BJA Education, 18(12): 364e370 (2018)

doi: 10.1016/j.bjae.2018.09.001
Advance Access Publication Date: 26 October 2018

Matrix codes: 1A02,

2A12, 3I00

Pharmacokinetics of anaesthetic drugs at extremes

of body weight
C.P. Hebbes1,2 and J.P. Thompson1,2,*
1
University Hospitals of Leicester NHS Trust, Leicester, UK and 2University of Leicester, Leicester, UK
*Corresponding author: jt23@le.ac.uk

Learning objectives Key points

By reading this article, you should be able to:

Discuss the use of total, predicted, ideal, lean, and
adjusted body weights for drug dosing.

Describe the effects of increasing weight on total
body weight, lean body weight, and adiposity.

Explain the effects of obesity and low body weight
on drug pharmacokinetics.

Use different measures of body weight to calcu-
late doses for drugs with reference to their phar-
macological characteristics at extreme weights.

The clinical effect of drugs can differ markedly in
patients at extremes of weight.

Total body weight does not account for the dis-
tribution or metabolic activity of fatty tissue.

Drugs that do not usually require weight-based
dosing may require adjustment at extreme
weights.

Ideal or adjusted body weight is a useful measure
to avoid errors in weight-based drug dosing.

Data are lacking for many drugs at extreme
weights, and careful titration to effect is needed.

Excessively high or low body weight, with cellular imbalance

between nutrient and energy supply and demand, causes
physiological changes that may affect drug dosing, handling,
and pharmacokinetic properties.1 Furthermore, the patho-
logical changes resulting from extremes of weight and their
associated co-morbidities affect the metabolism and elimi-
nation of many drugs. This paper summarises the measures
used to characterise body weight, the physiological effects of
Christopher Hebbes BSc, MMedSci (Med Ed), FRCA, FFICM is a
specialty trainee and clinical lecturer in anaesthesia and critical care
at the University of Leicester and University Hospitals of Leicester
NHS Trust. He has a longstanding interest in pharmacology,
completing a BSc in opioid pharmacology.
Jonathan Thompson BSc (Hons), MD, FRCA, FFICM is Honorary
Professor of anaesthesia and critical care at the University of
Leicester, and a consultant at Leicester Royal Infirmary. He is a
former editor of the BJA, current editorial board member of the BJA
and Perioperative Medicine, and current Editor-in-Chief of BJA Ed-
ucation. He is an expert advisor for the British National Formulary
and a past member of the Pharmacology Subcommittee of the Eu-
ropean Society of Anaesthesiologists.
extreme body weights, and their implications for pharmaco-
kinetics and drug dosing in anaesthesia and critical care.
Defining extremes of body weight
Several classifications may be used to describe obesity and
malnutrition, but these are deceptively complicated to define
and categorise. Many classifications are derived from
population-based estimates of ‘normal’ height, weight, and
size. The pharmacokinetic implications of being over- and
underweight originate from the mass of adipose tissue, its
distribution, and coexistent medical problems (such as fatty
liver). In practice, clinicians usually define obesity using BMI.
BMI is defined as weight (kg)÷height2 (m), with obesity being
defined as BMI >30 kg m2 in the UK (Table 1).2 Although
widely used, BMI does not quantify body composition or fat
distribution. Individuals with increased body weight because
of high muscle mass may be classified as obese by BMI, but
may not have the pathophysiological changes related to
excess adiposity. Coexistent conditions in those at extremes
of body weight, such as chronic kidney disease, fatty liver,
marasmus, or kwashiorkor, may also cause variations in un-
derlying pathophysiology and drug handling.

Accepted: 20 September 2018

© 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
For Permissions, please email: permissions@elsevier.com

364

Table 1 Diagnosis and classification of obesity, and over- and un-
derweight states based on recommendations by the National
Institute for Health and Care Excellence CG1892
Category BMI (kg m¡2) % IBW
Underweight <18.5 <70e80% IBW
Normal 18.5e24.9 IBW
Overweight 25e29.9
Obese Class 1 30e34.9 >120% IBW
Morbidly obese Class 2 35e39.9
Class 3 >40
Super morbidly obese >55
In view of these shortcomings, other measures, including
waist circumference and waistehip ratio, are sometimes
added to BMI for long-term cardiovascular risk stratification.
This approach can be a useful alternative to BMI, as it ac-
counts for the distribution of visceral fat and correlates with
the risk of obesity-related diseases.2 The fat-free mass index
(FFMI) is a measure of nutritional status that accounts for
muscle mass and fat. Direct measurement of fat mass is
impractical in clinical practice but FFMI can be approximated
using the formula FFMI¼fat mass (kg)÷height2 (m2).3 FFMI was
validated in experimental starvation and is reduced in
malnourished or underweight individuals, but is not validated
in the diagnosis or categorisation of obesity. Although useful
for risk stratification, BMI, FFMI, waist circumference, and
waistehip ratio are not useful for drug dosing.
Low-body-weight states are also challenging to define.
Much of the available data are from children in lower-income
countries suffering from proteinecalorie malnutrition,
marasmus, or kwashiorkor. Conversely, low body weight in
higher-income countries occurs more often later in life,
related to cancer, dementia, and malabsorption syndromes.
The underlying aetiologies may affect the growth and devel-
opment in the young, or contribute to frailty and susceptibility
to illness later in life. Malnutrition at all life stages contributes
to impaired drug handling.4
The diagnosis of abnormally low body weight can be based
on BMI, percentage of ideal body weight (IBW), magnitude of
weight loss, or the use of screening tools as composite mea-
sures. These tools use a combination of historical weight loss,
objective measures, and current illness to define the extent of
malnutrition. The subjective global assessment tool grades
AeC for nourished, mild undernutrition, and severe malnu-
trition, respectively, based on weight change, dietary intake,
gastrointestinal symptoms, and functional impact.5 Malnu-
trition leads to changes in composition and size of body
compartments, and alterations in proteins and body water
that can affect all aspects of drug handling.
The European Society of Parenteral and Enteral Nutrition
defines criteria for the diagnosis of malnutrition based on BMI,
weight, or FFMI.6 These criteria include: (i) BMI <18.5 kg m2;
(ii) unintentional weight loss >10%, or >5% within the past 3
months combined with either BMI <20 kg m2 if aged <70 yr,
or BMI <22 kg m2 if aged 70 yr; and (iii) FFMI <15 kg m2 in
women and <17 kg m2 in men.
Table 1 shows the UK guidelines for the diagnosis and
classification of obesity, and over- and underweight in-
dividuals based on BMI and % IBW.
The use of BMI for diagnosing and categorising extremes of
weight indexes disease severity and health risks in some
populations, but it does not give a practical measure of body
Pharmacokinetics at extremes of body weight
composition for use in drug dosing. Practical methods for drug
dosing are shown in Table 2; their formulae use measures
readily available in the clinical setting: sex, height, and TBW.
Effects of weight on body composition
In the normal-weight individual, the TBW comprises 20% fat
weight (FW) and 80% lean body weight (LBW), or fat-free mass.
In the underweight and malnourished individual, the lines for
TBW and LBW converge, as FW accounts for a decreasing
proportion of TBW (Fig. 1). Low body weight and
proteinecalorie malnutrition result in catabolism and loss of
fat and lean mass, which affects protein binding, drug distri-
bution, and clearance. During starvation, the loss of fatty tis-
sue is greatest at first, but with increasing starvation, muscle
and lean tissues are lost progressively. There is a gradual in-
crease in total body water, with reduced protein synthesis
resulting in oedema because of reduced intravascular oncotic
pressure. Catabolism affects many metabolic processes, and
can reduce metabolism and clearance by inhibiting the syn-
thesis and function of hepatic enzymes.
With increasing TBW in the obese, LBW increases rela-
tively slowly as the majority of the excess weight is because of
adipose tissue, so there is a relative increase in both the TBW/
LBW ratio (Fig. 1) and FFMI.11 With increasing body weight,
total body water also increases, although at extremes of
obesity, the proportion of total body water is reduced because
most of the excess weight is FW.11
There are limited data describing the effects of severe
malnutrition and low body weight on body composition.
However, as TBW and LBW converge, the relative fatty mass
decreases (Fig. 1).
FW comprises poorly vascularised adipose tissue into
which lipid-soluble drugs may be sequestered, particularly
with repeated doses or prolonged administration; such drugs
have a high volume of distribution VD at steady state. This is of
particular relevance in critical care, where prolonged infusion
or repeated administration over several days of morphine,
propofol, midazolam, and other drugs can result in a signifi-
cantly delayed offset. After cessation of a prolonged infusion,
as plasma or effect-site concentrations decrease, drugs
redistribute into plasma and to their effect sites from fatty
tissues, prolonging the effect and delaying the terminal
elimination. These phenomena are more marked in the obese
where FW is higher.
LBW predominately consists of muscle and vessel-rich
organs or tissues, in which drug distribution and elimination
are relatively fast. Lean tissues are highly active in metabolic
terms, and the proportion of LBW is related to basal metabolic
rate, drug metabolism, and clearance. Blood flow to fat ac-
counts for 5% of cardiac output (although this is as little as 2%
in the obese), compared to 22% for lean tissues.12,13
Calculations for predicted body weight (PBW), IBW, and
LBW are based on height and sex (Table 2). Therefore, in
obesity, the calculated weight for drug dosing using height-
and sex-derived measures in an individual of given height
remains the same as that for a non-obese individual of the
same height. Dosing drugs with high lipid solubility by pre-
dicted, ideal, or LBW in the obese could result in lower plasma
concentrations compared to the non-obese. Where drugs have
a low lipid solubility, dosing by adjusted body weight (ABW)
takes into account the distribution into the excess fatty tissue
by applying a drug-specific correction factor to the fat mass.
Gentamicin, as an example of a hydrophilic aminoglycoside,
BJA Education - Volume 18, Number 12, 2018 365
 Table 2 Measures used for calculating drug doses and associated formulae
366

Pharmacokinetics at extremes of body weight

Term Derivation Explanation Use Advantages Disadvantages

TBW (kg) LBWþFW TBW, as measured,
Dosing of many drugs;
Easy to measure
May lead to overdose if used
BJA Education - Volume 18, Number 12, 2018

LBW (kg)7 1.1TBWe0.0128BMI
TBW (male); 1.07
TBWe0.0148BMI
TBW (female)
IBW (kg)8 22height2 (m)
ABW (kg) LBWþC(TBWeLBW)
(where C is a drug-specific
correction based on the
solubility of the drug)
Body surface Weight0.425height0.725
area9 (m2) 0.007184
PNWT10 (kg) 1.57weight0.0183
BMIWT10.5 (male)
1.75Weight0.0242
BMIWT12.6 (female)
PBW (kg) 50þ[0.91(height in
cme152.4)] (males);
45.5þ[0.91(height in
cme152.4)] (females)
includes both fat most appropriate in the
and lean weight non-obese (where TBW
tends to LBW).

Succinyl choline.

TIVA maintenance
(accounts for larger
compartment size).
LBW comprised of
Useful for polar drugs
the non-adipose with a small VD, such
tissues as NMBAs

TCIs (bolus induction:
avoids overdosing
and instability)
The weight of an
Recommended for
individual based on calculation of local
height and assuming anaesthetic maximal
a normal BMI of 22 doses

Used for selection
of tracheal tube size

Originally shown to
be consistent with the
pharmacokinetics of
gentamicin
Assumes drug
Dosing of drugs with
distribution to lean a narrow therapeutic
tissues and a index (e.g. gentamicin)
proportion of the FW
depending on the
physiochemical
properties of the drug
Based on the surface
Mostly only used for
area given height and dosing chemotherapy
weight, both of which agents
are easily measured
Consists of lean and
Developed to overcome
fatty weight, corrected limitations of scaling
for the non-obese to LBW or TBW
individual, an
Not validated or in
extension of IBW widespread clinical
use currently
Based on the
Used for calculating
original ARDSNet ventilatory requirements
study, normalises
Does not have a
to lung size; significant role in
comparable to IBW drug dosing
and is widely used.

Validated for normal-
weight population.

Correlates with
metabolism and
clearance

Accounts for sex-related
differences in metabolism

Less prone to overdosing
in obese populations

Easily calculated (although
measures of height in
critically ill patients
can be challenging)

Drug specific

Easily calculated

Specifically derived for
drug dosing (rather than
classification of obesity)

Includes sex, weight
and height

Considers height,
weight, and sex
in the obese population.

Does not account for pharmacogenetics
or sex differences in metabolism.

TIVA boluses by TBW may
exaggerate haemodynamic
effects.

Several formulae for calculation,
and may be complex

Error prone, particularly at extremes
of weight, depending on formula used

Does not account for pharmacogenetic
differences in metabolism

Not possible to measure
directly in clinical practice

Does not account for pharmacogenetics
or age-related differences
in metabolism

Assumes 15% body fat,
which is not ‘normal’
across all age ranges

Requires calculation using a correction
factor specific to every drug

Uses LBW (which may be error prone,
depending on the formula used)

Does not account for pharmacogenetic
differences in metabolism

Requires calculation

Does not account for pharmacogenetic
differences in metabolism

Not validated; poor correlation
with clearance

Complicated to calculate

Does not account for pharmacogenetic
differences in metabolism

Not validated

Requires calculation (both height and
weight can be difficult to measure in
critical illness)

Fig 1 Changes in relative proportions of FW, LBW, and TBW with increasing BMI for a male 1.75 m in height.
is dosed by ABW to account for its relatively low distribution
into fatty tissue. The use of IBW would result in low plasma
concentrations, risking subtherapeutic dosing, as it does not
account for the excess fat.
The implications of weight for clinical practice depend on
individual patient- and drug-related factors. The lipid or water
solubility of a drug is important, and the effects depend on the
composition of body compartments. Water-soluble drugs
often have a low VD, in contrast to more lipid-soluble drugs,
which have a higher VD (Table 3).
Applied pharmacology at extremes of body
weight
Drug dosing
The traditional three-compartmental model describes the
initial drug distribution into a central compartment before
redistribution to peripheral compartments. Drugs may only be
cleared or eliminated from the central compartment,
although drug effect can terminate when the effect-site con-
centration decreases because of redistribution to other tis-
sues. Distribution is not uniform, and depends on drug
solubility, degree of ionisation, protein binding, and the blood
flow between compartments. All of these are affected by
obesity, malnutrition, and intercurrent illness. Therefore, the
weight used to calculate drug dose is only one determinant of
its pharmacological effect.
The combination of patient- and drug-related influences
on pharmacokinetics can become significant where a drug has
a narrow therapeutic range (risking toxicity), or requires time
above a minimum plasma concentration (for some antibi-
otics). Drugs not usually dosed on a milligrams per kilogram
body weight basis may require adjustment to account for the
effects of high or low weights (such as the recommended
reduction in the dose of paracetamol for patients with a TBW
<50 kg).
Table 3 Summary of changes in body composition with associated pharmacokinetic effects in obesity and malnutrition
Physiological variable Change in obesity Change in malnutrition
Total body water Increased Increased
Fat mass Increased Reduced
LBW Increased Reduced
Plasma proteins Increased Reduced
Cardiac output Increased Reduced
Pharmacokinetics at extremes of body weight
Several measures based on weight, height, and sex can be
used to calculate drug dosage (Table 2).7e10 Those, such as
TBW, fail to account for some changes in compartment size,
and therefore, derived indices approximating to compartment
size (such as IBW) or incorporating a correction for drug dis-
tribution (ABW) is preferable, especially where drug concen-
tration is critical. The distribution and metabolism of adipose
tissue are different in males and females; hence, some mea-
sures have sex differences.
Another approach is to adjust doses according to LBW,
which correlates well with drug clearance. In the non-obese,
the TBW approximates to LBW, so is often used without
adjustment. However, with increasing weight, the relative
proportion of FW increases significantly, so the LBW is much
less than the TBW (Fig. 1). In obese patients, it is often pref-
erable to use a measure of LBW, either assuming distribution
to lean tissues only (IBW), or to some of the additional fatty
mass (ABW), to account for drug lipid solubility. The predicted
normal weight (PNWT) corrects for the additional adipose
tissue, and takes into account height, weight, and sex. The
PBW is derived from the early Acute Respiratory Distress
Syndrome Network (ARDSNet) studies as a value to normalise
lung size to weight for calculating ventilatory requirements. It
includes a calculation of lean body mass, with an estimation
of the additional adipose tissue expected in the non-obese
individual, and is equivalent to the IBW or LBW. Neither
PNWT nor PBW has a role in drug dosing at present.
In summary, the TBW is used where absolute plasma
concentration is less important, and for drugs with a wide
therapeutic window (e.g. succinylcholine) with a risk of
overdosing hydrophilic drugs and underdosing hydrophobic
drugs. The lean body mass approximates to the distribution of
hydrophilic drugs and is best suited to their dosing (e.g. atra-
curium). The ABW is used for drugs with a narrow therapeutic
window, where the effects of lipid distribution may signifi-
cantly affect toxicity (e.g. gentamicin).
Pharmacokinetic consequence
Increased VD for water-soluble drugs
Increased dose in the obese to account for increased VD
Increased clearance in obese patients
Increased plasma protein binding in obese patients
Increased clearance in obese patients
BJA Education - Volume 18, Number 12, 2018 367
Pharmacokinetics at extremes of body weight
Pharmacokinetic changes at extremes of
weight
Absorption and distribution
Gastrointestinal function is largely preserved in the obese
with no significant differences in absorption or first-pass
metabolism. However, in the low-body-weight patient, espe-
cially those who are malnourished, gastrointestinal absorp-
tion is reduced, which may be because of underlying
malabsorption or as a consequence of refeeding syndrome.
The pharmacokinetic changes in drug distribution in the
obese and malnourished are influenced by changes in the size
and composition of tissue compartments and plasma protein
binding. Increased peripheral compartment volumes can
exacerbate drug sequestration within poorly perfused tissues
in the obese; an example is the delayed offset of fentanyl after
prolonged infusion because of saturation of poorly perfused
peripheral compartments.14 In the malnourished, the
increased total body water, reduced fat and lean masses, and
reduction in protein synthesis result in an increased free
fraction and VD of many drugs.
Metabolism
Drug metabolism depends on the site (hepatic, renal, and other
sites), extraction ratio, and drug delivery. In obesity, cardiac
output and hepatic and renal blood flow are all increased, so
drug delivery for metabolism in these organs is greater.
Therefore, the clearance and metabolism of flow-limited drugs
with a high extraction ratio (e.g. propofol, morphine, and ke-
tamine) are increased. Conversely, metabolic pathways may
be inhibited by the effects of fatty liver disease or coexistent
chronic kidney disease, or increased because of the effects of
other medications, alcohol, or smoking. The effects of obesity
on hepatic metabolism are inconsistent.
In extreme low-body-weight states, catabolism causes a
loss of LBW and adipose tissue, accompanied by reduced al-
bumin and total protein. The net result is a reduced resting
metabolic rate, glomerular filtration rate (GFR), and protein
binding. Reduced protein binding increases the fraction of
unbound drug available for hepatic metabolism. Therefore,
for drugs with a high extraction ratio, metabolism is relatively
unaffected, whereas for those with a low extraction ratio, the
higher free concentration may exceed the capacity for hepatic
metabolism, resulting in higher plasma concentrations, a
delayed offset, or prolonged terminal elimination.
Elimination and clearance
Clearance of drugs has been shown to correlate directly with
LBW, which increases in obese states, and is reduced in the
underweight because of catabolism. The increase in cardiac
output related to obesity increases the GFR. In malnutrition,
the GFR is relatively well preserved until the late stages.
Specific examples in anaesthesia
This section describes commonly used drugs in anaesthesia
and critical care. I.V. anaesthetic agents, neuromuscular
blocking drugs, local anaesthetics, and volatile agents are
used to illustrate the general principles and differences be-
tween drugs (see Supplementary Table 1). For other drugs not
discussed here, the same principles apply. Drugs should be
dosed with caution where they have a narrow therapeutic
368 BJA Education - Volume 18, Number 12, 2018
window (e.g. gentamicin and vancomycin), and therapeutic
drug monitoring is used where an assay is available. The
interested reader is directed to sources from the UK Clinical
Pharmacy Association, the Association of Anaesthetists, and
the British National Formulary; these provide information on
a wider range of drugs, the details of which are outside the
scope of this paper.15e17
I.V. anaesthetic agents
The effect of an i.v. anaesthetic agent is determined by its
effect-site concentration, which in turn depends on the initial
dose, VD, and lipid solubility. Offset of clinical effect is deter-
mined by redistribution, which reduces the effect-site con-
centration. Cardiac output is the most important determinant
of the onset and offset of i.v. anaesthetic agents; this corre-
lates with LBW.
As both cardiac output and VD are increased in obesity,
predictably, a higher bolus dose is required to achieve a given
effect. The increased clearance and redistribution are pro-
portional to LBW; therefore, LBW is recommended for use in
bolus dosing the obese patient, and is supported in studies of
propofol in obese patients.18 Studies examining the pharma-
cokinetics of anaesthetic agents in malnutrition are limited,
but there is some evidence of enhanced effects of propofol for
a given dose, as predicted by the reduced central VD.19
Where TIVA is used, the available models are all based on
assumptions from the normal-weight population, but esti-
mate the effect-site and plasma concentrations differently. Of
the common TIVA models, none of the Marsh, Schnider, or
Minto models are validated at extremes of weight; all require
adjustment and careful titration.
Target-controlled infusion (TCI) propofol is commonly
infused using the Marsh and Schnider models. The former is
based solely on total weight and may cause overdosing unless
a weight adjusted to IBW is input. The Schnider model uses
age, height, weight, and sex to derive compartment sizes, and
calculates a keo value (the rate constant for equilibration be-
tween plasma and effect-site concentrations) for individual
patients; this results in lesser degrees of overshoot and car-
diovascular instability. The Schnider model assumes a fixed
central compartment size, whereas the Marsh model tailors
this to patient’s weight, causing significant differences be-
tween the models for doses to induce anaesthesia. Apparent
differences in the calculated effect and plasma concentrations
are less significant when dosing for prolonged infusions.
The Schnider model calculates the LBW from the TBW
using James’s formula. When the Schnider model is used, the
anaesthetist inputs the patient’s TBW, but should be aware
that the internal algorithm is actually based on a calculated
LBW. Conversely, the Marsh model uses no correction, so the
LBW should be entered directly. However, both the Schnider
and Marsh models become inaccurate at a BMI >42 kg m2 for
males and >37 kg m2 for females. Hence, an alternative
approach, if using the Marsh model, is to use Servin’s formula
[IBWþ0.4(TBWeIBW)]; this has been validated for propofol
infusions in obese individuals. Servin’s formula adjusts the
IBW to account for the distribution of lipophilic drug into
some of the excess fatty tissue, but the overall dose is
increased compared with using the calculated LBW or IBW
without adjustment. The Servin adjustment results in higher
plasma concentrations, and this could cause exaggerated
cardiovascular effects in the unfit, elderly, or compromised
patient. These models have not been evaluated in low-body-

weight states; the Schnider model administers less propofol
for a given effect-site concentration and may be more
appropriate for underweight patients. However, the use of
TIVA at extremes of weight, regardless of model, requires
caution, and depth of anaesthesia monitoring is recom-
mended to prevent awareness and haemodynamic instability.
Opioids
Fentanyl is highly lipid soluble with a large VD, and its actions
are dose dependent. After a bolus, it has a rapid onset and
offset because of redistribution into peripheral tissues, and an
increased clearance in obesity.20 However, high lipid solubility
and VD cause significant accumulation in peripheral tissues
after high doses, repeated boluses, or an infusion, resulting in
prolonged elimination half-life, context-sensitive half-time
and delayed offset of clinical effect.
The offset of alfentanil also increases after multiple doses
or prolonged infusions, although this is related to its low
intrinsic clearance. After bolus doses, the plasma concentra-
tion of alfentanil should be reduced because of increased
cardiac output.21 In general, the context-sensitive half-time of
less lipid-soluble drugs should be lower than that of more
soluble drugs in obesity, because there is a reduced peripheral
accumulation, but limited data are available.
Remifentanil differs in its pharmacokinetics, as it un-
dergoes extensive and rapid tissue metabolism. Studies of the
pharmacokinetics of remifentanil in the obese have shown
that dosing by TBW can produce cardiovascular depression,
and remifentanil dosing should be calculated using LBW.22 For
TCI, remifentanil is modelled by the Minto model, which uses
weight, height, and age, and corrects to LBW. In all patients,
cautious titration is advisable.
Morphine is a classical opioid with a moderate onset and a
slow offset of action. Its metabolites include the active com-
pound morphine-6-gluconuride. The obese are at risk from
opioid-related respiratory depression because of coexistent
obstructive sleep apnoea and the risks of accumulation of
both morphine and its active metabolite. This necessitates
dosing by LBW and cautious titration and monitoring. Codeine
is metabolised to morphine and presents similar risks of res-
piratory depression, particularly in those with obstructive
sleep apnoea, further complicated by pharmacogenetic vari-
ations in metabolism to its active form.
Tramadol is an atypical opioid receptor agonist that also
inhibits noradrenaline uptake. As a relatively weak opioid
agonist, the risks of respiratory depression are theoretically
lower. However, the active metabolite, O-desmethyltramadol,
can cause significant respiratory compromise, and careful
monitoring is required. There are no studies of the pharma-
cokinetics of tramadol in the obese.
Neuromuscular blocking agents
The metabolism of succinylcholine by plasma pseudocholin-
esterase is largely independent of organ function. However,
reduced pseudocholinesterase caused by hepatic dysfunction
may slow metabolism. Therefore, in the obese patient, where
LBW, FW, and plasma volume increase, dosing by TBW en-
sures that an adequate dose is given, accounts for increased
pseudocholinesterase activity, and ensures optimal intuba-
tion conditions.23
The non-depolarising neuromuscular blocking agents
(NMBAs) are polar molecules that typically have a small VD
Pharmacokinetics at extremes of body weight
and undergo hepatic and renal metabolism. The rate of
metabolism is related to underlying LBW, and this is therefore
the recommended dosing scaler. This is supported by studies
showing that the duration of action for both ester and ami-
nosteroid NMBAs is significantly prolonged where TBW is
used for dosing in obesity.24 In the presence of malnutrition,
there is a risk of pseudocholinesterase deficiency and liver
damage with the potential for prolonged neuromuscular block
with succinylcholine.
There are few data on sugammadex in the obese. Chelation
of a drug distributing largely within the extracellular
compartment predicts that dosing by IBW is appropriate. A
weight-based study of sugammadex demonstrated that
dosing by IBWþ40% (an ABW, accounting for some distribu-
tion to fatty tissues) achieved an optimal time to reversal.25
Importantly, there was no failure of reversal or re-paralysis
when dosing at IBW, IBWþ20%, IBWþ40%, or TBW.
Local anaesthetics
The distribution and binding of local anaesthetics are affected
by nutritional state; increased a-acid glycoprotein may reduce
the free fraction of local anaesthetics and increase dose re-
quirements for nerve blocks in obesity, and central neuraxial
block can be unpredictable because of the physical effects of
obesity on the epidural space. In general, dosing by LBW is
recommended, although guidelines vary (see Supplementary
Table 1).16
Volatile anaesthetic agents
The effect-site concentration of volatile agents depends on
pulmonary uptake, fraction of inspired anaesthetic agent,
and cardiac output. In the obese, functional residual capacity
(FRC) is reduced, cardiac output is increased, and the poorly
vascularised peripheral compartment is increased in size.
Predictably, therefore, the increased pulmonary uptake
(reduced FRC) is offset by prolonged equilibration (increased
cardiac output). Moreover, the effects of an increased pe-
ripheral compartment are mitigated by its relatively poor
vascularity. For prolonged procedures, lipid-soluble agents
may accumulate and have a prolonged offset time, but in
practical use and for short procedures, there is little differ-
ence between the obese and non-obese.26 Studies in malnu-
trition are limited.
Summary
Drug dosing at extremes of body weight is challenging, and
traditional methods using body weight or derived measures
may lead to under- or overdosing and toxicity. Drugs typi-
cally given using a fixed dosing regimen may require dose
adjustment at extremes of weight to account for changes in
size, composition, and concomitant pathology. However, in
the absence of measures to quantify compartment size,
composition, and metabolism, clinicians should rely on IBW,
TBW, and ABW. In general, IBW is the most appropriate for
calculating dose, as it approximates clearance and meta-
bolism, reducing the potential for overdose and toxicity.
However, where there is a narrow therapeutic index, drugs
should be dosed according to renal and hepatic function, and
adjusted according to therapeutic levels (e.g. gentamicin) or
clinical effect (e.g. i.v. anaesthetics and remifentanil). This
area is complicated by a lack of evidence, as many
BJA Education - Volume 18, Number 12, 2018 369
Pharmacokinetics at extremes of body weight
pharmacokinetic studies have specifically excluded those at
high or low body weights.
Declaration of interest
J.P.T. is the current Editor-in-Chief of BJA Education. This paper
was handled by other members of the editorial board; he had
no part in the reviewing process or in the decision to accept it
for publication. C.P.H. has no declaration of interest.
Supplementary material
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.bjae.2018.09.001.
MCQs
The associated MCQs (to support CME/CPD activity) will be
accessible at www.bjaed.org/cme/home by subscribers to BJA
Education.
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