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the Health Consequences of Smoking Nicotine Addiction A Report of the Surgeon General 880000

Date: 1988 (est.)
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The Health Consequences Of Smoking NICOTINE ADDICTION a report of the Surgeon General 1988 U.S. DEVARfMENt CE HEALTH AND NUMRNIERYICES J EWIkN.u11NSw.k. C.nNn Ix q.MU CaHIM C.nl.r fa HuMr Pmne~bn.n0 Etluc.Um URk. nn SMkp wN Nxl/h FucL.uL,MVRrM]ULSi Ew rk y M 9uyM.wMea N Dr..u.n, U.f. C...n..a rNML Mlkt WuMq~e..D.C.H/E1
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CHAPTER I INTRODUGTION, OVERVIEW, SUMMARY, AND CONCLUSIONS
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Introductlon Development and Organization of this Report This Report was developed by the Office on Smoking and Dealth, Center for Health Promotion and F.ducatioh, Centera for Disease Control, Public Health Service of the U.S. Depnrtmenl of Ilealth and Humnn Services as part of lhe Depnrtment's responsibility, under Public Law 91-222, to report new and current infnrmatinn nn smoking and health to the United States Congress. The scientific content of this Report reflects the contributions of more than 50 scientists representing a wide variety of relevant disciplines. These experts, known for their understanding of mul work in specific content areas, prepared manuscripts for incorporm lion into this Report. The Office an Smoking and Ilealth mid its consultants edited and consolidated the individual manuscripis into appropriate chapters. These draft chapters were subjected to an extensive outside pcrer review (sce Acknowledgments for individuals and their affiliations) whereby each chapter was reviewed by up to l I experts. Based on the comments of these reviewers, the chaplers were revised and the entire rolunre was assembled. This revised editiun of (lie Report was resubjected to review by 20 distinguished scientists inside and outside lild Federal Gavernment, buth in this country and abroad. Parallel to this review, the entire Report was also submilled for review to 12 institules and agencies within the U.S. Public Health Service. The commenls frum the senior scientific reviewers nnd the agencies were usrcl to prepare the final volume of this Report. This Report canlains a Foreword by the Assistant Secretary for Health, a Preface by tbe Surgeon General of the U.S. Public ileahh Set•vice, and lhe following chapters and appendices: Chapter 1. Inlroductinn, Overview, Summnry, and Contiu. sions ClmpWrIl. Nicotine: Plmrmacokinelics, Mehdalism, and Phnrnmrndynamics Chapter III. Nicotine: Sites and Mechanisms of Actions (7mpterIV.'Tobaccn llse as Drug Dependence Uhnplrr V. 'I'obnecw lf,se Comlr,)rcd in /llher 1)rug Dependencies (Ympter VI. 6fhrtc of Nirnline 'fhrn t'hiy Prrrmale 'i'nbncco Use Chnplet' VII.'fre:urueid of Tobmcca Ilependence Apt*ndix A. Trends in Tobaccu Use in the United Slatix Appendix li. Toxicity of Nicotine h
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Overview This Report of the Surgeon General on tobacco and health focuses un the phnrmacologic basis of tobacco addiction, Previous Surgeon Generul's Reports have reviewed the medical and scientific evidence estnblishing flint cignrette smoking and tobacco use in other forms are delelerimis to health. Several reports emphasized particular disenses (e.g.. 1982 Report on cancer (US D11115 I96), 1983 Report on cardinvnsculnr disense (US DI1115 19fl3a), 1984 Report on chronic obstructive lung disease (US DII11S 1984n1); anme reports concentrnC ed on specific pnpuhdions (e.g., 1980 Report on women (US U111IS 198u); nnd some reports dealt with particular aspects of smoking (e.g., 1986 Report an involuntary smoking (US DHH3 19860. These roporls have been imporlnnL because so many individuals engage in n behavior flint causes morbidity and premature mortality. The present Report addresses a central issue of the tobacco and health problem: Why do people smoke and in other ways consume tobacco products? Specifically, this Report reviews the pharmacolog- ic basis of t6e disease-producing and lifedhreatening behavior of tobacco use. Psychological and social fnctors are also imporLant influences on tobacco use, but n detailed review of these factors is beyond lhe scope of this Report. Reviews of this literature include previous reports of the Surgeon General (US DfIEW 1979; US DII I IS 1980, 1982, 1983s. 1984a), research monographs from Lbe National Institute on Drug Abuse (NIDA )(Jarvik et a). 1977; Rrasnegor 1978, 1979a,b,c; Grabowski and Bell 1983), and articles by scientists who study tobacco use and nicotine (Russell 1971, 1976; Gritz 1980; Ilenningficld 1984). This Report reviews evidence flint tobacco use is addicting and that nicotine is tbe active phnrmtcologic agent of tobacco flint causes this nddicljve behnvior. Previous Surgeon General's Reports have focused on evidence flint cigarette smoking and tobacco use are health hnmrds. Now Ihal thuse relationships are well-documented end well-known, this Report addresses addictive properties of cigarettr smoking and mbncco use in order to help develop more effective prevention nnd cessation progfnms. This Report topic is particularly timely because of recent advances nnd extensive duta gathered in the 1980s relevant to the issue of tobaa:o nddiction. Since lhe early 19ilOs scientific literature and historical anecdoles have provided evidence that tobacco use is a form of drug addiction. In the 1970s, however, research efforts increased considerably on various aspects of tobacco nddiction, including nicotine pharmncokinetics, phnrmacodynamles, selGad. minlslruliun, wilhdrnwnl, dependence, and tolerance. In addition, advances in Ihe neurnsciences have begun to reveal effecls of nicnline in the brain and IxKly thot may belp to explain why tobacco use is reinl'nrcing und difficult to give up, These issues are addressed in this Ite)mrl. Finally, recent developments in the use of nicotine replacement in smoking cessalinn emphasize the imporlnnce of pharmamlogic aspects of cigarette smoking. Concepts of drug addiclion or drug dependence are discussed in detail in Chapters IV and V. It is useful to begin this Report wil.h a brief summnry of main pninls about drug dependence flint provi.le lhe foundation for tbe findings of the Report. The lerms "drug addiclimi" nud `drug delkmlence" me sciculifi- c:dly equivalent: Ioth lerms refer to Ibe lu:hnvinr of repelitively ingesling nroodaa)tcring substances by individuals. The term "drug dependence" has been increasingly adopted in the scienlific and mnikul lilmuture us n tnore Iechnicnl term, whereas the term "drug nddiclion'•, crontinura to be used by NIDA nnd other organizations when it is important to provide information at a more general level. Throughout this Report, both lerms are used and they nre used synonymously. The main conclusions of the Report are bnsed upon concepts nf drug dependence that have been developed by expert committees of the Warld Ilenlth Orgmtiztdion, as well as in publications of NIDA and the American Psychiatric Association. These concepts were used So develop a set of criteria to determine whether tobaccmdelivered nicotine is addicting. The criteria for drug dependence iucluda primary and additional indices and are summm'ized below. L'IiITERIA FOIi URIIG DI?I'6ND1?NC6 1'rimnry Criteria • Ilighly controlled m- compulsive use • Psychoactive effects • • Drug-reinfmred behavior Additionul Criteria J Addiclive behavior nttemiuvnlves: -slereotypic patterns of use -use despite harmful effects a•ehypse fnllowing abstinence recun'eut drug crnvings . fkpendencepradncing drugs nRen pt'oduce: lolernnce -physical dependence plensnnt (cuphmiaut) efft•cls The primmy crilerin listed above ut'e sldficienl to define drug dependenre ! Iigh1Y cmltrnlhvl nr rnmpulsive usr• indiealvs lhad drug. fi 7
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seeking and ttruK-lakin8 behavior is driven by strone, often irresisti- ble urges. It can persist despite a desire to quit or even repenled nttempts to quit. Such behavior is elso referred to as "hnbftuul" bchnvinr.'yo dislinguish drug dependence from habitual behaviors not involving drugs, it must he demonstrated tha6 a drug with facyrlIDHctive tnleadaltte.rtagt effects in lhe brain enters the blood stremo. Furthermore, drug dependence is defined by Ihe occm'rence of drug-mutivnted behavior; therefore, lhe psychoactive chemical must be capable of functioning as n rebrforcer that can directly strenglhen beinrvior leading lu further drug ingestion. Additionnl criteria nre often used tn help cbaracterize drut; dependence. Severd are associated with the drug-taking behavior itself: (1) lhe behavior may develop into regular terntmmctl and phy.aicnl patterns of usr• trrpetilive and stereolypic$ (21 drug use may persiaL despite adverse physical. psychotngical, or sncinl cunse- qnences; f9) quillinh ePis-odes nre often followed by t'esumplion of drug use (relapse); (4) urges (cravingsl to use the drug may Ix rrcurrentd and persistent especially during druK nizstinence. Similm• ' ly, several common effects of dependenee-producing drugs cnn ske•ngthen their control over behavior and increase the likelihnod of hnrm by contributing to the reRularity nnd overall level of drug hnnkc: /l) dintinished responsiveness (tolerance) to lhe effects of a drng occmx, and may be nccompnnied by increased intake uver time; (2) nhstinenee.ua.wmiated withdrawal reactions (dtm to physical dependence) enn motivate further drug intake; (91 effects lhat nre considered pleasant teuphorinntl to lhe drug user can he provided by the drug itself. fkpendence-producing drugs can also produce uffects Ihnl individunls find useftd. For example, many mldiclin8 drugs have therapeutic uses in medical treatments of various disorders. Most medicnlly apprnved drugs that are addicting, however, ore generally only available by prescription. Effects of a drug considered by the individual to be useful can promote initiation of drug use, strengthen the nddictiun, and contribute to retnpse following cos.vr lian of usc. 7bbncco mnl uiealino nre cnnsfdered ht lite Ilepnrl in light of Ihe nlwve criteriu. In brlet, the nrganizatinn of lhe Report is ns follows: revicw nf evidence that tobacco use is accompanied by orderly luulerns of uptaka of uicotino iu the body mtd brnimresultinli fn the developmeul nl' lulct'ancc (Chapter fit review of bow eftecis of nicntinc ln (he hrnin and tbe rest nf lbe body are chemically mrdialed It'haplel' 111); review of the evidence ihn( tobacco is mldicting and thnt nicetinc is an addicting drug lCbnplcr IV); Coleparlsull of Io1lacCo U5C with other adlhclions tlnd of nieoline wilh other nddiclinlf drugs (Chapter V); review of possible effects of nicotinc Ihat may promote the use of tobacco nnd present impedi- .mrnls lu quitlinR snmking (Chapter Vfl; review uf strategies for helping people to achieve nnd mninlaiu tnlmccn nlxtinenrn (Chnptcr VII). In addition, appendices nre included thnl sunmmrize inl'nrnrn- lion regarding lrends in lofmceo use (Appendix A) mtd informatinn regarding the toxicity of nicotine it.celf (Appendix RI. A summary nf the main findings of the Report folfows. Major Conclusions 1. Cigarettes and other forms (if tobacco are nt(tlicting. 2. Nicotlne is the dntg (n tobacco that cnuses addiction. 3. The phnrmacoingie and behavioral proces.ces thnt determine tobacco addiction are similar !n those tbat determine addiction to drugs such as heroin aud cllcaine. Brtel Hfstory Relevant to this Report Tabaccn products hnve Iwen ustd fnr centurics. The tobtccu plant was native to liw New Wurld. The oldest cited evidence of tnbactro asc npfmars on n Mayan stone carving dnhd front tiq) to 91A) A.A. There nre reports of tobacco smoking in Christopher Columbuti diary in 1492; reports of tobacco smoking ap)wm' in the (ngs uf othcr Eurofrenn explorers uf tbe Now World in the Ihth century. Since the colonial period, tobacco bos been nn int.earal part of the American ecnnomy (Robert 1J49). Tobacco use permeated the New World and quickly spread throughout the rest of the world during the Irilh and 17t1r centuries. As use of tobacco prsrel ucls spreml, so dkl controvetsy aver t be efkvas of these producls. TlumtFhout. history, while some furxons extolled the virtues of tobacco (including numerous alleged medicinal uses), others condenmed its use. George WnshinHlon is attributed with exhorting the home front dwinfC Ihc Revoluliotmry Wnr,'9f you cmi l send money, send lotwcco." In contrast, I)r. Benjamin Itush cundemned tobacco use in his 176W ba>k Fsxnrx. '1'he controversy croutinued into the 19111 century with no convincing scienlif'tc or medical evidence to suptmrt either pravitiun /ltobert 184J). in 18fiG-G7 the Iiritiair medicid jtmrnnl Lnnrrt published opininus nf .51) physicians on ttduuxo usc. Many opponents utlribuled in- crensed crinre, nervnus paralysis, less of intellectual nbilititx, uud visual impairment to tuhutxo nse-all of lhese' claims lackcrt convincing evidence. In restating lhe mnin arguurvnts nfthe tobncco profwnenls, lhe l.tmret edifom wrote thnt fnhnccu use "..anusl have some gaal or nt least fdensurable effecis, that, if its evil efl'ects were 9
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so drendfol as slnted Ibe hummn race would have ceased to exisl" (Lnncet 1857) . While the henlth-prmnoting and healLh-damnging effects of lnlmc- ru pnducts were being debnted thmughout the 171h and 18th eonturies, scientisls were n'ying to determine the chief active ingredient in Inlmrm. In Ilioe:(rly 18/N)s the oily essence of tobacco was discoverttl by Cerioli nnd by Vnuquelin. This scltive substance wns named "Nicolianine;" nfter,lean Nicol, who sent tobncco seeds front 1'ortugul to the French courl nt the end of lhe 16th cenlury. In 1828, 1'osseh nnd Itrimnnn at the University of Heidelberg isolated the pura form of Nicotimnine and rennmed it "Nikuliir" The chemicul's empirical fornwlu. COH,4N., was determined in,lhe 1g4/k, and "uicutine" was synthesized in the 1890s tltobert 1949). Since the lute 18(%Is, resenrch on the pharmacologic actions (If n icetine has contributed subvlnntially lo bnsic information nboul t he nervnus syslem lKhnrkevich IBfNI; Volle 19H0). The classic work hy Langley and Dickinson 118891 on nicotine's effects in nulonomic gangliu led to the postulules (hat chemicals transmit information between neumns und that there are receptnrs on cells that respond functionally to stimulation by speeific chumicals. As early as lhe 192(IS tmd 1930s, some investigators were concluding that nicotine was responsible for the compulsive use of tobacco products (Arm- strmng-Jones 1927; Horsey 1996; Lewin 1931). Johnston (1942) concluded that, "smeking tobacco is essentially a menns of adminis- tering nieut'ine, just ns smnking opium is u means of administering mmpbine." Throughout the 21kh century, research hns continued to investi- gale the role of nicotine in tobacco use. The 1964 Ileport of the Surgeon General's Advisory Committee on Smoking and Ilenlth (US PHS 1flfr1) held that: "The habitual use of tobacco is related primarily to psychological and social drives, reinforeed and perpetu- sted by the pharmaculogic actions of nicutine on the central nervous sylem. Nicotine-free tobacco or other plant materials do not sntisfy the needs of those who ucquire the tobacco hnbiL" The 1964 Report, relying upon a distinction (that is no longer mnde) between "habituatinK" mld "addicting" drugs, asserted that tobacco was hnbilualing and not addicting. The distinction in 1964 between hnbitualing drugslincluding cocnine and amphetamines) and addict- -ing drugs lincluding opiutes and barbiturates) was based on: (1) whether the drug produced clear physical dependence;(2) whether dnmupe wits moiuly to the individual usm- (hnbiLUnting drugs) or to ax•irly hlddirling drugsl; m.d (9) the strenglh of the hnbilunl behavior that dcveloped.'1'here was no question at the time of the 1964 Retwrt that nicotine was the critical pharmncologic agent for tobacco use, but its role was then considered to be more similar to cocaine nnd ampbetmnines thnn to opiates and barbiturates. Later in 1964 the World Ilenllh Grgnn{zntion drnpped this semantic distinction between habituating tmd addicting drugs Ilccause it was recognized that habitual use could be as strongly develn(w•d fur cocaine as for mnrphine, thnt socinl dnnmge generally necnmpnnied personnl damnge- and that behavioral charartcristics of drug use could be simllar fot'the sn-called hnbituuting and nddicliug drugs.In an el'fort to shift the focus to dependent pntterns ul' behavior nnd away from nmrnl tmd. social fssues associated with lhe Ierm nddiclion, the term de(xndence wns nrcornmended. It is now cleam Llwt even by the enrlier distinction iu nomencln- lure, cigarettes and other forms of lolwcco are addicting and actions of nicotine provide the phnrnmcologic basis of tobacco nddictinn.'1'he terln "dependence producing" may nlso be used to describe cigaretles mrd other fornls of tnhattn use, analogous to actions of other drugs (eg., opiates, coccaine/. Since 1964, considerable additional evidence hus been compiled that substantiates these cnnclusions.'fhe pre.ent Report reviews this information and the relevant literature. Previous Surgeon Geneml's Reports provided current reviews nf the health consequences of cigarette smoking particularly relevant to public health. For example, despite the accumulating evidence, in the early 196Um there was little recognition by the public of the health haznrds of smoking. Fvlch Report examined specific informa• lion considered to he important for public dissemination. A brief review of topics addressed in these reports provides the background for the present Report. In the late 1951k, the U.S. Public tlcnlllt Service, the National Cancer Instilute, the National Heurl. Institute, the American Cancer Society, and the American Ileart Assoeialinn appointed n study group to examine the availuble evidence on smoking and hetdth. This study group concluded that excessive cigarette smoking Is u causative factor in lung cancer. In 1962, Surgeon General Luther Terry established nn advisory committee on snloking and health. This committee released its Retrorl on January 11, 1964, concluding that cigarette smoking is a cause of lung cancer in men and a suspected cause of lung cancer in women, and increased the risk of dying front pubnonary emphysema. The next Report was issued in 19671US PIIS lUfienl and stated that "the case for cigarette smoking ns the principld cause of lung cancer is overwhelming." Furtheq the 1967 IteWrt concluded that: "There is an increasing convergence of many lypes of evidence ... which strongly suggests that cignrelte smoking can cnuse death I'n.m cmroiuiry hearl disease." 'fhe 1967 Repm also cnucluded that "Cigarette smoking is the mnst impm'lant of the causes nf chrnnic non-neoplastic bronchuprdmonary disease in the IJnilcel States." '1'he 196g and 1'.N'x4 Reports (US PIIS 1'J68b, 1669/ strengtlwned the concluaions renched iu 1967. The I Iq 1 Relwrt prnvided a detuillvl
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review of the evidence to date regarding health emrsequences uf smoking (US U11EW 19711. The subsequent reports (1972 to 1976) cnntinued to review the increasing evidence essociating cigarette smoking with many health hazards. The 1972 Report also discussed involuntary or passive smoking (US DIIEW 1972). The 1973 Report included some data on the health hazards of smoking pipes and cigars (IIS PUS 1973). The 1975 Report updated information nn the heahh effects of involuntary or passive smoking (US U1IEW 1975). The combimd 1977-78 Report discussed smoking-related problems unique to women (US DIIEW 1978). At lhe time of its release, the 1979 Report wns the most comprehensive review by n Surgeon Generars Report of the health consequences of smoking, smoking behavior, and smoking control. In addition to providing a thorough review of the health consequences of smoking, the 1979 Report discussed the health conseyuences of using forms of lohacen'other than cigarettes (pipes, cigars, and smokeless tobacco). Moreover, the 1979 Report expanded tile scope of the previous reports and examined behavioral, pharmacologic, mtd social factors influencing the initiation, malnlenance, and cessation of cigurette smoking. Relevant to the topic of the present Report, lhe 1979 Ileport concluded that "it is no exaggeration to say that smoking is the prototypical substance-abuse dependency and that improved knowledge of this process holds great promise for preven- tion of risk." Since the release of the 1979 Report, each subsequent Report has focused on a specific population or seliing (women in 1989 (US 11I111S 19t16), the workplace in 1988 (US DIffIS 1985)). n specific topic (health effects oflow-tar nnd low-nicotine cigarettes in 1981 (US DIINS 1981), involuntary smoking in 1986 (US DI11I5 1986a)1, or -a specific disease (cancer in 1982 (US D11115 1982), cardiovascular diseases in 1983 (US D11115 l9&9a),chronic obstruc- tive lung disease in 1984 (US UHI1S 19840)1n ln addition to lhe previous Surgeon General's Itepmtv, several other developments and publicalions provide relevant bnckground fnr lhe present Report. For example, numerous monngrophs pre- pared in the 1970s hby lhe National Institute on Drug Abuse (NIDA) considered tobacco use to a form of drug dependence. In 19130. the American Psychiatric Association, in its Diagnoslic und Statistical Mnnmd of Mental Disorders, included lobaccro dependence as a substance nbuse dismvler and tobacco withdrawal as an organic ment:d disorder (APA 19861. The 1987 revised edition of this manual (AI'A 1987), in ra:ognition of the role of nicotine, changed "tobacco withdrawal" to "nicotine withdrawul." In 1982, the Director of NIUA testified to Congress thut the positimt af NiDA was that totracco use could lead to dependence and that nicoline was n protoLypic dependence-pnxlucing drug. In a 1988 publication, "Why People Smoke Cignrettcw." the U.S Public Ileallh Service supported this t I position of NIDA regnrding tobacco and nicoline (US hl IIIS 198ab). In the 1984 NIDA'frienninl Report ln Congress, nicotine was lnbeled n prototypic dependence-producing drug nnd the role of niculine in tobacco uso was considered to be anulogous to the roles of morphine, cocaine, and ethanol, in the use of opium, coca-derived producta, and alcoholic beverages, respectively (US f)IUIS 1984b). In 1986,, a consensus conference of the National Institutes of Ilealth and the Report of the Advisory Commitlee to the Surgeon General on the health consequences of using smokeless tobacco concluded that smokeless tobacco can be addicting and that nicotine is a dupen- dence-producing (i.e., addicting) drug (US UIIIIS 198Gb). 'fhe pre.tent Report is the 2Gth such repnrL issued by the Public Ilealth Service on lhe health consequences of lobacco use. Tlle deleterious effects of cigarette smoking w'e now well known. Therefore, this Report focuses on hlim'macnloglc information to help understand why people smoke. Suth information will assist health professimmis in developing effective strategies to prevent initiation and to promote cessation. The literature reviewed in this Report indicates that tobacco use is an addictive behavior. It is the purpose of this Report to thoroughly review Ihe relevant literature. Chapter Concluslons In addition to the three overall conclusions of this Report, there are many other substantive conclusions. These points nre listed under the appropriate Chapter nnd Appendix headings. Chapter 11: Nicotine: Pharmacokinelics, Metabolism, snd Phar- macodynamfcs 1. All tobacco products contain sabstantiul amuunls of nicotine and other alkalouls. Tobaccos from low-yield aud bigh-yield cigarettes cnntuin similar amounts of nicotine. 2. Nicotine is absorbed readily fr-om tobacco smoke in the lungs and from smokeless tobacco in lhe mouth or nose. Levels of nicotine in Ihe blood are similar in magnitude in people using different forms of tobacco. With regular uae, levels of nicotine accumulate in tire body during the dny and persist overnigld. '1'hus, daily tohacco users nre exposed to lhe eR'ecls of nicotine for 24 hr each day. 3. Nicotine that enters the blood is rapidly distribuled to the brain. As a resull, effects of nicotine on the central nervous system occur rapidly after a pull of cigarette smoke or ufler a/uorption of nicotine from other routes of administration. 4. Acute and chronic tolerance develops to many effects of nicntine. Such tolerance is consislenl wilh reports that inilinl 12 11
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use of tobucco products, such us in ndolescents first beginning to smoke, is usunlly accompanied by a number of unpleasant symplnms which di.appenr foliowinil chronic trrhnecn use. Chapter III: Nicotine: Sites anA Mechanisms bf Actions I. Nicotine is u powerful pharmacnlogic agent that ncts in the hrain and throughout the body, Actions include eteclracortical nrtivntion, skelelnl muscle relaxation, and cardiovnscular and endocrine effects. The mmay biochemicul and electrocorticnl efYects of nicntine may act in concert to reinforce tobacco use. 2. Nicotine ncts on specific hinding sites or receptors throughoul the nervous system. Nicotine readily cn:sses the blood-hrnin barrier and accumulates in the brain shortly after it enletx the body. Once in the btvin, It interacts with specific receptors and tdlers brain energy nmhibtdism in a pattern consistent with the distribution of specific binding sites for the drug. 3. Nicotine nnd smoking exert effects on nearly nll cornponents nf llte endocrine and neurcendocrine systema(including catechol- nmines, serotonin, corticosteroids, pituitary hormones). Same of these eadoecrine effects tire niafinted by actions of nicotine an brain nellrolrilasmitter systems (e.g., hypothulam- ic-pituitary axisl. In addition, nicotine has direct peripherally ntediMed effects (e.g., on the ndrennl medulla and the adrenut rortex). Chapter IV: Tobacco Use ns Drug 1Tepmrdence 1. Cigarettes and other forms of tobacco are addicting. Patterns of tobacco use tire regular and camSmisive, and a withdrnwal syndrome usually accompanies tobacco abstinence. 2. Nicoline is the drug in tobacco tlmt causes addiction. Spccifi- catty, nicotine Is Ixychoactive ('Snood altering") and can provide plensuraUle effects. Nicotine can serve as a reinforcer to mntivnte tohacrosee.king and tohaccrousing behavior. Tuler- «ncr develops to actions of nicotine such that repen/ed nu• results in diminished effects and can be accmllpamed by inerensed intnke. Nicotine also causes physical dependence eharnctm'ineS by n withdrnwni syndronte thut usuntly nccompa- nies nicotine abstinence. 3. The physical characteristics of nieotine delivery systems can nffect their toxicity and addictiveness. Therefore, new nicotine delivery systems should be evaluated for their toxic and uddictive effects. Chapter V: Tobacco Use Cumpnred to Other i)rug ilependen- cies 1.`Phe phnrmucologic and behnvioral procesxes thut determine tobuctro addtetion are similar to lhase that determine nddictinn to drugs such as heroin and emraine. 2. Rnvironmenlnl factors including drug-associated stirouli nnd social pressure tire Important influences of initiation, patterns of use, quitting, and relapse to use of opioids, nlcohol, nicotine, and other addicting drugs. 3. Many persons dependent uptm opinids, nlcohol, nicotine, or other drugs are able to give up their drug use outside tlre context of trenlntent programs; other persons, however, re- quire the assiat:mre nf form:A res.wdion proNrntns to achieve lasting drug abstinence. . 4. Relapse to drug use often occurs among persons who have achieved abstinence front opioids, olcolwl, nicotine, or olhmdrugs. 5.ffehavioral and pturrmnroingic intervention techuiques with demonstrated efficacy are available for the treatment of addiction to opioids, nlc»hol, nicotine, rmd nther drugs. Chapter VI: Effeets of Nicotine That May Promote Tobnccu Dependence 1. After smoking cigarettes or receiving nivrotine, snwkere per- form better on sume cognitive tasks (including sustained attention and selective attention) than they do when deprived of cigarettes or nicotine. I lowever, xmukink nmt nicotine do not improve general learning. 2. Stre>s increases cigarette consumption umong smokers. F'un ther, stress has been idmtliGed ns a risk factor for inititdion of smoking in ndnlescence. 3. In general, cigarelle snmkers weigh less (approximately 7 ttr less on averagei than nonsmokers. Many smokers who quit smoking kain weight. 4. Food intake and prohahly, nteladwlic hrtnrs tire involved in 4hc inverse relationship between smoking nnd body weight. Thefe is evidence that nicotine plays an important role in the rolntionship between smoking nnd budy weight. Chapter Vlk Treutment of Tohaceo Uependence I. Tobacco dependence can be treated successfully. 2. F{fective interventions Include behavioral approaches nlone and behavioral approaches with adjunctive plrarmacologic treatment. 15 7
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J. Ilehavioral interventions nre most effective when they include multiple components (procedures such as aversive smoking, skills training, group support, and self-reward). Inclusion of teo many treatment procedures can lend to less successful out- come. 4. Nicotine replacement can reduce tobacco withdrawal symp- Imns nnd moy enhance tbe efficacy of behuviornl treatment. Appendix A: Trends in Tobacco Use In the United Slnles 1_ An estimnted'32.7 percent of men mrd 28.3 percent of womeu smoked cigarettes regularly in 1985. The overull prevalence of smoking in the United States decreased from 36.7 percent in 1976152.4 million adultsl to SQ.4 percent in 1985 (51.I million adults). 2. In 1985, the mean reported number of cigarettes smuked per day was 21.8 for male smokers and 18.1 for femnle smokers. 3. Smoking is more common in lower socioecronomtc categories (blue<ollar workers or unemployed persons, less educnted persons, and lower income groups) than in higher sociocconom- ic categories. For example, the prevalence uf smoking in 1985 among persons without a high school diploma was 35.4 percent, compared with 16.6 percent among persons with postgrnduate college educetion. 9. An estimated 18.7 percent of high schnol seniors reported duily use of ciguretles in 1986. The prevalence of daily use of one or more cigarettes among high school seniors declined between 1975 and 1986 by approximately:15 percent. Most of the decline occurred between 1977 and 1961. Since 1976, the smoking prevnlence nmong femrles has consistently been slightly higher than among males. 5. The use of cigars and pipes has declined 80 percent since 1954. 6. Smokeless tobacco use has increased substantially among young ncen nnd has declined among older men since 1975. An estimuted 8.2 percent of 17- to i9year-old men were users of smokeless tobacco products in 1966. ANpendlx It: Toxicity of Nicotine . 1. At high exposure levels, nicotine is a potent nnd potentially lcthnl Iroison. I luman pnisonings uccur primarily aa n result of nccidenlul ingestian nr skin contact with nlcotinecontaining insecticides or, in children, after ingestion of tobuceo nr lobncco juicen. 2. Mild nicotine iutoxicntion occurs in first-time smokers, nnn- snmking workciv who harvest tobaccn leaves, nnd people who i chew excessive amounts of nicotine polacrilex gum. Tolerance to these effects develops rapidiy. • 3. Nicotine exposure in long•term tobacco user® is substantial, affecting many organ systems tChapters 11 and lifi. Fhermaco- logic actions of nicotine may contribute to the pathogenesis of . smoking-related diseases, although direct causation has not yet been determined. Of particular concern ere cerdiovnscul~nr dlsease, complications of hypertension, reproductive disorders, cancer, and gastrointestinal disorders, including peptic ulcer disease and gastroesophngesl reflux. 4.1'he risks of short-term nicotine replacement therapy as an aid to smoking cessation in healthy people are acceptable and ' substantially outweighed by the risks of cigarette smoking. 16
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Relerences AhIP.RICAN 1:SYCIIIATIIIC ASF/K'IA'I'IDN. llinpnrnr/r mul Srnewml Alanunl rr/ Alnqul /hvmMc Wruhinptun. IIC.: Americnn 1'ayrhfWrk Awrtimkxr. 19&1 AMF.IIICAN 155'CIIIA'fI11C ASS(K:IATI(/N. fAnnnnrir anA Stoorurrral Mnnrrnl M Aln+lullhuvdern,1'M1Ld Fdition, fievlsN. WsllinIXlan. RC:: Amerknn I4yrhialrie Axwlnt!nn, IYXi. ' ARhitil'ItUNG.N/NFS. lt. Tolmrm. h.. use nml ydur.e Pmm thq urrrau and nrculul nxlmrt rmn[r /IN:&19, 1927. INIR5R1',.1.1.. ('nutrrd orI he Inbaccn 6nlril Annnlxn(hrrrrnnl A1Midu InMIGGX f21, 1!1:6 CIIAII(11YSK1. J.11EI•i.. CS AAvuurrvnnrr in Ihe Annfr:u nxdT-m/mrnnyBmn.frnp I4hnm•u; NIUA IlrnurcL Mnn.~RrnpL el. US Ib)mrtment of lirmltlr mM Homns Srrrkex, I'uhlia lbnhb Serrice. Alrnlwl. I1ruR Abnse, and Menlal Iknllh AAminiqrnlBxr. Nminual Inxriluro mr Dnn; Almr . DIIII51'nblimlinn Nn.IAbMI n:6/2M5, I9%7 (lltl'1"/., E It. Smnkirrq belwvtru' nurl IoLUecn nbuxe. In: hlellu. N.K o-A I Arfl+mccx m Sr.AxMnrr.lhnx. Vulume 1. Ureenwich,(bnuedicucJA11'reu, IRIAI, pp.91-IStl. I IRNNINCFIELIL J F. 14hnvhual p6anmuobrµy M cfRnreue nnwkinR.ln: ThmmM1Urn, t'.Ikexx, I'il, Hmreu.•I F.. uHs.IA•Ironcex rn /(chnniuu! I'Anrmnn•l,vn: Vrduna• / Urlwuln: Arr.d.mir ISru, I!sll, P, I:I62H1. .IAltl'IK. M1Lk,. (:ULLF:N. J. W, Clt/'IY.. E II, Y[N iT.'1'.M, 1S'F3C 1. J/xdx I Reurrrh •rn Snrnking Rchrrrhu~ NIUA Nenearch Mo<mgnqrl: 17. U S. Iklwr4nem of 1lealth. Rlucrtlion. nnA Welhrre, I'uhlic Ilerd!h Service, Alcohol. 11ruA Abuse, end Mentul Ilndlh Admini.rlnrtirm, Nnlhoml lnstiune on IIruR Alrune_ UI IR W I'nblkuUnn No. (AUM) iR uNl, 197] JUIINhT(W. 1•M. T•dcrrrn annrkinR nnd nirntin. Imnwl 2942, 1912, KIL1111(EVII'II. D A. IM f 1lnnrlA..t rN£.rl.rnrrmrnf /'hnr'nrmrdwn nr.rlen Sprineer.VnrlnR. 1`lH1, Ip. 1. 8 . KIIASNFXIOR, N.A- r<.1.I SrlFAdxuuisnnlirar /q AAusnf .Suhsrnnrrv.r: MrlArdr firr .Srur/r Nlfl.t Hesnurb MnnryrnPh 20 LfS.lklmrlnrrntnf1lealth. Ednrn!iun,nnA WHfore. 1'ubhr Iknllh Servke, AlcuhuL IhvR Alm,e. and Mrntnl Iloulth Admin!xlrnlhm, Nntinnnl hrsl ilutr nn UruR Almse. IIIIEW 1'ublknliun No. (ANMI 7/1-72T, 19118 . KIIASNF.rHIR, N A. trd.l I4lmrbxnl Arrnlvrir miJ bnrlmrnt rr(Srrhrtnno- Abru•, NIUA Hesenrrh Momqraph 25. L/.S. Ilep:rrtmmot of ifenitlr. Filucu(Xm, and Welfnrq 1'ublic Uenlth Srrvkx, Afuohol, DruR Abure, and hlenlal Ifenllb Alminixtratlon. Nn/emnl Lulitnrrmr Urug ALU.eu UIIEW PuMkmiun No IAIMII 79.&19, I.q]9n. RRASNFAOR, NA. /r•dl 7h. /kharimnl Ayn1s MSmokfny, NIIIA Ilanenrdr MorvrRrnMr 26 U S. IRfxn!nu•nl uf Ilerrllh Edurruion, nml W elfarq I'ublic llrailb Sr•rvkc, Mcuhnl. DraK AGne. nml Mentnl Ilenlth Adnrinislrmkm, NxlWmd Instilute un UruR Abuse. 1111E1V !'ublknlion No. (ADh11 79d162, 19Wm, KItASN&:(IR, N.A. IMI ( µrrrr//..qnrnAiup ns n 6yendenrc H.rrxr, NIDA IAwvneb Mnury;r.ryh 2J. U.S. IMlxuenx•nr M l lrnLb, F]lunuion. nnA W elfnrn 1'ublk I leanh Srrrerr. NrvrhrA. llnµ AWr.e, nurl Alrrvnl Ilrunh Adinfniatrmhm. Nnlinnnl Inullur on UmR Above. UIIEW 1'Slblkntinn Nn. tAUAII'nl-tM!IL IB7!k• LANt'FIl'. IFNiba'iN.l :'27t), Mureh I6, IR57. LANULIiY, J.N., IIICKINSI/N. W.1.. (In Ihe IorrA larml)aix uf Ilw 1'rrlldu:nJ Ranglla mld un IIU• nnrnevk/r1 of dI(frrrnl rlm:res of nelvr Hluv'a wi(h tIM'nr lyn.'. Rnrn/ 5'••c Lmnhw @142:1 1:11. IXR.). LF:WIN, i. IMnn/nrnrvr; M+nmrr nnd 9runnlnnaR /bqe+. ThruIhr nn•/ Ahuwe . I.nuMnr Pnul. 71rnc4.'frnhm•q 19:11. ROIIERT, J.(1. TAr.Sbrr rJ 7hMuvv in Anrerfm. (L:qwl Ilill: Ihrtvaxily of Norlh Fnmlinu ISr•nx. 1449 HUSSEI.4 M.A.11. (:inarette enrokirrR: Nwurnl Malorv of n JrlwnJenre n( JLuwLr. fW/fsh Jonrnef M Medronl fLycAnhKr 1N11.1-I6. Mxy 1911 . ' RIISSFl1.1.MA.II.Tobncc„amnkinRandukminedrpendr•rre_In:ORddru.IlJ,l..mrl, P., Kdan6I/., l'npham, R E., tichmML W., Smnrt, li D. fed.d RrmrmA Adrmnmx u. A1rnAnf and 7vru Rubfrnra. New York: .Nhn Wi1rY nnd Srns, 1976, Iqr 1-4q. U.S. DF.I'ARTMENT OF If6ALTl1 AND IIUMAN SERVICES. 71m Ilrnlth ('rnxer qurmrw nfSmokmq (r•r IP..mrn. A Rrpxr n(rAr Su.,rmn Onvml. U.S. Ilela'rlment of Ilenlttr and Iluman Servirn, I'uLllc IIenIIL Servicn Uffrc< M tlre AsalAlnnt Srcrelary for Uenlth. Uflce un Srunkinlt and Ileallh 1!WAI L7.S. UEPARTMF.NT (IF IIRALTII ANI) If(/MAN SEIIVICE.S. The Ilenllh frurxr quenrra o/.SmukinR' The FAnnpnY ('isvrrcur A Rrlxx t Mthr •Sm6ean L'eemrl. 11.5 ]kWrlmenl of lleallh and Iluman Setvicea. i'uLlir llenilh Servkr•, (IfRce uf Ihn Assislant Secretary fnr Ileulth Ollice on SmakinR mul Ilruhh. Ilf IIhS I'ulOkntimr No. 11'NS/ 8150156. 1981. US UF.i'ARTMENT OF IfEALTII AND IIIIMAN SEHVECP_S ])v Ifndrh Gm.x ' ynenrrs nJSmnkmk: Canrv. A R<ryrrr Mrhe.SSrrprrrn (Jrnrmf. L1.8. Depnrlnr<nl nf Ilrnith .nd Ilrrmnn Servirna, puh!ic llenlth Rer.ice, officr on SnmkinR mul IIrnHL. Df111S 1'ublkxUon No IPffS/ H2k)179, 1!M!2. ll S, UEI'ARTMF:N'f OF IIEALT'11 AND IIUMAN SEKVICFS. 7Xe l0ol/h Cwnequenrro MSmn4inR'Cardrnensrnfnr llismxr A Rrynul a(lbv Su,,rnr (mrrml. 11.5. DeHarlnrenl of Nea11L enrl Itu,n Servicet. rubllc 11ca10r Serrke. Orrrr• nrr SmnkinR and 14allb. UIIIIS PuAlicalion Nn. II'ILS! M/.ri6'PW, 14R7n. US. DEPARTMENT OF IIEALTII ANI/ II(IMAN SEILVICFS. R'hr 14M'Ir SnmAr C'rqnrrrles. US. Ikpnrtmmt nf IbnltL nnd I lumnn Srrvkex, I'nhlic Ilen!th Serrire. Ille.1b U.S. DEI'ARTMENT OF HEALTIf ANU l1UMAN SEI(VICF_S. The BmHh (>rnrr- 9urnr<x MSomAinp. Chrvnic Ubakur(irc GanR IAsmre. A Rrlx.r qrlhe SurKerxr Cenrrn/. LIS. Depurtmenl nf Ileafth and ifumnn Sr•rvkes, I'uLlk Ilval/h Ser.irc, fNfke nn SmokioR and Ileallh UIIIIS 1'ublkalMn No. /1'11S) R4:4Pn15, 1!IA4n. U.S. UEPARTMENTDF IIKALTII AND I IIIMAN S611VICES. fMnp Aburr nnd lhvp Ahuu Rr•ammA, Tn'mnml RryxaY In Cnnqresa (mnr rhe .Sn,mnt brynrlmrvrl rQ NenllA nnd lfummo .Snrdrra. If.S. Ihpnrlment of Uenlth nrul Ilumun Serdres, Pubik lleelth Servke, Alroho6lbnR Abuse, and Mrnlal fl.nlllr Administrutiun, Nutirrnnl lnalitute on I1ruR Ahuse. DIIIIS I'uMkaUmr No.IADMI Kb 1372. Junump 19R4h US. DEPARTMRNT (lF 11EACI'll AND II(IMAN SF.HVICFS The HrvJfh CLnxe quenrrs n/ SmrdinM CLnrer nnd Chnrnic LxnR lFrmae fn Ihe I9w4Flare A Ryxvf o/rh. Suqrron Renrml. 11.5. Ikpnrlment of Ikal/h nnd Ilurnen Svrvken. Fublic IleNth Serricq DRice nn SmukinR and IlralUr I11111S 1'uhlicntian Nn. tl'II51 RrSIYLUt, 1!1R5. LfS. DEPAR7'MF•NT OF IIEAI.TII AND IIUMAN SF.HVI('F5. 75e flmhA (im.xqm•nrer Mlmvrlumm~.Sbm}inR. A R.P+''l.y'rhe Snrhv+w Cruemf LLS DeVam of IIm11L and Ilurnnn Serviror, 1'uhlk Ilexlth Srrvke. (Hficr mr Smukinp' mWu•m 11<nlth. 1)IIIIS 1'ublh•miun No. 11'IK'1 07 KMJH. I~Wn U.4 IIF:I'ARTMENT (1F IIF.A1.1'll ANII IILIMAN SEIIVI/4S. The ffmlrh (Ovr.r• qurncesa nf Using Snn•hr/exs fldrrrrr.. A Itrprrr n( thr ddnrnxy Ciwuurtrr. ro rhr Surpwn (reneml. U.S Iklmrlrnenl of Ilmdlh :m.l Ilrurum Servicr•s. ('ublic Ile:drh Servire, Natiunal hntiwrea nf Ilr•nltb. NIII Ihiblkntirm No t!fi2nt/, IIMICTr. LI5 IIEPAIITMENT UF ((EAUfIt EDUPATIUN, ANI) WRLFAIIF.. 7'Ar flndrA (lmnynenraMSnmkinkARrlsrfr•/IheSmarrnf:nerrnl:I1N1 LIS IM/m'Irurnl of Ilwith. FAuotino, arul Wel4re. 1'uldk 1Mx116 Ser.irv, llenlth Sr•nkea nod Mentnl Ilydlh Adminiqmtirm. DIIRW ILblhawlon Nu. tlISMI 71 -0AI:1, 1971 1 1K
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f/A. IIhPARTMENT (IF IIKA1.1'IL NDI/CATION, ANI) WELFARF.. Tbe IfmisA (SnrcMnrnnryr.Swruknq(. A ftrlan( Mrhe SrnKrun (:mmrlr 1972. U.S Ilepartnu•nt o( Ileultlr. Faurorimr, urd Welfnre. I'ublic Ilualth Serrke, Ilealtlr Serricea nnd Mrnlal Itrnllh Mtminhlrntum. UIIBW PubliceUOn No. (fI5M1 727516, 1992. IIS. IJEI'AIIT'MF.N'F OF NF:ALTIL FIDF/(:ATION, AND WELFAIFE 77m Ilndlh C'unsepuMms u/ SmrJinp l95. U3. Deprtmenl of Nenlth, 6ducatlon, rval Welfnre. Publk Iir•nlt), 8mvirz, 4'<nter fer Dluase (:ontroF DIIEW Publkmimr No (('U(Y 77 8704. 19'15. I 119. IIF.I'AIITM6NT OF I/EALTII, FIl)UCATIDN, AND WELFAIIE. The NrnltH aa,..../rrrnrr„q(.SnruFmp 19771978 11.S. Depemnent of IlenllA, FAucalion, nnd Wri(ure, l'uhlic fleallh Sa•rvire. UfBte M the Auielnnt Secrelary for IlenDh. Uffim on Smokin und Ilealth. INIEW PuMioliun Na, IPIISI T959U64 1999. l/S UF:1'AR1'MEMf OF IfEALTII, F.UUCATIDN, AND WF,LFARR. Snmk(np mrd I1enItA: A HrPOrr n/tAe.SnrA Gexnnl. II S IM(wnmmfit of Ileellh, F4ucallnn, nnd Wcifnre, 1'uhlic Nenlth Servire, U(fHe of /he Aurrlnnl SeeMlary fM Ileellh. Off r on SnaMinR unJ IIed1A. UIIEW Publiartion No (PIIS) 7951yaYt, 1979. IIS. PIIRLIC IIHAL9'll SF.RVICE. SmuAinA and /fec/lh. Rrpurf rq fAe AdMexy f.wmirrre to lAe Smpnm flennnl n(the Pnhlfr I/mRA.Srrvice. 119. Ucpndmenl nf I lenllh, Edacallon, anA Wclfnrq Publir IbaUb Srrvim. Grreer for flisrase fbnlurl. IRIS Publicatiun Nc. 1103, 19fH. ILF. I'1111LIC 116AI,TI1 SERVICE 7Ae Ilmtth Cra..epurnrer el SrnokiaRA PuElir Serrtior Reriwn. 1967. US. Deperlnvnl of Ileell4 Fducalon, and WelGre, Ibbl'u IlenDh Serview, Iluallb Servicesnnd Mmdl Iledth Adminulnrinn. PIIS Peblkn• tbn Nu 1699 Itcrhed, 195t1o. fIS 1'liRi.lO NEAL711 SERVICE lfie /tralfh (bnsequenres n( Smnk/np 196A SnlNl.ment to the 1967 PoAArHrnRA Sernire Rruiexa U$.Ihlrrtmenl uf Nedrir, Fdurnlfon, nnd Welfare. Public Ile>Ith Servre. Iledtlr Services nnJ Mentnl ileai/h ddminbtmliun. I111t:W I'uMirnlinn Nn. Ic96, 19686. 11.3. 1'l/BLtC NF:A/.711 SF.RWCF.. 78e IlruliA PnnaMnnrcra u( Snrnkinx 19F9 Srrly'Imum to /Ar l9i7 N.Ahe Bml/h Sen.ce Rrmew Ikperbnenl of NeWh. Fducwton, nnJ Wel(.re, PuLlk NeNth Servitx, lledth Servicea and Menlul Ilealtlr AAsn{nietntion. IHIBW PubBcation Nu. /lMI)2, 1.969. IIS PURL/C NF.ALTII SF,R VIC& 7Mr NreltA 6tmsMnenret u/Snr.J/ng. A Rr•p.n," (Ac Surgtan (:enrraL U.S. Ihparlrroent nf fleollh, Educalwm and Wnlfare, ILblic Ileidtb Rrrvire, fknllh Servitta nnd Menml Flenllb Atlminislmlhm- UNKW flbRration No, 1113M1 T89991. 1973. U 4 PUR)AC 1IF.ALTII SF.RVICF 7rie NrnRh Ciwsepronm rt-SmnkinA. 1974. 11.5. Iklmrtment M IierJlh, Rduralien, nnd Welfun.l'ublic Ileulth Rervke, (krrter fnr Ulmnse (:onlrnl. OfIRW Publicn(ionNo. (CIM)) 74l70(. 197t. 11.5. Pll IILIC IIEACfI l SERV ICE. TAe Nenltk Qmerqurntw rrf,Snrokiryp. A ReRrenrr F.knr•wr 1916, IIS. Uepm Imrnl of Ilnhb, F.ducntFon, arvJ Welfare, Ivbhv Ileath Senice (knler for 1)iaerur l•ontrol. UIIEW Publioelion Na. (C11C1788757, 1976. VOLLE, R.1.. NicMiniv pnltliumrtimulalinR apenb. 1Marmandr,Ay n( (:nngllonir 7Mnsmicsi.m .4R81-:MR, 19ND. - CHAPTER II NICO'I'INE: PHARMACOKINETICS, METABOLISM, AND PHARMACODYNAMICS 2(1 21
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J CONTENTS ----- ---- -- In truduction ...........................................................25 Nicotine and Other Alkaloids in Various Tobacco f'rod- ucls ...................................................................26 Phannacokinetics and Metabolism uf Nicotine .............29 Absorption of Nicotine .......................................29 Distribution of Nicotine in Body Tissuen ...............31 b7liminntion of Nlcotine.... ............. .. .................33 Pathways of Nicotine Melabolism.._ ..............34 Rate of Nicotine Menabol(sm.........................37 Renal Excretion ..........................................37 Nicotine and Cotinine Rkwd Levels During Tobacco Use ..............................................................37 Nicotine Ixvels ...........................................37 Cotin ine Levels ...........................................36 Intake of Nicotine ........... .......................... ...... .AII Cigarette Smuking .......................................4Q Elimination Rate as a Determinant of Nicotine Intake by Cigarette Smoking .....................40 Biochemical Markers or Nicotine Intake......... 41 Analytical Methods for Measuring Nicoline and Cotinine in Biological Fluids .............................42 Phnrmncudynumics of Nicotine ..................................43 General Considerations .......................................43 Dose-Respunse ...................................................44 Totern nce .........................................................44 Acute Sensitivity ...............................................46 fluman Stu4ies ...........................................46 Animal Studies ................. ...........,..............46 Mechanisms of DiRerences in Acute Sensi tivity ...............................................47 Tachypbylaxis (Aqute Tolerance) ..........................47 tluman Studies .......................... .................47 Animal Studies ...........................................49 Mechanisms of Tucbyphylaxis....................... 4f1 Chronic 'folerance .................... ........... :.............. 50 Ilunum Studies .... ....................................... Cdi 23
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Animal Studies ...........................................61 Mechaniems of Chronic Tolerance ..................63 Pharmatodynamics of Nicotine and Cigarette Smok- ing ...............................................................66 Constituents of Tobacco Smoke Other Than Nicotine With Potential Dehavioral Effects ...........................66 Minor Tobacco Alketoide ...:................................. 66 "Ter" and Selected Constituents of Tobacco Smoke Which Contribute to Taste and Atoma ...............68 Carbon Monoxide ...............................................69 Acetaldehyde and Other Smoke Constituents..........60 Summary and Conclusions ........................................60 References .............................................................62 Introductton Chemiculs with behavioral and physiologicid ;rclivity are delivrrvd to tobacco users when they smoke a cigarette ur use other tobacco products. Whether these chemicals are absorbeA in quantities [hnt are of biological significance and whether such aburption is related to the behavior of the tobacco user are critical issues in undersbmd- ing their role in addictive tobacco use. The scientific study of the nbsurplion processes, distribution within the body, and elimimdion from the body of drugs and chemicals is called phnnnaenkittelice. The study or drug and other chemicnl actions on the Ixaly, over li;ne. is called pharmacodynamics. Phm'mucokinetic and pharnmenxlynnmic studies can bo dnue separately or logethcr. An example of the latter is when o drug is administered and its concentrations in the blood and its behuniornl nnd physiological actions ore nieasured over time. Such studies can reveal relationships among the dose of a drug, levels in the blasl, nnd effects on body functions. The phnrmarokinclics and phnrmacodynnmics of some tobncco smaka constituents, pnrticularly nicotine and carbon monoxide, lmve been extensively studied. These studies show an orderly relationship between the use of tobacco and the absorption of nicotine. Similarly, the effects on behavioral and physiological functions, ulthough complex, are orderly and related to the pharmncokinetics of nicotine. These data will be reviewed in this Section. Resenrcb shows lhnt nicotine is welt absorbed 6'om tobacco; that it is distributtvi rapidly and in biologically active concentrations to body argmcs, including the brain; and that nicotine is the major cause of the predominant behavioral effects of tobacco nnd sanle of its physiologic conse. quences. One effect of nicotine, development of tolerance to its own actians, is similar to that produced by other addicting drugs.'Poterance refers to decreasing responsiveness to a drug or chemical such that larger doses are required to produce the same magnitude of effect. Tolcrance to many actions of nicotine occurs in nnimnls and hummu. Evidence for tolerance to nicotine and mechanisnss of tolerance development will be reviewed in this Chapter lsee nlso Chapter VII. Although nicotine has long been considered as the primary pharmacologic reason for lobacco use, and the source of a number nf the physiological effects of tobnttu, thousands of other chemiculs m'e present fn tobacco. Most of these are delivered in such snmlt quantities that they appear to have little or no behavioral conse- quence. liowever, a few chemicals do oppear to have bchavioral effects and there is a potential for numerous chemical interactions that conceivably could have behavioral consequences. This Chapter will cunctude with an exumination of tob:mco smoke cunstituents 7 24 ' 25
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other titiot nicotine I/uu mny cnnlrihule In bohaviorul effects of' cigmrtle smoking. The tnxicity uf nicntine is discussed in delnil in Appendix R. Nicotine and Other Alkaloids in Various Tobacco Products Nicotine is a tertiary amine composed of a pyridine and a pyn'olidine ring (Figure I I. Nicotine may exist in two differerlt lhree- dimensionally struchurd ahapes. called stereoisomers. Tobacco contninn only (S)-nicotine (also callvd bnicotine), which is Ihe most phmmncologically uctive fnrrn. Tobacco smoke also contains the less potent IR).nicutine (also celled d-nicotinul in quantities up to 10 percent of lihe total nicotine present (Pool, (7odin, Crnoks 1985). Prexumnbly wmle racemiaatinn occurs during the combustion pro- cws. 'lbe nicutine yfeld uf cilprreurs, us determined by atsndnrdized nnmk6tg machine tests, is available for most brands. However, the amount of uicotiue in cigaretles or other tobacco products is not specified by mlmufnclurers. Necnuse lobscco is a plant product. there are dil'ferencea in Ihe umount of nicotine nmong and within different types tmd st rnins of tubncco, i ncluding variations in different pnrts of the plant, as well as difl'erences related (n growing conditions. Table I shows concentrations of nicotine and other alkaloids in several different tobacco lenves used in making commercial tobacan prod. ucts. Within a tobacco plant, leaves harvested from higher stalk positions have higher concenlralions of nicotine than from lower stalk frositions; rilxe nnd stems of the leaves have the least (Rath- kmap, Tso, / loftmnnn 1973). Combining different varieties of tobacco nnd di(ferent parts of the plant is a wny to clmnge the nicoliue concentrntion nf cnnmlerciai tobnccn. In a study of mnnunts of nicotine hr the tobacco of 15 American ciguretle br:mds of differing machine-determined yields (Ilenowitx, Ilail et nl. 1983), tnbncco,conlnined on average 1.5 percent nicotine by weight. Nicotine yield of the cignretles, as defined by Fedeml '1'radr Cnumtis+ion snmking nlnchine tests, was correlated inversely with nimliue cnncenlfalimts in the tobacco. Thus, hdmeco of lower- yield cignrelles trnded to have higher concentrations of nieoNtle than did tululrc» of higher-yieid cigarettes. ffowever, lower-yield cigareltes rd.so conlained less lol><teco per cigarette, so Ihe total nmomrl of nicotine contained per cignrette, averaging 8.4 mg, was simil-ar in different brands. Thus, low-yield cigarettes nre Imv yield not becnuse of lower concentrations of nicotine in the tobacco, but Imcause lhoy contain lese tohaccn arld have characteristics which remove I:u :utd nicotine by filtration or dilution of smoke with air. fkmcemrntinns of nicotine in commercial tobacco products are swnmmivd in 'I)Ible 2. wcalwt MInIMTn,alr.cnt.rt MrZnNE M nnOE pxvMrarxE) •NnMSrIE As"bn8[ME 1 MMFIInIAMAiMY! K4rn1YlM'ARAnME }yaeYnUn l„ t I ..,, r-nInNNBA9ME e6rrNROFrMPAIr/E FIGUIIE l.-Chemical structures of nicotine and minor tobacco alkalolds P.x•W r: bi..hl. Althougli l lre tnnjor alkaloid in tobacco is nicotine, there nre other alkaloids in tobacco which nray be of phnrmaculogic inlporlance. These include nornicntine, anafmshte, myosmine, nicotyrine, and anatobine (Figure 1).'Phese substances make up 8 lo 12 percent of the total alkafoid content of tobacco products 1Tnble 11(Piode and floffmann 191%1). In solne varieties of totwer.ro, nornicotine concenHn- tions exceed thuve of nicotine ISchmoltz and tluffmann 1977). Typical quantities of the minor alkaloids in the smoke of one cigarette are: nornicotine (27 to 88 pgl, cntinine (9 to 50 pg), anabasine (:1 to 12 pg), anatahine (4 to 14 pg), myosmine (9 pg). and 2,3' dipyridyl (T to 2? pgl. N'-meUtylannbusine, nicotyrine, nornicoty- rinq mid nicotine-N'~oxide have also been identified in cigarette smoke (Schtneltz and ifoffmann 19771. PutYing churacteristics, especially puff frequency, influence the delivery of the eompuuent alkaloids IRush, Gfliuwnld, Davis 1972). 2n 27
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'1'ARLE 1.--Alkaloid content of various tobaecos (mg/kg, dry basis) ' nnJ aron,xmal Idwn. B Bnky /1.yq /nnn 15.Y11 1?All/ Sm au aJJ ou yYl JW/ 51n no IW IM1Y YII nu 195 Itl YI HI a5 al 60 Su Im Ilil al m vs ~}lll 10 m TABLE 2.-Nicotine content of various tobacco products ryxmlr. ravemra,on 'rrrknl N.win+ in xn[le dn¢ ~.u¢I, d..v ~ Nfrc4x, n,1x< VM•Ik cu,..nrA I'„nl~x'1 InIN ImX/r I<4vfG Ir I,kMfW lu%, ,n n A+1 I51a:16N9rv nsl xl PMwp~alry;. nn,4 .null 1115 sl.lsf,1 11 w, Ibl mq15 r (T~+Inp IdVttu ~• 1418191.24 61 )a Ist I.nBxyrlOr T: '14wnnr.IL~11Hn1 'IIMY,'M..In.,.lelnl ,nM[,,IM1. •I~..r«,l..,r,nl ,In Nornicotine and anabasine hnve pharmacologic activity qualita- tively similar to that of nicotine, with potencies of 20 to 75 percent compared wit15 that of nicotine, depending on the test system nnd the nnimal ((linrk, Rand. Vanov 1985). [n addition to direct activity, snme of tire minor alkaloids may influence the effects of nicotine. For ex:unple, nicotyrinc inhibits the metnbolism of nicotine in animals (Stalhandske and Slanina 1982). Tbe pharmacology of the minor tobacco alkaloids is discussed in more detail in /he last sectian of lhis C15apter. 28 Pharmacoklnetlcs and Metabolism of Nicotine Absorption of Nicotine Nicotine is distilled from burning tobacco and is carried proximal- ly on lar droplets (mass median diameter 0.3 to 0.5 pm) and probably also in the vapor phnse (Eudy el al. 1985), which are inbeicd. Absorption of nicotine across biological membranes depends on pl l (Armitage and'furner 1970; Schievelbein et al. 1973). Nicotine is a weak ISUse with a pKu (index of ionic dissociation) of 8.0 (aqueous solution, 25nC). This Inenns that at piI 8.0, 50 percent of nicotine is ionized and 50 percent is nnnionized. In its ionized alate, such as in acidic environments, nicotine does not rapidly cross membrnnes. The pIl of tobacco smoke is important in determining absorplion of nicotine from different siles within the body. The pll of individual pufl's of cigarettes made of Rue-cured tobacco, the predominant tobacco in mosl American cigareltes, is acidic and decreases progres. sively with sequential puffs from pll 6.0 to 5.5 (Rrunnemann and Iloffmann 1974). At these pHs, Ille nicotine is almost completely iunized. As a consequence, there is little buccal absorption of nicotine from cigarelte smoke, even when it is held in the mouth (Cori, Renowitz, Lynch 1986). The smoke from air,cured tobaccos, lhe predominant tobacco In pipes, cigars, and in a few Furopean cigareltes, is alkaline with progressive puffs increasing ils pfi from 6.5 to 7.5 or higlter (l)runnemon and I[offmann IB7d). At alkaline pll, nicotine is largely tronionired nnd readily clussen memhnmes. Nicotine from products delivering smoke of alkaline pit is well nbsurbed through the nwulh (Armitage et al 1978; Russell, Ilaw, .larvis 1980). When tobacco smoke rnnches the small airways and nlveoli of the lung, the nicotine is rapidly absorbed. The rapid absorption of nicotine from cigarette smoke through the lurig occurs because of the huge surface area of the alveoli and small airways and because of dissolution of nieotine at physiological pff (approximately 7.4), which facilitates transfer across cell membranes. Concentrations nf nic- otine in blood rise quickly during cigarette smoking and peak at its completion (Figure 2). Armitage mrd coworkers (1975), measuring exhalation of rndiolnbeled nicotine, fmmd that four cigarette smnk. ers abeorbed 82 to 92 percent of the nicotine in mainstream smoke, another smoker presumed to be n noninhaley absorbed 29 percent, nud three nonsmokers (who were instructed to smoke us deeply ns lxnsible) absortaxl :k) to fifi perarnL Chewing lobucco, snuff, rmd nicotine polacrilex gum nre uf alkaline plt as a result of tobacco selection and/or buffering with rrddilivFS by tbe manufacturer. The alkaline ptt facilitates nbsorp- tion of nicotine through mucous membranes. The rate of nicotine absorption frorn smokeless tobacco depends m5 Ibe product nnd lhu 29 §
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o--o Cigareees k-•••A Oral srwll o---p CheWirg tobacco v-.-a Nicoli/ie gum N=10 FIGURE 2-Blond nicotine concenlrstfons during and after , smoking cigarettes (I 1/3 cigareltes/, using oral snnff (2.5 g), using chewing tobacco leverage, 7.9 g), and chewing nicotine gum (two 2-mg pfeces) .,.. ruutr of adminislantinn. With fine-ground nasal snuff, blood levels of rricnlin. rise shmrel as fast as those observed after cigarette smoking (Itussell ot ni. 198f 1. The rnle Of nicoline abwuplion with tlto use of ural snuff mtd chewin>; tobacco is more grnduul. Nicoline is Isnrrly absorbed frum lhe stomnch due to Ilte acidity of gnstric fluid ('t'ruvell 1960), but is well absorbed in the small inl(sline (femwq Cnrrod, flecketL 1973), which hns a more alkaline piI and n Inrge surface area. Binnvnilability nf nicoline frons the gnstruinteslinnl tract (thnt ls, swallowed niwtine) is incomplele because Of presyslemic (first pass) metnholisln. whereby, after obsorpliun into the pnrlal venous ciratlulion, nicotinee is meudmlized by Ihe liver before it renches the syslernie vmmus circulation. This is in cnntraslt to uicul.ine nbsorlred - through the Imtgs or urnl/nasal tnur.osn, which reaches lhe syslemic cfrculatiou without first ImcSing through the liver. Nicotine Irnse can be absnrbed through the skin. and Ihere hnve Irecn cases of poisoning after skin contact with peslicides enntaining niculine IFnulkner 19.33; Benowilz, I•rke et nl. 1987; Saxenn und Scheamn IJ&51. Likewise, lhere is evidence of culnneous nbsorptiun of mtd toxicity Gvm niculine in lnbne<n field wmkorx I(lehlbnch ol( al. I975/. 1lecnuse uf (lie semtpiexily of cigmvette snmking pnxrsses mul u+e of smokeless tobacco producls, the dostr of nicotine cannot be predicted from the nicotine content nf the tobacco m- its absoqdion chnracleristics. To dclermine the dnse, one needs to measure blood levels and know how fast Ihe individnal eliminnles nicotine. This topic, eetimalion of syslemic doses of nicotine consmned from various tobacco products, will be cvmsidered in n Inter section after discussion of relewmt phnrmacrrkinelie issues. Distribulion of Nicotine in Body Tissues After absorption into the blood, which is at pll 7.4, about (.J percent of lhe nicotine is ionixvl and 31 percent nonionired. Binding to plasnm pruleins is less than 5 prrcenl (Benowilx. Jacob et td. 1982). The drug is dislribWed exlenuively m body lissnes wilh n steady state volume of distribution avel'uging ILW liters (2.6 times body weighl (in kilagennwp /'Pable 31. This me:ms thnl when uicotfne concentrations luwe fully <vryillbrned, lbe tuuonnL of uiculine in tlte blNy tissues is 2.6 times Ilre amount predicted by the product of . blood r:uncenlrnlion and body weight. The pattern Of tissue uptake cannot be studied in humans, bot it Ims becn examined in tissues of rabbits by measuring concentrations of nicotine ft1 various tilsllefi edler infusion of nicotine to steady state (Table 4). Spleen, liver, lungs, and brain have high affinity fnr nicotinr. wherens the affinity of ndilxtse tissue is relatively low. After rapid intravennus (i.v.) injeclion, concenlrnlimts Of nicnline decline rapidly because of tissue uptake ol'lhe drug. Shortly nfler i.v. injeetion, concentrnlions in arterial blood, lun(;, aud bnein nre high, while ttIDCentrnlions in tissues such as nruscle and adiposu (major stnrage tissues nt stcudy shue) nre luw. Tllc ttmsiquencn of this ;II m
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TABLE 3.-1luman pharmacokinetics of nicotine and cotinine Nunnne CMlnine unll ore IM ntll, 1 nl n, t'ulua•.~ ~•I A,.IaIn:ru., IWI L . MI 1. nq.n,an Inb,l drn,.uue 1.11110 I12 lanq.k.v.n., sn n,L/n,in 12 ml.~nnn In[d u,:nel •'Ml.nvnrk.,,xnre I.IInnLmiu a1v.V,xe, vN'MI \- -v+'•1,I...Lr..lixitlAUn.-l4rx.wn,.ln~#nxl n'Ml•.,da-1 .xa.1.1.J n.kN TABLE 4.-Steady state distribution of nicotine T,rmn la bla! ralin eM.•1 la ] n Nn:nn: Mn•w•,.•YWb.T distribution pattern is Ihnl uptake into the brain is rapid, bccurring within I or 2 min, and blood levels fall because of peripheral tissue uptake for 20 or 30 min nfler administration. Thereldter, blood concentrations decline more slowiy, as determined by ruLes of eliminntion tmd rntes of distribution out of storuge tissues. Rnpid nindilm uptake into the brain has been demonstrated in rmimai studies. OIdendorf (1974) showed a high degree of nicotine uptake from blood in the first puss through the brains of rats. Schmiloq'16w and colleagues (1967) showed by sutorodiographic techniques thnL high levels of nicotine were present in the brain 5 min after i.v, injections in mice and that most nicotine had been cleared from the brain by 30 min. Stalhandske (1970) showed that intravenously injected 1'C-nicotine is immediately token up in the brains of Inice. reaching a maximum concentration within I min after injection. Similar findings based on positron emission lamogra• phy of the brain were seen after injection of'IPnicotine in monkeys (Muzibrc el al. 1976). Nicotine inhaled in tobacco smoke enters the blood almos} as rapidly as after rapid i.v. injection except that the entry point into the circulation is pulmonary rather than systemic venous. Because of delivery into the lung, peak nicotine levels may be higher and lag time between smoking and entry into the brain shorter than after i.v. injectiun. After smnking, the action of nicotine on the brain is expected to occur Iplickly. Rapid onset of effects after a puff is believed to provide optimal reinforcement for the development of drug dependenca The effect of nicotine decl ines as It is distributed to other tissues 'fhe distribution half life, which describes the move- ment of nicotine from the blood and other rapidly perfused tissues, such as the brain, to other body tissues, is about 9 min (Feyerabend et al. 1985). Distribution kinetics, rather lhan elimination kinetics (halGlife, about 2 hr), determine the time course of centrnl nervous system ICNS) actions of nicotine after smoking a single cigarette. Nicotine is secreted into sldiva (Russell and Feyerabend 1978). Passage of saliva containing nicotine into the stomach, combined with the trapping of nicotine in the acidic gastric fluid and reabsorption fronl the small bowel, provides a potential route for enteric nicotine recirculation. This recirculation may account for sonle of the oscillations in the terminal decline phase of nicotine blood levels after i.v. nicotine infusion or cessation of smoking h (Russell 1976). Nicotine freely crosses the placenta and has been found in mmrdotic fluid and the umbilical cord blood af neonates (Nibberd, 0'Connor, Corrod 1978; Luck et nl. 1982; Van Vunakis, Langone, Milunsky 1974). Nicotine is found in breast milk and the breast fluid . of nonlactating women (Petrakis el al. 1978; Hill and Wynder 1979) and in cervical mucous secretions (Sesson et al. 1985). Nicotine is also found iu the freshly shampooed hair of smokers and of nonsmokers environmentally exposed to tobacco smoke (Ilaley and Iloffmann 1985). Eliminatfon of Nicotine Nicotine isexlelLsively metabolized, primarily in the liver, but also to a small extent in the lung (Turner et el. 1rJ75). Renal excretion of unchanged nicotine depends on urinary pfl and urine flow, and may range from 2 to 35 percent, but typically accounts for 5 to 10 percent of Latul elimination (Denowita, Kuyt et at. 1983; Rosenberg et al. 1980). :12 33
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NKOIINE - IS.HYaXOXiNKO1MH NKOrpE1MH1HIM HKOIWE N'OXp/ FIGURE 3.-Major pathways of nicotine metabolism Pnt/lmqs's of Nilntine illeta6alisnl . The primary melaboliles of nicotine ore colinine and nicoline-N'- oxide IFigure 31, Cotinine is fnnned in the liver in n two-step process, the first of which involves nxidation of position 5 of Ihe pyrrolidine ring in a cylochrome P-450-medinled process to nicntine-41"~imini• uln ion (Peterson. Trevor, Custagnoli 19S7)t In the second step the iminium ion is metabolized by a cytoplnsnlic aldehyde oxidase to colinine (Ifibberd and Con'od 1983). Cotinine itself is also extensively mehlboliaed, with only about 17 percunt excreted unchmlged in the urine (Oenowitx. Krryt et al. 19H3).Severnl nlutaMdites ol'mtinine huve been reporled,including /rnnx-3'-hydroxycolinine (MeKennis. Turnbull et al. 1963), fr'-hydrox- yrotinine (IMwman and Mcl{ennis 1962). eotinine-N-oxide (Shulgin et el. 19871, and colinine melhanium ion (McKennis, Turnbuil, Bowman 19('i31(see Figure 4). l.itlle is known about the quanlitnl.ive importance of these metnbolites. Tmnx-3'-hydroxyrotinine appears to he m mnjor metabolite (Jacob, f3ennwilz, Shulgin 1988; NNeurath et nl- 19871, with urinary concentrations exceeding cotinine concentrn- tinnN bv twnfold to thrcefuld. Cotinine N-oxide is a minor metabolite in humons, acaounting fm' approximately 3 percent of ingested nicotine (Shulgin et nl. 1987)- Subsequent oxidative degradation of the pyrrolidine ring gives rise to 3-pyridylacetic acid. This compound has been identified in human urine (McKennis, Schwnrtz, Bowman 1!M4), but no quantitative data nre available. INwS.r NvGWXVCetNrq r.,lYe1,OXYCOIXMH NCOlNE nM1f1HMXIM XM COIXwrt 0 CoTXw,E n.o.qr NCOIryE N Ox" NOwucoTHE Yn IVneVLI YUllO N MFINY16UlYML,pE COL,.rtuErw,uX,ox FIGURE 4.-Structures of nicotine and Its major metabolites F,UKY: r J,.nn NI ,...X re,n,v.nn, ;i l 35
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Nicotiue-t'-N-oxide is quantitatively a minor metabolite of nic- otine.Oxidntion of the nitrogen atom of the pyrrolidine ring depends • on n microsomal Oavoprotein system and produces a mixture of the two diostedsomer& 1'{II)-'L'-f5)ris- and 1'dS1-2'-lS}trnna•nicotine-1'- N'-oxide (13ooth and Boyland 1970). After i.v. injection, IoO percent of Ncoline•N'-oxide is excreted unchanged in the uSine, indicating no IOf1Iln1' IIINININ)IIA01111nfkolIl fln)'Utlh ilallOpr 1071N}'Ilmvnvbrr 5ft9r ~11 Iq~llll IN lurllhll II I Ilo II Iil IM II ol uUl OINI Illn onll" nihUdul Ilhl 'Pu eoll IWII (N )IIHIII 1 III II Ih1llb IIII II II HII III ~' oxide In lhe gastrohdestinnl tract, teelul nchnlNlnltelk)Il bf Nlctlillla- N'.oxlde was performed for experimental purposes. Ixss than 10 percent was recovered in the urine as nicotine•N'-oxide (Becketl, Gorrod, Jenner 1970). These findings indicate reduction of nicotine- N'-oxide back to nicotine within the human gastrointestinal tract, believed to be a consequence of bacterial action. Experiments in rats'indicale that significant amounts or nicotine- N'-oxide are converted to nicotine both in vitro and in vivo (Uajsnl, Gorrod, Beckett 1975a,b). Nicotine and cotinine have been measured In the blood of ruts administered nicntlne-N,N'-dioxide and nicotine- N'-ox)de in drinking water (Sepkovic el al. 1984, 1986t Thus, while reduction of nicotine-N'-oxide to nicotine appears to be bacterial in humans, it may be mediated by endogenous enzymes in other species. Quantitative aspects of tbe conversion of nicotine to its melabo- liles have not been well defined. Studies of cotinine excretion in urine collected for 24 hr after i.v. nicotirre injection indicate less than 10 percent of nicotine is excreted as cotinine in nonsmokers compared with an average of 25 percent In smokers (Beckett, Gorrod, Jenner 1971b). Another study, comparing 24-hr urinary excretion of cotinine with nicotine content of cigarette butts after smoking, indicated 46 percent recovery as cotinine (.4ehievelbein 1982). 1)owever, both of these studies underestimate the conversion of nicotine to cotinine because the urine collection period was too short. In cigarette smokers, cotinine has a half-life averaging 18 to 20 hr (73enowitx Kuyt et al. 19&3), so that in 24 hr only a little more than half of calinine is recovered. Urine collection for at least 72 hr is necessary to recover more than 90 percent of cotinine in most subjects. In addition, since only 17 Irercent of cotinine is excreted unchanged (Benowilz. Euyt et al. 1983), urinary recovery analysis underestimates tlre cotinine generation rate. At stendy state, the rate o(inelabolite excretion reflects the rnte nt which the metabolites are generated. After i.v. dosing, 100 percent of nicotine-N'-oxide but only 17 percent of eotin(ne are excreted unchanged in the urine. Bosed on a ratio of urinary cotinine to nicotine-N'-oxide of 2.9 and based on excretion of that 17 percent of cotinine and 100 percent of nicotine-N'-oxide nnchanged in the urine, the relative generation rate of cotinine compared with that of nieotine-N'-oxide is calculated to be 17 to 1(Benowitz 1986b). Becnuse 4 percent of nicotine is excreted as nic.otine-N'-oxide (Jacob et at. 1986; Beckett, Gorrod, Jenner 1971n), about 70 percent of nicotine appears to be converted to cotin(ne. Quantitative data on other metuholites that mny have phnrmacningic activity, sucly as IIIIIIIIIIN It10111flllllllllllll UIII IIIIII 111111111'1d1116• i11G IIIII 9YIIIIIIIdh ~fllli, UM WIII)Iltll• ~I I IIIINli 6I 'nl 'Htr raln dh blrbllne ntnlulwllsu( cmt Itb de(eruWted Ly nwasurlhg blood levels ufter administration of a known nicotine dose. In one study, cigarette smokers were given i.v. infusions of nicotine for 30 to 60 min, nnd total and retal clearances were computed (Benowil„ Jacob et al. 1982). Total clearance (a term which describes the arpnc)ty to eliminate a drug) averaged 1,300 mL/min. Nmtrennl clearance averaged 1,100 mL/min (Table 3), which represents about 70 percent of liver. bloed flow. Because nicotine is metabolized mainly by the liver (dala in animals indicnte only a small degree of metabolism by the lung) (Turner, Sillett, McNical 1977), this means that about 70 percent of the drug is extracted front the blood in each pass through the liver. On the average, 85 or 90 percent of nicotine is metabolixed by the liver. Renal Excretion Nicotine is excreted by glomerular Gltration and tubular secretion within (he kidney. Uepending on urinary pit and urine flow rate, variable amounts of nicotine are reabsorbed by the kidney tubules. In acidic urine, where nicotine is moslly ionized and tubular reabsorption is minimized, renal clearance of nicotine may be as high as 600 mL/min (urinary p11 4.4) (Benowit, Kuyt et al. 19&3; Rosenberg et al. 1980). In alkaline urine, a larger fraction of nicotine is not ionized. Tubular reabsorption of nonionized nicotine results in lower rate of excretion and reduced renal clearances as low as 17 mL/min (urine ptI 7.0). When urine pll is uncontrolled, averaging 8.8, renal clearnnce averages about 1(H) mL/min, accounting for lbe elimination of t0 to 15 percent of the daily nicotine intake. Nicotine and Collnlnn I)lood Levels 1)ur)ng Tobacco Use Nicotine Isnefs Plasma nicotine concentrations (or concentrations in blood, which are similar) sampled in the afternoon in smokers generally range from 10 to 50ng/ml.. The increment in blood nicotine concentration after smoking a single cigarette ranges from 5 to 30 ng/mL, depending on how the cigarette ix smoked (Arm)tage et a). 197fg 9 :t6 37
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Ilerning el nl. 1983; Isnnc and Rand t972). Peak blood levels af nicotine are similaq although the rate of nicotine increase is slower for cigar smokers and snuff and chewing tobacco users compared with that for cigarette smokers (Armitage et al. 1978; Turner, Sillett. McNicol 1977; Grita et al. 1981; Russell. Rew, Jarvis 1980; Russell et al. 19811 (Figure 21 Pipe smokers, part5cularly those who have previouxly smoked cigarettes and who inhale, may have blood and urine levels of nicotine as'high as those or cigaretle emakers (McCusker, McNahb, Bone 1982; Turner. Sillett, McNicol 1977; Wuld et ul. 19841. 'fhe earliest published studies' of nicotine elimination kinetics reported half-lives of 20 to 40 min (Armitage et ai. 1975; Isaac and Itand 1972). In those studies, drug blaal levels were followed only for 3f/ to 60 min, which is not long enough to determine the elimination lull4life. Tlms, hulf-lives were based on blood levels which included the distribution phnse. When blood levels are followed far several hours after the end of nicotine infusion, a log-linear decline of blood levels with a half-life of about 2 hr is observed (Benowilr., Jacnb et al. 1982; Feyerahend, Ings, Russell 1986). The helGlife of u drug is useful in predicting its accumulation rate in the body with repetitive doses and the time course of its decline after cessation of dosing. Assuming a halGlife of 2 hr, one would predict nicotine to accumulate over 6 to S hr (3 to 4 LmlGlives) of regular smoking and persist at significant nicotine levels for 6 to 8 hr after cessation of smoking. If a smoker smakes until bedtime, significant nicotine levels should persist all night. Studies of blood levels in regulnr cigarette smokers confirm these predictions (Figure 5) (Russell and Feyernhend 1978; Benowitz, Kuyl, Jacob 1982). Peaks and troughs follow lhe use of each cigarette, but as the day progresses, tt'ough levels rise and the influence of peak levels becomes less important. Thus, nicotine is not a drug to which people nre exposed intermittently and that is eliminated rapidly from the hudy. 'fn the ronlrary, smoking represents a multiple dosing situation with considerable accumulation during smoking and with persistent levels fm• 24 hr of each day. Cutinine Iw•aef.c tbtinine Ierels are of particular interest as qualitative markers of lobacco use and quantitative indicators of nicotine intake. Cotinine is presentin the binod of smokers in much higher concentrations thmi nicoline. Cntininc bloml levels average about 2.50 to 310 ng/ml, in groups of cigarette smokers (Benowitz. Hall et al. 1983; lfaley, Axelrad, Tilton 1983; f.angone, Van Vunakis, Hill 1975; Zeidenberg et al. 1977). After stopping snmking, Ieve49 decline with a half-life averaging 18 to 20 hr (range 11 to 37 hr). But becuuse of the long - hnif-li/e, tbere is nurch less fluctuation in colinine concentrations J 50 E d ~ 40 0 ~ 'c 30 v ~ u u 20 c 0 c 10 ~o 0 m 0 12 c ~ 10 a c ~ 8 0 rn E d L x ro U 6 N '= 10 2t-I 0800 120° 16" 20`" 241n 0400 O8"0 Clock time FIGURE 6. Bloud nicotine and carboxyhemoglobin concentrations in subjects smoking high nicotine (2.5 mgl und low nicotine (0.4 mg) Kentucky reference cigarettes and their usual brand (average nicoline yield, 1.2 mg) of cigarettes nme!!A{n,,...µ.nwv,......n...w.yL.L...o-.,n,4.IM1wne.re-n.wrnnq•n• x...e.d .I]ILV+.n,r,.q,._ WWravy,M, . ..,µsl,a yn, Inl.xe ,4 ix., .InlvWl,.yu,el,. a,IIW'F. F..w+,l, Nv., --o-- Usualbrand -A- Low nicotine -.- I ligh nicoting :18 :19
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throughout the dny than ht nicotine concentrations. As expected.' there is a gradunl increase in cotinine levels during the day, peaking , at the end of smoking and persisting In high concentrations ovcrnighl. Intake of Nicotine CiRmTtte Smoking Nicotine intake from single cigarettes has been measured by spiking cigarettes with "Cdaheled nicotine (Armitage at al. 1975). That study of eight subjects, each smoking a single filtertipped cigarette, indicated an intake range of 0.36 to 2.62 mg. Intake was higher in smokers than in nonsmokers. Intake of nicotine from smoking n single cigarette or with daily cigarette smoking has been estimated by methods similar to those used in drug bionvailability studies (Renowitx and Jacob 1984; Feyerebend, Ings, Russell 1985). Metabolic clearance of nicotine was determined after i.v. injection. Metabolic clearance data were lhen used in conjunction with blood and iminary concentrations of nicotine measured during a period of smoking lo determine the intake of nicotine. In five subjects, average intnke of nicotine per cigarette was 1.06 mg (range, 0.58 to 1.49 mg) (Feyernhend, Ings, Russell 1985). In 22 cigarette smokers. 13 men and 9 women who smoked an averege of 36 cigarettes/day (range 20 to 6'21, the average daily intake was 37.6 mg, with a range from 10.6 to 78.6 mg (ftenowitz and Jacob 1984). Nicotine intake per cigarette averaged 1.0 mg (range 0.37 to 1.56 mg). Intake per cigarette did not correlate with yields obtained by smoking machine using standard Federal Trade Commission methods. This is because smoking machines smoke cigarettes in a uniform way, using a fixed puff volume (35 mIJ. flow rate (over 2 sec), and interval (every minute). Smokers smoke cigarettes differently, changing their puffing behav ior to obtain the desired amount of tobacco smoke and nicotine. Elimination Rate ns a Determinant of Nicotine Intake by Cigarette Smoking There is considerable evidence that smokers adjust their smoking behavior to try to regulate or maintain a particular level of nicotine in the body (Gritz 1990; Russelt 1976). For example, when the nvailability of cignrettex is restricted, habitual smokers can increase intnke of nicotine per cigarette 300 percent compared with the intake of unrestricted smoking (Denowitz, Jacob. Koslowski et al. 1986). ''rechniques for measming daily intake of nicotine (Denowilz and Jacob 1984) have been applied to study the influence of elimination nn nicotine intake. The rate of renal elimination of nicotine was mnniptAated by administration of ammonium chloride or sodium 44) I bicerbonate to acidify or nikalinire the urine, respectively (Ilenuwitz and Jacob 19g6L Compared with daily excretion during placebo treatmenL (3.9 mg nicotine/day), acid luading increased (to 12 mg/day) mtd alkaline loading decread (to 0.9 mg/day) daily excretion of nicotine. 7'he total intake of nicotine averaged 38 mg/day. Average blood nicotine concentrations were similar in placebo and bicarbonate treatment conditions but were 15 Ltercent lower during ammonium chloride treatment. Daily intake of nicotine was 18 percent higher during acid loading, indicating compensatinn - for increased urinary loss. The compensatory increase in nicotine consumption was only partial, replacing about half of the excess urinary nicotine loss. Bicarbonate treatment hed no effect on nicotine consumption, consistent with the sronll mngnitude of effect on excretions of nicotine in comparison to total daily intnke. These results seem compatible with lhe suggestion of Schachter (1978) that emotional atress, which results in more acidic urine, might accelerate nicotine eliminntion from the body aud thereby increase cigarette smoking. Ffut caution must be exercised in applying these findings lo usual smoking situations. These studies were performed under conditions of extreme urinary acidification or alkalinization, so that the changes in renal clearance would lie maximized. Even with extreme differences in urinary 1,11, differ- ences in overall nicotine elimination rate and smoking behavior were modest. This is because renal excretion is a minor pnthwny for elimination of nicotine; most is metabolived. Smaller changes in urinary p)f, such as occur spontaneously throughout the day or that might be related to stressful events, would not be expected to ~ substantially influence nicotine elimination or smoking behavior. Diorrkemicnf Markers of Nimtine Inrake Absorption of nicotine from tobacco smoke provides n means of verification and quantitation of tohsccn consumplion. The general strategy is to measure concentrations of nicotine, its ntetabolites (such as cotinine), or other chemicals aasocinled with tobacco smoke inbiological Ruidssuch as blood, urine, orsaliva. Different measures va,ry in sensitivity, specificity, and difficulty of analysis. Different -investigators have used blood or urinary nicotine concentrations, blood nrsnlivary or urinary cotinine concentrations, expired cnrbon monoxide or cnrhoxyhemoglobin concentrations, or plnsmn or sali- vary thiocymmte (a metabolite of hydrogen cyanide, a vapor phase constituent) concentrations as meusures of tobacco smoke cansump- tion. Relationships among daily intake of nicotine, daily exposure to nicotine (that is, blood concentrations nf nicotine integrated over 24 hr), various parameters of cigarette consumption, and different measures of nicotine intake have been examined experimentally 41 '
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during ad libilum cignrette smoking on a research ward (Benowitz and Jarob 1984). The best biochemical correlate to nicotine intake , and eaposure in this study was a random blood nicrotine concentrs- lion measured at 4 p.m. 7Yds level did not depend on when the last cigarette was amoked. This Onding is consistent with the observation that nicotine levels accunmlate throughout the day and plateau in the enrly afternoon (see Figure 6). At steady state, with regular smoking throughout the day, there should be a 1:easonably good correlation between nicotine concentrations and daily intake. Car- boxyhemoglobin (CAHhI concentrations in the afternoon were the next luust markers of nicotine intake. Also, morning (8 a.m.) levels of nicotine nnd CC116 correlated with inlake, presumably reRecting persistence of nicntine snd CCllb in the blood from exposure on the previous (lay. Although cutiniue is u highly specific marker for nicotine expo- sure, blood levels of cotinine across subjects in this study did not correlate as closely with nicotine intake as did blood levels of nieotine or CW11b (Benowitz and Jacob 1989). Thia is probably due to , individual variability in fractionel cnnversion of nicotine to cotinine and in the elimination rate of cotinine itself. Because of its relatively long half-life, cotinine levels are less sensitive than nicotine levels to smoking pattern, that is, when the last cigarette was smoked. For longitudinal within-subject-studiee, the cotinine level would be expected to be a good marker of changes in nicotine intake. Colinine measurements have become the most widely accepted method for assessing the intake of nicotine in long- lenn studies of tobacco use (see also Chapter V), . As expected by the known variation in renal clearance due to rf/'ects of urinmy Row and p11, urinary concentrations of nicotine did not correlate well with nicotine intake Ilknowitz and Jacob 1984). In controst, urinnry cotinine, which is less influenced by urinary Row, or pll, wa.t as good a marker as blood cotinine concentration. Salivary and urinary rolinine concentrations correlate well (r=0-8 to QJI with blood mtiniue concentrations (ffaley, Axelrod, Tilton 1983; Jarvis el nl. 1984). Therefore, salivary or urine cotinine concentretions should be ahnost as useful as blood levels in indieating nitroline inhtke. Analytical Methods for Measuring Nicotine and Colinine in Biological Fluids Ilelennination nf nicotine concentrations in biological Ruids requires a sensitive and specific method, because concentrations of nit'uline in snmker.s' blood are generally in the law nanogram per milliliter range and a number of inetaboliles are also present. Colinine concentrations in blood aregenerally about tenfold greater Ihnn nicotine cancentrations, and ns a result, less sensitive analyti- cul methodology may be acceMable. Methods with ndequale sensitiv- ity for determination of nicotine mrd cotinine in-smokers' blood • include gas chromatography ICCI 1Carveli, Knzemi-Valn, Enzell 1982; Davis 1986; Fcyerabend, Levitt, Russell 1975; Ilengen and Ilengen 1978; Jacob, Wilson, Benowilz 1981; Vereby, llel'ace, Mule 1982), radioimmunoassay (RIA) (Langone, Cjika, Van Vunakis 1973; Castro et ol. 1979; Knight et al. 19851, enzyme-linked immunnsorhgnt nssay (ELISA) (Bjercke et al. 1986), higb performance liquid chroma- logtnphy (I1PLC) (Machacek and Jiang 1986; Chfen, Bianu, Craoks, in press), and combined gns chromatograph-mess spectrornetry (CC- MS) (Dow and Hall 1978; Gruenke et al. 1979; Jones et al. t982; Uaenens et nl. 1985). For reasons of sensitivily, speciGcity, and economy, CC and R1A are the most frequently used metbods. CGMS is a highly sensitive and specific technique, but the expense has discouraged its rouline use. HI'I.C is Iesv sensitive than CC for nicotine and cotinine determination. Although recently reported methods (Machacek nnd ,littng 1986; Chien, 1)iann, Crooks, in press) appear to have adequate sensitivity for determining concentrations in plasma, relatively large sample volumes are required. Concentra- tions of nicotine and rotinine in urine are lenfold to hundredfold grenter than concentrations in plasma or saliva (Jarvis et al. 1984), and a variety of chromatographic and immunoassny techn iques meet sensitivity requiremenls. 'f'he choice of a particular melhod depends on the biological fluid to be assayed; the need for sensitivity, precision, and accuracy; and economic considerations. Chromatographic methods, particularly those utilizing high-resolution capillary columns and specific detec- tors such as nitrogen-phosphorus detectors or n mass spectrometer, provide the greatest specifmity. On the other hand, immunoassay techniques are operationally simpler, generally require smaller samples, and may be less expensive than chromntographic methods. A drawback to immunonssny methods is tbe potential fm' cross- reactivity of the nntihody with metabolitas or endogenons sub- stances. There is generally a good correlation between results obtained by CC and It1A for plasma cotinine concentrations (r=0.94) (Critz et al. 1981; Biber et al. 1987). In an interlaboratory compnrison study (Biber et al. 1987), colinine concentrations in smukers' urine measured by RIA were generally higher thun concentrations deter- mined by CC, whereas in nonsmokers urine spiked with rotinine RIA and CC values were similar. These results suggest lhnt nicotine metabolites cross-react with the antibody against colinine, at least in snme of the RIA methods. Pharmacodynam/ca of Mlcotlne General Considerations This Sgction will focus on the relationship between nicotine levels in the body and their effects on behavior and physiological function 4'1 43
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(phannacodynnmics). These data show how pharmncodynamic fno ~ tons determine some of the consequences of cigarette smoking. Two issues are particularly relevant in understanding the pharmacody- numics of nicotine: a complex dose-response relationship and the level of tolerance that is either preexisting or hs produced by administrntion of nicotine. I 1)ose-Respanse The relationship between the dose of nicotine and the resulting response(dose-response relalionship)is complex and varies with the specific response that Is measured. In pharmacology textbooks, nicotine is commonly mentioned as an example of a drug which in low doses causes ganglionic stimulation and in high doses causes gunglionic blockade following brief stimulation (Comroe 1960). This type of effect pattern is referred to as "biphasic." Dose-reepnnse characteristics in functioning organisms (in vivo) are often biphosic as well, although the mechanisms are far more complek. For example, at very low doses, similnr to those seen during cigarette smoking, cardiovascular effects appear to be mediated by lhe CNS, either lhrough activation of chemoreceptor afferent pathways or by direct effects on the brain stem ((lomrae 1960; Su 1982). The net result is sympathetic neural discharge with an Increase in blood pressure and heart rale. At higher doses, nicotine may act directly on Ihe peripheral nervous system, producing ganglionic stimulation and the release of adrenal calecholamines. With high doses or rapid administration, nicotine produces hypotension and slowing of heart rate, mediated either by peripheral vagal activation or by direct central depressor effects (Ingenito, Barrett, Procila 1972; Porsius and Van Zwieten 1978; Elenningfreld, Miyseato, Jnsinski 1986)- Toleranee A second pharmacologic Issue of importance is development of tolerance; that is, after repeated doses, a given dose of a drug produces less effect or increasing doses aro required to achieve a specified Intensity of response. Punclional or pharmacodynamic tolerance con be further defined as where a particular drug concentration at a receptor site (in humans approximated by the concentration in blood) produces less effect than it did after a prior expnsure. Dispositional or pharmnrokinelic tolerance refers to nccelernted drug elimination as a mechanism for diminished effect after repeated doses of a drug. Behavioral tolerance refers to compensatory behnviors that reduce the impact of a drug to adversely affect perfurmance. Such tolerance can occur following intermittent exposures to a drug such that there is minimal development of functional or dispositional tolerance. Most studies of drug tolerance have focused an tolerance which develops as a drug is chronically administered. If Lhe tolerance develops within one or two doses, it is referred to as acute tolerance or tachyphyloxis. If tolerance develops after more prolonged use, the tolerance is referred to as acquired or chronic tolerance. Individual differences in sensitivity to the lirst dose of a drug also frequpntly exist. Those individuals who exhibit a reduced response to a specified drug dose or require a grenter dose to elicit a specified level of response are said to be tolerant to the drug. This fonn of tolerance is referred to as first-dose lolernnce, drug sensitivity, or innate drug responsiveness. For sake of clarity, this Report will reserve the term tolerance to describe reduction in the response to nicotine during the course of or following n previous exposure and will use acute drug sensitivity to describe responsiveness to an initial dose. Studies of tolerance to nicotine began in the late 19th century. In a series of studies of fundnmentol importance to the understanding of the nervous system, as well as to understanding the phnrmacology of nicotine, Langley (1906) and Dixon and Lee (19121 studied the effects of repeated nicotine administration nn a variety of animal species and on in vitro tissue preparations. Severnl findings emerged which have been widely verified and extended to other species and responses. These include: (1) With repeated doshtg, responses dimin- ished to nearly negligible levels; (2) After tolerance occurred, responsiveness could be restored by increasing the size of the dose; (3) After a few hours without nicotine, responsiveness wns partially or fully reslored. After smoking a cigarette, people who hnve not smoked before 4 ("naive smokers") usually experience a number of effects that become generally uncommon among experienced smokers. For example, retrospective reports by smokers indicate that initial exposure to tobaeco smoke produced dizziness, nausea, vomiting, headaches, and dysphoria, effects that disappear with continued smoking and are rarely reporled by chronic smokers (Russell 1976; Gritx 1980). Tolerance may also develop to toxic effects, such as nausea, vomiling, and pallor, during the course of nicotine poisoning, despite persistence of nicotine In the blood in extremely higb concentrations (200 to 300 ng/ml.) (Benowitz, Imke et al. 1987). A systematic analysis of the various forms of tobacco smoke tolerance has not been carried out. There are a few studies compuring the effects elicited by an acute exposure to tobacco in nonsmokers and smokers. Clark and Rand G988) studied lhe effect of smoking cigarettes of varying nicotine content nn the knee-jerk reflex and reported llml high-nicotine cigarettes suppressed this reflex to a greater degree than did low-nicoline cigarettes. This effect was more pronounced at ench nicotine dose in nonsmokers and light smokers compared to heavy smokers. These findings suggcxted that 44 45
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tolerance is due to altered sensitivity to nicotine. Tolerance to nicotine is not complete because even the heaviest smokers experi- ence symptoms such as dizziness, nausea, and dysphoria when they suddenly increase their smoking rates (Dansher 1977), Evidence indicates that the majority of the psychological actions of tobacco smoke result from nicotine (Russell 1976; Chapter V)B. Thus, most of lhe tolerance to'effecls of tobacco smoke that oFcurs following chronic tobacco use is due to the development of tolerance to nicotine. Acute Sensitivity Fhmian Studies Studies which have Indicaled that individuals differ in response to tobacco smoke or nicotine have used smokers as the experimental subjects. Consequently, whether individual differences are due to differences in acute sensitivity to nicotine that have persisted during chronic tobacco use or are due to differences in the development of tolerance is unknown. Nesbitt (1973) and Jones (1986) noted that individual smokers differ with respect to the effects of smoking a standard cigarette on heart rate, but it is not clear from theae studies whether these differences in responsiveness are due to differences in sensitivity to nicotine or to differences in tbe doee and kinetics of nicotine. Renowitz and colleagues (1982) observed individual differences in the effects of i.v. injections of nicotine on heart rate, blood pressure, and fingertip skin temperature. Differences were not explained by ' differences in blood levels, indicating differential sensitivity to nicotine. Animal Studies . Studies using laboratory animals indicate that dlfferences in acute sensitivity to nicotine exist. Inbred rat and mouse strains differ in sensitivity to the effects of nicotine on locomotor activity (Garg 1969; BiRtig et at. 1976; Schlatter and Battig 1979; Hatchell and Collins 1980; Marks, Burch, Collins 1983b) Mouse strains also differ in the direction of the effect (increased or decreased activity). The mouse strains that differ in sensitivity to the effects of injected nicotine on loromotor activity also differ in the magnitude of response to a standard dose of tobacco smoke (Beer, McClearn, Wilson 1980). Inbred mouse strains also differ in sensitivity to the effecta of nicotine on body temperature, heart rate, and acoustic startle response (Marks, Burch, Collins 1983a; Marks et al. 1985, 1986), as well as in sensitivity to nicotine-indured seizures (Tepper, Wilaon, Schlesinger 1979; Miner, Marks, Collins 1984, 1986). These findings indicate that genetic factors may influence the sensitivity of rats and c miee lo the first duse of uicotine. The importnncre of genetically determined differences in humnn sensitivity to the effects of nicotine administered in tobacco smoke renwins to he determined. Mechanisms of Pif/'eratees in Artrte Sensitimfv Differences between inbred mouse and rat strains in sensitivity to the etfects elicited by a single injected dose of nicotine do not appear to result from differences in rate of nicotine nietabolisn, (petersen, Norris, Thompson 1984) or from differences in brain nicotine concentration following intraperitoncal injection (Ilalchell and Collins 1980; Rosennns 1972; flosecrans und Schechter 19721. Thus, rat and mouse strains differ in lissue sensitivity to the efkcts of nicotine. Differences umong mouse strnins in sensitivity to nicotine do not appear to be due to differences in the number or nffinily of brain nicotine receptors that are measured via the binding of '11- nicotine (Murks, Burch, Collins, 198661. Mnuse stocks that une mnre sensitive to nicotine-induced seizures do hnvee greater uumbers of hiplwcampal nicotine receptors that hind "'l-bungm»loxiu (B9'X) (Miner, Marks, Collins (984, 19II6). Some of the diffcreuces in sensitivity to nicotine between genetically defined stocks of animals may be related to differences in the number of nicotine receptors in specific regions of the brain. Tachyphylaxis (Acute Tolerance) Human Sturfies Systematic studies of tnchyphylaxis or acute tolerance to effects of tobacco in nonsmokers have not been t'epurted. There is evidence ry that lachyphylaxis does develop to effects of tobacco and nicotine in humens. Smokers frequently report that the first cigarette of the day is the best and that suhuquent cigarettes nre "tastele.cs" (liu.cull 1976; Ilemringfield 19g4f. Smoking a single sluncherd cigarette after 24 hr of abstinence increases hent ru(e, whm'cn9 smoking an identical cigarette during the course of a nmmal day fnils to change heart rate (West and Russell I987). Fewer standard puffs were required to produce neusea at the beginning of the day (following 8 to 11) hr of tobacco nbstinence) or from high-nicotine cigarettes thnn at the end of the day or from low-nicutine cigarettes (lienningfield 1984). Complete tolerance to nnuseo and vomiting developed over 8 hr in a woman in the course of an nccidenlal nicolino pnisnning, despite persistenlly toxic blood levels of nicotine (Iknowitz, latke et al. 1987). These findings suggest that tolernnce which is loat and regained during short periods of abstinence from luhnca> is tolerance to nicoline. Tolerance develops very rapidly to several effecLs of nicotine. Rosenberg and colleagues (1980) sstudied Ihe effects of i.v. nicotinu 47 46
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injections on arousnl Ievel, heart rate, and blood pressure. In these experiments, six healthy smokers, 21 to 35 years of age, received six series of nicotine injections spnced 30 min apart. Each series of injections consisted of 10 2-pg/kg injections spnced I min apart: Subjects reported a pleasant senzntion after the first series of injections, but this response wos not observed thereafter. Neart rate and blood pressure values remained above baseline,'but there was .little increment with euccessive.injections, despite nicotine blood level increases which were similar to those observed after the first series of injections. In contrast, skin temperature fell progressively during the period of nicotine dosing, gradually returning to buseline at the end of the study. These data indicated rapid development of tolerance to subjective effects and heart rate and blood pressure responses, but tolerance was not complete because heart rate and blood pressure remained above baseline. llenn(ngfield (1984) also assessed subjective responses of human subjects after I.v. injections with nicotine st 10-min intervals. The subjective response of "liking" the effects of nicotine was last after five or six injections. Renowitz and coworkers (1982) studied the effect of a 300.min Infusion of nicotine at a rate of 1 to 2 pg/kg/min. Shortly after initiation of Infusion, heart rate and blood pressure increased, but the Increase did not continue even though plasma nicotine concentrations continued to rise during the continuous infusion. Maximal cardiovas- cular changes were seen within 5 to 10 min, whereas maximal plasma nicotine levels were not reached unti130 min. These findings indicate that taclryphylaxis to the effects of nicotine may develop in humans within 5 to 10 min, the time required to smoke one cigarette. In contrast to heart rate, skin temperature (reRecting cutaneous vascular tone) declined and rose in associetion with changes in blood nirotine concentrations, showing no evidence of tolerance. The above studies indicate rapid developmentof tolerance to some (but not all) actions of nicotine in people. These etudies were performed with cigarette smokers who had abstained from smoking the night before the study. Since significant quantities of nicotine persist in the body even after overnight abstinence, there is probably some persistence of tolerance. Experimental data supporting this conclusion were obtained in a study of cardiovnscular responses to infused nicotine in smokers following either an overnight or 7yfay lobacco abstinence (fxe, Renowitz, Jacob 1987). tlearl rate and blood pressure responses were significantly greater after more prolonged abstinence. However, within 60 to 90 min, theblood concentra- tion-offect relationship in subjects after brief abstinence npproxi- mated that observed after prolonged abstinence. Thus, a significant level of tolerance persists throughout the daily smoking cycle, but is lost with prolonged abstinence. 'I'olerance, at least afteir abstinence for one week, is rapidly reestablished with subsequent exposure. Animaf Studies Many studies demonstrate that acute tolerance or tachyphylaxis develops very quickly to actions of nicotine. Darrass and coworkers (1969) demonstrated that pretreatment of mice with a single i.v. (lose (0.8 mg/kg) of nicotine resulted in an increase in the hD,o (dose whlch is lethal to 50 percent of animnls) far nicotine. Maxinml protection was seen 5 min after the injection, but this protection diminished steadily over the next hour. Tachyphylaxis develops td the effects of nicotine on locomotor activity. Stolerman, Bunker, and Jarvik (1974) noted that pretreating rats with a 0.75-mgikg dose of nicotine 2 hr before challenge doses of nicotine (0.25 to 4.0 mg/kg) resulted in a shift of the nicotine dose-response curves, indicating reduced sensitivity. The EDro values (doses that nre effective in producing lhe measured response in 50 percent of animals) for nlcotine-indueed decreases in lacomotor activity were newly 2.4-fold greater in nicotine-prelreated rats than in saline-pretreated animals. Nicotine pretreatment also results in tachyphyiaxis to the effects of nicotine on body, temperature (hypothermia) in cats (llall 1972), water-reinforced operant responding in rats (Stitzer, Monison, Domino 1970), discharge of lateral geniculate neurons of cats (Roppolo, Kawamura, Domhm 1970), repolariznlion of sartorius muscle in frogs (Hancock and Henderson 1972), blood pressure elevation in rats (Wenzel, Azmeh, Clark 1971), contractinn of uortic strips in rabbits (Shiham, Hattori, Sanders 1971), respiratory stimu- Intion in cats (McCarthy and Rorison 1972), and gastrointestinal contraction in squid (Wood 1969) and guinea pigs (Nabhigcr. Mitchel- son, Rand 1969). More recent studies hnve demonstrated that pretreatment with as little as one dose of nicotine will attenuute nicatine-induced elevations of plasma corticosterone (Rulfour 1980) and adrenocorticotropic hormone (ACTfU (Sharp and Reyer 1986) levels in rate (see also Chapter 111). The interval between the pretreatment and challenge doses of nicotine is a critical factor that determines whether lachyphylnxis is observed. Aceto and coworkers (1986) examined the effect of I.v. nicotine infusion on heart rate and blood pressure in (lie rnt, Tolerance did not develop when the interval between pretreunncnt and challenge doses was 30 min; marked tolernnce was detected when the interval was reduceal to 1 min. Ilowever, Stolennan, Fink, and Jarvik (1973) observed thut after a single in traperitoneal dose of nicotine to rats, acute tolerance to a second dose did not become mnximal until 2 hr after the initial injnction. Mechanisms of Tnchyphylnris Although tachyphylaxis has been described for a wide variety of nicotine`s.effects, very little is known about mechanisms. A nicotine 4!) 48
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metnlwlito tnuy pluy n role in the development of Lachypbylaxis. llarntss and colleagues (19691 argued flint nicotine metabolites may , block nicotine receptors and thereby antagonize nicotine's lethal effects. This argument was made because pretreatment with nic- utine-N'-ox{de prntected mice from the lethal effec/s of Inrge doses of nicotine. 1A.n values were increased approximately ninefold by prctreatment with nicotine-N'-oxide. These authors hypothesized flint tLis protection may involve conversion of nicotine-N'-oxide to hydroxynicMine.'fheir results indicnted that injection ofn reduction pn.)uct of coliniue, believed lo be hydroxynicotlne, gave inunediale prntectimt, whereas maximum protection was not seen until 40 min nfter injectinn of nicoline.N'-oxide. Thus it appears that metabolism, possibly to hydrnxynicoline, is required for the protective action of ninn.ine-N'-oxide. Another hypothesis is flint tachyphylaxis Iss the result of desensiti- zmion of nlcotine receptors. Desensitization of the receptor involves a conforma(imml change flint results in increased affinity of the nicotinic receptor for agonists coupled with decreased ability of the receptm• to transpm4 ions (Weiland et al. 1977; Sakmonn, Pntlak, Neher 19g); 13oyd and Cohen 1984). Desensitizat)on of nicotinic receptors at the motor end-plate was first described by Katz and Thesleff (1957) and has since been studied by a(orge number of investigators, using either skeletal muscle or the electric organs of the eel, 76rpeJn rnlifeunico. Although tachyphylaxis has been romnuuly suggested as being due to desensitization of brain nicotinic receptors, the role of desensitization in tachyphylaxis to specilic behavioral effects or nicotine Ims not been studied. This is Imnmse concentrations of nicotinic receptors in specific areas of the brain corresponding to the behavioral effects being measured are not high onough to use nvailahfe methods. Chronic Tolerance flummn Shn7irs Chronic tolerance to tobacco and nicotine has not been studied systematically in human subjects, but it is clear, as noted previously, flint snnre tolerance does develop. Tolerance is not complete; symptoms of nicotine toxicity such as nausea appear when smokers increase their normal tobacco consumption by as little as 50 percent (Dunaher 1977). These findings are consistenl with the observations that smokers incrense their tobacco cunsumption and intake of nicotine with extMrlence. Such escalating done patterns may be observed for severnl yenrs nfter initiation ol' either cigarette smoking or smok- eless tobacco use. Cigarette smokers may achieve such increases by augmenting lhe number of cignrettes smoked and by increasing the amount of nicotine exb'netcsl from ench cigarette. Fbr usem of emokeless tobacco, switching to products with greater nicotine delivery may also contribute to nicotine dose escalation (US DIIIiS 1986). Animal Studies Animal studies have proved useful in establishing the actual development of tolerance to nicotine, the magnitude of such tolei- once, and mechanisms that underlie this tolerance. The majority of these studies have used the rut and mouse as experimentnl subjects. . Most of the chronic tolerance studies using the rat have focused on the effects of nicotine on locomolor activity. Depression of locomotor activity typically occurs following the injection of nicotine in doses exceeding 0.2 mg/kg in drug-nnive ruts. Tolerance to this depression develops following chronic treatment (Keenan and Johnsun 1972; Stolerman, Fink, Jarvik 1973; Slolertnan, Kunker, Jorvik 1974). The magnitude of this tolerance is influenced by the dase and dosing interval. Tolerance persists for greater than 90 days when nicotine is Injected chronically. Tolerance to the effects of injected nicotine on depression of lacomotor activity could also be produced with nicotine administered in the rats' drinking water or through suhcutnneously implanted reservoirs (Stoterman, Fiuk, Jarvik 1973/. Under certain experimental conditions, rats trented chronically with nicotine exhibit an increase in locomotor activity following nicotine challenge (Morrison and Stephenson 1972; I)aA5ttig et al. 1976; Clarke and Kumar 1983a,b). A careful analysis of the response to an acute challenge dose of nicotine demonstrated flint soun after the first dose of nicotine, depressed locomotor activity was observed; after 40 min or more, increased locomotor activity became apparent (Clarke and Kumar 1983b). Chronically injected rats exhibited this enhanced activity progressively earlier postinjection. More recently, Ksir and others (1985, 1987) demonstrated flint chronic nicotine Injections may result in enhanced locomotor netivity immediately nfter nicotine injection if the rats were acclimated to the test apparatus for I hr before nicotine injection. These findings Indicate lha[ in the rat, tolerance develops to the depressant effects of nicotine and that thie tolerance uncuvera s latent stimulatory action. If miceare injected chronically with nicotine, tolerance develops to the loromotor depressant effects elicited by a challenge dose of nicotine (Hatchell and Collins 1977). The degree and rate of development of tolerance appear to be influenced by the sex, as well . as the strain, of the nnimals. Tolerance development has been studied by continuously infusing mice of severul inbred strains with nicotine and assessing tolerance by measuring locomotor activity, body temperalure, respiratory rate, heart rate, and acoustic startle response,following nicotine challenge. Such studies have demon- strated thnn (1) Tolerance !n nicotine increases with the nicotine ,u 51
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infusion dose (Marks, Burch, Collins 1983a); (2) Tolerance is specific . fornicoliniccholinergicegonistsinthntnicatine-Infusedanimalsare . not crusstulernnt to the muscarinic cholinergic agonist oxolremo- rine (Marks and Collins 1985); (3) Maximal tolerance is attained within 4 days following the initiation of infusion and is lost within 8 days following thecessation of infusion (Marks, Stitzel, Collins 1985); (4)Tolernncedevelopmentvariesbetweeninbredmousestrains,with some strains exhibiting marked tolerance and othet`etrains showing very little (Marks, Romm et al. 1986): and (5) Mouse strains that fail to develap tolerance to nicotine are also relatively insensilive to the effects elicited by an acute injection of nicotine (Marks, Stitzel, Collins 1986). More recently these investigators compared the effects of continuous and pulse infusions of nicotine on tolerance develop- ment (Marks, Stitzel, Collins 1987). Pulse infusion was used to simulate the conditions obtained when tobacco is smoked. Although the total dose infused was the same in continuously infused and pulse-infused animals, marked differences in tolerance were eeen. The pulse-infused animals exhibited a greater degree of tolerance. The degree of tolerance was most correlated with peak nicotine concentrations. Chronic nicotine administration results in tolerance to a number of other nicotinic effects. Tolerance develope to depression of operant responding elicited by high doses of nicotine, such that after sufficient chronic treatment, enhanced rather lhndepressed oper- ant responding is seen (Clarke and Kumar I ; Hendry and Rosecrans 1982). Attenuation of the effects of nico ne on electroen- cephalogram (EEC) activity is seen in the rat following chronic injection (Hubbard and Cohd 1976). These altered EEG responses paralleled the development of tolerance to behavioral effects de- scribed by these authors as "arousal." In contrast to the findings of ' Hubbard and Cohd (1975), other studies indicate that chronic tolerance does not develop to the behavioral stimulation effect of nicotine (Biittig et al. 1976; Morrison and Stephenson 1972; Clarke and Kumar 1983a,c). Likewise, little or no tolerance to,nicotineo induced prostration -after i.v. administration was observed after chronic exposure in rats (Ahoad et al. 198t, 1984). In eddition, tolerance hes been reported to develop to nicotiue- induced increases in plasma corticosterone, but not adrenal calechol- amine release in rats (Balfour 1980; Van Loon et al. 1987). Anderson and colleagues (1985) studied the effects of chronic exposure to cigarette smoke on neuroendocrine function of the rat hypothala- mus. These researchers observed that chronic exposure to cigarette smoke over a period of 9 days did not result in tolerance to the ability of acute intermittent exposure to cigarette smoke to reduce serum levels of prolactin, luteinizing hormone, and follicle stimulating hormone. dfechanfsms of Chrnnic Toffrmncr Chronic tolerance to drugs may be due to on increase in the rate nf drug metabolism or to a decrease in sensitivity of the tissue to the drug. Considerable differences exist among humans in tbe rate of nicotine metabolism (Benowitz et al. 1982). Metabolism is faster (shorter helf-life) in smokers than in nonsmokers (Schievelbein et al. 1978; Kyerematen et al. 1982; Kyeremnten, Uvorchik, Vesell 1983)~ The contribution of enhanced nicotine metnbolism to the develop- ment of.nicotine tolcrancq in hmnans is unclear, Studies or rats which clearly demonstrate titat chronic nicotine treatment results in tolerance to nicotine also indicate that chronic nicotine adminislra- tion does not incredse the rate of nicotine metnbolism in rats (Takeuchi, Kurognchi, Yamaoka 19541 or mice (Iiatchell and Collins 1977; Marks, Burch, Collins 1983b). These findings indicate that tolerance to nicotine primarily Invnlvere reduced sensitivity of tnrgel tissues. Chronic tolerance to nicotine may be due to alterations in brain nicotinic receptors (see Chapter III for further discussion of nicotine receptors). At least two types of nicotinic receptors exist in rodent brain (Marks and Collins 19821. One of these receptor types may be measured with 'fl-nicotine or 'H-acetylcholinc ('H-ACh) (Marks, Stitzel et al. 1986; Mnrtino-Borrows and Keller I987), while the other type may be measured with "'1-bungarotoxin (BTX)..7he nicotinc- bintting site has higher affinity for nicotine than does the BTX site (Marks and Collins 1982). Chronic nicotine injection, once or twice daily for approximately 7 days, increased the number of 'lf-nic- oline/'H-ACh-binding sites in the brain (Ksir et al. 1985, 1987; Morrow, Loy. Creese 1985; Schwartz and Kellar 1983, 1985). This ~ increase In nicotine-binding sites appeared to correlate wi(h the emergence of nicotine-induced increases in locomotor activity in the rat. Studies of tolerance to nirotine in one inbred mouse strain (BDA) alsu demonstrated that chronic nicotine treatment elicits an increase in the number of brain nicotinic receptors as measured with both't1- nicolineand BTX as the ligands (Marks, Burch. Coliins I993a; Marks and Collins 1985; Marks et al. 1985, 198G Marks, Stitxel, Collins 1985, 1986, 1987). These studies have also shown that the number of '11-nicotine-binding sites increases at lower doses of nicotine than do the BTX-hinding sites. An inerease in'IS-nico0ine binding (Marks. Durch, Collins 1983a) parallels development of tolerance to vnrious responses during chronic infusion. In chronically infused UIIA mice, tolerance acquisition and disappearance parallel the upregulntion and return to control, respectively, of brain '11-nicotine binding (Marks, Stitzel, Collins 19851. These findings suggest that the increase in 'H-nicotine binding is related to the development of tolerance to nicotine. However, further studies indicate that factors other thdn receptor number must also be considered, because mouse 52 5;1
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strains thnt do not develop tolerance to nicotine also demonstrate up- regulntion of nicotinic receptors followinPw chronic infusion (Marks et al. 1986; Marks, Stitzel, Collins 1986). - That chronic nirotine treatment results in a decrease in response to lhe drug (tolerance) and an increase in the number of nicotinic receptors was an unexpected finding. Marks, BPrch, and Collins (1983a) and Schwartz and Kellar (1985) have suggested that chronic nicotine treatment results in chronic desensitizntian of nicotinic receptors. Chronic desensitization of tbe nicotinic receplor is compa- rable to chronic treatment with an antagonist and could be the stinrulus for up-regulatinn of tile receplors. According to this hypothesis, there is nn increase in number of brnin nicntinic receptors but a decrease in the absolute number of "activatahle" (nondesensitixed) receptors. This would result in a decreased re. sponse to nicotine (tolerance). Marks nnd coworkers suggest that inbred mouse strains fniling to exhibit tolerance to nicotine, under the procedures used by these investigators, have brain nicotinic receptors that resensitice more rapidly than do those slrains that do exhibit tolerance. By treating rats chronically wilh the ncetylcholinesterase inhibi- tor disulfoton, Costa and Murphy (1993) have found a decrease in rat brain'fi-nicatine binding. Disulfolomtreated rats were also tolerant to the antinociceptive effects of nicotine. Thus, tolerance to nicotine effects may be seen when the number of nicotinic receptors is increased or decreased by chronic drug treatment. The obser.ation that tolerance to at least one effect of nicotine can be obtained by a technique that decreases brain nicotinic receptor numbers supptrte ' the iden that chronic nicotine trealmenhresults in an increase in the total number of receptors but a decrease in those that may be activated by nicotine; that is, a high fraction of the up-regulaled receptors are desensitixed. In contrast to the studies reviewed above, some investigators have found no change in the number or affinity of 'tl-nicotine-binding sites in the brains of rats chronically exposed to nicotine (Abood et al. 1984; Benwell and Dalfour 1985). Other potential neurochemical explanations for tolerance to nicotine have been considered. Several reports (Westfall 1974; Giorguieff et al. 1977; Arqueros, Naquira, 2unino 1978; Oiorguieff- Chesselet et al. 1979) indicate that nicotine stimulates dopamine release in vitro, and a recent study demonstrated that nicotinic agonists are less effective in stimulating dopamine release in slices of strintum obtained from rats that had been chronically treated with the nicotinic ngonist dimethylphenyl piperazin ium (DMPP) ( Westinll and Perry 19861. These findings are consistent with the Idea that chronic nicotinic agonist treatment results in a decrease in the nhsolute number of receptors that can be activated. Pharmacodynamics of Nicotine snd Cigarette Smoking As the fnregoing review has shown, the intensily of uirntine's effects is related to the dosee given, the lime since the last dose,und the level of preexisting or ncqnired Inlenmce. Since nicotine can produce effects that lead to further use (reinforcing effects) (Ilem ninglield and Goldberg 19&3) and can also produce effects that liTit use (aversive effects, usually at higher (losc levels) (Drmaher 1977), the strength of the effect of a given dose cnn determine whether more or less nicotine will be subsequently Iaken. Thus, factars such as tolerance cnn affect the manner in which nicotine controls behavior (Chapter IV). Similarly, nn individual's ability to develop tolerance to the loxir. actions may be critical in determining whether amoking will ncrur and, if smoking is initinted, whether there will be mt increase in the number of cigurettes ctmsumed each day. Phurmncodynomic considerations may help explain lhe pattern ol' cigm'etle smoking throughout the day. Intervals M3ween smoking cigarettes may be determincd at least in part by the time required for (nlermme to disnppem'. With reguhv smoking there is accumnuln- tinn of nicotine in the body resulting in a greater level of tolerance. Transiently high brain levels of nicotine following smoking individu- al cigarettes may partially overcome tolerance. But the eR'ects of individual cigarelles tend to lesson throughout the day. Overnight abstinence allows considerable resnnsitixalion to effects of nicotine, and the daily smoking cycle bigins again. Phnrmneedynamic observations wilh i.v. closing of nicotine explnin tile pnttern of cardiovascular changes observed in cigarette smokers. That brief infusions of nicotine inere;~se hearl rate to a maximum suggests that heart rate will increase most wilh tile first few cigarettes of the day, but stdostquenpy will not vary in relation to the amounl of nicotine consumed. Thut only partial tolerance develole; la heart rnte acceleratiun due to nicutine suggests that effects on heart rule may persist as long lls sigllihcnnl levels of nicotine pet'sist, including overnight. These predictions were can- firmed in n study in which volunleor cigaretle smokers smoked either high. or low-yield nonfilter resenrch cigarettes or abstained from smoking (Iienowil . Kuyl, Jantb 1984). Full conytensntion for the low-yield research cigarettes, which cunluined only snmll amounts of nicoline, was impossible. Resultant nicotine blood levels were differetrt by fourfold. As predicted, heart rnte (assessed by continunus nmbulutory electt'ncnrditry,ram (IiKC) monitoring) im creasedin the morning-utmr on smoking than nmrsmoking days- and tile increase oceurred with the first fow cigarettes of tbe day. Subsequent7y, heart rnle I'nllowed a normal circadian pattern, but was always higher during smoking than during abstinence. Also, as predicted, beart rale was no dilTerent during the smoking of low. 64 :u
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yield or irigh-yield cignrettes, despite the fourfold difference in bloal nicotine conceutration. 1'Imrnrncodynnmic aspects of the actions of nicotine nrny explain in part how cigarette smoking causes coronary heart disense (US DIIIIS 1983). As noted before, because of the accumulation of nicotine and its dose-redponse characteristics, heart rate is increased during cigarette smoking for 24 hr a day, Plasma catechnlamine cuncenlrations tmd-urinary catecholamine excrelion remain in• creased ns well (Benowi/z 1986c), consistent with the lhenry that cigarelte siaoking produces sympathetic neurai activation 24 hr each day. hersistent sympathetic activation could result in the following effects: (1) Alteration in lipid metalmlism, resulting in a more nlhorogenic lipid proble;(2) Promotion of platelet aggregntiun and hypercoagulability; (3) Induction of vasoconetriclion and coronary sposm; and (4) Increased heart rate and myocerdial contractility, thereby an increase in the oxygen demands of the heart and of circulating catechulamihes, which can promote cardiac arrhythmins. These factors could accelerate atherosclerosis and contribute to acute myocardial infaretion in a person with preexisting coronary atherosclerosis (Benowitz 1986a) (see also Appendix B). There is no nppnrenl correlation between acute coronary events and the time at which a person smokes a cigarette, perhaps because of the persistent effects of nicotine throughout the day. Constltuents of Tobacco Smoke Other Than Nlcollne With Polentlal Behavloral Effects Tobacco smoke contains more than 4,000 constituents, many of which may have biological activity (US DHIIS 1983). Although nicotine.is the major pharmacologic factor which determines the use of tobacco, other constituents may also be involved. The behavioral gffecls of tobacco constituents other than nicotine are described in Ihe Section below and in Chapter IV. This Section focnses more on the chemicals that may he involved, whereas Chapter IV focuses more on cigarette smoking behavior. Minor Tobncco Alknloids Most of the research on the minor tobacco alkaloids has been directed to determining physiological effects, such as the eBect on blood pressure and other cardiovascular responses and toxicological effects, rather thnn the potential for behovioral effects.'Phe plmrma. cologic effects of alkaloids of the nicotine group have been discussed by linvet and ILovet-Nitti (1948) and Clark, Itond, nnd Vanov (1965). Nornicotine and tmohasine were found to have qualitatively similar actions but lu be less Iwlent than nicotine. Imrson and fluag (1943) reported that the potency of nurnienline as dclcrmined by effecls mt hlood pressure in dogs was almut one-lwelfth that of nicotine. Nicotine analogs have been studied for discriminative stimulus effects by using animul models (Clmnce et al. 19781(see also Chapter IV). The only chemical shown to produce a positive response ih that test system was 3-methylpyridylpyrrolidine. Recent research hps focused on binding at specific brain receptor sites. Martin and coworkers compared binding characteristics of nicoline-related com- pounds (Mm•tin et al. 1986; Sloan et al. 1985). Lobeline, annbnsinc, and cytisine were evaluated for effects on heart rate, blood pressure, ' respiration rate, minule volume, and tidal volume (Slonn et al. t987). Loboline and nnnbasine hnurrd to low-nffinity sites in the btnin, whereas cytisine hound only at a high-affinity sile.'1'he binding data are consistent with thdpharmacologic data, indicating that lobeline and anabasine have different pharmucologic actions than cytisine. Kanne and others (1986) and Aboud and Grassi (1986) evaluated two nicotine analogs, including a new redioligand, to study brain nicotinic receptors. Kaclmr and others (1986) studied the pharmaco- logic effects of a bridged-nicotine analog (methylene bridge between the methyl of the pyrrolidine ring and the a-position of the pyridine ring). The magnitude of pressor effect depended on the particular ennntiomer and dosage. TThese results emphasize that compounds other lhan nicotine may act at the nicotine receptors; however, there may be subpopulations of reeeptors to which different agmrists and antagonists bind (Chapter 111). N-Methyluted derivatives of nicotine, including nicotine isometho- nium ion (N-melhylnicotinium ion, NMN), have been shown to have pressor and neuromnscular effects in some species (Shimamoto et al. 1958). Nicotine Isamethonium ion was first reported to be a metabolite of nicotine present in smokers' urine by McKennis and coworkers in the 1960s, and its presence in emokere' urine tms been recently confirmed (Neurath et al. 1987). Recently Crooks and coworkers (Cundy, Godin, Crooks 1985) have shown that only the (R)• isomer of nicotine is converted to nicotine (somethonium ion in vitro in guinea pig tissue homogenales or in vivo in guinea pigs. Consequently, it is uncertain as to whether the nicotine isomellwni. um ion present in smokers' urine arrives from the small amount of (11)nicotine present in tobaccosmoke,or whether Ihe human emr.yme systems have different specifications than the guinea pig enuymes. Because little if any nicotine isomeNmnium ion penetrates the Mood- brain barrier (Paul 1987; Aceto et al. 1983), it would appear that this metabolite could have behavioral actions only if it were formed in the CNS. T'hese findings emphasize the complexity of the pharmocnl. ogy of nicotine-related compounds. It can be concluded from research on these compounds that some do bind to specific brain receptors and may result in centrally rnediated physiological changes. Iluwever, 66 57
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3 there is inadequute evidence to date that any or these compounds produces either aversive or rewurding effects in human smokers. "Tar" and Selected Constituents (of Tobacco Smoke Which Contribute to Taste and Aroma "Tar" is used to describe the dry particulate ttsrtler without lbe uicnline in tobacco smoke (1'iltsbury et al. 1869). The possible role of Im' in the maintenance of llie cigarette smoking Imhit has been considered. Coldfatb und coworkers (19761 studied the effects of the tar content (determined by cigarette smoking machine lestingl on Ihc subjective renvlions to cigarette smoking. Ratings of strength were not related to the tar index u(' lhe cigarettes. The results were , interpreted ns indicating that tar did not have a role in the maintenance of cignretle smoking behavior. In n later sludy, Sullnn and coworkers (1982) found that when nicotine yield was hald constant, smokers of lower-tar cigarettes puffed more smoke and had higher drug plnsma Ievels. These results suggested that smokers were cnmpensating for redured delivery of tar by inhnling a greater volume of smoke. Secause these two studies used different experi- mental designs, it is difficult to draw a conclusion as to the role of tar in relatinn to smoking behavior. I fowever, based on knowledge about the taste and nroma constituents of cigncelte smoke, it is likely that snme of the chmnicals in the tar fraction contribute to tobacco u.se, if only by providing distinct sensnry stimuli (Chapter VII. Consistent with this possibility, minimal levels of tar are held by tobacco manufacturers to be important to the lnste characteristics of tobacco smoke. Several thousand compounds have been isolated from tobacco and tobnccu smoke (Dube and Green 19821, and many of these may be biologically active ((AHC 198fi). The precmsotxs to the carotenoids and diterpeniods, selected ni4ngenous and sulfur constituents, waxes and lipids, and phenolics and acids contribute to the taste and aroma of tobncco (P:nzell and Wahlberg 1980; Heckman et ni. 1981; Davis, Stevens, Jurd 1976). A number of the isoprenoid rompounds that influence the taste and aroma of smoke may be formed by sequential nxidation, resrrnngement, nnd reduction reactions (Davis, Stevens, Jurd 19761. Enzell and Wnhlberg (1980) described several norisoprenoid compounds which are derived from the cyclic carot- enoids and are importnnt to smoke aroma. The particular taste and ermmn uf a cigarette can be influenced by the selection of the grade (quality and leaf puilinn on the plnnt) nnd type of tnbncM used in ihe blend. Taste and sroell receplonv in lhe phnrynx, larynx, and nose provide the first sensory input to the smoker ns he or she lights up, an experience which•is generally perceived us pleasurable (Rose et al. 19851. The lnste and smell of tnbncco smoke may be important reinforcers for tobacco smoking Warvik 19771-nt least following repeated association with the reinforcing eftects of nirotine adminis- tration (Chapter VI). Ily such behavioral conditioning, sensory cues provided by lar nnd Onvor additives could come to control the lobseco-consuming belmvior of tlm tobacco user. Changes in smoking putterns when brands are switched and brand selection may be a response in part to the particular flavor and aroma of the produbt (Thornton 1978). Carbon Monoxide The Imiiostrenm and sidestream cnrlwn monoxide (C'O) deliveries nf eigareltos are influenced by cigarette design and puffing charac- teristics of the smokers. Depending upon these factors, the mnin- strenm delivery usually ranges from 10 lo 20 mg/cignrette. In a study of 'l9,fMl6 blood donors in 18 locations around the United States, smokers were fmmd to have median carboxylremoglobin ((:CHb) levels ranging 1'rom 8.2 to 6.2 percent (Stewart et al. 1974). Anderson, Rivera, and Bright (1977) found the U011b levels in 50 smokers tu vnry frrrtn 3.9 to 14.0 percent, with the mean of 8.1 percent. The mean increment in COHh immediately after smoking I cigarette was 0.64 percent. CCilb levels gradually decrease in blood after cessation of smuking. Carbon monoxide is eliminated in expired air. The rate of climinution depends on pulmonary blood flow and ventilatimt.'fhe halNife of COllb is 2 to 4 hr during daytime hours, but as CCHb is related to the level of exercise, the half-life may be as long as 8 hr during sleep (Wnld el al. 197H1. For these reasons, many smokers awaken in the morning with substmdial levels uf Coflb, . despite not smoking overnight (lienowilz, Kuyl, Jacob 1982). Persons smoking cigarettes wilh lower nicotine and CO yields have only slightly lower levels of CUHb when compared with those smoking higher-yield prodtmtslWald et nl. 1980, 1981; Sultmt et al. HHd2; Hi11, Ilaley, Wynder 1983; Iknowilz, Jacob, Yu et nl. 1986). 6enowitz and colleagues (1986) studied tar, nicotine, and CO exposure in smokers switched from their usunl brand to low-, high-, and ultra-low-yield cigaretles.'17tis study indicated that there were no differences in exposure comparing low- and high-yiefd, but tar and nicotine exposure were reduced by about 50 percent mtd CO by 36 percent while smoking ultrrrlow-yield cigarettes. Switching from a high to lower yiefd cigarette does not significantly reduce blood CCI lb allhough switching to ultra low cigarettes hns been shown to lead to a significrmt rednclion. ThetoxiceffectsofhighGYllevelsarewelldocumented(US1)1iH3 1983). Some sludies have tried lo delermine whether CC levels in the blood similar to thoso observed in smokers can affect behavior. Beard and Wertl(eim (1967) and Wright, Randell, and Shephard (1973) reporled performance decrements with CUlib levels below 5.0 59
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percerdt huwnver, Guillerman, Radziezewski, and Caitle (1978) found no luychonwtnr perforrwnc+e effects at COllb levels of 7 and 11 percunt. Thus, the data are inconclusive with regard to the possible influence of CO on paychomotor performance at levels normally encountered in smokera. Acoleldehyde dnd Other Smoke Constituents Acetaldehyde is a major constituent of tobacco smoke, with mainstream smoke levels in commercial cigarettes ranging from 0.6 to 1.2 mgleigarelle (IARC 1986). The delivery of valalile aldehydes is Influenced by cigarette design, with reductions achieved by specific filtration and air dilution techniques. Yields over 6.9 mg Imve been reported for large cigars (lloffmann and Wynder 1977). Acetalde- hyde is the primary metabolite of ethanol, and its toxic potency is 20 to 30 times that of ethanol. Aceteldelhyde has been suggested to have an adverse effecton the heart (James et at. 1970). Acetaldehyde and acrolein, another important aldehyde in the gas phase of cigarette smoke, activate the sympathetic nervous system (Egle and Itudgins 19741. Acetaldehyde, by relensing norepinephrine, results in n presser effecl(Kirpekar and Furchgott 1972; Green and Egle 1883). Depressor effects occur at high doses of the aldehydes in guanethidine-pretreated hypertensive rats. Frecker(198.3)indicated that condensation products of acelnldehyde may be active on endogenous opioid systems. Torreilles. Guerin, and Previero (19g6) reviewed the synthesis and biological properties of betaeerbolines, the condensation products of tryptophan and indole alkylamines with aldehydee. Beta-carbolines occur as plant constituents, includ- ing minor constituents in tobacco. For exnmple, harman (I-methyl-(f- carholine) hes been identified in tobacco and tobacco smoke (Snouk and Chortyk 19g4). Carbolines from other plant species have been used as hallucinogens. The research conducted to date indicates a potential pharmacologic effect of the aldehydes, especially with regard to cardiovascular physiology; however, the evidence is inadequale to determine if these volatile smoke constituents in the doses delivered in tobacco smoke contribute to the behavioral effects of cigarette smoking. Summary and Conclusions l. All tobacco products contain substantial amounts of nicotine and other ulkaloids. Tobaccos from low-yield and high-yield cigarettes contain similar amounts of nicotine. 2. Nicotine Is absorbed readily from tobacco smoke in the lungs and from smokeless tobacco in the mouth or nose. Levels of nicotine in the blood aresimilar in people usingdifferent forms of tobacco. With regular use, levels of nicotine accumulate in the body during the day and persist overnight. Thus, daily tobacco users are exposed to (be effects of nicotine for 24 hr each dny. 3. Nicotine that enters the blood is rapidly distributed to the brain. As a result, effects of nicotine on the central nervous systerh occur rapidly after a puff of cigarette smoke or after absorption of nicotine from other routes of administration. 4.Acute and chronic tolerance develops to many effects of nicotine. Such tolerance is consistent with reports that initial use of tobacco products, such as in adolescents first beginning to smoke, is usually accompanied by a number of unpleasant symptoms which disappear following chronic tobacco use. r fd) 61
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ANIIKILSS(IN, K.. ENKR(yF1i, P.. FLI%E. K., MAS(:AGNI. F.. AGNATI, I..F. Kffe<Ir of clvonFt exlrnsme to ciKamlte snloke nn amine Ievels mrd lurnovrr In rnrbms hypMhslnmk catedwlemine nerve lerminnl ayeteme and on the lreretion of piluitnry harmmmx in the Ilule rnl. NmrrwndorrixologY t 1161:462-466, Ikaember 1985. ARMI'fAGE. A.K., IX)LLERY, C.T., GEORGE, C.F.. I IOUSEMAN, T.1 L, LEW IS, PJ., TIIRNFIR, P.M. Absorptbn nnd metnbol'um of niclllne Uwn ciK.retles. Brirfah Afnl/ml .burna! 4(5',W219 1 3-316, Nurember 8. i915. AI/MITAGE, A.K., Itt)LI.F.RY, t:T., IIOUSEMAN. TIL, KOIINEIt, BM., LEWIS, P.1. Tl11tNER, RM. AbsrrMi'nl nf nkaine fmm.m.ll dgorx. (Yinirn! IMnrmarvdrwr,md Theruprrrlw, 23!21'.143-15U, Flbruury 1978. AIIh11TAU& A.K.. TIIRNF.R. 1).M. MssorMion of nkoline Iu ciRnre4e sIM cikar ermAe Nrrrnre 22K52521:1231-1232, June 27. 1970. AIR3tIFJU/5, 1.., NAVUIIIA, 1)., ZUNINQ, E. Nbeltneindua<d relenxe of cnteclrab ndnes frnm rnt hlpPacempus nrrH rtrialum. RincAemiml fMnrmmrrlrypy 271231:2961-2674. 1978. IIAF.It, US.. McCLEA1tN, G.E.. WIISON. J.R. Effecta nf chron& adminielrmbn of idmraa arnoke 1. mke: Rehnutord nnd nminbn6c mesrares. Ikp•h.yJrarnrarrJ,qev 67:191-137, 19NU. IIALFIItIR, D..LK Studies on !he bb(hemkal and behsvinral eQeNS of nnl nkatGla. AuAilwx InnnmrlLwnl>s rk PhnrnnlruJrunmir tl d,• 7Tnulne 248111:245:95-I/kA 19XR. IIARRA.4S RL'-, IILACKIl11RN,.1.W., UItIMBLFJX)MRF. R.W., RICiI. P. Morli('ra- ~ tion of niculine loxkily by prelreatlr/enl wlth different dru8x. BinrAewhnf ~ O IM.u'mnadqp UR9t21453152, Seplember 1!Ifi9, IIA'M'ill, K. DItIS(X)1,1. P.. Still LATTER, J.. USTF,II. 11.1 Effect uf nirntine on Ihe c.pbrnlury hwornulion pnllerm of female Rmnnn hi8h. and bw-nvoMnnce rols. ~ I'AnrmrrruLpr IIir.AOm-.rry and fkhnr•ir. 4:4J6-41W. April 1976. In:Al1n, Itll, WEICfl1KLM. U.A. IMlmubrnl bqminlrenl nweisleJ wilh rmall drra, -, ~ ~ uf rnlbnn mmm.idn Anlr•uam.M1wmud ry AJdlr NmRh 671U.21112-2112 2. NnveulI 1967 ~ rer . IIL:IRE1'f, A.I L. L'(/ltltt)IL.LSY, JENNF.It, 1'. Alwrpllnn uf I-4nieNilw•1'-Naxirle in , ~ .ml ilr redm'tbn in t1w knxlrolntnlinal 1ra411.e11erL.Ax,rrrnl n/ Phmmurv unJ /'brumnrnhycv 22t91]YC-i22. Seplmnlnr 1970 pelerences AR(KRk L.G., OItASSL S.I'111h1rthYkerbnmYkholfne, n Ixw rad!dlPnd for nludpink brain nkatinic rc<ry4onl. Rinrhlmrml Pharmandrgy 35(23M19B-1202, Iiecember 1, 1.Wi6. AIl(K)U, L.O, GIIASSI, S., (Y)STAN2A. M., JUNIO, J. Behedonl snd Mochemicel smdir•x in ndx afler chronic ex fusure lo nkoline. In: Shrrp. C.W. led.l A4fhenisrru n( Tid,nonre ,rn./ lkprnrfmce NIDA Monokraph 64. U.S. dr•parlmenl of Ileelth ,rrd Ilunron Rervife4-Public IleuIlh Servke, Alcohol. DruL-Abure, and Meniel Ih.d!h AdminisLnnion. UI111S Publicelion Nu. (ADMI84d320. 1984. PF MB-355. AII(K)R, Idi . RFIYNOLDS. D.T., II110T11, i l.. BIULACK, J.M. SIIee and merAnni.ms fnr niroline', ucllon in 1he Fnnin. Nrnro.rienre RinLrhmrinml RrMn•, N4t479-.4H 6, Winler 1961. A('F:T(l, M.I)., AIYAYA, 11.. MARTIN, B.R.. MAY. E.t.. AnlinorkeMiv< netlon of niaaine rmd its nrclhirrdide drr!.ellvn In nike alyd rnls. Brili+h Jrwrnnl 111rumncnlnye 7fK41:66Y-876. Aukurt 1951 ANnEItSfIN, W.11., RIVP.BMC., BNIGIIT. M. Grbonyhemo8lobin blood levelufler anwkinK one clgarelte in relation to puff profile. In: 192d Sympusfunr Niralin! and ('nd.nr Mrmneida Prm.rclinps-I. Univenlty of Kentucky, le.ln8lon, Kenlucky. June 1977, Pp. 190136. 62 BF%IKEIT, AAI., CtIRIKIU, J W.,,IF.NNER, 1'. The an:dY+in o(nkulirxin urine, in Ow Prexnce of nuvlt!ne nnd aN inine, nnd its ayplinrllun m lby sludy of in viva niarlin< melubrdiwn !m mln. Zmrnnf .Q IMnrn rr nd Phnrnmr.dnpr 2&SupplrrxenN.nSS-BIS, Ikcexdx•r 1971a. RECKEYr, A.il.. G(RIItOfk J.W., IKNNER, P. The rfferl of anokinK on nGmine memho6sin in vi.n in mxn- .lournal n( IMmmurr nru! 1Mnrmra•dnKv 7.k5vpplemrnN('~1S-F7E, 11erYnlbr•r 19711, . ItENUWI'1% N.1.. C'IinbN IrlmnnaculrrKY rd nicmlm• A.umul /trracx, ,r/ Ab.fifrna 37:21-92, 190On. , RF:NDWI'I'L, N L. Ilmenn Idlxrnrncnby;y rd n!cdine In: IlrpVYll, ILD) r•t nl. leds.l flrenurh Adnmrr+ln Ahnhr,lmn! Oruq Ihd•lr.n,.. V.nlun/e N. NYw Yrvk: 1'Irnum 1'rex., 19Wi1. BKNOWI'Fl., N.I. hwreaxrl 24tmur rnerR,v eyn•rlrlitnrr in ciKnnile a,wkcrx Ilcttur.l A'nr ASrqlnr/d hxmla/ rq' Alnbrim• :N4251:1fiM1-1841. hrrm 14 I`ptfic. ORNOWIT2.. N.I.-, IIAI.I.. S.M., IIEKNING, 11.1., JAUOB, 1'. Ill, J(INFS, RT., OSMAN. A-I. Smuken of bw yiYld viKnMle+&, nM amulmr• Ir•.x uk»Ilne Aru• Enqlom! Irxmml rrJ Afedirinr :MBk1VI:C6N2, JuIY 21, III9:I. IIENOtY177., N.i... JACX/II. 1'. Ill. IdllY inlnke nhlicMine durlnK riRnrellr xuxrkinK. Cfinimll'hmmnrvhyqr nnd lLeropwrirs 2M41:499,:ICbL April ttRt4. BF,NOWI9Z N.4, JAL'(Ilk P. III. Nkrrtille rmud r•xcretinm mie in0ulern nkuthle Inlnkr durinK riKnrrtle xnx,kink •L•mxn! ,f IYuvmar,.Lar and F.yxvinn•xAd 7n«u/nvnrx 'L'FKLk153..1+rn July 19R5. BENDW117., N.L.,IA(X)B. I'. III,.IUNES, II.T., ItUSEN1IERG,.1. hnYrindieidunl varuWlily In the melnl'nliaa auJ falJkmllncuInr vRecln of rlicW(Ile ir ma. dmrnal rr( PharmrrndµY. nml Erlwrinrmlul Trienrfmr6rx YEIrl1:a69-372, 1982. IIENOWtTL, N.l.., JA(1)B, I'. IIL K(12,IAWSKI, LT, YLI, 1. InOueme of smokine fewer dKnreun on exlxrslre In tar. nicot!Iro. nmi nnLon Innlmxide. Nerr ArKBuW .Amnmi nJ' AfnGoinr ,1I5211,1.t1U-131.'1 Nnrmsbcr 211, 1!8/f BKNf1WIT2, N.L, JAC(10, I'. Ill. 1'll, 1.., TALQJFL R.. IIAt.I., S., JUNFS. 117'. ItedaaM Irrr, nicnliue, and rnrhnm m,nnnGb eyvaure while am,kiryl ultrldnwbut nut Iow-yieM ciknretlex Jmnnnl r,( ehe .Lrmirrrn Atrvhrnl Asnwrn/nrn 25612t241-2e6, 1986. OENOWIT7 N I.. KLIY'Y, F.. JA(UII, P. IIL Clrca/inn bhxxl uicwine culn:entmlinnx during ciKareUe snrokinK. /Yinfan! !'AmwenJ.Wr nnJ Thnn(.neu.r 02UI1:75H 7fr4, December 114112 . RKNOWI'f„ N.L.. KUYT, F., JAC(111, 1'. 111. InRllence of niaotinc on a.rdiora.fulxr nnd Iwrmonnl effects uf ciKnrelte smnkink. ('limrol 1'M1xrrnnmfoRr nnd 7HnoNw rlr,:Kxlh74-BL 1984- BENOWITZ, N.I... KLIY'f. F.. JA(X)I1. P. 111. J(INES, IIT.. IkiMAN, A..1. (.rllnirlc dispovllGm and rffeclx. f7inimf IMnrmnmlr,py nu.l7hrnrlnv.brs :N81:1:19.142, 198:t. RF.NOWIT2. N.1.., LAKF„ T.. KELLEI; K IL, /F.F 11.1.. 1'rMmlRerl rrlwoqd"um weh de.elnprnenl nf Inierunrc to loxic effecla fnlluwinK culnnmus exl'asurr lu nirntirx•. ~CYinnnl lMnrmnmLr9p am! 7yrerupeulm, 4211t119-1211, IIIH7. RF:NOW f1R. N 1.. It]IR'I/kT. 1I., SILF:INE14 L., JAtY1H, 1'. Nifntinc nhwrpliun rurJ aRllnves<ular eRert,a with alnikl•Ifu I,dnµYr/ un- Gmnlntl'ir:Vtl wRh fNplrlIlYY and IlicMlne Kllnl (9rnlln! 1TormaroGr' nnd 7rieluprorrrM. III hn'ne RENWELL. M.EF1. IIALFOUit U.J.K. NkMine hindinK to Lrnbr t&we frwn drq;nxive nud nirolinrvln•ntrvl fnlc •Amrrml ry IMnnnm, nnJ lM.unrarnLy;e ,17:44K MI4, 1965. IIIRER A.. SCIIERFJI, G., IIOEI'PNF.Ft, 1.. AIlLK(/FF:R. F., IIKLLRft, tVJI., IIAIIIX)WrJ.E.. KNI(:117'. U.J. Ik•tmmim,lion ofnkMine nmlculinine /n Immmr umum xmi nrinr•An iulrr9n6nnmry AudY- lirvrvAry;,r Isltrrx .l'n4f.f2, IIIH] 6:l
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0.1EIIIIKE, R.J., COUK, C., RYt.71LlR, N., QJIKA, 118. .. VAN V1INAKLS IL, I.ANUONk. J J. Stereoapecife man«lonel entibodiu b nirotine and eatlnin• and thrir ux in ensymeilnked immuno.crbent e.rqr. Jeurnal of Immnnnfngiral MAheds 9tM21:2oYY213, Jyne 2(, 198& DO(1TI1, J., ROYLAND. E. The metabolum e/ nlcullne Into two opticelly acUve stereuitwnere of nicollncl'aslde by animal llsruee In Nlro end by dgarNte srnukera 1linrhemulry end Phnrmornlolty 19(3}733-742, March 1970. 1WVET. D. EOV@T-NITTI, F. Servaurr N Acliuild Phannacndynum/que der Mbliramenk Au Sprime Nervene VtFetntif.79risr S. Kargery 1949, pp. 1i26-616. R(IWMAN, Ell, MCKENNIa N. Jr. Studiee on lhe metabolism of f-Icolinine In the humnn. Jwvnnl u/1'AermnrolqeY and 6.perimcntul TArmyeutia 13s(31:3D6-311, 1982 HUYD, N.D., G'OHEN, J.R. Deseneltlratlon or inembrene-hound Trnpedo seeqkhollne recepkr by amine noneompetiRve anlegonide and aliphetie alcuhoW Studiea of ('II/ ocetylchollne binding and ^Ne• Ion nuwee. AiocArmlefp R3(19N02Y4033, ),u6ust 19g1. RRUNNEMANN, K D., IIOYFMANN. D. The pll ut lobeacu emake. Fuud and Cametks Tosicolep 1211t116-124, Febrvery 19i4. R(ISIL L.P., ORUNWALD, C.. DAVIS, D.L Inlluenn af puH frequency end puff vulum< mr lhc a14n1oM rontent of emoRe. Journal of Agrku/tum/ and Food Chrmiatry 2p31.67"78. Jenuery-Febru.ry 1972. CASTRO. A., MONJI, N, MALKI/S, H.. EISENHART, W.. MCKENNIS, H. Jr., W WMAN, E.R. Aummnted redioimmunoasely of nkoUne. Clinirv Chimiro Artn 9N3):473J191, August 1979. CI IANCE, W.T, KALLMAN, M.D., ROSECRANS, J.A., SPENCER, B.M. A comperl- mn of nicoline and slructurally relaled mmpouMs ae diecrlminative elimuli. Rrituh Journnl of PAnrnemlogy 69(11 6 03-616, Augwt 1978. CI I IEN, C: V.. DIANA. J.N., CROOKS, P.A. High performence Ilquid chromelogrephr with electruchemiul deteelia+r foe the determination af nkotlne In plesme. JmIrnal o( Phurmoreutlml Srirnns, in prew. CLARK. M.SG., RAND. M.J. Effea of tobacco nnuke an the knee-Jerk rellew in man. Enropean Jnurnal of PAarmaxlogy 3(41:294-202, July 1968. C.LA RK, MB G., RAND, MJ., VANOV, S. Camp.rhon uf Chvmesdogtcel acUvky ef nlrotine and rnlxl<d elkelakis occurring in cigereuw emake. AmAiurr Inter*atla- no/rs Ae 1Marmmrodynamir et dr TAerop4 156(2k363-379, 1966. CLAItKF 1•-R S. KUMAR. R. Tln effecl. of nimtine en locomotur utlrlly In non- . Inlerent and tolerent rels. Rriti.h Journal of PAnrmncob;l' 7&2k029-337, 19tlU CLARKE. 1'.D.S., KUMAR, R. Chal'ecteriutlon of the laeomutor atimulml ectkn of nimtine in tulernnt rala. IkiRah Journal a(Phnrmarclqpp Oq31:587-d94- Norent- ber 1983b. ('I.ARKF P.R.S.. KUMAR, R. Nicotine doea not Improve dlxriminatlon of brein rtimulalhm rewerdby ro/a. P+yrAoAharmarabp791219}2T1-277, Febwry 1893c. COMII(IF. J.11- The phnrmamlogkxl acliune of nkotine. Annals af the Ne+r York AcwleniY of Scienm 9IX11:48-61, SeptemYer 27, 1960. CYhSTA, 1.0., MURPIIY, S.D. PH)Nlcoline binding in rat brain: Alteration sfler chrnnk acelylchnlineaterex inhibWun. Journal o(J'Aermncnloqy and Erprrinen. ml 7hrrapcuNn 22612):392-397. August 1983. C(INDY. K.C. GODIN, CS, CROOKS, P.A. Stereoepecillc in vitro Nmethyietkn of nicotine in guinea pig tisaues bY aa &adeno.ylnwthbnlncdependent N-methyl- Iransknrae. IA1rrArmi,tll Pharmacu8+p 34:281-204, 1965. ('111tVAl.l., M. KA2F3tt1VALA. E.. ENZEL4 GR Simultanmms delermination uf niculine nnd col inlne in plesme uning cePlllery column gu chrwrrtagrephy with nltrylen senai6ve dctcrtion. Journal of Chruma/ag.ePhy 232:2&1293, 1982. UARNh:NS, 1'., I.ARIIEI.LY.. 1., CALLEWAERI', K.. Fu1181'I'F.R It, GAL6AZ21, Il., VAN RI)SYUM, J. D,irrminnti,n, el entinior in WohKKi<nl Ruidw by nrPillnq gnx cWo+nntuKfnpby.mn.vn npertrnnnroPV•Irrl,rkiun muuiturioA Jwumd,•(CArnmm I.WnyrAy 242:7(/-N7, 1985, UA.IANI, H.M., OORIIUD, J W, IIkY1KE1T, A.11 In vitru lu•pxic end extrahelwlic rMuelhm nf I-)-nlrWhwF.Nuxfde iu rnts. lbahrmm.l PAnrmwnG+gy 24:1119-I17, 1975e. IIAJANI. It M. UUItRfRI, J W, RE(:KE7T, All. ReducUan In vi.u of t-}niratino-l'- Nnxide hY gern.frre mul cnnrentiunol rM. l14x•hrwirnl Poummrvf.y;r 24:649-GaL 1475h DANAIII:IL Il/: Ib•~mardl an rnpM utmkinp: Intrriin .wmmary nnd ,vrmnmrnda- lians. Addirnrc IkM,riws 2141-tfi6, 1977. DAVL9, D1.,tifEVfiN$K.L.,JURII, 1.lbnn0lryoflulmccacmmlituents.Osidetkn nl rvkmone mul the arid enlnlymd teurrnnhre+nent of Okelo-aknune..lnurnaf e/ Aerieulrum/ and Nv.1 Chrnnxery 2M1k187-IBB. JnnunrY-Februnry 1976 IMVIS, ItA. The J.terminntimt of nicotiro and cotininr in pleamn. .Jmmud u( Ch+rmmd,eruphu Scirnre 24/4134-141. April 1986. I11XHN, IY R.. LEE, W E Tolernnrr 1. ofrothx. J. Erp Phvshd. It.mdon) 5:373-3&1, 1912. I)llllk:, M F., C•HFIEN. C.11. Meth«Ix uf aellMbn of mrmbe for emdylknl IwrWS,~ Itrrrnt Adlnnccr in 7bharrr Sreen,v 8:42-102, Dctnber 1962. ECLF. Al. Jr.. IIUIKHNB, 1'AI. Ikso-dePendent symMtbmnimctk eld cardbinhiWInry effa•cls nf acrnlrln nnd fnnnuldebPle in the xnealhel"real rnt. 7{uiedngr and Al'pfirv7 Phnrmn,vAµ,r 26:3.SB-KKi, 1974. F:N7.EL1., C.R-, WAIILIIEflG, I. Isaf compnsition in rel.9on to amuking quulily and eronm. Nerent Adnmrrs m Tobaav Srienre 6:64-122. October 1980. F.FIIlY.1.W.•'fIIDME• F A..IIRAVNER, D.1.., GREEN, C.R„ INOEIIRETIISEN, RJ- Shulics nn thr Vap,v ('nrnrr+fatoPM1m<lA'shibntiun q Envirw+mentnl Nirotine b,r Sef.rluf TrnlrydnK and Ikrrrtiux Mctho,lr. I'aper prexnted at the 79th Tabaccn (:hemiels' Iicxeurcb Cnnferen<r, Alonlrenl. (lctdror 25, 1985. FAULKNER, J.M. NicoUne pdsoning by obsmPliou /hrouKb tbe skln. Jmrrnnl o/rhe Anmirnn Mcdioul Asmcinnan Iqt21CI6W-IfiG'5, May 27. 1930.' FF,YERARk1Nb, C., INCS. H.M.. RUSSELL, M.A.II. Nlcotine pharmerokinetlee and Y iln ap(dinCfoo ln inlnke Irmn umn4lnK. thitish .Anlnm/ u/(Yiniraf fNarnuarub.Ay 1912P.239-247. February 1996. FEYRI7ARRND. C., LEVI'Ff.'P., IIUSSELL, M.A.II. A rapid geeliquid chromplo. grnpbk estimntkn of nlembw in biological Duida. JornmN ,rf IMannurr and YhnmmrofuKr 27(6t434-4J11. June 1976. FItE(MF.R, ItU. F:ve movemenl meesurcment end Ibe phnrmecwlynomks af lobame depndencr. in: Prncedinha n(Ihe 51h WurM ('w+(emmn nn S+noking m,d ifm11h 1:121-129, 1963. UA Itti, M. VndnUOn In eRerd nf nwvl ine iu f.mr d rnina nf rnt.. &1rhq,Anrmurnl„pin 11.432-43P• 19419. f.F:1ILRACIL 3.11., WIIJAAM9, W.A., PERRY. 1..11., F'ItF.Eh1AN, J.1., LANOONF„ J.J., PETA. LV., VAN VUNAKIS, N. Nicnlinr obserplion Iry wurkera bnrresting green Idurcu Canna II7Mi514781M1, Mnmh 1• 1975 GIU/t0(fIEFF, M F., Le F'IArC'l1, M 1., OIA)W INSKI, J.. BFSSDN. M J Inrolvement nf cholinergk Ixesyneptic r.xeptors of nkutinic md musrerink lypes in the amlml of lle• slxmlanenua release nf dopnmine from slrintnl dopxminergk tenoimds in Ibe rul. •Awrnuf .4 IMunnwnAV;r und A'yvrimrnlnl 7heruµvllcr 2t03k:a75-fM9, 1977 GIO114UII:F'FLTIESBELFT, 61.F, KKME4 M.1., WANUSf:IIEER, Il, GLOWINSI(1, J. Itegulmion o(dnpamine release by pm:rynapli<nkutinic xceplors in ral strletel siirea FJfecl of nirWine In o Inw rvnceulralien. Lifr 9irare 2YN1:1257-I2fi2, 1979. 65
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W FS'PF'ALI. LC. PERRY, 11. The nkotlnkinduceA releue ef endufencun dopemlM fronm rnl striutal qiees from animela chmnknlly e.pmcd lo dlmethylphenylplpera~ xb,ium IDMPPI. Nnrmrcienre f~uw 7U8t3f0J4/. Nn.ember 81, 1999. WMII; J U. ElectrophysioloKCel and phermrmlaslcd propatiee of the rlemaeh of lhe uluid lufipo rynlii ILerueurt. G'nrnporafiue Hiuhemelry and I'hy.fafaay fKK61X1YN21, Seplember l, 1%9 tVItIl111T, C.. RANOELL, P., SIiEp1IARU, RJ. Carbon monoxide and drfrfn` eklll.. NrAiwr M Enr+ronmenral Heafrh 1]f61:919-8M14, Oeeember 15T7. ZF.IUENOEItG. P.. JAYFE,.LfL, RANZLER, M., LEVITT, M.O., LANOONE, J.J., VAN VUNAKIS,II Nkotine Cetinine levale in blood dvrim reu.tion ofemokfn,,. 6'umFrrAenutr AnAintn /1M1L:9]-101, Jnnu.rpFebruery 1977. 1 / 74

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