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 progres-

sive cardiovascular condition in which the mean

blood pressure is consistently above the popula-

tion normal range for the patient’s age, but below

130 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 dis-

tinguish, 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 mechanisms

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 vas-

cular 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 infil-

tration, then articular erosion. Where immuno-

logical 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 mecha-

nisms, 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 condi-

tion 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 inci-

dence is the number of new cases of the disease;

it is usually expressed as per million of a popula-

tion

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 Figure

1.1. 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 subse-

quently 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 includes:

•

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 the

areas 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.