Central Nervous System Effects of Nicotine

their฀daily฀cigarette฀consumption,฀the฀time฀when฀the฀irst฀cigarette฀is฀smoked฀in฀the฀฀morning฀ and฀possibly฀their฀need฀to฀smoke฀during฀the฀night. Although฀the฀relationship฀between฀nicotine฀and฀changes฀in฀heart฀rate฀and฀blood฀pres- sure฀has฀been฀demonstrated,฀the฀relationship฀between฀nicotine฀and฀subjective฀effects฀such฀ as฀decreased฀craving,฀relaxation,฀sickness฀and฀decreased฀nervousness฀is฀less฀well-฀delineated.฀ Therefore,฀Guthrie฀et฀al.฀performed฀a฀study฀in฀which฀arterial฀nicotine฀levels฀were฀observed฀ in฀21฀smokers฀who฀smoked฀two฀average฀nicotine฀AN฀cigarettes฀and฀one฀low฀nicotine฀ LN฀cigarette฀ [53] .฀Craving฀for฀a฀cigarette,฀relaxation,฀sickness฀and฀decreased฀nervous- ness฀were฀rated฀on฀a฀visual฀analogue฀scale฀VAS฀before฀and฀after฀smoking฀each฀cigarette.฀ None฀of฀these฀subjective฀measures฀except฀craving฀for฀a฀cigarette฀was฀changed฀signiicantly฀ by฀smoking.฀The฀change฀in฀craving฀was฀signiicantly฀correlated฀with฀the฀area฀under฀the฀ plasma฀nicotine฀concentration฀vs.฀time฀curve฀r฀=฀−0.57,฀p฀=฀0.01฀calculated฀from฀the฀ ฀arterial฀nicotine฀samples฀drawn฀up฀to฀20฀min฀after฀the฀initiation฀of฀smoking฀the฀irst฀AN฀ cigarette.฀Although฀well-documented฀behavioural฀manipulations฀such฀as฀smoking฀denico- tinised฀cigarettes฀reduce฀craving,฀increases฀in฀plasma฀arterial฀nicotine฀concentrations฀after฀ smoking฀the฀irst฀cigarette฀of฀the฀day฀also฀reduce฀craving.฀The฀authors฀concluded฀that฀both฀ the฀psychology฀and฀pharmacology฀of฀nicotinetobacco฀smoking฀are฀involved฀in฀craving฀ reduction฀ [53] . The฀characteristics฀of฀nicotine฀are฀also฀very฀clearly฀different฀from฀those฀of฀other฀“addic- tive”฀substances.฀Dependence฀in฀the฀context฀of฀smoking฀is฀produced฀by฀the฀ultra-rapid฀ delivery฀of฀the฀alkaloid฀to฀the฀brain฀and฀can฀be฀abolished฀by฀the฀administration฀of฀nicotine฀ preparations฀over฀the฀course฀of฀several฀weeks฀in฀a฀gradually฀diminishing฀dosage฀regimen฀ see฀ Chap.฀11 .฀The฀effects฀of฀nicotine฀can฀be฀blocked฀with฀the฀antihypertensive฀ganglion฀ blocking฀drug฀mecamylamine,฀but฀not฀with฀substances฀with฀antimuscarinic,฀anticholin- ergic฀or฀anti-adrenergic฀activity฀ [54] .฀Experimental฀animal฀work฀may฀indicate฀that฀nicotine฀ promotes฀memory฀performance฀and฀lowers฀aggressive฀behaviour฀ [54] .฀Smokers฀also฀con- irm฀that฀the฀irst฀cigarette฀smoked฀in฀the฀day฀produce฀general฀relaxation,฀especially฀in฀ stressful฀situations฀ [49] .

4.4 Pharmacokinetics of Nicotine

Nicotine฀is฀absorbed฀at฀varying฀rates฀from฀different฀tobacco฀preparations.฀As฀a฀result฀of฀ tobacco฀chewing฀or฀snufing,฀large฀quantities฀of฀the฀alkaloid฀are฀absorbed฀more฀slowly฀ than฀from฀a฀cigarette฀see฀Fig.฀ 4.5 .฀During฀cigar฀or฀pipe฀smoking,฀varying฀amounts฀of฀ nicotine฀are฀absorbed฀through฀the฀mucosa,฀depending฀on฀the฀length฀of฀time฀for฀which฀the฀ smoke฀ is฀ held฀ in฀ the฀ oral฀ cavity.฀ In฀ contrast,฀ nicotine฀ from฀ inhaled฀ cigarette฀ smoke฀ is฀ absorbed฀extremely฀rapidly฀across฀the฀epithelium฀of฀the฀pulmonary฀alveoli฀and฀bypasses฀ the฀liver฀to฀reach฀the฀brain฀Fig.฀ 4.6 .฀There฀is฀a฀corresponding฀rise฀in฀CO-haemoglobin฀ levels฀in฀the฀blood฀Fig.฀ 4.7 ฀ [58] . Nicotine฀is฀metabolised฀in฀the฀liver฀by฀oxidative฀processes฀see฀Fig.฀ 4.8 ฀and฀is฀elimi- nated฀with฀a฀half-life฀of฀1.5฀h.฀Only฀about฀10฀of฀absorbed฀nicotine฀leaves฀the฀body฀in฀ unchanged฀form.฀The฀breakdown฀product฀cotinine,฀which฀is฀pharmacologically฀inactive,฀ 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]