BASIC SCIENCE

Clinical pharmacology: thebasicsJohn Posner

AbstractClinical pharmacology is the study of pharmacodynamics and pharmaco-

kinetics in humans. The relationship between dose, concentration and

pharmacodynamic response may be explored using biomarkers for both

desired and undesired effects of drugs. The action of drugs is due to

receptor affinity, efficacy and the concentration of drug at the site of

action. Factors affecting the concentration of drug include bioavailability,

determined by absorption and pre-systemic metabolism, distribution,

clearance and elimination. Drug interactions may occur due to pharmaco-

dynamic and pharmacokinetic factors, many of the latter being attribut-

able to changes in drug metabolism. As well as contributing to our

understanding of established treatments, clinical pharmacology plays

a critical role in the development of new medicines.

Keywords Affinity; biomarkers; clinical pharmacology; drug interactions;

efficacy pharmacodynamics; pharmacogenetics; pharmacokinetics;

potency; receptors

Introduction

What is clinical pharmacology?

Clinical pharmacology (CP) is a very broad subject involving

a variety of disciplines and is conducted in clinical, academic and

industry settings. A drug may be well established and useful as

a tool with which to investigate normal or pathological processes.

Alternatively, CP studies may be designed to investigate the

properties of the drug itself, often with the aim of assessing its

potential for development as a new medicine or for a new indica-

tion. Perhaps it is helpful to conceptualize the determinants of drug

activity as comprising two components: the properties of the drug,

by which it exerts its action on the body, pharmacodynamics

(PD), and the systems by which the body affects the fate of a drug

after its administration, pharmacokinetics (PK). In this article we

shall discuss some of the principles underlying PD and PK and how

they apply to the use of well-established therapeutic drugs and to

the evaluation of potential new medicines.

Pharmacodynamics

Drug targets and mechanism of action

Most drugs that have become available in the past few decades

have been the result of rational design; that is, a target has been

John Posner PhD FRCP FFPM is an Independent Consultant in Pharma-

ceutical Medicine and Visiting Senior Lecturer, School of Biomedical

and Health Sciences, King’s College London, UK. He is Director of

programmes for the Diploma and Certificate in Human Pharmacology of

the Faculty of Pharmaceutical Medicine of the Royal Colleges of

Physicians of the UK. Conflicts of interest: none declared.

SURGERY 30:4 174

identified, molecules synthesized with the intention of hitting

that target and the structureeactivity relationship has been

elucidated. Eventually, a lead compound with the appropriate

properties has been identified for development. Many of these

drugs are small chemicals of molecular weight typically in the

range of 300e600 Da; others are biologicals such as monoclonal

antibodies. Table 1 shows examples of rationally designed

molecules with well-understood mechanism of action.

It should be noted that most of the examples in Table 1 are

receptor antagonists, but the last two are receptor agonists.

Partial agonists bind to the receptor and elicit a response, but

their efficacy is less than that of a full agonist (e.g. buprenor-

phine at the mu opioid receptor). Many of the targets for drug

agonists and antagonists are G-protein-coupled receptors. These

include serotonergic (5-HT), muscarinic cholinergic, dopami-

nergic, adrenergic, opioid, and purinergic receptors.

Some drugs act by inhibition of enzyme activity. Table 2

shows some examples.

There are also important receptors sited in the cell nucleus

with a DNA-binding domain for the action of hormones such as

corticosteroids, thyroxine and cholecalciferol (vitamin D3) and

enzymes involved in DNA synthesis, targeted by some cytotoxic

agents.

Some drugs do not act on discrete receptors in the membrane

or nucleus but on ion channels. Table 3 provides some examples.

Finally, drugs may target transporter molecules, such as those

for reuptake of noradrenaline and 5-HT, targeted by tricyclic

antidepressants.

Biomarkers and surrogates for assessment of

doseeconcentrationeresponse

What matters to patients treated with medicines is the clinical

outcome. However, such outcomes may be difficult to measure

and dependent on treatment over a prolonged period. We need to

be able to predict outcomes and adjust our treatment on the basis

of biomarkers which serve as reliable surrogates for clinical

endpoints. A biomarker is defined as ‘a characteristic that is

measured and evaluated as an indicator of normal biological or

pathological processes or pharmacological responses to a thera-

peutic intervention’. We are used to biomarkers serving as

surrogates in routine clinical practice. Blood pressure is

a biomarker predictive of adverse cardiovascular events; there-

fore we implement antihypertensive therapy and adjust the dose

in light of the effect on blood pressure. Other examples of

surrogates in routine clinical use are plasma HbA1c for control of

glucose in diabetes and cholesterol in hypercholesterolaemia.

Biomarkers are used in CP to explore the relationships

between dose, concentration and response to a drug. They may

be mechanistic (e.g. the activity of an enzyme, hormone or

gene), or functional (e.g. cognition, blood flow, spirometry).

Caution must always be exercised in the interpretation of data

and biomarkers must undergo extensive validation, particularly

if used to investigate novel classes of drugs, when their ability to

serve as surrogates of clinical endpoints has not been

established.

To illustrate the use of biomarkers in CP, let us consider the

actions of an inhaled anti-inflammatory drug for asthma. We

can assess a bronchodilator effect by administering the drug

over a range of doses to a subject with constricted airways and

� 2012 Elsevier Ltd. All rights reserved.

Examples of receptor antagonists and agonists

Receptor Drugs Target effect Indication

H2 Cimetidine, ranitidine Inhibition of gastric acid secretion Peptic ulceration

b1 and 2

adrenoceptor

Propranolol, atenolol Antagonism of noradrenaline on heart and

blood vessels

Hypertension, angina, arrhythmias,

secondary prevention of myocardial

infarction, heart failure

Angiotensin-II Candesartan, losartan Antagonism of angiotensin-II Hypertension, left ventricular dysfunction

Nicotinic

cholinergic

Atracurium, rocuronium Blockade of skeletal neuro-muscular transmission Skeletal muscle relaxation with general

anaesthesia

5-HT3 Granisetron, ondansetron Antagonism of 5-HT (serotonin) actions in

central nervous system and gastrointestinal tract

Chemotherapy-induced and postoperative

nausea and vomiting

HER2 Trastuzumab Antagonism of HER2-mediated phosphorylation

leading to cell proliferation, inhibited apoptosis etc

Breast and gastric carcinoma

overexpressing HER2

EGFR Cetuximab Antagonism of EGFR-mediated phosphorylation

leading to cell proliferation, inhibited apoptosis etc

Colorectal and squamous cell carcinoma of

head and neck expressing EGFR

5-HT1B/1D

receptor

Sumatriptan, zolmitriptan Agonism leading to vasoconstriction of cerebral

vessels, reduced release of vasoactive peptides

and inhibition of nociceptive neurotransmission

Acute relief of migraine headache

and other symptoms

b2

adrenoceptor

Salbutamol, salmeterol Agonism leading to bronchodilatation Relief of airways obstruction in asthma and

COPD

Abbreviations: 5-HT, 5-hydroxytryptamine; HER2, human epidermal receptor 2; H2, histamine 2; EGFR, epidermal growth factor receptor; COPD, chronic obstructive

pulmonary disease.

Table 1

BASIC SCIENCE

measure airway calibre indirectly by the forced expiratory

volume in 1 second (FEV1) or airways conductance (sGaw)

using plethysmography. If the drug is an antagonist of an

inflammatory mediator involved in asthma (e.g. leukotrienes),

we might administer a bronchoconstrictor challenge with

a leukotriene agonist before administering the antagonist.

Another approach is to induce an allergic inflammatory

response by administering antigen and then explore the effect

on the ‘early’ and ‘late’ (bronchoconstrictor) asthmatic

responses, again using FEV1 and/or sGaw. To validate the

Examples of enzyme inhibitors

Enzyme Drugs Inhibitory effect

HMG-CoA reductase Simvastatin, atorvastatin Production of m

cholesterol

Monoamine oxidases

A and B

A: moclobemide

B: selegiline, rasagiline

Deamination of

Cyclo-oxygenases

I and II

Aspirin, indomethacin Production of pr

mediators and t

aggregation

Tyrosine kinases Sunitinib, Imatinib Cell signalling o

dependent path

Angiotensin-converting

enzyme

Captopril, enalaprilat Production of an

angiotensin I

HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A.

Table 2

SURGERY 30:4 175

experiment and to understand whether the magnitude of the

effect is likely to be clinically meaningful, the study should

include a placebo control and a positive comparator such as

a corticosteroid. We may also wish to perform bronchoalveolar

lavage to examine the changes in cells and secretion of medi-

ators such as cytokines to learn the nature and extent of its anti-

inflammatory effects.

To take a very different example, we might consider a drug

intended to treat schizophrenia. In this case, we cannot gain direct

access to the site of action either for drug administration or to

Indication

evalonate in synthesis of Hypercholesterolaemia and

prevention of myocardial infarction

monoamines A: Depression

B: Parkinson’s disease

ostanoid inflammatory

hromboxanes causing platelet

Arthritis, inflammation, pain,

prevention of coronary thrombosis

f epidermal growth factor

ways

Solid tumours and leukaemias

giotensin II from Hypertension, heart failure

� 2012 Elsevier Ltd. All rights reserved.

Examples of drugs acting on ion channels

Ion Channel Drugs Effect Indication

Voltage-gated calcium Nifedipine, amlodipine Arteriolar dilatation Hypertension, cardiac failure

GABAA-gated chloride channel Diazepam, midazolam Facilitation of channel opening,

increasing hyperpolarization-induced neuronal

inhibition

Anxiety, induction of sedation

Voltage-gated sodium channel Carbamazepine, Lamotrigine Inhibits fast voltage-dependent Naþ currents

and repetitive neuronal firing

Epilepsy

GABA, g-aminobutyric acid.

Table 3

BASIC SCIENCE

measure a response. All such antipsychotics act as antagonists at

the dopamine-2 (D2) receptor and D2 receptor occupancy in the

striatum of the human brain using can be measured by positron

emission tomography (PET scanning). Occupancy is measured

over a range of doses by displacement of an administered radio-

ligand 11C-raclopride, which binds specifically to the D2 receptor.

Less than 50% occupancy will usually result in failure to produce

benefit and greater than 80% occupancy is liable to be associated

with adverse effects without additional benefit.

Adverse effects may also be the prime focus of our studies

with biomarkers. The unwanted sedative effects of a drug may be

quantified using carefully performed tests of cognition and

psychomotor performance in healthy volunteers or patients.

Responses can be related to plasma concentrations and the

PK/PD relationship modelled. Studies must be performed

under double-blind conditions, usually employing a randomized,

cross-over design with more than one dose level of the test drug,

a positive control and a placebo.

Thus, biomarkers help us gain greater understanding of

mechanism of action and may be used to establish the dose-

concentration-response relationships for both desired and

undesired effects, thereby evaluating the ratio of benefit:risk in

the relevant dose range. The importance of understanding

doseeresponse cannot be over-emphasized. It is salutary to

consider how many effective and well-tolerated drugs in use

today, were associated with severe toxicity when they were

introduced. Failure to establish dose response at the outset led

to prescribing of grossly excessive doses. Examples include

captopril for hypertension and cardiac failure, zidovudine for

HIV disease and haloperidol for schizophrenia.

Affinity, efficacy and potency

Underpinning the assessment of all PD responses is the basic

principle of a drug binding to a target receptor which triggers

a series of cellular events. These, in turn, result in a measureable

response. The affinity of a drug is a measure of its ability to bind

to a particular receptor. This can be quantified by binding and

displacement of radioactive ligands to cloned receptors in vitro.

The relative specificity or selectivity of a drug for certain recep-

tors can thereby be characterized.

However, affinity does not tell us about function. Efficacy is

the ability of a drug to elicit a response, once bound to its target

and in terms of the doseeresponse curve it defines the maximum

SURGERY 30:4 176

response. This can be studied in vitro and in vivo in animals and

humans.

Efficacy should not be confused with potency, which refers to

the amount of drug required to produce a response of a certain

magnitude. Thus, the ED50 is the dose at which 50% of the

maximal effect is produced and the EC50 and IC50 are the

concentrations producing 50% of maximum effect or inhibition

respectively. It is often impossible to quantify these parameters

in humans, as the maximum effect would not be well tolerated or

is simply unattainable. However, based on data points obtained

over a range of concentrations, the maximum effect and the

nature of the relationship between PK and PD can often be

simulated using computer modelling. Of course, while the IC50

may be highly relevant as a guide to target concentrations for

many pharmacological agents, we usually need to know IC90 of

anti-infective agents, to achieve a satisfactory antiviral or

bactericidal response.

Pharmacokinetics

Drug absorption and disposition

As stated in our introduction, many factors other than dose

determine the concentration of drug at its sites of action. These

sites are rarely accessible; therefore, to understand how the body

is handling the drug (PK), concentrations are usually, but not

exclusively, assayed in plasma. Sometimes drugs are applied

topically (e.g. airway, skin, eye) but usually they are adminis-

tered orally or parenterally and are transported to the tissues via

the blood stream. Therefore plasma drug concentrations usually

serve as a reasonable surrogate for concentrations at the active

site. The brain is an important exception, as entry of many

molecules is prevented by the bloodebrain barrier.

The fate of a drug after absorption is called ‘disposition’.

Disposition comprises, distribution,metabolism and elimination.

Thus absorption and disposition are commonly summarized by

the acronym ‘ADME’. However, this is not entirely satisfactory

since it suggests that the processes are separate and occur

consecutively when, in fact, they are all inter-related and many

occur simultaneously. In reality, we need to consider the concepts:

bioavailability, distribution, clearance and elimination.

Bioavailability

To achieve adequate concentrations at the target sites of action

after oral administration we rely on:

� 2012 Elsevier Ltd. All rights reserved.

BASIC SCIENCE

� adequate absorption from the gut

� avoidance of metabolism in the intestinal mucosa

� portal blood flow to and through the liver

� avoidance of metabolism in the liver

� passage through the systemic circulation

� distribution to sites of action.

Bioavailability is the proportion of an administered dose that

reaches the systemic circulation. It is determined by the extent of

both absorption and pre-systemic or ‘first-pass’ metabolism in

the intestine and liver. For example, the anti-epileptic drug

lamotrigine is virtually completely absorbed and does not

undergo significant first-pass metabolism. In this case, the

bioavailability (100%) is highly predictable. On the other hand

bioavailability of the bisphosphonate alendronate is less than 1%

and very variable due to very poor and irratic absorption. The

bioavailability of oral morphine is also highly variable ranging

from 10% to 50% due to a combination of moderate absorption

(25e50%) and extensive first-pass metabolism (�50%). Owing

to the lag time for absorption and variability in dosage require-

ments, oral administration is not recommended for relief of acute

pain such as post-operatively or during a heart attack. On the

other hand, oral morphine is perfectly satisfactory for control of

pain due to cancer, when the dose can gradually be adjusted

according to need. Glyceryl trinitrate is usually administered

sublingually for relief of angina to obtain rapid and reliable

absorption with avoidance of first-pass metabolism.

Since drug administered intravenously (IV) is 100%

bioavailable, the absolute bioavailability of an oral formulation

is equal to the ratio of the dose-normalized area under curve

(AUC) of plasma concentrations administered by the oral and i.v.

routes on separate occasions. The comparative bioavailability

of a new oral formulation relative to a reference formulation is

calculated as the ratio of AUCs obtained after administration of

each formulation. Generic drug manufacturers are required to

demonstrate that their formulations are ‘bioequivalent’ to

a reference formulation in terms of the total exposure (AUC) and

the peak concentration (Cmax) reached, falling within defined

limits.

Apart from the formulation itself, many factors may affect

bioavailability. For example, ingestion of food at the time of

taking the drug may reduce absorption of a poorly soluble drug.

On the other hand, fatty food may increase absorption of a lipid

soluble drug and reduce the extent of first-pass metabolism,

thereby increasing bioavailability.

Distribution

Once drugmolecules have started to enter the systemic circulation,

they will be distributed to different tissues and may be bound, to

a greater or lesser extent, to plasmaproteins or enter red cells. After

IV administration, the (apparent) volumeof distribution (V) canbe

obtained directly by extrapolating the declining concentrations on

a log scale back to the time of dosing to give the concentration at

time zero (C0) i.e. before distribution since

V¼ Dose=C0

It should be appreciated that V is not a real volume but is simply

a parameter relating the concentration of drug in plasma to the

total amount in the body, wherever it may be. If the drug is

SURGERY 30:4 177

lipophilic, it distributes rapidly to fat and tends to accumulate

there. The plasma concentration will fall rapidly and it will

seem as though the drug has been distributed in a large volume.

On the other hand, if drug is mainly bound to plasma protein

and stays in the vascular compartment, the concentration of

bound and unbound drug together will be high and the V will be

small.

The magnitude of V determines what a loading dose should be

and the rate of distribution affects the onset of drug action. For

example, the anaesthetic thiopentone distributes to lipid tissue

including the brain, rapidly and for that reason is suitable for

induction of anaesthesia. By contrast, digoxin distributes to

tissues very slowly and will not exert its effect on the heart for

several hours; therefore, there is no point in giving an IV loading

dose of digoxin; several oral doses are preferred.

Clearance and elimination

Of critical importance for the duration of drug action is the rate at

which it is cleared. Clearance (CL) is a measure of the efficiency

with which a substance is removed from the systemic circulation.

Clearance is not reversible though drug-related material may still

be present in the body (i.e. it has not necessarily been

eliminated).

Clearance of a drug by the kidney is the volume of blood

cleared of that drug by the kidney per unit of time; it is measured

in units of ml/minute or litres/hour, often quoted per kg body

weight. The antidiabetic drug metformin is cleared almost

exclusively by the kidney and eliminated in urine.

Drugs may also undergo clearance by biotransformation to

metabolites. Examples of drugs undergoing oxidative metabo-

lism by cytochrome P450 enzymes in the liver include the anti-

diabetic sulphonylureas (e.g. glipizide), the coumarin

anticoagulant warfarin and the benzodiazepine sedatives e.g.

midazolam. The oxidative metabolites frequently undergo

further biotransformation to conjugates, such as glucuronides.

Some drugs do not undergo oxidative metabolism but are

conjugated directly.

Biotransformation per se does not eliminate the drug from the

body, since metabolites may continue to circulate and be

distributed in the tissues; they may indeed be pharmacologically

active (e.g. morphine-6-glucuronide). Excretion of drug in the

form of metabolites may occur in urine, faeces via the biliary

tract, in expired air or breast milk. For first order elimination,

which is applicable to most drugs, the rate of elimination is

proportional to the plasma concentration.

The plasma elimination half-life (t1/2) is the time taken for

the amount of drug in the body and the plasma concentration to

fall by 50%. The t1/2 predicts the time taken to eliminate most of

the drug after stopping dosing at steady state since the plasma

concentration will fall by 50% after one half-life, 75% after two,

87.5% after three, 93.75% after four and ca. 97% after five half-

lives. Similarly, it will take about five half-lives for a drug to

reach steady state after the start of repeat dosing.

The slope of the line of falling log concentration against time

represents the fractional rate of drug removal, called the elimi-

nation rate constant k. The t1/2 can be measured from this slope

and is determined by both CL and V as follows:

t1=2 ¼ the natural logarithm of 2=k or 0:693=k:

� 2012 Elsevier Ltd. All rights reserved.

BASIC SCIENCE

CL¼ k �V;therefore t1/2 ¼ 0.693 * V/CL.

The t1/2 of different drugsmay range froma fewminutes to days

or weeks; this should be taken into account when considering the

frequency of dosing and the effect of factors such as age, renal and

liver disease which affect clearance and hence half-life.

Factors affecting pharmacokinetics

Age and disease can have a profound effect on PK. The most

obvious example is the normal decline in glomerular filtration

rate with increasing age, which reduces the clearance of drugs

and their metabolites excreted in urine. Digoxin, lithium, met-

formin and aminoglycoside antibiotics are examples of drugs so

affected. Liver function is usually well conserved in the elderly

but chronic liver disease will reduce first-pass metabolism and

systemic clearance of a drug undergoing hepatic metabolism.

Studies are routinely required during drug development to

investigate the extent to which these factors affect the pharma-

cokinetics and the consequent dosage reduction that is required.

Heart failure reduces the clearance of drugs with a high hepatic

extraction such as lidocaine and associated poor renal blood flow

reduces glomerular filtration and hence excretion of its toxic

metabolites.

Race can have a profound effect on hepatic metabolism

due to pharmacogenetic differences. Cytochrome 2D6 is

subject to polymorphism; so-called ‘poor metabolizers’ (PMs)

occur with a frequency of 7e10% in Caucasian populations

but in 30% of Chinese populations. When CYP2D6 is a major

route of metabolic inactivation of the compound, such as for

the selective serotonin reuptake inhibitor antidepressant

fluoxetine and the antitussive dextromethorphan, dosage

reduction may be required in PMs. By contrast, ‘ultrarapid’

metabolism can also occur due to polymorphism of CYP2D6;

its frequency is 1e2% in Caucasian populations but 30% in

Egyptian populations.

Similarly CYP2C9 is subject to polymorphism and the

frequency of different alleles varies with race. It is the main

enzyme responsible for biotransformation of the antidiabetic

sulphonylureas. S-warfarin is also metabolized by this cyto-

chrome subtype; polymorphism accounts for some of the vari-

ability in dosage requirements.

Polymorphisms of metabolic enzymes are not restricted to

cytochrome oxygenases. Uridine diphosphate glucuronosyl

transferase 1A1 (UGT1A1) is the enzyme responsible for glu-

curonidation of bilirubin. A genetic polymorphism in the

UGT1A1 promoter (UGT1A1*28) can result in a UGT1A1 7/7

genotype, with resultant impairment of bilirubin conjugation,

known as Gilbert’s syndrome. UGT1A1 is responsible for

conversion of SN-38, the active metabolite of irinotecan,

a chemotherapeutic agent for colorectal cancer, to an inactive

glucuronide SN38G. Patients with Gilbert’s syndrome, who are

homozygous for the UGT1A1*28 allele are at greater risk of

irinotecan-induced diarrhoea and neutropenia. Heterozygotes

and other genotypes have less impairment of glucuronidation

and a lower incidence of toxicity but still greater than patients

without this allele. Before treatment with irinotecan, patients

should undergo genotyping and the dose adjusted in accordance

with the result.

SURGERY 30:4 178

Drug interactions

Treatment with several medicines at once, so called ‘poly-

pharmacy’ is extremely common. Patients with chronic disorders

such as type 2 diabetes and ischaemic heart disease usually

require treatment with more than one drug and the elderly

frequently have more than one chronic disorder. In addition to the

problems of adherence, concomitant administration of several

drugs can lead to a variety of drugedrug interactions (DDIs).

Many such interactions are not of clinical importance but some

can be life-threatening. An understanding of the pharmacological

mechanisms which underlie the majority of DDIs can help ratio-

nalize the innumerable possibilities and make most interactions

predictable. Again, the division into PD and PK is helpful.

Pharmacodynamic interactions

Two drugs exerting PD effects at the same site are likely to

interact, irrespective of the actual mechanism of action or

structure of the molecules. For example, any centrally acting

drug in combination with alcohol can result in life-threatening

impairment of driving ability. Similarly, two nephrotoxic drugs

such as an aminoglycoside and some cephalosporin antibiotics

are more likely to result in toxicity than either drug alone. PD

effects of concomitant medication may also be antagonistic such

as the effect of corticosteroids and oral hypoglycaemic agents on

blood glucose or NSAIDs and antihypertensives on blood

pressure.

Pharmacokinetic interactions

Pharmacokinetic interactions between drugs may be mediated at

the level of absorption by means of chelation, effects on the rate

of gastric emptying and neutralization of gastric acid. More

commonly, PK interactions are due to interference with metab-

olism. The synthesis and activity of cytochrome P450 enzymes in

the liver and gut may be increased by enzyme-inducing agents

such the anti-epileptic drugs carbamazepine and phenytoin, the

antibiotic rifampicin, chronic alcohol ingestion and the herbal

remedy St John’s wort. Increased clearance caused by enzyme

induction may result in inadequate anticoagulation with

warfarin, failure of oral contraception or inadequate immuno-

suppression with cyclosporin. Enzyme inducers frequently

induce their own metabolism, this auto-induction resulting in

progressively increased clearance of the drug. This is the reason

that carbamazepine dosage must be increased over a period of

weeks after initiation of treatment.

Conversely, drug clearance may be inhibited by an enzyme

inhibitor or by competition with another substrate resulting in

severe toxicity. Some potent inhibitors of CYP3A4, include the

antifungal agent ketoconazole, the antibiotic clarithromycin and

HIV antivirals ritonavir and saquinavir. These ‘strong’ inhibitors

typically increase exposure to a concomitant drug more than

fivefold. Other inhibitors, such as erythromycin and verapamil

(and grapefruit juice) increase exposure at least twofold. The

consequences of exposure to corticosteroids, statins, and some

calcium antagonists may be very serious.

PK drug interactions may be studied using probe substrates

(e.g. midazolam for CYP3A4) or examining the PK of one or both

drugs of interest, alone and in combination. Such studies need to

be carefully designed taking many factors into account. The

� 2012 Elsevier Ltd. All rights reserved.

BASIC SCIENCE

safety of participating subjects must not be compromised by

exposing them to inappropriate drug concentrations. The

respective half-lives of the drugs need to be considered and

whether steady state should be reached before addition of the

concomitant drug. Induction increases over a period of 2e3

weeks from initiation of dosing whereas enzyme inhibition is

usually manifest after a single dose.

Not all drugedrug interactions are harmful. For example

concentrations of penicillin can be maintained by co-

administration of probenecid, which inhibits its active secretion

from the kidney tubule. The bioavailability of ritonavir is

enhanced by concomitant administration of saquinavir by inhi-

bition of first pass metabolism. Inhibition of P-glycoprotein an

efflux transporter which pumps drugs out of cells of intestine,

brain and kidney, can be exploited with conazole antifungal

agents to increase CNS concentrations of saquinavir and

ritonavir.

Adverse reactions

Most, so-called, ‘side effects’ are simply undesired pharmacody-

namic effects related directly to the pharmacological properties of

the drug.All drugs have undesired aswell as desired effects and the

acceptable benefit:risk ratio depends on the indication and the

nature of the adverse reactions. Adverse reactions are often due to

excessive concentrations resulting from excessive doses and/or

reduced clearance attributable to a drug interaction, liver or renal

disease or a genetic variant of a metabolic enzyme. Adverse reac-

tions may be mediated by the same receptor-mediating effects at

different sites in the body or different receptors, since many drugs

are not highly selective for one type of receptor.

The effectiveness of a drug may be greatly impaired by poor

tolerability. For example, an anticholinergic drug prescribed for

overactive bladder may be of little benefit because the dose is

limited by undesired effects on saliva production (dry mouth)

and bowel transit (constipation). The narrow therapeutic index

not only limits the dose that is tolerable but is also liable to lead

to poor adherence to the prescribed dosing regimen.

While poor tolerability may be troublesome, other adverse

reactions may cause a drug to be unsafe, either directly (e.g.

opiate causing respiratory depression) or indirectly (e.g. sedative

in the elderly causing falls with resultant injury). Adverse reac-

tions are a common cause of hospital admissions with significant

morbidity and mortality.

Much of the effort in development of newmedicines is devoted

to establishing the benefit:risk ratio. This is feasible for very

common (>1 in 10) and common (1 in 100 to 1 in 10) adverse

reactions but it should be recognized that medicines are usually

licensed on the basis of experience limited to a few thousand

patients atmost. The chances of detecting anuncommon (1 in 1000

to 1 in 100), rare (1 in 10,000 to 1 in 1000) or very rare (<1 in

10,000) reaction are diminishingly small and, if serious, may lead

to withdrawal of the drug from the market.

Therapeutic drug monitoring

There is no need to measure plasma concentrations of most

drugs. If the bioavailability is high and concentrations are not

very variable, the relationship between dose and plasma

concentration is reasonably predictable and if the therapeutic

SURGERY 30:4 179

index is wide, the precise concentration is not critical.

Furthermore, if the effect of treatment is readily monitored

clinically, the dose can be adjusted according to response.

However, there are certain drugs for which the plasma

concentration or some other surrogate marker is needed to

monitor the therapy with the objective of maximizing benefit

and minimizing toxicity. Drugs for which therapeutic drug

monitoring (TDM) is of value in routine clinical practice have

the following features:

� narrow therapeutic index

� direct relationship between concentration and desired/

undesired effects with a defined therapeutic range

� marked variability in pharmacokinetics

� difficulty in measuring clinical endpoint.

Examples of drugs which fulfil these criteria include digoxin,

lithium, aminoglycoside antibiotics, phenytoin, methotrexate

and the calcineurin inhibitors cyclosporine and tacrolimus. It is

vital for interpretation of a plasma drug concentration that the

time of sampling relative to the last dose and duration of therapy

at this dose are known. For example, distribution of digoxin

takes several hours and the sample should not be taken for at

least 8 hours after an oral dose when distribution is complete.

The duration of treatment is important because the patient

should be at steady state. Thus, sampling for digoxin 2 days after

start of treatment is of little value since the half-life in a patient

with normal renal function is about 36 hours and the patient will

not be at steady state for four to five half-lives (i.e. about

a week). A patient with a low glomerular filtration rate will have

a longer half-life and steady state might not be reached for 2 or 3

weeks.

TDM of aminoglycoside antibiotics is important for two

reasons. A sample taken at the end of an intravenous infusion

can tell us whether the concentration achieved is sufficient to be

bactericidal. On the other hand, a trough concentration obtained

immediately before the next dose, can show whether drug is

accumulating and is likely to lead to nephrotoxicity or

ototoxicity.

Evaluation of new drugs

Starting with the first administration to humans, CP plays a crit-

ical role in exploring the tolerability, PD and PK of each new

molecular entity in early drug development. The aim is to learn

as much about the molecule as possible and thereby establish

whether the drug has the profile needed to justify commitment of

massive resources required to obtain a licence to market it,

a process taking an average of 10 years.

The first studies in humans require careful selection and

administration of a range of single doses based on the results of

in vitro and animal in vivo primary and safety pharmacology

studies, PK and toxicology. Safety is paramount but from the PK

and PD data generated from single, and subsequently multiple

doses, it is usually possible to establish a dose range which

achieves plasma concentrations of therapeutic interest. These

doses will be used in subsequent studies to focus on benefit:risk

and to address the specific questions which must be answered

about that molecule. If the data do not support the minimum

acceptable profile, development should be discontinued at the

earliest opportunity. If, on the other hand, the data are

� 2012 Elsevier Ltd. All rights reserved.

BASIC SCIENCE

encouraging, they can be used to optimize the design of subse-

quent clinical trials.

When prescribing a medicine for a patient, details of dosing

may be critical: a suitable starting dose, the maximum dose that

can be safely administered, frequency of dosing, whether

absorption is likely to be affected by food and hence whether the

dose should be taken before or after meals, whether it is better in

the evening or morning. Factors pertinent to the specific patients

must also be taken into account, such as contraindications or

special precautions due to age, renal function or other diseases

and whether the medicine is likely to interact with any

concomitant medication. All of these considerations will be

SURGERY 30:4 180

based on information from clinical studies summarized in the

Summary of Product Characteristics (SPC). A

FURTHER READING

Griffin JP, ed. The textbook of pharmaceutical medicine. 6th edn. Wiley-

Blackwell, BMJ Books, 2009. Chapters 4 and 5.

Ritter JM, Lewis LD, Mant TGK, Ferro A. A textbook of clinical pharma-

cology and therapeutics. 5th edn. Hodder Arnold, 2008.

Tozer TN, Rowland M. Introduction to pharmacokinetics and pharmaco-

dynamics. The quantitative basis of drug therapy. Lippincott Williams

& Wilkins, 2006.

� 2012 Elsevier Ltd. All rights reserved.