Download Drugs and sex differences: a review of drugs relating to anaesthesia.

British Journal of Anaesthesia 82 (2): 255–65 (1999)
REVIEW ARTICLE
Drugs and sex differences: a review of drugs relating to
anaesthesia
G. K. Ciccone1 and A. Holdcroft*
Department of Anaesthetics and Intensive Care, Imperial College of Science, Technology and Medicine,
Hammersmith Hospital, London W12 0HS, UK
1Present address: Department of Anaesthesia, Queen Elizabeth, Queen Mother Hospital, St Peter’s Road,
Margate, Kent CT9 4AN, UK
*To whom correspondence should be addressed
Br J Anaesth 1999; 82: 255–65
Keywords: sex factors; complications, drug effects; pharmacokinetics, anaesthetics; pharmacodynamics
Pharmacokinetic data are subject to considerable interindividual variation. This variation can be the result of age,
genetic constitution, disease state, chemical exposure and
the use of alcohol and tobacco. Sex as a genetic component
has received little attention from clinical pharmacologists,
yet headlines of ‘Women get greater pain relief than men’
in the British Medical Journal65 was soon followed by
‘Women recover faster than men from anaesthesia’ in the
Lancet.56 Over the years an awareness has developed that
in pharmacological studies the results from women should
be analysed separately from men. This has arisen not only
from sex differences determined by research into cellular
mechanisms such as opioid receptor function and the
genetics of cytochrome enzyme systems, but also from
clinical demands to investigate drugs for the treatment of
AIDS which have a potential for teratogenic effects in
childbearing women. For many years there has been a
paternalistic policy to exclude many women from participating in new drug trials because of fears of teratogenic effects.
This is still the situation in the UK and Europe. However,
access to contraception and pregnancy tests allows women
to be included in all phases of clinical trials. In 1993, the
Food and Drug Administration in the USA issued guidelines
recommending the positive enrolment of women in all
phases of drug testing. Even so, since then 25% of studies
have excluded women of childbearing age, solely because
they could get pregnant,48 but this undermines the right of
women to enter studies and presupposes a lack of compliance with contraception. However, a secondary anxiety has
emerged, that a women’s hormone cycles could interfere
with the metabolism and efficacy of some treatments. Few
pharmacokinetic studies in women make reference to the
phase of the menstrual cycle, although the use of oral
contraceptives is often documented.
There are clear physical differences between men and
women (Table 1) which can modify pharmacokinetic and
pharmacodynamic activity. One example is that cardiac
inotropic drugs are administered on a weight basis; women
on average have a lower range of body weight than men
and thus in men, by virtue of a larger body mass, there is
a larger population of adrenergic receptors. Another example
is the volume of distribution of a highly lipophilic drug,
such as diazepam, where women have a significantly greater
mean volume of distribution than men (1.28 compared with
1.0 litre kg–1).95 The physical factors which are responsible
for such sex differences are called sex-dependent effects.
Studies investigating sex-dependent effects would find no
difference in drug metabolism when data are corrected for
age and weight, whereas sex differences persist if sexspecific effects are significant. Sex-specific effects can be
measured either in relation to endogenous hormone production, such as cyclical reproductive changes (menstrual
cycle and pregnancy) or where exogenous hormones are
administered, such as oral contraceptives, hormone replacement therapy or supplementation to reduce tumour growth
of hormonal-dependent malignancies. In addition, there are
several steroid compounds available for misuse by athletes
which may also produce alterations in drug disposition.
Table 2 summarizes sex-specific and sex-dependent factors.
References only to the pharmacological effects of therapeutic sex steroid hormones will be made throughout
this review.
In anaesthesia, our preoperative assessment includes
prescribed medications and allergies to drugs. We also
consider factors, either directly or indirectly, which may
© British Journal of Anaesthesia
Ciccone and Holdcroft
Table 1 Typical body composition differences between average young men
and women
Water
Fat
Solids
Lean body mass (fat free)
Energy expenditure at rest
Male (70 kg)
Female (55 kg)
43 kg (61%)
11 kg (16%)
16 kg (23%)
59 kg (84%)
4.5 kJ min–1
26 kg (50%)
14 kg (25%)
15 kg (25%)
41 kg (75%)
3.8 kJ min–1
Table 3 Relative effect of sex hormones during the menstrual cycle (15
baseline; 11115maximum)
Follicular phase Ovulation
Approximate timing
Days 1–14
(day 15onset of menstruation)
Oestrogen
1 → 111
Follicle stimulating hormone 1
Luteinizing hormone
1
Progesterone
1
Testosterone
1
Luteal phase
Day 14
Days 15–28
1111
1111
1111
11
1111
11
1
1
1111
1
Table 2 Characteristics of sex-dependent and sex-specific drug effects
Sex-dependent
Sex-specific
Weight
Height
Basal metabolic rate
Body fat
Muscle mass
Receptor responses
Cyclical variation
Neurotransmitter differences
Cytochrome enzyme changes
Sex hormone induced
influence responses to drugs, such as age, genetic history,
metabolic phenotype, body fat content and body size, and
the general disease state which can alter drug metabolism
and excretion. When we observe such factors, appropriate
adjustments can be made in dose, monitoring and other
aspects of drug administration which we consider could
improve our patient’s outcome. For example, in a study of
25 981 patients during phase IV drug trials of propofol,
male sex was a significant factor for prolonged time to
awakening after anaesthesia.5 In addition, the report of a
significantly faster time to open eyes after propofol in
women than men (mean 7 (SD 5) min (n568) and 13 (10)
min (n538), respectively) even when controlled for weight
differences, suggests that sex should be considered in the
evaluation of anaesthetic outcome studies.29
It is reported that women have a significantly higher
incidence (two-fold) than men of adverse events to medications.49 This difference may arise simply because drug
doses are not weight-controlled and therefore women are
generally receiving a larger dose per kilogram of body
weight. Adverse reactions also include anaphylactic reactions. These are more common in women and the cause of
this sex-related effect is not clearly understood. This review
considers some of the potential pharmacokinetic and
pharmacodynamic differences between men and women
and the clinical manifestations of sex hormone-related
modifications of drug activity.
Sex steroid hormone effects
Table 3 shows the relative concentrations of sex hormones
during the menstrual cycle. The physiological effects of
sex hormones may manifest through: (1) sex-dependent
effects on body structure such as muscle mass; (2) hormones
themselves having direct time-related activity which is
either (a) genomic (with a delay in effect, for example
alterations in heptocyte CYP450 enzyme systems) or (b)
non-genomic (with a rapid effect, for example direct activity
on receptors such as progestogens acting on GABAA
receptors, mediating sedation); or indirectly via other mechanisms such as alterations in endogenous opioid concentrations; (3) reproductive events such as pregnancy and
lactation which, in addition to hormonal effects, have
associated bodily changes; and (4) other time-related events
such as age or cyclical hormone changes (e.g. menstrual
cycle).
Sex-related differences in drug metabolism have been
known since the 1930s through studies of steroid hormone
activity in rats.95 For example, male rats have significantly
higher concentrations of cytochrome P450 isoenzyme
(CYP3A) than females (yet they are most frequently used
in drug toxicity tests).50 Although a similar isoenzyme
variability is not present in humans, metabolic differences
between the sexes have been discovered and it has been
postulated that their development may be comparable with
the process determined in animals. In the development of
rat metabolic pathways, it is postulated that sex hormones
such as androgens can neonatally programme metabolic
pathways which later in life are not under the influence of
this hormone. It is not only the plasma concentration of the
controlling hormones but also their patterns of temporal
release which may determine their activity. There is often
no direct relationship between a hormone blood concentration and the measured response. In fact, the quality of sex
hormone effects is difficult to assess because they have
modulatory effects. They work as co-factors with a role
that is not dominant and they set up processes which change
physiological systems. What matters is the right mixture of
hormones together with pretreatment by the hormone milieu.
The physiological effects are almost always mild but when
hormones are given exogenously, such as in birth control,
hormone replacement therapy (HRT) or for cancer treatment,
their effects may become significant.
The interpretation of such sex- and hormone-related
effects can be illustrated by a log dose–response curve
where, in its middle portion, there is a steep curve, but at
the extremes the curve is flattened. It is possible for example
that sedative effects of progesterone affect the dose–
response curves of drugs during the menstrual cycle by
effects on the ED50 or at the extremes (i.e. ED10 and ED95).
In this latter case, these alterations may be apparent only
in some of the population, but for an individual patient
these effects would be important. If a specific dose–response
curve is considered for a drug such as morphine, there are
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both age- and sex-related changes in animals. As a rat ages,
a decrease in binding, affinity and concentration of opioid
receptors has been observed.68 The ED50 for morphine
dose–response function based on the tail flick test in rats
was found to be similar in young male and female rats, but
in more mature rats, significant sex differences became
apparent, with females demonstrating less antinociceptive
activity to morphine.44 A similar sex difference occurred
with visceral stimulation, such that after i.p. injection of
hypertonic saline, analgesia was produced with significantly
less morphine in male than female rats.6 Interestingly, the
increased sensitivity to morphine observed in males was
not present in ovariectomized females, so lack of oestrogens
was not responsible for the analgesia.
Unresolved questions include which of the gonadal steroids is involved, and what is their locus and mechanism of
action? What is certain is that other opioid peptides may
not demonstrate similar effects.51 This is partly because
the metabolism of morphine differs from other peptides.
Morphine is conjugated in part to morphine-6-glucuronide
which has intrinsic opioid activity77 whereas other opioid
peptides are degraded by hydrolytic enzymes such as
aminopeptidases, carboxypeptidases and endopeptidases.
Pharmacokinetics
In the past there has been an under-representation of women
in phase 1 studies during which the pharmacokinetics of
new drugs are evaluated in clinical trials. The effect
of changing hormonal influence of the menstrual cycle,
pregnancy, oral contraceptive therapy, the menopause and
HRT have seldom been considered. This has resulted in a
paucity of information on the pharmacology of drugs in
females compared with males, which persists even in
situations with potential sex-specific differences in drug
activity. Even with modern molecular biology techniques,
the pharmacokinetic influence of the menstrual cycle, pregnancy, oral contraception and HRT are poorly understood.
The combined oestrogen–progestogen oral contraceptive
steroids contain oestrogen in doses of 20 µg (low strength)
to 50 µg (high strength). They depress follicle stimulating
hormone secretion, inhibit ovulation and reduce secretion
of progesterone during a cycle. Depending on the dose
used, they may inhibit or induce hepatic metabolism of
other drugs or steroids. Oral contraceptives reduce plasma
albumin by 3–12% and increase α1 acid glycoprotein. They
can prolong the plasma half-life of pethidine12 and act by
reducing cytochrome metabolism by as much as 30%,
particularly in activating CYP3A4, and increasing the concentration of glucuronosyl transferase so that drugs such as
temazepam and paracetamol are conjugated more rapidly
(in the case of paracetamol up to 49% more).70
The potential pharmacokinetic differences between men
and women include drug absorption, protein binding, volume of distribution and metabolism. 30 48
Drug absorption
Drug absorption depends generally on the lipid solubility
of a particular agent, pKa and molecular weight, in addition
to the patient’s gastrointestinal function. The most commonly known example of sex differences in drug pharmacokinetics is that of alcohol, where the enzyme alcohol
dehydrogenase in the gastric mucosa is less active in females
compared with males.21 This leads to higher peak blood
alcohol concentrations and faster absorption in females
than males.
Changes in gastric acid secretion and stomach emptying
may explain the cyclical variations in peak salicylate
concentrations, with the lowest concentrations mid-cycle
when gastric emptying time is shortest.69 Studies of sex
differences in aspirin absorption have used different oral
doses and time measures. An oral dose of aspirin 1 g was
absorbed more rapidly in females than in males, as measured
by mean absorption times (16.4 and 21.3 min, respectively)1
but lower doses of 9 mg kg–1 produced a significantly
shorter time to peak plasma salicylate concentrations in
men than women.69 In a study of a fixed dose of aspirin
600 mg, a significantly greater plasma acetyl salicylic
acid concentration in females compared with males was
considered not to be associated with changes in gastric
activity but with metabolic rate,40 while pharmacokinetic
variables such as clearance and volume of distribution
based on weight-related values were similar. Where acute
administration of an oral drug is important, sex-related
differences in time of drug onset become important and
further investigation of oral analgesic drugs is required.
Another sex-specific difference which has been verified
repeatedly30 is intestinal transit times. A delay in transit of
a standardized meal has been observed in the luteal phase
of the menstrual cycle,92 during pregnancy and in females
taking exogenous sex hormones. Although fluctuations in
bowel habits during the menstrual cycle have been reported
by patients, almost nothing is known about the absorption
and action of drugs at different times of the menstrual cycle.
Drug binding
Protein binding is not a significant cause of differences in
drug activity between men and women. Most drugs bind to
albumin which shows no major influences from altered
concentrations of circulating sex hormones.91 There is one
potential consideration; concentrations of α1 acid glycoprotein are slightly lower in women than in men because
of the influence of oestrogen. Sex differences have been
reported for protein binding of diazepam and lidocaine,79
but this has little clinical significance unless women are
taking oral contraceptives when the free portion of lidocaine
can increase, from a baseline of 32% to 34% in males and
to 37% in females. During pregnancy, similar changes in
drug binding occur as with oral contraceptives and this
can change the free fraction of lidocaine, bupivacaine,
benzodiazepines and fentanyl.97
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Ciccone and Holdcroft
Binding of insulin to red and white blood cells varies
with concentrations of oestrogen and progesterone. This
has been studied during the menstrual cycle and the occurrence of an exacerbation of hyperglycaemia during the
luteal phase of the cycle in some women with insulindependent diabetes mellitus may be of clinical relevance to
the diabetic care of women during anaesthesia.94
Volume of distribution
Changes in volume of distribution have not been demonstrated to affect sex differences in drug activity, even though
changes in body composition would appear to be relevant,
particularly in relation to highly lipophilic compounds. Men
are heavier than women, mainly because of a larger muscle
mass, and females have a larger proportion of fat. Drugs
with a higher affinity for adipose tissue have a larger
initial volume of distribution and lower serum/plasma
concentration. However, with long-term administration, the
fatty tissue concentration increases and this potentially can
lead to increased tissue load with possible toxic effects if
the dose is not adjusted, and a prolonged half-life and
increased serum/plasma concentrations on drug withdrawal.
A further source of variability may be the physiological
changes that occur during the menstrual cycle with fluctuations in water and electrolyte balance. The luteal and
follicular phases differ in their plasma composition. Premenstrually, in the late luteal phase, there is retention of
water and dilutional hyponatraemia with tissue changes in
fluid load.
Renal excretion
Renal excretion is affected by body weight because first,
glomerular filtration is proportional to weight and second,
men produce more creatinine than women as they have a
relatively larger muscle mass; hence sex is taken into
consideration when estimating creatinine clearance.10 A
well publicized example of changes in glomerular function
is the effect on antiepileptic drugs in pregnancy, where
increased excretion requires dose adjustment.14 Tubular
secretion and reabsorption have seldom been investigated
with respect to sex. Quinine and quinidine inhibit renal
clearance of the antiviral agent amantidine in males but not
in females.24 It is not known what significance this has to
other drugs.
Drug metabolism
Drug metabolism and the variety of differences between
men and women have been investigated more extensively
than any other area of pharmacokinetics. There are general
metabolic effects of sex hormones on metabolic rate,18 such
that in a study of 46 women, those using oral contraceptives
(n524) had metabolic rates 5% higher than controls and
this significant difference persisted after exclusion of women
who exercised regularly.
Some drugs are cleared rapidly from plasma by esterases.
In anaesthesia, remifentanil is most well known for its
esterase metabolism. It has been studied after infusion in
female and male volunteers and many co-variates analysed,
such as weight, sex, lean body mass and body surface
area.72 The end-point for clinical effectiveness was EEG
changes, as measured by spectral edge frequency. High
infusion rates achieved maximum EEG effects in all participants and no sex differences were found. In contrast,
chronic drug administration of a calcium channel blocker
(diltiazem) and an ACE inhibitor (enalapril) in rats resulted
in plasma esterase activities which were very much higher
in female rats than in males.61 Such chronic studies of sex
differences are few and this may have an application for
the longer term treatment of patients in intensive care units.
Sex hormones belong to a group of steroids which act
mainly to influence enzyme activity in hepatocytes. They
determine the type and quantity of enzymes produced by
the cell on an acute and chronic basis.89 The molecular
mechanisms of sex hormone activities act through membrane receptors and second messenger systems. For
example, a hormone binding to its receptor may increase
or decrease the activity of adenylate cyclase and either
increase or decrease the concentration of intracellular cyclicAMP which phosphorylates nuclear (leading to alterations
in gene expression) or non-nuclear proteins. The final effect
on hepatic metabolism is complex, with the potential for
different hormonal concentrations having opposite effects.
In humans, sex differences have been difficult to detect.
Measurement of total clearance of a drug has limitations
for assessing sex differences because it does not differentiate
between the various enzyme systems involved in oxidation,
reduction, hydrolysis, glucuronidation and sulphuration.
Total clearance is affected by other factors such as age and
smoking. It is not surprising that studies which have
investigated potential sex differences have found conflicting
results because control for these factors was not included.
Hormonal changes during the menstrual cycle may also
contribute to differences in plasma drug concentration.
Failure to consider the effect of the menstrual cycle or the
choice of differing cycle times during drug trials have
probably confounded the results of pharmacokinetic investigations.
Increased knowledge of the isoenzymes involved in drug
metabolism may enable the influence of sex hormone
activity on drug metabolism to be determined. Twelve
cytochrome P450 gene families have been identified in
humans74: cytochrome P450 1, 2 and 3 families (CYP1,
CYP2 and CYP3) encode the enzymes involved in the
majority of all drug biotransformations and the CYP3A4 is
the most abundantly expressed isoform. The remaining
cytochrome P450 families are important in the metabolism
of endogenous compounds such as steroids and fatty acids.93
Improvement in analytical methodology has allowed observations to be made about the role of sex and related steroid
hormones on some isoenzymes.
There are some well researched effects of sex differences
258
Drugs and sex differences
in hepatic metabolism of drugs, for example caffeine.
Several drug metabolizing enzymes systems are involved
in caffeine metabolism. After the cytochrome P450
demethylation of caffeine (through the CYP1A2 family),
xanthine oxidase and other enzymes catalyse its further
oxidation. Increased xanthine oxidase activity and decreased
CYP1A2 activity have been reported in females compared
with males after collection of urinary metabolites of caffeine
in 342 volunteers.78 Using a sensitive radiochemical assay
on hepatic tissue from liver biopsies which assayed xanthine
oxidase activity directly from 189 biopsies,34 a 21% increase
in activity was measured in men compared with women,
but a group of patients were identified with low xanthine
oxidase activity. In addition, the half-life of caffeine varies
during the female menstrual cycle, with a decrease around
ovulation.55 Caffeine metabolism can be used as an indicator
for the oxidation of other drugs, for example azathioprine,
which are oxidized by xanthine oxidase.
A decrease in oxidation of benzodiazepines via the
CYP450 enzyme system in females is another accepted sex
variation.32 Enzymatic degradation of benzodiazepines (for
example, chlordiazepoxide, diazepam and desmethydiazepam) which are metabolized by oxidative pathways is
sensitive to both age and sex. This means that metabolic
differences disappear after the menopause. Benzodiazepines,
such as lorazepam, oxazepam and temazepam, which are
dependent on conjugation with glucuronic acid, and those
such as nitrazepam which are reductively metabolized,
are less sensitive to the effects of age and sex.95 Oral
contraceptives decrease the metabolic clearance of
diazepam2 but not other benzodiazepines, such as lorazepam
and oxazepam,3 where they appear to have no effect.
Unfortunately, because of varying study designs (e.g.
oral vs parenteral routes) the potential sex influence of
absorption and first pass metabolism is often conflicting. For
example, theophylline is metabolized by several different
pathways (CYP1A2, CYP3A4 and CYP2D6) and clearance
of the drug has been reported to be faster in young women
than in young men.73 However, it is not known which
pathways determine the sex differences.30 Smoking
increases theophylline metabolism, particularly increasing
the activity of CYP1A isoenzymes. This is more pronounced
in males45 and how much this determines study results is
unclear. In females, results are available which suggest that
the half-life of theophylline varies during the menstrual
cycle, with maximum plasma concentrations observed at
mid-cycle.8 Again, the specific metabolic enzyme pathways
responsible were not defined.
The CYP2 family displays genetic polymorphism but
sex-linked characteristics have not been observed. The
CYP3 family is involved in the metabolism of lidocaine,
erythromycin and midazolam, and is also responsible for
the enzymatic hydroxylation of steroid hormones. There is
substantial evidence which demonstrates that young women
have up to 40% more CYP3A4 activity than men, which
persists during aging.43 The steroids prednisolone and
methylprednisolone are excreted more rapidly by this family
of enzymes than in men.60 66 In young women taking oral
contraceptives, the half-life of prednisolone is significantly
longer than that in women of the same age who are not
taking birth control medication. A similar increase also
occurs in postmenopausal women who are receiving conjugated oestrogens, compared with a female control group.35
Little information is available on the influence of menopausal status and HRT on the CYP3 family.
Some isoenzymes (CYP2 and 3) appear to be male
specific or are regulated by male steroid hormones.93
The metabolic fate of some chiral drugs, for example
mephobarbitol, a barbiturate anticonvulsant drug, is sex
specific.42 The metabolic clearance of the (R)-isomer was
greater in young men than young women when taken
orally. This sex-specific effect was age dependent. (R)mephobarbitol is rapidly and stereoselectively hydroxylated
by CYP2C8 and CYP2C9 whereas (S)-mephobarbitol is
metabolized by other pathways, including N-demethylation.54 To explain these effects it was hypothesized that
the liver of old male rats becomes functionally feminized.23
This may explain why the sex-specific effect is also age
dependent. It is interesting to consider that as more chiral
drugs are introduced into clinical practice to reduce the side
effects of racemic mixtures or to enhance potency, these
specifically designed agents may be metabolized in a more
sex-specific manner.
After biotransformation, some drugs are conjugated with
glucuronides or sulphates to render them more water soluble.
For most drugs this is a second metabolic process, and sexdependent studies are not feasible because the initial CYPmediated hydroxylation is slower than conjugation. The
non-steroidal anti-inflammatory drugs (NSAID) are some
of the most commonly used analgesic agents, and can be
obtained over the counter and by prescription. NSAIDs
such as ibuprofen,33 diflunisal, paracetamol and clofibrinic
acid71 are conjugated primarily in the liver before renal
excretion. Diflunisal63 and paracetamol70 show higher clearances in men than in women. Metabolic clearance by the
three conjugative pathways (phenolic and acyl glucuronide
formation and sulphate conjugation) was increased for
diflusinal and paracetamol not only in men but also in
women receiving oral contraceptives, but significant differences were associated only with the glucuronide pathways.
Paracetamol clearance was 22% greater in males than in
control women but was 49% greater in women using oral
contraceptives. This enzyme induction may have clinical
and toxicological consequences, particularly relating to
surgery with mild to moderate postoperative pain for which
paracetamol is prescribed without consideration of dose in
women of childbearing age taking oral contraceptives.
Another factor in pharmacokinetic studies is whether or
not the drug is administered acutely or by long-term infusion,
and the number of patients studied. An investigation with
few patients may show no sex differences when these
differences are actually present. A study of alfentanil
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Ciccone and Holdcroft
clearance in 20 volunteers and 15 patients, aged 20–72 yr,88
found no sex differences. In a similar size group of 15
males and 21 females, aged 24–79 yr and of similar weight,
total drug clearance was greatest in the youngest women,
decreasing with age up to 50 yr, after which there was no
further age-related decrease in clearance.59 There was no
age-related clearance in total drug clearance in men. This
supports the same authors’ earlier work in female patients
where it was observed that the dose requirements of
alfentanil decreased with increasing age, and this could not
be explained by pharmacokinetic differences.58 Application
of a physiological model of organ weights and blood flows,
corrected for sex differences, to alfentanil kinetics in a
computer simulation failed to demonstrate sex-related
changes.7 Although changes in clearance may not affect
recovery from an acute bolus, the longer term infusion
characteristics may be changed by metabolic activity not
considered in these models. The difference observed
between females and males has been considered to represent
hormonal influences on CYP3A4 metabolism of alfentanil.99
As a result, alfentanil has been used as a probe of activity
of CYP3A4.52 The relevance of these studies to anaesthesia
could be that young women require higher infusion rates
of alfentanil than either older women or men.
Evidence is accumulating for sex-specific effects on
enzyme systems associated with drug metabolism, particularly where steroidal modulation of gene expression may
have immediate activity, such as would occur during the
menstrual cycle or where there may be more long-term
effects on gene expression. There is evidence that the
concentration of sex steroids during prenatal growth can
permanently alter the expression of genes regulating
CYP450 enzyme systems. Esterase activity may also be
regulated by both pre- and postnatal exposure to endogenous
sex steroids. Future work involving specific pathways
involved in the metabolism of drugs and control of gene
expression by sex hormones will clarify this area. It may
also provide a rational basis on which to predict potential
drug interactions before new drugs are introduced into
clinical practice.
Pharmacodynamics
Sex-related effects on pharmacokinetics may result in
increased or decreased bioavailability. This does not explain
pharmacodynamic differences. Those which are of interest
to anaesthetists are drugs acting at GABAA and opioid
receptors, neuromuscular blocking agents and the misuse
of drugs such as cocaine which can have deleterious effects
during anaesthesia.
The complex interaction between sex steroid hormones
and receptors, which is of interest to anaesthetists, can be
illustrated by the GABAA receptor complex where nongenomic, hypnotic and analgesic effects have been demonstrated. For example, the minimum alveolar concentration
of volatile anaesthetic agents changes during pregnancy in
humans27 and has been related to progesterone effects on
the GABAA receptor.15 Progesterone metabolites64 and
synthetic steroid general anaesthetic agents, such as alphaxolone,39 cause hypnosis by interaction at the GABAA
receptor complex. The antinociceptive effects of progesterone metabolites correlate with their binding efficacies at the
GABAA receptor complex.22 In rats, using pain thresholds to
electric foot shock, a combination of 17-beta-oestradiol and
progesterone resulted in a significant increase in pain
thresholds. This analgesia involved a central endogenous
opioid system based on activation of the spinal cord
dynorphin–kappa opioid system.16 These observations were
dependent on the entire pregnancy profile of sex steroid
hormones and were not reproducible with one or other
hormone given alone. Consistent with these findings are
the results that nociceptive activity is sensitive to the phase
of the oestrous cycle. There are a variety of experimental
methods which have observed such changes, including
electrically and heat-induced nociception80 83 and by noxious
stimuli applied to viscera.84 Administration of oestrogen
to oophorectomized women increased endogenous opioid
activity and a progesterone metabolite (medoxyprogesterone) potentiated these effects.86 This suggests that oestrogen can influence nociception but progesterone metabolism
can play a role in nociceptive regulation. In simplistic terms
this could be analogous to switching on a heater at the on–
off switch (oestrogen effect) and then turning up the
thermostat to regulate the amount of heat generated (progesterone effect).
Analgesic agents
In an important and comprehensive study in rats, Cicero,
Nock and Meyer showed that male rats were more sensitive
than female rats to the antinociceptive properties of both
systemically and centrally administered morphine.9 This
was not a function of altered serum concentrations because
there were no sex-related differences in serum concentrations at the time of peak antinociceptive activity. Sex
differences were assessed in three widely different nociceptive tests: tail flick, hot plate and abdominal constriction.
All nociceptive responses were different between the sexes.
The dose–response curves for male and female rats using
the hot plate test are shown in Figure 1 and the reaction
times for the same test in Figure 2. Clear sex differences
in morphine effects are demonstrated. These sex differences
may reflect interactions between sex steroid hormones and
central opioid receptors or a more long-term organizational
effect on the central nervous system during development.
Alternatively, they may be the result of a difference in
metabolism to active metabolites such as morphine-6glucuronide. Well designed studies such as these generate
more questions than they answer.
It has been demonstrated in both rats and humans that
pregnancy and parturition are associated with increased
pain thresholds11 28 in which activation of the spinal
cord dynorphin–kappa opioid system appears to be implic-
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Drugs and sex differences
Fig 1 Dose–response curves after administration of morphine s.c. in rats,
as described by Cicero, Nock and Meyer9 (mean (SEM)). MPE5Maximal
possible effect. (With permission from the Journal of Pharmacology and
Experimental Therapeutics.)
Fig 2 Reaction times of male and female rats after administration of
morphine s.c., measured by Cicero, Nock and Meyer9 (mean (SEM)). Time
0 represents baseline measurements without morphine administration.
Reaction times were measured at the times shown up to 4 h. (With
permission from the Journal of Pharmacology and Experimental
Therapeutics.)
ated.81 82 Clinically, mu opioid agonists do not provide
satisfactory analgesia for the pain of labour.41 75 Gear and
colleagues25 demonstrated a sex difference in the kappa
opioid pentazocine in patients undergoing dental surgery
for extraction of impacted third molars. Changes in pain
intensity were measured for 30 min using visual analogue
scores with baseline scores obtained before opioid administration. Pentazocine produced significantly greater postoperative analgesia in females (n510) than in males (n5
8). In a separate analysis, the analgesic response of female
patients undergoing dental surgery within 10 days of the
onset of menstruation were compared with those undergoing
surgery more than 10 days after its onset. There was no
significant difference between the two groups, although the
numbers were small and the groups too temporally large to
demonstrate a difference. This illustrates the complexities
of analysis of results by phase of the menstrual cycle. An
additional problem is that of consistency in hormonal
concentrations, even at the same time in the cycle, and the
presumption that has to be made is that in previous cycles
hormonal modulation of longer term cellular memory events
has been similar. Other kappa opioids such as nalbuphine
and butorphanol have also been shown by the same group
of workers to provide significantly greater analgesia in
women, although for a shorter duration than men for surgical
removal of third molars.26 The women reported more
pain in the initial postoperative period before the study
commenced. This may be relevant to the overall effectiveness of pain relief. There is further evidence for the
effectiveness of kappa compared with mu opioids in women
from a meta-analysis of eight studies of pain relief in labour
where the mu agonists pethidine and fentanyl were compared
with the kappa agonists butorphanol and nalbuphine for
patient satisfaction and incidence of nausea.37 The kappa
opioids provided similar pain relief to mu opioids but were
associated with greater patient satisfaction and less nausea.
These studies of kappa opioids have various limitations.
None of the so called ‘kappa’ opioids is a specific agonist
and all have mixed activity at opioid receptors. In addition,
there is no explanation for the mechanism for improved
analgesic response when kappa opioids are used in women.
Sex differences in the pharmacokinetic half-life of the
kappa opioids may be a possible explanation; the above
studies25 26 do not examine this issue, but the lack of
sex differences in other pharmacokinetic studies of kappa
agonists do not support this argument.87 96 Another explanation is that male hormones, such as testosterone, may
interact negatively with kappa opioid receptors. Alternatively, female-related hormones such as oestrogen and progestogen may potentiate the action of kappa opioid agonists.
Neuromuscular blocking agents
There is now increasing evidence for sex differences in the
effect of non-depolarizing neuromuscular blocking drugs.
Pharmacodynamic changes in neuromuscular block produced by atracurium using a dose determined by weight have
been measured in both sexes using the plasma concentration
profile and its effect on the electromyographic response of
the first twitch of the train-of-four.76 The rate of equilibration
of the effect site with plasma was greater in female patients,
but the slope of the concentration–response curve was not
significantly affected by sex. Another study, using a fixed
bolus dose of atracurium, demonstrated that the maximum
effect achieved was sex related.17 Cisatracurium did not
demonstrate these effects.90 Sex differences in the doses
of vecuronium required to achieve the same degree of
neuromuscular block revealed in one study that women
required 22% less vecuronium than men,85 and in another,
30% less.98 Furthermore, dose–response curves in men were
found to be significantly shifted to the right, indicating a
decrease in the sensitivity to vecuronium, as measured
mechanomyographically using train-of-four stimulation,
compared with women. When the same dose was adminis-
261
Ciccone and Holdcroft
tered on a weight basis (80 µg kg–1), neuromuscular block
with vecuronium was significantly longer in women than
in men with mean values of 65.9 (SD 20.7) min and 50.6
(16.0) min, respectively. These results can be explained, to
some extent, by physical and metabolic differences between
the sexes, for example a larger dose of neuromuscular
blocking drug is needed when there is less fat and more
muscle. The use of a dose related to weight can only partly
compensate for these differences, but sex is obviously a
factor which influences the pharmacokinetic and pharmacodynamic activity of neuromuscular blocking drugs.
Cocaine
Cocaine is a substance of abuse which can present unwanted
cardiovascular effects during anaesthesia. Few studies of
substance abuse have considered sex differences, but in a
drug abuse research centre the response to intranasal cocaine
administration has been measured using active and placebo
preparations in recreational users.62 In spite of males having
twice the plasma concentrations of females, clinical effects
on the cardiovascular system were similar and the data
suggested that women may be more sensitive than men to
the acute effects of cocaine. Further studies in progress are
confirming these sex differences and have relevance to
anaesthetic management risk.
Adverse drug events
The consequences of sex-related pharmacokinetic and
pharmacodynamic differences may be the apparent reduction or increase in effectiveness of a particular drug or even
an increase in adverse drug events. The World Health
Organization defines an adverse drug reaction as any
noxious, unintended and undesired effect of a drug which
occurs at a dose used in humans for prophylaxis, diagnosis
or therapy.19 Although women receive more drugs than
men, this does not account for women having twice as
many adverse drug reactions as men.36 Women may simply
receive a larger dose per kilogram body weight which can
increase blood concentrations when using a mean dose
regimen. Some of the pharmacokinetic factors outlined
above may result in higher peak drug concentrations both
in blood and tissues, and together these may generate a
greater incidence of pharmacological adverse events. One
exception has been the recent report that male sex has been
implicated as being a risk factor (odds ratio 1.7) for peptic
ulcer complications of NSAID in a large epidemiological
study from Scandinavia.38
A multicentre study in France of drugs and other agents
precipitating anaphylactic shock during anaesthesia assessed
a series of 1585 patients tested over 2 yr for IgE-dependent
anaphylaxis.57 The male:female ratio was 1:3 and the
majority of patients were adults. Neuromuscular blocking
agents were the commonest drugs identified as causing the
reaction, particularly succinylcholine and vecuronium, with
hypnotics, opioids and benzodiazepines being identified in
less than 4% of cases. The safety pharmacokinetics of a
drug are determined during phase 1 and 2 studies, but in
the UK, women of childbearing age have been excluded
from such studies and so the ability to predict adverse
reactions to anaesthetic drugs in women has been lost.
Adverse reactions to anaesthetic drugs are not restricted
to allergic reactions and may be manifest in the incidence
of postoperative side effects. As more information emerges,
sex differences may assume importance in assessing risk
factors for postoperative complications. Of concern is the
influence of opioid drugs on respiration. There are clinical
reports of postoperative respiratory depression after opioid
administration but sex differences are rarely analysed. One
study of sedation in children with fentanyl and midazolam
which observed respiratory events reported that females
were significantly at risk for a decrease in oxygen saturation,
with an odds ratio of 2.4.31 In a recent placebo-controlled
study of young adult volunteers given a hypercapnoeic
mixture of gases after injection of morphine on a dose/
weight basis, women had significantly more depression of
the ventilatory response than men.13 This study should
encourage further research on sex differences in respiratory
depression.
Variations in sex steroid hormone concentrations may
have the potential to influence adverse drug reactions.
During the menstrual cycle they may cause fluctuations in
the enzymes which metabolize drugs. For example, alcohol
dehydrogenase has a reduced activity during the luteal
phase of the menstrual cycle47 resulting in higher plasma
concentrations of alcohol in women. Another example is
in the activities of monoamine oxidase and the hepatic
cytochrome system which may fluctuate with varying concentrations of oestrogens and progesterone.46
Exogenous hormones may also influence drug metabolism
and cause adverse drug reactions. For example, oral contraceptives given to women currently receiving benzodiazepines can potentiate diazepam-induced psychomotor
impairment.20 53 In women using oral contraceptives there
is enhanced metabolism of many drugs affecting pain
management, including antidepressants. Plasma concentrations of the tricyclic antidepressant imipramine have been
found to be so increased in women taking oral contraceptives
that recommendations have been made to reduce its dose
by one-third.4 There is still inadequate information on the
influence of HRT on drug activity in different sexes. Time
of administration of such therapy occurs at the menopause
when the main male/female differences are beginning to
disappear.
The use of drugs at conception and during pregnancy
remains a concern where teratogenic effects in addition to
pharmacokinetic and pharmacodynamic changes may occur.
It is only through research in this complicated area that
our understanding will increase. Practical methods for
determining hormonal concentrations in women will facilitate research. The American Food and Drug Administration
(FDA) guidelines in 1977 excluded women with the capacity
262
Drugs and sex differences
Table 4 Guidelines for the evaluation of sex differences in clinical drug trials
1. Women of childbearing potential should not be excluded from all phases
of clinical drug trials. Precautions must be taken to avoid fetal exposure
to drugs by:
(a) use of reliable contraception
(b) test for pregnancy
(c) use of short-duration studies during or immediately after
menstration
2. Analyse:
(a) effectiveness
(b) dose–response
(c) adverse effects
3. Include both sexes in studies and analyse for:
(a) patient variables (age, sex, race)
(b) physical factors
(c) systemic disorders
(d) concomitant therapy (including hormonal therapies)
(e) smoking/alcohol
4. In women investigate:
(a) menstrual cycle status (postmenopausal)
(b) oestrogen therapies
(c) drug effects on oral contraceptive efficacy
5. If necessary in women, take measures to decrease or adjust for variability
by administering a drug at the same time of the menstrual cycle or study
a large number of subjects
to reproduce from phase 1 and early phase 2 drug studies.67
Women were included in studies only after efficacy of a
compound and animal teratogenicity studies were completed. This has limited the information available on
pharmacokinetics in women. Therefore, it is not surprising
that there is limited information on the possibility of
sex differences regarding dose, efficacy and adverse drug
reactions. The revised FDA guidelines for evaluation of
sex differences in the clinical evaluation of drugs are
summarized in Table 4. The American Food and Drug
Administration have now instituted a policy of including
women in all phases of clinical trials and examining the
pharmacokinetic and pharmacodynamic effects of drugs
during oestrogen supplementation and also the influence of
hormonal changes during the reproductive cycle and in the
menopause. Additional information from post-marketing
surveillance also adds to our knowledge of sex-related
adverse drug reactions, so that gradually more information
will become available to the clinician.
Conclusion
In anaesthesia, we take a drug history which includes sex
hormones. Of these the most commonly used are birth
control hormones and hormone replacement therapies. Do
these drugs make any difference to our anaesthetic management? Does the phase of a women’s menstrual cycle or her
pregnancy interfere with our prescription of drugs or fluids?
Do we consider the increased risks of adverse events in
women? Do we manage our anaesthetic differently when a
male patient is given oestrogens to treat cancer of the
prostate? How do we design clinical trials? Answers to
these questions can only be formulated when clinical studies
provide evidence. In the development of new anaesthetic
drugs, particularly with isomeric forms which may differ
not only in their specificity of pharmacological action but
also in their half-life or clearance, consideration should be
given to their interactions with sex steroid hormones. Before
clinical trials, this process may help to prevent needless drug
adverse events in the more susceptible female population.
As yet there are no absolute differential drug use recommendations for anaesthesia or treatment of pain in male
and female patients. Safe drug use depends on identifying
those factors which may adversely influence pharmacokinetics and pharmacodynamics, particularly if the drug
has a narrow therapeutic range, such as opioids, local
anaesthetics or benzodiazepines. Age and weight are important variables to control when considering studies of sex
differences. It is mainly in the young adult and middle ages
that hormonal modulation of drug effects is most prominent.
Clinical and pharmacological evidence suggests that several
factors should be taken into consideration when prescribing
drugs for a male or female patient. Similar schedules for
regular drug administration for men and women may not
adequately provide optimal drug therapy. In the patient,
where the effectiveness of a drug is not optimal, the
prescriber should be alerted to sex-specific effects in
pharmacokinetics and pharmacodynamics so that a change
in the type or dose of drug to suit the individual patient
can be considered.
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