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Na fa-~ a/- N/C IJIL~I~~~ Qc•~ P't t)i eo Se ' . .. r,I. Cigarette Smoking: A Dependence on High-Nicotine Boli* M. A. H. RUSSELL Addiction Research Unit Institute of Psychiatry no Maudsiey Hospital London, S. E. 5, Engisnd and C. FEYERABE\D Poisons Unit New Cross Hospital London, S.E. 14, England 1. INTRODUCTION .. . .. . .. . . . . . . . . . . . . . . ... . ... .. .. . . 30 .:• U. CIGARETTE S:.IOKIKG AND NICOTINE DEPENDENCE ........... .......................... 3 M. DEFINiTIO:r' OF "DEPET:DE2:CE" AND "A DDICTIO\" . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 IV. A'ICOTII:E AND ITS METABOLITES .................. 33 • V. : THE lA1PORTA:CCE OF pN .......................... 34 •Preseat.ed at S}•mpositm on Drug Disposition In.Man Deld In Sara- sota, Florida, November 6-11, 1977 under the auspices of the Ameri- can Society for Phsrmacology and E:cpcrtmental Therapeutics. 29 COpyfi{hl 0 1971 by Mair) 9t1\ct• Inc. All Ric1.11 Rrxr•rd \ttihU tLn -ort not any fart r.ay be upaolrccd or tnmmdasJ in sny form or by any mrinr, rt<cuon.c or mrchsnrcal..nc7uJirc phaotoFr,nt, mierofirmnj, and rreordinj, or by any ,ntormanon uo.+tr rnC ume.bl +)+rrm, ',,r14AYi p•itCWICt11A -.I1IR1 from IM p.b:uRrc.

VI. ABSORPTION OF NICOTIA'E . . . . . . . . . . . . . . . . . . . . . . . . 36 A. Buccaland Nasal ............................... 36 B. Ingestion of Nicotine ............................ 37 C. Absorption through -heLungs .................... 39 VII. PLASMA v1COTINE AFTER INHALATION AND 1\TR.aVE1Ol;S DOSAGE . ........... ......... 41 VIA. URI\ARY E?CCRETIONOF NICOTI\E ................ 43 1X. RECYCLING OF N1COT1NE ......................... 44 X. PROLONGED HEAVY S,'%1Oh7NG ..................... 44 \'I. PLAS%tA 1l?.LF-LIFE OF A'ICOTINE ................. 46 XII. DECAY CURVE REBOUNDS ......................... 49 XIII. DISTRIBUTION OF N1COTIrE TO THE BRAIN ........ 50 XIV. "PEAK-SEEKERS" AND "TROUGN-.NiAlINT.4IIERS" ... 51 XV. HISTORICALASPEI;TS ............................. 52 XVI. MCOTINE BOLL'S DEPENDENCE .................... 53 Acknoa•led.-mcnts .................................. 54 Refcrenccs ........................................ 54 1. INTRODUCTION Tobacco smoking is a form of drug dependence, and the modern cigarette is a highly efficient device for self-administering the drug nicotine. By inhaling, the smoker can get nicotine to his brain more rapidly than the beroin addict can get a"buzs" when he shoots heroin Into a vein. It takes only 7 sec for nicotine absorbed through the lungs to reach the bnin, compared with the 14 sec It takes for blood to flow from arm to brain. Furthermore, the smoker gets a "shot" of nicotine after each Inhaled puff. At 10 puffs per cigarette, the pack-a-day smoker gets more than 70,000 nicotine shots to his brain in a year. It is hardly surprising that cigarette smoking is so ad- dictive. In this paper we shall not go into the evidence showing that smokers. smoke for nicotL)e, nor shall we go into all the pharmacologic effects of nicotine which may be highly rewarding and a source of so much pleasure. This is a conference on drug disposition, not drug action. i

TV.~ ~;,y;. g p g g highly addictive. and noninhaled pi In tnbacoo chewin e and ci ar smokin ) is so ?=~ by it Is that cigarette smoking In particular (as opposed to snuff- 31 o:, A e shall, however, try to show that throughout history the way people ve used tobacco can be eNplained by the pharmacokinetlc chanc- ;.a"r%.•tertsttcs of nicotine within their bodies. We shall also try to show t -T`~L~~X . • L~.~i'•1iS` CIGARETTE SMOKl\G ~ • ^`~~w U. CIG?rRETTE S11OK1\G AND NICOTINE DEPENDENCE Three out of four smokers either wish to or have tried to stop smoking [1, 2), yet no more than one in four of them succeed in stopping permar,cntly befot•e the age of GO (3). Thus most people smoke not because they want to but because they cannot easily stop, andJor such cases smoking is obviously a compulsive activity rightly classed among the addictive behaviors. indeed, cigarette smoking is probably the most addictive and depinder.ce-producing form of object- specific self-administered gratification known to man (4, 5). This simply means that, throughout history, no other single biologically >'necessary object F3s meant so much to so ma.ny people who, after so few initiating experiences, have needed to have it so often and so regularly, for so many ycars. despite trying so lard to do without it; and for which there is no other adequate substitute. Stated plainly, tobacco smoking is a form of drug dependence different but no less difficult to overcome than dependence on other addictive drugs [G, 71. The majority of people who drink alcohol or use cannabis are able to limit themselves to occasional use and easily tolerate periods free of the pharmacological effects. No more than 5% or so of people who use these drugs become dependent. t1'ith cigarette smoking the situ- tion Is altogether different. No more than 5% of smokers limit them- selves to occasional smoking; once or twice a weck or less. The ma- jority are regular dependent smokers who seldom go more than an bour or two without smoking, and over 60% report that, when they have no cigarettes, they frequently feet a craving for one (1). Fur- thermore, dependence on alcohol or cannabis tends to arise In set- tings of social or psychological problems whereas with cigarette smoking the most stable, well-adjusted person will, it be smokes at all, sooner or later almost tnevitably become depcndent. The nsual smoking of more than 2 or 3 cigatettes during adolescence is almost invariably followed by eventual escalation to regular depen- dent smoking which then, in the majority, continues until middle-age or beyond [1).

32 RUSSELLAi.*D FEYERABEND For the past 20 years tbere have been all manner of antismoking eampaigns, in the press, on radio, on television, in schools, and at places of work. Health warnings have been put on cigarette packet.s. Restrictions have been imposed on smoking in certain public places. Advertising of cigarettes has been banned on television In some countrtes, and banned altogether In others. Cigarette withdrawal clinics have been opened (and closed). All this has-achieved very little. There has been a modest decline in smoking among men of middle-age and high socioeconomic status (6), but women and children smoke as much as ever (3). Some 20 million Britons and almost 60 million America:.s still smoke. Follow-up results after successful treatment at withdrawal clinics show the same high re- lapse rate for cigarette smoking as occurs in the case of treatment forheroin addiction and alcoholism (8). There is little doubt, therefore, that ciprette smoking Is a highly refractory dependence problem and there is much evidence that the main determinant is nicotine (5). Smoking doses of nicotine produce a g-reat variety of pharmacological effects, centrally and peripherally, by direct action and via the release of neuro-transmitters. Ilese ac- tions and the evidence for the centr.il role of nicotine in the generation of cigarette dependence have been recently reviewed elscwherc (5). III. DEFI\1TION OF "DEPEKDE\CE"AN*D "ADDIC7lO1" In essence, the terms "dependence" and "addiction" refer to a state In which the urge or need for something is so strong that the individual suffers or has great difficulty In going N•itbout it, and In extreme cases appears unable to stop using it voluntarily when it Is available. We do not propose to discuss here the nature of dependence or addiction, the interaction of conditioning and pharmacological factors, nor do we In- tend to go into a setnlntic and concepttal clarification of "physical" versus "psychological" dependence. We use the terms "dependence" and "addietton" Interchangeably to refer to the urge or need for an ob- ject or activity. How high a degree of dependence Is required before it Is labeled a"dcpendence disorder" or "oddtctlon" Is somewhat ar- bitrnry. Furthermore, pharmacologicai rewards, both primary (e.g.. stimulant, cuphoriar.t, anxiety-reducing actions) and acquired (relief or avoidance of physical withdrawal effects), are really no more than classes of reinforcer, just as psychological rewards or so- cial pressures are other classes. The degree of dependence on a par- ticular object or activity Is governed by its power as a reinforcer

~~•' j•::?..`x~~ ~ . ) i.~.n.-~:• '"'CIGARETTE SMOKING • 33 ~ r. '•~•.~•-•: + rp ..;. :t,'rather than the class of reinforcement It provides. Thus strong psy- ~ cbological or social rett•ards will make for a higher degree of depen- dence than weak pharmacological ones. If the term addiction Is used to denote strong depende:tce, it need not be restricted to refer only t;::• }.•: to strong pharmacological needs but could equally apply to strong non- ta;,._ t,•:• pharmacologic needs as in the case of addiction to gambling, television ,~ . ~IIj.'vieWing, or sweet tasting substances. SI:r.ilarly, dependence based '.+i.on powerful primary pharmacological effects, as in the case of cocaine '': : for example, can be as strong or even stronger than dependence which :'. lnvolves pharmacodynamic toler:.r,ce and physical withdrawal effects. With tobacco smoking there is no shorta;e of potential reinforcers. c•`:' Besides the variety of psychosocial, sensory, manipulatory, and oral rewards of smoking, nicotine produces a whole array of potentially rewarding pharmacological effects. Tolerance occurs :o some of its actior.s and there are ohe:t physical effects as well as psychological symptoms on withdrawal [5]. Thus whatever cri:er:a of dependence or addiction are applied, nicotine is an addictive drug and to5acco smoking a highly addictive bets~•iar. IV. NICOTINE AND ITS M F"fAIIO11TES \icotine Is one of the few natural liquid alkaloids. It is colorless, volatile, and strongly alkaline. It turns brown on exposure to air and gives off a characteristic tobacco smell. It is readily soluble in «•a- ter, alcohol, and etber, and forms water-soluble salts. Under at- mospheric pressure, it bolls at 346°C. It is volatilized in the cone of burning tobscco, 800°C, and the free base Is present In the smoke stspended on minute droplets of lar (0, 3 to 1.0 pm) which are small enough to reach the small airways and lung alveoli. Nicotine has the empirical formula CtoHt,Nz. Its molecular structure Is that of a pyrid(ae combined to a pyrrolidine ring (see Fig. 1). The metaboltsm of nicotine will not be discussed in detail here. Recent review•s are available [5, 9). The two main raetabolites of nlcottne excreted in the urine of smokers are cotinine and nicotine- 1'-N-oxide'(see Fig. 1). They are formed respectively by a-carbon oxidation and N-oxidation of the pyrrolidine ring. There are individ- ual and sex differences In the extent to which these two patbx•ays are used [10). Smokers metabolize a greater proportion than nonsmokers of as lajected doze of nicotine [11]. This may be due eitber to inher- ent differences or to taduction of enzymes in the smokers. ldeubo- Itaa of nicotine occurs mainly in the liver, also in several other

;\~ R S' ~~T~• ~i~ ~~~ '' L .o! ...~~.~vr/~w~.r~.~r~ ~rr•.~e ~ti5• ~.1~`}~~"'~S,-v_~i•t Nicotine-N-CaiOe FIG. 1. \icotine and its two main meLZbolites. The stx-atom ring is the pyridine ring; the five-atozl one Is the pyrrolidine ring. tissues, but not In the brain. Neither metabolite has any appmclable psychopharmacological activity, with the possible exception of co- tinine [12). Vfcotine-N-oNide Is reduced to nicotine by intestir.al bacteria. This recycling of nicotine Is discussed below. V. THE I>1PORTAICE OF pH The absorption of nicotine, its disposition, metabolism, and ex- cretion, have recently been reviewed elsewhere (5, 9, 13). In this paper we will not go over all this ground nor even attempt to sum- marize it. Instead, we will focus on those aspects which have par- ticular relevance to tobacco smoking and which may throw some light on the high dependence-producing potency of cigarettes. We will also present some prelitnfnary new data pertaining to these relevant areas. In contrast to the nlcotinium Ion, as the undissociated (free) base nicotine Is lipid-soluble and readily permeates cell membranes. As such, It Is rapidly absorbed. not only through the lungs but through the skin, the buccal snd nasal mucosae, and the gastrointestinal tract. As the free base, It 1s also rapidly reabsorbed through the bladder and renal tubules. The pKa of nlcotlne Is 7.9. Thus, under acfdlc conditions very little nicotine Is present as free base, whereas at pH 8 the proportion of free base Is 52%. The absorption and urinary excretion of nicotine are therefore pit dependent. Flirtbermore, pH partition considerations mean that where pH differences exist across cell membranes, the concentration of nicotine will be higher on the side where the pH is lower. Thus one would expect the concentration

ir:r r CIGARETTE SMOKING . rs, . .• ti220 200 1so 521iv7 20; 120 100 E9 60 40 1 y Plzsms U 0 10 20 30 U 50 bl ~ Time, min Nicotine injection FIG. 2. Plasma and salivary nicotine concentrations after rapid inlravenous injection of 1.711 mg nicotine base given over 1 min (see Fig. 6). 35 of nicotine in gastric juice to be many times bigher than in plasma; almilarly for parotid saliva which in man has a pH of about S. 5(14 ). The auloradiograms of mice following intravenous Injections of "C- nicotine by Schmiterlow and his colleagues (35) show clearly that nicotine is concentrated in the salivary glands and stomach. To our irnowledge, there are no published studies comparing plasma and salivary nicotine levels in man. Such study obviously requires that the nicotine be administered so as to avoid cootamirating the mouth. Figure 2 shows that following an Intravenous injection the concentra- tlon of nicotine is very much higher In saliva than in plasma. The average ratio of the saliva to plasma nicotine concentration In Fig. 2 is 12.7. The picture is much the same when nicotene is adrninistercd by ingestion In gelatinc-coated capsules (see Flg. 5 below). The high

36 RUSSELLAh'D FEYERABEI.'D salivary concentrations were not simply due to the fact that the sub- jects had been loaded with ammonium chloride to acidify the urine, for the ratio Is similar when urinary pli is not controlled in this way. VI. ABSORPTION OF NICOTIb°E A. Buccal and Nasal As mentioned above, The absorption of nicotine is pli dependent. The Influence of pH Is more strongly evident where the surface area is limited as to the case of the buccal and nasal :nucosae. Armitage and his colleagues have shown that the rate of nicotine absorption from solutions in the mouths of cats was very much higher at plt 3 than at pH 6(16). and the results are similar in man. [17]. It. is not only expcrimental solutions, however, that have pli ranges span- ning the rise of the nicotine dissociation curve. The pH of air-cured tobaccos used mainly in pipes and cignrs, but also in some brands of cigarette. Is apparently aUalir.e (about p1i 9.5), whereas smoke from flue-cured tobaccos present in most bi:inds of British cigarette pro- duces a relatively acidic smoke (about p14 5. 5). Buffering capacity of the smoke is another pertinent variable. Before it wos possible to reliably measure nicotine levels in blood, Armitage and his colleagues developed a bioassay technique (16, 1S- 20 j. In a series of Lmportar.t studies, they used The effect of nicotine on the femoral arterial blood pressure of anestbetized cats as an in- dex of nicotine dosage. They were thus able to show that 30 25-m1 puffs of cigar smoke (pH 8. 5) Introduced into the mouth at 30-sec in- tervals over 15 min produced an Increase in femoral blood pressure, whereas a similar amount of cigarette smoke (pH 5.4) bad no effect (16]. This difference occurred even though the cigarette smoke con- tained more nicotine than the cigar smoke. They were therefore able to clearly demonstrate the pH dependence of the buccal absorption of nicotine. However, the effect of buccal absorption of the 30 25-m1 puifs of cigar smoke was small and slow to develop; whereas, in sharp contrast, a single 25-m1 puff (whether of cigar or cigarette smoke) Introduced into the lungs produced a far larger and almost instanta- neous effect (20), showing that buccal absorption is very much slower and less efficient than absorption through the lungs and that rapid ab- sorption through the lungs occurs even when the smoY.e is acidic. While more recent plasma nicotine studies (Fig. 3) certainly oon- firm that nicotine is absorbed rapidly when cigarette smoke Is inhaled

CIGARETTE SMOKING 37 h t~ tto t~ FIG. 3. Plasma nicotine concentrations in an L^haling smo::cr and a noninhaler during and after smoking one cigarette which was dis- carded at D= 0 rain. Plasma nicotine was measured by gas chroma- tography (from Feyerabend, I.eti•itt, and Russell (21;). but negligibly when it Is not Inhaled, there are still no human studies sbow•ing that nicotine is absorbed from pipe and cigar smoking with- out inhalation. This would require the demonstration of an Increase in plasma nlcottne witbout a concurrent increase in carbox)-b2emo- globin (COHb). However, chewing-gvr.t containing 4 mg nicotine and a buffer w'blch Y.eeps the pH in the mouth at about 8.5 does produce plasma nicotine levels comparable to cigarette smoking, although the rate of absorption is slowcr (see Fig. 4). B. Ingestion of Nicottne When nicotine Is absorbed via the gut into the portal system, it is mostly metabolized In its first passage througb the liver. Animal stvdies have shoWV that fatal doses of nicotine have little effect when giYen Into the portal system [23] and that blood and brain nicotine

0= 09 10 ll 12 13 14 15 16 Time (hours) Cigarcttc smoked I t t t I t t Urine pi) 5.0 4.7 4.8 4.7 4.7 4.8 4.7 4.7 01 09 10 11 12 13 14 Time (hours) 15 16 ritltn chewed reo m ~ ® ~ ~ a Urine pH 4.8 4.9 4.8 4.9 4.8 4.d 4.0 3.9 FIG. 4. Plasma ntcotine Ievcls while subject smoked one cigarette per hour and while he took nicotine cbe•.vin-gt:m hourly. Urine con- trolled at acid p)t (from Russell et at. [22)). levels are very much lower after (ntr3peritoncal as opposed to sub- cutaneous or intravenous injections (24). This point Is not always appreciated. In one study, five capsules containing 10 mg "nicotine tartrate" were ingested c+aiiy by volunteer smokers. The form of