Journal of Addictive Behaviors,Therapy & RehabilitationISSN: 2324-9005

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Review Article, J Addict Behav Ther Rehabil Vol: 5 Issue: 3

Nicotine in Cigarette Smoke: Addiction, Health Effects, Detection Methods, and Smoking Cessation

Wasana Sumanasekera*, William Nethery and Son Nguyen
Sullivan University College of Pharmacy, Louisville, USA
Corresponding author : Wasana K. Sumanasekera
Sullivan University College of Pharmacy, 2100, Gardiner lane Louisville KY 40205, USA
Tel: (502) - 413 - 8954
Fax: (502) - 515 - 4669
E-mail: [email protected]
Received: July 11, 2016 Accepted: August 11, 2016 Published: August 17, 2016
Citation: Sumanasekera W, Nethery W, Nguyen S (2016) Nicotine in Cigarette Smoke: Addiction, Health Effects, Detection Methods, and Smoking Cessation. J Addict Behav Ther Rehabil 5:3. doi: 10.4172/2324-9005.1000154

Abstract

Background: Nicotine is an addictive substance present in cigarette smoke that causes a great number of health effects and is a leading cause of preventable death. Objective: This article provides information regarding the addictive nature of nicotine, adverse health effects, current detection methods, alternative approaches, and smoking cessation. Results and Discussion: An average cigarette allows a person to absorb approximately 1 mg of nicotine, which produces euphoria and establishes addiction. Nicotine binds to nicotinic receptors and activates cell signaling cascade leading to dopamine and other neurotransmitter release resulting in euphoria and pleasure. After exposure to nicotine for some time the receptors become unresponsive/desensitized. Later the receptors become responsive again due to abstinence, which is believed to play a role in dependence. A process called neuro adaptation also generates more nicotinic receptors in response to desensitization. Cigarette smoking produces harmful effects including cancer, cardiovascular disease, COPD, and congenital defects. Detection methods for nicotine include HPLC, HPLC MS/MS, semi-quantitative dipstick, liquid chromatographytandem mass spectrometry (LCTMS), and gas chromatography mass spectrometry (GCMS). Alternative products/approaches to smoking include cigars, pipe smoking, hookah, and e-cigarettes. Currently there is conflicting evidence comparing cigars, pipe smoking, and cigarettes on their effect on mortality. Many studies demonstrate modest efficacy for e-cigarettes as a smoking cessation tool; however, current guidelines recommend use of other forms of nicotine replacement, bupropion SR, or Varenicline. Implications: This article provides an overview of nicotine addiction through cigarette smoke, their health effects and detection methods. This article discusses the effects of alternative tobacco products and e-cigarettes compared to cigarettes. It also provides current treatment options for smoking cessation.

Keywords: Nicotine; COPD; CNS stimulant; Electronic cigarettes

Keywords

Nicotine; COPD; CNS stimulant; Electronic cigarettes

Introduction

Cigarette smoking has continued to become a major public health concern worldwide. There are many debates regarding the risks of disease from the inhalation of cigarette smoke (CS); both by direct inhalation and by passive inhalation. The exposure to CS is an established risk factor for respiratory infections and compromised lung function [1,2], cardiovascular diseases [3-7] and variety of cancer including lung [4,8-11], breast [12-15], cervical [16] and bladder [17] cancers. It has also been implicated in the progression of AIDS [18]. Cigarette smoking is the single most preventable cause of several adverse health effects in the world today.
Cigarette smoking is habitual in nature and it is very addictive. Smoking related diseases limit a person’s daily life by complicating their breathing, ability to work, and other activities. These complications associated with cigarette smoking negatively impact a person’s quality of life long before death. The adverse effects of CS cause smokers to live a shorter lifespan as compared to nonsmokers [19]. This significant health outcome has directed research to investigate detection and quantification of chemical substances in cigarettes.

Nicotine in Cigarette

Nicotine present in CS is an alkaloid from tobacco plant or it can be produced synthetically [20,21]. Some uses of nicotine include agriculture as an insecticide and therapeutically as an aid for smoking cessation. The distribution and absorption of nicotine into the pulmonary circulation is very rapid. It may penetrate the blood brain barrier and affect the central nervous system within 20 seconds of inhaled CS [22]. The rapid pharmacologic response of nicotine is assumed to be a key factor in nicotine dependence.
Cigarettes vary in their nicotine content. Nicotine levels are usually less than 20 mg of nicotine per gram of dry tobacco [23]. Bidi cigarettes, which is an alternative type of cigarette manufactured in India contains higher concentration of nicotine than conventional cigarettes. The nicotine content in bidi cigarettes is roughly estimated to be 21.2 mg/g, while the unfiltered commercial cigarettes contains 13.5 mg/g, and a filtered commercial cigarette is 16.3 mg/g [23,24]. Thai cigarettes have somewhat low nicotine content compared to bidi cigarettes, ranging about 1.64 – 5.77 mg/g [25]. Different brands of US cigarettes contain altered amount of nicotine. Marlboro cigarettes contain 0.50-1.63 mg of nicotine per cigarette [26]. The nicotine content of some of the US cigarettes such as Winston varies from 0.5 mg-1.3 mg per gram of tobacco and there is a 10% increase of nicotine content in the last decade [27].

Addictive Behavior of Nicotine

Nicotine acts as CNS stimulant contributing to dependence forming habits of smoking [28]. When CS is inhaled, nicotine provides the desired stimulatory effect. CS simulates mild euphoria that feeds into the established addiction. A cascade of events takes place activating neuronal stimulation that produces euphoric sensation (Figure 1). Nicotine is taken into the body from the tobacco in cigarettes through the inhalation of smoke; then it is transported by the smoke into the lungs where nicotine is absorbed into pulmonary circulation followed by arterial circulation, by which it enters the brain. In the brain, nicotine binds nicotinic receptors that activate a cascade of cation entry into cells and ultimately resulting in the release of neuro transmitters (Figure 1). Of note, dopamine is released from nucleus accumbens responsible for drug-induced reward and pleasure [28].
Figure 1: Figure 1 illustrates the mechanism for nicotine addiction. The involvement of nicotinic acetyl choline receptors (nAChR) and neurotransmitters that lead to nicotine addiction is described. This figure is based on a figure from Benowitz NL: Nicotine addiction. N Engl J Med 2010, 362:2295-303.
Other neurotransmitters that are involved in the mechanism of nicotine addiction are glutamate and γ-aminobutyric acid (GABA). Glutamate increases dopamine levels, whereas GABA inhibits dopamine release [29]. However, nicotinic receptors may become desensitized to nicotine with long-term exposure causing the inhibitory effect of GABA to be diminished [28]. Desensitization is due to ligand-induced closure of the receptor, but also causes the receptor to be unresponsive. Neuro-adaptation also occurs, which is an up-regulation of nicotinic receptors in the brain and is most likely due to desensitization [28].
When the level of nicotine in the body is below the threshold that leads to euphoria, the desire to smoke again is initiated and is coupled with feelings of discomfort. After the first puff on a cigarette, nicotine is absorbed quickly and travels to the brain. Thereby causing physical dependence and feeds into the cycle of addiction where the individual cannot resume normal functions without it [30]. Furthermore, social cues are conditioned with the behavior of smoking that stimulates an anticipatory effect for the euphoria created by nicotine. Examples of social cues that become associated with desire to smoke include specific moods (irritability), situations (friends who smoke), or environmental (taste or smell of smoking materials) [28].
Tobacco is a stimulating substance that causes the consumer to become restless [28,31]. However, the calming effect sought by addicts arises from obtaining a baseline concentration of nicotine. When this level goes down the body reacts by producing withdrawal symptoms. Restlessness is a common symptom of withdrawal that can be temporarily suppressed by increasing the nicotine level achieved by smoking [32]. However, the need for more tobacco causes dependence/addiction [33].

The Harmful Side Effects of Nicotine

Overdose as well as long term use of nicotine leads to serious side effects. In addition to nicotine, large amounts of chemicals and carcinogens are present in CS leading to several diseases. Nicotine causes constriction of blood vessels leading to heart and blood related diseases. Prolonged nicotine intake can result in coronary artery or cardiovascular diseases, leading to increased risk for myocardial infarction, stroke, or even death [34,35]. CS induced malfunction of cardiac stem cells has been reported by our group recently [36]. The team has reported that CS exposure has led to increased apoptosis, decreased cardiac stem cell migration and proliferation, increased cytotoxicity, and attenuated the integrity of cardiac stem cell membranes leading to “damaged” cardiac stem cells [36].
Excessive nicotine intake also causes gastrointestinal diseases such as dyspepsia, peptic ulcers, inflammatory bowel diseases, and even gastro intestinal cancer [37]. Nicotine has direct effects on the brain and the nervous system. With prolonged intake, it can lead to insomnia or sleep disturbances [38,39], feeling of dizziness, and massive headaches [40,41]. The majority of cigarette smokers suffer from a loss of appetite resulting in weight loss [42,43].
Several types of cancer including cancers of the oral cavity, larynx, esophagus [44,45], breast [14] and lung cancer [46] are attributed to excessive use of nicotine. Our group is currently investigating nicotine related progression of ovarian cancer in-vitro and our preliminary results indicate a positive correlation. Nicotine also has adverse effects in pregnancy such as low birth weight, decreased blood flow to the placenta, delivery complications, ectopic labor, and birth defects [47]. Additionally, smoking is related to a significantly high rate of sudden infant death syndrome in newborns [48,49]. Due to these complications, it is advisable that pregnant women should refrain from smoking.

Detection of Nicotine and Biomarkers

The liver regulates the metabolism of nicotine. The enzymes cytochrome P450 and aldehyde oxidase present in the liver are responsible for the metabolism of nicotine to its active metabolite, cotinine [50,51]. Cotinine has a long elimination half-life of 20 hours in biological fluids and eliminated 17% in the urine [3]. Nicotine and cotinine levels are used as biological markers to detect tobacco smoke exposure [51]. Monitoring nicotine and its metabolite concentrations is essential for researchers and medical professionals. These biological markers will help determine the toxic effect of CS and enhance patient diagnosis. There are many methods for nicotine and metabolite quantification in biological specimens such as high performance liquid chromatography (HPLC), rapid semi quantitative dipstick [52], liquid chromatography-tandem mass spectrometry (LCMS) [53,54] and gas chromatography mass spectrometry (GCMS) [50].
However, high performance liquid chromatography (HPLC) is the preferred method for the detection of nicotine and cotinine contents in the serum of smokers [55]. HPLC ensures a more accurate and measurable way of ascertaining the intake of nicotine [56]. It has been utilized in several studies [57] as a sensitive method for the determination of nicotine metabolism to cotinine. It is highly accurate, inexpensive, and provides rapid detection of nicotine and its metabolites.
HPLC MS/MS (high-performance liquid chromatography tandem mass spectrometry) can be utilized to detect serum and saliva cotinine levels in smokers [58]. In addition to cotinine, nicotine and its’ other metabolites such as trans-3-hydroxycotinine, and nor cotinine levels can also be detected using HPLC MS/MS [59]. It provides rapid results while utilizing small amount of sample, inexpensive to conduct, and allows for high throughput and fast turnaround.
Another recent methodology used to measure nicotine is the rapid semi quantitative dipstick method [52]. This method utilizes cotinine specific monoclonal antibodies. Cotinine metabolite detected in urine, saliva, or serum, provides a reliable means of determining smoking status and other tobacco product use or exposure [52]. A study utilizing this methodology indicates that the saliva test strip results had a sensitivity of 99% and a specificity of 96% [52]. The rapid semi quantitative dipstick method may be utilized in outpatient healthcare settings due to its rapid detection results.
A study demonstrated that gas chromatography-mass spectrometry (GC/MS) can also be utilized to detect and quantify nicotine and cotinine in human toenail, plasma and saliva. GC/MS may be utilized as an alternative method to detect long-term markers of smoke exposure. GC/MS may provide important smoking status information of patients [60].

Treatment/Alternative Approaches for Nicotine Addiction

Alternative cigarettes/electronic cigarettes
Electronic cigarettes are an alternative to smoking cigarettes and are marketed as being less harmful than regular cigarettes. However, there are no longitudinal studies that evaluate the safety or efficacy of e-cigarettes as an alternative [61]. The data that is currently available is limited. E-cigarettes may contain fewer toxicants than regular CS, but there is a high degree of variability of the level of aerosolized toxins depending on the e-liquid and the e-cigarette device used [62]. Even though it contains fewer toxicants, studies are inconclusive in regards to e-cigarettes being less harmful than regular cigarettes and are currently not approved as a smoking cessation measure by the Food and Drug Administration (FDA) [63].
Studies have demonstrated that e-cigarettes deliver less nicotine per puff compared to cigarettes utilizing automated smoking machines. Clinical studies show that inexperienced users of e-cigarettes only elevate nicotine levels modestly; however, clinical trials of experienced e-cigarette users demonstrate that similar systemic nicotine/cotinine concentrations can be achieved through e-cigarettes compared to traditional cigarettes and can produce systemic effects [64]. There are several pros and cons to the use of e-cigarettes (Table 1) and it is currently being debated if they have a place in smoking cessation or as a healthier option to cigarettes [61-71].
Table 1: Advantages and disadvantages of regular cigarettes vs e-cigarettes: A comparison between the two types of cigarettes.
Hookah, cigar, and pipe smoking
Hookah smoking, sometimes viewed as a healthier option to cigarette smoking due to less nicotine delivery, but produces higher levels of carbon monoxide and carcinogens. There is also communal hookah use, which increases the risk of contracting an infectious disease [72]. There is currently conflicting evidence regarding smoking cigars or pipe smoking. One study showed that there was no or only minor differences in any cause mortality or smoking related disease mortality between cigarette smokers and pipe smokers [73]. However, based on another report mortality rates of pipe smokers and cigar smokers demonstrated a lower mortality ratio compared to cigarettes smokers [74]. According to Baker et al., as the number of cigars smoked increases and the amount of smoke inhaled increases the mortality risk is similar to cigarette smoking. Cigars also have a higher concentration of carcinogens and carbon monoxide. Smoking cigars also did not reduce the risk of nicotine addiction [75].
Smoking cessation
Currently smoking cessation guidelines recommend 7 first line agents, which include bupropion SR, varenicline, and nicotine replacement (Table 2). Nicotine replacement could be by gum, inhaler, lozenge, nasal spray, or patch. Second line medications include clonidine or nortriptyline. Choice of therapy depends on patient preference, cost, adverse effect management, etc. Caution should be taken when administering nicotine in patients with cardiovascular disease, varenicline in patients with neuropsychiatric diseases, and bupropion in patients with seizures, anorexia, bulimia, or abrupt discontinuation of alcohol or sedatives [76,77]. The first line medications and dosages for smoking cessation [76,77] are depicted in Table 2. Counseling can also be a useful tool that can encourage a patient to quit. Medications and counseling should be combined to provide an effective treatment.
Table 2: First line medications used in smoking cessation are detailed in Table 2.
E-cigarettes have been explored as a smoking cessation tool, but are currently not recommended in clinical guidelines. A large crosssectional study was conducted and found that patients who used e-cigarettes were 1.63 times more likely to quit compared to users of nicotine replacement therapy and 1.61 times as likely than patients who attempted to quit without aid [78]. Bullen et al. reported a 7.3% verified abstinence rate of e-cigarettes versus 5.8% in nicotine replacement and 4.1% for e-cigarette placebo [65]. This study was not adequately powered to prove superiority of e-cigarettes to the other forms, but does show moderate evidence of e-cigarettes being a tool for cessation [65]. The role for e-cigarettes in smoking cessation therapy is still unclear due to limited data on efficacy and safety [61].

Discussion

The negative impacts of nicotine on the health of individuals are a major public health concern. CS, which contains considerable amount of nicotine, produces numerous adverse effects including cancer, cardiovascular disease, chronic obstructive pulmonary disorder, and can cause congenital defects. In the short-term, smokers are influenced by the calming and dependent effect of nicotine leading to its addiction. The mechanism behind the addictive behavior of nicotine is complex, but this addictive behavior affects health greatly. Long-term health impacts of nicotine addiction are debilitating and deadly. Although public awareness has been made and actions have been taken to remove tobacco advertisements, smokers still exist and continue to experience adverse health outcomes. In order to stop the downward trend of smoking, awareness and education on the harmful side effects of nicotine must be communicated to the public.
Nicotine detection methods are necessary for both research and clinical purposes. Detection methods can help researchers determine the level of nicotine absorption and is very useful in newer forms of nicotine delivery. It can also be useful clinically to assess a patient’s exposure to CS. Detection methods of nicotine include HPLC, HPLC MS/MS, semi-quantitative dipstick, liquid chromatography-tandem mass spectrometry, and gas chromatography mass spectrometry.
The introduction of e-cigarettes has brought a number of questions to the table. It is difficult to determine the place of e-cigarettes and other alternatives due to limited data on their safety and the limited data on their efficacy as a smoking cessation tool. Current first line pharmacologic options include nicotine replacement therapy, bupropion SR, and varenicline (Table 2). Clinicians need to be aware that these pharmacologic options have adverse effects and warnings that affect appropriate treatment.
In conclusion, nicotine in cigarettes produces more permanent harm than good. In order to prevent health related complications at advanced stages, healthcare providers and family are encouraged to support smokers in quitting. There are currently 7 first line options for pharmacotherapy that can be utilized to help smokers motivated to quit. The cessation of all tobacco products should be encouraged. Currently e-cigarettes are not approved for smoking cessation and it is unclear if they provide benefit or harm.

Acknowledgment

We would like to acknowledge Dr. Uyen Le and Dr. Lena Nguyen for reference search. We would also like to thank Dr. Lisa Tang for editing the manuscript.
Funding: None

Declaration of Interests

There is no conflict of interests to declare.

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