Cigarette smoking remains the leading cause of preventable premature morbidity and mortality in the United States and in many countries around the world. An average of 443,000 people in the United States die prematurely from tobacco-related disease in a year, which includes one of every three cancers and one in five overall deaths. A lifelong smoker has about a one in three chance of dying prematurely from a complication of smoking. Life expectancy is shortened by more than 10 years among current smokers. The increased risk for death from smoking is now equal between men and women in the United States, and the World Health Organization has estimated that more than a billion deaths in the 21st century will be attributed to tobacco consumption.
Smoking is particularly relevant to respiratory medicine, because it is by far the major cause of lung cancer and chronic obstructive pulmonary disease (COPD) in developed countries. Smoking is also a substantial causative factor in respiratory infections, including pneumococcal pneumonia, influenza, and tuberculosis.
Epidemiology of Cigarette Smoking
Currently about 42.1 million individuals (18.1% of the adult population) in the United States are cigarette smokers, including 20.5% of men and 15.8% of women. The percentage who smoked 30 or more cigarettes per day declined significantly, from 12.6% in 2005 to 9.1% in 2011, and the proportion of those who smoked 1 to 9 cigarettes per day increased from 16.4% to 22.0%. In the United States an increasing number of smokers (as many as 25% in some areas) are nondaily smokers. People who are less well educated and/or have unskilled occupations are more likely to smoke. For example, 33.8% of people with 9 to 11 grades of education are smokers, compared to 9.9% of those with a college degree. High rates are seen in those living below the federal poverty level (27.7%), those 18 to 24 years of age (23.8%), and those in construction and extraction industries (30%).
There are more than 1 billion smokers worldwide, the majority of whom live in low- and middle-income countries. Cigarette smoking and exposure to secondhand smoke together are responsible for about 6.3 million annual deaths worldwide and 6.3% of the global burden of disease. The World Health Organization Framework Convention on Tobacco Control aims to reduce both the demand and the supply of tobacco around the world through educational, political, and legislative means.
Toxicology of Cigarette Smoke
Tobacco smoke is an aerosol of droplets (particulates) containing water, nicotine and other alkaloids, and tar. Tobacco smoke contains several thousand different chemicals, many of which may contribute to human disease. Major toxic chemicals in the particulate phase of tobacco include nicotine, benzo(a)pyrene and other polycyclic hydrocarbons, N’ -nitrosonornicotine, β-naphthylamine, polonium-210, nickel, cadmium, arsenic, and lead. The gaseous phase contains carbon monoxide, acetaldehyde, acetone, methanol, nitrogen oxides, hydrogen cyanide, acrolein, ammonia, benzene, formaldehyde, nitrosamines, and vinyl chloride. Tobacco smoke may produce illness by way of systemic absorption of toxins and/or cause local pulmonary injury by oxidant chemicals.
Tobacco use is a major cause of death from cancer, cardiovascular disease, and pulmonary disease ( Table 46-1 ). Smoking is also a major risk factor for osteoporosis, reproductive disorders, and fire-related and trauma-related injuries.
|CANCER (See Table 46-2 )|
|Acute myocardial infarction|
|Peripheral arterial occlusive disease (including thromboangiitis obliterans)|
|Increased susceptibility to pneumonia and to pulmonary tuberculosis|
|Increased susceptibility to desquamative interstitial pneumonitis|
|Increased morbidity from viral respiratory infection|
|Lower birth weight|
|Premature rupture of membranes|
|Increased perinatal mortality|
|ORAL DISEASE (SMOKELESS TOBACCO)|
|Non–insulin-dependent diabetes mellitus|
|Tobacco amblyopia (loss of vision)|
|Age-related macular degeneration|
|Premature skin wrinkling|
|Aggravation of hypothyroidism|
|Altered drug metabolism or effects|
Smoking, the largest preventable cause of cancer ( Table 46-2 ), is responsible for about 30% of cancer deaths. Many chemicals in tobacco smoke may contribute to carcinogenesis as tumor initiators, co-carcinogens, tumor promoters, or complete carcinogens. Complexes of tobacco smoke carcinogens and DNA are thought to be a crucial step in cancer induction. Cigarette smoking induces specific patterns of p53 gene mutations that are associated with squamous cell carcinomas of the lung, head, and neck. Lung cancer is the leading cause of cancer deaths in the United States and is predominantly attributable to cigarette smoking. The risk for lung and other cancers is proportional to the number of cigarettes smoked per day and even more strongly to the duration of smoking. In current smokers the levels of DNA adducts (covalently bound carcinogens) in nontumor lung tissue or blood mononuclear cells are related to cigarette consumption. Of note, however, in former smokers DNA adduct levels were inversely associated with age of initiation of smoking. This finding suggests that young smokers are more susceptible to DNA damage and persistence of genetic alterations than are those who begin smoking at an older age, which has substantial implications for the need to prevent adolescent smoking. A recent genome-wide association study analysis of a cohort of smokers compared to a cohort of never smokers has confirmed that the expression of thousands of genes is altered by cigarette exposure. Additional information from deep sequencing of a lung cancer tumor provides a picture of widespread genetic mutational change with hundreds of point somatic variants and multiple large structural genetic changes such as chromosomal segment deletion.
|Cancer Site||Average Relative Risk|
|Oropharynx and hypopharynx||4.0–5.0 *|
|Nasal cavity, sinuses, nasopharynx||1.5–2.5|
Workplace exposure to asbestos or α-radiation (the latter in uranium miners) synergistically increases the risk for lung cancer in cigarette smokers. Alcohol use interacts synergistically with tobacco in causing oral, laryngeal, and esophageal cancer. The mechanism of interaction may involve alcohol solubilizing tobacco carcinogens and/or alcohol-related induction of liver or gastrointestinal enzymes that metabolize and activate tobacco carcinogens. Smoking is associated with 15% of leukemia cases in adults and 20% of colorectal cancers. Based on large cohort studies and a meta-analysis, cigarette smoking in women before having their first child is associated with increased breast cancer risk.
Chronic Pulmonary Disease
More than 80% of chronic obstructive lung disease in the United States is attributable to cigarette smoking. Cigarette smoking also increases the risk for respiratory infection, including pneumonia, and results in greater disability from viral respiratory tract infections. Pulmonary disease from smoking includes the overlapping syndromes of chronic bronchitis (cough and mucus secretion), emphysema, and airway obstruction. The lung pathologic conditions produced by cigarette smoking include loss of cilia, mucous gland hyperplasia, increased number of goblet cells in the central airways, inflammation, goblet cell metaplasia, squamous metaplasia, mucus plugging of small airways, destruction of alveoli, and a reduced number of small arteries. The mechanism of injury is complex and seems to include inflammation as well as direct injury by oxidant chemicals, increased elastase activity (a protein that breaks down elastin and other connective tissue), and decreased antiprotease activity. A genetic deficiency of α 1 -antiprotease activity produces a similar imbalance between pulmonary protease and antiprotease activity and is a risk factor for early and severe smoking-induced pulmonary disease.
In addition to the effects of cigarette smoke–induced injury, the delivery of carbon monoxide from cigarette smoke serves to worsen the level of functioning in smokers who have significant COPD. Carbon monoxide avidly binds to hemoglobin, reduces the capacity of hemoglobin to carry oxygen, and impairs oxygen release at the tissues. Thus carbon monoxide exposure produces a functional anemia. Carboxyhemoglobin levels are typically 5% to 10% in smokers, compared to 1% or less in nonsmokers. In a normal person, carbon monoxide from cigarette smoke causes few symptoms, but, in patients with pulmonary disease, carbon monoxide has the potential to cause significant impairment. Exposure to carbon monoxide at levels even less than that derived from cigarette smoking have been shown to reduce exercise tolerance in patients with COPD.
Cigarette smoking may contribute to the development of asthma, although this potential link could be confounded by the increased rate of pulmonary infections observed in smokers. A longitudinal study of 5800 individuals taking part in a British national study suggested that regular smoking was associated with asthma in people between the ages of 17 and 33 ( odds ratio [OR] = 4.4). The relationship between asthma and smoking was further studied in more than 14,000 Finnish adults, and the prevalence of asthma was higher among male smokers than among male nonsmokers (relative risk = 1.7), although no smoking effect was observed for women. Current smokers, compared to never and ex-smokers, demonstrate higher asthma severity scores, more frequent asthma symptoms, and more frequent asthma attacks (OR = 2.4). Silverman and coworkers evaluated 1847 emergency department patients presenting with acute asthma and found that 35% of patients were current smokers. Half of these smoking asthmatics reported that cigarette use worsened their asthma symptoms.
The link between secondhand smoke and asthma would support the hypothesis that tobacco exposure worsens bronchial hyperresponsiveness. A study evaluating infants in their first year of life exposed to smoking mothers demonstrated they were 2.1 times more likely to develop asthma than children of nonsmoking mothers. Likewise, the Swiss Study on Air Pollution and Lung Disease in Adults suggested that secondhand smoke was associated with an increased risk for asthma (OR = 1.4) or reactive airway disease in nonsmoking adults.
There are other links between smoking and inflammatory lung conditions such as asthma. In a small cohort of healthy nonasthmatic smokers, bronchoalveolar lavage fluid documented altered macrophage cytokine release, increased cellularity, and depressed levels of interleukin-6. These abnormalities would further suggest a plausible link between smoking and an increased incidence and severity of chronic lung inflammatory conditions.
Cigarette smoking has been associated with multiple non-neoplastic pulmonary disorders other than emphysema and chronic bronchitis. These include respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonitis, Langerhans cell histiocytosis, cryptogenic interstitial fibrosing alveolitis, and eosinophilic pneumonia. Ninety percent of patients with pulmonary Langerhans cell histiocytosis are smokers. Respiratory bronchiolitis and desquamative interstitial pneumonitis have similar histopathologic features and are characterized by the accumulation of pigmented macrophages within the alveoli. Respiratory bronchiolitis (“smoker’s bronchiolitis”) is most often an asymptomatic finding that can persist after smoking cessation. Desquamative interstitial pneumonitis often affects smokers in their fourth or fifth decade of life, and the symptoms are more frequent in smokers. Smoking may also have an association with idiopathic pulmonary fibrosis. Smoking is over-represented in patients with idiopathic pulmonary fibrosis compared to the general population, and the overall OR for smoking as a risk factor for idiopathic pulmonary fibrosis was 1.6.
Cigarette smoking is a major risk factor for respiratory tract and other systemic infections. Both active and passive cigarette smoke exposure increase the risk for infection. The mechanisms by which smoking increases risk are multifactorial and include structural and immunologic alterations. As mentioned previously, cigarette smoking causes structural changes in the respiratory tract. These changes include peribronchiolar inflammation and fibrosis, increased mucosal permeability, impairment of mucociliary clearance, changes in pathogen adherence, and disruption of the respiratory epithelium. A number of components of cigarette smoke, including acrolein, acetaldehyde, formaldehyde, free radicals produced from chemical reactions within the cigarette smoke, and nitric oxide, may contribute to the observed structural alterations in airway epithelial cells.
Immunologic mechanisms include alterations in cellular and humoral immune system function. These include a decreased level of circulating immunoglobulins, a depression of antibody response to certain antigens, a decrease in CD4 + lymphocyte counts, an increase in CD8 + lymphocyte counts, depressed phagocyte activity, and decreased release of proinflammatory cytokines. Many of the immunologic disturbances in smokers resolve within 6 weeks after smoking cessation, supporting the idea that smoking cessation is highly effective in a relatively short period of time in the prevention of infection.
Cigarette smoking is associated with an increased risk for bacterial and viral infections ( Table 46-3 ). Cigarette smoking is a substantial risk factor for pneumococcal pneumonia, especially in patients with COPD. Smoking is strongly associated with invasive pneumococcal disease in otherwise healthy adults. A population-based case control study showed smoking was the strongest independent risk factor for invasive pneumococcal disease among immunocompetent adults. The OR was 4.1 (95% confidence interval [CI], 2.4 to 7.3) for active smoking and 2.5 (95% CI, 1.2 to 5.1) for passive smoke exposure in nonsmokers compared to nonexposed nonsmokers. The attributable risk in this population was 51% for cigarette smoking and 17% for passive smoking, and this effect showed a strong dose response. The risk for pneumococcal disease declined to nonsmoker levels 10 years after cessation. Cigarette smoking has also been shown to be associated with a nearly twofold increased risk for community-acquired pneumonia, with 32% of the risk attributable to cigarette smoking.
|Odds Ratio (95% CI)|
|Legionnaires’ disease||3.5 (2.1–5.8)|
|HIV infection||3.4 (1.6–7.5)|
|Periodontal disease||2.8 (1.9–4.1)|
|Pneumococcal pneumonia||2.6 (1.9–3.5)|
|Meningococcal disease||2.4 (0.9–6.6)|
|Helicobacter pylori||2.2 (1.2–4.0)|
|Common cold||1.5 (1.1–1.8)|
Cigarette smoking increases the risk for developing and the severity of viral infections, including the common cold, influenza, and varicella. Influenza infections are more severe, with more cough, acute and chronic phlegm production, breathlessness, and wheezing in smokers. Influenza infections produce more lost workdays in smokers compared to nonsmokers. Influenza vaccination is effective in preventing the disease in smokers, and smoking should be considered to be a high-priority indication for influenza vaccination. The role of development of varicella pneumonitis in adults is reported to be substantially greater in smokers compared to nonsmokers.
Tuberculosis is perhaps the most important smoking-associated infection. Cigarette smoking is a risk factor for tuberculin skin test reactivity, for skin test conversion, and for the development of active tuberculosis. A large case-control study from India examined smoking and tuberculosis in men between 35 and 69 years of age. The tuberculosis prevalence relative risk was 2.9 (95% CI, 2.6 to 3.3) for ever smokers compared to never smokers, and the prevalence was higher with a higher level of cigarette consumption. The mortality from tuberculosis among men 25 to 69 years old showed a relative risk of 4.5 (95% CI, 4.0 to 5.0) and 4.2 (95% CI, 3.7 to 4.8) for urban and rural residents, respectively. The authors found that the proportion of deaths from tuberculosis attributable to smoking was 61% greater than the proportion of deaths from vascular disease or cancer attributable to smoking. Thus it is likely that smoking contributes substantially to the worldwide disease burden of tuberculosis.
Of historical interest is the relationship between tuberculosis and the risk for cigarette smoking in the early 20th century. Before that time, chewing tobacco was the preferred type of tobacco. Public fear that users of chewing tobacco who spit in public places might be spreading tuberculosis is one of the factors that led to the increase in cigarette sales in the United States. This is nicely described by Kluger as follows: “Chewing tobacco was no longer merely messy but socially disagreeable in more crowded urban America, and in its inevitable byproduct, spitting, was now identified as a spreader of tuberculosis and other contagions and, thus, an official health menace. The leisurely pipe all at once seemed a remnant of a slower-tempo age, and cigar fumes were newly offensive amid thronged city life. The cigarette by contrast, could be quickly consumed and easily snuffed out on the job as well as to and from work.”
Although not the focus of this textbook, cardiovascular disease is common in patients with respiratory disease. This relates to the facts that both diseases are common and both increase with age and that smoking is a major risk factor for both respiratory disease and cardiovascular disease.
Cigarette smoking accounts for about 20% of cardiovascular deaths in the United States. Risks are increased for coronary artery disease, sudden death, cerebrovascular disease, and peripheral vascular disease, including aortic aneurysm. Cigarette smoking accelerates atherosclerosis and promotes acute ischemic events. The mechanisms of the effects of cigarette smoking are not fully elucidated but are believed to include (1) hemodynamic stress (nicotine increases the heart rate and transiently increases blood pressure); (2) endothelial injury and dysfunction (nitric oxide release and resultant vasodilation are impaired); (3) development of an atherogenic lipid profile (smokers have on average higher low-density lipoprotein levels, more oxidized low-density lipoprotein, and lower high-density lipoprotein cholesterol than nonsmokers do); (4) enhanced coagulability; (5) arrhythmogenesis; and (6) relative hypoxemia because of the effects of carbon monoxide. As mentioned, carbon monoxide reduces the capacity of hemoglobin to carry oxygen and impairs the release of oxygen from hemoglobin to body tissues, both of which combine to result in a state of relative “anemia.” As a compensation for the reduced oxygen-carrying capacity, polycythemia develops in smokers, with hematocrits often 50% or more. The polycythemia and the increased fibrinogen levels that are found in cigarette smokers also increase blood viscosity, which adds to the risk for thrombotic events. Cigarette smoking also induces a chronic inflammatory state, as evidenced by increased neutrophil count and increased levels of fibrinogen and C-reactive protein in the blood of smokers. Chronic inflammation is thought to contribute to atherogenesis.
Cigarette smoking acts synergistically with other cardiac risk factors to increase the risk for atherogenesis, plaque rupture, and acute ischemic events. Although the risk for cardiovascular disease is roughly proportional to cigarette consumption, the risk persists even at low levels of smoking, that is, at one to two cigarettes per day. Cigarette smoking reduces exercise tolerance in patients with angina pectoris and with intermittent claudication; in smokers, vasospastic angina is more common and the response to vasodilator medication is impaired. Smoking substantially increases the number and total duration of ischemic episodes as assessed by ambulatory electrocardiographic monitoring in patients with coronary heart disease. The increase in relative risk for coronary heart disease because of cigarette smoking is greatest in young adults, who, in the absence of cigarette smoking, would have a relatively low risk. Women who use oral contraceptives and smoke cigarettes have a synergistically increased risk for both myocardial infarction and stroke. Data suggest that implementing smoking bans at the community level has an appreciable impact on lowering hospital admission rates for coronary artery disease.
After acute myocardial infarction, persistent smokers have an increased risk for recurrent myocardial infarction and half the expected survival over the next 12 years compared to quitters. Smoking also interferes with revascularization therapy for acute myocardial infarction. After thrombolysis, persistent smokers suffer a fourfold increased reocclusion rate than those who quit. Smokers also have an increased risk for reocclusion of a coronary artery after angioplasty or of occlusion of a bypass graft. Cigarette smoking is not a risk factor for hypertension per se but does increase the risk for complications, including the development of nephrosclerosis and progression to malignant hypertension. Cigarette smoking has been shown to be a substantial contributor to morbidity and mortality in patients with left ventricular dysfunction. The mortality benefit of stopping smoking in such patients is equal to or greater than the benefit of therapy with angiotensin-converting enzyme inhibitors, β-blockers, or spironolactone.
Wound Healing/Postoperative Complications
Cigarette smoking is associated with adverse postoperative events and delayed wound healing. Postoperative complications can be tied to impaired clearance of secretions, altered immune function, and altered collagen synthesis, as well as the influence of underlying tobacco-related diseases (e.g., COPD and altered cardiovascular function). The mechanisms that can delay wound healing include cutaneous vasoconstriction (reducing skin blood flow), local thrombosis, and reduced oxygen-carrying capacity.
Smoking cessation substantially reduces postoperative complications. Moller and colleagues published the results of a randomized, controlled trial of smokers awaiting elective hip or knee surgery at three hospitals in Copenhagen. They compared 56 patients in a smoking cessation intervention arm (83% stopped or reduced smoking) to 62 patients in a usual care arm targeting cessation 6 to 8 weeks before surgery. The overall complication rate was 18% in the smoking cessation arm and 52% in the controls, a highly significant difference. The greatest differences were seen in wound complication rates (5% versus 31%) and cardiovascular complications (0% versus 2%), without a significant difference in length of hospital stay.
A study of 489 adult patients undergoing ambulatory surgery demonstrated a significantly higher rate of respiratory complications in smokers compared to nonsmokers (32.8% in smokers versus 25.9% in nonsmokers) and wound infections (3.6% in smokers versus 0.6% in nonsmokers). Causes of major pulmonary events after pneumonectomy for lung surgery were sought in a retrospective analysis of 261 patients. Patients who continued to smoke within 1 month of operation were determined to be at an increased risk for pulmonary events, which was associated with increased postoperative mortality. Cigarette smoking is associated with an increased risk for hepatic artery thrombosis after liver transplantation, and cessation 2 years before transplantation was associated with a decreased risk. Similar data exist regarding renal transplantation and allograft survival in smokers compared to nonsmokers.
The optimal window for smoking cessation intervention may be at 8 weeks before elective surgery, as suggested by data demonstrating that patients who had stopped smoking at least 2 months preoperatively had nearly maximal reduction in postoperative respiratory complications. A meta-analysis found that smoking cessation reduced postoperative complications by 41% and that each week of cessation increased the magnitude of benefit by 19%. An important issue related to elective surgery is that patients are often highly motivated to quit smoking just before elective surgery and can benefit from cessation counseling before surgery as well as in-hospital cessation counseling and medication in the postoperative setting. Specific issues related to smoking cessation are discussed later in this chapter.
Other Complications of Cigarette Smoking
Cigarette smoking increases the risk for duodenal and gastric ulcers, delays the rate of ulcer healing, and increases the risk for relapse after ulcer treatment. Smoking is also associated with esophageal reflux symptoms. Smoking produces ulcer disease by increasing acid secretion, reducing pancreatic bicarbonate secretion, impairing the gastric mucosal barrier (related to decreased gastric mucosal blood flow and/or inhibition of prostaglandin synthesis), reducing pyloric sphincter tone, and increasing the risk for Helicobacter pylori infection. Cigarette smoking is an independent risk factor for the development of non–insulin-dependent diabetes mellitus, which is a consequence of development of resistance to the effects of insulin. The effects of nicotine seem to contribute at least in part to insulin resistance, and insulin resistance has been described in users of smokeless tobacco, who are not exposed to tobacco combustion products.
Cigarette smoking increases the risk for osteoporosis by reducing the peak bone mass attained in early adulthood and increasing the rate of bone loss in later adulthood. Smoking antagonizes the protective effect of estrogen replacement therapy on the risk for osteoporosis in postmenopausal women. Cigarette smoking is a major cause of reproductive problems and results in approximately 4600 U.S. infant deaths annually. Growth retardation from cigarette smoking has been termed “fetal tobacco syndrome.” Cigarette smoking causes reproductive complications by causing placental ischemia mediated by the hypoxic effects of chronic carbon monoxide exposure, endothelial dysfunction, and the general increase in coagulability produced by oxidant chemicals in cigarette smoke.
Other adverse effects of cigarette smoking include premature facial wrinkling, an increased risk for cataracts, age-related macular degeneration, olfactory dysfunction, and fire-related injuries. The last mentioned contributes significantly to the economic costs of tobacco use. Smoking reduces the secretion of thyroid hormone in women with subclinical hypothyroidism and increases the severity of clinical symptoms of hypothyroidism in women with subclinical or overt hypothyroidism, the latter effect reflecting antagonism of thyroid hormone action. Cigarette smoking also potentially interacts with a variety of drugs by accelerating drug metabolism or by the antagonistic pharmacologic actions that nicotine and/or other constituents of tobacco have with other drugs ( Table 46-4 ).
|Drugs||Interaction (Effects Compared with Nonsmokers)||Significance|
|Accelerated metabolism||May require higher doses in smokers, reduced doses after quitting|
|Oral contraceptives||Enhanced thrombosis, increased risk for stroke and myocardial infarction||Do not prescribe to smokers, especially if >35 years old|
|Cimetidine and other H 2 -blockers||Lower rate of ulcer healing, higher ulcer recurrence rates||Consider using mucosal protective agents|
|Propranolol||Less antihypertensive effect, less antianginal efficacy; more effective in reducing mortality after myocardial infarction||Consider the use of cardioselective β-blockers|
|Nifedipine (and probably other calcium blockers)||Less antianginal effect||May require higher doses and/or multiple-drug antianginal therapy|
|Diazepam, chlordiazepoxide (and possibly other sedative-hypnotics)||Less sedation||Smokers may need higher doses|
|Chlorpromazine (and possibly other neuroleptics)||Less sedation, possibly reduced efficacy||Smokers may need higher doses|
|Propoxyphene||Reduced analgesia||Smokers may need higher doses|
Health Hazards of Secondhand Smoke
Considerable evidence indicates that exposure to secondhand smoke is harmful to the health of nonsmokers ( Table 46-5 ). The U.S. Environmental Protection Agency classifies secondhand smoke as a class A carcinogen, which means that it has been shown to cause cancer in humans.
Secondhand smoke, also known as environmental tobacco smoke, consists of sidestream smoke that is generated while the cigarette is smoldering and mainstream smoke that has been exhaled by the smoker. Of the total combustion product from a cigarette, 75% or more enters the air. The constituents of secondhand smoke are qualitatively similar to those of mainstream smoke. However, some toxins, such as ammonia, formaldehyde, and nitrosamines, are present in much higher concentrations in secondhand smoke than in mainstream smoke. The Environmental Protection Agency has estimated that secondhand smoke is responsible for approximately 3000 lung cancer deaths annually in nonsmokers in the United States, is causally associated with 150,000 to 300,000 cases of lower respiratory tract infection in infants and young children up to 18 months of age, and is causally associated with the aggravation of asthma in 200,000 to 1 million children. Secondhand smoke exposure is also responsible for 40,000 cardiovascular deaths. An appreciation of the hazards of secondhand smoke is important to the physician because it provides a basis for advising parents not to smoke when children are in the home, for insisting that child care facilities be smoke-free, and for recommending smoking restrictions in work sites and other public places.
Tobacco use is motivated primarily by the desire for nicotine. Drug addiction is defined as compulsive use of a psychoactive substance, the consequences of which are detrimental to the individual or society. Understanding addiction is useful in providing effective smoking cessation therapy. Nicotine is absorbed rapidly from tobacco smoke into the pulmonary circulation; it then moves quickly to the brain, where it acts on nicotinic cholinergic receptors to produce its gratifying effects within 10 to 15 seconds after a puff. Smokeless tobacco is absorbed more slowly and results in less intense acute pharmacologic effects. With long-term use of tobacco, physical dependence develops, associated with an increased number of nicotinic cholinergic receptors in the brain. When tobacco is unavailable, even for only a few hours, withdrawal symptoms often develop, including anxiety, irritability, difficulty concentrating, restlessness, hunger, craving for tobacco, disturbed sleep, and, in some people, depression.
Addiction to tobacco is multifactorial, including a desire for the direct pharmacologic actions of nicotine, relief of withdrawal symptoms, and learned associations. Smokers report a variety of reasons for smoking, including pleasure, arousal, enhanced vigilance, improved performance, relief of anxiety or depression, reduced hunger, and control of body weight. Environmental cues—such as having a meal or a cup of coffee, talking on the phone, drinking an alcoholic beverage, or being with friends who smoke—often trigger an urge to smoke. Smoking and depression are strongly linked. Smokers are more likely to have a history of major depression than are nonsmokers. Smokers with a history of depression are also likely to be more highly dependent on nicotine and have a lower likelihood of quitting. When they do quit, depression is more apt to be a prominent withdrawal symptom.
Most tobacco use begins in childhood or adolescence. Risk factors for youth smoking include peer and parental influences; behavioral problems (e.g., poor school performance); personality characteristics such as rebelliousness or risk taking, depression, and anxiety; and genetic influences. The adolescent’s desire to appear older and more sophisticated, such as emulating more mature role models, is another strong motivator. Environmental influences such as advertising and smoking in movies also contribute. Although smoking rates among adults have been declining since the 1970s, initiation rates for youth have remained constant since the mid-1980s. Approaches to preventing tobacco addiction in youth include educational activities in schools, aggressive antitobacco media campaigns, taxation of tobacco products, changing the social and environmental norms (restricting indoor smoking, educating parents not to smoke around children), and deglamorizing smoking.
Neurobiologic Mechanisms of Addiction
Nicotine binds stereoselectively to nicotinic cholinergic receptors in the brain, autonomic ganglia, the adrenal medulla, and neuromuscular junctions. Most relevant to nicotine addiction are the neuronal nicotinic cholinergic receptors. These are found throughout the brain, with the greatest number of binding sites in the cortex, thalamus, and interpeduncular nucleus, and substantial binding in the amygdala, septum, brain-stem motor nuclei, and locus coeruleus. The nicotinic cholinergic receptor is a ligand-gated ion channel, composed of five subunits. Most brain nicotinic cholinergic receptors are composed of α- and β-subunits. Usually there are two α- and three β-subunits, with the α-subunits responsible for ligand binding and the β-subunits mediating other aspects of receptor function. There is much diversity of nicotinic cholinergic receptors with nine α-subunit isoforms (α 2 through α 10 ) and three β-subunit isoforms (β 2 through β 4 ) identified in brain tissues. Different nicotinic receptors are found in different parts of the brain and have different chemical conductances for sodium and calcium and different sensitivity to different nicotinic agonists. The different nicotinic receptors are believed to mediate different pharmacologic actions of nicotine, perhaps corresponding to the multiple effects of nicotine experienced by human smokers.
Nicotine receptors appear to be located both on cell bodies and at nerve terminals. All nicotine receptors are permeable to calcium ions. Nicotinic receptor activation works, at least in part and possibly in the main, by facilitating the release of neurotransmitters, including acetylcholine, norepinephrine, dopamine, serotonin, β-endorphin, gamma aminobutyric acid, and others. Nicotine enhances fast excitatory synaptic transmission, which may contribute to learning and memory. Nicotine also releases growth hormone, prolactin, vasopressin, and adrenocorticotropic hormone. The behavioral rewards from nicotine and perhaps nicotine addiction as well appear to be linked to dopamine release.
The two main dopamine systems in the brain are the mesocorticolimbic and the nigrostriatal systems. The mesocorticolimbic system includes the ventral tegmental area projecting to the nucleus accumbens, the cortex, and limbic regions. The nigrostriatal system includes the substantia nigra, pars compacta projecting to the dorsal striatum. Nicotine causes an increase in burst firing of ventral tegmental area neurons, resulting in release of dopamine in the nucleus accumbens. Dopamine release is potentiated and sustained by nicotine-mediated release of glutamate. Dopamine release in the outer shell of the nucleus accumbens is characteristic of the effects of many addicting drugs (e.g., heroin, cocaine, alcohol) and is thought to be an important site for drug-mediated reinforcement.
Whereas acute exposure to nicotine produces stimulation of dopaminergic neurons in mesolimbic pathways, chronic exposure to nicotine and other drugs of abuse produces other changes in mesolimbic function. Chronic nicotine exposure results in neuroadaptation or the development of tolerance, and the absence of nicotine results in subnormal release of dopamine and other neurotransmitters. Thus nicotine withdrawal may result in a state of deficient dopamine responses to novel stimuli in general and to a state of malaise and inability to experience pleasure. This has been termed “hedonic dysregulation” by Koob and LeMoal. Hedonic dysregulation may explain craving. The sensitivity to drug effects may explain why even a single slip might easily result in a return to compulsive drug use.
The release of various neurotransmitters discussed previously results in behavioral arousal, sympathetic neural activation, and a number of other effects that are believed to be rewarding. The release of specific neurotransmitters has been speculatively linked to the reported reinforcing effects of nicotine ( Fig. 46-1 ). For example, enhanced release of dopamine and norepinephrine may be associated with pleasure as well as appetite suppression, the latter of which may contribute to lower body weight. Release of acetylcholine may be associated with improved performance on behavioral tasks and improvement of memory. Release of β-endorphin may be associated with reduction of anxiety and tension.