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Anaesthesia, 2009, 64, pages 179–186 doi:10.1111/j.1365-2044.2008.05686.

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REVIEW ARTICLE
Smoking and anaesthesia: the pharmacological implications
B. P. Sweeney1 and M. Grayling2
1 Consultant Anaesthetist, Poole and Royal Bournemouth Hospitals, Bournemouth, BH7 7DW, UK
2 Consultant Anaesthetist, Royal Devon & Exeter NHS Trust, Exeter, EX2 5DW, UK

Summary
Anaesthetists are generally familiar with the peri-operative implications of cigarette smoking.
Although there are a number of publications dealing with the wider pharmacological implications
of cigarette smoking, the specific interactions which are of direct relevance to anaesthetists are less
well known. This review gives an overview of those interactions which are of clinical relevance to
anaesthetists and provides, where possible, an explanation of the mechanism. Recent improve-
ments in the understanding of biotransformation of drugs, including streamlining of the classifi-
cation of hepatic enzymes has allowed better understanding of drug interactions and enables the
mechanistic prediction of those involving new drugs.
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Correspondence to: Dr B. P. Sweeney
E-mail: bpsween@aol.com
Accepted: 13 July 2008

Cigarette smoke is a highly complex mixture of vaso- recent reductions in the overall number of smokers and
active substances including nicotine, together with a the implementation of smoke-free areas in the UK,
plethora of toxic hydrocarbons some of which are both passive smoking probably contributes up to one-fifth of
irritant and carcinogenic. The peri-operative implications all deaths in the general population aged 20–64 years
of cigarette smoking have been exhaustively dealt with in and around 8000 deaths among people over 65 years of
a number of reviews and are generally well known to age [7]. In the US each year 440 000 people die of a
anaesthetists [1, 2]. Although cigarette smoke is highly smoking-related illness [8]. Smoking-related morbidity is
complex in nature, the literature dealing with the multi-faceted and is related to the wide range of chemicals
pharmacological implications have dealt primarily with inhaled. The characterisation of the constituents of
the effects of nicotine [3]. Recent scientific breakthroughs cigarette smoke together with a comprehensive reclassi-
have, however, provided greater insights into the bio- fication of hepatic metabolic enzymes has led to a better
transformation of many of the other constituents of understanding of how cigarette smoke may interfere
cigarette smoke and elucidated the mechanism of various both with the action and metabolism of a wide range of
drug interactions, many of which are of relevance to commonly used medications. This review deals with both
anaesthesia. This article aims to review the current the implications of hepatic enzyme induction as well as
literature regarding the pharmacological effects, both other unexplained drug interactions such as those
direct and indirect, of cigarette smoking. involving neuromuscular blocking drugs.
Despite a number of government initiatives aimed at
reducing the consumption of tobacco, addiction to
The constituents of tobacco smoke
nicotine remains a significant cause of morbidity both in
the UK and abroad. In 2005 in the United States 24% of Over 4800 individual substances which have been isolated
men and 18% of women were recorded as smokers [4] from cigarette smoke [9, 10]. As well as nicotine and
and in 2006 in the UK 23% of men and 21% of women carbon monoxide, whose pharmacological effects are well
were recorded as smokers [5]. Although there has been an characterised, there are nitrogen oxides, volatile alde-
overall reduction in the prevalence of smoking over the hydes, alkenes and the toxin hydrogen cyanide (see
last 30 years, in some groups, such as high school Table 1). In addition cigarette smoke condensate has been
students, it has increased to around 35% [6]. Despite extensively studied and contains a range of carcinogenic

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B. P. Sweeney and M. Grayling Æ Smoking and anaesthesia Anaesthesia, 2009, 64, pages 179–186
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Table 1 Some of the constituents of cigarette smoke. known as mixed function oxidase enzymes and are
responsible for reactions (mainly oxidation and hydroxyl-
Gaseous portion Particulate portion ation), which alter the existing functional groups to
increase water solubility. The cytochrome P450 (CYP)
Aldehydes (for Acids Insecticides
example, acetaldehyde)
isoenzymes (the name derives from the enzymes’ absorp-
Ammonia Alcohols Lactams tion peak at 450 nm; the letter ‘p’ signifies pigment) are a
Arsenic Aldehydes Lactones family of haemoproteins that are the terminal oxidases of
Benzene Amides Nicotine
Carbon monoxide Brown pigments Nitrosamines
the mixed function oxidase system found on the mem-
Hydrogen cyanide Cadmium Polycyclic aromatic brane of the endoplasmic reticulum [12]. The present
hydrocarbons system of nomenclature for the various CYP iso-enzymes
Nitric oxide Carbohydrates Polyphenols
Nitrogen dioxide Esters Pyridines
employs a three tiered classification based on the
Toluene Imidazoles Vinyl chloride conventions of molecular biology: a numeral and a capital
Toluidine Imides letter designate the amino-acid sequence with a final
number indicating the individual enzyme, for example
CYP3A4 [13]. Italicised lettering signifies the gene which
Table 2 Some of the polycyclic aromatic hydrocarbons found in encodes the enzyme. Presently more than 270 different
cigarette smoke. CYP families have been described across the animal
kingdom, with 18 recorded in mammals [14]. In man
Chrysene Coronene there are 43 subfamilies and 57 individual enzymes each
Fluoranthene Benzofluoranthene
Naphthalene Dibenzanthracene of which is encoded by an individual gene.
Pyrene Ovalene The cytochrome P450 multi-enzyme system can be
Benzoperylene Phenanthrene considered an adaptive response to environmental chal-
Benzpyrene Anthracene
Benzfluoranthene Benzanthracene lenges in that exposure to a toxic or noxious substance or
a chemical challenge results in the expression of enzymes
responsible for the metabolism of the particular toxin.
substances which are known to possess interesting For the most part this is a beneficial response, but it may
pharmacological properties. These substances are collec- also result in the formation of a substance that is either
tively known as polycyclic aromatic hydrocarbons (PAHs) pharmacologically active or even carcinogenic. In man
and are the products of incomplete combustion of organic there are around 30 CYP enzymes which are responsible
matter such as wood, oil, tobacco and coal. Examples of for drug metabolism and these belong to families 1–4. It
these substances include naphthalene, phenanthrene, has been estimated, however, that 90% of drug oxidation
anthracene, benzanthracene, pyrene, benzpyrene and can be attributed to six main enzymes: CYP 1A2, 2C9,
benzfluoranthene (see Table 2). 2C19, 2D6, 2E1 and 3A4 [15]. The most significant CYP
In recent years research has focussed to a large extent isoenzymes in terms of quantity are CYP3A4 and
on the PAHs primarily because of their carcinogenic CYP2D6. CYP3A4 is found not only in the liver but
potential and in particular because they profoundly affect also in the gut wall where it may serve as a primary
the activity of the liver cytochrome P450 enzymes [11]. defence mechanism. The bulk of drugs acting on the
This enzyme system, which is ubiquitous throughout the CNS with the exception of volatile anaesthetic agents are
animal kingdom, has evolved as part of our primary metabolised by this enzyme. Interactions due to cigarette
defence against foreign substances which we may smoke involve primarily the substrates of enzymes
encounter in the environment and which may be CYP1A1, CYP1A2, and CYP2E1. These interactions
potentially harmful. are as a result of enzymatic induction which is due
primarily to the PAHs in cigarette smoke.
The CYP 1A family consists of two enzymes, 1A1 and
Biotransformation of xenobiotics
1A2. CYP1A1 is not significantly expressed in liver. It
All foreign substances which are ingested or inhaled, is found mainly in the lung, mammary glands, placenta
including drugs, pollutants or food contaminants (and and lymphoctyes. It is involved in the inactivation of
collectively referred to as xenobiotics) are broken down procarcinogens and is highly induced by PAHs [16].
by drug metabolising enzymes found mainly in the liver There is a strong association between the activity of
which act by making these substances more water- CYP1A1 and the risk of lung cancer [17].
soluble. Traditionally these enzymes are designated as The process of solubilisation of ingested or inhaled
being either Phase 1 or Phase II enzymes. Phase I xenobiotics is continued by phase II metabolism.
enzymes consist of cytochrome P450 enzymes, previously These reactions involve conjugation reactions occurring

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180 Journal compilation  2008 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2009, 64, pages 179–186 B. P. Sweeney and M. Grayling Æ Smoking and anaesthesia
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primarily in the cytosolic (that part of the cytoplasm regulation of UGT activity. The control of the individual
outside the organelles) fraction of cells. Although it is genes occurs via the interaction of the respective ligand or
usually considered that phase I precedes phase II reactions substrate and a number of intracellular receptors. These
this is not always the case; phase II reactions may precede receptors include the pregnane-X receptor (PXR), the
Phase I if there are polar substrates [18]. The conjugation constitutive androstane receptor (CAR) and the peroxi-
of polar compounds occurs via a number of reactions some proliferator-activated receptor (PPAR) [28]. To
involving sulphotransferases (SULT), N-acetyltransferases date around 24 human UGT genes have been identified
(NAT-1 ⁄ 2), methyl transferases such as thiopurine [29], and are involved in the glucuronidation of a number
methyl transferase (TPMT), glutathione transferase of physiologically important substances including steroid
(GST) and most commonly by glucuronosyl trans- hormones, bile acids, retinoids, fatty acids as well as a
ferases such as uridine-diphospho (UDP) glucuronosyl- number of commonly used drugs including temazepam,
transferases (UDPGT more commonly known as UGT). amitriptyline, valproic acid, NSAIDs and zidovudine [30].
Recently it has been demonstrated that one important
sub-type of this group, the UGT2B7 variant, can be
Enzyme induction and cigarette smoke
induced by PAHs found in cigarette smoke. This may
The molecular mechanism by which a chemical may have implications for the metabolism of morphine and
induce an enzyme has been extensively studied and is more codeine which are partly metabolised by this enzyme
clearly defined with respect to environmental pollutants [31–33].
than with therapeutic drugs [16, 19]. PAHs are potent
inducers of CYP1A1 and 1A2. Induction of CYP1A1
Anaesthetically relevant drugs
involves interaction of the respective chemical or ligand,
in this case the aromatic hydrocarbon, with a hydrophobic The actions of a number of drugs commonly used in
cytosolic receptor, termed the Ah (aromatic hydrocarbon) anaesthesia are modified in smokers, including the neuro-
receptor and translocation of the ligand-receptor complex muscular blocking drugs, opioids and sedatives (see
to the nucleus where it associates with the Ah receptor Table 3). In the case of the volatile agents, there are no
nuclear translocator (Arnt). This AhR-Arnt complex acts clear direct implications in terms of administration, but
as a transcription factor which binds to specific xenobiotic there is some circumstantial evidence that increased
response elements (XREs) that forms part of the promoter metabolism may generate higher levels of potentially
sequence of the respective gene which encodes the toxic metabolites.
enzyme. The de novo synthesis of new protein is then
regulated through the transcription of mRNA [20]. The Opioids
new CYP is completed by the association of haem. The It has been shown consistently that smokers have increased
hepatic effects of PAHs are rapid with induction occurring requirements for opioids postoperatively. In a study of
within 3–6 h with a maximum effect within 24 h. Enzyme morphine requirements after cholecystectomy, Glasson
induction is affected by age, the type of cigarettes and the et al. found that both smoking and alcohol consumption
method of inhalation. Heavy smokers have the greatest significantly influenced the requirement for pethidine and
enzyme induction [21]. morphine [34]. The mechanism underlying this observa-
CYP1A2 is expressed mainly in the liver and is induced tion is, however, poorly understood. It is possible that,
by cigarette smoking, and by the ingestion of some in addition to increased metabolism of substrates, other
foodstuffs such as cruciferous vegetables (such as cabbage, mechanisms may play a role. For example, there may be
Brussel sprouts and kale) and barbecued or charbroiled altered pain thresholds or receptor-mediated effects such
food [22]. Drugs which are known to be metabolised by as pharmacodynamic changes. In the case of morphine,
CYP1A2 include theophylline, imipramine, paracetamol enhanced metabolism due to enzyme induction of UGT
and phenacetin [23]. Alteration in CYP1A2 activity, is unlikely to have any appreciable affect on the bioavail-
for example by smoking, may alter the requirements ability of morphine since its liver clearance is primarily
for theophylline among asthmatics [24] and haloperidol blood-flow dependent.
among psychiatric patients [25]. Caffeine metabolism is The metabolism of morphine is complex and the
also induced by smoking and explains the increased relative activities of the major metabolites have been the
tolerance to caffeine among smokers [26]. CYP2E1 is source of some speculation. In man the major metabolites
induced by PAHs and nicotine [27]. of morphine are morphine-3-glucuronide (M3G) and
UGT is a membrane-bound glycoprotein found mainly morphine-6-glucuronide (M6G) [35]. Nevertheless, UGT
in the endoplasmic reticulum. A number of environ- 2B7 induction increases the amount of the M6G [36].
mental factors apart from cigarette smoke influence the The analgesic properties of M6G were recognised in the

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Journal compilation  2008 The Association of Anaesthetists of Great Britain and Ireland 181
B. P. Sweeney and M. Grayling Æ Smoking and anaesthesia Anaesthesia, 2009, 64, pages 179–186
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Table 3 The effect of smoking on anaesthetically relevant drugs. The relevant enzyme, where known, is given.

Substrate Metabolism Mechanism Effect References

Morphine UDP GT Mechanism unclear Increased dose requirements [34]


Pentazocine Probably CYP1A2 Possibly enzyme induction Increased dose requirements, increased clearance [38, 39]
Dextropropoxyphene Probably CYP1A2 Possibly enzyme induction Increased dose requirements [40, 41]
Codeine UGT CYP2D6 CYP3A4 Enzyme induction Increased clearance, increased glucuronidation [42, 43]
Phenylbutazone CYP1A2 Enzyme induction Increased clearance [51]
Fentanyl CYP3A4 Mechanism unclear Increased requirements, increase in side-effects [47]
Sufentanil CYP3A4 Greater pulmonary uptake [48]
Paracetamol CYP1A2 ⁄ CYP2E1 Enzyme induction Results inconclusive [49, 50]
Atracurium Hoffman degradation ⁄ Nicotinic effect on the NMJ No difference, but >10 h abstinence decreased [55]
hydrolysis requirements
Vecuronium CYP 1A1 ⁄ 2. Mechanism unclear Increased dose requirements [52]
Possibly CYP3A4
Rocuronium CYP 1A1 ⁄ 2. Mechanism unclear Increased dose requirements [53]
Possibly CYP3A4
Ropivicaine CYP 1A1 ⁄ 2 Enzyme induction Enhanced metabolism [56]
Lidocaine CYP3A4 ⁄ CYP1A2 Enzyme induction No significant effect on metabolism [57]
Theophylline CYP 1A1 ⁄ 2 Enzyme induction Increased dose requirements [58]
Halothane CYP 2E1 Enzyme induction Possible increased risk of liver damage [67]

early 1970s. It is around 50 times as potent as morphine uptake. Using mass balance calculations, Boer et al.
and recent work suggests that M6G might significantly showed that in a study of patients undergoing cardio-
contribute to the opioid analgesia after administration of pulmonary bypass, smokers had a significantly greater
morphine. This was demonstrated by Penson et al. who pulmonary sequestration of sufentanil (64.6% vs 38.5%),
showed higher correlations between M6G concentrations immediately after a 10-min infusion of the drug, and that
and analgesia than between morphine concentrations and lung concentrations remained higher for longer. It was
analgesia [37]. Other opioids are similarly influenced thought that the sufentanil was sequestered in the lipid-
by smoking. Patients require more pentazocine both macrophage component of the lungs. This is known to
peri-operatively [38] and postoperatively [39] and be increased in smokers. The authors did not propose
dextropropoxyphene is similarly affected [40, 41]. any clinical implications as a result of their findings but
Codeine metabolism has not been shown to be signi- it may be assumed that recirculation may be greater in
ficantly affected by cigarette smoking, although Rogers smokers [48].
et al. found that there was faster clearance in a group of
smokers given a standard 60 mg dose of codeine [42]. This Paracetamol and NSAIDs
is consistent with Yue’s findings who confirmed the faster There is no consistent evidence that smoking alters the
rate of glucuronidation of codeine in smokers without clinical effect of paracetamol [49]. In one study there was
affecting the O- or N-demethylation pathways [43]. an increase in glucuronated metabolites [50]. Similarly,
CYP3A4, which is induced by a number of commonly for NSAIDs there is no consistent evidence to support
used medications, breaks down codeine to the inactive altered pharmacokinetics among smokers. However,
N-methyl metabolite [44]. It has been suggested that Garg et al. showed that for phenylbutazone plasma
analgesic effects of codeine are primarily through phase I clearance was faster and the half-life shorter [51].
(CYP2D6) demethylation to morphine. An alternative
view, however, has been proposed by Vree who suggested Neuromuscular blocking agents
that among the active metabolites, codeine-6-glucuronide Two studies have shown that smoking decreases the
was the more likely candidate [45]. The metabolism of potency of aminosteroid muscle relaxants. In 1996
morphine is primarily by UGT and partly by the phase 1 Teiria et al. demonstrated that the dose requirement of
enzyme CYP3A4 to normorphine [46]. vecuronium in smokers was 25% greater than in non-
There are few studies relating smoking to the altered smokers [52]. Similar results have been found with
pharmacokinetics of the newer synthetic opioids. Stanley rocuronium [53], although the findings in the latter study
et al. observed that in smokers undergoing coronary were not corroborated [54]. There is as yet no clear
artery bypass grafting there was an increased requirement explanation for these results. Liver enzyme induction
for fentanyl together with an increase in side-effects does not sufficiently account for the effects seen with
such as chest wall rigidity and hypertension [47]. Sufen- rocuronium which is excreted mainly unchanged or
tanil undergoes significant ( £ 60%) first-pass pulmonary for vecuronium which is probably metabolised by

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182 Journal compilation  2008 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2009, 64, pages 179–186 B. P. Sweeney and M. Grayling Æ Smoking and anaesthesia
. ....................................................................................................................................................................................................................

CYP3A4 – which is not induced by cigarette smoke. manufacturing and the dry cleaning industry including
Puura et al. found that there was no difference in the benzene, styrene, acetone, vinyl chloride and N-nitro-
block characteristics of atracurium if the last cigarette was samines. Some of these substances are procarcinogens
within 3 h of anaesthetic induction. If the period of which are activated by CYP2E1.There are gender differ-
abstinence was greater than 10 h, however, then there ences in the expression of the enzyme and also obesity and
was a potentiation of the block. They concluded that the fasting may affect its activity [62]. There is evidence that
sensitivity of the neuromuscular junction was affected by CYP2E1 may be a key factor in the pathogenesis of
chronic nicotine abuse. This difference could be abol- alcoholic liver disease [63]. The enzyme is induced by
ished by application of transdermal nicotine patches [55]. both alcohol and nicotine [64]. This may explain the
It is possible, therefore, that for steroid relaxants, neuro- higher ethanol elimination rates among smokers.
muscular receptor characteristics are altered in some way.
Clearly more studies are needed to investigate the Halothane
influence of smoking on the pharmacokinetics of NMBs. Halothane undergoes hepatic biotransformation with the
At present the relevance of these findings for clinical production of trifluoroacetic acid (TFA), bromide and
practice is unclear. reactive intermediates that can acetylate liver proteins.
These metabolites can alter the antigenic structure of liver
Local anaesthetics cell membranes which may then induce an immune
There is no evidence of any clinically relevant drug response that can lead to liver damage and ultimately to
interaction as a result of exposure to cigarette smoke. fulminant hepatic failure [65]. Cytochrome CYP2E1 has
However, ropivicaine is partially broken down by been identified as the principal P450 isoform catalysing
CYP1A2 and CYP3A4 and there is an alteration in this process. On the basis of a CYP2E1-mediated illness
metabolism in favour of the 3-OH ropivicaine metabolite Kharasch et al. confirmed the hypothesis that a specific
rather than the xylidide metabolite [56]. Although both CYP2E1 blocker disulfiram would attenuate the meta-
CYP1A2 and CYP3A4 play a role in the breakdown of bolism of halothane to TFA [66]. Furthermore, it has
lidocaine, it is unlikely that enzyme induction or cigarette been demonstrated that specific induction of CYP2E1
smoking have any clinically significant effect on meta- using isoniazid leads to the increased expression of
bolism [57]. trifluoroacetylated liver microsomal proteins [67]. It was
proposed that the balance between metabolic activation
Theophylline of CYP2E1 and detoxication of reactive metabolites
The metabolism of theophylline is dependent on could be an important metabolic risk in the development
CYP1A2 and, as expected, cigarette smoking has an of halothane hepatitis [68]. Similarly, alcohol is also an
effect. In a study of 28 patients, Powell et al. showed that inducer of P4502E1 and is widely consumed. The
smokers required a dose of theophylline which was on consumption of alcohol leads to accelerated metabolism
average 50% greater than non-smokers due to a marked of CYP2E1 substrates including halogenated anaesthetic
reduction in half life (8.3 vs 5.4 h) [58]. Similarly, agents and therefore similar caveats should apply when
theophylline toxicity was found to be less common considering similar drug interactions [69]. It may be
among cigarette smokers, a finding consistent with its logical to assume however that the CYP2E1 induction
increased metabolism [59]. Although there have been no and the increased production of trifluoroacetylated inter-
studies specifically examining the pharmacokinetics of mediates from other agents may be an added risk in the
aminophylline, its similar metabolism suggests that the aetiology of liver disease.
same caveats should apply.
Other volatile agents
The biotransformation of other commonly used volatile
Metabolism of volatile anaesthetic agents
agents is primarily mediated by CYP2E1. Fulminant
The CYP2E family contains only one enzyme, CYP2E1 hepatic failure has been reported following exposure to
(previously known as dimethylnitrosamine N-demethyl- isoflurane [70], and there is substantial evidence that
ase) and is responsible for the metabolism of small organic exposure to enflurane may also be associated with a
compounds such as alcohol and carbon tetrachloride as halothane hepatitis-like syndrome associated with anti-
well as the halogenated anaesthetic agents halothane, bodies directed against altered hepatocellular components
enflurane, diethyl ether, trichloroethylene, chloroform, [71]. This may follow previous sensitisation with either
isoflurane and methoxyflurane [60, 61]. It is also respon- halothane or enflurane [72]. Metabolism of methoxyflu-
sible for the breakdown of many low molecular weight rane is dependent upon CYP2E1 and results in the release
toxins and carcinogens, many of which are used in of inorganic fluoride that may lead to high output renal

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Journal compilation  2008 The Association of Anaesthetists of Great Britain and Ireland 183
B. P. Sweeney and M. Grayling Æ Smoking and anaesthesia Anaesthesia, 2009, 64, pages 179–186
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failure [73]. The amount of fluoride released is dependent population. The various constituents of cigarette smoke
upon the duration of exposure, the concentration of the possess pharmacological properties which have implica-
agent and the degree of metabolism. Enzyme induction tions for both clinicians in general and anaesthetists in
markedly increases peak fluoride levels [74]. Renal and particular. The effects of a number of commonly used
hepatic toxicity will, therefore, be linked to the degree of anaesthetic drugs are modified in smokers. Despite recent
induction of the enzyme [75]. The extent to which this advances in the understanding of the mechanism of drug
risk becomes significant is difficult to quantify in a interactions involving cigarette smoke, there are a
condition as uncommon as halothane hepatitis. Admin- number of interactions including those involving opioids
istration of the volatile agent enflurane to patients who and neuromuscular blocking agents, whose mechanisms
smoke is similarly associated with increased inorganic have not been fully explained. Altered pharmacokinetics
fluoride levels, although the increased levels are not due to enzyme induction does not sufficiently explain
sufficiently high to cause renal impairment [76]. these interactions and, at present, alternative theories are
speculative. The use of other recreational substances is
increasing and it is likely that there are pharmacologi-
Alcohol and cigarette smoke
cal implications which have not, as yet, been fully
There is a synergy between alcohol ingestion and cigarette characterised.
smoking. Although alcohol is primarily metabolised by
alcohol dehydrogenase, CYP2E1 accounts for around 20%
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. ....................................................................................................................................................................................................................

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