John A. Dani, PhD, Thomas R. Kosten, MD, PhD, and Neal L. Benowitz, MD
CHAPTER OUTLINE
■ DRUGS IN THE CLASS
■ METHODS OF ABUSE
■ HISTORICAL FEATURES
■ PHARMACOKINETICS
■ PHARMACOLOGIC ACTIONS
■ NEUROBIOLOGIC MECHANISMS OF ACTION
■ SYSTEMIC TOXICITY
Tobacco use is the leading cause of death in the United States (1–3), causing approximately 440,000 deaths each year and producing nearly $100 billion in direct medical costs and nearly $100 billion in lost productivity annually (4). This chapter examines the pharmacology and actions of nicotine, which is the main addictive component of tobacco. Understanding the pharmacology of nicotine is important in devising effective interventions for smoking cessation and in developing nicotine as a therapeutic agent.
DRUGS IN THE CLASS
Nicotine is a naturally occurring alkaloid that serves as an insecticide in many plants. Nicotine is a tertiary amine that consists of a pyridine and a pyrrolidine ring (Fig. 12-1). There are two stereoisomers of nicotine. The (S)-nicotine form is the active isomer that binds to nicotinic acetylcholine receptors (nAChRs) and is found in tobacco. The (R)-nicotine form is a weak agonist at cholinergic receptors. During smoking, some racemization takes place, and small quantities of (R)-nicotine are found in cigarette smoke. In humans, nicotine is a psychostimulant and mood modulator (1,3). Like other psychostimulants, nicotine may temporarily improve alertness and wakefulness, but smokers also often use tobacco as a calming influence. After becoming addicted, smokers report arousal, relaxation, and relief from stress and hunger. Thus, nicotine becomes a mood leveler, causing arousal during fatigue and relaxation during anxiety (1).
FIGURE 12-1 The chemical structure of nicotine. The IUPAC chemical name is 3-(1-methylpyrrolidin-2-yl) pyridine, and the chemical formula is C10H14N2.
METHODS OF ABUSE
Nicotine and the reinforcing sensory stimulation associated with tobacco use are responsible for the compulsive use of tobacco in the form of cigarettes, bidis, cigars, pipes, snuff, and chewing tobacco (1,3,5,6). Nicotine replacement medications, which are used to facilitate smoking cessation, include nicotine polacrilex gum, transdermal patches, nasal spray, inhalers, buccal lozenges, and oral nicotine solutions. Recently, electronic cigarettes (e-cigarettes or electronic nicotine delivery systems) have become widely available. These are devices that look like cigarettes but are made of plastic and metal and heat a nicotine solution to generate a nicotine-containing vapor that is inhaled. In contrast to regular cigarettes, e-cigarette vapor is generated without combustion of plant material. E-cigarettes are promoted for use when one cannot smoke regular cigarettes and/or to cut down on or quit tobacco cigarette use (7). However, their effectiveness for smoking cessation or reduction is largely unknown, as is their safety. Like most addictive drugs, the method of administration modifies the addictive influence. Nicotine is much more addictive during rapid administration, as obtained by smoking tobacco, than during the slow administration associated with a patch.
HISTORICAL FEATURES
Native American tribes cultivated and used tobacco for many different purposes for thousands of years before the arrival of Europeans. Tobacco was first commercially grown for the European market at the first permanent English settlement in America, Jamestown, which was founded in 1607. Tobacco became an important economic influence in the British American colonies and the early United States (8). The World Health Organization estimates that one-third of the global adult population smokes, and because tobacco use is on the rise in developing countries, it is one of the few causes of death that is increasing (2).
PHARMACOKINETICS
Absorption, Distribution, Metabolism, and Elimination
The absorption of nicotine depends on its pH. Below pH 6, smoke contains less than 1% unprotonated (free) nicotine. As the pH rises, so does the proportion of unprotonated nicotine. At pH 7.26, 15% of the nicotine is unprotonated, increasing to 50% at pH 8. Unprotonated nicotine is present mainly in the vapor phase of the smoke, whereas protonated nicotine is contained primarily within particles in the smoke aerosol (9). Unprotonated nicotine is absorbed through the mucous membranes of the oral and nasal cavities (10,11). Tobacco products such as cigars, many pipe tobaccos, snuffs, and chewing tobaccos present nicotine either as an unionized (unprotonated), vaporized component of smoke or as an alkaline solution of nicotine. Tobacco smoke with pH levels above 6.2 contains increasing amounts of free ammonia, nitrates that are partially reduced to ammonia during smoking, and other volatile basic components (12).
Because alkaline smoke is irritating to the pharynx, it is harsh and difficult to inhale. Therefore, smoke from cigarettes and from some pipe tobaccos has an acidic pH. The ionized nicotine in such smoke is largely dissolved in the aerosol droplets. After small droplets of tar-containing nicotine are inhaled and deposited in small airways and alveoli, the protonated nicotine is buffered to a physiologic pH and absorbed. Inhaled nicotine avoids first-pass metabolism. It is quickly delivered from the large surface area of the alveoli and circulation in the lung to the arterial bloodstream and then to the brain and other tissues.
Nicotine reaches the brain approximately 20 seconds after inhalation, and it gradually increases occupancy of nAChRs over many minutes. Smoking a cigarette leads to significant occupancy of the high-affinity α4β2-containing nAChRs for greater than 3 hours (13). Although levels of nicotine bound to nAChRs in the brain continue to rise slowly and are maintained for hours (13), the initial relatively rapid rate of rise of nicotine at brain targets, which meaningfully occurs in minutes (13), is likely to be the determinant for nicotine’s immediate impact on the central nervous system (CNS). The delivery of nicotine from moist snuff (e.g., Copenhagen) is slower, with the plasma concentration of nicotine continuing to rise throughout a 30-minute period of use (14). Interestingly, the subjective nicotine craving decreased in relation to the nicotine dose and time course (14).
The relatively rapid delivery of nicotine to the brain in the smoking process allows precise dose titration so that the smoker can obtain the desired effects. Smokers can control nicotine intake by altering their puff volume, the number of puffs they take from a cigarette, the intensity of puffing, and the depth to which they inhale. Smokers also can increase smoke intake by blocking the ventilation holes of the filter with their fingers or their lips. Because of the complexity of smoking, the exact dose of nicotine cannot be accurately predicted from the nicotine content of the tobacco or a cigarette’s machine-rated yield (15). Individuals smoke to obtain desired levels of nicotine from cigarettes in ways that largely compensate for the engineering features that reduce the amount of nicotine deposited on a filter pad in standard smoking machine tests.
Nicotine is poorly absorbed from the stomach because of the acidity of the gastric fluid, but it is well absorbed in the small intestine, which has an alkaline pH as well as a large surface area. When nicotine is administered in capsules, peak concentrations are reached in just over an hour. Nicotine undergoes first-pass metabolism; its oral bioavailability is approximately 45% (16).
After nicotine is absorbed into the bloodstream, it has a volume of distribution of about 180 L, with less than 5% binding to plasma proteins. Nicotine crosses the placenta freely and has been found in the amniotic fluid and in the umbilical cord blood of neonates. Nicotine also is found in breast milk at concentrations approximately twice those found in blood.
Nicotine obtained from tobacco reaches high initial concentrations in the arterial blood and lungs. Subsequently, nicotine distributes into the brain, storage adipose, and muscle tissue from the arterial blood such that the levels of nicotine are two- to sixfold lower in the venous blood (17,18). The average steady-state concentration of nicotine in the body tissues is 2.6 times the average steady-state concentration of nicotine in the blood (16).
Based on a half-life of 2 hours or more, nicotine accumulates during a day of regular smoking (3 to 4 half-lives) and persists for 6 to 8 hours after smoking ceases. Steady-state plasma nicotine levels, which plateau in the early afternoon, typically range between 10 and 50 ng/mL. The increment in blood nicotine concentration after smoking a single cigarette ranges from 5 to 30 ng/mL, depending on how the cigarette is smoked (16). Peak blood concentrations of nicotine are similar for cigar smokers, users of snuff, chewers of tobacco, and those who smoke cigarettes. The rate of rise of nicotine concentrations is slower with use of snuff and chewing tobacco, with peak nicotine levels occurring at 20 to 30 minutes. Individual smokers seem to manipulate their nicotine intake to maintain a consistent level of nicotine from day to day (15). Based on positron emission tomography imaging, the distribution of nicotine onto nAChRs is slower than the rise in the bloodstream (13).
Smoking represents a multiple-dosing situation, with considerable accumulation of nicotine in the body tissues (including the brain). Nicotine persists in the body around the clock. Peaks and troughs in blood nicotine concentrations follow each cigarette, but those variations are smoothed out within the brain. As the day progresses for the regular smoker, the overall level of nicotine rises, and the potential influence of each dose becomes less important. Tolerance occurs, so that the effects of individual cigarettes tend to lessen throughout the day. Overnight abstinence allows considerable, but not complete, resensitization of nicotinic receptors to nondesensitized states (Fig. 12-2). The populations of nAChR subtypes begin to change as other molecular mechanisms involving neuroadaptations come into play after days and weeks of tobacco use (1,19,20).
FIGURE 12-2 A simulation of the plasma nicotine concentration throughout the day in relation to psychoactive effect.
Nicotine is extensively metabolized primarily in the liver and to a lesser extent in the lung and in the brain (16). On average, 80% of nicotine is metabolized to cotinine, with a smaller fraction (4%) metabolized to nicotine N-oxide. Cotinine is further metabolized to trans-3′-hydroxycotinine, the major nicotine metabolite found in the urine, as well as cotinine methonium ion, 5′-hydroxycotinine, and cotinine-N-oxide. About 17% of cotinine is excreted unchanged in the urine (16). CYP2A6 is primarily responsible both for the C-oxidation of nicotine to cotinine and for the oxidation of cotinine to trans-3′-hydroxycotinine. The ratio of trans-3′-hydroxycotinine to cotinine, which can be measured in blood, saliva, or urine of tobacco users, is a relatively stable biomarker of CYP2A6 activity and the rate of metabolism of nicotine. As discussed later, the rate of nicotine metabolism is a determinant of the level of nicotine dependence and response to smoking cessation therapies (21). Nicotine, cotinine, and trans-3′-hydroxycotinine are further metabolized by glucuronidation. Renal clearance accounts for 2% to 35% (about 10%) of total nicotine clearance.
Sex and race influence nicotine metabolism. Women metabolize nicotine faster than men, and women who take estrogen-containing oral contraceptives metabolize nicotine faster than women who do not (22). The metabolism of nicotine during pregnancy is even faster, consistent with a dose effect of estrogen on CYP2A6 activity (23). African Americans obtain on average 30% more nicotine per cigarette, and they clear nicotine and cotinine more slowly than do Caucasians (24). The slower nicotine clearance is due to the less rapid oxidative metabolism of nicotine to cotinine, related at least in part to a higher prevalence of CYP2A6 gene variants associated with reduced activity in African Americans (25). African Americans also exhibit population polymorphism in the rate of nicotine N-glucuronidation, with a subpopulation of slow metabolizers, not found in Caucasians (26). Black men also have a higher incidence of mortality from lung cancer than do White men, particularly at lower levels of cigarette consumption (27). Chinese Americans have both a lower nicotine intake per cigarette and smoke fewer cigarettes per day than do Caucasians (26). Chinese Americans also metabolize nicotine and cotinine more slowly than do Caucasians or Hispanic Americans. Slower metabolism in Chinese Americans is consistent with the higher prevalence of CYP2A6 alleles associated with slow metabolism among Asians (28). Because nicotine intake per cigarette is a marker for tobacco smoke exposure per cigarette, these findings suggest why Chinese American smokers have lower rates of lung cancer than either African Americans or Caucasians (27). Ethnic variations in nicotine intake per cigarette, the number of cigarettes smoked, and the metabolism of nicotine may form the basis for population-based differences in the incidence and prevalence of progression from nicotine use to addiction, as well as the associated risk of tobacco-related disease.
Biochemical Assessment of Exposure to Nicotine and Tobacco
Blood, salivary, and plasma cotinine are most commonly used as biochemical markers of nicotine intake (29). Other measures of smoking include expired breath carbon monoxide concentrations, blood carboxyhemoglobin concentrations, and plasma or salivary thiocyanate concentrations. Measurement of the minor tobacco alkaloids anabasine and anatabine in urine can be used as a biomarker of tobacco use in individuals who are using nicotine medications (30).
The 16-hour half-life of cotinine makes it useful as a plasma and salivary marker of nicotine intake. Salivary cotinine concentrations correlate well with blood cotinine concentrations (r = 0.82–0.90) (31). The cotinine level produced by a single cigarette is 8 to 10 ng/mL. It takes several hours for the cotinine to peak after a cigarette is smoked. A cotinine value greater than 14 ng/mL typically indicates smoking (32). A smoker with a plasma cotinine concentration of 100 ng/mL would have an estimated intake of 8 mg nicotine per day, which corresponds to smoking approximately a half pack of cigarettes per day (29). Cotinine blood levels average about 250 to 300 ng/mL in regular smokers but range from 10 to 900 ng/mL. Because of individual variability in the fractional conversion of nicotine to cotinine and in the rate of elimination of cotinine itself, blood levels of cotinine are not perfect quantitative markers of nicotine intake in individual smokers but are useful in studying populations of smokers. Cotinine levels may persist for up to 7 days after cessation of habitual smoking. The gold standard for estimating daily nicotine intake from tobacco use is the sum of nicotine and its metabolites in urine (33).
Breath measurements of expired air that contain more than 10 parts per million carbon monoxide (CO) usually indicate tobacco smoking within the past 8 to 12 hours (32). Elevated CO levels in the absence of smoking may be the result of exposure to environmental pollutants, such as faulty gas boilers, car exhausts, and smog. Persons who are lactose intolerant exhale hydrogen after ingesting milk. Several monitors misinterpret this exhaled hydrogen as CO (34).
Hydrogen cyanide is inhaled as a combustion product of nitrogen-containing compounds. It is metabolized in the body from thiosulfate to thiocyanate, which can be detected in the blood and saliva (35). Thiocyanate levels also may be affected by consumption of common foods (such as almonds, tapioca, cabbage, broccoli, and cauliflower). In addition, hydrogen cyanide is produced when burning other plant materials, in building fires, and car exhaust fumes. Assays of thiocyanate are insensitive to low amounts of smoking, and thiocyanate levels can remain elevated for weeks after smoking has ceased. CO and cotinine levels generally are preferred to thiocyanate levels in the assessment of smoking.
Unique to tobacco is the nicotine-derived nitrosamine 4-(methylnitrosamino)-1(3-pyridyl)-1-butanone (NNK), which is metabolized in the body to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which in turn is excreted in urine (36). NNAL has a much longer half-life than does cotinine (10 to 16 days) and may be a better biomarker of long-term or intermittent exposure.
Drug Interactions with Tobacco and Nicotine
Smoking accelerates the metabolism of many drugs, particularly those metabolized by CYP1A2 (37). Polycyclic aromatic hydrocarbons are believed to account for the enzyme-inducing effects of smoking, although other smoke components may play a role. Nicotine does not induce most enzymes but may increase CYP2E1 and inhibit CYP2A6 enzymatic activity. Cigarette smoking induces the metabolism of theophylline, propranolol, flecainide, tacrine, caffeine, olanzapine, clozapine, imipramine, haloperidol, pentazocine, estradiol, and other drugs. When smokers stop smoking, as often occurs during hospitalization for an acute illness, the doses of these medications may need to be lowered to avoid toxicity.
Several pharmacodynamic interactions arise between cigarette smoking and other drugs. Cigarette smoking results in faster clearance of heparin, possibly because of smoking-related activation of thrombosis, with enhanced heparin binding to antithrombin III. Cigarette smoking and oral contraceptives interact synergistically to increase the risk of stroke and premature myocardial infarction in women. Cigarettes appear to enhance the procoagulant effect of estrogens. For this reason, oral contraceptives are relatively contraindicated in women who smoke cigarettes. The stimulant actions of nicotine inhibit reductions in blood pressure and heart rate from beta-adrenergic blockers. Smoking results in less sedation from benzodiazepines and less analgesia from some opioids. Smoking also impairs the therapeutic effects of histamine H2-receptor antagonists used in treating peptic ulcers. Cutaneous vasoconstriction by nicotine can slow the rate of absorption of subcutaneously administered insulin.
PHARMACOLOGIC ACTIONS
Central Nervous System
Nicotine has a complex dose–response relationship (10). At low doses (such as those achieved by smoking a cigarette), nicotine acts on the sympathetic nervous system to acutely increase blood pressure, heart rate, and cardiac output and to cause cutaneous vasoconstriction. At higher doses, nicotine produces ganglionic stimulation and the release of adrenal catecholamines. At extremely high doses, nicotine causes hypotension and slowing of the heart rate, possibly via peripheral ganglionic blockade or vagal afferent nerve stimulation. Because of the development of tolerance, chronic nicotine exposure in and of itself does not cause hypertension, although blood pressure throughout the day while smoking is higher than when that person is not smoking (38). Nicotine also causes muscle relaxation by stimulating discharge of the Renshaw cells or pulmonary afferent nerves while inhibiting the activity of motor neurons.
Psychoactive Effects
The primary CNS effects of nicotine in smokers are arousal, relaxation (particularly in stressful situations), and enhancement of mood, attention, and reaction time, with improvement in performance of some behavioral tasks. Some of this improvement results from the relief of withdrawal symptoms in addicted smokers, rather than as a direct enhancing effect (39–41). Smoking may mainly reverse the effects of abstinence, rather than directly relieving stress and improving cognition. In a comparison of self-rated feelings of stress, arousal, pleasure, and evaluations of cognitive function in 25 cigarette smokers, 25 temporarily abstaining smokers, and 25 nonsmokers, the abstaining smokers reported significantly worse psychologic states on every assessment measure than did the nonsmokers and smokers, who did not differ from each other (42). Smokers may need regular doses of nicotine to feel normal rather than to enhance their capabilities.
The psychoactive effects of nicotine and tobacco are determined not only by the route and speed of drug administration and the pharmacokinetic parameters that determine the concentration at receptor sites over time but also by a variety of host and environmental factors. The magnitude of nicotine’s subjective effects may depend on the predrug subjective state, level of activity, genetic predisposition, history or current intake of other drugs, expectancy of the individual, and other situational factors (5,6,43–45). Nicotine’s effects are baseline dependent. For example, low-activity rats become more active on exposure to nicotine, whereas the reverse occurs in high-activity rats (46). Similarly, nicotine has stimulant-like effects on human electroencephalograms during quiet conditions but minimal effects during high-noise conditions (47).
Nicotine’s ability to cause stimulation when smoked at a low level of arousal (such as fatigue) and to affect relaxation when smoked at a high level of arousal (such as anxiety) underlies its reinforcing effects under a range of conditions (48). Smokers increase their smoking under both low- and high-arousal conditions (49). Subtle stimulation or relaxation effects may be thought beneficial by users who would like to fine-tune their disposition at a given time. The subtle modulatory effects preferred by tobacco users are in contrast to the flagrant intoxicating effects desired by some users of alcohol and other psychoactive substances.
Gender differences appear to affect nicotine responsiveness. Women have less sensitivity to changes in nicotine dose during nicotine discrimination experiments, and they may not benefit as much as men from nicotine replacement therapy during smoking cessation (50). Women may be influenced more by nonnicotine stimuli, such as the olfactory and taste attributes of cigarette smoke, indicating greater conditioned reinforcement (51).
Genetic Predisposition
Genetics mediate differences in sensitivity to nicotine (52). Different mice strains react differently to nicotine, self-administer nicotine to different extents (53), differ in the ability to develop tolerance, and have different numbers of nicotine receptor binding sites (54). In humans, monozygotic twins are more similar than dizygotic twins with respect to smoking behavior (43). Data from large twin registries suggest that about half of the total variance (range 28% to 84%) in smoking behavior can be attributed to genetic effects (44,55). Twin studies also demonstrate a genetic influence on nicotine withdrawal symptoms (41).
Family linkage studies and candidate gene association studies suggest a number of loci or particular genes that are associated with smoking behavior, but the smoking phenotypes vary considerably from study to study (43). Candidate genes coding for nicotine receptor subtypes, dopamine receptors or transporter, gamma-aminobutyric acid (GABA) receptors, and others have been identified in various studies as being associated with different aspects of smoking behavior (56). However, subsequent research has not replicated many of these earlier findings.
Genome-wide association studies have indentified single nucleotide polymorphisms in the CHRNA5–CHRNA3–CHRNB4 nAChR subunit cluster on chromosome 15q25 that are associated with number of cigarettes smoked per day and serum cotinine levels, as well as risk for lung cancer, peripheral arterial disease, and chronic lung disease (57). The other gene that clearly affects smoking behavior and cancer risk is the CYP2A6 gene, which codes for the primary enzyme responsible for the oxidation of nicotine and cotinine. CYP2A6 affects cigarette smoking behavior and cancer risk. This gene is polymorphic, and reduced function variants of the gene are associated with smoking fewer cigarettes per day and a lower risk of lung cancer (58,59). Other genome-wide association studies point to several other genes as potential genetic determinants of nicotine dependence, including the alpha-3 and beta-3 nicotinic receptor genes, neurexin 1, VPS13A (vacuolar sorting protein), KCNJ6 (a potassium channel), and the GABA A4 receptor genes (60,61). Some of these genes, such as the neurexin 1 gene, are related to cell communication. Other genome-wide association studies have identified a number of genes affecting cell adhesion and extracellular matrix molecules that are common among various addictions, consistent with the idea that neural plasticity and learning are key determinants of individual differences in vulnerability to drug addictions (62).
Rate of Nicotine Metabolism and Nicotine Dependence
The rate of nicotine metabolism varies widely among different smokers, even among those with similar CYP2A6 genotype. Rapid metabolizers smoke more cigarettes per day than slower metabolizers, presumably to maintain desired levels of nicotine. Studies using the ratio of the nicotine metabolites trans-3′-hydroxycotinine/cotinine (known as the nicotine metabolite ratio or NMR) have shown that slow metabolizers are more likely to quit smoking when treated with placebo or nicotine patches (63). The mechanism of this effect is not definitely known, but may be that fast metabolizers eliminate nicotine faster from the blood and so have more severe withdrawal symptoms between cigarettes, making smoking more of a negative reinforcer. The rate of nicotine metabolism is being evaluated as a way to personalize smoking cessation treatment.
Psychiatric Comorbidity
Tobacco use is most highly prevalent and more intense among psychiatric patients and among those who abuse other drugs (1). Among those with mental illness, 36% are current smokers, compared to 20% among adults with no mental illness (4). Individuals with schizophrenia, depression, and attention deficit hyperactivity disorder (ADHD) have a higher prevalence of cigarette smoking than the population as a whole. These groups of patients have more difficulty in quitting compared with smokers without mental illness, often experiencing greater depression after stopping smoking.
Among those with schizophrenia, 70% to 88% are smokers (64). People with schizophrenia have diminished sensory gating to repeated stimuli, an abnormality reversed for tens of minutes by nicotine and clozapine, but not haloperidol (65). Nicotine also reverses some haloperidol dose-related impairments on a variety of cognitive tasks (66) and relieves some of the negative symptoms (such as blunted affect, emotional withdrawal, and lack of spontaneity and flow of conversation) that occur with schizophrenia. Genetic linkage in families with schizophrenia supports a role for the α7 nicotinic receptor subunit, with potential linkage at the α7 locus on chromosome 15 (67). These data suggest there may be a shared underlying neurobiology for both cigarette smoking and schizophrenia. Smokers experience fewer side effects from antipsychotic drugs, presumably from the stimulating effects of nicotine, which also may contribute to a higher prevalence of smoking among people with schizophrenia.
Rates of nicotine dependence are substantially higher among adults with ADHD (40%) than in the general population (about 20%) (68). Among adult smokers, the presence of ADHD is associated with early initiation of regular cigarette smoking, even after controlling for confounding variables such as socioeconomic status, IQ, and psychiatric comorbidity (69). Nicotine administered through transdermal patches improves the attentional symptoms of ADHD (70).
Population-based epidemiologic studies (71) found a lifetime prevalence of depression of 59% among subjects who had ever smoked, compared with 17% in the general population. Other reports confirm that the prevalence of smoking in individuals with major depression is twice that observed in the general population (72). A history of major depression may speed the progression from nicotine use to dependence. Twin studies support a model with common risk factors for both depression and cigarette smoking (73).
Depression sensitizes smokers to the influence of stress (1,74), making the individual more susceptible to drug reward. Depression and anxiety often accompany nicotine withdrawal, particularly for abstinent smokers with psychiatric illness. Relief from specific aspects of those symptoms motivates relapse. Thus, smokers become conditioned to expect nicotine to provide partial relief from stress and depression, as it does from the symptoms of withdrawal (74). Smokers with a history of depression who stop smoking are at risk of developing more severe withdrawal symptoms, have poorer outcomes, and are more likely to experience a depressive episode, especially during the first 3 months after stopping smoking (1,74).
Discrimination and Self-Administration
Squirrel monkeys and rodents are able to distinguish the subjective effects of nicotine and nicotine analogues from drugs of other classes. This effect is attenuated by pretreatment with mecamylamine, a centrally acting nicotinic receptor antagonist, but not with hexamethonium, a peripheral antagonist that does not enter the brain. Animals will self-administer nicotine, but the environment, dose, and timing of the reinforcement schedule are more critical with nicotine than with, for example, cocaine. Likewise, human volunteers will self-administer intravenous nicotine (71). They describe the experience as pleasurable and similar to that evoked by cocaine. Human smokers also regulate the nicotine levels that they self-administer (15). Smokers pretreated with mecamylamine smoke more to overcome the blocking effects of this antagonist (39).
Human smokers get “secondary reinforcement” from the irritant effects of nicotine on the tissues of the mouth and throat. Experienced smokers can use the tissue irritant effects to assess how much nicotine they are receiving when smoking (5). A short-term reduction in cigarette craving is seen when the sensory input from tobacco smoke is simulated with ascorbic acid or black pepper extract. Products that replicate the taste, flavor, throat, and chest sensations of cigarette smoking or the sensorimotor handling of a cigarette may reduce craving and some of the symptoms of nicotine withdrawal. Some of these products are being developed as smoking cessation aids.
Dependence, Tolerance, and Withdrawal
Nicotine obtained through chewing tobacco and cigarettes often precedes the use of other drugs (75). The earlier the age at which use begins, the more difficult it is for the user to quit. Many persons have been exposed to nicotine in utero as a result of smoking by their mothers (76). Nicotine exposure alters nicotinic receptor numbers and influences their function. In smokers who progress to chronic use, tolerance develops rapidly to the headache, dizziness, nausea, and dysphoria associated with the first cigarette. However, tolerance is incomplete; the ingestion of as little as 50% more than the usual dose can result in symptoms of toxicity. Chronic use is associated with the regular ingestion of quantities far larger than those used initially, even though consumption levels typically remain steady for many years after addiction has been established.
Conditioned cues (drug-associated memories) become established during the fine-tuned dosing of nicotine. Desiring a cigarette becomes associated with everyday events such as driving a car, finishing a meal, talking on the telephone, waking from sleep, and taking a break. Tobacco users link the need to modulate their moods with smoking. The imagery promoted by cigarette advertising adds to this expectation. Thus, a person who begins smoking a pack of cigarettes per day at age 17 would experience thousands of finely tuned doses of nicotine-conditioned internal emotional states and external cues by their mid-20s. The quantity and power of this conditioning is unique to cigarette smoking, and it is one of the reasons that smokers find cigarette smoking so difficult to quit.
The regular use of tobacco commonly leads to its compulsive use (77). There have been attempts to correlate the severity of nicotine addiction with factors such as the duration of smoking, potency of cigarettes, puff frequency, puff duration, and inhalation volume. However, these variables only weakly correlate with biochemical measures, and they do not predict the intensity and extent of withdrawal symptoms. The Fagerström Test for Nicotine Dependence is one of the most widely accepted measures of the severity of nicotine physical dependence (78). Many studies show a relationship between the Fagerström Test for Nicotine Dependence and the ability to achieve tobacco cessation.
There is a high rate of relapse among individuals who try to quit smoking (1). Population surveys consistently find that up to 75% of adults who smoke want to stop. About one-third actually try to stop each year, but less than 3% succeed unaided (79). Among persons who experience myocardial infarctions, laryngectomies, chronic obstructive pulmonary disease, and other medical sequelae of smoking, ≥50% revert to cigarette use within days or weeks after leaving the hospital.
Withdrawal
Tobacco use is sustained, in part, by the need to prevent the symptoms of nicotine withdrawal, that is, negative reinforcement (1,39,40). The symptoms of withdrawal vary in severity from person to person, but those symptoms include craving for nicotine, irritability and frustration or anger, anxiety, depression, difficulty concentrating, restlessness, and increased appetite. Performance measures such as reaction time and attention are impaired during withdrawal. Although these symptoms often are distressing and can be disruptive to interpersonal functioning, they are not in themselves life threatening. Most acute withdrawal symptoms reach maximum intensity 24 to 48 hours after cessation and then gradually diminish over a few weeks. Some (including dysphoria, mild depression, and anhedonia) may persist for months. The extinction of tobacco-associated conditioned cues requires months to years. That nicotine itself is responsible for the withdrawal symptoms is supported by the appearance of similar symptoms with sudden withdrawal from the use of chewing tobacco, snuff, or nicotine gum and relief of those symptoms provided by nicotine replacement. Another motivating factor for some abstinent smokers is an average weight gain of 3 to 4 kg during the 1st year after smoking cessation.
There is evidence that the activation of the extrahypothalamic corticotropin-releasing factor (CRF)-CRF1 receptor system contributes to negative affect during nicotine withdrawal. During precipitated nicotine withdrawal in rats, which is associated with anxiety-like behavior, CRF is released in the central nucleus of the amygdala (80). CRF activation produces anxiety behavior, and pharmacologic blockade of CRF1 receptors inhibits the anxiogenic effects of nicotine withdrawal. Withdrawal from other drugs of abuse such as alcohol, cocaine, opiates, and cannabinoids is also associated with activation of the extrahypothalamic CRF system, suggesting that this is a common mechanism of affective manifestations of drug withdrawal. Both the hypoactivity of the dopaminergic system and the activation of the CRF system appear to mediate nicotine withdrawal symptoms that often precipitate relapse to smoking.
NEUROBIOLOGIC MECHANISMS OF ACTION
Nicotinic Receptors
nAChRs belong to a superfamily of ligandgated ion channels that includes GABA, glycine, and 5-hydroxytryptamine (serotonin) receptors. The basic conformational states of a nAChR channel are the closed state at rest, the open state, and the desensitized state (81). After binding the endogenous agonist, acetylcholine (ACh), or an exogenous agonist, nicotine, the nAChR ion channel is stabilized in the open conformation for several milliseconds. The open pore of the receptor/channel complex then returns to a resting state or closes to a desensitized state that is unresponsive to ACh or other agonists for varying lengths of time usually in the millisecond to second time range. While open, nAChRs conduct cations that cause a local depolarization of the membrane and produce an intracellular ionic signal. Although sodium and potassium ions carry most of the current through nAChR channels, calcium also can make a small but significant contribution.
The nicotinic receptor–channel complex consists of five polypeptide subunits assembled like staves of a barrel around a central water-filled core (81). Various subunit combinations produce many different nAChR types. Three broad functional classes of nAChRs are recognized: muscle nAChRs (not discussed here), neuronal nAChRs formed from alpha and beta subunit combinations (α2 to α6 and β2 to β4), and neuronal nAChRs formed only of alpha subunits (α7 to α9 or α10 with α9). Some evidence suggests that subunits of the separate classes are capable of combining to form nAChRs, but such combinations may be rare.
Genetic and neurophysiologic studies in mice indicate the alpha-4 beta-2–containing (α4β2*, where * indicates the potential presence of other nAChR subunits) nAChRs are primarily responsible for nicotine dependence. In β2-subunit knockout mice, nicotine is less able to release dopamine in the brain, and these animals do not self- administer nicotine (45). Genetic manipulation of the α4 subunit alters sensitivity to the effects of nicotine (82). The expression of somatic withdrawal symptoms mainly depends upon the α5, α2, and β4 nicotinic subunits.
Cholinergic Systems
Cholinergic neurons project throughout the CNS, providing diffuse, sparse innervation to practically all of the brain (81). Despite its generally sparse innervation in the CNS, cholinergic activity influences a wide variety of behaviors. By acting initially on nAChRs, nicotine or nicotinic cholinergic innervation can increase arousal, heighten attention, influence stages of sleep, produce states of euphoria, decrease fatigue, decrease anxiety, act centrally as an analgesic, and influence cognitive function. It is thought that cholinergic systems affect discriminatory processes by increasing the signal-to-noise ratio and by helping to evaluate the significance and relevance of stimuli.
Nicotinic Mechanisms in the CNS
The most widely observed synaptic role of nAChRs in the mammalian CNS is to influence neurotransmitter release (81). Presynaptic nAChRs are thought to initiate a direct and indirect calcium signal that boosts the release of neurotransmitters. Exogenous application of nicotinic agonists enhances, and nicotinic antagonists often diminish, the release of ACh, dopamine, norepinephrine, serotonin, GABA, and glutamate. In many cases, the α7* nAChRs, which are highly calcium permeable, mediate the increased release of neurotransmitter, but in other cases, different nAChR subtypes are involved.
Nicotinic AChRs also have roles in neuronal development and plasticity (83). The density of nAChRs varies during the course of development, and nAChRs can contribute to activity-dependent calcium signals. Nicotinic regulatory, plasticity, and developmental influences may be important in the etiology of disease. Biologic changes that inappropriately alter nicotinic mechanisms could immediately influence the release of many neurotransmitters and alter circuit excitability. Moreover, nicotinic dysfunction could have long-term developmental consequences that are expressed later in life.
The tremendous diversity of nAChRs provides the flexibility necessary for them to play multiple, varied roles (81). Broad, sparse cholinergic projections ensure that nicotinic mechanisms modulate the neuronal excitability of relatively wide circuits. Although fast nicotinic transmission (as seen at the neuromuscular junction) is not the predominant mechanism in the CNS, it can contribute excitatory input to many synapses at one time. Nicotinic receptors located on presynaptic terminals or located on axons before the presynaptic terminals (i.e., preterminal) modulate the release of many neurotransmitters. The activity of nAChRs at those locations induces a local depolarization that may initiate a local action potential, or the activity may directly or indirectly induce a calcium signal. Both the local action potential and calcium signal influence neurotransmitter release if the effects invade active release sites that are most commonly located in presynaptic terminals. In addition, ACh also diffuses from release sites depending on the local density of acetylcholinesterase (AChE), which is the enzyme that breaks down (hydrolyzes) ACh. Although AChE is widely distributed in the CNS, evidence indicates that the density and location of AChE do not always match the location of ACh release sites. Consequently, ACh diffuses and acts at lower concentrations substantial distances away from the release site in a process called volume transmission. Owing to volume transmission, nAChRs influence broad circuit excitability owing to nAChR effects occurring well outside of the synaptic sites (81).
Nicotine’s Influence on Dopaminergic Neurons
Much evidence supports the theory that nicotine is the major addictive component of tobacco (1,84–86). Although many areas of the brain participate, the mesocorticolimbic dopamine (DA) system serves a vital role in the acquisition of behaviors that are reinforced by addictive drugs. An important dopaminergic pathway originates in the ventral tegmental area (VTA) of the midbrain and projects to the prefrontal cortex, as well as to limbic and striatal structures, including the nucleus accumbens. Blocking DA release in the nucleus accumbens with antagonists or lesions reduces nicotine self-administration in rodents (87).
Nicotine Activates and Desensitizes nAChRs on Mesocorticolimbic Neurons
In rat brain slices, nicotine, at concentrations comparable to those seen in tobacco users, activates and desensitizes nAChRs on VTA DA neurons and thereby potently modulates the firing of VTA neurons (1,86,88). Nicotine reaches nAChRs at every brain location, including those at presynaptic, postsynaptic, and nonsynaptic (including somal) locations. On the DA neuron’s cell bodies and postsynaptically, most nAChRs contain α4β2 subunits with a high affinity for nicotine; those subunits are often in combination with α5 or α6. α4β2-containing (α4β2*) nAChRs also predominate on inhibitory GABAergic neurons innervating this area. The DA neurons from the posterior VTA that provide the main project to the nucleus accumbens commonly express α6 and β3 with the α4 and β2 subunits (89,90). At the low concentrations of nicotine achieved by smokers, the presence of the α6 subunit, particularly in α6α4β2* nAChRs, slows the rate and degree of desensitization seen with the higher-affinity α4β2 nAChRs (91). Therefore, those α6-containing receptors are important to maintain the more prolonged activation of DA neurons caused by nicotine from tobacco (89). In addition, α4β2* nAChRs containing the α6 subunit regulate DA release in target areas such as the nucleus accumbens. The α7* nAChRs, which have a much lower affinity for nicotine, are at lower density in the midbrain; they are more commonly located on the presynaptic terminals of excitatory glutamatergic afferents into this midbrain area (in rodent studies). This arrangement of nAChRs is hypothesized to underlie their enhancement of excitatory synaptic potentiation (1,86).
When nicotine first arrives in the midbrain DA area, it excites nAChRs, particularly the high-affinity α4β2* nAChRs and related nAChR subtypes and, to a lesser degree, the lower-affinity α7* nAChRs. Activation of the presynaptic nAChRs enhances the release of glutamate. The postsynaptic (and somal) α4β2* nAChRs, including those containing α6, contribute to the depolarization of DA neurons, helping N-methyl-D-aspartate receptors to participate in glutamatergic synaptic potentiation (81). After the initial exposure to nicotine and potentiation of glutamatergic afferents, there is significant, but incomplete, desensitization of the high-affinity α4β2* nAChR subtypes, particularly owing to the presence of α6 in some receptors that are not strongly desensitized. Consequently, some of the inhibitory GABA transmission decreases because the α4β2* nAChRs desensitize, and the GABAergic inhibition of the DA neurons decreases because any afferent cholinergic activity that normally boosted GABA release no longer can act on all the α4β2* receptor subtypes.
Glutamatergic excitation of the DA neurons remains elevated because the synaptic potentiation that was initiated by the transient α4β2* nAChR activity persists for longer time periods (known as long-term synaptic potentiation). In addition, the presynaptic α7* nAChRs on glutamatergic afferents are much less desensitized by the low concentrations of nicotine that are present. Therefore, α7* nAChRs continue to enhance glutamate release, particularly at the potentiated synapses that provide ongoing excitation of DA neurons (1,81,86).
Distinct nAChRs subtypes contribute to the manifestations of the withdrawal syndrome. The withdrawal syndrome is not mediated by the same mechanisms or by the same neural circuits that initiate addiction or dependence. The epithalamic habenular complex and its targets appear to be critical for the withdrawal syndrome. The medial habenula (MHb) and one of its primary targets, the interpeduncular nucleus (IPN), richly express β4 and α5 nAChR subunits (and α2 only in the IPN) that are necessary for the neuroadaptations that lead to somatic withdrawal symptoms during nicotine abstinence (92–94). In mouse models, the absence of α5 or β4 nearly eliminates the somatic signs of withdrawal (93,94). This phenotype is in sharp contrast with that of β2-lacking mice, which display normal somatic signs of withdrawal (93,95). Another nicotinic subunit that contributes to the somatic signs of withdrawal is the α2 subunit (94), which is selectively expressed in the IPN and the olfactory bulb of rodents (96,97). The α7 subunit plays a smaller role (98).
The α5, α2, and β4 subunits are highly expressed in MHb and IPN (99,100). Microinjection of the nAChR antagonist mecamylamine into the Hb and IPN was sufficient to precipitate nicotine withdrawal symptoms in mice chronically treated with nicotine. Furthermore, mice lacking α5 in the MHb self-administer nicotine at doses that elicit strong aversion in wild-type mice. This result suggests that α5-containing nAChRs in the MHb are key to the control of the amounts of nicotine self-administered (101). Taken together, these data suggest a prominent role of the MHb/IPN axis in mediating nicotine’s aversive effects and the somatic symptoms of withdrawal (94). Because the single nucleotide polymorphism (SNP) rs16969968 within CHRNA5 correlates with nicotine dependence risk, heavy smoking, and the pleasurable sensation produced by a cigarette (61,102–104), it may be hypothesized some people with that SNP smoke more and become addicted at a younger age because of less functional α5* nAChRs in the MHb/IPN axis. The presence of fewer aversive effects (even at higher nicotine doses) during the initial contact with the drug would promote the hedonic drive, thereby promoting the transition from use to abuse and dependence.
Hypotheses to Extrapolate Cellular Results to Smokers
On the basis of cellular studies of nAChR activation and desensitization, it is possible to infer some of the effects of smoking cigarettes, each of which delivers about 20 to 100 nM nicotine to the brain (13,105). Initially, the brain is free of nicotine, and nAChRs should be responding normally to cholinergic synaptic activity. When nicotine first arrives, nAChRs are activated, causing the neurons to depolarize and fire action potentials. This process has multiple consequences throughout the brain (106) (Fig. 12-3). DA neurons are activated, contributing to the increase in DA in the nucleus accumbens. Present theories hold that these neuronal events reinforce the behaviors that produce the DA release (1,84–86,107). Thus, smoking and associated behaviors, whether incidental or meaningful, are reinforced (in a type of learning process). As the nicotine from the cigarette lingers, desensitization of nAChRs begins. This process decreases the effect obtained by smoking more than a few cigarettes in a row. However, the desensitization process is not complete, and, in fact, there is considerable variability in desensitization of the various nAChR subtypes.
FIGURE 12-3 A simplified cycle for continued tobacco use, based on nicotine’s cellular actions. Nicotinic acetylcholine receptors (nAChRs) are initially and transiently activated when nicotine first arrives. The desensitization of the receptors follows as the concentration of nicotine slowly decreases. The increased number of nAChRs and the neuroadaptations are hypothesized to develop after chronic use of nicotine. The learned associations occur over the course of tobacco use as nicotine causes reinforcements via the midbrain dopaminergic systems. (From Dani JA, Heinemann S. Molecular and cellular aspects of nicotine abuse. Neuron 1996;16(5):905–908.)
Nicotinic receptor desensitization has other effects (1,81,86). When nicotine obtained from tobacco is present, the high-affinity nicotine sites (including α4β2* nAChRs) are more likely to desensitize. At cholinergic synapses, nAChRs experience repeated exposures to synaptic ACh and are exposed to nicotine from the cigarette. The combination of agonist exposures increases the probability that nAChRs at active cholinergic synapses will desensitize. Thus, smoking will turn down the gain for information arriving via nicotinic cholinergic synapses because fewer nAChRs will be able to respond to the released ACh. In summary, nicotine not only sends inappropriate information through the mesocorticolimbic DA system, but it also decreases the amplitude for normal nicotinic cholinergic information processing.
Long-term nicotine exposure leads to neuroadaptations; the most well known is an increase in the number of some nAChR subtypes (108). After long periods (weeks, months, or years) of smoking, nAChRs increase in number as a homeostatic reaction of decreased sensitivity (i.e., desensitization).
When nicotine is removed from the brain, some of the excess nAChRs recover from desensitization, resulting in an excess excitability of the nicotinic cholinergic systems of smokers. This hyperexcitability, where nAChRs have been up-regulated, could contribute to the unrest and agitation that contribute to the smoker’s motivation for the next cigarette, which “medicates” the smoker by desensitizing the excess number of nAChRs back toward a more normal level.
These receptor changes may underlie the most common pattern of cigarette smoking. Most smokers report that the first cigarette of the day is the most pleasurable (77,88,109). After a night of abstinence, nicotine concentrations in the brain are at their lowest level. Thus, smoking the first cigarette most strongly activates nAChRs, possibly causing the largest activity of the midbrain DA areas and contributing to the most reinforcing effects (Fig. 12-3, Step 1). After a few cigarettes, there is significant (albeit incomplete) desensitization, causing some acute tolerance and less effect from additional cigarettes (Fig. 12-3, Step 2). The process of activation and desensitization affects different nAChR types differently and influences synaptic plasticity, contributing to the long-term changes associated with addiction. When smoking continues for long periods, the nicotinic system undergoes various neuroadaptations, including an increase in the number of high-affinity nAChRs (Fig. 12-3, Step 3). Cigarettes are smoked throughout the day, in part driven by smaller variable rewards and by the agitation arising from the excess nAChRs and hyperexcitability at cholinergic synapses experienced during abstinence (Fig. 12-3, Step 4).
Episodes of cigarette smoking are often separated by hours of abstinence. During that time, nicotine levels drop, and some nAChRs recover from desensitization. Smokers often report that cigarettes smoked during the day help them to focus and relax so that they can work more efficiently (77,109). As an individual smokes several times during the course of a day, the background level of nicotine slowly increases. Therefore, a smoker experiences some exposure to nicotine throughout the day, ensuring that some subtypes of nAChRs visit states of desensitization. These episodes of nAChR desensitization ensure that the number of nAChRs becomes and remains elevated (owing to mechanisms of neuroadaptations). If nicotine is avoided for a few weeks, the number of nAChRs begins to return to the lower value seen in nonsmokers (81). Although this readjustment suggests the “quitting” process is underway, the nicotine-associated learning and memory are not extinguished. Thus, smoking-associated conditioned cues can continue to motivate tobacco use for long periods beyond this stage.
Most attempts to quit fail (110,111). Over years of smoking, long-term synaptic changes result in learned associations, including associations with the events, people, and context in which smoking takes place. Because these behaviors are repeatedly and variably reinforced by cigarettes, associations become conditioned cues that motivate tobacco usage, such that the desire for cigarettes extinguishes slowly and sometimes incompletely. Desire for cigarettes may be experienced even years after having quit, cued by learned associations (1,39,40,107).
Monoamine Oxidase and Tobacco Dependence
Cigarette smoking is associated with reduced activity of the enzymes monoamine oxidase A (MAO A) and monoamine oxidase B (MAO B), as demonstrated by positron emission tomography scanning of the brain using MAO substrates (112,113). Inhibition of MAO is produced not by nicotine but by condensation products of acetaldehyde with biogenic amines, such as benzoquinones, 2-naphthylamine, harman, and other chemicals (112–114). A main function of MAO is to metabolize catecholamines, including dopamine. Inhibition of MAO would be expected to increase brain levels of dopamine after exposure to tobacco. Studies in rats show that pretreatment with drugs that inhibit MAO makes nicotine more rewarding and increases the likelihood and rate of acquisition of nicotine self-administration (115). Therefore, MAO inhibition may contribute to the overall addictiveness of smoking. In addition, given that medications that inhibit MAO have antidepressant action, smoking-induced inhibition of MAO might contribute to the perceived benefit of smoking by some depressed patients.
SYSTEMIC TOXICITY
Particulate and Gaseous Components of Tobacco Smoke
Tobacco smoke is composed of volatile (gaseous) and particulate phases that contain substances other than nicotine that are primarily responsible for human morbidity and mortality. The volatile phase contains more than 500 gaseous compounds, including nitrogen, CO, carbon dioxide, ammonia, hydrogen cyanide, and benzene. There are more than 3,500 different compounds in the particulate phase, including the pharmacologically active alkaloids nornicotine, anabasine, anatabine, myosmine, nicotyrine, and nicotine. Assays for some of these alkaloids are used as biomarkers of tobacco use (30). The “tar” in a cigarette is composed of the particulate matter minus its alkaloid and water content. Tar contains many carcinogens, including polynuclear aromatic hydrocarbons, N-nitrosamines, and aromatic amines.
Cardiovascular, Pulmonary, and Oncologic Toxicities
Smokers are exposed to about 4,000 different chemicals, including at least 50 known carcinogens. The increased risk of cardiovascular disease among cigarette smokers likely is related to exposure to oxidant chemicals and CO, as well as hydrogen cyanide, carbon disulfide, cadmium, and zinc (116). Although CO reduces oxygen delivery to the heart, oxidant chemicals are primarily responsible for endothelial dysfunction, platelet activation, thrombosis, and coronary vasoconstriction (117).
Cigarette smoking has significant detrimental effects on both the structure and function of the lung. Cigarette smoking causes an imbalance between proteolytic and antiproteolytic forces in the lung and heightens airway responsiveness. Chronic obstructive lung diseases are linked to exposure to tar, nitrogen oxides, hydrogen cyanide, and volatile aldehydes, resulting in oxidative stress and generation of superoxide radicals and hydrogen peroxide and lung damage (118).
The agents contributing most significantly to lung and other cancers are expected to be the carcinogenic polynuclear aromatic hydrocarbons and the tobacco-specific N-nitrosamines, followed by polonium-210 and volatile aldehydes. Catechol, volatile aldehydes, and nitrogen oxides that can serve as precursors in the exogenous and endogenous formation of N-nitrosamines enhance tobacco smoke-induced tumorigenesis (119). Active smokers with elevated levels of DNA damage from polynuclear aromatic hydrocarbons in their white blood cells (DNA adducts) are three times more likely to be diagnosed with lung cancer 1 to 13 years later than are smokers with lower adduct concentrations (odds ratio, 2.98; 95% confidence interval, 1.05 to 8.42; p = 0.04) (120). As with other tobacco-related diseases, the risk of cancer of the mouth, larynx, esophagus, lung, stomach, pancreas, kidney, urinary bladder, and uterine cervix as well as leukemia is directly related to the intensity and duration of exposure to cigarette smoke.
Other Physiologic Effects and Toxicities
Cigarette smoking is associated with skin changes, including yellow staining of fingers, vasospasm and obliteration of small skin vessels, precancerous and squamous cell carcinomas on the lips and oral mucosa, and enhanced facial skin wrinkling. Tobacco smoke and exposure to ultraviolet A radiation each cause wrinkle formation. When excessive sun exposure (>2 hours per day) and heavy smoking (>35 pack years) occur together, the risk of developing wrinkles is 11.4 times higher than that of nonsmokers and those with less sun exposure at the same age (121). The induction of matrix metalloproteinase-1, mediated by reactive oxygen species (especially in people with low glutathione content in fibroblasts), is thought to be an important mechanism underlying premature skin aging caused by cigarette smoking and exposure to ultraviolet A radiation.
Current smokers of 20 or more cigarettes per day have statistically significant increases in nuclear sclerosis and posterior subcapsular cataracts compared with individuals who never smoked. After adjusting for age and average number of cigarettes smoked per day, former smokers who had quit smoking 25 or more years previously have a 20% lower risk of cataracts than current smokers but still higher than among subjects who never smoked (122). Current smokers of more than 20 cigarettes per day also have an increased risk of age-related macular degeneration (123).
Cigarette smoking in women is associated with lower levels of estrogen, earlier menopause, and increased risk of osteoporosis (124). The alkaloids in tobacco smoke diminish estrogen formation by inhibiting an aromatase enzyme in granulosa cells or placental tissue.
In men, smoking may impair penile erection, primarily in people with underlying vascular disease, through the impairment of endothelium-dependent smooth muscle relaxation (125). Smoking doubles the likelihood of moderate or complete erectile dysfunction associated with other risk factors, such as coronary artery disease and hypertension. Because the prevalence of erectile dysfunction in former smokers is no different from that in individuals who never smoked, erectile dysfunction is believed to improve with smoking cessation (125).
Nicotine both suppresses appetite and increases metabolic rate (126,127). Smokers weigh an average 2.7 to 4.5 kg (6 to 10 lb) less than nonsmokers. With smoking cessation, individuals typically crave sweets. Individuals who stop smoking typically gain weight to approximately the levels of never smokers in the 6 to 12 months after smoking cessation.
Through release of catecholamines, nicotine increases lipolysis and releases free fatty acids, which are taken up by the liver (128). This could contribute to the increase in very low-density lipoprotein and low-density lipoprotein and the decrease in high-density lipoprotein seen in smokers.
Cigarette smoking is associated with the occurrence and delayed healing of peptic ulcers. Mechanisms include decreases in the mucous bicarbonate barrier in the stomach, reduction in the production of endogenous prostaglandins in the gastric mucosa, and increased proliferation of Helicobacter pylori (129).
Tobacco and Pregnancy
Smoking during pregnancy nearly doubles the relative risk of having a low birth weight infant; the relative risks of spontaneous abortion and perinatal and neonatal mortality are increased by about one-third (130). The components of tobacco smoke responsible for obstetric and fetal problems have not been definitively identified. CO clearly is detrimental because it markedly reduces the oxygen-carrying capacity of fetal hemoglobin (131).
The effect of smoking in lowering birth weight is influenced by the metabolic genes CYP1A1 and GSTT1 (130). Infants born to smoking mothers who had genetic variants associated with reduced CYP1A1 activity—Aa and aa (heterozygous and homozygous variant types)—and reduced or absent GSTT1 activity had greater reductions in birth weight than did infants born to smoking mothers who had the normal metabolic activity genes CYP1A1 AA (homozygous wild type) or GSTT1 genotype. The CYP1A1 and GSTT1 enzymes have roles metabolizing and excreting some toxic chemicals in cigarette smoke.
In the developing fetus, nicotine can arrest neuronal replication and differentiation and can contribute to sudden infant death syndrome (132). Nicotine activates nicotinic cholinergic receptors in the fetal brain, resulting in abnormalities of cell proliferation and differentiation that lead to shortfalls in cell numbers and eventually to altered synaptic activity. Comparable alterations occur in peripheral autonomic pathways and are hypothesized to lead to increased susceptibility to hypoxia-induced brain damage, perinatal mortality, and sudden infant death (16,130,132).
Secondhand Smoke
Secondhand smoke (SHS) is the complex mixture formed by the escaping smoke of a burning tobacco product, as well as smoke that is exhaled by a smoker. Sidestream smoke contains higher concentrations of some toxins than does mainstream smoke. SHS characteristics change as it combines with other constituents in the ambient air and ages (133). Exposure to SHS is causally associated with acute and chronic coronary heart disease, lung cancer, nasal sinus cancer, and eye and nasal irritation in adults and with asthma, chronic respiratory symptoms, and acute lower respiratory tract infections such as bronchitis and pneumonia in children (133). SHS also is causally associated with low birth weight and sudden infant death syndrome in infants (133). Young children’s exposure to tobacco smoke comes mainly from smokers in the home, especially parents. Maternal smoking has the greatest effect on children’s measured cotinine levels (133). Additional contributors include paternal smoking, smoking by other household members, and smoking by child care personnel.
An average salivary cotinine level of 0.4 ng/mL corresponds to an increased lifetime mortality risk of 1/1,000 for lung cancer and 1/100 for heart disease (134). Assuming a prevalence of 28% for unrestricted smoking in the workplace, passive smoking would yield 4,000 heart disease deaths and 400 lung cancer deaths annually in the United States (134).
Morbidity and Mortality
Each pack of cigarettes sold in the United States costs the nation an estimated $7.18 in medical care expenditures and lost productivity (135). Smoking is a leading cause of preventable death in the United States, accounting for about 440,000 premature deaths annually. This includes roughly 150,000 deaths from cardiovascular causes, 150,000 deaths from cancer, and 100,000 deaths from nonmalignant pulmonary disease (135). Cigarette smoking also increases the risk of developing and increases the severity of respiratory tract infections, including influenza, pneumococcal pneumonia, and tuberculosis (136). On average, adult men and women smokers lost 13.2 and 14.5 years of life, respectively. In contrast, the annual mortality attributable to passive smoking between 1995 and 1999 was nearly 40,000 deaths, including 35,000 from cardiovascular diseases, 3,000 from lung cancer, and 1,000 from perinatal conditions (135).
Tobacco and Other Addictions
There is a strong correlation between smoking and alcohol abuse (1). More severely dependent drinkers smoke more and are less likely to quit. Tobacco also synergizes with alcohol in causing a number of medical complications. Smoking and heavy drinking, in combination, are associated with substantially increased rates of oral and esophageal cancers (137). Because lit cigarettes smolder when they fall onto upholstered furniture, alcohol use combines with smoking to cause household fires that claim more than 1,000 lives per year among children and adults (138). Persons recovering from other substance use disorders often die from tobacco-related illnesses. In a landmark population-based retrospective cohort study, death certificates were examined for 214 of 854 persons who were admitted between 1972 and 1983 to an inpatient program for the treatment of alcoholism and other nonnicotine drugs of dependence (139). Of the deaths reported, 50.9% were caused by tobacco use, whereas 34.1% were attributable to alcohol use. The cumulative 20-year mortality was 48.1% versus an expected 18.5% for a demographically matched control population (p < 0.001).
Benefits of Cessation
The good news is that smoking cessation has benefits for smokers of all ages. The immediately decreased risk of cardiovascular death in those who stop smoking may reflect a decrease in blood coagulability, improved tissue oxygenation, and reduced predisposition to cardiac arrhythmias. Among former smokers, the reduced risk of death compared with continuing smokers begins shortly after quitting and continues for at least 10 to 15 years. After 10 to 15 years’ abstinence, the risk of all-cause mortality returns nearly to that of persons who never smoked (140).
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