Part 1 Basic strategy and introduction to pathology

1.Therapeutics: general strategy

This book is about the rationale of therapeutic decision making, and in particular the logic of drug 

selection. Thus, it must start with an account of where pharmacotherapy (drug therapy) fits into 

the overall management of a patient, and the factors that govern the selection of a drug regimen. The medical process starts with the case history, which includes examination, investigation and 

diagnosis, and culminates in a decision about management. A similar if less elaborate process 

must be followed by a pharmacist to respond to symptoms presented by a patient. All this infor-

mation is gathered together to provide a systematic classification of information about a patient. However, before considering the case history, the terminology and systematic description of disease must be introduced. Pharmacists are familiar with classifying knowledge about a drug into such categories as ‘indications’ and ‘side-effects’. This enables the comparison of similar drugs, and facilitates learning about a new drug and anticipating its properties by assigning it to an existing class. In an analogous way, knowledge about disease is systematically described using specific categories, and this enables similar diseases to be distinguished by certain features, and helps learning about a newly encountered disease. The medical process and the systematic description of disease form the framework for the discussion of specific conditions and disease groups in subsequent chapters.

Terminology of disease

Definition

An account of a disease starts with a description of its general nature, including the organ system 

affected and important features that differentiate it from similar conditions. The following are two 

examples:

Essential hypertension is a chronic slowly progresive cardiovascular condition in which the mean blood pressure is consistently above the population normal range for the patient’s age, but below130 mmHg and not rising rapidly.

- Rheumatoid arthritis is a severe chronic progressive inflammatory erosive polyarthropathy, primarily articular synovitis, but with systemic features.

Aetiology and pathology

These categories are sometimes difficult to distinguish, especially when the cause of a disease is 

uncertain Aetiology is concerned with general causes of a disease and the circumstances (‘risk 

factors’) that predispose an individual to suffer from its effects: it may be thought of as answer-

ing the question, ‘why?’ (see Table 1.1). Aeti-ology makes no assumptions or assertions about 

the processes by which these factors bring about the condition. Thus, the aetiology of tubercu-

losis (TB) involves poor public and domestic hygiene, reduced patient immune status and the 

mycobacterium;  that  of  cancer  may  include genetic predisposition, viral infection and envi-

ronmental toxins; that of essential hypertension involves obesity, salt intake and stress, etc

Pathology is concerned with the mechanims of the disease process, what the disease does, and 

how it does so. It answers the question, ‘how did it cause the observed symptoms?’ Ideally it will 

explain the steps by which the aetiological risk factors lead to the malfunction. It then describes 

the changes caused in body function resulting from the disease and the body’s response to this. 

The pathophysiology  of a disease relates its effects to the disruption of normal physiological 

functions, e.g. the pathophysiology of essential hypertension involves a raised peripheral vascular resistance and possibly an expansion of the  intravascular  fluid  volume.  Pathogenesis describes  the  development  or  progression  of the disease process. Thus, the pathogenesis of rheumatoid   arthritis (RA)   involves   synovial hyperplasia followed by inflammatory cell infiltration, then articular erosion. Where immunological processes are known to be involved in the  disease,  e.g.  the  autoimmune  pancreatic destruction in type 1 diabetes mellitus, the term immunopathology is used

There are a few general pathogenic mechanisms, such as inflammation and ischaemia, 

that occur as fundamental bodily responses to very  many  diseases. These  are  described  in 

Chapter 2

Epidemiology

It is important to know how common a condition is, and whether any particular population 

group is more susceptible by virtue of birth or environment. It answers the question, ‘who?’ 

There  may  also  be  significant  differences  in disease occurrence between the sexes, different 

ethnic groups and different age groups. The incidence is the number of new cases of the disease; 

it is usually expressed as per million of a population  per  year.  The  lifetime  incidence  is  the 

proportion of the population likely to suffer from the disease at some time in their life, e.g. 

the lifetime incidence of duodenal ulcer among British males is about 1 in 10.

Prevalence refers to the number of active cases of a disease at any one time, e.g. the overall 

prevalence of Parkinson’s disease is about 1 in 1000, affecting men and women equally, but is 1 in 200 among those over 70 years of age. The term morbidity is sometimes used more loosely to describe the prevalence of a disease; thus heart disease has a relatively high morbidity, renal 

cancer a low morbidity. Comorbidity refers to any other disease the patient has

The relationship between incidence and preva-

lence  depends  on  the  natural  history (usual 

course) of the condition. Although the annual 

incidence of the common cold may be up to 1 

in  2  in  the  UK,  the  prevalence  at  any  given 

time will vary between perhaps 10 million and

merely several hundred thousand, depending on 

the season, as colds are acute in onset and short-

lived. On the other hand, the prevalence of 

chronic renal failure depends on the annual 

incidence and the average survival time following 

diagnosis

Knowledge   about   the   epidemiology   of   a disease may provide clues about its aetiology. For example,  the  incidence  of  stomach  cancer  is higher in Japan than the USA, but the prevalence among Japanese immigrants to the USA is similar to that of Americans. This strongly suggests that environmental  factors  such  as  diet  are  more important than genetic ones.

Clinical features

Signs  and  symptoms,  often  thought  to  be 

synonymous, are distinct terms. Symptoms are 

subjective; they are noticed by the patient and 

either reported - the things a patient complains 

of - or elicited on questioning. Signs are usually 

found objectively on examination by the clini-

cian, although occasionally may be noticed by 

the  patient.  Both  are  important:  the  former 

emphasise what are likely to be the patient’s 

major concerns; the latter aid precise diagnosis The typical pattern of clinical features caused 

by a disease is called its presentation. Many 

diseases have such consistent presentations as 

to be almost diagnostic, e.g. a spiking fever, stiff 

neck  and  photophobia  in  meningitis;  such 

definitive features are called pathognomonic. A 

well-defined  group  of  clinical  features  that 

commonly occur together is sometimes called a 

syndrome,  e.g.  proteinuria,  hypoproteinaemia 

and oedema together are known as the ‘nephrotic 

syndrome’.

Investigations

In describing a disease it is helpful to include the 

tests or procedures used to confirm a diagnosis, 

distinguishing  between  closely  related  condi-

tions (the differential diagnosis) or monitoring 

progress. For example, although the measure-

ment of urinary glucose is a poor method of 

assessing  control  in  a  patient  with  diabetes

mellitus, , it is quite useful for screening large 

groups for possible diabetes

Natural history

Knowledge of the usual course of a disease from 

its onset and pretreatment phase through to its 

final outcome is important for several reasons. It 

enables predictions to be made about a patient’s 

likely recovery or degree of eventual disability, 

i.e.  the  prognosis. It  also  helps  in  judging 

whether improvements in a patient’s condition 

are due to treatment or to natural remission. Many chronic diseases progress by a series of 

exacerbations,   remissions   and   relapses,   and 

improvements cannot with certainty be ascribed 

to any treatment that is being given The patient may have improved even without the treatment

Different disease subgroups may be differenti-

ated by different natural histories. For example, RA typically has an insidious onset, but if there is a sudden onset of multi-joint inflammation 

the prognosis is better. Furthermore, some two-

thirds of RA patients will have such a slowly progressive disease that they can expect little 

disablement within a normal lifespan

  Knowing the average duration of the disease and its pattern of activity is important. Some 

diseases  start  with  a  period  of  characteristic warning signs, known as the prodromal phase. 

Acute illness starts suddenly (acute onset) and 

resolves either of its own accord or following 

treatment. A chronic disease usually starts insid-

iously, and continues for a long time, possibly 

lifelong. For chronic disease in particular we also 

need  the  answers  to  several  important  ques-

tions. Does it remain stable or tend to deteriorate 

steadily (progressive disease) and if so, at what 

rate? Is there any residual disability after the 

disease has resolved, or can it be cured? ? Does 

it follow a continuous or a fluctuating course, 

with remissions and relapses or exacerbations? Many   diseases   also   have   typical   secondary 

complications, e.g. haemorrhage in peptic ulcer-

ation. What is the prevalence of complications, 

especially in different age or sex groups?

  The likelihood of a fatal outcome (the mortal-

ity)  is  usually  expressed  as  the  proportion 

of patients expected to die within a specified

time. Conversely, survival is the proportion of 

patients alive at a specified time after diagnosis. 

Both are commonly cited as medians, e.g. a 3-

year median survival means that half of patients 

are expected to be still alive after 3 years. For 

example, the median survival of severe heart 

failure is 1 year. Alternatively, we might speak of, 

for example, mortality at 5 years being x%, or an 

annual mortality rate of y%. It is important to 

distinguish between the mortality and morbidity 

of a particular disease, in order to compare the 

suitability  of  different  treatments.  Thus,  skin 

diseases generally have a high morbidity but very 

low mortality, so toxic therapy is rarely indicated. 

However,  malignant  melanoma,  while  having 

a low morbidity, has a very high mortality, so 

aggressive therapy is warranted.

Management and treatment

Management embraces all the decisions made to 

deal with the patient’s complaint; it describes 

the strategy. Its first task is to decide realistic 

aims, based on a knowledge of the presentation, 

investigations and natural history. Within the 

broad area of management, treatment comprises 

the range of interventions, like drugs, surgery or 

physiotherapy, that can be used to achieve these 

aims. Of course, this can include doing very lit-

tle if the condition is self-limiting. On the other 

hand, in very advanced or incurable disease, 

management might involve no more than symp-

tom control, nursing care, simple reassurance 

and appropriate counselling, i.e. palliative care.

  The assessment of the balance of harms and benefits  of  different  treatments (the  risk-to-

benefit or harm-to-benefit ratio) must be based on knowledge of the severity and mortality of the condition, the risks of not treating and the toxicity of the treatment

Aims

The various possible general aims of manage-

ment may be set in a hierarchy (Table 1.1). In 

complex diseases several aims may be legitimate, 

for  different  aspects  of  the  disease  and  its 

complications. Prevention may be the ultimate 

aim  of  medicine,  but  symptomatic  relief  is frequently  all  that  can  be  offered.  Only  by having clearly defined aims can it be judged to what extent the treatment has been successful, and thus whether such treatment should be 

continued or changed.

     Prophylaxis

This can only follow from an understanding of 

the aetiology and pathology, but that alone is not 

always sufficient. Some infectious diseases have 

been almost completely eliminated in some coun-

tries by a systematic combination of public health 

measures and vaccination, e.g. diphtheria. Small-

pox is the only disease that has been completely 

eradicated worldwide, and poliomyelitis is close 

to eradication. Yet although much is known about 

the  causes  of  chronic  obstructive  pulmonary 

disease (COPD)  and  ischaemic  heart  disease, 

prevention  here  probably  resides  more in the 

domains of education and social and economic 

policy than in medicine. On the other hand, there 

is at present little hope of preventing most cases of 

chronic renal failure or cancer because so little is 

understood of their aetiology.

  Reversal

Prevention has clearly failed if a patient presents 

with symptoms. Some diseases are intrinsically 

temporary, self-limiting and reversible, such as 

minor gastric upset. For others, the ideal would 

be to reverse the disease process and leave the 

recuperative powers of the body to restore health 

completely. This amounts to a cure, and it is 

sobering to reflect that there are few important 

diseases for which this is a realistic aim. When 

patients have recovered from an infection, they 

are  usually  physiologically  just  as  they  were 

before their illness. In almost all other common 

serious chronic diseases the sad truth is that we 

do not do a very good job, for example in heart 

disease and cancer, which together account for 

over 50% of all premature deaths in the West. 

This is not to obscure the fact that immense 

good is done by modern medicine, and medi-

cines, in the relief of the misery associated with 

serious illness, in particular the damaging effects 

of acute exacerbations of chronic diseases

Transplantation  is  a  growing  area,  and  can 

reverse some diseases (although immunosuppres-

sant therapy prevents completely normal life). In

the future, gene therapy promises tremendous advances in this area

Arrest progress

Many  measures  may  slow,  arrest  or  stabilise 

a   condition,   preventing   deterioration   and 

minimising exacerbations or relapses. Thus in 

COPD, stopping smoking will avoid further lung 

damage, and prompt antibiotic treatment will 

minimise  infective  exacerbations.  Anticonvul-

sant drugs will prevent most epilepsy seizures 

but  will  not  rectify  the  underlying  disease 

process. Replacement therapy in endocrine defi-

ciency  diseases  such  as  diabetes  will  restore 

normal function, although it cannot restore the 

original organ. In many chronic diseases, by the 

time a diagnosis is made there is often fixed, 

irreversible organ damage.

  Symptomatic relief and palliation

Included in this category are the many inter-

ventions that pharmacists make in minor self-limiting conditions, where advice and symp-

tomatic over-the-counter (OTC) medication are all that is needed.

   Of course, under some circumstances there is 

no prospect of influencing the disease process, 

and all that can be done is to treat the symptoms 

as  they  arise,  and  more  generally  make  the 

patient feel better. Terminal cancer is the prime 

example. Analgesics, parenteral nutrition and 

surgery to relieve obstruction or nerve pressure 

may all be directed at improving the patient’s 

quality of life, not at controlling the disease

   Some would claim that many medical and 

pharmaceutical efforts do no more than meet 

this aim: for example, do antidepressants or anti-

inflammatory   drugs   really   do   more   than suppress symptoms? Yet the relief of suffering and improvement in the quality of life are surely worthwhile benefits in themselves

Duration

Treatment can be acute, to manage a short-term 

condition, or may need to be continued long 

term  as  maintenance,  in  order  to  keep  the 

disease under control. In other cases treatment 

can be prophylactic, to prevent further illness. 

For example in anxiety, drug therapy should be used   only   for   acute   management;   diabetes 

requires lifelong maintenance; and atheroscle-

rotic cardiac disease usually requires prophylaxis 

with antiplatelet and lipid-lowering medicines.

Modes

Having decided on a realistic aim, it is necessary 

to make appropriate selections from the many 

available modes of treatment. . Thus serious joint 

disease may need social and economic help, as 

well as support from a multidisciplinary team 

including  clinicians,  nurses,  pharmacists  and 

social workers, to alleviate the condition. Treat-

ment may involve surgery, and nearly always 

physiotherapy,  to  achieve  or  maintain  joint 

mobility. Nursing skills are of paramount impor-

tance, both in hospital and in the home, if the 

rheumatoid patient is to return as quickly as 

possible to their normal activities. And of course 

drug therapy is essential.

   Medicines  play  an  important  part  in  the 

management of many diseases, but they must be seen as only one part of the patient’s whole treat-

ment. When individual diseases are discussed in later chapters, the role of drug therapy - and its limitations - will be emphasised in relation to the other important modes of therapy.

  Monitoring

Decisions about aims are incomplete unless ways 

of determining to what extent they are being 

achieved are also specified. The type of moni-

toring will depend on the nature of the abnor-

mality (e.g. blood glucose level in diabetes, blood 

pressure  in  hypertension)  and  the  aims  of 

therapy (e.g. symptom control or tumour size in 

cancer). Similarly, certain treatments carry with 

them   the   obligation   to   watch   for   adverse 

effects (e.g. regular blood counts in cytotoxic 

chemotherapy).   Pharmacists   are   playing   an 

increasing role in these monitoring processes

Case history

A case history is a systematic account of the 

progress of a patient’s disease, including the information and reasoning behind diagnosis and 

management decisions. It is the core of the 

medical process and provides a central database 

for all concerned with the care of the patient. Taking a history and making a coherent record of 

it are two of the most fundamental skills of 

medicine,   and   they   are   being   increasingly 

adapted for use by paramedical professions such 

as nursing and pharmacy.

 Taking a ‘good history’ involves more than simply obtaining information and examining 

the patient. It is a subtle mixture of comprehen-

sive clinical knowledge, detective work, lateral thinking,  and  communication  skills  such  as listening and questioning. Unless the results are systematically recorded in a standardised way, its purpose may be largely defeated.

The way that these data fit into the general flow of information gathering is shown in Figure1.1. The categories of information reported in a case history will be considered next. This will 

introduce some further essential medical termi-

nology  and  should  help  the  pharmacist  to 

understand case reports in the medical literature 

(Table 1.2). Although in some cases the complete work-up will not seem immediately appropriate - the 

accident victim admitted through the Accident and Emergency Unit need not be questioned 

about  childhood  illnesses -  but  a  thorough 

history prevents important facts such as a drug allergy possibly being missed, or less obvious diagnoses being overlooked

Patient details

A case history report is conventionally prefaced 

by a brief description of the patient and their 

complaint. This serves to orientate the reader

and also to summarize data that will subsequently be important for both diagnosis and 

treatment

    Age,  sex,  ethnic  origin  and  occupation  are 

recorded because certain diseases are more preva-

lent in particular groups (e.g. type 2 diabetes in 

the elderly, haemoglobinopathies in people of 

Mediterranean origin), and numerous diseases are 

occupationally related. Exotic disease might be suggested by the ethnic group or recent travel: in 

the UK, fever in a non-travelling Londoner would be regarded differently to that in a newly arrived African  or  Asian  immigrant.  Decisions  about

 treatment may also be affected by such data, e.g. pharmacogenetic differences in drug handling and religious or ethnic dietary preferences.

It is usual to note how the patient came to 

medical attention and with what complaint; this 

gives an idea of the urgency of the problem and 

how it is perceived by the patient. An experi-

enced  clinician  can  also  tell  a  lot  from  the 

patient’s general appearance. The section might 

include circumstantial observations such as a 

walking stick or medication at the bedside, or 

nicotine-stained  fingers. Thus,  a  case  history 

might start:

Mr M, a 45-year-old slightly obese Caucasian busi-

nessman, was admitted 3 days ago through casualty after collapsing at work, complaining of a crushing chest  pain  of 3 h   duration. On  admission  he appeared pale, anxious and in great pain.

Past medical history

Certain childhood diseases, and recent or cur-

rent chronic illnesses, may have a bearing on the 

present  illness. For  example,  rheumatic  fever 

often causes heart disease in later life, chicken-

pox may manifest itself later as shingles, and 

asthma suggests an allergic predisposition. After 

using open questions, e.g. ‘tell me about any 

serious illnesses you have had’, , the patient will 

be asked specifically about the more common 

chronic  conditions  such  as  epilepsy,  asthma, 

hypertension, diabetes, jaundice and TB

Medication history

A medication history should ideally comprise a 

list of current medication and recent medication 

used for the presenting complaint, including 

self-medication bought OTC and remedies rec-

ommended by a pharmacist. Sources for this 

information include the patient’s recollection, 

medication  list  or  medication  bag,  and  their 

GP  or  community  pharmacist’s  records.  The 

effectiveness  of  each  medication  and  any 

adverse effects encountered, including allergy or 

sensitivity, need to be recorded. Patients may 

need prompting, especially for self-medication, 

because  even  certain  prescription  items  are 

frequently not regarded as medicines, e.g. oral 

contraceptives, nasal sprays, ophthalmic prepa-

rations,  etc.  Patients  also  tend  to  be  rather 

unreliable or imprecise on adverse effects, e.g. 

the term ‘allergy’ may be used colloquially to 

describe almost any adverse effect, even mild 

dyspepsia.   Unfortunately,   an   accurate   and 

complete record is seldom easy to obtain, even 

when there is access to medical notes.

   There is evidence that pharmacists can obtain 

more complete medication histories than clini-

cians, perhaps because of their wider product 

knowledge

Family history

Because many diseases have a significant genetic basis, a knowledge of any chronic illness in 

siblings and parents, and the causes of death if appropriate,   may   provide   vital   clues.   The connection may be direct, e.g. type 2 diabetes, or indirect, e.g. hay fever in the sibling of someone with dermatitis or a wheeze, implying a familial allergic (atopic) predisposition

Social history

Enquiries about a patient’s circumstances and way 

of life (‘lifestyle’) have a number of aims. Clearly, 

(anti-)social habits such as smoking, drinking and 

illicit drug use have a bearing on illness, although 

patients seldom give a reliable estimate (as a 

general rule, double the number of drinks or 

cigarettes admitted to). Excessive tea or coffee 

consumption  may  also  be  significant.  Special 

dietary  habits  are  important,  especially  with 

ethnic minorities, vegans, obsessive slimmers, etc.

  Equally  important  is  information  about  a 

patient’s financial and domestic circumstances. Can they afford to be ill? Are they the sole bread-

winner, or a single parent? What will be the 

economic  impact  of  hospital  admission,  or 

attendance  at  a  clinic?  Is  unemployment  a 

factor? Are their living conditions contributing 

to their illness? What can be done for a patient 

with heart failure living on the tenth floor and 

with unreliable lifts? Who does the shopping?

   If a patient has a chronic condition, how are 

they coping? It is also necessary to ascertain 

whether the patient is psychologically and intel-

lectually able to comprehend the diagnosis and 

treatment,  and  to  give  genuinely  informed 

consent to surgery or other invasive procedures

History of presenting complaint

So far, little has been said about the patient’s 

actual problem, but a comprehensive picture has 

been built up which will be useful both for the 

diagnosis of the current condition and for future 

reference. There is now an opportunity for the 

patient to relate their ‘story’. Patients should, as far as possible, be allowed to express themselves at  their  own  pace  and  in  their  own  words, although occasionally some pertinent prompt-

ing or ‘constructive interruption’ is required. The aim is to discover how the symptoms arose, what they are like, how they have developed, and 

what has been done so far

  Consider pain, for example. The nature and 

intensity of pain are often significant, such as the 

difference between crushing cardiac chest pain 

and the burning retrosternal pain of gastroin-

testinal origin. How did it start? Is the pain 

constant, short-lived, episodic or persistent? Is it 

predictable? What makes it better or worse, e.g. 

warmth,  cold,  a  particular  posture?  Has  the 

patient already consulted a relative, pharmacist, 

NHS Direct or GP, and what was their advice? Has 

any treatment been tried, and if so, to what 

effect

  Note that the clinician need not yet have 

actually seen the patient. Indeed, much of the 

history so far could have been obtained by an 

assistant  or  a  computer;  in  fact,  trials  using 

computers are sometimes quite effective. It is 

estimated  that  up  to 75%  of  diagnoses  in 

primary care can be made correctly using the 

data obtained by this stage, so consistent is the 

presentation of most illness. This explains how 

some doctors are sometimes able temporarily to 

‘diagnose’ and prescribe by telephone, although 

it is hardly the technique of choice

Systematic examination (review of systems)

The next stage is to look in detail at each body 

system. Although it is impossible to avoid this 

examination being influenced by information 

obtained so far, ideally it should be objective and 

complete, so that nothing obscure or unusual is 

overlooked and the data can be used later for 

reference. The examination usually starts with 

general observations of the patient’s appearance 

and condition, in particular his or her colora-

tion, body surface markings, etc. Traditionally, 

the presence or absence of jaundice, anaemia, 

cyanosis, clubbing and oedema are noted

    The details relevant to each body system will be  discussed  as  appropriate  in  the  following chapters. For each there are five stages:

1. Directed   questioning  (functional   enquiry)

about symptoms likely to follow malfunction

of that system

2. Observation  and  examination  for  physical signs

3. Palpation (feeling)

4. Auscultation (listening with a stethoscope)

5. Percussion (tapping an area and listening to

the sound)

    Thus, for the cardiovascular system the patient 

will be asked about tiredness, swelling, palpita-

tions and shortness of breath, especially at night. 

He or she will then be observed for objective 

signs such as exercise tolerance, gasping and 

oedema (ankles, abdomen). The pulses will be 

felt at different parts of the body, and the extent 

of any peripheral oedema estimated by local 

pressure.  Auscultation  uses  a  stethoscope  to 

check cardiac rhythm and valve sounds. Percus-

sion of the chest shows the extent of pulmonary 

oedema

    Obviously, history and examination must be 

guided by urgency and the presence of obvious 

symptoms or signs: a road traffic accident victim 

with head and chest injury is not asked about 

their bowel habit or the presence of athlete’s 

foot. Nevertheless, a full review of systems would 

always be performed at some stage after hospital 

admission, as part of the clerking process

Investigations

By this stage, a further 20% of diagnoses will 

have been made. This leaves perhaps 5% that 

require further investigation. Simple investiga-

tions may be done in a GP’s surgery, e.g. oph-

thalmoscopy, peak respiratory flow and blood 

pressure measurement, and urine dipstick tests. 

Many  practices  now  have  electrocardiogram 

(ECG)   equipment.   Blood   biochemistry   and 

microbiology   samples   are   collected   in   the 

surgery and usually sent to a local laboratory. 

The most common test for which the patient 

will be referred to a hospital (in the UK) is simple 

X-ray imaging.

   If the diagnosis is still in doubt, investigations 

of  increasing  sophistication  and  expense  are 

gradually  employed,  so  that  an  ever  greater complexity of test is used to diagnose an ever diminishing proportion of cases

Diagnosis

A definitive diagnosis is usually clear by this 

stage - or it may be provisional, awaiting confir-

mation from investigations. If several possible 

diagnoses seem to fit the history, this differential 

diagnosis will be resolved by further investiga-

tions. Sometimes, the diagnosis remains provi-

sional. If the patient recovers, there may be no 

benefit in subjecting them to invasive, uncom-

fortable and possibly dangerous further investi-

gation if the result will not affect subsequent 

management

Management

Each history should conclude with a manage-

ment plan, which summarises the aims and the 

modes prescribed to meet them, monitoring and 

expected outcomes. In the problem-orientated 

approach, the record of management starts with 

a summary of all the patient’s present problems, 

which appears at the front of the patient’s notes. 

The summary include:

•  The current complaint (an ‘active problem’, 

e.g. hypertension)

•  Important past medical history (either active, e.g. peptic ulcer disease, or inactive, e.g. a past

myocardial infarction)

•  Behaviour  that  requires  modification  (e.g.

smoking, poor diet)

•  Possibly, psychological and social problems

A plan is outlined for each active problem. This 

includes any further investigations required for 

diagnostic   confirmation   or   assessment   of 

severity, the aim of management, the recom-

mended treatment, the means of monitoring 

and  the  period  of  follow-up,  e.g.  a  further 

appointment in so many weeks. Progress reports 

recorded in the patient’s notes will then be based 

on this management plan, dealing with each 

problem for which treatment has been recom-

mended, and the management strategy may be 

modified  according  to  the  patient’s  response to treatment. This systematic approach is also sometimes known by the acronym SOAP:

•  Subjective: patients  reported  or  perceived problems

•  Objective: data   recorded   by   clinician   or 

obtained from investigations

•  Assessment of problems

•  Plan of action

Whether or not such a formal approach is expli-

citly used, the history always includes progress 

notes. The outcome or progress of each manage-

ment aim is recorded and the reasoning behind 

any changes in treatment explained, e.g. adverse 

drug effects

  For a hospital admission, the final component is the discharge summary, usually in the form of a letter to the patient’s GP

Drug disposition

Before  considering  the  factors  guiding  drug 

choice, the basic concepts of clinical pharma-

cology will be briefly reviewed. These concepts 

underpin  the  drug  selection  decision-making 

process. Included are the principles of absorp-

tion,  distribution,  metabolism  and  excretion, 

and a brief summary of how these affect dosing 

and drug interactions. For details, the reader is 

referred to the References and further reading 

section

Absorption and first-pass metabolism

The administration of a drug is the first stage of 

the process that eventually results in the drug 

acting on a receptor to produce the desired clin-

ical action. Before it reaches the receptor it has a 

number of barriers to surmount, because the 

body has evolved very effective mechanisms to 

defend  itself  against  foreign  chemicals.  This 

process is represented in Figure 1.2. Following 

oral  administration,  the  first  barrier  is  the 

gastrointestinal  epithelium,  which  favours  at 

least partially lipophilic compounds. If success-

fully absorbed, the drug is carried directly to the 

liver via the portal vein, where it is exposed to metabolising enzymes, e.g. cytochromes. Many drugs are at least partly deactivated at this stage, so-called first-pass metabolism

Distribution

If not extracted by first-pass metabolism, the 

drug reaches the general circulation. Some drugs 

will  then  become  bound  to  some  extent  to 

plasma protein. This process is reversible but 

bound drug, as opposed to free drug, is unavail-

able for clinical action, further metabolism or 

renal excretion

   From the plasma (where only a few drugs have 

their primary action, e.g. antiplatelets), the drug 

can potentially diffuse into all body tissues. This 

wide distribution is responsible for many drug 

side-effects, as a result of action at sites other 

than those intended. The extent of distribution 

depends on the drug’s plasma level, and theareas to which it is distributed depend largely on 

its hydrophilic-lipophilic balance; e.g. only very 

lipophilic   drugs   can   cross   the   blood-brain 

barrier. Eventually, if the administered dose raises 

the plasma level above a threshold value, the 

concentration at the intended receptor is suffi-

cient  to  elicit  a  pharmacological  response. 

Although we can rarely measure the drug con-

centration at the receptor site, plasma concentra-

tion  is  an  acceptable  substitute  because  it  is 

usually proportional to the concentration at the 

receptor

Clearance

Clearance refers to the (rate of) removal of active 

drug from the body. Drugs may be cleared by 

chemical modification (metabolism), usually in 

the liver, or by physical excretion  from the 

body, usually by the kidney. Hydrophilic drugs are easily cleared renally but a lipophilic drug 

filtered at the glomerulus is likely to be reab-

sorbed in the tubule, so clearance is very ineffi-

cient.   Thus   the   main   function   of   hepatic 

metabolism is not, as is sometimes believed, to 

‘detoxify’ the drug, but to chemically convert it 

to a more hydrophilic form for renal excretion. 

That this process often reduces or eliminates the 

drug’s   pharmacological   action   is   incidental; 

indeed,  some  drugs  are  actually  activated  or 

potentiated this way, e.g. codeine to morphine

   Figure 1.2 also shows how some alternative 

methods of administration can circumvent first-

pass metabolism to enhance bioavailability (e.g. 

buccal absorption of glyceryl trinitrate; can evade 

possible   destruction   by   stomach   acid (e.g. 

injected insulin); or can permit faster action or 

target the dose (e.g. inhaled salbutamol, rectal 

steroid

Drug selection

This  introduction  concludes  with  a  general 

review of the factors that determine or influence 

the choice of drug therapy following diagnosis. 

The  following  chapters  demonstrate  the  way 

these principles are applied in common diseases

The decision process

The typical sequence is illustrated in Figure 1.3. 

Clinical findings may suggest several appropriate 

groups of drugs (or that none at all is needed). 

This must then be progressively narrowed down 

to one group, then a particular member of that 

group; finally a route of administration and dose 

must be chosen

   Consider, for example, managing hypertension. 

Precise diagnosis of the condition may suggest a 

particular drug group: quite different strategies 

will be needed depending on whether the condi-

tion is primary benign (essential) hypertension or 

secondary to some other disease state, e.g. reno-

vascular disease or adrenal tumour. Clinical find-

ings will also indicate the urgency of treatment. 

In primary hypertension the first choice would be 

from   among   the   thiazides,  the  angiotensin-

converting  enzyme  inhibitors (ACEIs)  or  the 

calcium-channel blockers (CCBs); in high renin 

disease an ACEI may be indicated; in the third case, 

surgery might be feasible. In a patient with essen-

tial hypertension and concurrent ischaemic heart 

disease, beta-blockers may be indicated, but should 

the  beta-blocker  be  selective  or  non-selective, 

short- or long-acting, lipophilic or non-lipophilic? 

Finally, having selected the most appropriate drug 

entity,  what  should  be  the  preferred  route  of 

administration, dose and formulation?

In  making  these  decisions,  clinical  factors 

such  as  precise  diagnostic  class,  drug  factors 

such  as  mode  of  action  and  half-life,  and 

patient factors such as age and renal function, 

are all important. The choice from among the 

various drugs indicated at each stage is deter-

mined initially by drug factors (i.e. the drugs of 

choice for the particular disease, independent of 

the  particular  patient).  Early  in  the  decision 

process the considerations are principally phar-

macodynamic  (i.e.  pharmacological,  including 

toxicological).  As  the  choice  becomes  more 

focused,  biopharmaceutical  and  pharmacoki-

netic  factors  become  more  relevant.  Thus  for 

essential hypertension there are several types of 

drugs indicated, related to their pharmacolog-

ical effect on blood pressure. Once a drug group 

has  been  decided  upon,  selecting  a  particular 

member must take account of the spectrum of 

pharmacokinetic properties of the group, or the 

formulations available

At each stage the selection based on drug 

factors may then be modified or constrained by 

patient factors, such as the patient’s response to 

the agent (pharmacodynamics), their handling 

of it (pharmacokinetics), or possibly concurrent 

disease or drug therapy. Thus the choice of a 

renally cleared drug might have to be changed in 

a patient with renal impairment; a patient with compliance  problems  might  benefit  from  a 

modified-release  preparation;  a  patient  with 

diabetes  should  avoid  thiazides.  Finally,  one 

should not forget cost: from a number of com-

parably  efficacious  and  safe  drugs  the  most 

economic one must always be first choice

There  are  also  prescriber  factors,  i.e.  the 

clinician’s  own  preference,  exercised  on  the 

basis  of  familiarity  and  experience,  and  these 

may be as good a guide as any when choosing 

from  among  a  range  of  very  similar  prepara-

tions.  On  the  other  hand  this  may  occasion-

ally   be   based   on   unsystematic   anecdotal 

evidence  or  outdated  habits.  In  their  role  as 

pharmaceutical  advisers,  pharmacists  are  now 

helping  GPs  to  make  evidence-based  choices 

and construct rational formularies to facilitate 

drug  selection. Increasingly, they also prescribe 

independently

Drug factors

   Pharmacodynamics and toxicity

These are the primary criteria. Occasionally the 

diagnosis will indicate a unique drug group or 

even  one  specific  drug,  e.g.  levothyroxine  in 

hypothyroidism, but usually there are a num-

ber   of   approximately   equivalent   strategies 

available at this stage. Precise pharmacological 

properties then become important, the choice 

depending  on  the  clinical  presentation.  For 

example, an arterial vasodilator may be more 

useful  than  a  venodilator  in  certain  types  of 

heart failure; a cough suppressant rather than 

a decongestant  may  be  preferred  for  a  cough 

unproductive   of   mucus.   Receptor   subtype 

specificity  may  also  be  relevant,  e.g.  cardio-

selectivity  of  beta-blockers,  selective  amine 

re-uptake blockade in antidepressants

   A  drug’s  therapeutic  index  must  also  be considered: what is the risk-to-benefit ratio of treatment? The severity of the condition may 

justify using a more potent but more toxic agent, but can the plasma level or adverse effects be easily monitored? Does the plasma level corre-

late with the concentration at the presumed site of action or the therapeutic benefit, or with the intensity of adverse effects?

     Biopharmaceutics

The formulation of a medicine is important in 

selection for a number of reasons, e.g. for IV 

preparations, where stability and pharmaceutical 

compatibility  are  crucial,  and  dermatological 

preparations, where penetration, skin hydration, 

miscibility,   etc.   can   influence   effectiveness. 

Formulation   can   also   affect   bioavailability, 

which is particularly important for drugs with a 

narrow   therapeutic   index   used   to   stabilize 

serious  chronic  conditions,  e.g.  phenytoin  in 

epilepsy   or   theophylline  in   asthma,   where 

changes   in   formulation   might   compromise 

disease control or cause toxicity

   Some drugs are unsuitable for certain routes, e.g.  benzylpenicillin  is  destroyed  by  gastroin-

testinal enzymes and so is unsuitable for oral 

administration, aminophylline requires too high a dose mass for aerosolization, and phenytoin is too irritant for IM use

Pharmacokinetics

A drug’s physicochemical properties (especially 

its   hydrophilic/lipophilic   balance,   pKa   and 

molecular size) affect its absorption, distribution to the required site of action, mode and rate of clearance and route of elimination

Hydrophilic/lipophilic balance

The  characteristics  conferred  by  predominant 

hydrophilic  or  lipophilic  properties (summa-

rized  in  Table 1.3)  are  particularly  noticeable 

within a series of otherwise similar drugs, e.g. 

the beta-blockers (see below). Most drugs need 

both  properties:  lipophilic  to  cross  mem-

branes; hydrophilic to enable transport in and 

distribution  by  body  fluids.  For  lipophilicity 

the drugs will need some non-polar groups in 

their  structure  and,  if  such  drugs  are  ionic, 

they  will  exist  to  a  significant  extent  in 

unionized  form  at  body  pH,  i.e.  their  pKa 

should be near 7.4. Strongly hydrophilic drugs 

are  often  highly  polar,  and  those  that  are 

ionic  have  pKa  values  significantly  greater  or 

less than 7.4

   Membrane  permeability,  which  determines 

many biological properties, is highly dependent 

on polarity. Lipophilic drugs (e.g. most general 

anaesthetics), pass biological membranes easily, 

whereas ionized molecules (e.g. aminoglycoside 

antibiotics)   generally   penetrate   membranes poorly in the absence of specific transmembrane pumps

   Taken orally, lipophilic drugs are more likely 

to undergo first-pass hepatic metabolism, with 

consequent reduced bioavailability, e.g. propran-

olol. Highly lipophilic drugs partition into body 

fat, and so may have a high volume of distribu-

tion  and  prolonged  half-life,  e.g.  diazepam.  If 

the metabolite of a lipophilic drug is also active, 

the  activity  will  be  further  prolonged,  e.g. 

carbamazepine

   Hydrophilic drugs such as atenolol are cleared 

mainly by renal excretion, which often tends to 

give them a shorter half-life, especially if they 

undergo tubular secretion. Lipophilic drugs such 

as propranolol are likely to be metabolized rapidly 

by the liver to produce a more hydrophilic mole-

cule that can then be more easily excreted by the 

kidney

   Although lipophilic molecules are freely fil-

tered at the renal glomerulus, they are equally 

freely reabsorbed from the tubules, so their net 

renal clearance is inherently low. In contrast, 

hydrophilic molecules are less efficiently reab-

sorbed and are more likely to pass out in the 

urine

pKa

Acidic  drugs  (e.g.  aspirin)  are  generally  more 

highly bound to plasma albumin, giving a lower 

volume of distribution, i.e. they tend to stay in 

the  plasma  rather  than  distribute  to  the  tis-

sues (Table 1.4).  Basic  drugs (including  many 

CNS-acting agents such as phenothiazines) are the-

oretically more prone to binding to acid glyco-

protein, an acute phase inflammatory plasma 

protein; however, albumin also has binding sites 

for basic drugs. Acidic drugs tend to interact by 

displacement   from   protein   binding.   Plasma 

protein binding reduces the free (unbound) drug 

plasma   concentration,   and   thus   both   drug 

activity and clearance, because it is this fraction 

that is available equally for pharmacodynamic 

effect, and also for hepatic extraction and renal 

excretion

   Interactions may occur intrarenally owing to 

competition  for  the  special  tubular  secretory 

transport mechanisms that exist for weak acids 

and bases. The pH of the urine can affect clear-

ance: a more acid urine promotes the clearance of  basic drugs, and vice versa. This is the basis of forced acid or alkaline diuresis to treat poison-

ing, e.g. urinary alkalinization for barbiturate or aspirin overdose

Molecular size

Membrane permeability is also affected by mole-

cular size. Ionized or highly polar molecules 

greater than 100 Da do not cross membranes. 

Hydrophilic  hepatic  metabolites  greater  than 400 Da are likely to be excreted in the bile, while smaller molecules are excreted renally

Overall effect

The sum of all the pharmacokinetic properties of 

a drug will determine important parameters of 

its use:

•  The half-life

•  The time a single oral dose will take to reach peak concentration, which affects the useful

ness in an emergency and the best timing of plasma level sampling.

•  The time to reach steady state, which may in turn affect the time to initial onset of useful

action, and the minimum advisable interval between dose changes

•  Peak and trough plasma levels: the former determines toxicity, the latter clinical effect

•  The frequency of dosage, which may affect compliance

Physicochemical factors may also influence toxi-

city, e.g. the more lipophilic beta-blockers readily cross the blood-brain barrier and may cause adverse central nervous system (CNS) effects.

  As  an  example  of  how  these  factors  affect choice, consider a drug for the oral prophylaxis of recurrent urinary-tract infection. To be effective it must be well absorbed, should not be signifi-

cantly deactivated by the liver and should be 

excreted in antimicrobially significant concentra-

tions in the urine. Because prophylactic therapy is often  associated  with  compliance  problems,  a long-acting drug or formulation with a once-daily dosage regimen would be preferred

Patient factors

There is often a wide interpatient variation in 

response,  both  therapeutic  and  toxic,  to  a 

standard dose of a drug. Thus, despite careful 

attention to all the above factors, there is still 

a need to carefully review the choice of drug 

and  dose  for  an  individual  patient.  This 

variation  arises  because  of  a  combination  of 

differing  pharmacodynamics (Table 1.5)  and 

differing pharmacokinetics (Table 1.6)

Response

Drug response varies with age. The elderly and 

the very young may have atypical responses to 

many drugs. These may be due to anomalous or 

exaggerated sensitivity, especially to drugs acting 

on the CNS, e.g. aggression in some elderly 

patients taking benzodiazepines. Alternatively, 

there may be impaired physiological or homeo-

static mechanisms, e.g. among the elderly, an 

exaggerated  hypotensive  effect  with  vasodilators, or hyponatraemia with diuretics. In some 

cases there are genetic or racial differences in 

drug response, e.g. thiazide diuretics are much 

more effective antihypertensives in people with 

a dark skin, who respond less favourably than 

people with a white skin to beta-blockers

   If there are unexpected responses, particularly 

apparent   ineffectiveness,   the   possibility   of 

patient non-compliance should always be borne 

in mind. There are many possible reasons for 

non-compliance   and   pharmacists   have   an 

important role in detecting it and improving the 

situation. In some cases a change in drug or 

formulation may encourage better compliance, 

e.g. a long-acting, once-daily form for essential 

hypertension. In other cases, an inappropriate 

dose or exaggerated sensitivity to adverse effects 

may be to blame. Sensitive enquiry of the patient 

will  often  uncover  an  innocent  or  perfectly 

reasonable   explanation,   frequently   deriving 

from poor communication or imperfect patient 

understanding. The recommended ideal is to 

develop a concordance between prescriber and patient, i.e. mutual confidence, mutually agreed objectives and constraints and mutually agreed treatment

   Concurrent   diseases   may   increase   the 

patient’s sensitivity to some drugs; for example, 

the myocardium is more sensitive to digoxin after 

infarction,  or  in  thyroid  imbalance.  Other 

diseases  may  indirectly  make  a  patient  less 

tolerant of the drug, e.g. beta-blockers are contra-

indicated in asthma. The patient’s biochemical 

and physiological status is often important, e.g. 

digoxin  toxicity  is  greatly  increased  in  the 

presence of hypokalaemia

   Previous  or  sustained  exposure  to  a  drug 

may  produce  an  unexpected  tolerance  to 

either the therapeutic effect (e.g. prophylactic 

nitrates  in  ischaemic  heart  disease)  or  an 

adverse   effect(e.g.   anticholinergics).   The 

patient  may  be  taking  interacting  drugs, 

which may be antagonistic (e.g. corticosteroids 

and  thiazides  both  antagonize  oral  hypogly-

caemic drugs), or additive or synergistic, such 

as a sedative OTC antihistamine taken with an 

anxiolytic

   For reasons that are poorly understood, some patients   have   anomalous   or   idiosyncratic adverse reactions to certain drugs, the penicillins being   the   best   example.   These   are   often 

immunologically-based,non-dose-dependent type B adverse effects

  Finally, in women, the possibility of the drug having an effect on conception, pregnancy or 

breastfeeding requires special consideration

Handling

Interpatient variation in pharmacokinetic para-

meters may be inborn or acquired, and is partic-

ularly important in dosage and route selection, 

but also sometimes affects which drug group is 

selected

Absorption

Many diseases can affect oral absorption. Disease 

of the gut itself may of course affect absorption 

(e.g. vomiting, diarrhoea, inflammatory bowel 

disease), but so too can cardiovascular disease, 

which may compromise gastrointestinal perfu-

sion.  The  elderly  are  more  prone  to  such 

diseases, especially heart failure. Oral absorption is only affected by extreme age. Oral intolerance, e.g. gastric upset, is a common adverse effect and  a  reason  for  both  non-compliance  and potentially serious morbidity

  There may be unwanted interactions with the patient’s diet or other drug therapy, e.g. tetracy-

cline absorption is impaired by concurrent milk or antacid consumption

  Absorption  from  any  site  depends  on  an 

adequate blood supply. SC or IM injections may 

be ineffective if the circulation is compromised, 

because blood is redirected to the core visceral 

circulation. Thus morphine must always be given 

intravenously following myocardial infarction. 

Diabetics should understand that insulin absorp-

tion from a limb injection site is more variable 

than  from  an  abdominal  one,  because  limb 

perfusion depends on physical activity

  There  may  be  other  barriers  to  absorption. 

Bronchodilators   will   not   easily   penetrate 

constricted airways, and transdermal absorption 

will vary according to the skin thickness of the 

area to which a dermatological or transdermal 

preparation is applied and to the local blood 

flow (which,  for  example,  is  increased  in 

inflammation)

  If IV infusion is planned, the condition of the patient’s veins must be considered, and whether the patient can tolerate the fluid load of the 

vehicle or any associated ions, e.g. sodium or potassium with penicillin

Distribution

Distribution  is  affected  by  the  proportion  of 

adipose  tissue  to  lean  body  mass (which  is 

aqueous), and by the plasma protein level (which 

may affect the free drug plasma level, depending 

on its kinetics). This can affect both the overall 

volume of distribution, the distribution between 

different compartments, and access to the organs 

of elimination, chiefly the liver and kidney

  The elderly have a lower lean body mass and 

so  a  relatively  smaller  aqueous  compartment 

than middle-aged adults, and the very young 

have a higher proportion of body water. Both the 

elderly and the very young have reduced plasma 

albumin,  which  reduces  drug  binding.  The 

patient’s  nutritional  state  and  hydration  will 

similarly   affect   drug   distribution   between 

various compartments, as will a large volume of oedema fluid. A large volume of distribution will result in lower plasma levels

  Delivery  to  the  target  site  is  dependent 

primarily on the regional blood perfusion. This 

may be seriously impaired in heart failure, shock, 

peripheral vascular disease or diabetic blood vessel 

disease. For example, it is difficult to treat an infec-

tion in a diabetic’s foot with systemic antibiotics

  Distribution may be further modified by the 

body’s   internal   barriers.   For   example,   the 

blood-brain  barrier  impedes  polar  molecules, 

but this effect is much reduced if it is inflamed, 

e.g. in meningitis. Pus is poorly penetrated by 

some antibiotics, and sputum concentrations of 

antibiotics are frequently far lower than plasma 

concentrations

  Other  drugs  that  a  patient  may  be  taking 

might compete for plasma protein binding sites, 

causing an increase in the free drug levels of the 

one displaced. However, despite the many theo-

retical  possibilities  of  such  interactions,  rela-

tively few are clinically significant and only a 

small number are serious. A drug will only cause 

a significant elevation in the free concentration 

of another by displacement if both are avidly 

bound to the same site, are in high concentra-

tion in the plasma, and have a low volume of 

distribution, i.e. most of the drug in the body is 

in the plasma

  Moreover, clearance of the displaced drug may be increased, and this tends to counteract any 

rise in plasma level. Only certain drugs are likely to cause clinically significant problems by this mechanism:   these   include   potentially   toxic drugs  with  a  narrow  therapeutic  index,  and those whose doses are carefully titrated to stabi-

lize a chronic condition, e.g. antiepileptics, oral hypoglycaemics and anticoagulants

  Concurrent disease may also influence bind-

ing. Endogenous metabolites such as bilirubin, 

which is elevated in jaundice, may compete for 

binding sites. A high blood urea level, e.g. in 

renal   failure,   impairs   protein   binding,   and 

hypoproteinaemia in liver failure, malabsorption 

and   the   nephrotic   syndrome,   will   reduce 

available sites

Clearance and elimination

The function of either of the main organs of 

clearance may be impaired by disease, age or concurrent drug therapy. A knowledge of the 

patient’s   renal   and   hepatic   function,   their 

medication history and the mode(s) of elimina-

tion of the drug to be used, are essential when 

selecting therapy. The use of drugs in hepatic 

impairment is considered in Chapter 3 (p. 159) 

and in renal impairment in Chapter 14 (p. 914)

Evidence-based medicine

Patient management is moving rapidly away 

from being derived from observational studies 

and expert opinion to evidence based on critical 

and   objective   comparison   of   the   clinical 

outcomes of different treatment strategies. The 

favoured technique is meta-analysis, whereby 

objective   data   from   as   many   comparable 

randomized controlled trials (RCTs) as possible 

are pooled and aggregated. Obviously the skill 

here lies not least in ensuring comparability. 

Meta-analysis can increase the statistical power 

and therefore the reliability of the conclusions, 

making the recommendations far stronger than 

if they had been based on any individual compo-

nent trial, each with far smaller patient numbers. 

Failing meta-analysis, less rigorous systematic 

reviews of RCTs can be used, but with less confi-

dence. If RCTs are not available, case-control or 

cohort studies can be used. Least reliable are 

individual case reports or expert opinion

  This produces a hierarchy of levels of evi-

dence  upon which recommendations can be 

based,   with   the   higher   levels   subdivided according to the quality of the analysis. These can be summarized as

•  Level 1  (1,1 or 1): meta-analyses or systematic review of RCTs

•  Level 2 (2, 2or 2): systematic reviews of case-control or cohort studies

•  Level  3:  non-systematic  studies,  e.g.  case reports or case series

•  Level 4: expert opinion

As a result a management guideline  for the 

condition being treated is devised. The recom-

mendations in guidelines are normally graded for strength or reliability according to the level of evidence on which they are based:

•  Grade A: level 1 meta-analysis directly applicable to the target population of the guidance

•  Grade B: level 2 evidence directly applicable to the target population of the guidance, or 

evidence extrapolated from level 1 evidence

•  Grade C: level 2 evidence directly applicableto the target population of the guidance, 

or  evidence  extrapolated  from  level 2

Evidence

•  Grade D: level 3 or 4, or extrapolation from level 2 evidence

This is a simplification of a subtle and rigorous statistical process. The key point is that such an approach to drug selection does not need to 

consider directly many of the factors discussed above. These would all have been part of the 

original design of the RCTs. The evidence-based medicine approach is simply, ‘does it work, and at what cost of adverse effects?’. This is partly what  the  National  Institute  for  Health  and Clinical Excellence (NICE) does, although it also has to consider the economic cost

  To this extent, evidence-based medicine guide-

lines may be seen as relieving the prescriber of 

making some of the decisions discussed in this 

chapter. However, no guideline can anticipate all 

possible  combinations  of  circumstances,  and 

clinical judgement will always need to be exer-

cised, even if it ultimately supports following the 

guideline. Moreover, a professional practitioner 

is obliged not just to blindly follow guidelines, 

but  to  understand  the  rationale  behind  the 

recommendations

Pharmaceutical care

As stated in the Preface, this is not a textbook of 

clinical pharmacy. However, it is relevant to note 

at this point the involvement of pharmacists in 

patient care. Pharmacists are increasingly taking more responsibility for the management and 

optimization of the entire spectrum of a patient’s 

pharmacotherapy. This has extended the con-

cept  of  clinical  pharmacy  beyond  validating 

indications  and  screening  contra-indications, 

interactions and dosage regimens. Pharmacists 

now have a commitment to anticipate or iden-

tify all possible drug-related problems. Pharma-

ceutical care involves devising an appropriate 

pharmaceutical care plan and specifying how 

this will be implemented and monitored for suc-

cess and adverse events. Pharmacist prescribing 

is extending this process significantly