Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction

Understanding the basic and clinical pharmacology of nicotine provides a basis for improved prevention and treatment of tobacco addiction. Nicotine acts on nicotinic cholinergic receptors in the brain to release dopamine and other neurotransmitters that sustain addiction. Neuroadaptation and tolerance involve changes in both nicotinic receptors and neural plasticity. Nicotine addiction can occur in the context of physical dependence characterized by self-medication to modulate negative affect and/or to relieve withdrawal symptoms, as well as, in light or occasional smokers, primarily for positive reinforcement in specific situations. Nicotine is metabolized primarily by CYP2A6. Its clearance exhibits considerable individual variability that is determined by genetic, racial, and hormonal (sex) factors. Genetically slow metabolism of nicotine appears to be associated with a lower level of dependence. Nicotine dependence is highly heritable and appears to be influenced by genes coding for some nicotine receptor subtypes, some neurotransmitter genes, and genes involved in neural connectivity. Novel pharmacotherapies for nicotine dependence include partial agonists for nicotinic receptors and nicotine vaccines. Pharmacogenetic studies suggest various candidate genes and a nicotine metabolism phenotype that influence outcome. Human pharmacology studies of nicotine and smoking behavior also provide a basis for assessing the benefits and risks of long-term nicotine use for harm reduction and for a potential cigarette regulatory strategy that includes reducing nicotine content of cigarettes to nonaddictive levels.     

Metabolism and biochemical effects of nicotine for primary care providers

Nicotine is a colorless and volatile liquid alkaloid naturally occurring in the leaves and stems of Nicotiana tabacum and Nicotiana rustica. Nicotine, the primary component of tobacco, is responsible for both tobacco product addiction (with chronic exposure) and the odor associated with tobacco. In addition to cigarettes, nicotine is found in chewing gum, transdermal patches, nasal spray, and sublingual tablets. Following its inhalation and absorption, nicotine and its metabolic products exert diverse physiologic and pharmacologic effects. This article covers the absorption and metabolism of nicotine, nicotine toxicity, pharmacologic effects of nicotine, nicotine-drug interactions, and the use of nicotine for the treatment of disease.     

Cigarette smoking and nicotine addiction.

Smokers smoke in large part because of the addictive effects of nicotine. Nicotine affects mood and performance and has been clearly implicated as the source of addiction to tobacco. People smoke to deliver desired doses of nicotine to their bodies, with certain rates of delivery and intervals between doses; these behaviors tend to be consistent for a person from day to day. Rational treatment of the pharmacologic aspects of tobacco addiction includes nicotine substitution therapy. New formulations of nicotine substitutes will provide more options to the physician for tailoring treatment to the needs of individual smokers. Other pharmacotherapies, particularly antidepressant drugs, hold promise for certain smokers.     

Physiologic effects of nicotine polacrilex

Nicotine is the pharmacologically active agent in tobacco responsible for the maintenance of cigarette smoking behavior. Paradoxically, nicotine also offers the most promise in the successful treatment of cigarette smoking when it is delivered to the central nervous system in a safer and more manageable form. By transferring the physiologic dependence from nicotine contained in tobacco to nicotine bound in a polacrilex, the behavioral aspects associated with cigarette smoking can be removed with a minimal amount of discomfort or risk of relapse. Nicotine bound to a polacrilex and administered as a chewing gum is currently the replacement of choice since many of the systemic effects of nicotine delivered via this route are similar to the effects of nicotine delivered in cigarette smoke without the accompanying exposure to carbon monoxide and tar. Factors such as administered dose, schedule of dosing, and rate and vigor of chew, however, can significantly alter the desired effects. This paper provides a summary of the physiologic changes which may affect the effectiveness of nicotine gum as a pharmacologic adjunct in the treatment of tobacco dependence.     

Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity

BACKGROUND: Nicotine and a variety of other drugs and toxins are metabolized by cytochrome P450 (CYP) 2A6. Our objective was to evaluate the use of oral nicotine with measurement of the trans-3'-hydroxycotinine (3HC)/cotinine (COT) metabolite ratio as a noninvasive probe of CYP2A6 activity. METHODS: Sixty-two healthy volunteers received an oral solution of deuterium-labeled nicotine (2 mg) and its metabolite cotinine (10 mg). Plasma nicotine and plasma and saliva cotinine and 3HC concentrations were measured over time. RESULTS: The 3HC/COT ratio derived from deuterium-labeled cotinine, measured in either plasma (2-8 hours after administration) or saliva (at 6 hours), was strongly correlated with the oral clearance of nicotine (r = 0.76-0.83, depending on the time of measurement). The 6-hour 3HC/COT ratio from nicotine derived from tobacco in 14 smokers was highly correlated with the ratio derived from deuterium-labeled nicotine (r = 0.88) and was also highly correlated with the oral clearance of nicotine (r = 0.90). Two subjects homozygous for inactive CYP2A6 alleles produced no 3HC, confirming the specificity of the metabolite ratio. The 3HC/COT ratio was also highly correlated with the clearance and half-life of cotinine, consistent with the fact that cotinine is also primarily metabolized by CYP2A6. CONCLUSIONS: The 3HC/COT ratio derived from nicotine either administered as a probe drug or from tobacco use, measured in either plasma or saliva, is highly correlated with the oral clearance of nicotine. The ratio appears to be a useful noninvasive marker of the rate of nicotine metabolism (which is important in studying nicotine addiction and smoking behavior), as well as a general marker of CYP2A6 activity (which is important in studying drug and toxin metabolism).     

Nicotine and angiogenesis: a new paradigm for tobacco‐related diseases

The pathophysiology of tobacco‐related diseases is complex and multifactorial. Among the approximately 4,000 compounds in tobacco smoke are carcinogens such as nitro‐samines, irritants such as a variety of phenolic compounds, volatiles such as carbon monoxide, and of course nicotine. Nicotine itself has quite complex actions, mediated in part by nicotinic cholinergic receptors that may have extraneuronal, as well as neuronal distribution. This review discusses the mechanisms by which nicotine contributes to tobacco‐related disease, with a focus on the surprising new finding that nicotine is a potent angiogenic agent. Nicotine hijacks an endogenous nicotinic cholinergic pathway present in endothelial cells that is involved in physiological, as well as pathological angiogenesis.     

Smoking behavior and related cancers: the role of CYP2A6 polymorphisms

Smoking exerts complex central and peripheral nervous system, behavioral, cardiovascular, and endocrine effects in humans and is a primary risk factor for various cancers. Nicotine, a major constituent of tobacco, is the compound that is responsible for the development and maintenance of tobacco dependence. The absorbed nicotine is rapidly and extensively metabolized to inactive cotinine by CYP2A6 in human livers, which has a major impact on nicotine clearance. Progress has been made in understanding the relationship between the inter-individual variability in nicotine metabolism and genetic polymorphisms of CYP2A6. Recent findings have increased our knowledge concerning ethnic differences in the allele frequencies of the CYP2A6 variants, nicotine metabolism, and cancer risk. In this review, the potential associations between the CYP2A6 polymorphisms and smoking behavior or the risk of cancer are also discussed.     

Alternative nicotine delivery systems (ANDS)--public health-aspects

This paper deals with a relatively new category of pharmaceuticals, namely alternative nicotine delivery systems (ANDS). We do not refer to products like smokeless tobacco or other smoking devices. ANDS are designed to provide nicotine without the harmful substances contained in cigarette smoke. Several different nicotine replacement preparations exist, which are used in nicotine replacement therapy to obtain tobacco abstinence. There is a bulk of scientific literature on the clinical use of ANDS, but very little has been published on the public health aspects of the same. Nicotine dependence is associated with heavy consumption, tolerance, regulation of intake and withdrawal. We described a new symptom of extreme nicotine dependence, namely the nocturnal sleep disturbing nicotine craving (NSDNC), and developed a concept of a nicotine pre-abstinence syndrome (NPAS). Five nicotine replacement preparations are currently available: gum, patch, nasal spray, oral inhaler and sublingual tablet. As far as safety issues are concerned, scientific evidence shows that the use of ANDS involves almost no risk for consumers and patients, especially when compared with the consumption of tobacco products. New concepts developed by our group are the following: definition of possible endpoints of smoking control measures, reduced smoking, nicotine dependence and preventive oncology, chemoprevention of lung cancer by ANDS, public health impact by OTC availability of ANDS and the "let them choose approach" of ANDS focusing on the specific preferences and needs of the individual client. One may also speculate whether ANDS will, at some stage, replace cigarettes as the major source of nicotine for people who need this psychoactive drug.     

戒烟治疗的必要性与技巧

烟草依赖是一种慢性高复发性的精神和行为疾病,临床医生必须在充分认识到烟草依赖足一种慢性疾病,有其自身的疾病规律和特点的基础上,以对待疾病治疗的方法对烟草依赖进行规范的治疗。吸烟是COPD最常见和最主要的敛病因素,日前公认戒烟是COPD防治最重要和最有效的方法。烟草依赖的治疗包括尼古丁替代疗法类药物（尼古丁贴剂、尼占丁咀嚼剂、尼占丁舌下含片、尼占丁吸入剂、尼古丁鼻喷雾剂等）、尼古丁疫苗、盐酸安非他酮、酒石酸伐尼克兰等药物治疗,以及心理及行为辅导。规范戒烟治疗,有助于提高COPD药物治疗有效性,减少COPD发病率。     

Pharmacologic Determinants of Tobacco Dependence

Nicotine is one of the most widely abused psychoactive drugs and far more people trying it progress to regular use than those trying heroin, cocaine, or alcohol. Since the early 20th century, it has been understood that tobacco use is driven largely by nicotine's pharmacological actions. Nicotine produces reinforcing effects, tolerance and physical dependence, and pharmacological effects that smokers enjoy, such as modulation of mood, appetite, and task performance. Pharmacokinetic properties of tobacco-based nicotine products optimize abuse potential. Cigarette smoke inhalation delivers high nicotine concentrations to the brain and other organs within 10 s of inhalation. Nicotine's acute effects dissipate in a few minutes, encouraging the smoker to smoke frequently throughout the day to maintain its pleasurable effects and prevent withdrawal symptoms. Nicotine and other constituents of smoke also provide sensory stimuli which, through repeated pairings, become conditioned reinforcers and further strengthen tobacco self-administration, creating an extremely persistant behavior. Nicotine replacement medications provide relief of cigarette withdrawal symptoms and are effective aids in smoking cessation; however, sustaining long-term abstinence can still be very difficult.     

Nicotine and angiogenesis: a new paradigm for tobacco-related diseases

The pathophysiology of tobacco-related diseases is complex and multifactorial. Among the approximately 4,000 compounds in tobacco smoke are carcinogens such as nitrosamines, irritants such as a variety of phenolic compounds, volatiles such as carbon monoxide, and of course nicotine. Nicotine itself has quite complex actions, mediated in part by nicotinic cholinergic receptors that may have extraneuronal, as well as neuronal distribution. This review discusses the mechanisms by which nicotine contributes to tobacco-related disease, with a focus on the surprising new finding that nicotine is a potent angiogenic agent. Nicotine hijacks an endogenous nicotinic cholinergic pathway present in endothelial cells that is involved in physiological, as well as pathological angiogenesis.     

Nicotine--drug addiction--AIDS. Drug use habits of Vienna addicts]

In Austria it is illegal to sell tobacco to young adolescents. A diverse sample of 358 narcotic addicts was investigated at the Psychiatric University Clinic of Vienna. Data were obtained from on site confidential interviews and a HIV-test was conducted. The individual drug use history was recorded and, interestingly, tobacco addiction was the first stage in starting a drug career. Furthermore, a strong correlation was observed between onset of heroin use and HIV-1 infection. It is concluded that in Austria not only the availability nicotine and alcohol to young adolescents should be prohibited, but also their use should be punishable. Easy access to nicotine as in public restaurants or from automatic distributors, has to be withdrawn. Tobacco advertisements may drive vulnerable young adolescents to early nicotine abuse and this may be followed by addition to other drugs and diseases causing death, including AIDS. Socioeconomic data, as well as the methadone data are presented. 180 out of the 358 patients were on methadone maintenance. Methadone treatment offers a first step toward social rehabilitation for drug addicts who have been living as criminals on the fringe of society. Physicians have a clear responsibility to lead the effort on all fronts against tobacco, especially in view of the HIV epidemic.     

Nicotine dependence and gender differences in smokers accessing community mental health services

Despite evidence of differences in smoking behaviour between women and men, few studies have assessed these differences in individuals with mental illnesses. In this cross-sectional study, we explored gender differences in smoking behaviour among 298 individuals (60% male) accessing community mental health services. Individuals with a psychotic disorder as compared with a non-psychotic disorder, and individuals using a greater number of substances were more likely to be male. Readiness to change, daily cigarette consumption and level of nicotine dependence did not differ between men and women; however, subjective ratings of tobacco addiction were higher in women than in men. Among women, only scores on the subjective tobacco addiction scale were associated with nicotine dependence, while among men, a variety of variables were associated with nicotine dependence. These factors are important for understanding individual differences in tobacco dependence among clients with mental illnesses, and are expected to inform future studies examining tobacco use in mental health treatment populations.     

Simultaneous analysis of nicotine,nicotine metabolites,and tobacco alkaloids in serum or urine by tandem mass spectrometry,with clinically relevant metabolic profiles

BACKGROUND: Assessment of nicotine metabolism and disposition has become an integral part of nicotine dependency treatment programs. Serum nicotine concentrations or urine cotinine concentrations can be used to guide nicotine patch dose to achieve biological concentrations adequate to provide the patient with immediate relief from nicotine withdrawal symptoms, an important factor in nicotine withdrawal success. Absence of nicotine metabolites and anabasine can be used to document abstinence from tobacco products, an indicator of treatment success. METHODS: The procedure was designed to quantify nicotine, cotinine, trans-3'-hydroxycotinine, anabasine, and nornicotine in human serum or urine. The technique required simple extraction of the sample with quantification by HPLC-tandem mass spectrometry. RESULTS: The procedure for simultaneous analysis of nicotine, its metabolites, and tobacco alkaloids simultaneously quantified five different analytes. Test limit of quantification, linearity, imprecision, and accuracy were adequate for clinical evaluation of patients undergoing treatment for tobacco dependency. The test readily distinguished individuals who had no exposure to tobacco products from individuals who were either passively exposed or were abstinent past-tobacco users from those who were actively using a tobacco or nicotine product. CONCLUSIONS: Nicotine, cotinine, trans-3'-hydroxycotinine, nornicotine, and anabasine can be simultaneously and accurately quantified in either serum or urine by HPLC-tandem mass spectrometry with imprecision <10% at physiologic concentrations and limits of quantification ranging from 0.5 to 5 micro g/L. Knowledge of serum or urine concentrations of these analytes can be used to guide nicotine replacement therapy or to assess tobacco abstinence in nicotine dependency treatment. These measurements are now an integral part of the clinical treatment and management of patients who wish to overcome tobacco dependence.     

Treatment of nicotine dependence

Nicotine dependence is characterized by periods of relapse and remission. Health care workers can have a pivotal role in the treatment of nicotine dependence. Smokers should be identified and categorized based on their readiness to change. Smokers who are preparing to stop smoking should be given multicomponent therapy in a step-care approach using behavioral treatment, addiction treatment, pharmacotherapy, and techniques of relapse prevention. Pharmacotherapies approved by the Food and Drug Administration for smoking interventions include sustained-release bupropion, nicotine gum, the nicotine inhaler, nicotine nasal spray, and nicotine patches.     

Intravenous nicotine and caffeine: subjective and physiological effects in cocaine abusers

The subjective and physiological effects of intravenously administered caffeine and nicotine were compared in nine subjects with histories of using caffeine, tobacco, and cocaine. Subjects abstained from tobacco cigarette smoking for at least 8 h before each session. Dietary caffeine was eliminated throughout the study; however, to maintain consistency with the nicotine intake, subjects were administered caffeine (150 mg/70 kg b.i.d.) in capsules, with the last dose administered 15 to 18 h before each session. Under double-blind conditions, subjects received placebo, caffeine (100, 200, and 400 mg/70 kg), and nicotine (0.75, 1.5, and 3.0 mg/70 kg) in mixed order. Physiological and subjective data were collected before and repeatedly after drug or placebo administration. Compared with the highest dose of caffeine, the highest dose of nicotine produced greater subjective ratings on a number of scales. At doses that produced comparable ratings of drug effect (1.5 mg/70 kg of nicotine and 400 mg/70 kg of caffeine), both drugs produced similar increases in ratings of good effect, liking, high, stimulated, and bad effect. Nicotine showed a somewhat faster time to peak subjective effects than caffeine (2 versus 4 min). Subjective ratings that differentiated caffeine and nicotine were ratings of rush, blurry vision, and stimulant identification (elevated by nicotine) and ratings of unusual smell and/or taste (elevated by caffeine). Both caffeine and nicotine decreased skin temperature and increased diastolic blood pressure; however, caffeine decreased whereas nicotine increased heart rate. The study documents both striking similarities and some notable differences between caffeine and nicotine, which are among the most widely used mood-altering drugs.     

The role of advanced practice psychiatric nurses in treating tobacco use and dependence.

Tobacco use is treatable and the benefits of smoking cessation are impressive, yet like other health care providers, psychiatric nurses have failed to consistently assess and treat tobacco use effectively. Tobacco use continues to cause illness, disability, and death at unprecedented rates. Nicotine addiction is drug abuse and it is a chronic disease and needs to be treated as such. There are clear health benefits to smoking cessation regardless of the age of smoking initiation or the age of smoking cessation. Advanced practice psychiatric nurses (APPNs) are in a unique position to make an impact on a smoker's risk of suffering from tobacco-related diseases: the treatment of choice is the combination of pharmacotherapy and psychosocial interventions, both within the realm of APPN practice; psychiatric and substance abusing patients consistently demonstrate increased rates of cigarette smoking compared with healthy controls; and tobacco use is drug abuse, a treatable chronic disease. The ability of APPNs to deliver psychotherapeutic and pharmacologic care secures a position in the forefront of treating tobacco use. In addition to intervention, psychiatric nurses need to step up and take an active role in initiating and supporting tobacco control policy and legislation.     

Smoking and the young.

Over one quarter of the risk of death due to the sudden infant death syndrome (cot death) is attributable to maternal smoking. Maternal smoking during pregnancy and infancy is one of the most important avoidable risk factors for infant death. Nicotine is a drug of addiction. Many young smokers are addicted to nicotine and develop withdrawal symptoms on stopping. Smoking is an important marker for other types of drug abuse, e.g. alcohol, cannabis and cocaine. The earlier children start smoking, the greater the risk of lung cancer and heart disease. Smoking affects immunity and has been associated with an increased risk of acquiring human immunodeficiency virus-1 infection.     

New tobacco trends: Waterpipe (hookah) smoking and implications for healthcare providers

Purpose: To inform healthcare providers about waterpipe smoking, a new trend in tobacco use that is gaining popularity among adolescents and young adults.
Data sources: American Lung Association Tobacco Policy Alert on Waterpipe Smoking, World Health Organization Tobacco Regulation Advisory Note on Waterpipe Smoking, and pertinent publications available in the literature.
Conclusions: Waterpipe smoking is a new trend in tobacco use that is associated with multiple health problems, including addiction. Healthcare providers should be aware of new tobacco trends that may affect patients, such as waterpipe smoking, that are potential gateways to nicotine addiction.
Implications for practice: Tobacco comes in many forms, all of which are addicting. Healthcare providers must be knowledgeable about new forms of tobacco to address all types of tobacco use with patients. Healthcare providers also have a responsibility to educate patients about the health risks inherent in these products to help prevent the long-lasting problem of nicotine addiction.