Organ Effects and Toxicity

cardiac฀ganglia฀or฀by฀the฀discharge฀of฀adrenaline฀from฀the฀adrenal฀medulla.฀Conversely,฀ nicotine฀may฀slow฀the฀heart฀rate฀by฀paralysis฀of฀sympathetic฀or฀stimulation฀of฀parasympa- thetic฀cardiac฀ganglia฀or฀by฀a฀combination฀of฀the฀two฀mechanisms.฀These฀opposite฀effects฀฀–฀ in฀some฀respects฀–฀are฀dependent฀on฀dose,฀route฀of฀administration,฀and฀time฀after฀dosing.฀ Small฀nicotine฀doses฀or฀moderate฀smoking฀produce฀a฀slight฀increase฀in฀heart฀rate฀and฀blood฀ pressure. The฀effect฀of฀nicotine฀on฀the฀gastrointestinal฀tract฀is฀intensiied฀by฀acetylcholine,฀cate- cholamines฀and฀peptide฀hormones.฀Gastric฀acid฀secretion฀is฀not฀regularly฀stimulated,฀and฀ yet,฀tobacco฀smoking฀may฀be฀assumed฀to฀possess฀an฀ulcerogenic฀effect.฀Intestinal฀peristal- sis฀is฀clearly฀stimulated฀and฀this฀may฀lead฀to฀multiple฀bowel฀movements฀ [46] ,฀often฀a฀rea- son฀why฀smokers฀do฀not฀want฀to฀do฀without฀their฀morning฀cigarette. Respiration฀is฀stimulated฀and฀the฀vomiting฀centre฀is฀activated฀by฀stimulation฀of฀nAChRs฀ in฀the฀carotid฀and฀aortic฀bodies. Nicotine฀is฀classed฀as฀a฀powerful฀poison฀that฀is฀effective฀in฀almost฀the฀same฀doses฀as฀ prussic฀acid฀HCN.฀For฀an฀individual฀who฀is฀not฀accustomed฀to฀nicotine,฀it฀is฀estimated฀ that฀a฀single฀dose฀of฀60฀mg฀will฀have฀a฀lethal฀effect฀ [47] .฀Relatively฀high฀doses฀of฀nicotine฀ elicit฀convulsions.฀Ingestion฀of฀toxic฀doses฀leads฀to฀central฀stimulation,฀respiratory฀paraly- sis฀and฀circulatory฀collapse.฀Furthermore,฀nicotine฀causes฀depolarisation฀with฀blockade฀of฀ neuromuscular฀ transmission;฀ if฀ the฀ nicotine฀ dose฀ is฀ suficiently฀ high,฀ death฀ may฀ ensue฀ within฀a฀few฀minutes฀due฀to฀respiratory฀paralysis฀see฀Table฀ 4.3 .

4.3.3 Metabolic and Hormonal Effects of Nicotine

Smokers฀are฀known฀to฀have฀a฀lower฀body฀weight฀than฀non-smokers,฀and฀this฀difference฀is฀ overcompensated฀ for฀ following฀ smoking฀ cessation.฀ Weight฀ reduction฀ associated฀ with฀ smoking฀is฀caused฀by฀the฀reduced฀intake฀of฀calories,฀especially฀sweets,฀as฀well฀as฀by฀an฀ increased฀metabolic฀rate฀and฀the฀increased฀secretion฀of฀catecholamines฀from฀the฀adrenal฀ medulla฀and฀steroid฀hormones฀from฀the฀adrenal฀cortex฀ [48] .฀Besides฀apparently฀playing฀a฀ crucial฀role฀in฀these฀reactions฀ [49,฀50] ,฀nicotine฀also฀stimulates฀the฀secretion฀of฀anti-diuretic฀ hormone฀and฀b-endorphin. A฀similar฀reaction฀is฀observed฀in฀terms฀of฀the฀secretion฀of฀anterior฀pituitary฀lobe฀hor- mones฀e.g.฀ACTH฀ [51] ,฀though฀nicotine฀has฀much฀smaller฀effects฀than฀smoking฀per฀se฀in฀ this฀context.฀Moreover,฀in฀female฀smokers,฀differences฀in฀oestrogen฀secretion฀and฀prema- ture฀onset฀of฀menopause฀are฀thought฀to฀be฀related฀to฀smoking฀ [52] .

4.3.4 Central Nervous System Effects of Nicotine

Nicotine฀in฀low฀doses฀stimulates฀the฀CNS,฀an฀effect฀that฀is฀frequently฀accompanied฀by฀a฀ine฀ tremor.฀Emotions฀are฀blunted฀and฀the฀ability฀to฀concentrate฀is฀reported฀to฀be฀enhanced. The฀dependence-producing฀effects฀of฀nicotine฀have฀been฀beyond฀doubt฀now฀for฀a฀num- ber฀of฀years.฀The฀degree฀of฀nicotine฀dependence฀of฀smokers฀can฀be฀deduced฀on฀the฀basis฀of฀ 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,฀