Ever since the United States Surgeon General’s report in 1964 warned about the hazards of smoking, there has been some decline in the use of cigarettes. Despite these declines, tobacco smoking is still the leading preventable killer worldwide. Cigarette smoking can be held culpable for four million deaths annually throughout the world (108
). It is estimated that by 2030, more than 10 million people will die annually of cigarette-related afflictions. It is estimated that in Canada alone, 45,000 people will die prematurely due to tobacco use, and at least 1000 people will die annually from secondhand smoke exposure (109
). There are nearly 1.2 billion smokers worldwide (108
), including approximately 45 million Americans (110
) and five million Canadians (111
). According to McCullough (112
), approximately 62% of First Nation Canadians are smokers, whereas 31% of the remaining Canadians are smokers. Approximately 1.21 million Canadians aged 12 to 24 years are occasional or daily smokers (111
). According to Ontario’s Ministry of Health, smoking is the leading cause of preventable deaths, killing an estimated 16,000 people in the province every year. Tobacco-related diseases cost Ontario’s health care system nearly $1.7 billion annually and result in $26 billion in productivity losses.
Within populations, smoking is especially prevalent among people with a lower socioeconomic status. These people buy cigarettes to fuel an addiction they cannot afford, thus perpetuating a vicious cycle. Tobacco companies are taking advantage of this addiction, and are promoting their products to low- and middle-income countries and populations, leading to soaring levels of cigarette use in those groups and geographical regions. Because of these reasons, the smoking rates in developing countries are steeply increasing, and cigarette smoking among Asian males is exorbitant: India (48%), Japan (53%), China (63%), Indonesia (69%) and Vietnam (73%) (108
). In addition, tobacco companies have started to target their advertisement campaigns at a highly impressionable and susceptible group of people, namely, teenagers and adolescents.
Smoking during pregnancy causes intrauterine growth retardation, premature delivery and learning disabilities in the children whose mothers smoked during pregnancy. Because nicotine is excreted into breast milk, children of nursing mothers may become addicted to nicotine and may have nicotine withdrawal symptoms once weaned (113
). Whalley et al (114
) investigated the effect of smoking on childhood IQ and cognitive changes from 11 to 64 years of age. The results of this follow-up population-based Scottish Mental Survey showed an association between smoking, impaired lung function and rapid decline in cognitive performance at 64 years of age. The postulated mechanisms by which smoking may have adversely affected cognitive function in old age may be attributable to impaired lung function and cardiorespiratory support of brain function, as well as the direct deleterious effects of smoking on the lungs and brain. Smoking is also regarded as a risk factor for Alzheimer’s disease (115
By analyzing the data of 4411 respondents aged 15 to 54 years from the National Co-morbidity Survey, Lasser et al (116
) observed that the likelihood of smoking is far greater in people with mental disorders (eg, depression, schizophrenia, bipolar illness or panic disorder) than those without. These findings emphasize the importance of focusing smoking prevention and cessation efforts on distinct populations, such as mentally ill patients.
There is overwhelming epidemiological and clinical evidence linking cigarette smoking with respiratory diseases (eg, cancer, chronic bronchitis, emphysema or asthma), development of thromboembolic complications, acute MI and stroke (108
). The INTERHEART study investigators observed a clear dose-response relationship between smoking and the risk of acute MI. The harmful effects of smoking were seen even at relatively low levels, ie, those who smoked one to five cigarettes per day experienced a 40% increase in MI risk compared with nonsmokers, whereas those who smoked six to 10 cigarettes per day had a twofold increase in risk, and those who smoked 20 cigarettes per day had a fourfold increase in risk of heart disease. This large international case-controlled study also found that irrespecitve of the device used for tobacco smoking (ie, filtered or nonfiltered cigarettes, bidis [a popular South Asian cigarette], pipes or cigars), all had similar risks for MI (11
); therefore, it appears that any amount and any form of tobacco smoking is injurious to health.
Cigarette smoking increases the risk of hypertension, CAD, stroke and peripheral vascular disease. Smoking-induced endothelial dysfunction and inflammation promote atherosclerotic plaque and thrombus formation. In addition, smoking seems to enhance the multiplicative effects of other risk factors associated with CAD. According to Burns (123
), smoking per se increases the risk of developing CAD twofold. However, when combined with other risk factors such as elevated serum lipid concentrations, uncontrolled hypertension and diabetes, the risk of CAD is compounded exponentially, to the extent that a combination of any three risk factors would correspondingly increase the development of CAD eightfold.
Besides other health problems, smokers are at a greater risk of developing erectile dysfunction or male impotency. Smoking cessation improves not only erectile function, but also response to pharmacotherapy (eg, sildenafil, tedalafil and vardenafil) of erectile dysfunction. Chronic smoking has been shown to decrease the activity of endothelial nitric oxide synthase and impair the release of nitric oxide in penile tissue. Nitric oxide activates the enzyme guanylyl cyclase, which results in increased concentrations of cyclic GMP. The increased concentrations of cyclic GMP cause smooth muscle relaxation in the corpus cavernosum and allow for an increased flow of blood into the penis, resulting in erection (124
The three main biologically active ingredients in cigarette smoke that have been touted as causal constituents for heart disease and stroke are nicotine, carbon monoxide and oxidant gases. Nicotine causes stimulation of autonomic ganglia and the central nervous system. By increasing the activity of the sympathetic nervous system, nicotine increases the release of catecholamines, which in turn elevates heart rate and BP, resulting in wear and tear on the arterial walls. Nicotine affects other systems as well, including the release of other endogenous opioids and glucocorticoids. Nicotine is readily absorbed through the skin, mucous membrane and lungs. Because of its rapid absorption from the pulmonary route, inhalation of cigarette smoke delivers approximately 15 ng/mL blood of nicotine within the first 10 min, whereas other sources and routes of administration, such as chewing tobacco, nicotine gum, nasal snuff and nicotine patches, take at least 30 min to release the same amount of nicotine into the bloodstream. The average plasma half-life of nicotine in smokers is 40 min. The biotransformation of nicotine takes place in the liver, where CYP2A6 converts it to its major metabolite cotinine, which is further metabolized by oxidation to hydroxycotinine and a ring cleavage product. Only approximately 5% of nicotine is excreted unchanged in the urine along with its metabolites. Nicotine is a highly addictive and dependence-producing substance, as is exemplified by the high failure rate among smokers who try to quit (125
Carbon monoxide has a high affinity for hemoglobin and competes with oxygen for uptake by red blood cells. The production of carboxyhemoglobin leads to reduced oxygen supply to the tissues, thereby producing hypoxemia. To compensate for lowered oxygen uptake, more red blood cells are generated, leading to polycythemia and increased blood viscosity, and consequently increasing the risk of thrombus formation.
Smoking-induced hypoxemia elevates the degree of oxidative stress in the body. Oxidative stress is thought to generate free radicals that contribute to endothelial inflammation and dysfunction, plasma lipid abnormalities through oxidation of LDL, and platelet adhesion activation. Lipid peroxidation also plays a vital role in atherogenesis because it leads to the development of foam cells (the initial components of endothelial plaques). All of these combined actions of cigarette smoking play an important role in the initiation and development of CVD. A diagram of the pathophysiological actions of cigarette smoking and acute coronary events is shown in (122
Figure 7) Diagram of the pathophysiological effects of cigarette smoking. The main biologically active ingredients in cigarette smoke are nicotine, carbon monoxide and various other oxidant gases. ↑ Increased; BP Blood pressure; CNS Central nervous system; (more ...)
Although various clinical and epidemiological studies have shown the harmful effects of chronic smoking on cardiovascular health (117
), other studies have reported that quitting smoking not only improves cardiovascular health, but also enhances longevity (110
). It has been shown that smoking cessation improves overall health and reduces the risk of heart disease and stroke; however, risk remains elevated for approximately a decade after discontinuation (123
). For example, Wiggers et al (121
) reported that after one year of smoking cessation, the risk of CAD may be reduced by greater than 50%, and within several years of discontinuation, risk returns to that of life-long abstainers. This type of evidence clearly suggests that sustained health benefits may be achieved by quitting smoking and by introducing health promotion and preventive measures for smoking cessation.
Considering the mortality and morbidity rates, as well as hospitalization costs, the health protection and promotion authorities of all countries should design intervention frameworks to deal with long-term smoking-associated problems. At the same time, both the regulators and citizens should challenge the marketing of hazardous products by the tobacco companies.
A few years ago, the Canadian Federal Government introduced legislation that banned cigarette smoking inside government buildings. Currently, legislation is being enacted by the Government of Ontario to outlaw smoking in all public and work places by May 2006. The antismoking legislation is also expected to cover retail displays of cigarettes, banning the power-wall cigarette displays found in various variety stores and gas stations. Some municipalities have enacted bylaws to ban smoking in bus shelters, buses, trains, restaurants, bars and municipal buildings. Despite these laudable legislative measures, cigarette smoking remains a major health concern in adults and teenagers in Canada.
Because cigarette smoking is the leading preventable cause of death and cardiorespiratory diseases, global public health interventions for stopping smoking should focus on all populations. Special attention, however, should be paid to selected groups, such as pregnant and nursing mothers, teenagers and adolescents, persons with mental illness and those with a lower socioeconomic status.
Effects of smoking on drug disposition and therapeutic implications
Cigarette smoke is a complex mixture of volatile and particulate matter. Some 500 gaseous compounds, including nitrogen, carbon monoxide, carbon dioxide, ammonia, hydrogen, cyanide and benzene, have been identified in the volatile phase, whereas approximately 3500 different compounds have been detected in the particulate material, of which, the major compound is the alkaloid nicotine. The polycyclic aromatic hydrocarbons present in tobacco smoke are thought to be responsible for the induction of cytochrome P450 (CYP) isozymes, namely, CYP1A1, CYP1A2 and CYP2E1. CYP1A1 is primarily an extrahepatic enzyme found in the lungs and placenta, whereas CYP1A2 and CYP2E1 have been identified in the liver, lung, small intestine, brain and kidneys. Some isoforms of uridine 5′-diphosphate glucuronosyltransferase that are involved in phase II glucuronidation reactions are also induced by chronic smoking. In mice, cigarette smoke causes the induction of CYP2E1 in the liver, lungs and kidneys, and nicotine accelerates the metabolism of CYP2E1 substrates in liver microsomes of the rat (126
). Animal studies (126
) also indicate that nicotine may have an inducing effect on CYP2B1 and CYP2B2, and may also modify the activity of CYP2A1 and CYP2A2. Carbon monoxide tends to have inhibitory effects on some hepatic CYP isozymes and, in rats, it has been shown to inhibit the metabolism of some drugs. Heavy metals such as cadmium, present in cigarette smoke, may decrease the activity of CYP2E1 (126
Cigarette smoking can significantly enhance the activity of CYP2E1 in humans and, consequently, can accelerate the metabolism and disposition of psychoactive drugs (eg, imipramine, haloparidol, pentazozine and oxazepam) and cardiovascular drugs (eg, propenalol, theophylline and heparin). CYP2E1 metabolizes a number of compounds, including acetaminophen and ethanol, as well as activating many carcinogens, including nitrosamines. Induction of CYP2E1 activity by cigarette smoking is indicated in tobacco-induced cancer, alcohol-induced liver disease and increased risk of acetaminophen hepatotoxicity (126
Cigarette smoking is associated with a faster clearance of heparin, possibly due to an increased binding of heparin to antithrombin III, which thereby increases the prothrombotic effects of cigarette smoking. Owing to the shorter half-life of heparin in cigarette smokers, these patients may require larger doses of heparin to achieve an anticoagulant effect equivalent to that in nonsmokers. The anticoagulant action of warfarin is not significantly affected during smoking. However, evidence indicates that β-blockers and antiarrythmics are rendered less effective because of their faster metabolism and renal clearance in smokers (126
In humans, phenotypic differences have been reported in the inducibility of drug metabolizing enzymes, suggesting that the effects of smoking on drug metabolic pathways are not absolutely predictable (127
). The impact of cigarette smoking on drug metabolism and disposition should be carefully assessed not only when prescribing drugs to smokers, but also when selecting patients for clinical trials, because pharmacokinetic and pharmacodynamic results obtained in smokers may not be applicable to the nonsmoking population.