Summary by Coreen B. Domingo, DrPH, and Thomas R. Kosten, MD, MA
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Based on “Principles of Addiction Medicine” Chapter by John A. Dani, PhD, Thomas R. Kosten, MD, MA, and Neal L. Benowitz, MD
Tobacco use is the leading cause of death in the United States, and this chapter examines the pharmacology and actions of nicotine, which is the main addictive component of tobacco.
DRUGS IN THE CLASS
Nicotine is a psychostimulant and mood modulator, but smokers also report relaxation and relief from stress and hunger. Thus, nicotine causes arousal during fatigue and relaxation during anxiety.
METHODS OF ABUSE
Nicotine and tobacco come in the form of cigarettes, bidis, cigars, pipes, snuff, and chewing tobacco. Nicotine is much more addictive during rapid administration, as obtained by smoking tobacco or e-cigarettes, than during the slow administration associated with a patch.
PHARMACOKINETICS
Absorption, Distribution, Metabolism, and Elimination: Gender and Ethnic Differences
The relatively rapid delivery of nicotine to the brain when smoking allows precise dose titration by altering puff volume, the number of puffs taken, and the depth inhaled. After nicotine is absorbed into the bloodstream, it has a volume of distribution of about 180 L, with <5% binding to plasma proteins. Based on a 2-hour half-life, nicotine accumulates during a day of regular smoking and persists for 6 to 8 hours after smoking ceases. Steady-state plasma nicotine levels in the early afternoon typically range between 10 and 50 ng/mL. Nicotine is extensively metabolized to cotinine in the liver, lung, and brain by CYP 2A6. Women metabolize nicotine faster than do men. African Americans obtain on average 30% more nicotine per cigarette, and they clear nicotine and cotinine more slowly than do Caucasians. Chinese Americans have both a lower nicotine intake per cigarette and smoke fewer cigarettes per day than do Caucasians due to slower metabolism CYP 2A6 alleles.
Biochemical Assessment of Exposure to Nicotine and Tobacco
Blood, salivary, and plasma cotinine as well as expired breath carbon monoxide concentrations, blood carboxyhemoglobin concentrations, and plasma or salivary thiocyanate concentrations are biochemical markers of nicotine intake. Anabasine and anatabine in urine can be used as a biomarker of tobacco use in individuals who are using nicotine replacement medications.
A cotinine value >14 ng/mL typically indicates smoking. A plasma cotinine concentration of 100 ng/mL corresponds to smoking approximately a half pack of cigarettes per day, and regular smokers range up to 900 ng/mL with levels persisting for up to 7 days after stopping. 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. Thiocyanate can be detected in the blood and saliva for weeks after smoking has ceased.
Drug Interactions with Tobacco and Nicotine
Smoking accelerates the metabolism of many drugs, particularly those metabolized by CYP 1A2 such as theophylline, propranolol, olanzapine, clozapine, imipramine, haloperidol, pentazocine, and estradiol. Nicotine also inhibits reductions in blood pressure from beta-adrenergic blockers, ulcer treatment with histamine H2-receptor antagonists, sedation from benzodiazepines, and analgesia from some opioids.
PHARMACOLOGIC ACTIONS
At low doses (such as smoking a cigarette), nicotine acutely increases blood pressure, heart rate, and cardiac output and causes cutaneous vasoconstriction. At extremely high doses, nicotine causes hypotension and slowing of the heart rate.
The primary CNS effects of nicotine in smokers are arousal, relaxation during stress, and enhancement of mood, attention, and reaction time. Thus, smokers increase their smoking under both low- and high-arousal conditions to get these contrasting effects.
About half of the total variance (range 28% to 84%) in smoking behavior and withdrawal can be attributed to genetic effects. Candidate genes include the CHRNA5-CHRNA3-CHRNB4-CHRNB3 nicotinic acetylcholine receptor subunits.
Rapid metabolizers of nicotine smoke more cigarettes per day than slower metabolizers.
Among those with mental illness, 36% are current smokers, compared to 20% among adults with no mental illness. Among schizophrenics, 70% to 88% are smokers. Among adults with ADHD, 40% smoke. The lifetime prevalence of depression is 59% among subjects who had ever smoked, compared with 17% in the general population.
Nicotine exposure alters nicotinic receptor numbers and influences their function, leading to tolerance. Tobacco withdrawal includes craving for nicotine, irritability and frustration or anger, anxiety, depression, difficulty concentrating, restlessness, and increased appetite. Symptoms reach maximum intensity 24 to 48 hours after cessation and diminish over a few weeks.
NEUROBIOLOGIC MECHANISMS OF ACTION
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that are closed at rest and can be opened by nicotine but then become desensitized for several seconds. The nicotinic receptor channel is in cholinergic neurons and consists of five polypeptide subunits assembled like staves of a barrel around a central water-filled core. The alpha4beta2-containing nAChRs are primarily responsible for nicotine dependence. Cholinergic neurons provide diffuse, sparse innervation to practically all of the brain including the dopamine reinforcement pathways where nicotine potently enhances the firing of dopamine neurons through glutamatergic afferents. The withdrawal syndrome is mediated by the α5-containing nAChRs in the habenula to produce nicotine’s aversive effects and the somatic symptoms of withdrawal.
Cigarette smoking is associated with reduced activity of the enzymes monoamine oxidase (MAO) A and MAO B, which might contribute to the perceived benefit of smoking by some depressed patients.
SYSTEMIC TOXICITY
Smokers are exposed to at least 50 known carcinogens. The increased risk of cardiovascular disease is due to CO reductions in oxygen delivery to the heart, and oxidant chemicals are primarily responsible for endothelial dysfunction, platelet activation, thrombosis, and coronary vasoconstriction. Cigarette smoking causes an imbalance between proteolytic and antiproteolytic forces in the lung and heightens airway responsiveness and chronic obstructive lung diseases.
Current smokers have increased rates of posterior subcapsular cataracts and age-related macular degeneration. Women smokers have lower levels of estrogen, earlier menopause, and increased risk of osteoporosis. In men, smoking may impair penile erection. Since nicotine both suppresses appetite and increases metabolic rate, smokers weigh 2.7 to 4.5 kg (6 to 10 pounds) less than nonsmokers and typically gain weight after smoking cessation. They also have higher low-density lipoprotein and lower high-density lipoprotein. Smoking delays healing of peptic ulcers.
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. 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.
The effect of smoking in lowering birth weight is influenced by the metabolic genes CYP 1A1 and GSTT1. Infants born to smoking mothers who had genetic variants associated with reduced CYP 1A1 activity—Aa and aa (heterozygous and homozygous variant types, respectively)—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 CYP 1A1 AA (homozygous wild type) or GSTT1 genotype. The CYP 1A1 and GSTT1 enzymes have roles of 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. 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.
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. 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. SHS also is causally associated with low birth weight and sudden infant death syndrome in infants. 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. 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. 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. More than 95% of SHS-exposed office workers exceeded the significant risk level for heart disease mortality and more than 60% exceeded the significant risk level for lung cancer mortality established by the Occupational Safety and Health Administration.
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. 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. Cigarette smoking also increases the risk of developing and increases the severity of respiratory tract infections, including influenza, pneumococcal pneumonia, and tuberculosis. 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.
Tobacco and Other Addictions
There is a strong correlation between smoking and alcohol abuse. 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. 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. 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. 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.
KEY POINTS
1. Nicotine causes arousal during fatigue and relaxation during anxiety.
2. Blood, salivary, and plasma cotinine as well as expired breath carbon monoxide concentrations, blood carboxyhemoglobin concentrations, and plasma or salivary thiocyanate concentrations are biochemical markers of nicotine intake.
3. Tobacco withdrawal includes craving for nicotine, irritability and frustration or anger, anxiety, depression, difficulty concentrating, restlessness, and increased appetite. Symptoms reach maximum intensity 24 to 48 hours after cessation.
4. Smokers are exposed to at least 50 known carcinogens and have an increased risk of cardiovascular disease leading to adult men and women smokers losing 13.2 and 14.5 years of life, respectively.
5. 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, when the risk of all-cause mortality returns nearly to that of persons who never smoked.
REVIEW QUESTIONS
1. Steady-state plasma levels of nicotine during the afternoon in most smokes range from:
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