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Absorption of Nicotine in Cigarette and Cigar Smoke Through the Oral Mucosa

Date: 19700627/P
Length: 2 pages
00398026-00398027
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Abstract

Discusses dose level of nicotine in cigarettes and cigars. Describes the inhalation process of cigarette smoking and corresponding dose level of nicotine vs. cigar smoking. Questions if a cigar smoker, who does not inhale, gets a similar does of nicotine. Describes an experiment to test this question by examining the absorbtion of nicotine in cigarette and cigar smoke through the oral mucosa. Observes that the amount of nicotine was greater in cigarette smoke, but the pharmacological response was greater to cigar smoke. States that the pharmacological response is dependent on the amount of nicotine in the mouth as free base.

Fields

Author
Armitage, A
Turner, Deborah (Scientist)
1995 USA
Hypothesis
Free Nicotine
Keyword
Absorption
Substances chemically integrated into each other
Blood nicotine
Dose-response
Free nicotine (Unprotonated or unionized nicotine)
Smoke Constituent
Nicotine
Subject
Smoke Nicotine (Measures)
Pharmacology (Effects)
Cigars/Cigarillos (Products)

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Page 1: yit61e00
- _ . . ,• _- r"" ~,~ - --- ----s----- -- --=- , 3 JUNE 27 lg; f inspired part i,•h re beeause,it ]rr c; position of punti l, cl.cn for cl+'at•al u, in tho ml;tcssi,,., ure was apptuct, li: rn cilinry retnrn.. - from the cou,tt;,• . from the pnrtir•I, - productive cot,).I, T from the luu, : of radioactii-it, presont subjj,~,t, +d' only neglihil,i„ porimental perin,l s was int•estigiu,,I e not more th.u, + adherent isotnp,. icles. NATURE VOL. 226 JUNE 27 1970 ,..A,Iikrti it. E.. and Arnett•,L. C., dreh. ?.'rlriramt. Ileallh;12, 90 (1D55): •13uudo, J., bluir, D. C;1''•, and Thon:eon, ~ lk otel. DA n,ti1C. ,215- rw (1967), n / 1wrt;1, 131 (1'JGH)'. ,11trr1t. G. Z., and ?3.~nJamin, nl, Brit: ttl<d: J., 3,82 (1D!lt)): t<,t, J. E., L+1Mp Function, eeccnd ed. (ISiackwell 3cientill6 Publicatlons, uStbrd, 10(i8): IAphmaan,:lL,xnd Albert. II: E., 3mer:Ind. I1v0.9aaoc. J., 30i,257 (1480). „ T.,Iy;o, A.,, Imarisio; J. J., Dturm211, ii., and Lepper, 31. N., Amer. Rev. J1tFpirat. lr1s., 87, 487 (1UU2)i ~Vadcl, J. A., and Cbmroe, J. IG.,,)un., J. dpp1. Ph}laio1:,18, 715 (1961): This article has been revised in the light of constructive criticisms from a referee, but seems not to meet the following ,•„gcnt criticisms: "From the average age of the subjects in the 1231 EFFIcn:YTB. FO$ SE\'f t.. C7.E-IRANCE4.. 5 h olearance F 3tultiple oorrclatimt Uoetficientd by 6_ -0•_3 A. K. ARMITAGE 80 0-08 M. TURNER D 50 0•0D. . 07 0•00 Department of Pharmacology, 011 0•O1 Tobacco Research Council Laboratories, 05 0•05 Harrogate 40 -0-05 d particles an,l wses reversilili~ -tals. Although. srently fiutct'ion ing, it' is possi ble after a smoke, and overnight. nvever sensitivc emical irritants, t human 1t1nC, :;roup although dust and fumes okers, exposing :il for a grant, the volunteer dctirity (persamon Rer. Rr.tpirat. Di+.., C., Arch. Eurii•on. :69, 1161 (1o6S): Uia., 93. 03'(1966): tol: .Utd:, 88, 41J tuann, D., Canrer, pmnnn, 1(., .a rch. 1. 515' (jp65); Enriron, Hratth, M. Xealth,1s, ; 3s dmer. h'tc. Itea- (. \..)tuu,A)n,r. 533 (l0641): study, tho workers wero approaching a survivor population. If long term smoking dbes aff-ct the mucociliary mechanism of a human lung it is likely that this occurs in tho cohort of smokers who dovvlop smoking related lung disease. By latu midtllo age thesu subjccts will either have died or will at least show evidence of lung disease. The sourco of the subjects (thu staff of the school, and volunteers from old peoplo's homes) could noG be representative of a survivor population. Those with most severe lung discase will have already been excluded.. The paper states that, of the sixty-ono subjects examined, twenty-two wore then reject'ed becauso of lung, diseaso. I feelt this is an error of study dbsign such that the findings cannot bz interpreted with reference to long term effects of cigarette smoking."-Editor: Absorption of Nicotine in Cigarette and Cigar Smoke through the Oral Mucosa Nicotine in cigar smoke (pH 8'5) is much more readily absorbed through the mucous membranes of the mouth than is nicotine in cigarette smoke (pH 5•3) because there is a higher concentration of unionized nicotine in the relatively alkaline cigar smoke. A CIGARETTE smoker who inhales will obtain a dose of , nicot'ine) during the five or ten minutes he is smoking his cigarette,, equivalent' to a series of intravenous inject'ions between 1 and 2 ug,/kg'. Such a dose of nicotine may well result in increased alertncss'. It is usually believed that the, majority of cigafette smokers inhale to varying degrees the smoke which they take into their mouths, whereas the majority of cigar smokers do not. The ques- tion then arises,, does a cigar smoker -,%°ho does not inhalee get a similar dose of tucotino to a cigarette smoker who inhales ? Kershbaum et al.s concluded that he does noti,, because they found that cigarette smokers excreted rnoree nicotine in the urine during a 4 It period of smoking than did cigar smokers. The object of the experiments dl;- scribed'here was to ascertainmore directly the degree, and particularly the rate, of absorption of nicotine in cigarette and' cigar smoke through the oral mucosa. Cats, anaesthetized'with chloralose„had the trachea and oesophagus tied high in the neck. Breathing occurred through, a tube irr.5erted' in the trachea. 25 ml. of tobaccoo smoke was introduced! into the mouth every 30 s from a smoking, simttlator1 through a thin rubber dam held firmly in position over the mouth by artery clips. After 10 s the smoke was blown outl. The changes in blood pressure and movements of the cat's ears caused by tobacco smoke or bv buffered solutions of nicotine intro- dtzeed into the mouth were recorded. Twit'ching, of the ' ears is an action which is highly specific for nicotine and compounds withi nicotine-like actions, and is an indication that nicotine has reached the brains. Blood Pressure and Ear Twitching It was necessary to administer bctwoen twenty and' thirty puffs of tobacco smoke in order to elicit a measur- able pharmacological response, and this was the quantity of smoke~used in all eight oxpcritncnt's. In four oxperi- tnents, cig,tirotte, smoko liad no effect on blood pressuro; in the other four, there was a risc in blood pressuro varyiiig from 8 to 35 m¢n H'g. In only one of the eight experiments did cigarotte smoke camso twitching of tho cnrs. Cigar smolce, on tho other hetind,,caused a rise in blood pressuro in all experiments, the smallest recorded' rise being, 20 00308026 and the largest 125 mm Hg. Ea° ttivitching occurred in five of the experiments with cigar smoke ; it began towards the end of the smoke administration period and persisted for approximately ten minutes. These observations indi- cate that there was a gradual accumulation of nicotine in the brain followed by gradual decline. Fig. lb shows the slow rise in blood pressure caused by thirty 25 ml. puffs of cigar smoke introduced into the mouth during 14•5 min. A similar quantity of cigarette smoke, however, had no effect on blood pressure (Fig. la). Standard! cigarettes manufactured from a flue-cured blend of tobaeco (T 29)s and standard cigars (C 1), were smoked in the simulator at a rate of one puff every 30 s. The whole of each 25 ntl. puff was collected' on a Cam- bridge glass-fibre filter disk andi the filters were analy sed for nicotine by a method based on that of Willits et a1.646 The average nicotine content of twenty puffs of cigarette smoke was 3133'mg, and of thirty puffs 4•44 mg, and was in fact greater than that of the same number of puffs of cigar smoke (2•32' and 4•00 mg respectively). Yet the cigar smoke invariablyy caused a bigger pharmacological response. What is the explanation of this apparent anomaly ? One of t.ho most striking differences between cigarette and cigar smoke is the pH of the smoke. The pF'I of T 29 cigarettes determined by the method of Grob7 «<as 5-35, whereas the pH of the C' 1 cigars was 8-5. The buffer capacity of the two smokcs was about the same. The percentage nicotine present as free base in aqueous soln- tion, calcultited from the Henderson equation, is 0T40 at pH 5,35, 1•7 at pH' 6, 15 at pYT 7. 04 at pH 8 and 85 at pH 8+5. Although tobacco snto):o is an aerosol and not an aqueous solution, the percentage nicotine as free ba;o at' the different pHs will probably differ otily~~ proportionately. The rulclui.rgecdtue.atine~ basoa-ill clearly diffuse into~ the bloodstream more readily than the nicotine ion°•'. pH and Nicotine Absorption. Fig. 1(a' and b') shows part of an experiment in which solutions of nicotine in 0•1 111 phosphate buffer in a concentration range of 0•2'-2-0 mg/ml. were put in the mouth for 10 min. The riso in blood pressure caused by
Page 2: yit61e00
1232 ,/ © 100 NATURE VOL. 226 JUNE 27 1970 LETTE 100 Cigarette smoke a' 90 Cigar smoke 1 b b' i , NATURE VOI f i Possible P from the ! VASSEUR C'1 al. suggest', appea emits a flux energy > 50 _lX spark chambe great significa for t'lie field of evidence for marginal=. We the data in th suggest. The two hi, ref. 1) shoir pl their occurrin less than 2 f lioo-ev.er, no r data presentel following as nngular resolt period. The F nn the order tt ere carried • the variable~ Itlive sufficien- ihereforewe ,rf the influen j~'aks in the In evaltiat t ion cones c showed evi( precise geon -ist+een tiral-s not all cor_ta: ' e included: 1 i 5°) used ir of adjacent rather than ±ir,m of thc c in combinat lanstA te1t illr (3):iar antllors trie T-100nst iN'1'iod ba:•e Ivith approl try•riod used 1lutnnel oc•F '4t y.one p. t111t1tvFE3. Itrll;by tt•r•r, n tuty lto, 1'hms for "+>;h durin ':+' that th, ' dlr,tvx. TI •r tnnmw•h t li°:rD arrs t ' ' 1"hr ttd, r Nle 1•2 yH 7 N)c 0•2 pH 8 Ftg. 1. Records of femoral blood pressure. Thirty puffs of cigar smoke irttroduced intb the mouth of an anaesthetiied cat during 14!5 min caused a slow rise in blood'pressure (b) whereas a similar quantity of cigarette smokc had very-littl6 ettect(a) In another ezperiment, a' and b•'show the effects of buffered solutions of nicotine containirg-1•2'mg/tul: nicotine base atpH 7 and 0 2 mgimla base aYpH 8, when-put into the mouth aud left there for 10 min. by 0 2 1.2 mn- mf: nicot i 7 was closely matched myii ! a, vkL 8, The concentration of nieotlile as free base was 0• 18 ang/nll. a t pH 7 and 0• 13 mg/tnl . at pH 8, sholi-illg- that the pharmacological response is clearly dependent on the amount of nicotine in the mouth, as free base. Fig. 2 shows the mean carotid blood levels of nicotine in ng,lml. after the introduction~ into the mouth for 10 mim af solutions of ninot•ine at pH 6, 7-and 8 each of which con- tained 0•4 mg,!ml. (1'•3 µCi/,m1.) (2'='aC); nicotine. \icotine concentrations in blood (2 mlh samples) were determined by the method described by Turner10: The graphs were drawn from data olitaiiied in nine experiments. Whether nicotine exerts a pharmacological response depends on the rate at which, it appears in the blood and' on the peak concentration attaitled''1. ThA nezik concentr t.inn of nic at .1H 8 was a rosimatel 2.5 at at pH 7 and~ our tunes !~rt',at pH6. The rate at which, the 'toncentratton~ of nicotino ln t e blood increased in the first 2•5 milLat vH 8' waa about 3-5 tilnes the rate at 0.5 1 1•5 2 Tituc (h); FSR: 2. Carotid hlou?d lt,v(•is of nu•utine lu nq/nil. after the preeence iu thoreoutltfur10mihu111~~uiti~mdmulhtinrgofnicartiuc:,tuitG(ip O); pti 7(p -- •!s) and lrlt I:,trh~Fras.h is the mean of three experiments: the bars show staudam rMrrut of the rnean: 11 pH 7 and eight times that at pH 6. These striking dif. # ferences are consistent w~fi 1-tPiS"'dtfterences in the pharttut cological effects of the relatively large amounts of cigarctac and cigar smoke used in the present experiments. ti'1'e have recently shown that twenty intravenous itlji•r•• tiotls of nicotine (4 µg/kg)i given rapidly at nunutr intervals for 20 min„ caused during the first 2,5 ntiii :r 15 ngJrnl./min rise in the concenfration~ of nicotino nr carotlid blood' and a peak concentration of 100 ng/ntl. at. 20 min. This is probably the sort of blood; concen'ra! ir,:r ~ pattern that must be achieved to elicit a stimulant ro•-- i ~ ponse. The data illustrated' in Fig: 2 show that sur lrf blood levels are achieved (hut only just at pH ti} nicotine is present in the mouth continuously for 14) t-rur at the relatively high concentration of 0-8 mgfml. l~ttrire_ the smoking of a cigarette or cigar, however, stuo[c « taken into the mouth, intermittently and held therr i,u only a fe«-seconds. The concentration of nicotine batlin1:: the mucous membranes of the mouth is not, known, 1 rr:l, clearly the conditions are less' favourable for absorpl om than in the ehperiments o£ Fig. 2. The present• evide:r'- indicates that cigarette smakcrs uho~ do not inhale trn,,~ r not obtain a"stitnulant" dose of nicotine from relrttix, , lY acidic cigarette smoke. It may, ho-wever,, be posytltli• !•'rl a cigar smoker to obtain such a doGe without inhalii:_: We thank Mr C. A. Grant for the nicotine analys"'wrll pH determinations of cigarette and cigar smoke, Dr li. Roderiak for providing the (- )-(2'-10C) nicotine hydr-,-r tartrate, Mr C. M. Sellers an6 Mrs D. Kendall for tccluucnl assistanee and 1Pir B. Emmett for preparing the figvirr•;. Received January 28; reviacd .lfareh 2tt, 1970. ' Armitage, A. S,,,Etit. J. Phannacol., 25, 515 (1'J05): •" O : Armita'ge, A. K., Ha]l, 0:1-1., and Morrison, C. F., Nahrre,217, 33t(1.- ' Hrr+hbaums A., Bellet, S:, liirahal•ashi, ll., Feinberg, F. J., and ),,Ir• R., ArcJr. Intern. Med., 120, 311i (1967). : ' Annitnge, A. K., Hall, (3: H., and Neneage, F.:, Bril, J. Pharamrcd:, 36 (196'J). . ~ • Armita~e, A. S;, ~lilton, A. S., and I~torribon, C. F., Drit. J. Pharora> 1.=+• ~ sa(106e). '\1 ilfitP, C. t1,,Fwain, ht. w., Counllq„J. A., and Brice, B. A. Arral (4e'"•• O 22, 480 (1950): 11,~ r Grub, K., llcitr. TnLae, ForgY., -No: 3, 07(15151), 'Albert, A., in Srlrctfre ?bzicily/, chapter 8(licthu~t, Londun.,10"'"' ~ t ~ 'Triwgs; ]:'. J., theib,,Uhiversity of London, 130 (1067). "'1'urner, L: AL, J1iocJrero. J:,115, BB9t (10'90); l " AYrnitnFe, A. K., and btilton. A. 9.• in Tobvuen, Alkalulrtg arr i' Cuurporoalb (cdlt. by von ttiuier, U, S,);,20L (Hergamun. Uxford f .

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