaphylaxis). 
‘Anaphylactoid’ reactions present similarly but occur 
through a direct non-immune-mediated release of the 
same mediators or result from direct complement 
activation (p. 75). Hypersensitivity reactions may occur via 
other mechanisms such as antibody-dependent (IgM or 
IgG), immune complex-mediated or cell-mediated 
pathways.
• Drug toxicity. Adverse effects of a drug that occur 
because the dose or plasma concentration has risen 
above the therapeutic range, either unintentionally or 
intentionally (drug overdose; see Fig. 2.2 and p. 137).
• Drug abuse. The misuse of recreational or therapeutic 
drugs that may lead to addiction or dependence, serious 
physiological injury (such as liver damage), psychological 
harm (abnormal behaviour patterns, hallucinations, 
memory loss) or death (p. 1184).
Prevalence of ADRs
ADRs are a common cause of illness, accounting in the UK 
for approximately 3% of consultations in primary care and 7% 
of emergency admissions to hospital, and affecting around 
15% of hospital inpatients. Many ‘disease’ presentations are 
eventually attributed to ADRs, emphasising the importance of 
always taking a careful drug history (Box 2.6). Factors accounting 
for the rising prevalence of ADRs are the increasing age of 
patients, polypharmacy (higher risk of drug interactions), increasing 
availability of over-the-counter medicines, increasing use of herbal 
or traditional medicines, and the increase in medicines available 
via the Internet that can be purchased without a prescription 
from a health-care professional. Risk factors for ADRs are shown 
in Box 2.7.
 2.7 Risk factors for adverse drug reactions
Patient factors
• Elderly age (e.g. low physiological reserve)
• Gender (e.g. ACE inhibitor-induced cough in women)
• Polypharmacy (e.g. drug interactions)
• Genetic predisposition (see Box 2.5)
• Hypersensitivity/allergy (e.g. β-lactam antibiotics)
• Diseases altering pharmacokinetics (e.g. hepatic or renal 
impairment) or pharmacodynamic responses (e.g. bladder instability)
• Adherence problems (e.g. cognitive impairment)
Drug factors
• Steep dose–response curve (e.g. insulin)
• Low therapeutic index (e.g. digoxin, cytotoxic drugs)
Prescriber factors
• Inadequate understanding of principles of clinical pharmacology
• Inadequate knowledge of the patient
• Inadequate knowledge of the prescribed drug
• Inadequate instructions and warnings provided to patients
• Inadequate monitoring arrangements planned
(ACE = angiotensin-converting enzyme)
 2.6 How to take a drug history
Information from the patient (or carer)
Use language that patients will understand (e.g. ‘medicines’ rather 
than ‘drugs’, which may be mistaken for drugs of abuse) while 
gathering the following information:
• Current prescribed drugs, including formulations (e.g. modifiedrelease tablets), doses, routes of administration, frequency and 
timing, duration of treatment
• Other medications that are often forgotten (e.g. contraceptives, 
over-the-counter drugs, herbal remedies, vitamins)
• Drugs that have been taken in the recent past and reasons for 
stopping them
• Previous drug hypersensitivity reactions, their nature and time 
course (e.g. rash, anaphylaxis)
• Previous ADRs, their nature and time course (e.g. ankle oedema 
with amlodipine)
• Adherence to therapy (e.g. ‘Are you taking your medication 
regularly?’)
Information from GP medical records and/or pharmacist
• Up-to-date list of medications
• Previous ADRs
• Last order dates for each medication
Inspection of medicines
• Drugs and their containers (e.g. blister packs, bottles, vials) should 
be inspected for name, dosage, and the number of dosage forms 
taken since dispensed
(ADR = adverse drug reaction)


22 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
 2.9 DoTS classification of adverse drug reactions
Category
Example
Dose
Below therapeutic dose
Anaphylaxis with penicillin
In the therapeutic dose range
Nausea with morphine
At high doses
Hepatotoxicity with paracetamol
Timing
With the first dose
Anaphylaxis with penicillin
Early stages of treatment
Hyponatraemia with diuretics
On stopping treatment
Benzodiazepine withdrawal syndrome
Significantly delayed
Clear-cell cancer with 
diethylstilboestrol
Susceptibility
See patient factors in Box 2.7
(INR = international normalised ratio)
 2.8 Drugs that are common causes of adverse 
drug reactions
Drug or drug class
Common adverse drug reactions
ACE inhibitors
(e.g. lisinopril)
Renal impairment
Hyperkalaemia
Antibiotics
(e.g. amoxicillin)
Nausea
Diarrhoea
Anticoagulants
(e.g. warfarin, heparin)
Bleeding
Antipsychotics
(e.g. haloperidol)
Falls
Sedation
Delirium
Aspirin
Gastrotoxicity (dyspepsia, 
gastrointestinal bleeding)
Benzodiazepines
(e.g. diazepam)
Drowsiness
Falls
β-blockers
(e.g. atenolol)
Cold peripheries
Bradycardia
Calcium channel blockers
(e.g. amlodipine)
Ankle oedema
Digoxin
Nausea and anorexia
Bradycardia
Diuretics
(e.g. furosemide, 
bendroflumethiazide)
Dehydration
Electrolyte disturbance 
(hypokalaemia, hyponatraemia)
Hypotension
Renal impairment
Insulin
Hypoglycaemia
NSAIDs
(e.g. ibuprofen)
Gastrotoxicity (dyspepsia, 
gastrointestinal bleeding)
Renal impairment
Opioid analgesics
(e.g. morphine)
Nausea and vomiting
Delirium
Constipation
(ACE = angiotensin-converting enzyme; NSAID = non-steroidal anti-inflammatory 
drug)
ADRs are important because they reduce quality of life for 
patients, reduce adherence to and therefore efficacy of beneficial 
treatments, cause diagnostic confusion, undermine the confidence 
of patients in their health-care professional(s) and consume 
health-care resources.
Retrospective analysis of ADRs has shown that more than 
half could have been avoided if the prescriber had taken more 
care in anticipating the potential hazards of drug therapy. 
For example, non-steroidal anti-inflammatory drug (NSAID) 
use accounts for many thousands of emergency admissions, 
gastrointestinal bleeding episodes and a significant number of 
deaths. In many cases, the patients are at increased risk due 
to their age, interacting drugs (e.g. aspirin, warfarin) or a past 
history of peptic ulcer disease. Drugs that commonly cause 
ADRs are listed in Box 2.8.
Prescribers and their patients ideally want to know the 
frequency with which ADRs occur for a specific drug. Although 
this may be well characterised for more common ADRs observed 
in clinical trials, it is less clear for rarely reported ADRs when the 
total numbers of reactions and patients exposed are not known. 
The words used to describe frequency can be misinterpreted by 
patients but widely accepted meanings include: very common 
(10% or more), common (1–10%), uncommon (0.1–1%), rare 
(0.01–0.1%) and very rare (0.01% or less).
Classification of ADRs
ADRs have traditionally been classified into two major groups:
• Type A (‘augmented’) ADRs. These are predictable from 
the known pharmacodynamic effects of the drug and are 
dose-dependent, common (detected early in drug 
development) and usually mild. Examples include 
constipation caused by opioids, hypotension caused by 
antihypertensives and dehydration caused by diuretics.
• Type B (‘bizarre’) ADRs. These are not predictable, are not 
obviously dose-dependent in the therapeutic range, are 
rare (remaining undiscovered until the drug is marketed) 
and often severe. Patients who experience type B 
reactions are generally ‘hyper-susceptible’ because of 
unpredictable immunological or genetic factors (e.g. 
anaphylaxis caused by penicillin, peripheral neuropathy 
caused by isoniazid in poor acetylators).
This simple classification has shortcomings, and a more 
detailed classification based on dose (see Fig. 2.2), timing and 
susceptibility (DoTS) is now used by those analysing ADRs in 
greater depth (Box 2.9). The AB classification can be extended 
as a reminder of some other types of ADR:
• Type C (‘chronic/continuous’) ADRs. These occur only 
after prolonged continuous exposure to a drug. Examples 
include osteoporosis caused by glucocorticoids, 
retinopathy caused by chloroquine, and tardive dyskinesia 
caused by phenothiazines.
• Type D (‘delayed’) ADRs. These are delayed until long 
after drug exposure, making diagnosis difficult. Examples 
include malignancies that may emerge after 
immunosuppressive treatment post-transplantation (e.g. 
azathioprine, tacrolimus) and vaginal cancer occurring 
many years after exposure to diethylstilboestrol.
• Type E (‘end-of-treatment’) ADRs. These occur after 
abrupt drug withdrawal (see Box 2.3).
A teratogen is a drug with the potential to affect the development 
of the fetus in the first 10 weeks of intrauterine life (e.g. phenytoin, 
warfarin). The thalidomide disaster in the early 1960s highlighted 
the risk of teratogenicity and led to mandatory testing of all new 
drugs. Congenital defects in a live infant or aborted fetus should 


Adverse outcomes of drug therapy • 23

of prescribers of a particular drug are issued with questionnaires 
concerning the clinical outcome for their patients, and the 
collection of population statistics. Many health-care systems 
routinely collect patient-identifiable data on prescriptions (a 
surrogate marker of exposure to a drug), health-care events 
(e.g. hospitalisation, operations, new clinical diagnoses) and 
other clinical data (e.g. haematology, biochemistry). As these 
records are linked, with appropriate safeguards for confidentiality 
and data protection, they are providing a much more powerful 
mechanism for assessing both the harms and benefits of drugs.
All prescribers will inevitably see patients experiencing ADRs 
caused by prescriptions written by themselves or their colleagues. 
It is important that these are recognised early. In addition to the 
features in Box 2.10, features that should raise suspicion of an 
ADR and the need to respond (by drug withdrawal, dosage 
reduction or reporting to the regulatory authorities) include:
• concern expressed by a patient that a drug has 
harmed them
• abnormal clinical measurements (e.g. blood pressure, 
temperature, pulse, blood glucose and weight) or 
laboratory results (e.g. abnormal liver or renal function, low 
haemoglobin or white cell count) while on drug therapy
• new therapy started that could be in response to an ADR 
(e.g. omeprazole, allopurinol, naloxone)
• the presence of risk factors for ADRs (see Box 2.7).
Drug interactions
A drug interaction has occurred when the administration of one 
drug increases or decreases the beneficial or adverse responses 
to another drug. Although the number of potential interacting drug 
combinations is very large, only a small number are common in 
clinical practice. Important drug interactions are most likely to 
occur when the affected drug has a low therapeutic index, steep 
dose–response curve, high first-pass or saturable metabolism, 
or a single mechanism of elimination.
Mechanisms of drug interactions
Pharmacodynamic interactions occur when two drugs produce 
additive, synergistic or antagonistic effects at the same drug 
target (e.g. receptor, enzyme) or physiological system (e.g. 
electrolyte excretion, heart rate). These are the most common 
interactions in clinical practice and some important examples 
are given in Box 2.11.
Pharmacokinetic interactions occur when the administration 
of a second drug alters the concentration of the first at its site 
of action. There are numerous potential mechanisms:
• Absorption interactions. Drugs that either delay (e.g. 
anticholinergic drugs) or enhance (e.g. prokinetic drugs) 
gastric emptying influence the rate of rise in plasma 
concentration of other drugs but not the total amount of 
drug absorbed. Drugs that bind to form insoluble 
complexes or chelates (e.g. aluminium-containing 
antacids binding with ciprofloxacin) can reduce drug 
absorption.
• Distribution interactions. Co-administration of drugs that 
compete for protein binding in plasma (e.g. phenytoin and 
diazepam) can increase the unbound drug concentration, 
but the effect is usually short-lived due to increased 
elimination and hence restoration of the pre-interaction 
equilibrium.
provoke suspicion of an ADR and a careful exploration of drug 
exposures (including self-medication and herbal remedies).
Detecting ADRs – pharmacovigilance
Type A ADRs become apparent early in the development of a 
new drug. By the time a new drug is licensed and launched 
on to a possible worldwide market, however, a relatively small 
number of patients (just several hundred) may have been exposed 
to it, meaning that rarer but potentially serious type B ADRs 
may remain undiscovered. Pharmacovigilance is the process of 
detecting (‘signal generation’) and evaluating ADRs in order to 
help prescribers and patients to be better informed about the 
risks of drug therapy. Drug regulatory agencies may respond to 
this information by placing restrictions on the licensed indications, 
reducing the recommended dose range, adding special warnings 
and precautions for prescribers in the product literature, writing 
to all health-care professionals or withdrawing the product from 
the market.
Voluntary reporting systems allow health-care professionals and 
patients to report suspected ADRs to the regulatory authorities. 
A good example is the ‘Yellow Card’ scheme that was set up 
in the UK in response to the thalidomide tragedy. Reports are 
analysed to assess the likelihood that they represent a true 
ADR (Box 2.10). Although voluntary reporting is a continuously 
operating and effective early-warning system for previously 
unrecognised rare ADRs, its weaknesses include low reporting 
rates (only 3% of all ADRs and 10% of serious ADRs are ever 
reported), an inability to quantify risk (because the ratio of ADRs 
to prescriptions is unknown), and the influence of prescriber 
awareness on likelihood of reporting (reporting rates rise rapidly 
following publicity about potential ADRs).
More systematic approaches to collecting information on 
ADRs include ‘prescription event monitoring’, in which a sample 
 2.10 TREND analysis of suspected adverse 
drug reactions
Factor
Key question
Comment
Temporal 
relationship
What is the time 
interval between the 
start of drug therapy 
and the reaction?
Most ADRs occur soon after 
starting treatment and 
within hours in the case of 
anaphylactic reactions
Re-challenge
What happens when 
the patient is 
re-challenged with 
the drug?
Re-challenge is rarely 
possible because of the 
need to avoid exposing 
patients to unnecessary risk
Exclusion
Have concomitant 
drugs and other 
non-drug causes 
been excluded?
ADR is a diagnosis of 
exclusion following clinical 
assessment and relevant 
investigations for non-drug 
causes
Novelty
Has the reaction 
been reported 
before?
The suspected ADR may 
already be recognised and 
mentioned in the SPC 
approved by the regulatory 
authorities
De-challenge
Does the reaction 
improve when the 
drug is withdrawn or 
the dose is reduced?
Most, but not all, ADRs 
improve on drug 
withdrawal, although 
recovery may be slow
(SPC = summary of product characteristics)


24 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
consequences of drug–drug interactions by taking a careful 
drug history (see Box 2.6) before prescribing additional drugs, 
only prescribing for clear indications, and taking special care 
when prescribing drugs with a narrow therapeutic index (e.g. 
warfarin). When prescribing an interacting drug is unavoidable, 
good prescribers will seek further information and anticipate the 
potential risk. This will allow them to provide special warnings for 
the patient and arrange for monitoring, either of the clinical effects 
(e.g. coagulation tests for warfarin) or of plasma concentration 
(e.g. digoxin).
Medication errors
A medication error is any preventable event that may lead to 
inappropriate medication use or patient harm while the medication 
is in the control of the health-care professional or patient. Errors 
may occur in prescribing, dispensing, preparing solutions, 
administration or monitoring. Many ADRs are considered in 
retrospect to have been ‘avoidable’ with more care or forethought; 
in other words, an adverse event considered by one prescriber 
to be an unfortunate ADR might be considered by another to 
be a prescribing error.
Medication errors are very common. Several thousand 
medication orders are dispensed and administered each day 
in a medium-sized hospital. Recent UK studies suggest that 
• Metabolism interactions. Many drugs rely on metabolism 
by different isoenzymes of cytochrome P450 (CYP) in the 
liver. CYP enzyme inducers (e.g. phenytoin, rifampicin) 
generally reduce plasma concentrations of other drugs, 
although they may enhance activation of prodrugs. CYP 
enzyme inhibitors (e.g. clarithromycin, cimetidine, grapefruit 
juice) have the opposite effect. Enzyme induction effects 
usually take a few days to manifest because of the need 
to synthesise new CYP enzyme, in contrast to the rapid 
effects of enzyme inhibition.
• Excretion interactions. These primarily affect renal 
excretion. For example, drug-induced reduction in 
glomerular filtration rate (e.g. diuretic-induced dehydration, 
angiotensin-converting enzyme (ACE) inhibitors, NSAIDs) 
can reduce the clearance and increase the plasma 
concentration of many drugs, including some with a low 
therapeutic index (e.g. digoxin, lithium, aminoglycoside 
antibiotics). Less commonly, interactions may be due to 
competition for a common tubular organic anion 
transporter (e.g. methotrexate excretion may be inhibited 
by competition with NSAIDs).
Avoiding drug interactions
Drug interactions are increasing as patients are prescribed more 
medicines (polypharmacy). Prescribers can avoid the adverse 
 2.11 Common drug interactions
Mechanism
Object drug
Precipitant drug
Result
Pharmaceutical*
Chemical reaction
Sodium 
bicarbonate
Calcium gluconate
Precipitation of insoluble calcium carbonate
Pharmacokinetic
Reduced absorption
Tetracyclines
Calcium, aluminium, and 
magnesium salts
Reduced tetracycline absorption
Reduced protein binding
Phenytoin
Aspirin
Increased unbound and reduced total phenytoin 
plasma concentration
Reduced metabolism:
 CYP3A4
Amiodarone
Grapefruit juice
Cardiac arrhythmias because of prolonged QT 
interval (p. 476)
Warfarin
Clarithromycin
Enhanced anticoagulation
 CYP2C19
Phenytoin
Omeprazole
Phenytoin toxicity
 CYP2D6
Clozapine
Paroxetine
Clozapine toxicity
 Xanthine oxidase
Azathioprine
Allopurinol
Azathioprine toxicity
 Monoamine oxidase
Catecholamines
Monoamine oxidase inhibitors
Hypertensive crisis due to monoamine toxicity
Increased metabolism (enzyme 
induction)
Ciclosporin
St John’s wort
Loss of immunosuppression
Reduced renal elimination
Lithium
Diuretics
Lithium toxicity
Methotrexate
NSAIDs
Methotrexate toxicity
Pharmacodynamic
Direct antagonism at same receptor
Opioids
Naloxone
Reversal of opioid effects used therapeutically
Salbutamol
Atenolol
Inhibits bronchodilator effect
Direct potentiation in same organ 
system
Benzodiazepines
Alcohol
Increased sedation
ACE inhibitors
NSAIDs
Increased risk of renal impairment
Indirect potentiation by actions in 
different organ systems
Digoxin
Diuretics
Digoxin toxicity enhanced because of hypokalaemia
Warfarin
Aspirin, NSAIDs
Increased risk of bleeding because of gastrotoxicity 
and antiplatelet effects
Diuretics
ACE inhibitors
Blood pressure reduction (may be therapeutically 
advantageous) because of the increased activity of 
the renin–angiotensin system in response to diuresis
*Pharmaceutical interactions are related to the formulation of the drugs and occur before drug absorption.
(ACE = angiotensin-converting enzyme; NSAID = non-steroidal anti-inflammatory drug)


Adverse outcomes of drug therapy • 25

7–9% of hospital prescriptions contain an error, and most are 
written by junior doctors. Common prescribing errors in hospitals 
include omission of medicines (especially failure to prescribe 
regular medicines at the point of admission or discharge, i.e. 
‘medicines reconciliation’), dosing errors, unintentional prescribing 
and poor use of documentation (Box 2.12).
Most prescription errors result from a combination of failures 
by the individual prescriber and the health-service systems in 
which they work (Box 2.13). Health-care organisations increasingly 
encourage reporting of errors within a ‘no-blame culture’ so 
that they can be subject to ‘root cause analysis’ using human 
error theory (Fig. 2.5). Prevention is targeted at the factors in 
Box 2.13, and can be supported by prescribers communicating 
and cross-checking with colleagues (e.g. when calculating doses 
adjusted for body weight, or planning appropriate monitoring 
after drug administration), and by health-care systems providing 
clinical pharmacist support (e.g. for checking the patient’s previous 
medications and current prescriptions) and electronic prescribing 
(which avoids errors due to illegibility or serious dosing mistakes, 
and may be combined with a clinical decision support system 
to take account of patient characteristics and drug history, 
and provide warnings of potential contraindications and drug 
interactions).
 2.13 Causes of prescribing errors
Systems factors
• Working hours of prescribers (and others)
• Patient throughput
• Professional support and supervision by colleagues
• Availability of information (medical records)
• Design of prescription forms
• Distractions
• Availability of decision support
• Checking routines (e.g. clinical pharmacy)
• Reporting and reviewing of incidents
Prescriber factors
Knowledge
• Clinical pharmacology principles
• Drugs in common use
• Therapeutic problems commonly encountered
• Knowledge of workplace systems
Skills
• Taking a good drug history
• Obtaining information to support prescribing
• Communicating with patients
• Numeracy and calculations
• Prescription writing
Attitudes
• Coping with risk and uncertainty
• Monitoring of prescribing
• Checking routines
 2.12 Hospital prescribing errors
Error type
Approximate 
% of total
Omission on admission

Underdose

Overdose

Strength/dose missing

Omission on discharge

Administration times incorrect/missing

Duplication

Product or formulation not specified

Incorrect formulation

No maximum dose

Unintentional prescribing

No signature

Clinical contraindication

Incorrect route

No indication

Intravenous instructions incorrect/missing

Drug not prescribed but indicated

Drug continued for longer than needed

Route of administration missing

Start date incorrect/missing

Risk of drug interaction
< 0.5
Controlled drug requirements incorrect/missing
< 0.5
Daily dose divided incorrectly
< 0.5
Significant allergy
< 0.5
Drug continued in spite of adverse effects
< 0.5
Premature discontinuation
< 0.5
Failure to respond to out-of-range drug level
< 0.5
Fig. 2.5 Human error theory. Unintended errors may occur because the 
prescriber fails to complete the prescription correctly (a slip; e.g. writes 
the dose in ‘mg’ not ‘micrograms’) or forgets part of the action that is 
important for success (a lapse; e.g. forgets to co-prescribe folic acid with 
methotrexate); prevention requires the system to provide appropriate 
checking routines. Intended errors occur when the prescriber acts 
incorrectly due to lack of knowledge (a mistake; e.g. prescribes atenolol for 
a patient with known severe asthma because of ignorance about the 
contraindication); prevention must focus on training the prescriber. 
Planned
action
Prescribing
Intended
action
Correct
action
Intended
outcome
Unintended
action
Lapse
Slip
Wrong plan selected
(Causes include
poor training and
lack of experience)
Correct plan known
but not executed
(Causes include
workload, time
pressures, distractions)
Prescription not
as intended
Prescriber unaware
Prescription incomplete
or forgotten
Prescriber may remember
Violation
Mistake
Prescription as intended
but written based on
the wrong principles or
lack of knowledge
Prescriber unaware
Deliberate deviations
from standard practice
Prescriber aware


26 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
cell lines, molecular cloning and purification processes. After the 
patent for the originator product expires, other manufacturers 
may develop similar products (‘biosimilars’) that share similar 
pharmacological actions but are not completely identical. 
‘Biosimilars’ are considered distinct from ‘generic’ medications, as 
complex biological molecules are more susceptible to differences 
in manufacturing processes than conventional small-molecule-type 
pharmaceuticals.
The number of new drugs produced by the pharmaceutical 
industry has declined in recent years. The traditional approach 
of targeting membrane-bound receptors and enzymes with small 
molecules (see Box 2.2) is now giving way to new targets, such 
as complex second-messenger systems, cytokines, nucleic acids 
and cellular networks. These require novel therapeutic agents, 
which present new challenges for ‘translational medicine’, the 
discipline of converting scientific discoveries into a useful medicine 
with a well-defined benefit–risk profile (Box 2.15).
Licensing new medicines
New drugs are given a ‘market authorisation’, based on the 
evidence of quality, safety and efficacy presented by the 
manufacturer. The regulator not only will approve the drug 
but also will take great care to ensure that the accompanying 
information reflects the evidence that has been presented. The 
summary of product characteristics (SPC), or ‘label’, provides 
detailed information about indications, dosage, adverse effects, 
warnings, monitoring and so on. If approved, drugs can be made 
available with different levels of restriction:
• Controlled drug (CD). These drugs are subject to strict 
legal controls on supply and possession, usually due to 
their abuse potential (e.g. opioid analgesics).
 2.14 Clinical development of new drugs
Phase I
• Healthy volunteers (20–80)
• These involve initial single-dose, ‘first-into-man’ studies, followed by 
repeated-dose studies. They aim to establish the basic 
pharmacokinetic and pharmacodynamic properties, and short-term 
safety
• Duration: 6–12 months
Phase II
• Patients (100–200)
• These investigate clinical effectiveness (‘proof of concept’), safety 
and dose–response relationship, often with a surrogate clinical 
endpoint, in the target patient group to determine the optimal 
dosing regimen for larger confirmatory studies
• Duration: 1–2 years
Phase III
• Patients (100s–1000s)
• These are large, expensive clinical trials that confirm safety and 
efficacy in the target patient population, using relevant clinical 
endpoints. They may be placebo-controlled studies or comparisons 
with other active compounds
• Duration: 1–2 years
Phase IV
• Patients (100s–1000s)
• These are undertaken after the medicine has been marketed for 
its first indication to evaluate new indications, new doses or 
formulations, long-term safety or cost-effectiveness
Responding when an error is discovered
All prescribers will make errors. When they do, their first duty 
is to protect the patient’s safety. This will involve a clinical 
review and the taking of any steps that will reduce harm (e.g. 
remedial treatment, monitoring, recording the event in the notes, 
informing colleagues). Patients should be informed if they have 
been exposed to potential harm. For errors that do not reach 
the patient, it is the prescriber’s duty to report them, so that 
others can learn from the experience and take the opportunity to 
reflect on how a similar incident might be avoided in the future.
Drug regulation and management
Given the powerful beneficial and potentially adverse effects 
of drugs, the production and use of medicines are strictly 
regulated (e.g. by the Food and Drug Administration in the USA, 
Medicines and Healthcare Products Regulatory Agency in the 
UK, and Central Drugs Standard Control Organisation in India). 
Regulators are responsible for licensing medicines, monitoring 
their safety (pharmacovigilance; p. 23), approving clinical trials, 
and inspecting and maintaining standards of drug development 
and manufacture.
In addition, because of the high costs of drugs and their 
adverse effects, health-care services must prioritise their use in 
light of the evidence of their benefit and harm, a process referred 
to as ‘medicines management’.
Drug development and marketing
Naturally occurring products have been used to treat illnesses 
for thousands of years and some remain in common use today. 
Examples include morphine from the opium poppy (Papaver 
somniferum), digitalis from the foxglove (Digitalis purpurea), 
curare from the bark of a variety of species of South American 
trees, and quinine from the bark of the Cinchona species. 
Although plants and animals remain a source of discovery, the 
majority of new drugs come from drug discovery programmes 
that aim to identify small-molecule compounds with specific 
interactions with a molecular target that will induce a predicted 
biological effect.
The usual pathway for development of these small molecules 
includes: identifying a plausible molecular target by investigating 
pathways in disease; screening a large library of compounds for 
those that interact with the molecular target in vitro; conducting 
extensive medicinal chemistry to optimise the properties of lead 
compounds; testing efficacy and toxicity of these compounds 
in vitro and in animals; and undertaking a clinical development 
programme (Box 2.14). This process typically takes longer than 
10 years and may cost up to US$1 billion. Manufacturers have 
a defined period of exclusive marketing of the drug while it 
remains protected by an original patent, typically 10–15 years, 
during which time they must recoup the costs of developing 
the drug. Meanwhile, competitor companies will often produce 
similar ‘me too’ drugs of the same class. Once the drug’s patent 
has expired, ‘generic’ manufacturers may step in to produce 
cheaper formulations of the drug. Paradoxically, if a generic drug 
is produced by only one manufacturer, the price may actually 
rise, sometimes substantially. Newer ‘biological’ products are 
based on large molecules (e.g. human recombinant antibodies) 
derived from complex manufacturing processes involving specific 


Drug regulation and management • 27

Managing the use of medicines
Many medicines meet the three key regulatory requirements 
of quality, safety and efficacy. Although prescribers are legally 
entitled to prescribe any of them, it is desirable to limit the choice 
so that treatments for specific diseases can be focused on 
the most effective and cost-effective options, prescribers (and 
patients) gain familiarity with a smaller number of medicines, and 
pharmacies can concentrate stocks on them.
The process of ensuring optimal use of available medicines 
is known as ‘medicines management’ or ‘quality use of 
medicines’. It involves careful evaluation of the evidence of 
benefit and harm from using the medicine, an assessment 
of cost-effectiveness, and support for processes to implement 
the resulting recommendations. These activities usually involve 
both national (e.g. National Institute for Health and Care 
Excellence (NICE) in the UK) and local organisations (e.g. drug 
and therapeutics committees).
Evaluating evidence
The principles of evidence-based medicine are described on 
page 10. Drugs are often evaluated in high-quality randomised 
controlled trials, the results of which can be considered by 
systematic review (Fig. 2.6). Ideally, data are available not only for 
comparison with placebo but also for ‘head-to-head’ comparison 
with alternative therapies. Trials are conducted in selected patient 
populations, however, and are not representative of every clinical 
scenario, so extrapolation to individual patients is not always 
straightforward. Other subtle bias may be introduced because 
of the sources of funding (e.g. pharmaceutical industry) and 
the interests of the investigators in being involved in research 
that has a ‘positive’ impact. These biases may be manifest in 
the way the trials are conducted or in how they are interpreted 
or reported. A common example of the latter is the difference 
between relative and absolute risk of clinical events reported in 
prevention trials. If a clinical event is encountered in the placebo 
arm at a rate of 1 in 50 patients (2%) but only 1 in 100 patients 
(1%) in the active treatment arm, then the impact of treatment 
can be described as either a 50% relative risk reduction or 
1% absolute risk reduction. Although the former sounds more 
impressive, it is the latter that is of more importance to the 
• Prescription-only medicine (PoM). These are available only 
from a pharmacist and can be supplied only if prescribed 
by an appropriate practitioner.
• Pharmacy (P). These are available only from a pharmacist 
but can be supplied without a prescription.
• General sales list (GSL). These medicines may be bought 
‘over the counter’ (OTC) from any shop and without a 
prescription.
Although the regulators take great care to agree the exact 
indications for prescribing a medicine, based on the evidence 
provided by the manufacturer, there are some circumstances in 
which prescribers may direct its use outside the terms stated in 
the SPC (‘off-label’ prescribing). Common situations where this 
might occur include prescribing outside the approved age group 
(e.g. prescribing for children) or using an alternative formulation 
(e.g. administering a medicine provided in a solid form as an oral 
solution). Other important examples might include prescribing 
for an indication for which there are no approved medicines or 
where all of the approved medicines have caused unacceptable 
adverse effects. Occasionally, medicines may be prescribed 
when there is no marketing authorisation in the country of use. 
Examples include when a medicine licensed in another country 
is imported for use for an individual patient (‘unlicensed import’) 
or when a patient requires a specific preparation of a medicine 
to be manufactured (‘unlicensed special’). When prescribing is 
‘off-label’ or ‘unlicensed’, there is an increased requirement for 
prescribers to be able to justify their actions and to inform and 
agree the decision with the patient.
Drug marketing
The marketing activities of the pharmaceutical industry are well 
resourced and are important in the process of recouping the 
massive costs of drug development. In some countries, such 
as the USA, it is possible to promote a new drug by direct-toconsumer advertising, although this is illegal in the countries of 
the European Union. A major focus is on promotion to prescribers 
via educational events, sponsorship of meetings, advertisements 
in journals, involvement with opinion leaders, and direct contact 
by company representatives. Such largesse has the potential to 
cause significant conflicts of interest and might tempt prescribers 
to favour one drug over another, even in the face of evidence 
on effectiveness or cost-effectiveness.
 2.15 Novel therapeutic alternatives to conventional small-molecule drugs
Approaches
Therapeutic indications
Challenges
Monoclonal antibodies
Targeting of receptors or other molecules 
with relatively specific antibodies
Cancer
Chronic inflammatory diseases (e.g. rheumatoid 
arthritis, inflammatory bowel disease)
Selectivity of action
Complex manufacturing process
Small interfering RNA (siRNA)
Inhibition of gene expression
Macular degeneration
Delivery to target
Gene therapy
Delivery of modified genes that supplement 
or alter host DNA
Cystic fibrosis
Cancer
Cardiovascular disease
Delivery to target
Adverse effects of delivery vector (e.g. virus)
Stem cell therapy
Stem cells differentiate and replace damaged 
host cells
Parkinson’s disease
Spinal cord injury
Ischaemic heart disease
Delivery to target
Immunological compatibility
Long-term effects unknown


28 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
Implementing recommendations
Many recommendations about drug therapy are included in clinical 
guidelines written by an expert group after systematic review of 
the evidence. Guidelines provide recommendations rather than 
obligations for prescribers and are helpful in promoting more 
consistent and higher-quality prescribing. They are often written 
without concern for cost-effectiveness, however, and may be 
limited by the quality of available evidence. Guidelines cannot 
anticipate the extent of the variation between individual patients 
who may, for example, have unexpected contraindications to 
recommended drugs or choose different priorities for treatment. 
When deviating from respected national guidance, prescribers 
should be able to justify their practice.
Additional recommendations for prescribing are often 
implemented locally or imposed by bodies responsible for 
paying for health care. Most health-care units have a drug and 
therapeutics committee (or equivalent) comprised of senior 
and junior medical staff, pharmacists and nurses, as well as 
managers (because of the implications of the committee’s work 
for governance and resources). This group typically develops 
local prescribing policy and guidelines, maintains a local drug 
formulary and evaluates requests to use new drugs. The local 
formulary contains a more limited list than any national formulary 
(e.g. British National Formulary) because the latter lists all licensed 
medicines that can be prescribed legally, while the former contains 
only those that the health-care organisation has approved for 
local use. The local committee may also be involved, with local 
specialists, in providing explicit protocols for management of 
clinical scenarios.
Prescribing in practice
Decision-making in prescribing
Prescribing should be based on a rational approach to a series 
of challenges (see Box 2.1).
individual patient. It means that the number of patients that needed 
to be treated (NNT) for 1 to benefit (compared to placebo) was 
100. This illustrates how large clinical trials of new medicines 
can produce highly statistically significant and impressive relative 
risk reductions and still predict a very modest clinical impact.
Evaluating cost-effectiveness
New drugs often represent an incremental improvement over 
the current standard of care but are usually more expensive. 
Health-care budgets are limited in every country and so it is 
impossible to fund all new medicines. This means that very 
difficult financial decisions have to be taken with due regard 
to the principles of ethical justice. The main approach taken is 
cost-effectiveness analysis (CEA), where a comparison is made 
between the relative costs and outcomes of different courses of 
action. CEA is usually expressed as a ratio where the denominator 
is a gain in health and the numerator is the cost associated with 
the health gain. A major challenge is to compare the value of 
interventions for different clinical outcomes. One method is to 
calculate the quality-adjusted life years (QALYs) gained if the 
new drug is used rather than standard treatment. This analysis 
involves estimating the ‘utility’ of various health states between 
1 (perfect health) and 0 (dead). If the additional costs and any 
savings are known, then it is possible to derive the incremental 
cost-effectiveness ratio (ICER) in terms of cost/QALY. These 
principles are exemplified in Box 2.16. There are, however, 
inherent weaknesses in this kind of analysis: it usually depends 
on modelling future outcomes well beyond the duration of the 
clinical trial data that are available; it assumes that QALYs 
gained at all ages are of equivalent value; and the appropriate 
standard care against which the new drug should be compared 
is often uncertain.
These pharmacoeconomic assessments are challenging and 
resource-intensive, and are undertaken at national level in most 
countries, e.g. in the UK by NICE.
Fig. 2.6 Systematic review of the evidence from randomised 
controlled clinical trials. This forest plot shows the effect of warfarin 
compared with placebo on the likelihood of stroke in patients with atrial 
fibrillation in five randomised controlled trials that passed the quality 
criteria required for inclusion in a meta-analysis. For each trial, the purple 
box is proportionate to the number of participants. The tick marks show 
the mean odds ratio and the black lines indicate its 95% confidence 
intervals. Note that not all the trials showed statistically significant effects 
(i.e. the confidence intervals cross 1.0). However, the meta-analysis, 
represented by the black diamond, confirms a highly significant statistical 
benefit. The overall odds ratio is approximately 0.4, indicating a mean 60% 
risk reduction with warfarin treatment in patients with the characteristics of 
the participants in these trials. 
Odds ratio
Favours treatment
0.1
0.2
0.5




Favours placebo
 2.16 Cost-effectiveness analysis
A clinical trial lasting 2 years compares two interventions for the 
treatment of colon cancer:
• Treatment A: standard treatment, cost £1000/year, oral therapy
• Treatment B: new treatment, cost £6000/year, monthly intravenous 
infusions, often followed by a week of nausea.
The new treatment (B) significantly increases the average time to 
progression (18 months versus 12 months) and reduces overall 
mortality (40% versus 60%). The health economist models the survival 
curves from the trial in order to undertake a cost–utility analysis and 
concludes that:
• Intervention A: allows an average patient to live for 2 extra years at 
a utility 0.7 = 1.4 QALYs (cost £2000)
• Intervention B: allows an average patient to live for 3 extra years at 
a utility 0.6 = 1.8 QALYs (cost £18 000).
The health economists conclude that treatment B provides an extra 
0.4 QALYs at an extra cost of £16 000, meaning that the ICER = 
£40 000/QALY. They recommend that the new treatment should not 
be funded on the basis that their threshold for cost acceptability is 
£30 000/QALY.
(ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life year)


Prescribing in practice • 29

Excretion
Drugs that depend on renal excretion for elimination (e.g. digoxin, 
aminoglycoside antibiotics) should be avoided in patients with 
impaired renal function if suitable alternatives exist.
Efficacy
Prescribers normally choose drugs with the greatest efficacy in 
achieving the goals of therapy (e.g. proton pump inhibitors rather 
than H2-receptor antagonists). It may be appropriate, however, 
to compromise on efficacy if other drugs are more convenient, 
safer to use or less expensive.
Avoiding adverse effects
Prescribers should be wary of choosing drugs that are more 
likely to cause adverse effects (e.g. cephalosporins rather than 
alternatives for patients allergic to penicillin) or worsen coexisting 
conditions (e.g. β-blockers as treatment for angina in patients 
with asthma).
Features of the disease
This is most obvious when choosing antibiotic therapy, which 
should be based on the known or suspected sensitivity of the 
infective organism (p. 116).
Severity of disease
The choice of drug should be appropriate to disease severity 
(e.g. paracetamol for mild pain, morphine for severe pain).
Coexisting disease
This may be either an indication or a contraindication to therapy. 
Hypertensive patients might be prescribed a β-blocker if they 
also have left ventricular impairment but not if they have asthma.
Avoiding adverse drug interactions
Prescribers should avoid giving combinations of drugs that might 
interact, either directly or indirectly (see Box 2.11).
Patient adherence to therapy
Prescribers should choose drugs with a simple dosing schedule 
or easier administration (e.g. the ACE inhibitor lisinopril once daily 
rather than captopril 3 times daily for hypertension).
Cost
Prescribers should choose the cheaper drug (e.g. a generic 
or biosimilar) if two drugs are of equal efficacy and safety. 
Even if cost is not a concern for the individual patient, it is 
important to remember that unnecessary expenditure will ultimately 
limit choices for other prescribers and patients. Sometimes a 
more costly drug may be appropriate (e.g. if it yields improved 
adherence).
Genetic factors
There are already a small number of examples where genotype 
influences the choice of drug therapy (see Box 2.5).
Choosing a dosage regimen
Prescribers have to choose a dose, route and frequency of 
administration (dosage regimen) to achieve a steady-state drug 
concentration that provides sufficient exposure of the target 
tissue without producing toxic effects. Manufacturers draw up 
dosage recommendations based on average observations in 
many patients but the optimal regimen that will maximise the 
benefit to harm ratio for an individual patient is never certain. 
Making a diagnosis
Ideally, prescribing should be based on a confirmed diagnosis 
but, in reality, many prescriptions are based on the balance of 
probability, taking into account the differential diagnosis (e.g. 
proton pump inhibitors for post-prandial retrosternal discomfort).
Establishing the therapeutic goal
The goals of treatment are usually clear, particularly when relieving 
symptoms (e.g. pain, nausea, constipation). Sometimes the goal 
is less obvious to the patient, especially when aiming to prevent 
future events (e.g. ACE inhibitors to prevent hospitalisation and 
extend life in chronic heart failure). Prescribers should be clear 
about the therapeutic goal against which they will judge success 
or failure of treatment. It is also important to establish that the 
value placed on this goal by the prescriber is shared by the 
patient (concordance).
Choosing the therapeutic approach
For many clinical problems, drug therapy is not absolutely 
mandated. Having taken the potential benefits and harms into 
account, prescribers must consider whether drug therapy is in 
the patient’s interest and is preferred to no treatment or one 
of a range of alternatives (e.g. physiotherapy, psychotherapy, 
surgery). Assessing the balance of benefit and harm is often 
complicated and depends on various features associated with 
the patient, disease and drug (Box 2.17).
Choosing a drug
For most common clinical indications (e.g. type 2 diabetes, 
depression), more than one drug is available, often from more 
than one drug class. Although prescribers often have guidance 
about which represents the rational choice for the average 
patient, they still need to consider whether this is the optimal 
choice for the individual patient. Certain factors may influence 
the choice of drug:
Absorption
Patients may find some formulations easier to swallow than 
others or may be vomiting and require a drug available for 
parenteral administration.
Distribution
Distribution of a drug to a particular tissue sometimes dictates 
choice (e.g. tetracyclines and rifampicin are concentrated in the 
bile, and lincomycin and clindamycin in bones).
Metabolism
Drugs that are extensively metabolised should be avoided in 
severe liver disease (e.g. opioid analgesics).
 2.17 Factors to consider when balancing benefits 
and harms of drug therapy
• Seriousness of the disease or symptom
• Efficacy of the drug
• Seriousness of potential adverse effects
• Likelihood of adverse effects
• Efficacy of alternative drugs or non-drug therapies
• Safety of alternative drugs or non-drug therapies


30 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
Duration
Some drugs require a single dose (e.g. thrombolysis post 
myocardial infarction), while for others the duration of the course 
of treatment is certain at the outset (e.g. antibiotics). For most, 
the duration will be largely at the prescriber’s discretion and will 
depend on response and disease progression (e.g. analgesics, 
antidepressants). For many, the treatment will be long-term (e.g. 
insulin, antihypertensives, levothyroxine).
Involving the patient
Patients should, whenever possible, be engaged in making 
choices about drug therapy. Their beliefs and expectations affect 
the goals of therapy and help in judging the acceptable benefit/
harm balance when selecting treatments. Very often, patients 
may wish to defer to the professional expertise of the prescriber. 
Nevertheless, they play key roles in adherence to therapy and 
in monitoring treatment, not least by providing early warning of 
adverse events. It is important for them to be provided with the 
necessary information to understand the choice that has been 
made, what to expect from the treatment, and any measurements 
that must be undertaken (Box 2.20).
A major drive to include patients has been the recognition that 
up to half of the drug doses for chronic preventative therapy are 
not taken. This is often termed ‘non-compliance’ but is more 
appropriately called ‘non-adherence’, to reflect a less paternalistic 
view of the doctor–patient relationship; it may or may not be 
intentional. Non-adherence to the dose regimen reduces the 
likelihood of benefits to the patient and can be costly in terms 
Rational prescribing involves treating each prescription as an 
experiment and gathering sufficient information to amend it if 
necessary. There are some general principles that should be 
followed, as described below.
Dose titration
Prescribers should generally start with a low dose and titrate 
this slowly upwards as necessary. This cautious approach is 
particularly important if the patient is likely to be more sensitive 
to adverse pharmacodynamic effects (e.g. delirium or postural 
hypotension in the elderly) or have altered pharmacokinetic 
handling (e.g. renal or hepatic impairment), and when using 
drugs with a low therapeutic index (e.g. benzodiazepines, 
lithium, digoxin). There are some exceptions, however. Some 
drugs must achieve therapeutic concentration quickly because 
of the clinical circumstance (e.g. antibiotics, glucocorticoids, 
carbimazole). When early effect is important but there may be a 
delay in achieving steady state because of a drug’s long half-life 
(e.g. digoxin, warfarin, amiodarone), an initial loading dose is 
given prior to establishing the appropriate maintenance dose 
(see Fig. 2.4).
If adverse effects occur, the dose should be reduced or an 
alternative drug prescribed; in some cases, a lower dose may 
suffice if it can be combined with another synergistic drug (e.g. 
the immunosuppressant azathioprine reduces glucocorticoid 
requirements in patients with inflammatory disease). It is 
important to remember that the shape of the dose–response 
curve (see Fig. 2.2) means that higher doses may produce 
little added therapeutic effect and might increase the chances 
of toxicity.
Route
There are many reasons for choosing a particular route of 
administration (Box 2.18).
Frequency
Frequency of doses is usually dictated by a manufacturer’s 
recommendation. Less frequent doses are more convenient 
for patients but result in greater fluctuation between peaks and 
troughs in drug concentration (see Fig. 2.4). This is relevant if the 
peaks are associated with adverse effects (e.g. dizziness with 
antihypertensives) or the troughs are associated with troublesome 
loss of effect (e.g. anti-Parkinsonian drugs). These problems 
can be tackled either by splitting the dose or by employing a 
modified-release formulation, if available.
Timing
For many drugs the time of administration is unimportant. There 
are occasionally pharmacokinetic or therapeutic reasons, however, 
for giving drugs at particular times (Box 2.19).
Formulation
For some drugs there is a choice of formulation, some for use by 
different routes. Some are easier to ingest, particularly by children 
(e.g. elixirs). The formulation is important when writing repeat 
prescriptions for drugs with a low therapeutic index that come 
in different formulations (e.g. lithium, phenytoin, theophylline). 
Even if the prescribed dose remains constant, an alternative 
formulation may differ in its absorption and bioavailability, and 
hence plasma drug concentration. These are examples of the 
small number of drugs that should be prescribed by specific 
brand name rather than ‘generic’ international non-proprietary 
name (INN).
 2.18 Factors influencing the route of 
drug administration
Reason
Example
Only one route possible
Dobutamine (IV)
Gliclazide (oral)
Patient adherence
Phenothiazines and thioxanthenes 
(2 weekly IM depot injections rather 
than daily tablets, in schizophrenia)
Poor absorption
Furosemide (IV rather than oral, in 
severe heart failure)
Rapid action
Haloperidol (IM rather than oral, in acute 
behavioural disturbance)
Vomiting
Phenothiazines (PR or buccal rather 
than oral, in nausea)
Avoidance of first-pass 
metabolism
Glyceryl trinitrate (SL, in angina pectoris)
Certainty of effect
Amoxicillin (IV rather than oral, in acute 
chest infection)
Direct access to the site 
of action (avoiding 
unnecessary systemic 
exposure)
Bronchodilators (INH rather than oral, in 
asthma)
Local application of drugs to skin, eyes 
etc.
Ease of access
Diazepam (PR, if IV access is difficult in 
status epilepticus)
Adrenaline (epinephrine) (IM, if IV 
access is difficult in acute anaphylaxis)
Comfort
Morphine (SC rather than IV in terminal 
care)
(IM = intramuscular; INH = by inhalation; IV = intravenous; PR = per rectum; 
SC = subcutaneous; SL = sublingual)


Prescribing in practice • 31

Stopping drug therapy
It is also important to review long-term treatment at regular 
intervals to assess whether continued treatment is required. 
Elderly patients are keen to reduce their medication burden 
and are often prepared to compromise on the original goals of 
long-term preventative therapy to achieve this.
Prescribing in special circumstances
Prescribing for patients with renal disease
Patients with renal impairment are readily identified by having 
a low estimated glomerular filtration rate (eGFR < 60 mL/min) 
based on their serum creatinine, age, sex and ethnic group 
(p. 386). This group includes a large proportion of elderly patients. 
If a drug (or its active metabolites) is eliminated predominantly by 
the kidneys, it will tend to accumulate and so the maintenance 
dose must be reduced. For some drugs, renal impairment makes 
patients more sensitive to their adverse pharmacodynamic effects. 
of wasted medicines and unnecessary health-care episodes. An 
important reason may be lack of concordance with the prescriber 
about the goals of treatment. A more open and shared decisionmaking process might resolve any misunderstandings at the outset 
and foster improved adherence, as well as improved satisfaction 
with health-care services and confidence in prescribers. Fully 
engaging patients in shared decision-making is sometimes 
constrained by various factors, such as limited consultation 
time and challenges in communicating complex numerical data.
Writing the prescription
The culmination of the planning described above is writing an 
accurate and legible prescription so that the drug will be dispensed 
and administered as planned (see ‘Writing prescriptions’ below).
Monitoring treatment effects
Rational prescribing involves monitoring for the beneficial and 
adverse effects of treatment so that the balance remains in favour 
of a positive outcome (see ‘Monitoring drug therapy’ below).
 2.19 Factors influencing the timing of drug therapy
Drug
Recommended timing
Reasons
Diuretics (e.g. furosemide)
Once in the morning
Night-time diuresis undesirable
Statins (e.g. simvastatin)
Once at night
HMG CoA reductase activity is greater at night
Antidepressants (e.g. amitriptyline)
Once at night
Allows adverse effects to occur during sleep
Salbutamol
Before exercise
Reduces symptoms in exercise-induced asthma
Glyceryl trinitrate
Paracetamol
When required
Relief of acute symptoms only
Regular nitrate therapy (e.g. isosorbide 
mononitrate)
Eccentric dosing regimen (e.g. twice 
daily at 8 a.m. and 2 p.m.)
Reduces development of nitrate tolerance by allowing 
drug-free period each night
Aspirin
With food
Minimises gastrotoxic effects
Alendronate
Once in the morning before breakfast, 
sitting upright
Minimises risk of oesophageal irritation
Tetracyclines
2 hours before or after food or 
antacids
Divalent and trivalent cations chelate tetracyclines, preventing 
absorption
Hypnotics (e.g. temazepam)
Once at night
Maximises therapeutic effect and minimises daytime sedation
Antihypertensive drugs (e.g. amlodipine)
Once in the morning
Blood pressure is higher during the daytime
(HMG CoA = 3-hydroxy-3-methylglutaryl-coenzyme A)
 2.20 What patients need to know about their medicines*
Knowledge
Comment
The reason for taking the medicine
How the medicine works
Reinforces the goals of therapy
How to take the medicine
May be important for the effectiveness (e.g. inhaled salbutamol in asthma) and safety (e.g. alendronate 
for osteoporosis) of treatment
What benefits to expect
May help to support adherence or prompt review because of treatment failure
What adverse effects might occur
Discuss common and mild effects that may be transient and might not require discontinuation
Mention rare but serious effects that might influence the patient’s consent
Precautions that improve safety
Explain symptoms to report that might allow serious adverse effects to be averted, monitoring that will be 
required and potentially important drug–drug interactions
When to return for review
This will be important to enable monitoring
*Many medicines are provided with patient information leaflets, which the patient should be encouraged to read.


32 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
Examples of drugs that require extra caution in patients with 
renal disease are listed in Box 2.21.
Prescribing for patients with hepatic disease
The liver has a large capacity for drug metabolism and hepatic 
insufficiency has to be advanced before drug dosages need to 
be modified. Patients who may have impaired metabolism include 
those with jaundice, ascites, hypoalbuminaemia, malnutrition or 
encephalopathy. Hepatic drug clearance may also be reduced 
in acute hepatitis, in hepatic congestion due to cardiac failure, 
and in the presence of intrahepatic arteriovenous shunting (e.g. 
in hepatic cirrhosis). There are no good tests of hepatic drugmetabolising capacity or of biliary excretion, so dosage should 
be guided by the therapeutic response and careful monitoring 
for adverse effects. The presence of liver disease also increases 
the susceptibility to adverse pharmacological effects of drugs. 
Some drugs that require extra caution in patients with hepatic 
disease are listed in Box 2.21.
Prescribing for elderly patients
The issues around prescribing in the elderly are discussed in 
Box 2.22.
Prescribing for women who are pregnant 
or breastfeeding
Prescribing in pregnancy should be avoided if possible to minimise 
the risk of adverse effects in the fetus. Drug therapy in pregnancy 
may, however, be required either for a pre-existing problem (e.g. 
epilepsy, asthma, hypothyroidism) or for problems that arise 
during pregnancy (e.g. morning sickness, anaemia, prevention 
of neural tube defects, gestational diabetes, hypertension). 
About 35% of women take drug therapy at least once during 
 2.23 Prescribing in pregnancy
• Teratogenesis: a potential risk, especially when drugs are taken 
between 2 and 8 weeks of gestation (4–10 weeks from last 
menstrual period). Common teratogens include retinoids (e.g. 
isotretinoin), cytotoxic drugs, angiotensin-converting enzyme 
inhibitors, antiepileptics and warfarin. If there is inadvertent 
exposure, then the timing of conception should be established, 
counselling given and investigations undertaken for fetal 
abnormalities.
• Adverse fetal effects in late gestation: e.g. tetracyclines may 
stain growing teeth and bones; sulphonamides displace fetal 
bilirubin from plasma proteins, potentially causing kernicterus; 
opioids given during delivery may be associated with respiratory 
depression in the neonate.
• Altered maternal pharmacokinetics: extracellular fluid volume 
and Vd increase. Plasma albumin falls but other binding globulins 
(e.g. for thyroid and steroid hormones) increase. Glomerular filtration 
increases by approximately 70%, enhancing renal clearance. 
Placental metabolism contributes to increased clearance, e.g. of 
levothyroxine and glucocorticoids. The overall effect is a fall in 
plasma levels of many drugs.
• In practice:
Avoid any drugs unless the risk:benefit analysis is in favour of 
treating (usually the mother).
Use drugs for which there is some record of safety in humans.
Use the lowest dose for the shortest time possible.
Choose the least harmful drug if alternatives are available.
 2.22 Prescribing in old age
• Reduced drug elimination: partly due to impaired renal function.
• Increased sensitivity to drug effects: notably in the brain (leading 
to sedation or delirium) and as a result of comorbidities.
• More drug interactions: largely as a result of polypharmacy.
• Lower starting doses and slower dose titration: often required, 
with careful monitoring of drug effects.
• Drug adherence: may be poor because of cognitive impairment, 
difficulty swallowing (dry mouth) and complex polypharmacy 
regimens. Supplying medicines in pill organisers (e.g. dosette boxes 
or calendar blister packs), providing automatic reminders, and 
regularly reviewing and simplifying the drug regimen can help.
• Some drugs that require extra caution, and their mechanisms:
Digoxin: increased sensitivity of Na+/K+ pump; hypokalaemia due 
to diuretics; renal impairment favours accumulation → increased 
risk of toxicity.
Antihypertensive drugs: reduced baroreceptor function → 
increased risk of postural hypotension.
Antidepressants, hypnotics, sedatives, tranquillisers: increased 
sensitivity of the brain; reduced metabolism → increased risk of 
toxicity.
Warfarin: increased tendency to falls and injury and to bleeding 
from intra- and extracranial sites; increased sensitivity to 
inhibition of clotting factor synthesis → increased risk of 
bleeding.
Clomethiazole, lidocaine, nifedipine, phenobarbital, propranolol, 
theophylline: metabolism reduced → increased risk of toxicity.
Non-steroidal anti-inflammatory drugs: poor renal function → 
increased risk of renal impairment; susceptibility to gastrotoxicity 
→ increased risk of upper gastrointestinal bleeding.
 2.21 Some drugs that require extra caution in 
patients with renal or hepatic disease
Kidney disease
Liver disease
Pharmacodynamic effects enhanced
ACE inhibitors and ARBs (renal 
impairment, hyperkalaemia)
Metformin (lactic acidosis)
Spironolactone (hyperkalaemia)
NSAIDs (impaired renal function)
Sulphonylureas (hypoglycaemia)
Insulin (hypoglycaemia)
Warfarin (increased 
anticoagulation because of 
reduced clotting factor synthesis)
Metformin (lactic acidosis)
Chloramphenicol (bone marrow 
suppression)
NSAIDs (gastrointestinal 
bleeding, fluid retention)
Sulphonylureas (hypoglycaemia)
Benzodiazepines (coma)
Pharmacokinetic handling altered (reduced clearance)
Aminoglycosides (e.g. gentamicin)
Vancomycin
Digoxin
Lithium
Other antibiotics (e.g. 
ciprofloxacin)
Atenolol
Allopurinol
Cephalosporins
Methotrexate
Opioids (e.g. morphine)
Phenytoin
Rifampicin
Propranolol
Warfarin
Diazepam
Lidocaine
Opioids (e.g. morphine)
(ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; 
NSAID = non-steroidal anti-inflammatory drug)
pregnancy and 6% take drug therapy during the first trimester 
(excluding iron, folic acid and vitamins). The most commonly used 
drugs are simple analgesics, antibacterial drugs and antacids. 
Some considerations when prescribing in pregnancy are listed 
in Box 2.23.


Prescribing in practice • 33

Hospital discharge (‘to take out’) medicines
Most patients will be prescribed a short course of their medicines 
at discharge. This prescription is particularly important because it 
usually informs future therapy at the point of transfer of prescribing 
responsibility to primary care. Great care is required to ensure 
that this list is accurate. It is particularly important to ensure that 
any hospital medicines that should be stopped are not included 
and that those intended to be administered for a short duration 
only are clearly identified. It is also important for any significant 
ADRs experienced in hospital to be recorded and any specific 
monitoring or review identified.
Prescribing in primary care
Most of the considerations above are equally applicable to 
primary care (GP) prescriptions. In many health-care systems, 
community prescribing is electronic, making issues of legibility 
irrelevant and often providing basic decision support to limit 
the range of doses that can be written and highlight potential 
drug interactions. Important additional issues more relevant to 
GP prescribing are:
• Formulation. The prescription needs to carry information 
about the formulation for the dispensing pharmacist (e.g. 
tablets or oral suspension).
• Amount to be supplied. In the hospital the pharmacist will 
organise this. Elsewhere it must be specified either as the 
precise number of tablets or as the duration of treatment. 
Creams and ointments should be specified in grams and 
lotions in mL.
• Controlled drugs. Prescriptions for ‘controlled’ drugs (e.g. 
opioid analgesics, with potential for drug abuse) are 
subject to additional legal requirements. In the UK, they 
Drugs that are excreted in breast milk may cause adverse 
effects in the baby. Prescribers should always consult the summary 
of product characteristics for each drug or a reliable formulary 
when treating a pregnant woman or breastfeeding mother.
Writing prescriptions
A prescription is a means by which a prescriber communicates 
the intended plan of treatment to the pharmacist who dispenses 
a medicine and to a nurse or patient who administers it. It should 
be precise, accurate, clear and legible. The two main kinds of 
prescription are those written, dispensed and administered in 
hospital and those written in primary care (in the UK by a GP), 
dispensed at a community pharmacy and self-administered by 
the patient. The information supplied must include:
• the date
• the identification details of the patient
• the name of the drug
• the formulation
• the dose
• the frequency of administration
• the route and method of administration
• the amount to be supplied (primary care only)
• instructions for labelling (primary care only)
• the prescriber’s signature.
Prescribing in hospital
Although GP prescribing is increasingly electronic, most hospital 
prescribing continues to be based around the prescription and 
administration record (the ‘drug chart’) (Fig. 2.7). A variety of 
charts are in use and prescribers must familiarise themselves 
with the local version. Most contain the following sections:
• Basic patient information: will usually include name, age, 
date of birth, hospital number and address. These details 
are often ‘filled in’ using a sticky addressograph label but 
this increases the risk of serious error.
• Previous adverse reactions/allergies: communicates 
important patient safety information based on a careful 
drug history and/or the medical record.
• Other medicines charts: notes any other hospital 
prescription documents that contain current prescriptions 
being received by the patient (e.g. anticoagulants, insulin, 
oxygen, fluids).
• Once-only medications: for prescribing medicines to be 
used infrequently, such as single-dose prophylactic 
antibiotics and other pre-operative medications.
• Regular medications: for prescribing medicines to be taken 
for a number of days or continuously, such as a course of 
antibiotics, antihypertensive drugs and so on.
• ‘As required’ medications: for prescribing for symptomatic 
relief, usually to be administered at the discretion of the 
nursing staff (e.g. antiemetics, analgesics).
Prescribers should be aware of the risks of prescription error 
(Box 2.24 and see Box 2.13), ensure they have considered the 
rational basis for their prescribing decision described above, and 
then follow the guidance illustrated in Figure 2.7 in order to write 
the prescription. It is a basic principle that a prescription will be 
followed by a judgement as to its success or failure and any 
appropriate changes made (e.g. altered dosage, discontinuation 
or substitution).
 2.24 High-risk prescribing moments
• Trying to amend an active prescription (e.g. altering the dose/
timing) – always avoid and start again
• Writing up drugs in the immediate presence of more than one 
prescription chart or set of notes – avoid
• Allowing one’s attention to be diverted in the middle of completing a 
prescription – avoid
• Prescribing ‘high-risk’ drugs (e.g. anticoagulants, opioids, insulin, 
sedatives) – ask for help if necessary
• Prescribing parenteral drugs – take care
• Rushing prescribing (e.g. in the midst of a busy ward round) 
– avoid
• Prescribing unfamiliar drugs – consult the formulary and ask for 
help if necessary
• Transcribing multiple prescriptions from an expired chart to a new 
one – take care to review the rationale for each medicine
• Writing prescriptions based on information from another source 
such as a referral letter (the list may contain errors and some of the 
medicines may be the cause of the patient’s illness) – review the 
justification for each as if it is a new prescription
• Writing up ‘to take out’ drugs (because these will become the 
patient’s regular medication for the immediate future) – take care 
and seek advice if necessary
• Calculating drug doses – ask a colleague to perform an 
independent calculation or use approved electronic dose 
calculators
• Prescribing sound-alike or look-alike drugs (e.g. chlorphenamine 
and chlorpromazine) – take care


34 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
Fig. 2.7 Example of a hospital prescription and administration record (‘drug chart’). A Front page. The correct identification of the patient is 
critical to reducing the risk of an administration error. This page also clearly identifies other prescriptions charts in use and previous adverse reactions to 
drugs to minimise the risk of repeated exposure. Note also the codes employed by the nursing staff to indicate reasons why drugs may not have been 
administered. The patient’s name and date of birth should be written on each page of the chart. The patient’s weight and height may be required to 
calculate safe doses for many drugs with narrow therapeutic indices. B ‘Once-only medicines’. This area is used for prescribing medicines that are 
unlikely to be repeated on a regular basis. Note that the prescriber has written the names of all drugs legibly in block capitals. The generic international 
non-proprietary name (INN) should be used in preference to the brand name (e.g. write ‘SIMVASTATIN’, not ‘ZOCOR’). The only exceptions are when 
variation occurs in the properties of alternative branded formulations (e.g. modified-release preparations of drugs such as lithium, theophylline, phenytoin 
and nifedipine) or when the drug is a combination product with no generic name (e.g. Kliovance). The only acceptable abbreviations for drug dose units 
are ‘g’ and ‘mg’. ‘Units’ (e.g. of insulin or heparin) and ‘micrograms’ must always be written in full, never as ‘U’ or ‘μg’ (nor ‘mcg’, nor ‘ug’). For liquid 
preparations write the dose in mg; ‘mL’ can be written only for a combination product (e.g. Gaviscon liquid) or if the strength is not expressed in weight 
(e.g. adrenaline (epinephrine) 1 in 1000). Use numbers/figures (e.g. 1 or ‘one’) to denote use of a sachet/enema but avoid prescribing numbers of tablets 
without specifying their strength. Always include the dose of inhaled drugs in addition to stating numbers of ‘puffs’, as strengths can vary. Widely accepted 
abbreviations for route of administration are: intravenous – ‘IV’; intramuscular – ‘IM’; subcutaneous – ‘SC’; sublingual – ‘SL’; per rectum – ‘PR’; per 
vaginam – ‘PV’; nasogastric – ‘NG’; inhaled – ‘INH’; and topical – ‘TOP’. ‘ORAL’ is preferred to per oram – ‘PO’. Care should be taken in specifying 
‘RIGHT’ or ‘LEFT’ for eye and ear drops. The prescriber should sign and print their name clearly so that they can be identified by colleagues. The 
prescription should be dated and have an administration time. The nurse who administered the prescription has signed to confirm that the dose has been 
administered.
OTHER MEDICINES CHARTS
CODES FOR NON-ADMINISTRATION OF PRESCRIBED MEDICINE
PREVIOUS ADVERSE REACTIONS
(This must be completed before prescribing on this chart)
Hospital/Ward:
Consultant:
Name of patient:
Hospital number:
(Attach printed label here)
D.O.B.:
Weight:
Date
Date
Time
Medicine (approved name)
Dose
Route
Time
given
Given
by
Prescriber – sign and print
If a dose is not administered as prescribed, intial and enter a code in the column with a circle drawn round the code according to the
reason as shown below. Inform the responsible doctor of the appropriate timescale.
1. Patient refuses
2. Patient not present
3. Medicines not available – CHECK ORDERED
4. Asleep/drowsy
5. Administration route not available – CHECK FOR ALTERNATIVE
6. Vomiting/nausea
7. Time varied on doctor’s instructions
8. Once-only/as-required medicine given
9. Dose withheld on doctor’s instructions
10. Possible adverse reaction/side-effect
Type of chart
Medicine
Description of reaction
Completed by
Date
Height:
If rewritten, date:
DISCHARGE PRESCRIPTION
PRESCRIPTION AND ADMINISTRATION RECORD
Standard Chart
ONCE-ONLY MEDICINES
Date completed:–
Completed by:–
A
B
must contain the address of the patient and prescriber 
(not necessary on most hospital forms), the form and the 
strength of the preparation, and the total quantity of the 
preparation/number of dose units in both words and 
figures.
• ‘Repeat prescriptions’. A large proportion of GP 
prescribing involves ‘repeat prescriptions’ for chronic 
medication. These are often generated automatically, 
although the prescriber remains responsible for regular 
review and for ensuring that the benefit-to-harm ratio 
remains favourable.
Monitoring drug therapy
Prescribers should measure the effects of the drug, both beneficial 
and harmful, to inform decisions about dose titration (up or down), 
discontinuation or substitution of treatment. Monitoring can be 
achieved subjectively by asking the patient about symptoms or, 
more objectively, by measuring a clinical effect. Alternatively, if the 
pharmacodynamic effects of the drug are difficult to assess, the 
plasma drug concentration may be measured, on the basis that 
it will be closely related to the effect of the drug (see Fig. 2.2).


Prescribing in practice • 35

REGULAR MEDICINES
AS-REQUIRED THERAPY
C
D
Drug (approved name)
Dose
Date
Time


















Prescriber–sign and print
Notes
Start date
Pharmacy
Route
Drug (approved name)
Dose
Prescriber–sign and print
Notes
Start date
Pharmacy
Route
Drug (approved name)
Dose and frequency
Prescriber–sign and print
Start date
Indication/notes
Pharmacy
Route
Date
Time
Dose
Initials
Date
Time
Dose
Initials
Drug (approved name)
Dose and frequency
Prescriber–sign and print
Start date
Indication/notes
Pharmacy
Route
Date
Time
Dose
Initials
Date
Time
Dose
Initials
Drug (approved name)
Dose
Prescriber–sign and print
Notes
Start date
Pharmacy
Route
 C ‘Regular medicines’. This area is used for prescribing medicines that are going to be given regularly. In addition to the name, dose 
and route, a frequency of administration is required for each medicine. Widely accepted Latin abbreviations for dose frequency are: once daily – ‘OD’; 
twice daily – ‘BD’; 3 times daily – ‘TDS’; 4 times daily – ‘QDS’; as required – ‘PRN’; in the morning – ‘OM’ (omni mane); at night – ‘ON’ (omni nocte); 
and immediately – ‘stat’. The hospital chart usually requires specific times to be identified for regular medicines that coincide with nursing drug rounds and 
these can be circled. If treatment is for a known time period, cross off subsequent days when the medicine is not required. The ‘notes’ box can be used 
to communicate additional important information (e.g. whether a medicine should be taken with food, type of inhaler device used, and anything else that 
the drug dispenser should know). State here the times for peak/trough plasma levels for drugs requiring therapeutic monitoring. Prescriptions should be 
discontinued by drawing a vertical line at the point of discontinuation, horizontal lines through the remaining days on the chart, and diagonal lines through 
the drug details and administration boxes. This action should be signed and dated and a supplementary note written to explain it (e.g. describing any 
adverse effect). In this example, amlodipine has been discontinued because of ankle oedema. There is room for the ward pharmacist to sign to indicate 
that the prescription has been reviewed and that a supply of the medicine is available. The administration boxes allow the nurse to sign to confirm that the 
dose has been given. Note that these boxes also allow for recording of reasons for non-administration (in this example ‘2’ indicates that the patient was 
not present on the ward at the time) and the prevention of future administration by placing an ‘X’ in the box. D ‘As-required medicines’. These 
prescriptions leave the administration of the drug to the discretion of the nursing staff. The prescription must describe clearly the indication, frequency, 
minimal time interval between doses, and maximum dose in any 24-hour period (in this case, the maximum daily dose of paracetamol is 4 g). 
Fig. 2.7, cont’d
Clinical and surrogate endpoints
Ideally, clinical endpoints are measured directly and the drug 
dosage titrated to achieve the therapeutic goal and avoid toxicity 
(e.g. control of ventricular rate in a patient with atrial fibrillation). 
Sometimes this is impractical because the clinical endpoint 
is a future event (e.g. prevention of myocardial infarction by 
statins or resolution of a chest infection with antibiotics); in 
these circumstances, it may be possible to select a ‘surrogate’ 
endpoint that will predict success or failure. This may be an 
intermediate step in the pathophysiological process (e.g. serum 
cholesterol as a surrogate for risk of myocardial infarction) or a 


36 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
Interpreting the result
A target range is provided for many drugs, based on average 
thresholds for therapeutic benefit and toxicity. Inter-individual 
variability means that these can be used only as a guide. For 
instance, in a patient who describes symptoms that could 
be consistent with toxicity but has a drug concentration in 
the top half of the target range, toxic effects should still be 
suspected. Another important consideration is that some 
drugs are heavily protein-bound (e.g. phenytoin) but only 
the unbound drug is pharmacologically active. Patients with 
hypoalbuminaemia may therefore have a therapeutic or even 
toxic concentration of unbound drug, despite a low ‘total’ 
concentration.
Further information
Websites
bnf.org The British National Formulary (BNF) is a key reference 
resource for UK NHS prescribers, with a list of licensed drugs, 
chapters on prescribing in renal failure, liver disease, pregnancy and 
during breastfeeding, and appendices on drug interactions.
cochrane.org The Cochrane Collaboration is a leading international 
body that provides evidence-based reviews (around 7000 so far).
evidence.nhs.uk NHS Evidence provides a wide range of health 
information relevant to delivering quality patient care.
icp.org.nz The Interactive Clinical Pharmacology site is designed to 
increase understanding of principles in clinical pharmacology.
medicines.org.uk/emc/ The electronic Medicines Compendium (eMC) 
contains up-to-date, easily accessible information about medicines 
licensed by the UK Medicines and Healthcare Products Regulatory 
Agency (MHRA) and the European Medicines Agency (EMA).
nice.org.uk The UK National Institute for Health and Care Excellence 
makes recommendations to the UK NHS on new and existing 
medicines, treatments and procedures.
who.int/medicines/en/ The World Health Organisation Essential 
Medicines and Pharmaceutical Policies.
measurement that follows the pathophysiology, even if it is not a 
key factor in its progression (e.g. serum C-reactive protein as a 
surrogate for resolution of inflammation in chest infection). Such 
surrogates are sometimes termed ‘biomarkers’.
Plasma drug concentration
The following criteria must be met to justify routine monitoring 
by plasma drug concentration:
• Clinical endpoints and other pharmacodynamic (surrogate) 
effects are difficult to monitor.
• The relationship between plasma concentration and clinical 
effects is predictable.
• The therapeutic index is low. For drugs with a high 
therapeutic index, any variability in plasma concentrations 
is likely to be irrelevant clinically.
Some examples of drugs that fulfil these criteria are listed in 
Box 2.25.
Measurement of plasma concentration may be useful 
in planning adjustments of drug dose and frequency of 
administration; to explain an inadequate therapeutic response 
(by identifying subtherapeutic concentration or incomplete 
adherence); to establish whether a suspected ADR is likely to 
be caused by the drug; and to assess and avoid potential drug 
interactions.
Timing of samples in relation to doses
The concentration of drug rises and falls during the dosage 
interval (see Fig. 2.4B). Measurements made during the initial 
absorption and distribution phases are unpredictable because 
of the rapidly changing concentration, so samples are usually 
taken at the end of the dosage interval (a ‘trough’ or ‘pre-dose’ 
concentration). This measurement is normally made in steady 
state, which usually takes five half-lives to achieve after the 
drug is introduced or the dose changed (unless a loading dose 
has been given).
 2.25 Drugs commonly monitored by plasma drug concentration
Drug
Half-life (hrs)*
Comment
Digoxin

Steady state takes several days to achieve. Samples should be taken 6 hrs post dose. Measurement is 
useful to confirm the clinical impression of toxicity or non-adherence but clinical effectiveness is better 
assessed by ventricular heart rate. Risk of toxicity increases progressively at concentrations > 1.5 μg/L, 
and is likely at concentrations > 3.0 μg/L (toxicity is more likely in the presence of hypokalaemia)
Gentamicin

Measure pre-dose trough concentration (should be < 1 μg/mL) to ensure that accumulation (and the risk of 
nephrotoxicity and ototoxicity) is avoided; see Fig. 6.18 (p. 122)
Levothyroxine
> 120
Steady state may take up to 6 weeks to achieve (p. 640)
Lithium

Steady state takes several days to achieve. Samples should be taken 12 hrs post dose. Target range 
0.4–1 mmol/L
Phenytoin

Measure pre-dose trough concentration (should be 10–20 mg/L) to ensure that accumulation is avoided. 
Good correlation between concentration and toxicity. Concentration may be misleading in the presence of 
hypoalbuminaemia
Theophylline (oral)

Steady state takes 2–3 days to achieve. Samples should be taken 6 hrs post dose. Target concentration is 
10–20 mg/L but its relationship with bronchodilator effect and adverse effects is variable
Vancomycin

Measure pre-dose trough concentration (should be 10–15 mg/L) to ensure clinical efficacy and that 
accumulation and the risk of nephrotoxicity are avoided (p. 123)
*Half-lives vary considerably with different formulations and between patients.