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British Journal of Anaesthesia82 (2): 25565 (1999)

REVIEW ARTICLE

Drugs and sex differences: a review of drugs relating toanaesthesia

G. K. Ciccone1 and A. Holdcroft*

Department of Anaesthetics and Intensive Care, Imperial College of Science, Technology and Medicine,

Hammersmith Hospital, London W12 0HS, UK1Present address: Department of Anaesthesia, Queen Elizabeth, Queen Mother Hospital, St Peters Road,

Margate, Kent CT9 4AN, UK

*To whom correspondence should be addressed

Br J Anaesth 1999; 82: 25565

Keywords: sex factors; complications, drug effects; pharmacokinetics, anaesthetics; pharmaco-

dynamics

Pharmacokinetic data are subject to considerable inter-

individual 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 theLancet.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 participat-

ing 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 compli-

ance with contraception. However, a secondary anxiety has

emerged, that a womens hormone cycles could interfere

with the metabolism and efficacy of some treatments. Few

pharmacokinetic studies in women make reference to the

British Journal of Anaesthesia

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 isa 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 kg1).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 sex-

specific effects are significant. Sex-specific effects can be

measured either in relation to endogenous hormone produc-

tion, such as cyclical reproductive changes (menstrual

cycle and pregnancy) or where exogenous hormones are

administered, such as oral contraceptives, hormone replace-

ment 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 thera-

peutic 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


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Ciccone and Holdcroft

Table 1 Typical body composition differences between average young men

and women

Mal e ( 70 kg) F emal e ( 55 kg)

Water 43 kg (61%) 26 kg (50%)

Fat 11 kg (16%) 14 kg (25%)

Solids 16 kg (23%) 15 kg (25%)Lean body mass (fat free) 59 kg (84%) 41 kg (75%)

Energy expenditure at rest 4.5 kJ min1 3.8 kJ min1

Table 2 Characteristics of sex-dependent and sex-specific drug effects

Sex-dependent Sex-specific

Weight Receptor responses

Height Cyclical variation

Basal metabolic rate Neurotransmitter differences

Body fat Cytochrome enzyme changes

Muscle mass 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 patients 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 (n68) and 13 (10)

min (n

38), respectively) even when controlled for weightdifferences, 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 medica-

tions.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 reac-

tions. 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-relatedmodifications 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

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Table 3 Relative effect of sex hormones during the menstrual cycle (

baseline; maximum)

Follicular phase Ovulation Luteal phase

Approximate timing Days 114 Day 14 Days 1528

(day 1onset of menstruation)

Oestrogen Follicle stimulating hormone

Luteinizing hormone

Progesterone

Testosterone

receptors, mediating sedation); or indirectlyvia other mech-

anisms such as alterations in endogenous opioid concentra-

tions; (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 ofthis 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 concentra-

tion 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 doseresponse 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 ED50or 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 doseresponse

curve is considered for a drug such as morphine, there are


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Drugs and sex differences

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

doseresponse 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 becameapparent, 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 ster-

oids 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 becausethe 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, preg-

nancy, oral contraception and HRT are poorly understood.

The combined oestrogenprogestogen oral contraceptive

steroids contain oestrogen in doses of 20g (low strength)

to 50 g (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 312% and increase1acid 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 con-

centration 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, vol-

ume of distribution and metabolism. 30 48

257

Drug absorption

Drug absorption depends generally on the lipid solubility

of a particular agent, pKa and molecular weight, in addition

to the patients gastrointestinal function. The most com-

monly known example of sex differences in drug pharmaco-

kinetics 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)1but lower doses of 9 mg kg1 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 toalbumin which shows no major influences from altered

concentrations of circulating sex hormones.91 There is one

potential consideration; concentrations of 1 acid glyco-protein 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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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 occur-

rence of an exacerbation of hyperglycaemia during the

luteal phase of the cycle in some women with insulin-

dependent diabetes mellitus may be of clinical relevance tothe diabetic care of women during anaesthesia.94

Volume of distribution

Changes in volume of distribution have not been demon-

strated 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, thefatty 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 fluctu-

ations in water and electrolyte balance. The luteal and

follicular phases differ in their plasma composition. Pre-

menstrually, 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

(n24) 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.

258

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. Highinfusion rates achieved maximum EEG effects in all partic-

ipants 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 mem-

brane 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 cyclic-

AMP 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 investi-

gations.

Increased knowledge of the isoenzymes involved in drugmetabolism 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 obser-

vations to be made about the role of sex and related steroid

hormones on some isoenzymes.

There are some well researched effects of sex differences


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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 decreasedCYP1A2 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 desmethy-

diazepam) 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 lorazepamand 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 isunclear. 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

259

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 conjug-ated oestrogens, compared with a female control group.35

Little information is available on the influence of meno-

pausal 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-demethyl-

ation.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 sex-

dependent studies are not feasible because the initial CYP-mediated 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 clear-

ances 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 differ-ences 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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clearance in 20 volunteers and 15 patients, aged 2072 yr, 88

found no sex differences. In a similar size group of 15

males and 21 females, aged 2479 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 noage-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, particu-

larly 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 canpermanently 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 non-

genomic, hypnotic and analgesic effects have been demon-

strated. For example, the minimum alveolar concentration

of volatile anaesthetic agents changes during pregnancy in

260

humans27 and has been related to progesterone effects on

the GABAA receptor.15 Progesterone metabolites64 and

synthetic steroid general anaesthetic agents, such as alphax-

olone,39 cause hypnosis by interaction at the GABAAreceptor complex. The antinociceptive effects of progester-

one metabolites correlate with their binding efficacies at theGABAAreceptor 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

dynorphinkappa 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 nociception8083 and by noxious

stimuli applied to viscera.84 Administration of oestrogen

to oophorectomized women increased endogenous opioid

activity and a progesterone metabolite (medoxyproges-

terone) potentiated these effects.86 This suggests that oestro-

gen 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 (proges-

terone effect).

Analgesic agentsIn 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 concentra-

tions at the time of peak antinociceptive activity. Sex

differences were assessed in three widely different nocicep-

tive tests: tail flick, hot plate and abdominal constriction.

All nociceptive responses were different between the sexes.

The doseresponse curves for male and female rats using

the hot plate test are shown in Figure 1 and the reactiontimes 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-6-

glucuronide. 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 dynorphinkappa opioid system appears to be implic-


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Fig 1 Doseresponse curves after administration of morphine s.c. in rats,

as described by Cicero, Nock and Meyer 9 (mean (SEM)). MPEMaximal

possible effect. (With permission from theJournal 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 surgeryfor extraction of impacted third molars. Changes in pain

intensity were measured for 30 min using visual analogue

scores with baseline scores obtained before opioid adminis-

tration. Pentazocine produced significantly greater post-

operative analgesia in females (n10) than in males (n

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

261

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 groupof 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 effect-

iveness 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 explana-

tion is that male hormones, such as testosterone, may

interact negatively with kappa opioid receptors. Alternat-ively, female-related hormones such as oestrogen and pro-

gestogen 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 pro-

duced 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 concentrationresponse 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, doseresponse 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-


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tered on a weight basis (80 g kg1), neuromuscular blockwith 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 neuromuscularblocking 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 pharmaco-

dynamic 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 placebopreparations 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 reduc-

tion or increase in effectiveness of a particular drug or evenan 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 agreater 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

262

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 restrictedto 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 hepaticcytochrome system which may fluctuate with varying con-

centrations of oestrogens and progesterone.46

Exogenous hormones may also influence drug metabolism

and cause adverse drug reactions. For example, oral contra-

ceptives given to women currently receiving benzodiaz-

epines 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 concentra-

tions 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 doseby 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 facilit-

ate research. The American Food and Drug Administration

(FDA) guidelines in 1977 excluded women with the capacity


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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 aftermenstration

2. Analyse:

(a) effectiveness

(b) doseresponse

(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 com-

pleted. 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 aresummarized 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 manage-

ment? Does the phase of a womens 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

263

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 recom-mendations for anaesthesia or treatment of pain in male

and female patients. Safe drug use depends on identifying

those factors which may adversely influence pharmaco-

kinetics and pharmacodynamics, particularly if the drug

has a narrow therapeutic range, such as opioids, local

anaesthetics or benzodiazepines. Age and weight are import-

ant 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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