Pharmacokinetics of Nicotine ebooksclub.org Tobacco or Health Physiological and Social Damages Caused by Tobacco Smoking Second Edition

Cigarettes Snuff Chewing tobacco Chewing gum 20 15 10 5 15 10 5 −10 0 30 60 90 120 −10 0 30 60 90 120 Minutes Nicotine Plasma Level [ngml] 15 10 5 15 10 5 Fig. 4.5 ฀฀฀Changes฀in฀plasma฀nicotine฀levels฀in฀response฀to฀cigarettes,฀snuff฀tobacco,฀chewing฀tobacco฀ and฀nicotine฀chewing฀gum฀single฀dose฀ [52,฀55] .฀Consumption฀of฀one฀cigarette฀12฀puffs฀over฀9฀ min,฀2.5฀g฀tobacco฀kept฀in฀the฀mouth฀for฀30฀min,฀8฀g฀chewing฀tobacco฀chewed฀for฀30฀min฀and฀ 4฀mg฀chewing฀gum฀chewed฀for฀30฀min 1 3 5 7 9 11 20 40 Nicotine Plasma Le vel [ngml] 60 80 P1 P2 P3 P1 P2 P3 100 arterial level venous level Controls Time [min] after smoking of a cigarette Fig. 4.6 ฀฀฀Arterial฀and฀venous฀ plasma฀levels฀of฀nicotine฀ following฀inhalation฀of฀one฀ cigarette.฀Data฀for฀three฀ smokers;฀open฀symbols:฀ arterial,฀solid฀symbols:฀venous฀ plasma฀levels฀of฀nicotine฀ [56] 50 40 30 20 10 12 10 8 6 4 2 8 12 16 20 24 4 8 [h] n = 10 Nicotine [ngml blood] co-Hb n = 7 Fig. 4.7 ฀฀฀Mean฀nicotine฀ plasma฀levels฀and฀ CO-haemoglobin฀levels฀in฀ cigarette฀smokers.฀The฀ subjects฀smoked฀one฀ cigarette฀of฀low฀dotted฀ lines฀and฀high฀nicotine฀ content฀solid฀line฀every฀฀ 30฀min฀from฀08:30฀to฀23:00฀ a฀total฀of฀30฀cigarettesday.฀ The฀cigarettes฀in฀question฀ were฀produced฀for฀research฀ purposes฀ [57] N Nicotine Nicotin-iminium Aldehyde oxidase Cotinine 5-Hydroxy-nicotine Urinary excretion Nicotine-N-oxide Flavoenzyme N N N N N N N H H OH H H H P450 N N CH 3 CH 3 CH 3 CH 3 CH 3 O O Fig. 4.8 ฀฀฀Metabolism฀of฀nicotine฀schematic฀illustration accumulates฀and฀is฀eliminated฀much฀more฀slowly฀half-life฀20–30฀h,฀with฀the฀result฀that฀ it฀can฀be฀used฀for฀assay฀purposes฀in฀smokers฀and฀passive฀smokers฀ [59] .฀Quantitative฀meth- ods฀e.g.฀gas฀chromatographymass฀spectrometry฀or฀GCMS฀for฀measuring฀urine฀cotinine,฀ which฀has฀a฀longer฀half-life,฀are฀valid฀and฀reliable,฀though฀costly฀and฀time-consuming.฀ Recently฀developed฀semi-quantitative฀urine฀cotinine฀measurement฀techniques฀i.e.฀urine฀ immunoassay฀test฀strips฀or฀ITS฀address฀these฀disadvantages,฀though฀the฀value฀of฀ITS฀as฀ a฀means฀of฀identifying฀abstaining฀smokers฀has฀not฀been฀evaluated.฀Therefore,฀Acosta฀et฀al.฀ examined฀ITS฀as฀a฀measure฀of฀smoking฀status฀in฀temporarily฀abstaining฀smokers฀ [60] .฀ A฀total฀of฀236฀breath฀and฀urine฀samples฀were฀collected฀from฀smokers฀who฀participated฀in฀ two฀ separate฀ studies฀ involving฀ three฀ independent,฀ 96-h฀ i.e.฀ Monday–Friday,฀ Latin- square-ordered,฀abstinence฀or฀smoking฀conditions;฀a฀minimum฀72-h฀washout฀separated฀ each฀condition.฀Each฀urine฀sample฀was฀analysed฀with฀GCMS฀and฀ITS.฀Under฀these฀study฀ conditions,฀CO฀demonstrated฀moderate฀sensitivity฀83.1฀and฀strong฀speciicity฀100,฀ whereas฀ITS฀assessment฀showed฀strong฀sensitivity฀98.5฀and฀weak฀speciicity฀58.5.฀ In฀this฀study฀of฀short-term฀abstinence,฀ITS฀classiied฀as฀non-abstinent฀nearly฀half฀of฀the฀ samples฀collected฀from฀abstaining฀smokers.฀However,฀it฀classiied฀nearly฀all฀non-absti- nent฀smokers฀as฀currently฀smoking.฀The฀researches฀concluded฀that฀the฀validation฀of฀ITS฀ using฀GCMS฀results฀from฀smokers฀undergoing฀more฀than฀96฀h฀of฀abstinence฀may฀be฀ valuable฀ [60] . Nicotine฀N-oxide฀is฀not฀of฀pharmacological฀interest฀ [58] .฀The฀extensive฀hepatic฀metab- olism฀of฀nicotine฀may฀mean฀that฀elimination฀is฀delayed฀where฀liver฀function฀is฀clearly฀ impaired;฀ the฀ administration฀ of฀ nicotine฀ should,฀ therefore,฀ be฀ assessed฀ with฀ caution฀ in฀ individuals฀with฀very฀marked฀impairment฀of฀hepatic฀and฀renal฀function. The฀specialist฀literature฀contains฀accurate฀descriptions฀of฀the฀pharmacokinetic฀properties฀ of฀nicotine฀from฀cigarettes,฀one฀particular฀feature฀being฀that฀its฀extremely฀rapid฀delivery฀to฀the฀ CNS฀is฀not฀achieved฀by฀any฀product฀used฀for฀nicotine฀replacement฀therapy฀Figs.฀ 4.5 ,฀ 4.9 ฀and฀ Figs.฀ 11.1 – 11.3 ฀in฀ Chap.฀11 ฀ [62,฀63] .฀The฀amount฀of฀nicotine฀absorbed฀daily฀as฀a฀result฀of฀ cigarette฀smoking฀depends฀on฀the฀number฀of฀cigarettes฀smoked,฀their฀nicotine฀yield,฀the฀num- ber฀of฀puffs฀taken฀and฀the฀depth฀to฀which฀the฀smoke฀is฀inhaled.฀Within฀a฀few฀hours,฀a฀“depen- dent฀smoker”฀can฀attain฀plasma฀nicotine฀levels฀that฀are฀perceived฀as฀suficient฀for฀a฀whole฀ day.฀The฀body฀absorbs฀nicotine฀more฀slowly฀from฀nicotine฀preparations฀inhalers฀฀nasal฀ spray฀฀chewing฀gum฀฀patch฀than฀from฀cigarette฀smoking฀Fig.฀ 4.9 .฀These฀products฀never฀ achieve฀the฀peak฀nicotine฀levels฀attained฀by฀smoking,฀although฀considerable฀inter-individual฀ differences฀exist. 5 2 4 6 8 10 12 14 10 15 20 25 Minutes Increase in nicotine concentration ngmL 30 Cigarette Gum 4 mg Gum 2 mg Inhaler Nasal Spray Patch Fig. 4.9 ฀฀฀Comparison฀of฀ plasma฀nicotine฀levels฀ following฀inhalation฀of฀one฀ cigarette฀with฀levels฀ following฀nasal฀spray฀ 1฀mg,฀inhaler฀1฀mg฀and฀ chewing฀gum฀2฀mg฀ [61] For฀the฀most฀part,฀pharmacokinetic฀studies฀with฀nicotine฀preparations฀take฀account฀of฀ plasma฀nicotine฀levels฀over฀time,฀whereas฀in฀clinical฀studies,฀plasma฀cotinine฀or฀฀thiocyanate฀ levels฀also฀yield฀important฀information.

4.5 Nicotine Dependence

The฀German฀word฀for฀dependence฀“Sucht”฀comes฀from฀the฀verb฀“siechen”฀cognate฀with฀ our฀English฀word฀“sick”฀and฀thus,฀implies฀an฀illness฀requiring฀medical฀assistance.฀The฀ tobacco฀industry฀has฀known฀for฀about฀50฀years฀that฀nicotine฀is฀an฀addictive฀substance.฀ None฀of฀the฀other฀constituents฀of฀tobacco฀smoke฀are฀responsible฀for฀the฀development฀of฀ dependence฀ [64] .

4.5.1 Types of Dependence

Nicotine฀stimulates฀the฀release฀of฀mediator฀substances,฀such฀as฀noradrenaline฀NA,฀acetylcho- line,฀dopamine,฀5-hydroxytryptamine฀5-HT,฀g-aminobutyric฀acid฀GABA฀and฀endorphins.฀ As฀a฀reward฀system,฀the฀dopaminergic฀system฀is฀primarily฀inluenced฀by฀nicotine฀ [65] . Unlike฀alcohol฀or฀heroin,฀nicotine฀possesses฀hardly฀any฀psychotoxic฀activity;฀among฀other฀ things,฀this฀also฀means฀that฀even฀the฀heavily฀dependent฀smoker฀is฀only฀minimally฀conspicu- ous฀socially.฀The฀psychological฀effects฀of฀nicotine฀are฀summarised฀in฀Table฀ 4.4 .฀A฀magnetic฀ resonance฀imaging฀MRI฀study฀showed฀that฀intravenous฀administration฀of฀nicotine฀in฀doses฀ from฀ 0.75฀ to฀ 2.25฀ mg70฀ kg฀ of฀ weight฀ to฀ 16฀ active฀ smokers฀ induced฀ a฀ dose-dependent฀ increase฀in฀behavioural฀parameters,฀including฀feelings฀of฀“rush,”฀“high”฀and฀“drug฀liking.”฀ Likewise,฀ there฀ was฀ an฀ accumulation฀ of฀ nicotine฀ in฀ various฀ brain฀ regions,฀ including฀ the฀ nucleus฀accumbens,฀amygdala,฀cingulate฀and฀frontal฀lobes.฀The฀activation฀of฀these฀structures฀ Effects Consequences Binds฀to฀nicotine฀receptors฀ in฀the฀CNS Facilitates฀release฀of฀transmitter฀substances฀dopamine,฀ NA,฀acetylcholine,฀5-hydroxytryptamine,฀g-aminobutyric฀ acid,฀b-endorphin Mood Increases฀sensation฀of฀pleasure,฀has฀a฀stimulant฀and฀ anxiolytic฀effect Performance Increases฀attention,฀improves฀performance฀for฀repetitive฀ tasks Body฀weight Suppresses฀appetite,฀accelerates฀metabolic฀processes,฀ weight฀reduction Neuroadaptation฀of฀nicotine฀ receptors฀repeated฀doses Development฀of฀tolerance,฀withdrawal฀symptoms฀ ฀irritability,฀restlessness,฀drowsiness,฀dificulty฀ concentrating,฀diminished฀performance,฀anxiety,฀ hunger,฀weight฀gain,฀sleep฀disturbances,฀craving฀for฀ cigarettes Table 4.4 ฀฀฀Effects฀of฀nicotine฀associated฀with฀dependence is฀consistent฀with฀nicotine’s฀behaviour-arousing฀and฀behaviour-reinforcing฀properties,฀espe- cially฀since฀the฀identiied฀brain฀regions฀participate฀in฀the฀reinforcing,฀mood-elevating฀and฀ cognitive฀properties฀ [66] . Van฀Den฀Eijnden฀et฀al.฀addressed฀in฀2003฀that฀besides฀nicotine,฀other฀chemicals฀in฀to฀bacco฀ smoke฀such฀as฀norharman฀may฀contribute฀to฀the฀addictive฀properties฀of฀cigarettes฀ [67] .฀ More฀speciically,฀elevated฀blood฀plasma฀levels฀of฀norharman฀may฀reduce฀feelings฀of฀crav- ing฀among฀tobacco-dependent฀individuals.฀To฀test฀this฀hypothesis,฀plasma฀concentrations฀ of฀norharman฀were฀measured฀in฀38฀male฀smokers฀at฀least฀15฀cigarettesday฀at฀three฀time- points฀on฀3฀different฀days฀spread฀over฀a฀4-month฀period.฀The฀irst฀measurement฀T0฀was฀ conducted฀in฀the฀morning฀at฀8.30฀a.m.,฀after฀12฀h฀of฀smoking฀abstinence.฀The฀T1฀and฀T2฀ measurements฀were฀conducted฀at฀13.00฀p.m.฀and฀16.30฀p.m.,฀respectively,฀during฀a฀period฀ of฀ad฀libitum฀smoking฀after฀the฀T0฀measurement,฀participants฀were฀not฀restricted฀in฀their฀ smoking฀behaviour฀ [67] .฀At฀each฀of฀the฀nine฀time-points,฀craving฀was฀assessed฀by฀means฀ of฀a฀shortened฀version฀of฀the฀Questionnaire฀of฀Smoking฀Urges.฀The฀Fagerström฀Test฀of฀ Nicotine฀Dependence฀was฀used฀to฀obtain฀an฀indication฀of฀nicotine฀dependence.฀The฀study฀ showed฀that,฀after฀a฀period฀of฀smoking฀abstinence,฀craving฀was฀stronger฀in฀those฀with฀a฀