Instant Clinical Pharmacology

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Instant Clinical
Pharmacology
Evan J. Begg
BSc, MB, ChB (Auckland), MD (Otago), FRACP
Professor in Medicine/Clinical Pharmacology
Christchurch School of Medicine
University of Otago
Christchurch
New Zealand
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2003 by Blackwell Publishing Ltd
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ICPA01 21/5/05 12:12 PM Page iv
Contents
Inducers of drug metabolism/inhibitors of
drug metabolism, 52
Drug/food interactions, 54
4 Pharmacovigilance, 57
Drug development, 58
Therapeutic drug monitoring (TDM), 60
Drugs involved in therapeutic drug
monitoring, 62
Overdose/poisoning, 64
Common poisonings, 66
Pharmacological aspects of drug
dependence, 68
5 Optimal therapeutics, 71
Principles of drug action, 72
Applied pharmacology, 74
Compliance with medication, 76
Principles of therapeutics, 78
Patients and their drugs, 80
The drug prole, 82
Evidence-based medicine, 84
Pharmacoeconomics, 86
Drug information/resources, 88
6 Appendix, 91
Important equations in pharmacology, 92
The pharmacokinetic triangle, 93
Glossary/abbreviations, 94
Test questions, 96
Test answers, 98
Index, 101
Introduction, vi
What is clinical pharmacology?, vii
1 Clinical pharmacokinetics, 1
General overview of pharmacokinetics, 2
Pharmacokinetics, 4
Drug clearance, 6
Volume of distribution, 8
The half-life, 10
Oral availability, 12
Protein binding, 14
pH and pharmacokinetics, 16
2 Factors affecting dosing, 19
Drug metabolism, 20
Saturable metabolism, 22
Pharmacogenetics, 24
Dosing in liver disease and other disease
states, 26
Renal drug elimination, 28
Dosing in renal impairment, 30
Dosing in the elderly, 32
Dosing in children, 34
Drugs in pregnancy, 36
Drugs in human milk, 38
3 Altered drug effect, 41
Adverse drug reactions, 42
Drug-induced allergy, 44
Adverse drug events, 46
Preventing adverse drug events, 48
Drug/drug interactions, 50
v
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This book is written mainly for medical stu-
dents and doctors undergoing postgraduate
training. Students of allied health profes-
sionals, such as pharmacy, nursing, dentistry
and physiotherapy may also nd it useful.
The aim is to provide essential informa-
tion about the core topics in clinical pharma-
cology. There is general agreement across
the world about what constitutes this core
curriculum. These topics are covered, the
emphasis reecting my own biases.
The book assumes a knowledge of basic
pharmacology and does not embrace spe-
cic therapeutics. It aims to bridge the gap
between basic pharmacology and the thera-
peutic use of drugs in humans.
Some readers may be put off by the
slightly mathematical nature of the initial
section on clinical pharmacokinetics. I apo-
logize for this, but unfortunately this is the
basis of clinical pharmacology. The book
gets easier after this.
Any feedback would be appreciated, par-
ticularly in terms of improving the user-
friendliness of the book.
I acknowledge with warm gratitude the
input and inspiration of all the members of
my department, both past and present. The
book is dedicated to my students, whose
humour and wide-eyed enthusiasm makes
teaching so worthwhile.
How to use the book
Mindful of the ckle nature of the learning
process, I have tried to keep things simple
and to encapsulate each topic within two
facing pages. Hopefully, this will enable the
reader to complete a topic in a short learn-
ing session before the inevitable build-up of
boredom!
Happy learning!
Evan J. Begg
vi
Introduction
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vii
For example, once a diagnosis has been
made and drug therapy is considered appro-
priate, a particular drug must be chosen. The
ideal drug is chosen, based on the best evid-
ence. This drug is then examined to see if it is
appropriate for this patient.
Is the patient allergic to this drug or class?
Are there any potential interactions with
the patients other drugs?
Does the patient have other diseases that
might be made worse (or better) by the addi-
tion of the new drug?
Is compliance likely to be a problem?
If the drug passes this rst test, then a dosage
regimen must be chosen. The starting point
is the normal dose regimen that would be
appropriate for the average patient. This
dosage regimen is then adjusted to tailor it
to this patient.
Is the patient old? (may need a lower dose)
Is there any renal impairment/liver im-
pairment? (may need a lower dose or a
longer dose interval)
Are there any drug interactions that might
require dose alteration?
Problems with these ideals
It is easy to preach a holier than thou
approach to therapeutics, but harder to
achieve this in practice. Individualizing
drugs to the patient may be different in
different settings. Prescribing in outback
Australia is likely to be very different from
prescribing in central Sydney. Access to
laboratories and medical follow-up will be
different. The ideal drug, based on evidence,
may be totally impractical for your particu-
lar patient.
Clinical pharmacology is concerned with the
rational, safe and effective use of medicines.
Clinical pharmacology
The principles behind the prescribing process
as opposed to
Therapeutics
The process of medical treatment
Clinical pharmacology involves the com-
plex interaction between the patient and the
drug. The patient is a unique individual,
with many distinguishing features that need
to be taken into account during prescribing.
The patient can be described in terms of the
patient prole. The drug, likewise, is unique,
with its own distinguishing features. It may
be described in terms of the drug prole.
Good prescribing involves tailoring the
drug and dosing regimen to the unique pati-
ent. Clinical pharmacology provides the
basis of this.
Patient prole Drug prole
Age Name (generic)
Weight Class
Sex Action
Race Pharmacokinetics
Allergies Indications
Smoking history Contraindications/
Alcohol history precautions
Diseases Interactions
Pregnant/lactating Side effects
Current therapy Dosing regimen
Intelligence Monitoring
Overdose
What is Clinical Pharmacology?
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The rational, safe and effective use of
medicines must be tolerant of all this. Pre-
scribers should not be expected to achieve
perfection, but to pursue the greatest poss-
ible effectiveness, with minimal risks, and
to respect the patients choice. The word
rational is relevant here, denoting not only
scientic rationality, but also situational
rationality.
What is Clinical Pharmacology?
viii
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1 Clinical pharmacokinetics
General overview of pharmacokinetics, 2
Pharmacokinetics, 4
Drug clearance, 6
Volume of distribution, 8
The half-life, 10
Oral availability, 12
Protein binding, 14
pH and pharmacokinetics, 16
1
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Clinical pharmacokinetics General Overview of Pharmacokinetics
2
1
General Overview of
Pharmacokinetics
The aim of drug therapy is to achieve ef-
cacy without toxicity. This involves achiev-
ing a plasma concentration (Cp) that is above
the minimal effective concentration (MEC),
but below the minimal toxic concentration
(MTC).
Clinical pharmacokinetics is about all the
factors that determine the Cp and its time-
course, i.e. it is about variability. The vari-
ous factors are dealt with in subsequent
chapters.
Constant IV infusion
In order to achieve early effect (e.g. treating
status epilepticus with phenytoin) it is im-
portant to get the Cp up to the effect zone as
soon as possible. This is achieved with a
loading dose.
The factor determining the loading dose is
the volume of distribution (Vd).
Oral dosing
Cp
Time
MTC
Cp
SS
MEC
Cp
Time
MTC
Cp
SS
MEC
The Cp rises to reach the desired steady state
concentration (Cp
SS
). The main determinant
of the Cp
SS
is the dose and the clearance (Cl).
Loading dose (IV injection followed by a
constant infusion)
Cp
Time
MTC
MEC
Dose Dose Dose Dose
The curve reects assimilation and elimina-
tion, and intermittent administration.
Cp higher than desired
Cp
Time
MTC
Cp
SS
MEC
The two factors involved are excessive dos-
age and/or decreased Cl.
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General Overview of Pharmacokinetics Clinical pharmacokinetics
3
1
Factors causing decreased Cl are:
normal variation
saturable metabolism
genetic enzyme deciency
renal failure
liver failure
old age
very young age (neonate)
enzyme inhibition.
Cp lower than desired
This is determined by the t
1/2
of the drug. It
takes 4 t
1/2
to achieve >90% of the steady-
state concentration.
Time for drug elimination
Cp
Time
MTC
Cp
SS
MEC
Dose may be too low, or Cl too high.
Factors causing increased Cl are:
normal variation
poor absorption
high rst-pass metabolism
genetic hypermetabolism
enzyme induction
non-compliance.
Time to steady state
Cp
0
MTC
MEC
1 2 3 4 5 6
Half-lives
Cp
Half-lives
MTC
MEC
1 0 1 2 3 4 5
1.0
0.5
0.25
0.125
0.0625
Drug stopped
This is determined by the t
1/2
of the drug. It
takes 4 t
1/2
for concentrations to reduce to
<10% of the starting value.
Components of the line of
steady state
Cp
3
Cp
SS
Half-lives
0 1 2 4 5 6
The line of steady state is effectively made up
of the sum of the line of accumulation and
the line of elimination. i.e. the net effect of
input and output.
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Clinical pharmacokinetics Pharmacokinetics
4
1
of the body. From a dosing point of view it
is the concentration of drug at the site of
action that is important. This is difcult to
measure. Under steady-state conditions the
plasma concentration (Cp) is in equilibrium
with sites of action. In practice it is usually
the Cp that is measured.
Input
(dose)
Drug in
body
Output
(elimination)
Pharmacokinetics involves the study of the
movement of the drug into, within and out
Cp C
biophase
Receptors
Site of action (biophase)
The pharmacokinetics of a drug are usually
studied using an intravenous injection or
infusion, as the dose can then be considered
to be 100% assimilated into the body. The
values of Cl, Vd and t
1/2
for a drug are derived
from the curve of concentration versus time.
Zero-order elimination
It would be very simple if the Cp declined
linearly with time after a simple intravenous
injection. This situation, called zero-order
elimination, occurs only rarely. A familiar
example is ethanol, concentrations of which
decline at a constant rate of approximately
15 mg/100 mL/h.
Cp
Time
(NB linear scale)
Pharmacokinetics
Pharmacokinetics:
The study of the movement of drugs into,
within and out of the body
i.e. what the body does to the drug
as opposed to
Pharmacodynamics:
The study of drug effect, and
mechanisms of action
i.e. what the drug does to the body
It is important to know the pharmacokinet-
ics of a drug so that the drug can be used in a
rational and scientic manner, and the dose
tailored to the patient.
The most important pharmacokinetic
parameters from a dosing point of view are
the clearance (Cl), the volume of distribu-
tion (Vd) and the half-life of elimination
(t
1/2
). The Cl determines the maintenance
dose, the Vd the loading dose, and the t
1/2
the
dose interval.
One-compartment model
The most simple model is the one-compart-
ment model. In this, the body is considered
as a single container (one compartment) in
which the drug is instantaneously and uni-
formly distributed.
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Pharmacokinetics Clinical pharmacokinetics
5
1
First-order elimination
The more common situation is rst-order
elimination, in which the decline in plasma
concentrations is not constant with time, but
varies with the concentration. The higher
the concentration, the greater the rate of
elimination. The concentration declines ex-
ponentially with time.
where Cp
t
is the concentration at any time t
Cp
o
is the concentration at time zero
and k is the elimination rate constant
This equation is difcult to use (for most
of us!) and can be simplied by transforming
it to a linear expression. This is done by tak-
ing the natural logarithm of each side:
ln Cp
t
= ln Cp
o
kt
This now has the form of a linear equation
y = mx + c, or in this case because the line is
declining, y = c mx, where m is the slope
and c the intercept on the y-axis.
Cp
Time
(NB linear scale)
First-order elimination
This curve can be described by:
Cp
t
= Cp
o
* e
kt
(In) Cp
Time
(NB log scale)
k
Cp
o
Important pharmacokinetic abbreviations
Abbreviation Denition Abbreviation Denition
t
1/2
the half-life of elimination ss Steady state
Vd Volume of distribution Cp Plasma concentration
Cl Clearance Cp
t
Plasma concentration at time = t
AUC Area under the curve Cp
o
Plasma concentration at time = o
F Fractional oral availability Cp
ss
Plasma concentration at steady state
fu fraction excreted unchanged Ab Amount in body
PB Protein Binding e The natural logarithm
T
max
Time to maximum concentration (value = 2.7183)
C
max
Peak concentration ln log to the base e
(Concentration maximum) k the rate constant of elimination
ICPC01 21/5/05 12:15 PM Page 5
Clinical pharmacokinetics Drug Clearance
6
1
Cp
Time
(NB linear scale)
First-order elimination
The graph shows that the rate of elimination
(RE) is different at different concentrations,
i.e. it is driven by concentration.
rate of elimination Cp
rate of elimination (mg/h) = constant
(L/h) * Cp (mg/L)
This constant is the clearance (Cl) and by
deduction has units of volume/time (e.g.
L/h), since the units for rate of elimination
are mg/h, and for concentration mg/L.
0
Cp
3
Cp
SS
Half-lives
2 1 4 5 6
Administration
Elimination
Drug Clearance
Drug clearance (from plasma) is dened as:
The volume of plasma cleared of drug
per unit time;
or
A constant relating the rate of elimination to
the plasma concentration (Cp)
i.e. rate of elimination = Cl * Cp
Units: vol/time (e.g. L/h)
Clearance (Cl) is the single most important
pharmacokinetic parameter. Cl determines
the maintenance dose-rate, i.e. dose per unit
time, required to maintain a plasma concen-
tration.
Clearance does not apply to drugs with
zero-order kinetics, but only to those with
rst-order (exponential) kinetics. This applies
to the majority of drugs.
i.e. rate of elimination = Cl * Cp
Thus, Cl is A constant relating the rate of
elimination to the plasma concentration;
and
The volume of plasma cleared of drug per
unit time.
The equation can be rearranged as
follows:
Achievement of a constant steady-
state plasma drug concentration
(Cp
SS
)
In order to maintain a target Cp, the drug
must be administered at a rate equal to the
rate of elimination at that concentration, i.e.
rate of administration = rate of elimination
Since
rate of elimination = Cl * Cp, then
rate of administration = Cl * Cp
SS
, or
Maintenance dose-rate = Cl * Cp
SS
Cl L/h
rate of elimination mg/h
Cp (mg/l)
( )
( )
=
ICPC01 21/5/05 12:15 PM Page 6
Drug Clearance Clinical pharmacokinetics
7
1
Cp
Time
Area
1 2 3 4 5 6 7
Physiological relevance of
drug clearance
The main organs responsible for drug clear-
ance are the liver (metabolism) and the kid-
neys (removal of unchanged drug). Total
body Cl is the sum of all clearance processes,
i.e.
Cl (total) = Cl (renal) + Cl (liver) +
Cl (other)
Determination of Cl
Plasma Cl is usually determined from the
area under the plasma concentration vs time
curve (AUC) after IV administration.
The AUC is determined using the trape-
zoidal rule.
AUC = Area 1 + Area 2 + Area 3 + . . .
Area n, where each area is approximated by
a trapezium.
Area under the curve (AUC)
The bigger the AUC, the smaller the Cl.
After oral administration:
where F = oral availability.

Cl
F * Dose
AUC
=

Cl
Dose
AUC
=
ICPC01 21/5/05 12:15 PM Page 7
Clinical pharmacokinetics Volume of Distribution
8
1
volume of the body (50100 L) is compared
with Vds of drugs, e.g. heparin (5 L); gen-
tamicin (15 L); digoxin (500 L); and quin-
acrine (20 000 L).
Highly lipid soluble drugs such as quin-
acrine have much larger Vds than very polar,
water soluble drugs such as heparin.
Determination of Vd
To calculate Vd, the Ab and Cp need to be
known. The only time Ab is known accur-
ately is immediately after the drug has been
given intravenously (prior to elimination),
i.e. the dose. If the Cp at time zero (Cp
o
) is
known, then the Vd can be calculated. The
Cp
o
can be determined from the lnCp vs time
curve after intravenous (IV) administration.
After initial distribution, there is a log-
linear decline in plasma concentration. The
Cp
o
can be determined by back-extrapolat-
ing the linear portion of the curve to its inter-
cept on the y-axis. Vd can then be calculated.
(In) Cp
Time
Cp
o
i.e. At time zero, Ab = dose
then dose = Vd * Cp
o
or Vd = dose/Cp
o
Calculation of loading dose (LD)
It follows from the above that to achieve a
target Cp, the Vd of the drug must be known
Volume of Distribution
The volume of distribution is:
The volume into which a drug appears
to be distributed with a concentration
equal to that of plasma,
or
A proportionality constant relating
the plasma concentration (Cp) to the
amount of drug in the body (Ab).
i.e. Ab = Vd * Cp
Units: Volume or vol/kg
The volume of distribution (Vd) is the second
most important pharmacokinetic parameter
(after Cl). It determines the loading dose, i.e.
the dose required to achieve a target plasma
concentration (Cp) as soon as possible.
In order to achieve a target Cp, the tissues
into which the drug distributes (i.e. the vol-
ume of distribution) must be lled up.
The Vd is therefore the volume into
which a drug appears to be distributed with
a concentration equal to that of plasma.
After distribution is complete, the amount
of drug in the body (Ab) is proportional to
the plasma concentration (Cp).
i.e. Ab Cp
or Ab = constant * Cp
This constant has units of volume (e.g. L)
since the Ab is in mass units (e.g. mg) and Cp
is in concentration units (e.g. mg/L).
Hence the Vd is A proportionality con-
stant relating the plasma concentration to
the amount of drug in the body.
i.e. Ab = Vd * cp
or
The Vd is often called the apparent Vd
since the volume has no real anatomical
meaning. This can be appreciated when the

Vd
Ab
Cp
=
ICPC01 21/5/05 12:15 PM Page 8
Volume of Distribution Clinical pharmacokinetics
9
1
1 0
steady-state
Cp
2.0
1.5
1.0
0.5
0.0
2 3 4 5
Time (units of t
1/2
)
line of
0.5
0.75
0.875
A
B
LD = Vd * target Cp
e.g. to achieve a target Cp of digoxin (Vd
~ 500 L) of 1.5 g/L, a loading dose (LD) of
750 g, or 0.75 mg is needed, i.e.
LD (g) = 500 (L) * 1.5 (g/L)
= 750 g
With a loading dose, steady-state concentra-
tions can be achieved quickly.
Curve A a loading dose followed by main-
tenance dosing.
Curve B a maintenance dosing every
half-life.
In summary, the most important thing
about Vd is that it enables the calculation of
a loading dose to achieve any desired Cp.
LD = Vd * Cp
ICPC01 21/5/05 12:15 PM Page 9
Time-course of drug elimination
If a drug is discontinued after an infusion,
the Cp will decline exponentially to <10% of
its starting value after four half-lives.
Clinical pharmacokinetics The Half-Life
10
1
Time-course of drug accumulation
If a drug is started as a constant infusion, the
Cp will accumulate to approach steady-state
(>90% of steady state concentration) after
four half-lives.
1 0
Cp
6
5
4
3
2 3 4 7
Time (h)
2
1.5
1
5 6
t
1/2
= 2.5 h
(NB log scale)
Cp
Half-lives
1 0 1 2 3 4 5
1.0
0.5
0.25
0.125
0.0625
Drug stopped
Cp
0
Cp
SS
1 2 3 4 5 6
Half-lives
The Half-Life
The half-life of elimination (t
1/ 2
) is:
The time for the concentration of
the drug in plasma (or the amount of
drug in the body) to halve.
Units: Time (usually h)
The t
1/2
provides an index of:
1 the time-course of drug elimination;
2 the time-course of drug accumulation; and
3 choice of dose interval.
Derivation of t
1/2
The half-life of elimination (t
1/2
) can be
derived by plotting actual concentrations on
semilog graph paper, or logged concentra-
tions on linear graph paper. It is the time
taken for any concentration to halve, e.g.
from 3 to 1.5 mg/L.
ICPC01 21/5/05 12:15 PM Page 10
The Half-Life Clinical pharmacokinetics
11
Components of the line of
steady state
The line of steady state is effectively the com-
bination of accumulation and elimination.
i.e. it is the sum of the effect of dose and elim-
ination at any time point.
Relationship between t
1/2
, Vd and Cl
1
Choice of dose interval
The dose interval is usually chosen based on:
1 the t
1/2
2 the therapeutic index of the drug
3 compliance ait is best, if possible, to have
dosing once or twice a day.
If drug Cl decreases (say in renal dysfunc-
tion), it may be possible for a drug that is
normally given three or four times a day to be
given twice or once daily, with greater chance
of compliance. This is good therapeutics.
0
Cp
3
Cp
SS
Half-lives
2 1 4 5 6
Accumulation
Elimination
(In) Cp
Time
larger Vd
larger Cl
It is logical that the larger the Vd, the longer
the t
1/2
, i.e. it takes longer to remove drug
from deep within the tissues. Similarly, it is
logical that the larger the Cl, the shorter the
t
1/2
. In other words:
This relationship can be turned into an equa-
tion by multiplying the right side by 0.693.
This strange number is the natural logarithm
of 2 (i.e. ln 2) and gets into the equation
because the t
1/2
involves a halving, i.e. the
inverse of 2.
This is one of the most important equations
in clinical pharmacokinetics.
It indicates that the t
1/2
is dependent on Vd
and Cl.
Vd and Cl are the independent variables.
t
0.693Vd
Cl
12 /
=
t
Vd
Cl
1 2 /

ICPC01 21/5/05 12:15 PM Page 11
Clinical pharmacokinetics Oral Availability
12
1
Absorption
This refers to the ability of the drug to cross
a biological barrier into the blood. In the
case of oral absorption, it refers to crossing
the gut wall into the portal circulation.
Absorption is usually a passive process gov-
erned by the principles of diffusion (i.e. ows
down a concentration gradient). Sometimes,
active transport is involved (e.g. l-dopa).
Factors favouring absorption include high
lipid solubility and low ionization. pH may
also inuence absorption, but probably
affects the rate more than the extent.
First-pass metabolism
This refers to metabolism of the drug prior
to reaching the systemic circulation, i.e.
presystemic elimination. Some drugs, such
as highly lipid-soluble drugs, are so highly
metabolized that on rst-pass through the
liver there is substantial presystemic elim-
ination. Presystemic elimination can occur
in the gut wall (e.g. oestrogens), in the portal
circulation (e.g. aspirin salicylic acid) or
in the liver (the majority).
Effect of food on oral availability
Interestingly, food affects absorption and
rst-pass metabolism in opposite ways. Food
usually decreases the oral availability of
sparingly lipid-soluble drugs that are subject
to absorptive problems, e.g. food decreases
the oral availability of atenolol by 50%.
However, food usually increases the oral
availability of drugs that are subject to high
rst-pass metabolism. This is because food
increases portal venous blood ow, thereby
increasing the presentation of absorbed drug
to the liver, partially saturating metabolizing
Cp
Time
AUC
po
AUC
IV
Determinants of oral availability
1 Absorption.
2 First-pass metabolism.
Oral Availability
Oral availability is:
The fraction of drug that reaches the
systemic circulation after oral ingestion
Oral availability denes how much drug gets
on board after oral ingestion. Absorption
and rst-pass metabolism are the main
determinants of oral availability.
Oral availability is usually dened by
comparison with the total availability of
drug in the systemic circulation after IV dos-
ing, i.e. the fraction (F) of drug that gets into
the body after oral (po) versus IV adminis-
tration:
i.e.
The total amount of drug in the systemic
circulation is dened by the area under
the concentrationtime curve (AUC). The
AUC may be different after oral compared
with IV administration. The oral availab-
ility may have a value of one, or less than
one.

F
AUC
AUC
po
IV
=
ICPC01 21/5/05 12:15 PM Page 12
Oral Availability Clinical pharmacokinetics
13
1
T
max
is less important than the total oral
availability. A short T
max
may be useful
where an immediate effect is desired, e.g.
analgesia for a headache. A short T
max
may
also be a problem e.g. adverse effects related
to the peak concentration.
Slow-release preparations
A delayed T
max
and a longer drug action may
be achieved using tablets or capsules de-
signed to release their contents slowly. This
attens the concentrationtime prole, giving
a more even drug response.
Cp
Time
T
max
(time to peak concentration)
C
max
(peak concentration)
Cp
Time
Slow-release preparation
(lower C
max
, delayed T
max
)
pathways and opening up shunts that by-
pass metabolizing pathways. The net result
is greater oral availability, e.g. food increases
the oral availability of metoprolol by 50%.
Some foods, e.g. grapefruit juice, compete
with drugs for presystemic elimination,
thereby causing increased oral availability of
the drug (e.g. calcium antagonists, some
statins).
Confusing terminology
There is sometimes confusion between the
terms oral availability, bioavailability
and absorption. Oral availability is the pre-
ferred term because it is unambiguous.
Bioavailability has a strict historical
denition a the rate and extent of absorp-
tion. One problem with bioavailability is
its reference to absorption. As noted above,
absorption is only one part of the process of
drug attaining the systemic circulation. The
other problem with bioavailability is that it
is a single term that denes two processes a
the rate of absorption, and the extent. It is
more instructive to think of each of these
components independently, i.e. oral avail-
ability denes the extent, and another term,
T
max
, denes the rate.
Time to peak concentration (T
max
)
T
max
denes the time to maximum
(or peak) concentration
ICPC01 21/5/05 12:15 PM Page 13
Clinical pharmacokinetics Protein Binding
14
1
concentration of free drug, not total drug,
that is actually important in terms of desired
effects and side effects.
Free drug concentration is dependent on
free drug clearance (see Clearance, page 6),
and does not vary in relation to changes in
plasma proteins. Therefore, except for rare
exceptions, no alteration in dosage is required
in states of altered protein binding.
The fallacy of protein-binding
drug interactions
Many so-called protein-binding drug inter-
actions have been reported. While drugs can
compete for protein binding sites, especially
on albumin, this does not affect the free
concentration.
Bound drug Free drug
Measured drug
Altered albumin or
1
-acid glycoprotein con-
centrations will alter the measured (total)
concentrations of drugs bound highly to these
proteins.
However, it is free drug that acts on recep-
tors to produce effect. Therefore, it is the
Without displacer With displacer
This is an
artificial
test-tube
situation
If a drug in the body was not subject
to drug elimination, then introduction of a
protein-binding displacer would increase
the concentration of the free drug.
In reality drug elimination does occur.
Since the steady-state free drug concen-
tration is only dependent on maintenance
dose and free drug clearance (remember,
Maintenance dose = Cl * Cp), then free drug
concentration returns to its predisplacement
level. However, the total drug concentration
is now lower than it was.
Protein Binding
The major message about protein binding
(PB) is that it is usually not important.
Protein binding is only important in the
interpretation of measured plasma
concentrations
There is enormous confusion about the
importance of protein binding and the drug
effects attributed to it. While drugs may dis-
place each other from protein-binding sites,
this is almost always unimportant. Most
alleged protein binding interactions of clin-
ical importance have an additional mech-
anism operating, such as altered drug
clearance, that is the reason underlying the
observed clinical effects.
Acidic drugs bind largely to albumin.
Basic drugs bind mainly to
1
-acid glycopro-
tein (i.e. orosomucoid), an acute phase react-
ant, and to albumin and -lipoproteins.
The signicance of protein binding lies in
the interpretation of plasma concentrations
of drugs. If plasma concentrations are not
measured, protein binding can largely be
ignored.
NB: When plasma concentrations of drugs
are measured, it is total drug, i.e. bound +
unbound, that is measured. It is possible, but
not routine (except perhaps for phenytoin),
to measure free or unbound drug.
ICPC01 21/5/05 12:15 PM Page 14
Protein Binding Clinical pharmacokinetics
15
1
Interpretation of measured plasma
concentrations during therapeutic
drug monitoring
Protein binding problems arise from the
fact that the measured drug concentration is
total drug (bound + unbound). In hypoalbu-
minaemia (e.g. in renal disease) an acidic drug
such as phenytoin will have a lower total drug
concentration because of lower protein bind-
ing. Free drug concentration will, however, be
the same as in the non-hypoalbuminaemic
state (assuming free drug Cl is constant).
The same principles apply with displacing
drugs in normoalbuminaemia. e.g. phenytoin
(therapeutic range 1020 mg/L total con-
centration, 12 mg/L free concentration).
In hypoalbuminaemia free concentration
(and effect) is identical but total measured
concentration is half. If the dose was in-
creased to give a total concentration of
10 mg/L, the free concentration would be
2 mg/L and may be toxic. Note that the
situation for hypoalbuminaemia is identical
to that involving drug displacement inter-
actions (see above).
Drugs with saturable protein
binding
Some drugs at clinical concentrations sat-
urate the available protein-binding sites.
In this situation total drug concentration
(bound + unbound) does not increase lin-
early with dose. Interpretation of measured
concentrations is difcult. If free concentra-
tions were measured, these would be seen to
rise linearly with dose.
Drugs with saturable protein binding
include ceftriaxone, hydrocortisone, pred-
nisone, thioridazine and sodium valproate.
Of these, the only one that has clinical
importance is sodium valproate, because
this is sometimes measured during thera-
peutic drug monitoring. Saturable protein
binding makes interpretation of valproate
concentrations difcult. For the other drugs
protein binding does not need to be taken
into account during dosing, because drug
concentrations are not usually measured,
and free concentrations behave predictably.
Without displacer With displacer
Free conc.
1 mg/L
Bound
conc.
4 mg/L
Total
conc.
5 mg/L
Bound
conc.
9 mg/L
Total
conc.
10 mg/L
Free conc.
1 mg/L
Normal
albuminaemia
(i.e. 90% PB)
Marked
hypoalbuminaemia
(i.e. 80% PB)
Free conc.
1 mg/L
Bound
conc.
4 mg/L
Total
conc.
5 mg/L
Bound
conc.
9 mg/L
Total
conc.
10 mg/L
Free conc.
1 mg/L
ICPC01 21/5/05 12:15 PM Page 15
Clinical pharmacokinetics pH and Pharmacokinetics
16
1
may show variation in the ionized/unionized
ratio at pHs encountered in physiology.
Similarly, weak bases with pK
a
values
between 5 and 11 may show variation in the
unionized/ionized ratio.
When is this important?
Drug absorption from the stomach
Drug elimination via the kidneys
Drug distribution into milk
Drug distribution across the placenta.
Drug absorption from the stomach
Gastric pH is usually between 1 and 4. Acids
are therefore largely unionized and may be
absorbed in the stomach (e.g. aspirin).
However, because of the far greater absorpt-
ive surface area in the small intestine, the
bulk of absorption occurs there, even for
acids.
Drug elimination in the kidney
The pH in the urine varies from 4.5 to 7.5.
Weak acids may vary from unionized at
pH 4.5 to largely ionized at pH 7.5.
Reabsorption from the renal tubular lumen
into the blood will occur if the drug is in the
unionized state. Therefore, reabsorption
will occur in acid urine, while elimination
will occur in alkaline urine. Conversely,
weak bases will be reabsorbed in alkaline
urine and eliminated in acid urine. This prin-
ciple is sometimes used in enhancing the
elimination of drugs after overdoses (e.g.
aspirin elimination can be enhanced by
administration of bicarbonate).
pH and Pharmacokinetics
In some situations drug disposition varies in
relation to pH differences across biological
barriers. The disposition of some weak acids
and bases is susceptible to small pH dif-
ferences because of variation in the state of
ionization and hence the ability to cross
membranes.
Background theory
Acids are ionized in basic media
Bases are ionized in acidic media
i.e. H
+
+ X

HX
(ionized) (unionized)
If more H
+
ions are added (i.e. adding acid-
ity), the equilibrium moves to the right. If
base (e.g. OH

) is added, H
+
ions are con-
sumed, and the equilibrium moves to the
left. Unionized drug crosses lipid biological
barriers (e.g. membranes) better than ion-
ized drug.
HendersonHasselbalch equation
For acids:
For bases:
NB The pK
a
is the pH at which a drug is
50% ionized and 50% unionized. Weak
acids, with pK
a
values between 3 and 7.5,
pH pK
[unionized]
[ionized]
a
log = +

10
pH pK
[ionized]
[unionized]
a
log = +

10
ICPC01 21/5/05 12:15 PM Page 16
pH and Pharmacokinetics Clinical pharmacokinetics
17
Drug distribution into milk, across
the placenta, and into 3rd spaces
Milk, the fetus, and most 3rd spaces have
pH values that are acidic (~7.0) in relation to
plasma (~7.4). Therefore bases tend to con-
centrate in these compartments because
they are relatively ionized on the acidic side,
and effectively trapped. This is called ion
trapping. It applies to any situation where a
pH gradient exists across a biological bar-
rier, and where the principles of diffusion
apply, e.g. abscesses, synovial uid.
1
Drugs with pH-dependent
elimination
Acids (elimination enhanced by alkaline
diuresis)
phenobarbitone
salicylates.
Bases (elimination enhanced by acid diuresis)
amphetamines
methadone
mexiletine
phencyclidine
phenylpropanolamines (e.g. ephedrine,
pseudoephedrine)
quinidine.
ICPC01 21/5/05 12:15 PM Page 17
ICPC01 21/5/05 12:15 PM Page 18
2
2 Factors affecting dosing
Drug metabolism, 20
Saturable metabolism, 22
Pharmacogenetics, 24
Dosing in liver disease and other disease states, 26
Renal drug elimination, 28
Dosing in renal impairment, 30
Dosing in the elderly, 32
Dosing in children, 34
Drugs in pregnancy, 36
Drugs in human milk, 38
ICPC02 21/5/05 12:14 PM Page 19
and methylation. Glucuronidation is quantit-
atively the most important.
Cytochrome R450 metabolism
(CYP)
CYP reactions are catalysed by the cytoch-
rome p450 mixed function oxidases, mostly
in the liver. These are iron-containing
enzymes, named p for pigment, and 450 for
the wavelength, in nM, at which spectro-
photometric absorption occurs. At least
13 CYP gene families exist in humans, with
various subfamilies. Each CYP family is
encoded by a separate gene. The nomencla-
ture is:
Factors affecting dosing Drug Metabolism
20
2
Phase I
Derivative
Conjugate
Drug
Phase II
Phase II
Phase I reactions include oxidation, reduc-
tion and hydrolysis. The most common are
oxidation reactions (adding oxygen, or
removing hydrogen). Oxidation reactions
include dealkylation, hydroxylation, deam-
ination and desulphuration. Most occur via
the cytochrome p450 enzymes.
Phase II reactions involve conjugations, such
as glucuronidation, acetylation, sulphation
CYP 3 A 4
cytochrome p450 family subfamily isoform
Drug clearance by the liver
The fraction of drug removed from blood in
one passage across the liver is the extraction
ratio (ER).
where C = drug concentration
Hepatic drug clearance depends on the
extraction ratio, but also on the hepatic
blood ow (HBF) since the greater the blood
ow the greater the presentation of drug to
the liver. Thus,
Hepatic Cl = HBF * ER
High Cl, ow-dependent elimination: If the
extraction ratio approaches 1 (complete
extraction), then hepatic Cl approaches hep-
atic blood ow. In this case the elimination
ER
C C
C


=

in out
in
Drug Metabolism
Variation in drug metabolism is a major
cause of variation in drug clearance
Some drugs are excreted unchanged through
the kidneys because they are polar and are
not reabsorbed in the renal tubules. Other
drugs, especially those that are lipid-soluble,
are reabsorbed in the renal tubules and
would circulate forever if they were not
biotransformed to more readily excretable
forms.
Metabolic biotransformation converts
drugs to more polar and excretable forms.
The resulting metabolite may be inactive,
less active or occasionally more active (e.g.
metabolite of a prodrug) than the parent
molecule.
Where does biotransformation
occur?
Metabolism occurs mainly in the liver, but
also in the kidney, lung, GI mucosa, plasma,
the CNS and probably most tissues. Some
drugs undergo sequential biotransformation.
ICPC02 21/5/05 12:14 PM Page 20
Drug Metabolism Factors affecting dosing
21
is said to be blood ow dependent, or high
clearance.
Low Cl, ow-independent elimination: If
the extraction ratio is small, there is no
blood ow dependence, since presentation
of more drug to the liver will not result in
greater elimination.
First-pass metabolism: Drugs entering the
portal system after absorption have to pass
through the liver prior to reaching the sys-
temic circulation. If the extraction ratio
approaches 1, little drug will reach the sys-
temic circulation. In this case, rst-pass
elimination approaches 100%, and oral avail-
ability (F) approaches zero. For example,
lignocaine has an extraction ratio of 0.7, and
therefore an F of 0.3.
There are three situations in which the
extent of rst-pass metabolism decreases,
resulting in increased oral availability:
1 High oral doses a Drugs such as prop-
ranolol saturate the metabolizing enzymes,
resulting in less rst-pass metabolism, and
greater oral availability.
2 High blood ow a Increased liver blood
ow, such as after food, delivers more drug
to the metabolizing enzymes, sometimes
saturating them. This results in less rst-pass
metabolism for high clearance drugs such as
propranolol.
3 Chronic liver disease a There is lower
intrinsic clearance, as well as increased
shunting.
2
Some examples of high and low clearance drugs.
High clearance Low clearance
Antidepressants NSAIDs
Antipsychotics Anticonvulsants
Calcium antagonists Most benzodiazepines
Narcotics
Nitrates
Most antiparkinsons
Most statins
Many b-blockers
Clinical signicance of high-
clearance drugs
Subject to rst-pass metabolism
Subject to ow-dependent elimination
May require dose-reduction in situations
of decreased blood ow, e.g. congestive
heart failure (CHF)
May be subject to pre-systemic drug
interactions, e.g. with grapefruit juice.
ICPC02 21/5/05 12:14 PM Page 21
Enzyme inhibitors which act by compet-
ing with other drugs for metabolism by the
same enzyme, will not change the V
max
, but
will increase the Km. Enzyme inhibitors that
act by direct inhibition of the enzyme will
decrease the V
max
and may or may not alter
the Km.
Factors affecting dosing Saturable Metabolism
22
2
R
a
t
e

o
f

h
e
p
a
t
i
c
m
e
t
a
b
o
l
i
s
m

(
d
c
/
d
t
)
Concentration (Cp)
dc
dt
=
V
max
* Cp
Km + Cp
V
max
(maximum rate of reaction)
Km
1
/2 max
The curve asymptotes to a maximum rate
of reaction (V
max
). The Km (Michaelis con-
stant) is the concentration at which half the
maximum rate of reaction occurs.
V
max
relates to the total amount of enzymes
available for metabolism. Km is inversely
proportional to the afnity of the drug for
the enzyme, i.e. the higher the afnity the
lower the Km.
Enzyme inducers, which increase the
amount of available enzymes, will therefore
increase V
max
but will not alter Km.
dc
dt
V * Cp
Km Cp
max


=
+
R
a
t
e

o
f

r
e
a
c
t
i
o
n
Cp
Enzyme induction
(same Km, higher E
max
)
R
a
t
e

o
f

r
e
a
c
t
i
o
n
Cp
Enzyme inhibition (non-competitive)
(same Km, lower E
max
)
Enzyme inhibition (competitive)
(higher Km, same E
max
)
NB Below the Km, the rate of elimination is
almost directly proportional to the plasma
concentration (i.e. RE Cp. This is equival-
ent to Cp to the rst power, or rst order).
This is therefore a rst-order reaction, and
graphically is a straight line if log Cp is plot-
ted against T.
Above the Km, the rate of elimination be-
comes independent of concentration. This is
called zero-order elimination because it is not
dependent on Cp (equivalent to Cp
o
where
any number to the power of zero equals 1).
Saturable Metabolism
Saturable metabolism causes
drug concentrations to rise
disproportionately (non-linearly)
compared with dose
It is theoretically possible for all drugs to sat-
urate their metabolizing pathways. For most
drugs the concentration at which saturation
begins to be evident is usually above the con-
centration range used in therapeutics. For
a few drugs, however, saturation occurs at
therapeutic concentrations.
Consider the MichaelisMenten curve:
ICPC02 21/5/05 12:14 PM Page 22
Saturable Metabolism Factors affecting dosing
23
In practice, most drugs have Km values
well above their therapeutic concentrations,
and therefore have rst-order kinetics.
A select group of well-known drugs
saturate at or around their therapeutic con-
centrations. For these, concentrations may
increase more than proportionally for a
given increase in dose, e.g. phenytoin.
2
100
C
P

(
m
g
/
L
)
Dose (mg)
Minimum toxic concentration
70
60
50
40
30
20
10
0
500
Minimum effective concentration
400 300 200 0
Phenytoin has a Km of around 7 mg/L and
therefore saturates at or around the lower end
of the therapeutic range (1020 mg/L).
Aspirin saturates after only one or two
300 mg tablets.
Alcohol has a Km of approximately
0.01 g/100 mL, and therefore metabolism
is essentially zero order at almost all con-
centrations (usual driving limits 0.050.08 g/
100 mL).
Some drugs with non-linear elimination (i.e. dose-
dependent, saturable).
Drug Pathway
alcohol alcohol dehydrogenase
aspirin various conjugations
clonidine active renal tubular excretion
uoxetine CYP2D6
methotrexate active renal tubular excretion
paroxetine CYP2D6
phenytoin CYP2C9/2C19
propafenone CYP2D6
verapamil CYP3A4
For drugs with saturable elimination dose
increases should be made in small increments
ICPC02 21/5/05 12:14 PM Page 23
topurine (6-MP) are metabolized to a variety
of active and inactive products. In patients
with TPMT deciency, 6-MP is shunted
down alternative pathways, increasing both
efcacy and adverse effects, especially bone
marrow depression. One in 300 Caucasians
are essentially without TPMT activity, while
10% have intermediate activity.
Factors affecting dosing Pharmacogenetics
24
2
AZATHIOPRINE
Hypoxanthine-guanine
PhosphoribosyItransferase
(HGPRT)
6-MERCAPTOPURINE
(6-MP)
6-METHYLMERCAPTOPURINE 6-THIOGUANINE
NUCLEOTIDES
6-THIOURIC ACID
Thiopurine
methyltransferase
(TPMT)
Xanthine oxidase (XO)
Glutathione-S-transferase
Dihydropyrimidine dehydrogenase
(DPD)
5-uorouracil is metabolized by DPD. Abso-
lute and partial DPD deciency occurs in
around 0.13% of the Caucasian popula-
tion, and in these patients excessive toxicity
may be observed.
Cytochrome P450 metabolism
(CYP)
The most important isoforms for drug meta-
bolism are CYP3A4, CYP2D6, CYP2C19,
CYP2C9, CYP1A2 and CYP2E1. Of these,
only CYP2D6, CYP2C9 and CYP2C19 have
clearcut and clinically important genetic
polymorphisms. More will undoubtably be
found, however.
Cytochrome P450 (CYP)
polymorphism
The rst evidence of CYP polymorphism
was the discovery of slow hydroxylation
of sparteine and debrisoquine. Both are
Pharmacogenetics
Some pathways of drug metabolism are
affected by genetic polymorphism,
with marked dosing implications
Fast/slow acetylation
Acetylation is a phase II conjugation re-
action catalysed by N-acetyl transferase.
Among Caucasians, approximately 50%
are fast and 50% are slow acetylators.
Acetylation status is determined by parent/
metabolite ratios in the plasma or urine.
Drugs affected by acetylator status include:
procainamide and hydralazine (increased
risk of SLE in slow acetylators)
sulphonamides (increased risk of haemo-
lysis in slow acetylators)
isoniazid (increased risk of peripheral
neuropathy in slow acetylators; increased
risk of hepatitis in fast acetylators).
Glucuronidation
Glucuronidation, the other major phase II
reaction, is also subject to genetic polymor-
phism. Patients with Gilberts disease have
decient glucuronyl transferase, reected by
higher bilirubin concentrations.
Aldehyde dehydrogenase
Around 50% of persons of Mongoloid
descent have aldehyde dehydrogenase de-
ciency. They are unable to metabolize acet-
aldehyde produced from ethanol and may
develop a disulram reaction abuild-up of
acetaldehyde causing ushing and vomiting.
Pseudocholinesterase deciency
One in 3000 individuals cannot metabolize
succinylcholine and require articial respira-
tion for some hours after succinylcholine
usage (e.g. during anaesthesia).
Thiopurine methyl transferase
(TPMT)
Azathioprine and its metabolite 6-mercap-
ICPC02 21/5/05 12:14 PM Page 24
Pharmacogenetics Factors affecting dosing
25
mediated by CYP2D6. Around 40% of CYP
metabolism is carried out by polymorphic
enzymes. Interestingly, the major CYP group,
CYP3A4, does not appear to be subject to
genetic polymorphism.
Determination of CYP status
CYP status may be determined by examin-
ing the phenotype (metabolic ratio) or the
genotype. The metabolic ratio is the ratio of
the parent drug to the metabolite.
CYP2D6
Homozygotes and heterozygotes exist, with
appropriate fast and intermediate metabolic
ratios. Total absence of the gene results in
slow metabolism. There may also be gene
duplication or multiple copies resulting in
ultrarapid metabolism and very low drug
concentrations.
Five to ten per cent of Caucasians and 1
3% of Mongoloid, Polynesian and Negroid
people are poor metabolizers. Clinically
relevant examples of CYP2D6 poor meta-
bolism include:
Perhexiline aneuropathy/liver toxicity
Phenformin alactic acidosis
Timolol eye drops asystemic -blockade
Flecainide a? arrhythmic deaths.
Codeine requires CYP2D6 to be metabol-
ized to its active metabolite morphine. Since
poor CYP2D6 metabolizers have no active
CYP2D6 enzyme, codeine does not relieve
pain in these patients.
CYP2C9
Around 13% of patients on warfarin
require only around 1 mg per day for clinical
anticoagulation (cf a mean of 7 mg/day in
normals), due to poor metabolism.
CYP2C19
Eighteen to 23% of Mongoloid and 35%
of Caucasian and Negroid people are slow
metabolizers. The area under the curve
(AUC) of omeprazole (a proton pump
inhibitor [PPI]) is increased around 12-fold
in patients with slow metabolism.
2
Characteristics of major CYP drug metabolizing enzymes.
3A4 2D6 2C9 2C19 1A2 2E1
Chromosome 7 22 10 10 15 10
Probe(s) Nifedipine Sparteine Tolbutamide Mephenytoin Phenytoin Ethanol
Debrisoquine (Phenytoin) Caffeine
Dextromethorphan
Subject to enzyme ++ + +++
induction
Subject to enzyme ++ ++ + + +
inhibition
Subject to genetic No but wide Yes Yes Yes ? ?
polymorphism variability
% of total CYP 50% 25% 510% 23% 510% 5%
drugs metabolized
by this CYP
Major substrates Diverse Lipophilic bases Mainly acids Diverse Diverse Mainly
Steroids Lipophilic b-blockers NSAIDs PPIs Xanthines hydrocarbons
Ca
2+
antagonists Antidepressants S-warfarin R-warfarin Paracetamol Hydrocarbons
Macrolides Neuroleptics Phenytoin Phenytoin Anaesthetics
Statins Antiarrhythmics Losartin Moclobemide
Protease Codeine
inhibitors Tramadol
ICPC02 21/5/05 12:14 PM Page 25
to synthesize drug metabolizing enzymes.
However, these measures are insensitive to
rapid changes in liver function and only
indicate severe, chronic dysfunction. An
albumin concentration of <30 g/L (normal
3655 g/L) or a raised prothrombin ratio (or
INR) indicates severe liver dysfunction.
Chronic liver disease is associated more
predictably with impaired metabolism than
acute liver disease. Acute liver failure may
however be associated with severely im-
paired drug metabolic capacity.
Diseases of the liver that decrease drug
metabolism include: cirrhosis (any cause),
alcoholic liver disease, viral hepatitis (may
increase or decrease metabolism), porphy-
ria, and hepatoma. Paradoxically, alcoholic
liver disease may, if not severe, result in in-
creased metabolism of some drugs through
enzyme induction.
NB: Cirrhosis, porphyria and hepatoma
do not appear to alter glucuronidation reac-
tions, and therefore drugs solely undergoing
glucuronidation are less likely to be affected,
e.g. morphine, lorazepam.
Cholestatic jaundice
In cholestatic jaundice, drugs or their active
metabolites may have impaired elimination
if they are extensively cleared unchanged via
the bile. In addition, if a drug is cleared as a
glucuronide and is subject to enterohepatic
cycling (after deconjugation in the gut), this
process will be impaired.
Pharmacodynamics
In severe liver disease, hepatic encephalo-
pathy can be precipitated by inappropriate
dosing of drugs that cause CNS depression,
e.g. sedatives.
Factors affecting dosing Dosing in Liver Disease and Other Disease States
26
2
Some examples of high and low clearance drugs.
High clearance Low clearance
Antidepressants NSAIDs
Antipsychotics Anticonvulsants
Calcium antagonists Most benzodiazepines
Narcotics
Nitrates
Most antiparkinsons
Most statins
Many b-blockers
Assessment of liver impairment
The albumin concentration and the pro-
thrombin indices (such as INR) reect the
ability of the liver to synthesize proteins and
therefore are indicative of the livers ability
Dosing in Liver Disease
and Other Disease States
Liver disease
The best indices of impaired liver metabolic
capacity are a low albumin concentration
and raised prothrombin ratio
There is no easily available measure of liver
functional impairment (unlike CrCl for renal
impairment a see page 28). However, a
reduction in drug metabolism in liver disease
may occur for three reasons:
1 decreased enzyme metabolizing capacity
2 decreased liver blood ow
3 intra/extra hepatic shunting.
Dosage adjustment may be necessary for
extensively metabolized drugs, particularly
those with a low therapeutic index.
Drugs with very high metabolic clearance
are likely to be affected by decreased blood
ow as well as decreased enzyme capacity,
and therefore are more susceptible to altera-
tions in liver function.
ICPC02 21/5/05 12:14 PM Page 26
Dosing in Liver Disease and Other Disease States Factors affecting dosing
27
Decreased tissue perfusion causing de-
creased Vd of lipophilic drugs, e.g. lignocaine
Decreased mesenteric blood ow causing
altered rates of absorption, e.g. frusemide.
Dosing in cardiovascular disease
The main caution is with high clearance,
ow-dependent drugs (see Table). Apply
the start slow, go slow strategy. For other
drugs, dose in relation to CrCl and albumin/
INR status.
Dosing in gastroenterological
disease
The small intestine is the most important site
of drug absorption. This applies even to acidic
drugs, since the huge surface area of the
small intestine overshadows other physico-
chemical factors (e.g. pK
a
, ionization, etc.)
which might appear to favour absorption
from the stomach. Altered rates of stomach
emptying will affect the RATE of availabil-
ity of oral drugs, e.g. migraine decreased
rate of absorption of analgesics.
However, for most drugs the EXTENT of
availability is more important, and this is
rarely altered signicantly in GI disease.
Diseases most studied have been Crohns
disease, coeliac disease, and gastroenteritis.
No simple rules can be made except per-
haps that in any circumstance of shortened
bowel transit time the potential exists for
decreased extent of availability of sparingly
soluble or poorly absorbed drugs (e.g. some
antibiotics).
2
Dosing in liver disease
A useful rule, which is somewhat arbitrary,
is to:
1 reduce the dose by 50% for high clearance
drugs (affected by both blood ow and
enzyme capacity).
2 reduce the dose by 25% for low Cl drugs
(affected by enzyme capacity only).
Extra caution is advised with drugs with a
low therapeutic index. The usual tenet of
start low, go slow applies in liver disease.
Sometimes it may be more predictable to use
glucuronidated rather than oxidized drugs,
e.g. lorazepam rather than diazepam, or
change to a renally eliminated drug e.g. from
metoprolol to atenolol.
Dosing in liver disease
(if [albumin] <30 g/L or INR elevated)
High CI drugs 50%
Low CI drugs 25%
Change to renally eliminated drug
Cardiovascular disease
The main problem affecting pharmacokin-
etics is decreased cardiac output (CO), which
decreases blood ow to both the liver and
the kidney. Effects of decreased cardiac out-
put include:
Decreased hepatic blood ow causing
decreased Cl of high Cl, ow-dependent
drugs, e.g. lignocaine
Decreased renal blood ow causing de-
creased Cl of drugs with high fu, e.g. digoxin
ICPC02 21/5/05 12:14 PM Page 27
process is not restricted by protein bind-
ing because it is so rapid that drug is
easily removed from the protein-binding
site. There is also a pathway for basic drugs,
e.g. digoxin, dependent on a carrier protein
called P-glycoprotein. This is the site of the
digoxinquinidine interaction. An increas-
ing number of drugs are observed to com-
pete at the P-glycoprotein pathway. Active
transport enables renal clearance to be larger
than the GFR, and theoretically as large as
renal blood ow (up to 1500 mL/min).
Reabsorption
Passive reabsorption can occur in the renal
tubules. This follows standard principles of
diffusion a i.e. depends on concentration
gradient, lipid solubility, and sometimes urin-
ary pH (see pH and Pharmacokinetics, page
16). Active reabsorption can occur, e.g. pro-
benecid inhibits the reabsorption of uric acid.
Drug clearance and renal function
For drugs excreted entirely through the
kidneys unchanged drug clearance varies in
proportion to creatinine clearance (CrCl).
Drug Cl CrCl
Fraction excreted unchanged (fu)
The fu is the index describing the fraction
excreted unchanged through the kidneys.
An fu = 1 describes a drug totally cleared
renally unchanged. An fu = 0 describes a
drug without renal elimination. An fu some-
where in between (e.g. 0.5) describes mixed
elimination.
Factors affecting dosing Renal Drug Elimination
28
2
Renal Drug Elimination
For drugs that are not metabolized
and are cleared renally unchanged
Drug CI CrCl
Some drugs, e.g. digoxin, are cleared almost
entirely unchanged through the kidneys.
Others, e.g. phenytoin, are cleared entirely
by metabolism. Some prodrugs, e.g. enala-
pril, are converted to active metabolites that
are cleared unchanged through the kidneys.
Other drugs may be cleared by a combina-
tion of the above processes.
Renal clearance of drugs
Glomerular ltration
Drugs pass through the glomerulus where
their non-protein-bound component (i.e.
free drug) equilibrates across the glomerular
membrane. Maximum drug clearance via
glomerular ltration alone is therefore equal
to the glomerular ltration rate (GFR), i.e.
around 1.5 mL/s. Protein binding restricts
clearance in proportion to the percentage
protein bound, i.e. if protein drug binding is
50%, then drug clearance via glomerular
ltration is 50% of the GFR.
Active secretion
Drug not cleared by glomerular ltration
continues in the blood to the capillaries ad-
jacent to the proximal renal tubules. Some
acids (e.g. penicillins, NSAIDs, probenecid,
methotrexate) are actively transported from
the blood to the tubular lumen, and subject
to energy dependence, saturability, competi-
tion, and relative substrate specicity. The
ICPC02 21/5/05 12:14 PM Page 28
Renal Drug Elimination Factors affecting dosing
29
Drug elimination entirely unchanged by
the kidney (fu = 1) (e.g. gentamicin)
For a drug with fu = 0.5, 50% of the drug is
excreted unchanged through the kidneys. If
CrCl is half normal, that fraction of the dose
should be halved. The metabolized fraction
is unaffected, so the total dose should be
75% of normal.
2
Creatinine clearance
Drug Cl
For these drugs, doses should be reduced in
direct proportion to the degree of impair-
ment in CrCl. For example, if CrCl is half
normal, dose should be half normal.
Drugs eliminated entirely by metabolism
(fu = 0) (e.g. phenytoin)
Creatinine clearance
Drug Cl
No dose reduction is necessary in renal
impairment.
Drug eliminated by both metabolism
and by renal elimination (e.g. fu = 0.5)
(e.g. captopril)
Creatinine clearance
Drug Cl
ICPC02 21/5/05 12:14 PM Page 29
Factors affecting dosing Dosing in Renal Impairment
30
2
* Cockcroft DW, Gault MH. Prediction of creatinine
clearance from serum creatinine. Nephron 1976, 16:
3141.
Dosing in Renal
Impairment
Drugs excreted unchanged through the kidney
may need dose alteration in renal impairment
Whenever any active drug moiety is excreted
renally unchanged, dose adjustment in rela-
tion to renal function may be necessary,
especially if the drug has a low therapeutic
index.
Dose adjustment in renal
impairment
1 Check fu of drug or active metabolite
excreted unchanged renally (see Table).
2 Calculate CrCl using an equation such as
the Cockcroft & Gault equation* which takes
into account the patients age, weight and
sex [use of serum Cr alone is not accurate].
NB: (a) Multiply by 0.85 for females
(because of decreased muscle mass)
(b) If patient is obese, use ideal body weight,
or an approximation of this
(c) Replace 50 000 by 815 for CrCl in
mL/min

CrCl(mL/s)
age wt[kg
Cr](mmol/L)

( ) ]
[
=

140
50 000
(d) The equation is not valid for children
<12 yrs
(e) Normal CrCl is >1.5 mL/s
(f) If [Cr] is <0.06 mmol/L, use 0.06 in the
equation.
3 For drugs excreted 100% unchanged by
the kidneys:
In this case the dose-rate (DR) is decreased in
direct proportion to the impairment in renal
function (e.g. gentamicin).
4 For drugs excreted <100% unchanged by
the kidneys:
Obviously dose-adjustment need only be
made for that fraction of drug excreted
unchanged by the kidney (fu). A general
equation that takes into account the fu, the
fraction metabolized (1-fu) and the frac-
tional renal function is as follows:
5 Should dose be decreased or dose-interval
prolonged? The nal decision is whether
dose adjustment should be by reducing the
dose itself or by prolonging the dose-interval.
A useful rule is to aim for dosing once or
twice a day to allow maximum compliance.

DR(patient)
DR(normal)
fu fu
calculated CrCl
1.5
( ) = +

1
DR(patient)
DR(normal)
calculated CrCl
1.5
=
ICPC02 21/5/05 12:14 PM Page 30
Dosing in Renal Impairment Factors affecting dosing
31
Drugs which may require dose-adjustment in renal impairment.
Low therapeutic index
(and fu > 0.5)
(Dose-adjustment essential)
Drug fu
Aminoglycosides
gentamicin 0.9
tobramycin 0.9
netilmicin 0.9
Cytotoxics
cisplatin 0.9
carbiplatin 0.9
methotrexate 0.90.5**
ucytosine 0.95
ACE inhibitors
lisinopril 0.9
enalapril* (enalaprilat) 0.9
quinapril* (quinaprilat) 0.9
cilazapril* (cilazaprilat) 0.9
ramipril* (ramiprilat) 0.9
captopril 0.5
Other
digoxin 0.8
allopurinol* (oxypurinol) 0.8
lithium 1.0
vancomycin 0.9
metformin 0.9
vigabatrin 0.6
* metabolite with high fu; ** less with higher doses.
2
High therapeutic index
(and fu > 0.7)
(Dose-adjustment may decrease side effects)
Drug fu
b-Blockers
atenolol 0.9
nadolol 0.75
sotalol 0.9
bisoprolol 0.6
Penicillins
benzylpenicillin 0.9
amoxycillin 0.9
(clavulanate) 0.5
ucloxacillin 0.7
dicloxacillin 0.7
piperacillin 0.8
Cephalosporins
cephalothin 0.75
cefuroxime 0.9
cefaclor 0.7
cefoxitin 0.8
cephazolin 0.9
H
2
-Antagonists
cimetidine 0.7
ranitidine 0.7
famotidine 0.7
Other
aciclovir 0.7
amantadine 0.9
baclofen 0.8
dalteparin 0.7
uconazole 0.8
pethidine (norpethidine) 0.9
ICPC02 21/5/05 12:14 PM Page 31
Factors affecting dosing Dosing in the Elderly
32
2
Dosing in the Elderly
Physiological function declines with age
More than 90% of the elderly population
(>65 yrs) receive prescription medicines and
it is estimated that 30% of these patients
suffer from adverse drug reactions (cf. 10%
of patients aged 2030 years).
Elderly patients are not the same as the
younger population in their response to and
handling of drugs. Pharmacokinetics and
pharmacodynamics may both be altered in
the elderly patient.
Pharmacokinetics
Clearance (Cl): this is by far the most import-
ant parameter with respect to dosing. Both
renal and liver clearance decline with age.
Renally eliminated drugs (i.e. large fu)
Drug Cl of drugs with high fu is
consistently impaired in the elderly
The principles outlined in Dosing in Renal
Impairment, see page 30, apply. The elderly
patient may have a normal serum creatinine
[Cr] but the CrCl may be considerably im-
paired. This is because [Cr] is a reection
of both production (from muscles) and eli-
mination through the kidneys. Production
of creatinine is considerably lower in the
elderly than in t young adults. The Cock-
croft & Gault equation adjusts for age and
weight to allow for the decrease in creatinine
production.
0.85 (in females because of a higher ratio
of fat to lean body weight).
CrCl(mL/s)
age wt[kg
Cr](mmol/L)

( ) ]
[
=

140
50000
The dose-rate (DR) is then calculated as in
renal impairment:
For drugs with fu close to 1
For drugs with fu >0.5 but <1
As always this is especially important for
drugs with a low therapeutic index.
Metabolized drugs
Drug Cl of metabolized drugs is
usually impaired in the elderly
There is increasing evidence of impaired
metabolism of drugs in the elderly, though
this is less well dened compared with
renally eliminated drugs.
Perhaps the best advice is start low, go
slow. Practically, this means beginning with
the lower end of the recommended dose
rates, and adjusting doses carefully there-
after. Dose intervals for drugs with short
half-lives can often be longer in the elderly.
Choose once or twice daily dosing where
possible to assist compliance.
Volume of distribution (Vd): The elderly
have decreased lean body mass, decreased
body water, and increased body fat com-
pared with younger counterparts. Loading
doses of water-soluble drugs (smaller Vd)
should be based on ideal body weight, while
loading doses of fat-soluble drugs (larger
Vd) should be based on total body weight.
DR(patient)
DR(normal)
fu fu
calculated CrCl
1.5
( ) = +

1
DR(patient)
DR(normal)
calculated CrCl
1.5
=
ICPC02 21/5/05 12:14 PM Page 32
Dosing in the Elderly Factors affecting dosing
33
The half-life (t
1/2
): The t
1/2
is often pro-
longed in the elderly. Longer t
1/2
means that
the time to steady-state is longer, drug elim-
ination takes longer, and dose-intervals may
be longer. Often a longer half-life can be
used to advantage if it allows for a once daily
or twice daily regimen instead of three or
four times daily.
Pharmacodynamics
Homeostatic adaptation is less efcient and
target organ sensitivity may be altered in the
elderly.
Homeostatic responses tend to be blunted,
e.g. orthostatic hypotension is more pro-
nounced in elderly patients due to a reduced
ability of the baroreceptors to compensate
for changes in blood pressure.
Target organ sensitivity is often altered
(usually blunted). Alterations in receptor
function may occur with age, e.g. im-
pairment of cholinergic and adrenergic
function.
2
Enhancing compliance
(see Compliance with Medication, page 76)
It is especially useful in the elderly to follow
all the rules for enhancing compliance.
Economy in the use of drugs, single-dose
regimens, once or twice daily dosing, clear
instructions and the use of compliance aids
can enhance therapeutics markedly. Com-
pliance aids include cards listing all the
drugs and their dosing regimens, patient in-
formation leaets and unit dose packaging.
General guidelines
1 Consider dosing reduction in patients over
55 yrs
2 Use estimate of CrCl to adjust dose of
drugs with high fu
3 Start low, go slow for metabolized drugs
4 Aim for twice or once daily dosing
5 Monitor more frequently, especially for
drugs with a low therapeutic index
6 Use as few drugs as possible
7 Provide a card listing the patients
drugs and dose regimen
8 Give patient information leaets if available
9 Consider unit dose packaging
ICPC02 21/5/05 12:14 PM Page 33
e.g. theophylline (p450 oxidation)
chloramphenicol (glucuronidation)
gentamicin (glomerular ltration)
These are all impaired in the neonate.
Approximate values of Cl at different ages.
Post-conceptual age Cl (cf adults)
2428 weeks 5%
2834 weeks 10%
3440 weeks 33%
4044 weeks 50%
4468 weeks 66%
>68 weeks 100%
Volume of distribution (Vd): The infant has
more body water and less fat than an adult
as a percentage of total weight, i.e. up to
85% water in the premature neonate (cf
60% in an adult). The Vd is therefore
increased for water soluble drugs and
decreased for lipid soluble drugs. However,
these effects are small compared with the
changes in Cl in this age group, and dose-
adjustment, if any, is small.
Protein binding (PB): PB is decreased in
neonates due to decreased albumin, de-
creased binding capacity and the presence
of displacers such as free fatty acids and
bilirubin. However, this has little signic-
ance apart from in the interpretation of
drug concentrations (see Protein Binding,
page 14).
Drug availability: The extent of oral availab-
ility is not altered signicantly. Skin absorp-
tion of some compounds may be enhanced
because of a thinner stratum corneum, and a
higher degree of hydration of the skin. Drugs
should be applied sparingly.
Factors affecting dosing Dosing in Children
34
2
Dosing in Children
A child is not a little adult
The seven ages of pharmacological man
Premature neonate 24/4040/40
Neonate 02/12
Infant 2/121 year
Child 112 years
Adolescent 1220 years
Adult 2065 years
Aged >65 years
There are seven distinct age groups that are
associated with different drug Cl and hence
dosing requirements. Note that four of these
ages are related to the paediatric age group.
This reects that the child is a continually
changing pharmacokinetic and pharmaco-
dynamic environment. The younger the child,
the greater the rate of change.
Dosing in children under 6 months of age
is very complicated a specialist advice is
usually needed.
Pharmacokinetics
Clearance (Cl): The major mechanisms of
drug elimination begin to develop during
fetal life and continue to develop postpartum.
Functional maturity is reached between 6
months and 1 year of age. After this, Cl is
actually greater than that of adults on a mg/
kg basis. It then relates better to surface area.
The major metabolic pathways, p450 oxi-
dation and glucuronidation, and the renal
pathways, all mature at a similar rate and
can be considered together in their effects on
drug Cl and dosage.
ICPC02 21/5/05 12:14 PM Page 34
Dosing in Children Factors affecting dosing
35
2
2 Without nomograms:
A useful guide is:
Body weight (kg) SA
10 0.5
20 0.75
30 1.0
40 1.25
Interpolate and extrapolate as necessary and
use in above equation.
3 Using a calculator:
In the absence of an estimate of surface
area, an adjusted body weight can be used as
follows:
This equation is derived from the fact that
weight to the power of 0.7 (wt
0.7
) relates bet-
ter to surface area than to weight alone.
Maintenance dose
Wt[kg]
70
adult dose
0.7
=
Pharmacodynamics
Paediatric patients may be more sensitive
to the effects of some drugs, e.g. aspirin
toxicity. The bloodbrain barrier is slow
to develop enabling enhanced CNS effects
with some drugs, e.g. increased transport
of bilirubin into the brain may result in
kernicterus. There may be paradoxical reac-
tions, e.g. stimulation with benzodiazepines;
control of hyperactivity with amphetamines.
Dosing guidelines
Under 6 months
Specialist advice necessary.
6 months12 years
Use surface area (SA) approach
1 Using nomograms:
Read SA from a nomogram

Maintenance dose
SA[m ]
1.73 m
adult dose
2
2
=
ICPC02 21/5/05 12:14 PM Page 35
(a) Teratogenicity: This is difcult to predict
prior to marketing. Information comes from
retrospective studies and/or animal data
(often unreliable). The FDA classify drugs
(see below), in increasing order of potential
toxicity.
(b) Pharmacological risks: These are risks
that are generally predictable based on the
known pharmacology of the drug, e.g.
NSAIDs may cause premature closure of the
ductus arteriosus in the latter stages of preg-
nancy (patency requires the presence of
prostaglandins).
At term, excessive effects (e.g. tricyclics)
and withdrawal syndromes (e.g. opiates,
selective serotonin reuptake inhibitors
[SSRIs]) may be seen in neonates following
maternal use.
Effects of pregnancy on drugs
Clearance (Cl): Pregnancy is generally a
hyperdynamic physiological state. Drug
clearance may be increased, whether it be via
renal elimination or liver metabolism. The
maternal cardiac output is increased by up
to 30% during pregnancy, increasing the
renal blood ow and GFR. The hormonal
state in pregnancy is also associated with
enzyme induction of some drugs. Main-
tenance doses of drugs often need to be
Factors affecting dosing Drugs in Pregnancy
36
2
Category A Controlled studies in animals and women have not shown risk.
Category B Animal studies have not shown risk but there are no controlled studies in pregnant
women or animal studies have shown risk but controlled studies in women have not. (e.g. paracetamol,
-lactams, methyldopa, NSAIDs [NSAIDs not safe in 3rd trimester]).
Category C Animal studies have shown risk but studies in women have not done so. (e.g.
antipsychotics, most cardiac medicines, laxatives, antihistamines).
Category D Positive evidence of some human risk exists but benets may in some circumstances
outweigh risk. (e.g. anticonvulsants, ethanol, warfarin, antidepressants, tetracyclines, diuretics, lithium).
Category X Too dangerous contraindicated. (e.g. thalidomide, vitamin A analogues, some
cytotoxics).
Drugs in Pregnancy
All drugs pass across the placenta
to some extent, and therefore
some fetal exposure will occur
Up to 95% of women take four or more
drugs (not counting vitamin supplements) at
some stage during pregnancy.
There are two major considerations
regarding drugs in pregnancy.
1 The effects that the drugs have on the
pregnancy.
2 The effects that the pregnancy has on the
drugs.
Effects of drugs on the pregnancy
The majority of drugs attain concentrations in
the fetus similar to those of maternal plasma.
It is important to remember that approx-
imately 35% of all live births are associated
with a fetal abnormality. Drugs are thought
to be responsible for only 15% of these (i.e.
0.030.25% of all malformations). Associ-
ation does not necessarily imply causation.
Exposure during the rst 16 weeks of
pregnancy is associated with an increased
incidence of physical malformations. How-
ever, less obvious effects such as decreased
neuronal function or impaired intellectual
development may occur following exposure
at any time during pregnancy.
ICPC02 21/5/05 12:14 PM Page 36
Drugs in Pregnancy Factors affecting dosing
37
increased during pregnancy, to compensate
for increased Cl.
Volume of distribution (Vd): Vd may be
increased by ~20% for both lipid- and
water-soluble drugs. Increased loading doses
may be required because of an increase in
both body fat and water.
Protein binding (PB) [see page 14]: Maternal
albumin concentrations decrease through-
out pregnancy to a low at term. Measured
drug concentrations of highly protein-
bound drugs (e.g. phenytoin) may be lower,
but this is usually unimportant, as free
concentrations are not affected (see Protein
2
Drugs associated with teratogenicity.
Drug Outcome
Alcohol Fetal alcohol syndrome
Anticonvulsants
carbamazepine Fetal carbamazepine syndrome
similar to fetal hydantoin syndrome
microcephaly, short nose
phenobarbitone Similar to fetal hydantoin syndrome
phenytoin Fetal hydantoin syndrome
impaired growth, craniofacial defects, mental deciency, hypoplastic
phalanges/nails
sodium valproate Neural tube defects
Antithyroid drugs Goitre, hypothyroidism
Cytotoxics Multiple abnormalities, especially craniofacial/skeletal
Diethylstilboestrol Masculinized genitalia
Vaginal adhesions/carcinoma
Lithium Ebsteins anomaly (structural cardiac deformity)
Penicillamine Skin hyperelasticity
Tetracyclines Tooth staining in offspring
Thalidomide Phocomelia (limb reduction defects)
Vitamin A derivatives
retinoic acid Spontaneous abortion
tretinoin Craniofacial abnormalities
etretinate
Warfarin Fetal warfarin syndrome
skeletal abnormalities
hypoplastic nose
Binding, page 14). Assessment requires
specialist advice.
The risk/benet ratio must be considered
when drugs are used in pregnancy
General advice
1 Avoid all drugs if possible, including
social drugs (e.g. smoking, alcohol, caffeine)
2 Avoid drugs in the rst trimester
3 Choose drugs of proven safety or least
toxicity
4 Use short courses and the smallest doses.
ICPC02 21/5/05 12:14 PM Page 37
Factors affecting dosing Drugs in Human Milk
38
2
Drugs in Human Milk
All drugs diffuse into breast milk to some
extent it is the extent that is important
Infant exposure to drugs during breast
feeding is almost always less than
exposure during pregnancy
The infant derives no benet from the
drug an innocent bystander
Most drugs pass into milk by passive diffu-
sion of the free (unbound) and unionized
form. They are distributed within the aque-
ous, protein and lipid phases of milk. Milk
contains more fat and less protein than
blood. Therefore drugs that are highly
lipid soluble, with low protein binding,
and unionized at physiological pH achieve
higher concentrations in milk. Few drugs
have concentrations in milk higher than
those of maternal plasma.
The risk to the infant of medicine ingested
via maternal milk may be considered from
three viewpoints.
1 The dose of medicine ingested by the
infant.
2 The resulting infant plasma concentration.
3 The potential toxicity of that con-
centration.
The dose ingested by the infant
The most commonly used index that enables
the dose to be calculated is the milk/plasma
ratio (M/P). The most valid M/P ratio is that
based on the AUC of drug in milk compared
with the AUC in maternal plasma (i.e.
M/P
AUC
). The M/P ratio enables the concen-
tration of the drug in milk to be estimated
from knowledge of the maternal plasma
concentration (C
mat
).
The infant dose can be estimated from the
maternal plasma concentration, the M/P
ratio and the volume of milk (V
milk
) ingested
(150 mL/kg/day).
Dose
infant
= C
mat
* M/P * V
milk
A better index of dose is the actual amount
of drug present in the milk over the maternal
dosage interval.
The infant dose can be put into clinical
perspective by comparison with the mater-
nal dose (mg/kg), or with doses used thera-
peutically in the infant.
The weight-adjusted maternal dose
(WAMD) is the dose the infant receives via
milk, compared with the mothers dose,
corrected for respective weights. It is usually
expressed as a percentage, which if <10%
(for a relatively non-toxic drug) indicates
that the drug may be considered compatible
with breast feeding.
The infant plasma concentration
(C
infant
)
This depends on the dose-rate, the oral avail-
ability (F) and the drug clearance in the
infant.
F is usually assumed to be equivalent to that
of adults, although this may not be so. Drug
clearance is considerably impaired in infants
less than 3 months of age, and especially so
in the premature neonate. Thus an appar-
ently small dose may result in clinically
signicant plasma concentrations in the
infant. Approximate values of Cl at differ-
ent ages that enable calculation of appro-
priate concentrations in infants are shown
below.

C
dose-rate * F
Cl
infant
=
ICPC02 21/5/05 12:14 PM Page 38
Drugs in Human Milk Factors affecting dosing
39
Post-conceptual age Cl (cf adults)
2428 weeks 5%
2834 weeks 10%
3440 weeks 33%
4044 weeks 50%
4468 weeks 66%
>68 weeks 100%
The potential toxicity of the drug
in the infant
Breast-feeding during maternal ingestion of
even small amounts of some very toxic drugs
(e.g. antineoplastic drugs), is probably not
2
wise even if the likely concentration in the
infant is low. For other drugs, an arbitrary
decision has to be made as to safe concen-
trations in the infant. Predicted infant
plasma concentrations of 10% of maternal
concentrations are a useful cut-off point.
General advice regarding drugs in milk
1 Avoid drugs if possible
2 Weigh up the risk/benet ratio
3 Exercise more caution with toxic agents
4 Feed baby just prior to the next dose
5 Alternate breast feeding with bottle feeding
to decrease possible exposure
Drugs considered to be safe when breast-feeding full-term healthy babies. (This table is a guide
only, consult experts readily.)
Drug classes Individual drugs
ACE inhibitors aciclovir mebendazole
Antihistamines 5-aminosalicylic acid methadone
Benzodiazepines carbamazepine methyldopa
b-lactam antibiotics chlorothiazide metoprolol
Calcium antagonists citalopram moclobemide
Oral contraceptives clarithromycin morphine
NSAIDs (except piroxicam) codeine nefopam
Phenothiazines cotrimoxazole nitrofurantoin
Tricyclic antidepressants digoxin paracetamol
domperidone paroxetine
erythromycin phenytoin
famotidine propranolol
heparin trimethoprim
insulin valproic acid
labetalol warfarin
lignocaine
ICPC02 21/5/05 12:14 PM Page 39
Drugs considered to be unsafe during breast-
feeding.
Amiodarone
Antineoplastic drugs
Ergotamine
Fluoroquinolones
Immunosuppressants
Iodine-containing agents
lithium
Retinoids
Tetracyclines
Social drugs, e.g. alcohol, cannabis,
Illegal drugs
Factors affecting dosing Drugs in Human Milk
2
40
ICPC02 21/5/05 12:14 PM Page 40
3
3 Altered drug effect
Adverse drug reactions, 42
Drug-induced allergy, 44
Adverse drug events, 46
Preventing adverse drug events, 48
Drug/drug interactions, 50
Inducers of drug metabolism/inhibitors of drug metabolism, 52
Drug/food interactions, 54
ICPC03 21/5/05 12:14 PM Page 41
slow hydroxylator a perhexiline peri-
pheral neuropathy
saturable kinetics aphenytoin ataxia
drug interactions a erythromycin/ter-
fenadine torsades de pointes.
Pharmacodynamic mechanisms: Some pati-
ents experience a type A ADR at a normal
concentration, while others do not, reect-
ing natural variability. Similarly, underlying
disease may shift the concentrationresponse
curve to favour an ADR at a normal
concentration, e.g. sedation in hepatic
encephalopathy.
Prevention
Take a careful history for predisposing
factors.
Use as small a dose as possible commen-
surate with desired effect.
Adjust dosage to therapeutic end-points,
e.g. BP or INR.
Adjust dosage to optimum plasma con-
centrations, e.g. digoxin.
Adjust dosage in relation to renal func-
tion, hepatic function, other disease states,
or other drugs.
Management
Decrease dose
Substitute drug with different pharma-
cokinetics (e.g. metoprolol (metabolized) by
atenolol (renally cleared))
Consider alternative route of administra-
tion (e.g. transdermal vs oral)
Substitute a more specic agent (e.g.
moclobemide for tranylcypromine)
Add drugs (carefully) to antagonize
unwanted effects (e.g. addition of decar-
boxylase inhibitor to levodopa therapy (e.g.
Sinemet, Madopar)
Altered drug effect Adverse Drug Reactions
42
3
Adverse Drug Reactions
An ADR is any response to a drug which is
noxious, unintended, and occurs at doses used
in man for prophylaxis, diagnosis or therapy.
WHO, 1976
Adverse drug reactions (ADRs) are a signi-
cant cause of morbidity and mortality and
are responsible for around 5% of hospital
admissions. Patients predisposed to ADRs
are the elderly, females, and those with mul-
tiple disease, taking other drugs, and with a
history of previous adverse reactions.
Classication
Type A (Augmented) Type B (Bizarre)
Predictable Unpredictable
Dose-dependent Dose-independent
High incidence Low incidence
(90% ADRs) Often serious
May respond to Generally need
dose adjustment to stop drug
Type A (Augmented)
These reactions are predictable from the
known pharmacology of the drug. They may
result from an excessive desired response
(e.g. hypotension from an antihypertensive)
or non-specicity (e.g. anticholinergic effects
with tricyclic antidepressants).
Pharmacokinetic mechanisms: Any patient
with higher plasma concentrations than
usual, due to inappropriate dosage or im-
paired clearance, is liable to type A adverse
reactions. Examples are:
renal dysfunction a aminoglycoside
nephro/ototoxicity
hepatic failure aprolonged sedation with
benzodiazepines
slow acetylator a isoniazid peripheral
neuropathy
ICPC03 21/5/05 12:14 PM Page 42
Adverse Drug Reactions Altered drug effect
43
Add another drug to allow reduced dose
(e.g. diuretics + -blockers).
Type B (Bizarre)
These are less common, less predictable, may
be severe and result from various mechan-
isms. Examples are:
immunologic apenicillin allergy
pseudoallergy aasthma with NSAIDs
genetic ahaemolysis in G6PD
deciency
disease a amoxycillin rash in glandular
fever
idiosyncratic a malignant hyperpyrexia
in anaesthesia.
Prevention
Take a careful drug history, especially of
allergies
Family history a allergies and genetic
disease
Avoid drugs susceptible to ADRs in par-
ticular disease states, e.g. clozapine in bone
marrow depression.
Management
Stop drug and treat symptomatically
Avoid drugs with chemically similar
groups, e.g. sulphonylureas and thiazide
diuretics
Do not rechallenge
Notify CARM (Centre for Adverse Reac-
tion Monitoring)
Consider a Medic-Alert bracelet.
Assessing an ADR
The probability increases if the reaction:
is appropriate to timing of drug adminis-
tration
follows a recognized pattern of response
disappears on withdrawal of the drug
reappears on rechallenge with drug
responds appropriately to a specic
antidote
has happened before with the same or like
drug
is supported by measured toxic concen-
trations
cannot be explained otherwise.
Reporting an ADR (to centre of
adverse reactions)
The following information is needed:
Case identication and patient data
Description of ADR and its outcome
Patients diagnosis
Concomitant drugs
Predisposing/contributing factors
Estimation of probability of drug causing
the ADR
The reporting doctor/pharmacist.
3
ICPC03 21/5/05 12:14 PM Page 43
Type III (immune complex)
Mediated by IgG immune complexes and
complement. The immune complexes block
small blood vessels and cause a local inam-
matory response. Serum sickness (urticaria,
arthralgia, lymphadenopathy and fever), is a
classical presentation (e.g. serum sickness
due to sulphonamides or penicillins).
Extreme form a StevensJohnson syn-
drome.
Type IV (cell mediated)
Mediated by T-lymphocytes and macro-
phages. Sensitized cells release cytokines on
contact with antigen (e.g. contact dermatitis
by poison ivy).
Drug-induced autoimmune disease
This is not conveniently classiable into the
above. The drug alters a protein in the body
so that the protein is no longer recognized as
self (e.g. drug-induced SLE).
Pseudoallergic reactions
(anaphylactoid)
These are sometimes indistinguishable clin-
ically from type I reactions. They are, how-
ever, mediated pharmacologically and not
immunologically (e.g. aspirin and NSAIDs
in asthma). The fact that they do not occur in
everyone indicates some predisposition (e.g.
genetic). This is why this type of reaction is
considered to be type B rather than type A.
Cross-sensitivity occurs with drugs which
have the same action, but not structure, cf.
true allergy.
Altered drug effect Drug-Induced Allergy
44
3
Drug-Induced Allergy
Drug allergy is an adverse reaction, type B,
mediated by an immunological mechanism
Drug-induced allergy results from previous
sensitization to a particular chemical, or one
that is structurally similar. The term hyper-
sensitivity is sometimes used for allergy
but has a broader meaning. Drug allergy is
under-recognized, under-reported and pro-
bably represents about 20% of ADRs.
Most drugs have small molecular weights
(often ~300 D) and are too small to be anti-
genic in themselves. They act as haptens,
binding to endogenous proteins to form
antigenic complexes that incite antibody
production. This process usually takes 12
weeks. Reexposure to the chemical results in
an antigenantibody interaction that pro-
vokes the typical manifestations of allergy a
release of mediators (e.g. histamine) cell
damage or cell death.
Types of allergic reactions
Type I (immediate, anaphylactic)
Mediated by IgE and involves release of
histamine, leukotrienes and prostaglandins
causing vasodilation, oedema and a general-
ized inammatory response (e.g. anaphylaxis,
urticaria and bronchospasm due to penicillin).
Type II (cytotoxic)
Mediated by IgG and IgM through comple-
ment activation. The major targets are cells
in the circulatory system (e.g. penicillin
haemolytic anaemia, quinidine thrombocy-
topenia, sulphonamide neutropenia).
ICPC03 21/5/05 12:14 PM Page 44
Drug-Induced Allergy Altered drug effect
45
Important points about drug-
induced allergy
May be due to the drug itself, a metabo-
lite, or an excipient in the formulation.
Usually highly specic to a chemical, but
there may be cross-reactivity within a drug
class, e.g. penicillins ~50% chance.
The probability of cross-reactivity with
chemically unrelated drugs is low.
Patients with atopy may be predisposed to
type I reactions.
Many patients develop antibodies to
drugs, but only a few develop clinically evid-
ent allergy.
There is no correlation with known phar-
macological properties of the drug.
There is no consistent relationship with
drug dose (although severity varies with dose).
Usually resolves on cessation of drug.
Reappears on rechallenge (often worse).
Short-term desensitization is sometimes
possible.
It is unclear how long allergy may last,
?life-long, ?1020 years.
Assessment as for ADRs (page 42).
Percutaneous testing
Skin testing is theoretically attractive but has
problems:
May cause a severe reaction.
False positives: Some drugs cause skin
irritation, resembling wheal and are (e.g.
morphine). Others may sensitize topically
without a systemic reaction (e.g. muscle
relaxants).
False negatives: Some drugs may not react
topically, while producing a reaction sys-
temically, e.g. allergy due to the metabolite
rather than the drug (e.g. penicillin).
Prevention
Avoid the use of drugs where cross-sensit-
ivity is likely, especially if previous reaction
to a chemically similar drug was severe.
Use a small test dose.
Have treatment ready, e.g. adrenaline,
antihistamine, steroids.
For example, if a patient about to be
treated reports an allergy to penicillin, it is
important to determine what reaction actu-
ally occurred (e.g. mild rash versus anaphy-
laxis), and how long ago it happened. This
will help decide whether a penicillin or other
-lactam (e.g. cephalosporin) could be used
if they are drugs of choice for the condition.
If the previous reaction was anaphylaxis,
then both penicillins and cephalosporins
(reported 510% cross-sensitivity) would be
contraindicated. If, however, the previous
reaction was minor, then a cephalosporin,
or even a penicillin, might be considered rea-
sonable. Of course in these circumstances a
small test dose should be used, and treat-
ment (e.g. adrenaline) should be readily
available.
3
ICPC03 21/5/05 12:14 PM Page 45
Altered drug effect Adverse Drug Events
46
3
Adverse Drug Events
An adverse drug event (ADE) is actual or
potential damage resulting from medical
intervention related to medicines
Terminology is a problem here, because of
confusion with adverse drug reactions (ADR)
(see page 42). Other terms such as medica-
tion error have been used but adverse drug
event (ADE) seems to have been adopted the
most widely. ADE covers a wider spectrum
than adverse drug reaction and involves
doctors, pharmacists, nurses, caregivers and
patients themselves. Omitting a dose is an
ADE, while a rash is an ADR.
What comprises an ADE?
Prescribing error:
incorrect drug selection
incorrect dose or frequency
incorrect route of administration
inappropriate duration of therapy
incorrect prescription
incomplete prescription
illegible prescription
unforeseen drug interaction.
Medication error:
transcription error
dispensing error
infusion error
failure to uplift prescription
non-compliance
inadequate monitoring.
Why are ADEs important?
ADEs are common and result in signicant
morbidity and mortality. Alarming statistics
from the US, UK and Australia suggest that
ADEs may be one of the leading causes of
death (behind heart disease, cancer and
stroke). The cost of this is huge and the incid-
ence is increasing. More important, how-
ever, is that most of these are preventable.
Why do ADEs occur?
ADEs are primarily a result of system
problems, not people problems.
Dr Lucian Leape, Harvard School of Public Health
On the surface ADEs appear to be the result
of human error. However human error
abounds when systems predispose.
Major systems failures: (from JAMA, 1995;
274: 3543). The following are responsible
for over 70% of errors:
Lack of knowledge about drugs e.g. failure
to recognize that a drug is renally cleared.
Lack of information about patient e.g.
failure to recognize that a patient has renal
failure.
Violation of rules: e.g. incomplete pre-
scription such as route not stated.
Slips and memory lapses e.g. doctor for-
gets to prescribe post-op analgesia.
Transcription errors e.g. wrong dose.
Faulty drug identication e.g. moclobe-
mide for metoclopramide.
Preventing errors
Efforts that focus on the individual who
made the error (shoot the messenger) are
usually unfruitful. The essence is to alter
systems to minimize the chance of errors
occurring. Each of the above system failures
should be addressed.
Drug knowledge: Information about all
aspects of the drug prole must be readily
available at the time the drug is prescribed/
used.
ICPC03 21/5/05 12:14 PM Page 46
Adverse Drug Events Altered drug effect
47
Patient information: Clinical informa-
tion, results of laboratory tests, drug history
and allergies, current medications and doses
must be accessible and known at the time of
using the drug.
Following the rules: Poor prescribing
should not be tolerated and covered for by
pharmacists. Quality assurance programs
with feedback can assist. See Preventing
Adverse Drug Events, page 48.
Slips and memory lapses: Excessive work-
loads should be avoided. Quality assurance
programs with no blame should be
encouraged.
Transcription errors: Single point of data
entry should be encouraged.
Drug identity: Avoid illegibility e.g.
UPPER CASE letters for drug names.
A computerized prescribing system linked
to drug and patient information databases
could x many of the above problems.
Unfortunately, this requires quite a commit-
ment both nancially and from top-level
management. It is also complex to develop.
3
ICPC03 21/5/05 12:14 PM Page 47
Poor knowledge of drug, e.g. cleared
renally, but dose not adjusted;
Missed drug interactions;
Poor prescription: illegible, incomplete,
prescriber unidentiable.
Pharmacist:
Mis-reading prescription;
Transcribing error;
Dispensing error.
Nurse:
Drug given to wrong patient;
Wrong drug given;
Wrong dose given.
Patient:
Failure to uplift prescription;
Non-compliance.
Adverse prescribing culture:
Understafng;
False economies;
Poor communication;
Tolerance of laxity.
Modern drug therapy:
increasing complexity;
multiple medications;
drug interactions.
Altered drug effect Preventing Adverse Drug Events
48
3
Examples of common errors in prescribing (all aggravated by illegibility).
qd (once daily) confused with qid (4 times daily) use qid
IU (international units) confused with IV (intravenous) write I units
U (units) confused with 0 (zero) write units
pm (afternoon or night) confused with prn (as required) use nocte
2.0 mg (2 mg) confused with 20 mg write 2 mg
.5 mg (half a mg) confused with 5 mg write 0.5 mg
mg (microgram) confused with mg (milligram) write mcg
< or > (less or greater than) confused with 4 or 7 write in full
Preventing Adverse
Drug Events
An ADE is any event (or potential event)
that occurs as a result of an error in any
part of the process of drug administration
Examples of medication errors that
have caused death
Wrong drug: frusemide instead of ut-
amide. Outcome a death from acute renal
failure.
Wrong dose: mg instead of mcg. Outcome
adeath from overdose.
Wrong route: vincristine into intrathecal
space. Outcome adeath from neurotoxicity.
Wrong instructions: chronic lorazepam
withdrawn over 3 days instead of 3 weeks.
Outcome a rebound panic/anxiety causing
suicide.
Some reasons for medication
errors
Prescriber:
Poor knowledge about patient (e.g. his-
tory of allergy, serum creatinine);
ICPC03 21/5/05 12:14 PM Page 48
Preventing Adverse Drug Events Altered drug effect
49
How to avoid errors
Acknowledge the problem:
Allow for human nature;
Non-punitive reporting system.
Cooperative approach between:
doctor/pharmacist/nurse.
Encourage favourable behaviour patterns.
Computerized prescribing system.
Risk reduction strategies
(see Patients and their drugs, page 80)
Prescriptions:
Avoid abbreviations where possible (write
in full);
Only use acceptable, non-ambiguous
abbreviations;
Write clearly;
Provide adequate detail (specic instruc-
tions);
Use UPPER CASE letters for drug names;
Write prescribers name in UPPER CASE
alongside signature;
Do not alter a prescription arewrite it;
Take particular care with decimal points.
3
Encouraging compliance:
Medication card;
Patient Information leaets;
Unit dose packaging devices.
Acceptable abbreviations
bd aTwice daily
tds aThree times daily
qid aFour times daily
qXh aEvery X hours
mane ain the morning
nocte aat night
prn aAs required
ac aBefore food
pc aAfter food
im aIntramuscular
iv aIntravenous
po aOral
pr aRectal
sc aSubcutaneous
If ambiguity is possible in a prescription,
write the details out in full
ICPC03 21/5/05 12:14 PM Page 49
Altered elimination
Interactions may occur at metabolic or renal
sites of elimination. Metabolic interactions
include enzyme induction or inhibition. These
happen especially with drugs metabolized
by cytochrome-P450-mediated metabolism.
Enzyme induction
Strong enzyme inducers affect many drugs
and include:
anticonvulsants (phenytoin, carbamaze-
pine)
rifampicin
smoking and alcoholism.
Enzyme induction involves increased
synthesis of the enzyme involved. Most
types of metabolism are inducible, although
there are notable exceptions, e.g. CYP2D6.
The effect of enzyme induction is to increase
rst-pass metabolism, increase clearance,
decrease t
1/2
and lower average steady-state
concentrations.
Altered drug effect Drug/Drug Interactions
50
3
R
a
t
e

o
f

r
e
a
c
t
i
o
n
Cp
Enzyme induction
(same Km, higher E
max
)
Enzyme inhibition
Strong enzyme inhibitors affect many drugs
and include:
erythromycin
selective serotonin reuptake inhibitors
(SSRIs)
Drug/Drug Interactions
A drug interaction occurs when the
effects of one drug are increased
or decreased by the previous
or concurrent administration
of another
Patients on six or more drugs have an
80% chance of a drug interaction. (NB: hos-
pital in-patients receive, on average, around
six drugs at any one time).
Consequence of a drug interaction is that
dose alteration may be necessary, or alterna-
tive medications prescribed.
Interactions are most important for drugs
with a low therapeutic index.
The sicker the patient, the greater the
risk of a drug interaction.
Not all interactions are bad.
Mechanisms
Pharmacokinetic
Pharmacodynamic
Pharmaceutic
Pharmacokinetic
A change in blood concentration occurs
causing a change in effect.
Altered availability
Chelation within the gut
e.g. tetracyclines/Ca
2+
[tetracycline]
Altered motility
e.g. metoclopramide/digoxin
[digoxin]
Altered rst-pass metabolism
e.g. oestrogens/ascorbic acid
[oestrogen]
Altered bacterial ora
e.g. antibiotics/sulphasalazine cleav-
age of sulphasalazine in large intestine.
ICPC03 21/5/05 12:14 PM Page 50
Drug/Drug Interactions Altered drug effect
51
ketoconazole
amiodarone
cimetidine
grapefruit juice.
Enzyme inhibition causes less rst-pass
metabolism, decreased clearance, longer
t
1/2
and higher average steady-state con-
centrations.
Competition for active secretion in prox-
imal tubule
e.g. probenecid/penicillin [penicillin]
Competition for ionic cotransport
e.g. Li
+
/Na
+
Li
+
accumulation with
diuretics.
Pharmacodynamic
Drug effect is altered through receptor, cel-
lular or other physiological mechanisms.
Enhancement or antagonism may occur.
e.g. -agonist/-blocker-mutual competi-
tion at receptor site.
Pharmaceutic
Physicochemical interactions may occur
prior to systematic availability
e.g. inactivation of phenytoin within IV
giving sets if pH is <7.0.
Practical notes
1 Take full drug history, including asking
about over-the-counter (OTC) preparations.
2 Interactions are likely with more than
three concurrent drugs.
3 Use as few drugs, for as short a time, as
possible.
4 Monitor effect or Cp assiduously.
5 Review all medication frequently.
6 Pharmacodynamic interactions are likely
to be shared within same drug class.
3
R
a
t
e

o
f

r
e
a
c
t
i
o
n
Cp
Enzyme inhibition (competitive)
(higher Km, same E
max
)
Enzyme inhibition (non-competitive)
(same Km, lower E
max
)
Some drug classes and drugs with important interactions
antiarrhythmics cause enzyme inhibition cyclosporin
anticonvulsants cause enzyme induction digoxin
anticoagulants multiple mechanisms hypoglycaemic agents
antidepressants cause enzyme inhibition lithium
protease inhibitors cause enzyme inhibition theophylline
All types of drug metabolism may be
affected by enzyme inhibition. Some inhibi-
tions are so profound that the average
steady-state concentrations increase greater
than 10-fold, e.g. grapefruit juice increases
lovastatin concentrations by up to 16-fold
through inhibition of CYP3A4 rst-pass
metabolism.
Renal excretion
Altered pH of urine
e.g. HCO

3
aspirin excretion
ICPC03 21/5/05 12:14 PM Page 51
Inducers of Drug Metabolism
Class Drug CYP enzyme affected
Anticonvulsants phenobarbitone 3A4, 2C9, 2C19
phenytoin 3A4, 2C9, 2C19
carbamazepine 3A4, 2C19
Antibiotics rifampicin 3A4, 2C9, 2C19, 1A2
rifabutin 3A4
griseofulvin 3A4, 2C9, 2C19
sulphaphenazole 2C9
isoniazid 2E1
Steroids glucocorticoids 3A4
progesterone 3A4
Social drugs alcohol 2E1
marijuana 1A2
cigarettes 1A2
Foods barbequed foods 1A2
cruciferous vegetables (cabbage, broccoli, 1A2
brussel sprouts, cauliower)
Environmental toxins cyclic hydrocarbons 1A2
dioxane, DDT 1A2
Other phenylbutazone 2C9
omeprazole 1A2
ritonavir 1A2
efavirenz 3A4
nevirapine 3A4
barbiturates 3A4, 2C9, 2C19
St Johns Wort 3A4
Altered drug effect Inducers of Drug Metabolism
52
3
ICPC03 21/5/05 12:14 PM Page 52
Inhibitors of Drug Metabolism Altered drug effect
53
Inhibitors of Drug Metabolism
Class Drug CYP enzyme affected
Microsomal
Antiarrhythmics amiodarone 1A, 2C9, 2D6, 3A4
propafenone, quinidine 2D6
Antibiotics chloramphenicol 2C9
sulphonamides 2C9
trimethoprim 2C9
azole antifungals 1A2, 2C9, 2C19, 3A4
macrolides 1A2, 3A4
quinolones 1A2, 3A4
Antiulcer cimetidine 1A2, 2C9, 2C19, 2D6, 3A4
omeprazole 1A2, 2C9, 2C19, 3A4
lansoprazole 2C19
Calcium antagonists diltiazem 3A4, 2D6
verapamil 3A4
Antidepressants uoxetine 2C19, 2D6, 3A4
paroxetine 2D6
moclobemide 2C19, 2D6
nefazodone 3A4
Antipsychotics chlorpromazine, uphenazine 2D6
haloperidol, thioridazine 2D6
Protease inhibitors indinavir, saquinavir, nelnavir 3A4
ritonavir 2C9, 2D6, 3A4
Statins uvastatin, lovastatin 2C9
Other isoniazid 2C9, 2C19, 3A4
oral contraceptives 3A4
metoprolol, propranolol 2D6
sodium valproate 2C9, 2C19, 2D6, 3A4
ticlopidine 1A2, 2C19
methylphenidate 2C9, 2C19, 2D6
dextropropoxyphere 3A4, 2D6, 2C9
terbinane 2D6
Extramicrosomal
disulram aldehyde dehydrogenase, 2E1
ascorbic acid sulphation
allopurinol xanthine oxidase
MAOIs MAO
3
ICPC03 21/5/05 12:14 PM Page 53
Grapefruit juice
A component(s) in grapefruit inhibits the
CYP3A4 enzymes responsible for metaboliz-
ing many drugs as they pass through the gut
wall. This may lead to large increases in serum
concentrations of susceptible drugs. Drugs
affected have the following characteristics:
Metabolized largely by CYP3A4
Subject to marked rst-pass metabolism.
Increases in the AUC of up to 16-fold have
been reported, e.g. lovastatin.
Altered drug effect Drug/Food Interactions
54
3
Drug/Food Interactions
Food may alter the pharmacokinetics
of a drug, and/or its action
Food and pharmacokinetics
Food may alter drug availability (absorption
and rst-pass metabolism), drug distribu-
tion and drug clearance.
Absorption
Altered rate or extent of absorption may
occur. Altered RATE is of little import-
ance unless immediate effect is required, e.g.
analgesics. Large, hot, fatty, solid meals
decrease, and uid-based meals increase the
rate of absorption.
Food may decrease the extent of absorp-
tion, particularly of polar, hydrophilic, lipid
insoluble drugs, e.g. atenolol. Stimulation of
gastric enzymes and acid may degrade some
drugs, e.g. ucloxacillin.
Iron, calcium and other divalent or trival-
ent ions (e.g. dairy products or in supple-
ments) may chelate some drugs decreasing
extent of absorption, e.g. quinolones and
tetracyclines are chelated by antacids, and
by calcium in milk.
First-pass metabolism
In general, food increases liver blood ow
from the gut causing increased extent of
availability of drugs subject to high rst-pass
metabolism (see page 12). This happens be-
cause increased presentation of drug to the
hepatocytes saturates metabolic processes,
allowing more drug to get through to the cir-
culation, e.g. metoprolol.
Drugs affected by grapefruit juice
amlodipine lovastatin
atorvastatin midazolam
buspirone nifedipine
carbamazepine nimodipine
cisapride saquinavir
cyclosporin simvastatin
diltiazem tacrolimus
ethinyloestradiol triazolam
felodipine verapamil
Drug distribution
Altered drug distribution is not usually a
major problem because distribution is not
relevant to steady-state plasma concentra-
tions. However, if distribution to a site of
drug activity is affected then it is important,
e.g. high protein diet decreases the uptake
of l-dopa into the CNS by competition
between amino acids and l-dopa at the
bloodbrain barrier.
Drug clearance
Drug clearance may be enhanced by foods
associated with enzyme induction, e.g. high
protein meals, barbequed food, cruciferous
vegetables (broccoli and cabbage). This
mainly affects CYP1A2. In order for this to
ICPC03 21/5/05 12:14 PM Page 54
Drug/Food Interactions Altered drug effect
55
be a problem, the diet must be constant,
because enzyme induction takes 23 weeks
to reach a new equilibrium.
Altered drug effects
Some foods contain substances that act on
the same receptors or sites of action as drugs.
Agonistic or antagonistic effects may be
observed.
Liquorice contains glycyrrhizic acid
which is similar to aldosterone, and causes
water retention, increased BP and antag-
onism of antihypertensive drugs.
Foods high in vitamin K (beef liver,
avocado, leafy green vegetables, egg
yolk, broccoli, soybeans, chickpeas, lentils)
may antagonize warfarin by competitive
inhibition.
Alcohol may cause sedation/respiratory
depression with CNS depressants, e.g.
benzodiazepines, antidepressants, antipsy-
chotics, opiates.
Effects of drugs on food
Drugs may alter the concentration or
effect of substances in foods and drink. For
example:
Stimulant laxatives (senna, biscodyl) and
diuretics may cause electrolyte losses.
Orlistat and bile-acid sequestrants may
decrease the absorption of fat-soluble vit-
amins (A, D, E, K).
Enzyme inducers (rifampicin, anticonvul-
sants) may induce the metabolism of vitamin
D and folate causing respective deciencies.
Metronidazole causes a disulram-like
reaction with alcohol.
MAOIs cause the cheese reaction with
tyramine-containing foods causing a hyper-
tensive crisis.
3
ICPC03 21/5/05 12:14 PM Page 55
ICPC03 21/5/05 12:14 PM Page 56
4
4 Pharmacovigilance
Drug development, 58
Therapeutic drug monitoring (TDM), 60
Drugs involved in therapeutic drug monitoring, 62
Overdose/poisoning, 64
Common poisonings, 66
Pharmacological aspects of drug dependence, 68
ICPC04 21/5/05 12:14 PM Page 57
Drug Development
The development of a new drug is complex
and expensive. The cost, from molecule to
market, has been estimated to be in excess
of US$250 million. The process takes many
years.
The Holy Grail in drug development is the
magic bullet. This describes the ideal drug
that is assimilated into the body with total
predictability, homes in on its target with
great specicity, interacts with no other
receptors (i.e. adverse effect receptors), has
no drug interactions, and is then eliminated
predictably. This is impossible, of course. As
Isaac Newton once said, Every action has
an equal and opposite reaction.
Drug discovery
Historically, drugs were often discovered
serendipitously, e.g. penicillin. Targeting of
drugs followed, using in vitro models that
suggested desired activities. More recently
a drug is usually discovered by design, e.g.
specic receptor antagonist.
Preclinical drug development
Once puried, or synthesized, the drug is
subject to a series of preclinical studies in
animals. These are designed to conrm the
activity, to explore doseresponse relation-
ships, to characterize the pharmacokinetics,
to explore doseresponse relationships, and
to observe toxicological effect including
mutagenicity and carcinogenicity. In recent
years, these processes have come under
intense scrutiny in relation to animal ethics,
and are only conducted under rigidly con-
trolled conditions. Where possible, com-
puter modelling is used to minimize animal
involvement.
Attention to formulation and pharma-
ceutical stability occurs concurrently. Only
about 1% of compounds are judged suitable
to move on to clinical testing.
Clinical drug development
This involves testing the drug in humans.
The ethics of this are particularly important,
and the process is subject to important regu-
lations such as the Declaration of Helsinki.
This states that Concern for the interests of
the subject must always prevail over the
interests of science and society.
There are three phases, although the exact
margins between the phases are sometimes
blurred:
Phase I: (rst time in humans) basic
clinical pharmacology
These studies are designed to observe the
spectrum of pharmacological effects pro-
duced by a range of doses (i.e. doseresponse
evaluation) and the pharmacokinetic beha-
viour of the drug. The aim is to nd a safe
dose for more detailed evaluation. An initial
search for metabolites that might be differ-
ent from those in animals is also undertaken.
These are open (not blind) studies, usually
in small numbers (10100) of normal volun-
teers (though sometimes in patients if the
drug is particularly toxic, such as an anti-
neoplastic agent), starting with low doses
(suggested from animal studies). The studies
are well supervised, usually by a clinical phar-
macologist, and have a good safety record.
Phase II: Clinical investigation
These studies are designed to establish thera-
peutic effectiveness in patient volunteers
who are suffering from the condition the
drug is meant to help. Side effects are also
studied. These are generally controlled trials
Pharmacovigilance Drug Development
58
4
ICPC04 21/5/05 12:14 PM Page 58
Drug Development Pharmacovigilance
59
(vs placebo or active comparator) and
blinded (single or double blind), but in small
numbers (100300 total) and of short dura-
tion. The aim is to get a signal that the drug
actually works and warrants the move to
full-sized, statistically signicant, random-
ized controlled trials. The pharmacokinetics
in the relevant patient group are also exam-
ined, and perhaps in other selected patients
such as those with renal or hepatic dysfunc-
tion. These studies are conducted by clinical
pharmacologists and clinical investigators
who are specialized in the patient group
under study.
Phase III: Therapeutic trials
These are large-scale, randomized, con-
trolled (vs placebo or active comparator)
clinical trials in the patient group for whom
the drug is intended, designed to prove con-
clusively that the drug has the desired effect
and is suitably safe. These studies are well
designed statistically, with adequate power
to demonstrate clinically signicant effects.
The total number of patients studied is usu-
ally 10003000. The studies are undertaken
by suitably qualied clinical investigators.
Adverse effects are also monitored to detect
incidences of >1 in 100 or thereabouts.
Post-marketing surveillance
(sometimes termed phase IV)
During clinical development insufcient
patients have been studied to detect rare
and perhaps serious adverse events. There
are intensive monitoring schemes in most
countries to detect such events. In addition,
unexpected benets in patient groups or dis-
eases other than those initially targeted may
be observed, and drug interactions detected.
Regulatory process
The same general process follows in most
countries although the detail might differ.
IND Investigational New Drug
application
The preclinical (animal) evidence is evalu-
ated in order to allow studies to proceed to
phase I studies.
NDA New Drug application
The clinical evidence (Phase I, II, and III) is
evaluated for approval to allow the drug to
be marketed.
Ethical considerations
At all stages of drug development (including
animal studies) ethical approval is required
before a study can proceed. General ethical
guidelines were drawn up in 1947 under the
Nurenburg Code. In 1964 the Declaration
of Helsinki was adopted by the World
Medical Association. This has been revised
three times since then and remains the cor-
nerstone of ethical principles behind drug
studies.
The process, while clearly laudable and
politically correct, has become increasingly
stringent, and is in danger of actually pre-
venting advancement. This must be guarded
against.
4
ICPC04 21/5/05 12:14 PM Page 59
Indications for TDM
(a) Improvement in efcacy
Prophylactic drugs a some drugs such as
antiarrhythmics and anticonvulsants are
used to prevent undesired effects. Waiting
for an end-point to occur such as ventricular
tachycardia is too dangerous.
Drugs with pharmacokinetic problems a
drugs with a poor doseconcentration rela-
tionship have a poor dose-effect relationship
(e.g. phenytoin anon-linear kinetics).
Drug interactions or disease states (espe-
cially liver of renal dysfunction) may alter
the doseconcentration relationship.
(b) Avoidance of toxicity
Drugs with a low therapeutic index require
individualized dosing.
Pharmacovigilance Therapeutic Drug Monitoring
60
4
Dose Effect Cp
Therapeutics
Pharmacokinetics Pharmacodynamics
Measurement of plasma concentrations (Cp)
gets us closer to the effect compartment.
Assumption aEquilibrium exists between
plasma and tissue concentrations.
NB: When plasma concentrations are
measured, the Cp refers to total drug in
plasma, including protein bound drug,
unless specically stated:
Cp = bound drug + unbound drug
%

E
f
f
e
c
t
log concentration
100
50
0
Low therapeutic index
Desired
effect
Adverse
effect
(i) Low therapeutic index
Therapeutic Drug
Monitoring (TDM)
TDM describes the monitoring of
concentrations of drugs in body uids,
usually plasma, for therapeutic purposes
Why?
Therapeutic drug monitoring (TDM) helps
(for relevant drugs) to increase efcacy, to
decrease toxicity, and to assist diagnosis.
Theoretical basis and assumptions
For some drugs the relationship between
dose and effect is so variable that the choice
of dose regimen is difcult.
ICPC04 21/5/05 12:14 PM Page 60
Therapeutic Drug Monitoring Pharmacovigilance
61
(c) Diagnosis
Failure of therapy: TDM helps distinguish
between genuine drug resistance (inappro-
priate agent), non-compliance, and adverse
effects that mimic the disease state.
Overdose: Cp measurement may distinguish
drug-induced from organic disease (e.g.
coma caused by sedative overdose). A deci-
sion to use an antidote can be assisted and
prognosis assessed by using nomograms that
relate Cp to likely toxicity, e.g. paracetamol.
Drug abuse: Conrmation of abstinence,
e.g. narcotic treatment programmes, athletic
screening.
For which drugs?
See page 62.
When to measure?
The timing of blood sampling and the last
dose is critical and must be recorded.
A trough concentration (i.e. just prior to
the next dose) is the usual measure of drug
accumulation. Occasionally, sampling at the
time of symptoms may detect peak concen-
tration toxicity.
Some drugs, e.g. gentamicin, may require
measurement of two concentrations within
the dosing interval, to assess peak and trough
concentrations, or to calculate an AUC.
Steady-state concentrations (i.e. >4 half-
lives after dose initiation or change in dose)
are relevant to chronic therapy.
The therapeutic range
This is the range of drug concentrations
associated with a reasonable probability of
efcacy, without undue toxicity in the
majority of patients. In practice this range
is not well established for most drugs, and is
a guide only.
4
%

E
f
f
e
c
t
log concentration
100
50
0
High therapeutic index
Desired
effect
Adverse
effect
(ii) High therapeutic index
%

E
f
f
e
c
t
log concentration
100
50
0
Therapeutic
range
Mild
toxicity
Severe
toxicity
Problems with TDM
The illusion of scientic accuracy, the dubi-
ous validity of some therapeutic ranges,
laboratory variation, active (unmeasured)
metabolites, and failure of the basic assump-
tions all make the use of TDM difcult.
Consult readily.
Treat the patient, not the laboratory value
ICPC04 21/5/05 12:14 PM Page 61
Drugs Involved in
Therapeutic Drug
Monitoring
Remember:
therapeutic drug monitoring only assists
clinical judgement
most reference ranges refer to trough
concentrations
Pharmacovigilance Drugs Involved in Therapeutic Drug Monitoring
62
4
Drugs that should be monitored routinely.
Class Reference range Comment
Aminoglycosides
Gentamicin
#
AUC 70100 mg/L.h How to monitor once daily aminoglycosides still debated
Tobramycin
$
Trough <0.5 mg/L
Netilmicin
#
AUC 150200 mg/L.h
Amikacin
$
Carbamazepine 1648 mmol/L Upper limit subject to debate
412 mg/L
Cyclosporin Induction 100300 mg/L Different ranges quoted for different transplants
Maintenance 100200 mg/L
Flucytosine 200800 mmol/L Bone marrow toxicity >800 mmol/L
25100 mg/L
Lithium Acute mania 0.81.2 mmol/L
Prophylaxis 0.40.8 mmol/L
Phenytoin 4080 mmol/L Saturable kinetics
1020 mg/L In hypoalbuminaemia measure free concentrations
Free 48 mmol/L
check units of measurement (mg/L vs
mol/L)
consult readily.
ICPC04 21/5/05 12:14 PM Page 62
Drugs Involved in Therapeutic Drug Monitoring Pharmacovigilance
63
Drugs for which monitoring may be useful.
Class Reference range Comment
Amiodarone
Aspirin
Carboplatin
Chloramphenicol
Digoxin
Flecainide
Isoniazid
Itraconazole
Lamotrigine
Lignocaine
Methadone
Methotrexate
Paracetamol
Perhexiline
Phenobarbitone
Tacrolimus
Teicoplanin
Theophylline
Valproic acid
Vancomycin
4
14 mmol/L (parent), 0.52.5 mg/L
Rheumatic fever 250400 mg/L
Overdose >400 mg/L
AUC 80120 mg/L.h
AUC 5080 mg/L.h
1520 mg/L
12.5 nmol/L, 0.82 mg/L
0.21 mg/L
17 mg/L, Toxic >20 mg/L
Trough >250 g/L
314 mg/L
1.55 mg/L, Toxic >9 mg/L
0.31.3 mmol/L 100400 mg/L
Toxic >10
6
mmol/L at 48 h
Rx leucovorin
Toxic >1 mmol/L, >150 mg/L
0.542.16 mmol/L, 0.150.6 mg/L
65130 mmol/L, 1530 mg/L
520 g/L (whole blood)
0.52 mg/L (plasma)
1020 mg/L
2030 mg/L for deep infection
55110 mmol/L, 1020 mg/L
50100 mg/L, 350700 mmol/L
Trough 510 mg/L
Very long t
1/2
Saturable kinetics at higher doses
Ovarian/testicular cancer
Dose-related toxicity
Trough concentration or >8h post-dose
Subject to slow CTP2D6 polymorphism
Monitor for efcacy
Revised upwards from 14 mg/L
Toxic metabolite
Considerable variation
Monitor during high-dose therapy
Treatment level for N-acetylcystein (NAC)
Subject to CYP2D6 polymorphism
Long t
1/2
Poorly established
Value of peaks not well established
ICPC04 21/5/05 12:14 PM Page 63
Pharmacovigilance Overdose/Poisoning
64
4
Overdose/Poisoning
All substance are poisons . . . It is
only the amount that distinguishes
a poison from a remedy.
Paracelsus
Poisoning accounts for ~1% of all admis-
sions. Of these, <1% of patients die, largely
a tribute to supportive care.
The rst priority is to keep the patient alive
A Airways
B Breathing
C Circulation
First aid, supportive measures and
decontamination
The most important early management.
Maintain uid and electrolyte balance.
Support vital systems, especially kidneys.
Provide good nursing care.
For the unconscious patient, monitor
carefully, clear airway and place in coma
position. Use CPR if necessary.
If poisoned by gas, remove from source.
Useful early management may include
oxygen, naloxone and glucose.
If conscious, give oral uid.
Corrosive, acids, alkalis:
Rinse mouth.
Get patient to drink copious uids.
Drench affected skin, eyes, mucus mem-
branes with water.
Do not induce vomiting.
Petroleum products:
Biggest danger is inhalation.
Do not induce vomiting.
Give a cupful of milk initially.
Diagnosis (see page 66)
Circumstantial evidence a pills, bottles,
needles.
Clinical features a skin colour, pupils, BP,
convulsions.
Laboratory a gastric aspirate, vomitus,
blood, urine.
Measurement of concentrations
This may be useful as a prognostic indica-
tion and for determining whether active
treatment is indicated.
Drugs for which Cp measurement may be
useful see page 66.
Decreasing exposure
(i) Prevention of absorption
Emesis a May have a place in pre-hospital
ingestion of drug by children. Not appropri-
ate for adult ingestion.
Gastric lavage a indicated in the unconsci-
ous within 4 hours of ingestion, or longer for
salicylates and poisons that delay gastric
emptying. Contraindicated if cough reex
absent and cuffed endotracheal tube cannot
be inserted.
Oral absorbents a activated charcoal
adsorbs drug preventing further absorption.
There is debate about their true place.
(ii) Enhanced elimination
Appropriate in <5% of poisonings and should
be undertaken only by the experienced.
pH-adjusted diuresis: Alkaline diuresis may
be useful in a few selected cases, e.g. aspirin.
Benets of acid diuresis more controversial.
ICPC04 21/5/05 12:14 PM Page 64
Overdose/Poisoning Pharmacovigilance
65
4
Drugs for which pH-adjusted
diuresis may help
Alkaline diuresis (for acids)
Phenobarbitone
Salicylates
Acidic diuresis (for bases)
Amphetamines
Methadone
Mexiletine
Phencyclidine
Phenylpropanolamines (e.g.
pseudoephedrine, ephedrine)
Quinidine
Continuous activated charcoal: Drugs that
continue to enter the gut via enterohepatic
circulation or diffusion may be bound by
charcoal and eliminated. Drug character-
istics a low PB, small Vd, low Cl drugs,
e.g. theophylline.
Drugs for which continuous oral
charcoal may be useful
Theophylline
Phenobarbitone
Carbamazepine
Dioxins
Polychlorinated biphenyls
Haemodialysis: This may be useful in severe
poisonings with dialysable drugs (low PB,
small molecules) that have small Vd and
meaningful enhancement in Cl, e.g. lithium.
Drugs for which haemodialysis is the
method of choice in severe poisonings
Salicylates
Phenobarbitone
Lithium
Methanol
Ethanol
Ethylene glycol
Haemoperfusion: Blood is passed through
adsorbent particles that bind and remove
drug. May be more effective than haemo-
dialysis and is not limited by high protein
binding. Disadvantages include removal
of blood contents, especially platelets and
calcium.
Drugs for which haemoperfusion is the
method of choice in severe poisoning
Theophylline
Barbiturates
Trichloroethanol derivatives
(iii) Antidotes
Specic antagonists are available for a few
compounds. The effects may be dramatic.
NB: these are also potential toxins. Be
aware of the time-course of action of these
compared with the drug being treated, e.g.
naloxone has a shorter t
1/2
than many nar-
cotics and may need repeated dosing.
Drugs for which antidotes may be useful
Poison Antidote
Cyanide Dicobalt edetate
Carbon monoxide Oxygen
Opiates Naloxone
Benzodiazepine Flumazenil
Paracetamol N-acetyl cysteine
Iron Desferriozamine
Organophosphate Atropine
Pralidoxime
Methanol Ethanol
Ethylene glycol Ethanol
Digoxin Feb antibodies
ICPC04 21/5/05 12:14 PM Page 65
Pharmacovigilance Common Poisonings
66
4
Common Poisonings
Aspirin (salicylates)
Benzodiazepines
Carbon monoxide
Cyanide
Ethylene glycol
Lithium
Methanol
Narcotics
Organophosphates
Paracetamol
Continued
Major effects
Acidbase disturbance
Uncoupling oxidative phosphorylation
Disordered glucose metabolism
Resp. alkalosis/metabolic acidosis
More dangerous in children
CNS depression
Loss of functioning Hb
Metabolic acidosis cherry pink
colour (carboxyhaemoglobin)
Inhibits cellular oxidation
Metabolic acidosis
Bitter almond smell
Inebriation
Metabolic acidosis
Hyperosmolality (osmolar gap)
Pulmonary oedema
GI symptoms
CNS stimulation/coma
Nephrotoxicity
Metabolic acidosis
Hyperosmolality (osmolar gap)
Drowsiness or coma
Pin-point pupils
Respiratory depression
Cholinergic effects
Pulmonary oedema
Convulsions
Symptoms often absent
Hepatic necrosis
Renal tubular necrosis
Specic management
Measure serum salicylates
Alkaline diuresis
Haemodialysis
Administer umazenil (with repeats prn)
for diagnosis and treatment
100% oxygen
Hyperbaric oxygen
Na thiosulphate: CN SCN
Amyl NO
2
: metHb CNmetHb
Dicobalt edetate: chelation
Measure serum concentrations
Measure serum osmolality
Ethanol infusion
Haemodialysis
Measure serum concentrations
Haemodialysis
Measure serum concentrations
Measure serum osmolality
Ethanol infusion
Haemodialysis
Naloxone IV repeat often if necessary
Monitoring ++
Atropine antagonizes ACh
Pralidoxine reactivates
acetylcholinesterases
Measure serum concentrations
N-acetylcysteine IV
Monitoring ++
ICPC04 21/5/05 12:14 PM Page 66
Common Poisonings Pharmacovigilance
67
4
Continued
Major effects Specic management
Paraquat
Theophylline
Tricyclics
Necrosis of lung (pulmonary brosis),
kidney, liver, heart, adrenals
GI symptoms
Cardiac stimulation
CNS stimulation
Hypokalaemia
Anticholinergic effects
Metabolic acidosis
CNS effects excitability + coma
Cardiotoxicity HR, wide QRS
Measure serum concentrations
Activated charcoal
Fullers earth
Magnesium sulphate
Oxygen contraindicated
Activated charcoal
Measure serum concentrations
Supportive treatment
Haemoperfusion
Activated charcoal
Supportive treatment
Serum concentrations sometimes helpful
Monitor ICU
ICPC04 21/5/05 12:14 PM Page 67
Pharmacovigilance Pharmacological Aspects of Drug Dependence
68
4
Sports enhancing (not discussed further)
Anabolic steroids
Erythropoietin
Growth hormone
Phenylpropanolamines
-Blockers.
Features of psychoactive drugs
(i) Rapid delivery to brain: The drugs are
usually highly lipid soluble, well assimilated
into the body and cross readily into the
brain. Rapid assimilation is achieved by
administration IV, or by inhalation.
Susceptible individual
Experimentation
Positive reinforcement
Repeat usage
Tolerance
Increased doses
Withdrawal
Drug seeking
Drug dependence
Drug dependence cascade
Drugs involved
Psychoactive
Opiates
CNS stimulants
amphetamines
ecstacy (MDMA)
cocaine
Cannabis
LSD
Alcohol
Nicotine
CNS depressants
benzodiazepines
barbiturates
GHB (gammahydroxybutyrate)
Volatile substances aglue snifng.
Cp
Time
MTC
MEC
(Minimum Euphoric Concentration)
(ii) Positive psychoactive effects: The effects
are reinforcing for that particular indivi-
dual, e.g. euphoria, empowerment, disinhibi-
tion, heightened sensory awareness, calming
effect (in stress).
(iii) Tolerance:
Constant dose less effect
Larger dose same effect
Tolerance is greater with larger doses
given for longer periods.
Metabolic tolerance a Drug clearance
increases through enzyme induction, caus-
Pharmacological Aspects
of Drug Dependence
Drug dependence: Preoccupation with a
drug to the detriment of other interests or
responsibilities, and compulsion to take it
without concern for the consequences.
ICPC04 21/5/05 12:14 PM Page 68
Pharmacological Aspects of Drug Dependence Pharmacovigilance
69
4
ing lower concentrations for a given dose
(i.e. autoinduction) i.e. same dose less
effect. Metabolic cross-tolerance can occur
when induced enzymes metabolize other
drugs.
Neuroadaptation a With homeostasis,
the body adapts to the insult, to return the
settings to normal. Adaptation occurs via
receptor up- or down-regulation, alteration
in membrane integrity, etc. The new setting
requires drug to be present to maintain the
newly acquired equilibrium. Increased doses
are needed to achieve the reinforcing psy-
choactive effects. Cross-tolerance occurs
between drugs with similar effects, e.g. alco-
hol/benzodiazepines.
Pharmacological treatment of
drug dependence
This is adjunctive to psychotherapy, beha-
vioural modication, environmental modi-
cation, etc.
Many people have no trouble stopping,
but more trouble quitting.
(i) Drug substitution therapy: A similar
drug with different pharmacokinetic prop-
erties (usually longer t
1/2
) is used to decrease
the intensity of, and to protract, the with-
drawal process, e.g.
methadone for opiate addiction
benzodiazepines for alcohol withdrawal
nicotine patches for smoking
The dose of the substituted drug is then
tapered in a controlled way.
%

E
f
f
e
c
t
log concentration
100
50
0
Receptor down regulation
(iv) Withdrawal symptoms: the unopposed
consequences of drug-induced neuroadapta-
tion. Absence of drug results in a deciency
state characterized by symptoms opposite
to those induced by the drug itself, e.g.
sedative withdrawal agitation, seizures
stimulant withdrawal sedation,
depression
The duration of the withdrawal syndrome is
directly related to the half-life of the drug
and active metabolites, i.e.
longer t
1/2
longer syndrome.
The magnitude of the withdrawal syndrome
is inversely related to the t
1/2
of the drug, i.e.
shorter t
1/2
more intense syndrome.
Cp
Time
MTC
MEC
Morphine IV
or 1 cigarette
Methadone orally
or nicotine patch
(ii) Drug antagonist therapy: After with-
drawal has been completed, antagonists
may prevent the reinforcing effects of a
rechallenge, e.g. naltrexone versus heroin.
There is little proof of the efcacy of this.
(iii) Aversive therapy: A drug may cause
aversive symptoms if the drug of dependence
is resumed, e.g. disulram/alcohol.
Perspective
From a global point of view, the damage
caused by nicotine and alcohol far exceeds
that of any other drug of abuse.
ICPC04 21/5/05 12:14 PM Page 69
ICPC04 21/5/05 12:14 PM Page 70
5
5 Optimal therapeutics
Principles of drug action, 72
Applied pharmacology, 74
Compliance with medication, 76
Principles of therapeutics, 78
Patients and their drugs, 80
The drug prole, 82
Evidence-based medicine, 84
Pharmacoeconomics, 86
Drug information/resources, 88
ICPC05 21/5/05 12:13 PM Page 71
occurs is called EC
50
(effective concentra-
tion, 50%) and is an index of potency. These
terms may be understood more easily with
graphs using the log of the concentration.
Optimal therapeutics Principles of Drug Action
72
5
Dose Effect Cp
Therapeutics
Pharmacokinetics Pharmacodynamics
ConcentrationEffect (CE) relation
Drug effect cannot rise indenitely as con-
centrations increase, e.g. an artery can only
dilate to a certain extent or it will explode! It
follows that the relationship between con-
centration and effect cannot be linear, but
follows a curve as shown.
NB: C, rather than Cp, is used for the con-
centrations since this is the concentration at
the site of activity (the biophase).
%

E
f
f
e
c
t
C
Effect =
E
max
C
EC
50
+ C
EC
50
100
50
E
max
This curve is analogous, and functionally
related, to receptor occupancy. As receptor
occupancy by drug approaches total occu-
pancy, maximum effect (E
max
) is reached.
The concentration at which 50% effect
%

E
f
f
e
c
t
log concentration
100
50
0
E
max
EC
50
Effect (or efcacy) and potency are differ-
ent concepts. Maximum effect denes the
ultimate achievable response, while potency
denes the dose at which responses occur. A
full agonist has greater efcacy than a partial
agonist independent of potency, e.g. mor-
phine (full opiate agonist) is a better anal-
gesic than buprenorphine (partial agonist).
However, buprenorphine (usual oral dose
0.2 mg) is more potent than morphine
(usual oral dose 10 mg).
%

E
f
f
e
c
t
log concentration
100
50
0
High potency
Large effect
Low potency
Large effect
High potency
Small effect
From the shape of the concentrationeffect
curve, it can be seen that the law of dimin-
ishing returns applies.
Principles of Drug Action
Pharmacodynamics:
What the drug does to the body
The relationship between pharmacokinetics
and pharmacodynamics is shown in the fol-
lowing diagram.
ICPC05 21/5/05 12:13 PM Page 72
Principles of Drug Action Optimal therapeutics
73
Law of diminishing returns
C Effect (%) Gain (%)
1 EC
50
50 50
2 EC
50
67 17
3 EC
50
75 8
4 EC
50
80 5
9 EC
50
90 10
Therapeutic and adverse
drug effects
There are separate concentrationeffect
curves for desired (therapeutic) and unde-
sired (adverse) effects. Hopefully for most
drugs the EC
50
for desired effects is consider-
ably lower than that of undesired effects,
i.e. there is a large therapeutic index.
The site of the effect compartment
Some drugs act in the central compart-
ment. Their effects will therefore relate
directly to the plasma concentration. If,
however, the biophase is somewhere out in
the tissues, then the concentration in that
peripheral compartment is relevant, and not
the Cp.
5
%

E
f
f
e
c
t
log concentration
100
50
0
Low therapeutic index
Desired
effect
Adverse
effect
Time
Cp
Tissue concentration
C
Dose and dose interval should be titrated to
achieve desired concentrations in the effect
compartment.
If this is so, dosing is easy. However, many
drugs have a low therapeutic index (e.g. can-
cer chemotherapy) and there is a thin line
between the good and the bad.
%

E
f
f
e
c
t
log concentration
100
50
0
High therapeutic index
Desired
effect
Adverse
effect
ICPC05 21/5/05 12:13 PM Page 73
Applied Pharmacology
Tachyphylaxis/tolerance
Response may change with time, usually as a
homeostatic response of the body to the
intrusion of the drug.
Tachyphylaxis (= quick protection) refers
to a rapid diminution in response to a drug,
usually within minutes or hours. Response
also returns rapidly on removal of the drug,
e.g. nitrates in angina. The mechanism is
usually depletion of a secondary messenger,
or receptor internalization, (i.e. the receptors
are temporarily removed from exposure to
the drug by reorientation to face inside the
cell membrane rather than outside).
Tolerance refers to a more gradual decline
in effectiveness of a drug, usually over days
or weeks. It is reected in increasing dose
requirements, e.g. opiates in drug addiction.
The mechanism is usually a change in recep-
tor number (up or down-regulation), or the
development of an opposing physiological
response, e.g. Na
+
and water retention with
a vasodilator. The time-course of reversal is
similar to that of onset.
Withdrawal/rebound
Withdrawal symptoms are the unopposed
consequences of drug-induced physiological
adaptation. The absence of the drug results
in a deciency state characterized by symp-
toms opposite to those induced by the drug
itself, e.g. after withdrawal of -blockers,
rebound hypertension or angina/myocardial
infarction can occur, as a result of un-
masking of up-regulated -receptor num-
bers. Ceasing drugs can be very dangerous
and should be undertaken slowly and
judiciously.
Optimal therapeutics Applied Pharmacology
74
5
Dose Effect Cp
Therapeutics
Pharmacokinetics Pharmacodynamics
Pharmacodynamic considerations
Concentrationeffect curves look simple,
but normal variation suggests that the E
max
and the EC
50
will vary considerably between
individuals. This needs to be taken into
account in dosing.
Some people will get a good response at a
very low concentration, while others will
require a higher concentration. Some peo-
ple, even after dose escalation, never achieve
an adequate response, and may require a
different type of drug.
The approach to dosing depends on the
therapeutic situation, the therapeutic index
of the drug and on the shape of the
doseresponse curve. If the drug has a high
therapeutic index, e.g. penicillin, then it is
reasonable to give a big dose early on so that
the chances of success are very high, e.g. a
dose designed to be sure of maximum effect
in everyone. If the drug has a low thera-
peutic index, e.g. digoxin, it is important to
dose more cautiously and titrate to desired
response.
The more urgent a situation, the more
risk can be tolerated, e.g. it may be neces-
sary to load digoxin to control a tachy-
arrhythmia even though some patients
might experience some nausea.
ICPC05 21/5/05 12:13 PM Page 74
Applied Pharmacology Optimal therapeutics
75
Pharmacokinetic considerations
Loading doses
Vd determines the size of the loading dose.
The Vd is often disturbed in sick people
because of dysfunction of biological barriers,
e.g. larger Vd of antibiotics in infection.
Maintenance doses
Cl, the determinant of the maintenance
dose, may be altered by age, disease states,
other drugs, genetics or autoinduction/
autoinhibition. Variation between indi-
viduals needs to be considered at the time
the maintenance dose is initiated, while
variation within individuals is important
thereafter.
Dose interval
The t
1/2
is the major pharmacokinetic deter-
minant of the dose interval, although many
other factors, such as compliance, therapeu-
tic index of the drug, the locus of the effect
compartment, and the mode of administra-
tion (e.g. tablet, slow-release preparation,
5
IV infusion, etc.) are also important. A drug
with a t
1/2
that allows once or twice daily
dosing is good for compliance.
Therapeutic plan
The therapeutic plan embraces all of the
above, but also takes into account thera-
peutic objectives, monitoring and possible
dose tapering. The therapeutic plan needs to
be revised any time the condition changes or
a new drug is added or deleted.
Dose tapering
Upon achievement of the therapeutic object-
ive (e.g. attainment of a target BP), it may
be possible to back-titrate the dose until
control deteriorates again, then increasing
the dose slightly. In this way the minimum
dose that achieves the desired effect can be
approached.
The concept of a single dose for
everyone is pharmacologically naive.
Treat the individual
ICPC05 21/5/05 12:13 PM Page 75
Promoting compliance
(i) The patient (the central gure)
It is important to recognize the patients
need for self-determination. An appropriate
educational strategy for each patient needs
to be devised, taking into account their level
of understanding and potential barriers to
compliance. Compliance aids should be pro-
vided if appropriate.
(ii) The prescription (things you should
think about)
Is the drug really necessary?
Use as few drugs as possible, for as short a
time as possible.
Regularly review drug therapy.
Do not change long-term therapy without
good cause.
Use once-daily or twice-daily dosing regi-
mens where possible.
Provide medication chart if >2 drugs, or in
elderly / confused patients.
If titrating, provide specic instructions
(e.g. asthma plan).
Use consistent names (e.g. generic).
(iii) Medication details (give to patient
verbally, and as patient information
leaets [PILs] )
Name of medication and why given.
How and when to take it.
What to do if dose missed.
How long to take it.
Benets expected and when they will
occur.
Possible problems to expect (e.g. side
effects).
Optimal therapeutics Compliance with Medication
76
5
Doctor
Patient
Doctor Patient
Compliance
Concordance
Reasons for non-compliance
Patients do not want to be sick
Patients may not want to take drugs
Patients may fear the (perhaps unknown)
effects of long-term therapy
Cost
Inconvenience
Complexity.
A less patronizing approach by doctors, rec-
ognizing that non-compliance should actu-
ally be expected, is likely to reap dividends.
Compliance with
Medication
Compliance and non-compliance mean
success or failure in following instructions
Non-compliance is probably the biggest
problem in therapeutics. Very few people
take a full course of medication exactly as
prescribed, e.g. how many of us actually
complete a course of antibiotics exactly as
prescribed? Failure to achieve the desired
therapeutic endpoint as a result of non-
compliance occurs in 3050% of treatment
courses.
One problem with compliance is the term
itself. It is too authoritarian. An alternative
term, adherence, has been used as a sub-
stitute, but is little better. Recently concord-
ance has been proposed as a better term as it
embraces an agreement between the patient
and the doctor, about the proposed plan.
ICPC05 21/5/05 12:13 PM Page 76
Compliance with Medication Optimal therapeutics
77
How to manage side-effects.
Food/drinks/other drugs (including over
the counter) to avoid.
How to obtain further information.
Follow-up appointment for review.
Education/compliance aids
(see Patients and their drugs, page 80)
Patient Information Leaets (PILs).
Medication charts (Yellow cards).
Pill organizers.
Detecting non-compliance
Expect it!
Discuss it openly.
Assess extent (e.g. total non-compliance
vs occasional missed doses).
Avoid imposing guilt a generalize the
problem and offer excuses for the patient.
Take blame yourself.
5
Managing non-compliance
Discuss the good and not so good about
taking medication.
Negotiate (as part of the concordance
strategy) e.g. Where do you want to go from
here?.
Make a realistic contract (the agreement)
with realistic goals, e.g. Do the best as you
see it.
Review a establish specic time, place
and person.
Elicit help anurse and pharmacist.
1 Recognize that compliance is a problem
2 Redene it as concordance
3 Make an effort to address it
ICPC05 21/5/05 12:13 PM Page 77
Principles of
Therapeutics
1 Accurate diagnosis
Without an accurate diagnosis all thera-
peutic endeavours are inappropriate.
2 Is drug therapy necessary?
Remediable causes of disease should be
addressed rst, e.g. smoking, alcohol, obes-
ity, high-fat diet.
3 Choose the right drug
What is the best theoretical drug for the
condition?
How good is the evidence?
Is this drug appropriate for this patient?
(Examine the patient prole and the drug
prole).
4 Use the drug correctly
Is a loading dose necessary?
Should the starting dose be low?
What is the usual maintenance dose?
Is this dose appropriate for this patient?
adjust for age?
adjust for renal dysfunction?
adjust for liver dysfunction?
adjust for drug interactions?
What is the best dose interval?
Which route of administration?
5 Dene therapeutic objectives
Cure? e.g. antibiotic for infection
Relieve symptoms? e.g. palliative care for
cancer
Replace deciencies? e.g. insulin for
diabetes.
6 Monitor drug effect
Measure desired end-point (e.g. BP)
Side effects
Measure drug concentrations.
7 Duration of therapy
Single dose? e.g. sumatriptan
Short course? e.g. antibiotics
For life? e.g. antihypertensives.
8 Promote compliance
Talk to patient about their drugs
Keep drug regimen simple
Compliance aids
Concordance.
9 Know your drugs
Use a few drugs well rather than many
badly.
10 Therapeutic parsimony
Use the lowest dose of as few drugs for as
short as possible to achieve the desired
effect.
11 Review therapy
at time of new consultations
on admission to hospital
whenever adding new drugs
when anything untoward occurs.
12 Avoid overprescribing
antibiotics for viral infections
antidepressants for normal life situations
sedatives for occasional sleep disturbance
vitamins when diet adequate.
13 Avoid underprescribing
narcotics (fear of addiction)
antidepressants (fear of disease label)
aminoglycosides (underdosage for fear of
toxicity).
14 Accurate prescription
Clear
Concise
Correct
Complete.
Optimal therapeutics Principles of Therapeutics
78
5
ICPC05 21/5/05 12:13 PM Page 78
Principles of Therapeutics Optimal therapeutics
79
Essentials of a good prescription
A prescription is a written communication.
It is vitally important that the information
transmitted within a prescription is accur-
5
Physicians name and registration number
Address
Phone number
Patient Name
Address
Date of birth (preferable)
Date:
Rx: Drug name (preferably generic, and
UPPER CASE), dose and strength
Directions for administration
Quantity to be dispensed
Any specific instructions
Any repeats
Prescribers signature:
Prescribers name in UPPER CASE
Dr A Prescriber LN2693
10 Dispensary Drive
Drugsville
(03) 271 8281
Mrs May B Compliant
39 Tempup Lane
Illsbury
9/5/45
01/01/01
AMOXYCILLIN, 250 mg tablets
Take one t.d.s. p.o. with food
15
Take until course finished
Nil
A Prescriber
A PRESCRIBER
ate, unambiguous, and complete. Where
ambiguity is possible, write details in full.
The prescribers name must be recognizable,
and he/she readily traceable.
ICPC05 21/5/05 12:13 PM Page 79
Discharge prescribing a How to make
things easier for the patient.
Information/devices that should be given
to appropriate patients at the time of dis-
charge or at the end of an out-patient
appointment.
1 Changes made to the medication regimen
2 Any dose changes required (e.g. reducing
doses of corticosteroids)
3 An unambiguous prescription (helps phar-
macist, and indirectly the patient)
Clear
Concise
Complete
Written in Capitals
Prescriber identiable
4 A medication card
5 A unit dose packaging device
6 Patient information leaets.
Medication card
A medication card (locally called the yellow
card) is a useful reminder to the patient of
what drugs they are taking, when and why.
They are good for any patient with complex
or multiple prescriptions, especially the aged
and the inrm. They should be carried by the
patient whenever possible, and certainly to
any visits to medical, paramedical personnel
or hospital.
Medications cards may contain the fol-
lowing information:
Name of patient
Any allergies
Name of patients regular (primary)
doctor
Drug name
Drug form and strength
Dosage and time taken (e.g. breakfast,
dinner, lunch)
Purpose of drug
Special instructions.
Optimal therapeutics Patients and their Drugs
80
5
Patients and their Drugs
Talk to the patient about their drugs
Patient outcomes and compliance can be
improved greatly if attention is paid to
all aspects of communication between them
and their health professional about their
drugs.
Taking a drug history a What to ask pati-
ents about their drugs.
1 What drugs are you currently taking?
2 How long have you been taking them?
3 What doses, and how frequently?
4 Have there been benets from them?
5 Any side effects?
6 What drugs have you had previously for
the same condition(s)?
7 Why did you stop these?
8 Are you taking any other drugs?
regularly?
occasionally?
forgotten drugs e.g. oral contraceptives?
purchased over the counter?
herbal or alternative medicines?
9 Do you have any drug allergies/intoler-
ances?
10 Alcohol/smoking/illegal drug history.
Patient education a What to tell the patient
about their drugs.
1 Name of the medication
2 Why it has been prescribed
3 How and when to take it
4 How long it should be taken for
5 Benets expected and when they might
occur
6 Possible problems to expect, and how to
deal with them
7 Food/drink/other drugs (including over
the counter) to avoid
8 What to do if a dose is missed
9 How to obtain further information
10 Follow-up appointment for review.
ICPC05 21/5/05 12:13 PM Page 80
Patients and their Drugs Optimal therapeutics
81
Unit dose packaging devices
Drug administration devices in which drugs
are organized into convenient compart-
ments are useful to assist ordered drug com-
pliance, e.g. drugs taken at breakfast time
will be in one compartment. These are par-
ticularly useful for patients with multiple
medications, those who might forget to take
their medications, and those (e.g. patients
with arthritis) who cannot open pill bottles.
Patient information leaets (PILs)
There is increasing pressure, both medically
and legally, for patients to be given simple,
written information about their drugs that
they can take away and refer to in their own
time. This is because it is impossible for
patients to remember all the information
given to them at the time of discharge or
at the end of a consultation. The informa-
tion should be written as simply as possible,
usually aiming for a reading age of about
10 years. PILs that have been prepared by
pharmacy/clinical staff with great attention
to presentation style and simplicity are the
best.
Information contained in PILs may
include:
Drug name (generic and trade)
What does it do?
How it should be taken (e.g. with food,
with water etc.)
What to do if a dose is forgotten
Can other medicines be taken (including
herbal and OTC)
Side effects and recommended action if
they occur
Other information.
5
ICPC05 21/5/05 12:13 PM Page 81
A consistent template approach to formu-
lating drug proles assists in both transmis-
sion of drug information and the learning
process.
Most modern information sources follow
a fairly uniform template pattern in their
approach to providing drug information
(see Drug Information/Resources, page 88).
An example of a drug prole is printed on
the facing page.
Optimal therapeutics The Drug Prole
82
5
The Drug Prole
Each drug has its own drug prole, all
aspects of which are considered in relation
to the patient prole during prescribing.
The drug prole is made up of the follow-
ing major headings.
Drug name (generic)
Class/therapeutic category
Action
Pharmacokinetics
Factors affecting pharmacokinetics
Indications (registered/unregistered)
Contraindications/precautions
Adverse reactions
Interactions
Dosing information
Monitoring
Overdose (symptoms/signs/treatment)
ICPC05 21/5/05 12:13 PM Page 82
The Drug Prole Optimal therapeutics
83
5
Class:
Action:
Pharmacokinetics:
Factors affecting
pharmacokinetics:
Indications:
(* registered)
Contraindications/
Precautions:
Adverse reactions:
Interactions:
Dosing:
Monitoring:
Overdose:
FLUOXETINE
(Prozac, Lovan)
Selective Serotonin Reuptake Inhibitor (SSRI)
Major: antidepressant
Minor: inhibits reuptake of 5-HT at synapses
Oral availability: >0.6 (rst-pass) Vd: 2450 L/70 kg (7703290)
P.B: 0.94 t
1/2
: 53 hr (1294) [6.42.5days noruoxetine]
fu: < 0.03 Cl: 40 L/hr/70 kg (1169)
Metabolism: CYP2D6, 3A4
FLUOXETINE NORFLUOXETINE INACTIVE METABOLITES
CYP2D6 (active) CYP3A4
Hepatic disease: Cl in cirrhosis
Genetics: subject to CYP2D6 polymorphism
(510% Caucasian, 13% Asians slow)
depression*, obsessive compulsive disorder*, bulimia*, ?panic disorder,
premenstrual tension
MAOIs, dose in liver disease
Pregnancy: FDA B [Animal studies havent shown a risk but no controlled
studies in humans OR animal studies have shown an ADR not
conrmed in controlled studies in women in 1st trim + no evidence
of risk in later trimesters; 1
st
trim spontaneous abortions; 3
rd
trim
perinatal complications]
Lactation: % maternal dose (wt adjusted): 613% [includes noruoxetine and
uoxetine]
>10% CNS: headache, nervousness, insomnia, drowsiness
GI: nausea, diarrhoea, dry mouth
110% CNS: anxiety, dizziness, fatigue, sedation
Endo: SIADH, hypoglycaemia, hyponatraemia
GI: anorexia, dyspepsia, constipation
Misc: sweating, rash, pruritis, tremor, sexual dysfunction, weight loss
<1% Misc: extrapyramidal reactions, anaphylactoid reactions, allergies, visual
disturbances, suicidal ideation
Many interactions:
Pharmacokinetic:
CYP2D6 inhibition: Cp of diazepam, lipophilic b-blockers, antipsychotics
CYP2C9 inhibition: warfarin Cp. NB. Also antiplatelet effect bleeding
Also inhibits CYP3A3/4 therefore Cp terfenadine, cisapride etc.
Pharmacodynamic:
Serotonin syndrome with other 5-HT enhancers (e.g. MAOIs, TCAs, Lithium, 5-HT
precursors, St Johns wort)
2080 mg/day. Higher for bulimia?
Adverse reactions, serum Na
+
Signs/symptoms: potentially dangerous in overdose serotonin syndrome
particularly in combination with other 5-HT enhancers (see list above in
interactions).
Treatment: supportive
ICPC05 21/5/05 12:13 PM Page 83
based approach should recognize this and
make use of all the information that is avail-
able. If there is no robust RCT available to
answer a question (very common), this is not
an excuse to ignore all the information that
does exist.
The Randomized Controlled Trial (RCT):
This remains the Gold Standard, even if it is
far from perfect.
Key features:
Uniform patient selection a strict inclu-
sion and exclusion criteria ensure maximum
chance of detecting signal from noise.
Randomization a to active (new drug)
or control (placebo or active comparator)
groups.
Blinding a usually double-blind, which
means both patient and observer do not
know which patient is in which group.
Problems:
Lack of generalizability a patient selec-
tion is stringent and therefore the results
may not apply to your patient.
Articial clinical environment a the
patients is treated by a highly motivated
researcher who does not know which com-
pound the patient is receiving, and has little
exibility in dosage adjustment etc.
Blinding is rarely possible a drugs have
effects that are discerned by both patient and
observer, e.g. slowed pulse with -blocker.
Meta-analysis: This is a complicated stat-
istical technique for pooling the data from
multiple similar clinical trials, in order to
increase the statistical power. It has its
own problems including generalizing re-
sults from trials with different methodo-
logies, subjective selection of trials to be
included, and publication bias (negative
trials are less likely to be published, in-
creasing the likelihood of a positive net
outcome).
Optimal therapeutics Evidence-based Medicine
84
5
Evidence-based Medicine
The explicit and judicious use of current
best evidence in making decisions about
the care of individual patients.
Sackett et al., Evidence-Based Medicine. New
York, NY: Churchill Livingstone; 1997.
There is an increasing expectation for
healthcare professionals to practise evid-
ence-based medicine. At the same time, the
increasing volume and complexity of infor-
mation, in the setting of time constraints,
makes this very difcult. Further, as in crim-
inal law, there are various degrees of evid-
ence. Truth is hard to nd.
Evidence-based medicine is a laudable
concept with natural appeal, that has itself
become quite an industry (e.g. Cochrane col-
laboration). Used correctly, it is an essential
guide to patient management. Misused, it
can approach a religion, and mislead.
It is important to maintain a healthy scep-
ticism not only about the evidence itself, but
also about the doctrine of evidence-based
medicine.
Evaluation of scientic evidence
1 Identify the specic clinical concern
2 Retrieve all contributory information
3 Categorize studies according to their
strength of evidence
4 Use all of the best studies to derive clin-
ical recommendations.
Strength of evidence (decreasing order)
I Randomized controlled trials (RCTs)
II Controlled trials without randomization
III Cohort, case-control or cross-sectional
studies
IV Uncontrolled studies
V Descriptive studies/opinion.
In reality, scientic support for a notion is
often conicting or absent. The evidence-
ICPC05 21/5/05 12:13 PM Page 84
Evidence-based Medicine Optimal therapeutics
85
Controlled trials without randomization:
These are similar to RCTs, but patients are
not truly randomized, e.g. every alternate
patient may enter respective groups. These
are weaker than RCTs.
Cohort studies: These track people forward
in time, from exposure to outcome. Exposed
and unexposed groups are followed to see
if outcomes differ. They are slow and
expensive.
Casecontrol studies: These track people
backwards from outcome to exposure.
Groups with and without a condition are
examined retrospectively to see if proposed
risk factors differed in prevalence. While
more efcient than cohort studies, it is dif-
cult to choose a truly equivalent control
group.
Cross-sectional studies: These are a snap-
shot (prevalence study) of outcome and
5
exposure at a single time-point. They are
easy to conduct.
Descriptive studies: These merely describe
the characteristics of a condition. They may
lead to hypotheses that can be tested more
formally to establish causal association.
Statistical analysis: Condence intervals
(often but not necessarily the 95% limits)
around measures distinguishing index and
control groups indicates the precision and
chance of the results. They are preferred
over p-values, which address only chance at
an arbitrary value.
Let us agree that good clinical medicine will
always blend the art of uncertainty with the
science of probability. But let us also hope
that the blend can be weighted heavily
towards science, whenever and wherever
evidence is brought to light.
William Osler
ICPC05 21/5/05 12:13 PM Page 85
fer in their clinical effectiveness on a single
health outcome, and also differ in costs. Sup-
erior efcacy is weighed against increased
costs. The measure is the C/E ratio (cost to
effectiveness), e.g. cost per life saved.
Costutility analysis (CUA): This is similar
to CEA but the alternative therapies are
compared against multiple outcomes (e.g.
effectiveness, morbidity, mortality). Each
outcome may be weighted by patient pref-
erence. The summarized measure of effect-
iveness is the QALY (quality adjusted life
years). The measure is the C/E ratio, where E
is the QALY.
Costbenet analysis (CBA): This com-
pares benets, expressed in monetary terms,
with costs. The measure is the B/C ratio
(benets to costs).
Which is best?
The CUA is the most universal, and there-
fore overall the best approach. However, it
requires more information, more assump-
tions and more subjectivity, so unless the
data is good the results may mislead, i.e.
garbage in, garbage out!
What are costs?
Costs may be direct, indirect, or intangible.
Direct costs: These include the actual cost
of the drugs and everything associated with
their delivery. E.g. diagnostic tests, monitor-
ing, treating side effects.
Indirect costs: These include days lost
from work/school, or lost employment
opportunities, e.g. through arthritis.
Intangible costs: These include less den-
able things such as pain and suffering.
It is clear that many of these costs are very
difcult to quantify accurately.
Optimal therapeutics Pharmacoeconomics
86
5
Pharmacoeconomics
Pharmacoeconomics is about maximizing the
net benets of the drugs purchased by society
Health resources are never unlimited.
Allocation decisions must be made, and
pharmacoeconomics provides a framework
for this. It is not a system for reducing
costs.
The science of pharmacoeconomics is
imperfect, and uncertainty abounds. This is
reected by the different perspectives, biases
and abilities of the analysts, the various
types of analyses used, and the subjectivity
involved in many of the assessments. This
very looseness allows for potential misuse of
the components of the process, and abuse of
the outcomes.
Perspectives
Pharmacoeconomic analysis can be under-
taken from a variety of perspectives.
Society
Patient
Provider
Drug company.
The widest perspective, and therefore usu-
ally the best, is that of society as a whole. It is
easy to see the potential biases of the other
perspectives.
Types of pharmacoeconomic
analysis
Cost-minimization analysis (CMA): This
approach may be used when alternative
therapies have identical outcomes (well
established) but differ in costs. The measure
is simply cost. The best treatment is the
cheapest.
Cost-effectiveness analysis (CEA): This
may be used when alternative therapies dif-
ICPC05 21/5/05 12:13 PM Page 86
Pharmacoeconomics Optimal therapeutics
87
How is the pharmacoeconomic
analysis performed?
There are various models, mostly computer
based, including decision trees, Markov dia-
grams and other complex algorithms that I
do not understand! These are specialized
tools that require expert knowledge.
How to manage uncertainty
This is done by a technique called sensitivity
analysis. Values of the various parameters
in the model are altered to see how this
affects the overall decision. In this way un-
important parameters can be identied and
ignored.
5
Unless the evidence basis, assumptions,
biases and uncertainties are stated very
explicitly, the results of pharmacoeconomic
studies should be treated with great caution
Checklist for evaluating
pharmacoeconomic studies
1 Are the aims clearly stated?
2 Are the alternative therapies clearly dened?
3 Is the perspective of the analyst apparent,
and appropriate?
4 Is the type of analysis appropriate?
5 Have all outcomes been identied and
measured?
6 Have all costs been identied and measured?
7 Has sensitivity analysis been performed?
8 Have all assumptions been dened explicitly?
9 Are the results presented clearly and fairly?
10 Are the conclusions justied?
ICPC05 21/5/05 12:13 PM Page 87
erized databases that provide access to the
major world literature, to provide evidence-
based medicine.
Some useful resources include:
Martindale a The Complete Drug
Reference
American Hospital Formulary Service
(AHFS)
Drug Interactions, Stockley
Drugdex System, Micromedex 2002
Medline CD ROM
Embase CD ROM.
3 At libraries/drug information services:
These include specialist texts covering
highly specic details in relevant areas of
interest (e.g. drugs in pregnancy or lactation,
drug interactions, adverse drug reactions).
Some useful resources include:
Therapeutic Drugs, Dollery
Goodman and Gilmans The Pharma-
cological Basis of Therapeutics
Averys Drug Treatment
Daviess Textbook of Adverse Drug
Reactions
Meylers Side Effects of Drugs
Drugs and Human Lactation, Bennett
Drugs in Pregnancy and Lactation,
Briggs.
Types of questions asked of a drug
information service
Analysis of our own drug information ser-
vice database reveals that the majority of
questions come from the following categ-
ories. This may indicate where resources
should be directed.
Optimal therapeutics Drug Information/Resources
88
5
Drug Information/
Resources
The basis of good prescribing is the ready
availability of good drug information
The ideal is to have comprehensive informa-
tion available at time of need. This is usu-
ally at the time of writing a prescription.
Information available to health profes-
sionals can be thought of in three tiers:
1 Instantly available (portable, on desk):
These include local guidelines, preferred
medicines lists, national formularies, drug
information handbooks, and computerized
databases (including palmtop). These con-
tain drug prole information for routine
prescribing, such as:
Mechanism of action
Pharmacokinetics
Factors altering pharmacokinetics
Indications
Contraindications/precautions
Adverse drug effects
Interactions
Dosing information
Monitoring
Overdose.
Some useful resources include:
British National Formulary
Australian Medicines Handbook
Drug Information Handbook
Epocrates
Drdrugs.
2 Readily available (in wards, in group
practice libraries, in dispensaries): These
include larger resources with more detailed
information about the same general areas of
the drug prole. They include large comput-
ICPC05 21/5/05 12:13 PM Page 88
Drug Information/Resources Optimal therapeutics
89
Category % total
Adverse reactions 21
Contraindications/precautions 20
Drug interactions 19
Administration/dosage 13
Drug choice/selection 7
Other 20
Useful further information
on pharmacology/clinical
pharmacology
Clinical Pharmacokinetics, Rowland, M.
and Tozer, N. 3rd ed. (1995). Williams &
Wilkins, London.
Pharmacokinetics made easy, Birkett, D.J.
(1999). McGraw Hill, Sydney
Pharmacology, Raffa, R.B. (1999). Black-
well Science, Oxford.
How to access the resources
British National Formulary (2001). British
Medical Association and Royal Pharma-
ceutical Association of Great Britain.
Australian Medicines Handbook 2nd ed.
(2002). Australian Medical Handbook
Pty Ltd, P.O. Box 240, Rundle Mall,
Adelaide, South Australia.
Drug Information Handbook, Lacy, C.F.,
Armstrong, L.L., Goldman, M.P. and
Lance, L.L. 9th ed. (20012002). Lexi-
comp Inc., Hudson, Cleveland.
Epocrates (Palm OS) www.epocrates.com
Drdrugs (Win CE) www.skyscape.com
Martindale a The Complete Drug Refer-
ence 33rd ed. (2002). Pharmaceutical
Press, London.
American Hospital Formulary Service
(AHFS) (2002). AHFS, Washington.
Drug Interactions, Stockley, I.H. 5th ed.
(1999). Pharmaceutical Press, London.
Drugdex System, Micromedex 2002 Health-
care Series, Computer program.
Medline CD-ROM, 19662002.
Embase CD-ROM, 19882002.
Therapeutic Drugs, Dollery, C. 2nd ed.
(1999). Churchill Livingstone, Edinburgh.
Goodman and Gilmans a The Pharma-
cological Basis of Therapeutics, 10th ed.
(2002) (ed. Hardman et al.) McGraw Hill,
New York.
Averys Drug Treatment 4th ed. (1997).
Adis International, Auckland.
Daviess Textbook of Adverse Drug Reac-
tions 5th ed. (1998). Chapman & Hall,
London.
Meylers Side Effects of Drugs 14th ed.
(2000). Elsevier, Amsterdam.
Drugs and Human Lactation, Bennett, P.N.
2nd ed. (1996). Elsevier, Oxford.
Drugs in Pregnancy and Lactation, Briggs,
G.G. 5th ed. (1998). Williams & Wilkins,
Baltimore.
5
ICPC05 21/5/05 12:13 PM Page 89
ICPC05 21/5/05 12:13 PM Page 90
6
6 Appendix
Important equations in pharmacology, 92
The pharmacokinetic triangle, 93
Glossary/abbreviations, 94
Test questions, 96
Test answers, 98
ICPC06 21/5/05 12:13 PM Page 91
Appendix Important Equations in Pharmacology
92
6
F
CrCl
(* 0.85 for women)
Dose adjustment in renal failure
Dose adjustment in renal failure
when fu < 1
dose rate
dose rate
(1 fu) fu
CrCl
CrCl
patient
normal
patient
normal
*
+

_
,

dose rate
dose rate
CrCl
CrCl
patient
normal
patient
normal
*

CrCl (mL/s)
(140 age) * weight[kg]
50000 * [creatinine]


F
AUC
AUC
po
iv

Important Equations in
Pharmacology
Vd
Loading dose Vd * Cp
desired
Cl
Maintenance dose Cl * Cp
t
1/2
t
0.693Vd
Cl
12 /

Cl
F * Dose
AUC


RE Cl * Cp or Cl
RE
Cp

Ab Vd Cp or Vd
Ab
Cp
*
ICPC06 21/5/05 12:13 PM Page 92
The Pharmacokinetic Triangle Appendix
93
The Pharmacokinetic
Triangle
6
Ab RE k
Cp
Vd Cl
R
a
t
e

o
f

e
l
i
m
i
n
a
t
i
o
n

C
l

*

C
p
A
m
o
u
n
t

i
n

b
o
d
y

V
d

*

C
p
Rate of elimination k * Ab
t1/2
ICPC06 21/5/05 12:13 PM Page 93
Glossary/Abbreviations
Ab: Amount of drug in the body.
ADE: Adverse drug event. Any actual or
potential damage resulting from medical
intervention related to medicines.
ADR: Adverse drug reaction. Any response
to a drug which is noxious, unintended,
and occurs at doses used in man for
prophylaxis, diagnosis or therapy.
AUC: Area under the plasma, usually
plasma curve concentration vs time curve.
Biophase: The immediate vicinity of the site
of activity of a drug.
CBA: Cost-benet analysis.
CEA: Cost-effectiveness analysis.
Clearance: The volume of plasma cleared of
drug per unit time.
Or,
A constant relating the rate of elim-
ination to the plasma concentration.
Clinical pharmacology: The principles
behind the prescribing process.
CMA: Cost-minimization analysis.
C
max
: Maximum concentration.
Compliance: In drug therapy this describes
how much a patient is able to follow a
full course of medication exactly as
prescribed.
Concordance: This is the more modern,
less authoritarian, interpretation of
compliance that recognizes that a
prescription embraces an agreement
between the patient and the doctor.
Cp: Plasma concentration.
Cp
o
: Plasma concentration at time zero.
Cp
ss
: Plasma concentration at steady state.
Cp
t
: Plasma concentration at time t.
CrCl: Creatinine clearance.
CUA: Cost-utility analysis.
CYP: Cytochrome P450.
Dose interval: The time interval between
administration of doses.
Dose tapering: Back-titration of a dose of
a drug after effect has been achieved,
in order to achieve the minimum dose
commensurate with desired effect.
e: The natural logarithm (value 2.7183).
EC
50
: The concentration of a drug at which
effect is 50% maximum.
E
max
: The maximum effect of a drug.
F: fractional oral availability.
First-order: A number to the power of
one. In pharmacokinetics, it refers to
elimination that is dependent on
concentration (i.e. Cp
1
Cp), as occurs
with most drugs.
First-pass metabolism: Metabolism
that occurs between the gut and the
systemic circulation during the rst
passage of the drug through the portal
system and the liver to the inferior
vena cava.
Flow-dependent elimination: The
elimination of high clearance drugs is so
rapid that it is susceptible to the rate of
presentation to the eliminating organ,
and hence to blood ow.
fu: fraction excreted unchanged by the
kidney.
Half-life: The time for the concentration of
the drug in the plasma (or the amount of
drug in the body) to halve.
k: rate constant of elimination: the fraction
of drug removed per unit time. Applies to
drugs with rst-order elimination (i.e.
most drugs).
Km: The Michealis constant. The
concentration at which the rate of
reaction is half the Vmax.
ln: the natural logarithm.
Loading dose: The dose required to achieve
a target plasma concentration as soon as
possible.
M/P ratio: Milk to plasma ratio.
MEC: Minimal effective concentration.
MTC: Minimal toxic concentration.
OTC: Over the counter.
Appendix Glossary
94
6
ICPC06 21/5/05 12:13 PM Page 94
Glossary Appendix
95
P.B.: Protein Binding usually expressed
as a fraction or percentage.
pH: The negative of the log (base 10) of the
concentration of hydrogen ions.
Pharmacodynamics: The study of drug
effect, and mechanisms of action, i.e.
What the drug does to the body.
Pharmacokinetics: The study of the
movement of drugs into, within, and out
of the body. i.e. what the body does to
the drug.
Phase I metabolism: Simple chemical
alteration of a molecule by oxidation
(most commonly), reduction or
hydrolysis. It occurs often by cytochrome
p450 enzymes.
Phase II metabolism: Conjugation reactions
including glucuronidation (most
commonly), acetylation, sulphation and
methylation.
pH-dependent elimination: Varying renal
elimination of drugs with susceptible pKa
values whose degree of ionization varies
within the range of pH values of the urine
(pH 4.58).
PILs: Patient information leaets.
pKa: The pH at which a drug is 50%
ionized, and 50% unionized.
Potency: An index of the concentration
of a drug required for a given effect. The
lower the concentration the greater the
potency.
Prodrug: A drug that is inactive in itself,
but which is converted to an active
metabolite.
QALY: Quality adjusted life years.
RCT: Randomized controlled trial.
Saturable metabolism: Drug concentrations
rise disproportionately as a result of a
change from rst-order to zero-order
elimination.
SIADH: Syndrome of inappropriate
antidiuretic hormone.
ss: Steady state
T
1/2
: The half life.
Tachyphylaxis: Literally means quick
protection. It refers to a rapid
diminution of response to a drug,
usually within minutes or hours.
TDM: Therapeutic drug monitoring. Refers
to the monitoring of drug concentrations
as a surrogate for true pharmacodynamic
end-points.
Teratogenicity: Literally means propensity
to form a monster. It refers to the
propensity of a drug to cause a fetal
malformation.
Therapeutic index: The ratio of
concentration associated with toxicity
vs efciency.
Therapeutic range: The range of drug
concentrations associated with a
reasonable probability of efcacy,
without undue toxicity in the majority
of patients.
Therapeutics: The process of medical
treatment.
T
max
: Time to maximum concentration.
Tolerance: A gradual decline in
effectiveness of a drug, usually over days
or weeks, as a result of compensatory
homeostasis (often receptor up or down
regulation).
V
max
: The maximum velocity of a chemical
reaction.
Volume of distribution: The volume
into which a drug appears to distribute
with a concentration equal to that of
plasma.
Or,
A proportionality constant relating the
plasma concentration to the amount of
drug in the body.
Zero-order: A number to the power of zero
(i.e. always equals one i.e. X
0
1).
In pharmacokinetics, it refers to
elimination independent of
concentration (i.e. Cp
0
1), as
occurs with ethanol.
6
ICPC06 21/5/05 12:13 PM Page 95
Test Questions
Answers are on page 98.
1 Pharmacokinetics
Cephazolin, 1000 mg, is given intravenously
to a patient at 12:00 h as a 5-minute push.
The following concentration-time data was
collected.
Time (h) Concentration (mg/L)
12:30 76
13:00 58
14:00 46
16:00 22
18:00 12
(i) Plot the data on semi-log paper.
(ii) Calculate the patients Vd.
(iii) Calculate the t
1/2
.
(iv) Calculate the AUC.
(v) Calculate the Cl.
2 Loading and maintenance doses
You prescribe theophylline to a 28-year-old,
50 kg asthmatic. The target concentration is
15 mg/L.
(i) Calculate the loading dose.
(ii) Calculate the maintenance dose.
Assume:
Vd 0.5 L/kg
Cl 0.04 (L/h)/kg.
3 Dosing in altered metabolism
The metabolism of theophylline is induced
by around 100% in smokers. The average
maintenance dose to achieve a Cp of 10 mg/
L in a non-smoker is 500 mg theophylline
per day.
What maintenance dose would be needed
in a smoker to achieve a Cp of 15 mg/L?
4 Saturable kinetics
A 5th-year medical student (70 kg) drinks
eight 100 mL glasses of wine in one hour
(naughty, naughty!). How long after start-
ing to drink does he have to wait before it is
safe for him to drive home?
Assume:
Cp of alcohol decreases at 15 mg/100
mL/h
Vd of alcohol is 50 L
100 mL of wine contains 12.5 g alcohol
driving limit is 80 mg/100 mL.
5 Dosing in renal failure
What maintenance dose of digoxin would
be required in a 70-year-old, 70 kg man
with a serum creatinine of 0.13 mmol/L, to
maintain a serum digoxin concentration of
1 g/L?
Assume:
Digoxin cleared entirely renally
Normal CrCl 1.5 mL/sec
The dose in normal renal function is
0.25 mg/day.
Appendix Test Questions
96
6
ICPC06 21/5/05 12:13 PM Page 96
Test Questions Appendix
97
6 Dosing in the elderly
What practical dose of quinapril is needed
for an 80-year-old, 60 kg woman with
serum creatinine of 0.10 mmol/L?
Assume:
fu quinaprilat (active metabolite) 0.8
Usual dose in normal renal function is
20 mg/day
Tablet size is 5 mg, 10 mg, 20 mg.
7 Dosing in children
If the maintenance dose of a drug for 70 kg
adult is 100 mg per day, what is the appro-
priate dose for a 15 kg child?
8 Drugs and lactation
A 67 kg mother on 100 mg of drug X is
breast feeding her 6.7 kg baby. The maternal
Cp
ss
is 1 mg/L.
(i) Calculate the dose of drug the infant will
receive.
(ii) Is this compatible with breast feeding?
Assume:
M/P ratio for drug X 1
Milk consumption is 150 mL/kg/day.
9 Drugs/food interaction
Simvastatin is 100% absorbed but only 5%
reaches the systemic circulation because of
extensive rst-pass metabolism. Grapefruit
juice totally inhibits this rst-pass metabol-
ism, through CYP3A4.
What AUC increase would you expect if
grapefruit juice and simvastatin were
administered together?
6
ICPC06 21/5/05 12:13 PM Page 97
Test Answers
1 Pharmacokinetics
(i)
T6 is a guess to innity, approximated at
12 h
AUC 42 + 35 + 54 + 68 + 34 + 36 269
(v)
3.72 L/h
or
3.85 L/h

. . 0 693 11 1
2

Cl
Vd
t

.
/

0 693
1 2

1000 mg
268(mg/L) h
Cl
Dose
AUC

T
Cp
6
6
0
2
6 36


+

_
,

T
Cp Cp
4 6
5
2
2 34


+

_
,

T
Cp Cp
2 4
4
2
2 68


+

_
,

T
Cp Cp
1 2
3
2
1 54


+

_
,

T
Cp Cp
0.5 1
2
2
0 5 35

.
+

_
,

T
Cp Cp
o 0.5
1
2
0 5 42

.
+

_
,

Appendix Test Answers
98
6
C
p

(
m
g
/
L
)
Time (h)
Cp
o
90 mg/L
7
100
80
60
40
20
10
46 mg/L
23 mg/L
t1
/2
2 h
6 5 4 3 2 1 0
(ii) Estimate Cp
o
by back extrapolation
~ 90 mg/L
11.1 L
(iii) t
1/2
2 h (see graph)
(iv) AUC Sum of trapezoids

)
(
1000
90
(mg
mg/L)
Vd
Dose
Cp
o

C
p

(
m
g
/
L
)
Time (h)
Trapezoid 1 (T
1
)
7
100
75
50
25
0
6 5 4 3 2 1 0 10 8 9
T
2
T
3
T
4
T
5
T
6
(triangle )
ICPC06 21/5/05 12:13 PM Page 98

CrCl(mL/s)
(140 age) wt (kg)
50000 serum Cr (mmol/L)

Test Answers Appendix

99
2 Loading dose (LD) and
maintenance dose (MD)
(i) LD Vd Cp
(0.5 50) 15
(L) (mg/L)
375 mg
(ii) MD Cl Cp
(0.04 50) 15
(L/h) (mg/L)
30 mg/h
720 mg/day
3 Dosing in altered metabolism
Intuitive approach
Clearance is doubled the dose required to
achieve Cp of 10 mg/L is double in a smoker.
i.e. 1000 mg/day.
to achieve 15 mg/L will require 1500 mg/
day.
Formal approach
MD Cl Cp
or Cl
50 L/day
smokers Cl 100 L/day
MD (smoker) 100 15
(L/day) (mg/L)
1500 mg/day

500 mg/day
10 mg/L

MD
Cp
4 Saturable kinetics
Calculate maximum Cp possible:
Cp
(from Ld Vd Cp)
2 g/L
200 mg/100 mL
To reach 80 mg/100 mL he needs to drop
120 mg/100 mL. At 15 mg/100 mL/h this
will take:
5 Dosing in renal failure
Calculate CrCl, using CockcroftGault
equation:
0.75 mL
i.e. half normal
dose is half normal
i.e. 0.125 mg/day

.
70 70
50000 0 13
120 mg/100 mL
15 mg/100 mL/h
h 8

100
50
g/L

. ( ) ( )
( )
12 5 8
50
L g
L
Dose
Vd
6
ICPC06 21/5/05 12:13 PM Page 99
6 Dosing in the elderly
Calculate CrCl using CockcroftGault
equation:
0.6 mL/s
Patient dose
0.52 of normal dose
1 10 mg tablet per day
7 Dosing in children
Using surface area, SA 0.62 m
2
:
+

_
,

. .
.
.
0 2 0 8
0 6
1 5
( )
.
1
1 5
+

_
,

fu fu
Patients CrCl
CrCl(mL/sec)
( )
.
.

1
]
1
1

140 80 60
50000 0 10
0 85
From weight:
Maintenance dose
34 mg per day
8 Drugs and lactation
(i) Dose
infant
Cp
ss
(mat) M/P V
milk
1 1 (0.15 6.7)
(mg/L) (L)
1 mg per day
(ii) This is 1/100 of the maternal dose, but
the infant weighs 1/10 of mothers weight.
Therefore the infant dose (corrected for
weight) is 1/10 the maternal dose. This is
right on the notional 10% cut-off level for
safety of drugs during breast feeding.
9 Drugs/food interaction
Since the oral availability is only 5%, 95% is
metabolized on rst-pass. Complete inhi-
bition of this metabolism will increase the
oral availability to 100%.
Therefore the AUC will increase 20-fold.

_
,

(
.
15
70
100
0 7
mg)

_
,

.
wt (kg)
adult dose
70
0 7
Appendix Test Answers
100
6
Maintenance dose
SA (m )
1.73 m
adult dose
2
2

36 mg per day


.
.

0 62
1 73
100
ICPC06 21/5/05 12:13 PM Page 100
Index
cohort studies85
compliance767
elderly patients33
promotion of767
concentration-effect relationships723
cost-benet analysis86
cost-effectiveness analysis86
cost-minimization analysis86
cost-utility analysis86
creatinine clearance28
cross-sectional studies85
CYP see cytochrome P450
cytochrome P45020, 245
2C925
2C1925
2D625
polymorphism245
dihydropyrimidine dehydrogenase deciency
24
discharge prescribing80
distribution17
drug/food interactions54
diuresis, pH-adjusted65
dose tapering75
dosing
cardiovascular disease27
children345
elderly patients323
gastroenterological disease27
liver disease27
renal impairment301
dosing interval11, 75
drug abuse61
drug action723
drug dependence689
drug development589
clinical589
ethical considerations59
preclinical58
drug discovery58
drug history80
drug information889
drug interactions501
pharmaceutic51
pharmacodynamic51
pharmacokinetic501
absorption12, 16
drug/food interactions54
acetylation24
acids, antidotes65
adverse drug events467
prevention of489
adverse drug reactions423
assessment43
classication42
reporting43
type A (augmented)423
type B (bizarre)43
aldehyde dehydrogenase24
alkalis, antidotes65
allergic reactions, drug-induced445
anaphylaxis44
cell mediated44
cytotoxicity44
immune mediated44
percutaneous testing45
prevention45
anaphylactoid reactions44
anaphylaxis44
antidotes65
applied pharmacology745
area under the curve (AUC)7
autoimmune disease, drug-induced44
availability, drug interactions affecting
50
bioavailability13
biotransformation see drug metabolism
breast milk, drugs in17, 389
dose ingested by infant38
infant plasma concentration389
toxicity of drug to infant39
cardiovascular disease27
children345
clearance (Cl)4, 67
children34
determination of7
drug/food interactions545
elderly patients32
hepatic201
physiological relevance7
in pregnancy367
101
ICPD01-Index 21/5/05 12:13 PM Page 101
drug metabolism201
inducers52
inhibitors53
saturable223
drug prolevii, 823
drug/food interactions545
absorption54
clearance545
drug distribution54
rst-pass metabolism54
grapefruit juice54
pharmacokinetics54
EC
50
72
elderly patients323
elimination
drug interactions affecting50
non-linear23
pH-dependent17
presystemic12
renal16, 289
time for3, 10
E
max
72
emesis64
enzyme induction50
enzyme inhibition501
evidence-based medicine845
rst-order elimination5
rst-order reactions22
rst-pass metabolism12, 21
drug/food interactions54
fraction excreted unchanged289
gastric lavage65
gastroenterological disease27
Gilberts disease24
glomerular ltration28
glucuronidation20, 24
half-life (t
1/2
)4, 1011
derivation of10
elderly patients33
HendersonHasselbalch equation16
homeostatic responses in elderly patients33
intravenous infusion2
Investigational New Drug application
(IND)55
ion trapping17
line of steady state3, 1011
liver disease267
liver, drug clearance201
loading dose2, 75
calculation of89
maintenance dose75
medication card80
medication errors489
meta-analysis84
Michaelis constant (K
m
)223
MichaelisMenten curve22
minimal effective concentration (MEC)2
minimal toxic concentration (MTC)2
neuroadaptation69
New Drug application (NDA)55
non-compliance
detection of77
management of77
reasons for76
one-compartment model4
oral availability1213
determinants of12
food effects on1213
oral dosing2
overdose/poisoning61, 647
antidotes65
decreasing exposure645
diagnosis64
rst aid64
measurement of concentrations64
oxidation reactions20
P-glycoprotein28
patient education80
patient information leaets81
patient prolevii
penicillamine, teratogenicity37
pH1617
pharmacodynamics
applied pharmacology74
children35
elderly patients33
liver disease26
pharmacoeconomics867
pharmacogenetics 245, 25
pharmacokinetic triangle93
pharmacokinetics25
applied pharmacology75
children34
drug/food interactions54
and pH1617
phase I reactions20
phase II reactions20
placental drug transport17
Index
102
ICPD01-Index 21/5/05 12:13 PM Page 102
Index
103
plasma concentration (Cp)
higher than desired23
lower than desired3
steady state6
pregnancy367
clearance in367
effects on drugs367
effects of drugs on36
pharmacological risks36
protein binding in37
teratogenicity36, 37
volume of distribution in37
prescriptions789
presystemic elimination12
protein binding1415
in children34
in pregnancy37
saturable15
pseudoallergic reactions44
pseudocholinesterase deciency24
quality adjusted life years86
randomized controlled trials84
regulatory process59
renal clearance28
renal elimination16, 289
drug interactions affecting51
renal impairment301
saturable metabolism223
sensitivity analysis87
slow-release preparations13
sparteine hydroxylation25
statistical analysis85
tachyphylaxis74
target organ sensitivity in elderly patients33
teratogenicity36, 37
therapeutic drug monitoring603
indications for601
therapeutic index60
therapeutic principles789
therapeutic range61
thiopurine methyl transferase deciency24
time for drug accumulation10
time for drug elimination3, 10
time to peak concentration (T
max
)13
time to steady state3
tolerance74
trapezoidal rule7
unit dose packaging devices81
volume of distribution (V
d
)2, 4, 89
children34
determination of8
elderly patients323
in pregnancy37
weight-adjusted maternal dose38
withdrawal symptoms69, 74
zero-order elimination4, 22
ICPD01-Index 21/5/05 12:13 PM Page 103
ICPD01-Index 21/5/05 12:13 PM Page 104