Tobacco Documents Online

,x (17) DEBIAS, D.A., BANERJEE, C.M., BIRKHEAD, N.C., HARRER, W.V., KAZAL, L.A. Carbon monoxide inhalation effects following myocardial infarction in monkeys. Archives of Environmental Health 27: 161-167, September 1973. (18)' DEBIAS, D.A., BIRKHEAD, N.C., BANERJEE, C.M., KAZAL, L.A., HOL- BURN, R.R., GREENE, C:H., HARRER, W.V., ROSENFELD, L.M., MEN- DUKE, H., WILLIAMS,, N., FRIEDMAN, M.H.F. The effects of chronic exposure to carbon monoxide on the cardiovascular and hematologic systems in dogs with experimental myocardial infarction. Internationales Archiv fuer Arbeitsmedizin 29: 253-267,1972: (19) FECHTER, L:D.,, ANNAU~ Z. Toxicity of mild prenatali carbon monoxide exposure. Science 197: 680:682, August 12, 1977: (20) FEYERABEND, C.,, LEVITT, T., RUSSELL, M.A.H: A rapid gas-liquid chromatographic estimation of nicotine in biological fluids. Journal of Pharmacyand~ Pharmacology 27: 434-486,1975. (21) FISHER, E.R., ROTHSTEIN, R., WHOLEY, M.H., NELSON, R. Influence of nicotine on experimental atherosclerosis and its determinants. Archives of Pathology 96: 298=304, November 1973. (22) FRASCA, J.M., AUERBACH, 0., PARKS, V.R:, JAMIESON, J.D. Electron microscopic observations on pulmonary fibrosis and emphysema in smoking dogs. Experimentaliand'Molecular Pathology 15(1): 108-125, August 1971. (23), FREEMAN, G., DYER, R.L:, JUHOS, L.T:, ST. JOHN, G.A., ANBAR, M. Identification of nitric oxide (NO) in human blood. Archives of Environmental' Health 33: 19-23i January/February 1978. (24) GUERIN; M.R.,, MADDOX, W.L., STOKELY, J.R. Tobacco smoke inhalation exposure: concepts and devices. In: Gori, G.B. (Editor). Proceedings of the Tobacco Smoke Inhalation Workshop. U.S: Department of Health, Education,, and Welfare, Public Health Service,, National Institutes of Health„ DHEW Publication No. (NIH) 75-906,1975, pp. 31-44. (25) HANSSON, E.~, SCHMITERLOW, C.G. Metabolism of nicotine in various tissues. In: von Euler,, U.S. (Editor), Tobacco Alkaloids and Related Com- pounds. Oxford, Pergamon?ress,1965, pp. 87-99. (26) HRUBES, V., BAETTIG, K. Effects of inhale& cigarette smoke on swimming endurance in the rat. Archives of Environmental Health 21: 2fl-24; July 1970. (27) ILEBEKK, A., LEKVEN, J. Cardiac effects of nicotine in dogs. Scandinavian Journal of Clinical land ~ Laboratory Investigation 33: 153-159, 1974. (28) LANGLOSS, J.M., HOOVER, E1A., KAHN, D.E. Diffuse alveolar damage in cats induced by nitrogen dioxide or feline calicivirus. American Journal of Pathology 89(3)r 637-644, December 1977. (29) MADDOX, W.L., DALBEY, W.E., GUERIN, M.R., STOKELY„J.R, CREASIA,. D.A., KENDRICK, J. A tobacco smoke inhalation exposure device for rodents.. Archives of EnvironmentaliHealth133: 64-71, Mareh/Aprili1978. (30) MCGILL, H.C~, JR., ROGERS;,W:R, WILBUR, R.L:, JOHNSON, D.E. Cigarettee smoking baboon model: Demonstration of feasibility (40119). Proceedings of the Societyfor Experimental Biology and Medicine 157: 672-676,1978. (31) MILLER, R.P., ROTENBERG, K.S:, ADIR, J. Effect of dose on the pharmacoki- netics of intravenous nicotine in the rat. Drug Metabolism and Disposition 5(5): 436-443, 1977. (32), MORDELET-DAMBRINE, M., STUPFEL, M., DURIEZ, M. Comparison of tracheal pressure and'circulatory modifications induced in guinea pigs and in rats by carbon monoxide inhalation. Comparative Biochemistry and Physiology 59A: 65-68, 1978. 14-8$

(33). NETTESHEIM, P., GUERIN, M.R., KENDRICK, J., RUBIN„I., STOKELY, J., CREASIA, D:, MADDOX, W., CATON, J.E. Control and maximization of tobacco smoke dose in chronic animal studies. In: Gori, G.B. (Editor). Proceedings of the Tobacco Smoke Inhalation Workshop. U.S. Department of Health, Education„and Welfare, Public Health Service„National Institutes of Health, DHEW Publication No. (NIH)~75-906, 1975„pp: 17-26. (84) NORMAN, V., KEITH, C. H. Nitrogen oxides in tobacco smoke. Nature 205(4974): 915-916, February 27, 1965. (35) PARK, S.S., KIKKAWA, Y., GOLDRING„I.P., DALY„M.M., ZELEFSKY, M.,, SHIM, C., SPIERER, M., MORITA, T. An animal model of cigarette smoking in beagle dogs. American Review of Respiratory Disease 115: 971-979, 1977. (36) REECE, W.O., BALL, R.A. Inhaled cigarette smoke and treadmill-exercised dogs. Archives of Environmental Health 24: 262-270, April 1972. {3~) RINK, R. D. The acute effects of nicotine, tobacco smoke and carbon monoxide on myocardial oxygen tension in the anaesthetized cat. British Journal of Pharmacology 62: 591-597, 1978. (38) i RYLANDER, R. Relative role of aerosol and' volatile constituents of cigarette smoke as agents toxic to the respiratory tract. Toward a Less Harmful Cigarette. National Cancer Institute Monograph No. 28. U.S. Department of Health, Educatfionj and Welfare; Pubiic Health Service, National Institutes of Health, National Cancer Institute, 1968, pp. 221-229. (39) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Report' of the Surgeon General: 1972. U.S. Department of Health, Educationj . and Welfare, Public Health Service, Health Services and Mental Health Administration~ DHEW Publication No. (HSM) 72-7516, 1972, 158 pp. 14-84

Pharmacology of Cigarette Smoke For the habitual smoker, the smoking of a cigarette is a rewarding experience, evidenced by the consumption of over 600 billion cigarettes annually in~ the United~ States. It is a reward which is highly anticipated by smokers, one that seems to satisfy a smoker's physiological and psychological needs. Because of the myriad compounds present in cigarette smoke, it should be kept in mind that the pharmacologicalleffects of smoking are not related solely to nicotine; rather, it is the combine& effect of the whole smoke. Nevertheless, nicotine is generally accepted as the principal constituent responsible for cigarette smokers' pharmacologic response (6, 20), and will be reviewed on this criterion. Nicotine is a powerful, quick-acting, ganglionic stimulant, eliciting its effects initially by depolarizing the ganglionic cells, stimulating both the sympathetic and parasympathetic ganglia (15). Nicotine Absorption Clearly, before any pharmacologic response can be elicited by nicotine from cigarette smoke, absorption must occur. The phenomenon of cigarette smoke absorption has been addressed~ by several investigators ('2, 4, 6, 9, 16). Some absorption takes place in the oral cavity. Based on monitoring carotid blood~ levels and radiolAbeled nicotine: cigarettes, estimates from three studies (2,,4, 6) show that less than 30 percent of the inhaled dose is absorbed. Further,,Artho and Grob (6)~observed that there were striking differences in nicotine absorption that are largely determined by the pH of the total smoke. The pKb values of nicotine are 6.16 and' 10.96 (9); From these data, the portions of the diprotonated nicotine and monoprotonated nicotine as well as the free nicotine can be calculated for a given pH. Because cigarette smoke typically has a pH of 5-7, the diprotonated form need not be considered in this discussion. The percentage of nicotine present as the free base is 0.40 at pH 5.35, 1.7atpH6,,15at'pH7,64at'pH8,and85atpH'8.5. The basic, lipid-soluble, uncharge& nicotine is the form absorbed by the oral muscosa (8): A contributing factor to its absorption is that nicotine, as the free base, is volatile, which allows for rapid absorption from the gas phase. The relationship of the effects of pH are described in Figure 9(9): Figure 10 (4)' describes the oral absorption of nicotine from an identical dose of a buffered nicotine solution at pH 6, 7, and 8. Nicotine which passes the oral cavity, as in cases of deep inhalations is absorbed to a much greater extent than in the: oral cavity. It is estimated'that more than 90'percent of the inhaled nicotine is absorbed in the lungs (2, 6; 16): It should be noted' also that retention~ of other cigarette smoke components by absorption is approximately 82 to 99' 14-85

FIGURE 9.-Degree of protonation of nicotine in relation to pH (pH = pKa 10g 1 - a/a (Henderson/Hasselbach)). SOURCE: Aviedo, D.M.,(7): 500 1 FIGURE 10.-Carotid blood levels of nicotine in ng/nil, after the presence in the mouth for 10 minutes of buffered solutions of nicotine at pH 6, pH 7, and pH 8. The bars show standard error of the mean. SOURCE: Artho, A.A. (s). 14-86

® lu M percent, depending on the study. In any case, it is clear that the lung uptake of the nicotine in cigarette smoke is very efficient. Whether cigarette smoke or a nicotine aerosol is used seems to make little difference on nicotine absorption in the lung. Herxheimer (28) found that inhalation from smoke and inhalation from a nicotine aerosol in approximately equivalent amounts (about 100 µg every 30 seconds), produced similar increases in pulse rate and blood pressure in healthy volunteers. The equivalence is only approximate, however, because the nicotine delivered per puff increases as the cigarette is smokedl This increase could explain why, although similar, the peak effects occurred later with cigarette smoking than with inhalation of the aerosol. Although pH of the smoke is a major factor in nicotine absorption, other factors such as tobacco smoke contact time with mucus membranes, pH of the mucus membrane, pH of body fluids, depth and degree of inhalation, d'egree of habituation of t'he smoker, nicotine and moisture content„and puff frequency must be considered (12, 20). Armitage, et al. (3) recently studied the effects of nicotine absorptiom in humans, comparing nicotine levels obtained' in arterial blood. They found that arterial blood plhsma concentrations of nicotine were comparable; however, the level rose more slowly in the smokers of small cigars. This may be due to a greater amount of the small cigar smoke being absorbed via the oral cavity as compared to cigarette smoke, which is primarily absorbed via the lung. Alteration of Enzyme Systems The: nature of tolerance to nicotine and tobacco smoking has received attention and a complex picture has emerged (25). Studies with humans using, high and~ low doses of nicotine presented apparently conflicting results regarding nicotine-cotinine metabolism. The authors suggested that acute higb doses of nicotine produced inhibition of nicotine metabolism while lower daily doses on chronic exposure produced induction of the enzyme systems. These results are not uniformly accepted, however(51). Gorrod and Jenner (25) concluded that the effect of nicotine is complex, but that the data suggest the importance of dosage, length of administrations and stress-induced effects. They also stated that a component of cigarette smoke other than nicotine may be responsible for the changes in nicotine metabolism observed in humans: In any case, tobacco smoke is a known inhibitor of enzyme systems, including dehydrogenases and oxygenases, so that inhibition of nicotine metabo- lism or other metabolic products is a distinct possibility (27). Catecholamine Responses Since nicotine: is a ganglionic stimulant on both the sympathetic and parasympathetic nervous systems, it is not surprising that investiga- 14-87 4~

Y 350 150 0 I 1 -10 0 10 20 30 M INUTES FIGURE 11.-Mean (± S:E.) plasma norepinephrine and epineph- rine concentrations in association with smoking (closed symbols) and sham smoking (open symbols). The arrows indicate the period of smoking (or sham smoking). SOURCE: Cutting, W.C. (T5). tors have looked at catecholamines as possible indicators of the nicotine-induced effects. Moreover, the catecholamines are usually considered to be released in~ stress-related responses: The source of the catecholamines is reported to be in the myocardial chromaffin tissue and the adrenal gland (11, 29, 34), and therefore consistent with this hypothesis. Armitage (1) claims that the amount of nicotine inhaled during smoking is sufficient to cause release of catecholamines, but there is not uniform agreement on this subject ('60,, 63). Timing may be a critical factor in determining any catechokamine response because the response is likely to be transient. Cryer and coworkers (14) have graphically shown~ the rapid response of nonepinephrine and epineph- rine as a consequence of cigarette smoking (see Figure 11). Naquira and coworkers (48) studied the chronic administration (14 days) of nicotine in rats. They observed increase& tyrosine hydroxylase 14-88

and dopan-aine-a-hydroxylase in the hypothalamus and adrenal medul- la, but did not observe changes in tyrosine hydroxyiase in the striatum. The data suggest that chronic nicotine administration can produce similar long-term alterations in both catecholamine-forming enzymes in the hypothalamus and adrenal medulla. Catecholamines, released as a consequence of the nicotine-induced' response, have been associated~ with or implicated ini several biological responses. Cardiovascular-related diseases, bronchoconstriction and related pulmonary manifestations, fat metabolism, hyperglycemic effects, and the patellar reflex response have implicated catechol- amines as being either directly or indirectly involved in these biological endpoints. In the United States, more people die from coronary heart disease than from any other disease, and heart disease is the single most important cause of death among cigarette smokers(62). Epidemiologi- cal studies su& as those reported by Mulcahy, et all (45) who found a positive association between coronary heart disease mortality rate and the calculated per capita cigarette consumption in 21 countries, the Framingham study (19, 23, 33, 50), and reviews by Aronow (5) and Kannel' (32) leave little doubt as to the consequences of cigarette smoking with respect to heart disease. Cardiovascular and Related Effects It is generally agreed that the acute cardiovascular effects of tobacco smoking, can be attributedl to the nicotine content of the cigarette and' the amount absorbed (14„ 20); similar effects have been observed by Irving and Yamamoto on~ administration of a comparable amount of nicotine by injection (31). The responses observed are those expected from stimulation of the sympathetic nervous system (15), including stimulation of the sympathetic ganglia, adrenal medulla, and the release of endogenous catecholamines (14 Responses are known to include increased heart rate and blood' pressure (2, 28), cardiac output stroke volume, velocity of contraction, myocardial~ contractile force and oxygen consumption, and coronary blood~ flow and: arrythmias (15, 20). Activation of the chemoreceptors of the carotid and aortic bodies results in vasoconstriction, tachycardia; and elevated blood pressure. Nad'eau and'James (44have shown that the cardiac/stimulating effect of nicotine can be attributed to vagal stimulation. The possible role of elevated serum corticoids, following, smoking of high nicotine ciga- rettes, in sensitizing the myocardium to the effects of the catechol- amine has been suggested (5, 29) as also possibly contributing to ventricular arrythmias and myocardial infarctions. Further research has been suggested to resolve this issue (5). Armitage and coworkers (3)' have graphically described the dose- response effects of nicotine intravenous injection and~ cigarette 14-89

smoking as they affect blood pressure and heart rate. These results are described in Figure 12. Pulmonary Effects The respiratory effects of nicotine from smoke exposure are more difficult to quantify than cardiovascular effects because respiratory function~ may also be influenced by the solid particles or gases in cigarette smoke (i.e., CO and~ C0z). For example, Reintjes and coworkers (50) were able to show that airway resistance values obtained immediately after smoking were, elevated, but they did not identify the response as being caused! by the nicotine in cigarette smoke. Aviado and coworkers (7) demonstrated that cigarette smoke causes acute bronchoconstriction by release of histamine and by stimulation of the parasympathetic nervous: system ini the lungs, Similar responses were shown to occur with arterial injections of nicotine. The effect is followed, however, by bronchodilation attributed to sympathetic stimulation. Fat' Metabolism Changes in free fatty acids and mobilization of free fatt'y acids (FFA) have also been reviewed (40) as secondary effects of catecholamine stimulation. Kershbaum and coworkers (35) were led to the conclusion that nicotine had' no direct lipolytic effect on cat or dog adipose fat tissue. Their findings lent support t'o the concept that mobilization of FFA by nicotine and cigarette smoke was a result of their stimulation of sympathetic nervous system activity and catecholamine secretiom In a related study (36) comparing 4 mg of nicotine ini intravenously- and intratracheally-administered cigarette smoke, the authors suggested that tobacco smoking and nicotine caused an increased utilization of FFA in addition to their known effect of FFA mobilization. It was suggested that the greater FFA utilization was caused by increased cardiac output due to nicotine. The authors further suggested thatt nicotine changes the ratio of FFA incorporated int'o neut'ral' lipid, and phospholipids. Hyperglycemic Effects Another secondary response t'o the catecholamines present in the blood stream is believed to be a hyperglycemic condition as described in a recent review (40). Such a response would be consistent with a st'ressr related situation requiring an energy source for quick response. Milton (44) has suggested that in cats the hyperglycemic mobilizing action of smoking doses of nicotine is due entirely to stimulation of the adrenal gland, while the hyperglycemic effect at high doses is presumably due to stimulation of ganglia throughout the body resulting, in the release of more epinephrine: 14-90 N

e II TT O t'O~ N' O O O O09 O~ aD OD n r2l S S POOM RuieVe1/6TY (LnwJsleeq)',s7ei lmeH' .9 9 ~+ v (6Hww) d® 8 R 8 9 N1 0 T 0 FIGURE 12.-Arterial blood levels of 14C=nicotine (0) and 14C- cotinine (0), heart rate (°), and blood pressure (0) during and after smoking a cigarette labeled with "C-nicotine (a)„and during and after intravenous administration of 1 mg 14C-nicotine in 10 divided doses (b). SOURCE: Beckett, A.H. (8). 14-91,

Other Central Nervous System Effects It has recently been reported that nicotine also causes a diminution in the monosynaptic patellar reflex (18): This reduction in the patellar reflex was not seen after smoking nontobacco cigarettes. The effect thus appears to be closely related to nicotine. This was later confirmed by Domino and Baumgart:en (18) after studying the response to an~ inhaled nicotine aerosolL Metabolism of Nicotine The metabolism of nicotine has been examined and reviewed by several investigators (25, 27, 61). The major part of the absorbed nicotine is metabolized rapidly in the body, and studies have established the liver as the major organ of detoxication. McKennis, et al. (20a. 20d) have d'emonstrated~ that cotinine is the major metabolite of nicotine in human and animal urine. Other detected metabolites are summarized in Figure 13. Hansson and Schmiterlbw (27), using radiola,beled nicotine, were able to detect radiolabeled products only in cotinine and C02. In studying tissue slices, they determined that nicotine is metabolfized in the kidney and lung as well as in the liver, but not in the brain, diaphragm, spleeny stomach„ small intestine, or adrenal glands. Armitage (2), in comparing the: effects of injected nicotine an& innaled' cigarette smoke, found that the half-life of nicotine in the arterial blood of smokers ranged from 24 to 84 minutes, with a mean value of 40 minutes when on11y the inhalation experiments were ~ taken into account. In examining the relationship between intravenous injections of nicotine: and subsequent metabolism, Miller, et al. (43) found nicotine had a t1/2 of 55 to 64 minutes, with peak levels in the range of 297 ng/ml of plasma. While there was no effect of the administere& dose on disappearance rate, there was a suggestion that the dose affected the distribution of nicotine. This woul& appear reasonable,, in view of the known vasoconstrictive properties mentioned earlier, and could explain some of the conflict's in characterizing nicotine's pharmacologic properties. Tsujimoto and coworkers (59) studied the tissue distribution of nicotine in dogs and rhesus monkeys. Five minutes after injection the adrenal medulla and cerebral cortex contained the highest concentra- tion of nicotine. Other tissues containing significant quantities of nicotine included the spleen, adrenal cortex, kidney, and pancreas. The effect of urinary pH on the excretion of nicotine and its metabolites has been studied by Beckett, et al. (8), Gorrod and Jenner (25), and' Feyerabend and Russell (21). They determined that the amount of unchanged nicotine excreted in the urine after oral administration was dependent on pH, while cotinine was dependent on 14-92