RESUMEN
OBJECTIVES: Smoking patients undergoing a plastic surgery intervention are exposed to increased risk of perioperative and postoperative complications. It seemed useful to us to establish an update about the negative impact of smoking, especially on wound healing, and also about the indisputable benefits of quitting. We wish to propose a minimum time lapse of withdrawal in the preoperative and postoperative period in order to reduce the risks and maximize the results of the intervention. METHODS: A literature review of documents from 1972 to 2014 was carried out by searching five different databases (Medline, PubMed Central, Cochrane library, Pascal and Web of Science). RESULTS: Cigarette smoke has a diffuse and multifactorial impact in the body. Hypoxia, tissue ischemia and immune disorders induced by tobacco consumption cause alterations of the healing process. Some of these effects are reversible by quitting. Data from the literature recommend a preoperative smoking cessation period lasting between 3 and 8 weeks and up until 4 weeks postoperatively. Use of nicotine replacement therapies doubles the abstinence rate in the short term. When a patient is heavily dependent, the surgeon should be helped by a tobacco specialist. CONCLUSIONS: Total smoking cessation of 4 weeks preoperatively and lasting until primary healing of the operative site (2 weeks) appears to optimize surgical conditions without heightening anesthetic risk. Tobacco withdrawal assistance, both human and drug-based, is highly recommended.
Asunto(s)
Procedimientos de Cirugía Plástica , Complicaciones Posoperatorias/fisiopatología , Fumar/fisiopatología , Cicatrización de Heridas/fisiología , Estimulantes Ganglionares/efectos adversos , Estimulantes Ganglionares/farmacocinética , Humanos , Hipoxia/fisiopatología , Isquemia/fisiopatología , Nicotina/efectos adversos , Nicotina/farmacocinética , Fumar/efectos adversos , Cese del Hábito de Fumar , Dispositivos para Dejar de Fumar TabacoAsunto(s)
Electrónica , Estimulantes Ganglionares/administración & dosificación , Nicotina/administración & dosificación , Control Social Formal , Productos de Tabaco , Publicidad , Contaminación de Medicamentos , Estimulantes Ganglionares/farmacocinética , Humanos , Exposición por Inhalación , Nicotina/farmacocinética , Fumar , Cese del Hábito de Fumar , Productos de Tabaco/efectos adversos , Productos de Tabaco/clasificación , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Tissue distribution and urinary excretion of nicotine, cotinine, and hydroxycotinine after multiple oral administration of nicotine to rats for 4 weeks were studied. Physiological change and serum biochemical parameters were also measured to check dysfunction of organs. Significant change of glutathione S-transferase, aspartate aminotransferase, blood urea nitrogen, and physiological parameters indicated the toxicity in liver and kidney, at the dose of 5 and 10 mg/kg/day. Only the concentration and total amount of cotinine, not nicotine or hydroxycotinine, in the liver and the kidney showed a proportional dose-dependent increase and were highly correlated with toxicity. Saturation of metabolizing enzymes for nicotine was estimated by the change of urinary excreted amount ratio between nicotine and its metabolites. Metabolizing enzyme to produce cotinine from nicotine was saturated after multiple oral dosing for 4 weeks in a low dose (1 mg/kg/day), but within 1 week in the dose of 5 and 10 mg/kg/day.
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Cotinina/orina , Estimulantes Ganglionares/farmacocinética , Estimulantes Ganglionares/toxicidad , Nicotina/farmacocinética , Nicotina/toxicidad , Animales , Aspartato Aminotransferasas/sangre , Análisis Químico de la Sangre , Nitrógeno de la Urea Sanguínea , Encéfalo/efectos de los fármacos , Encéfalo/patología , Cotinina/análogos & derivados , Estimulantes Ganglionares/orina , Cromatografía de Gases y Espectrometría de Masas , Glutatión Transferasa/sangre , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Nicotina/orina , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
Nicotine in mainstream cigarette smoke is predominantly present in the particulate phase. Interestingly, however, the deposition efficiency of smoke particles in the respiratory tract is less effective than is the nicotine retention. In the literature, four nicotine deposition mechanisms are identified: (a) direct gas deposition, (b) evaporative gas deposition, (c) particle deposition with evaporation, and (d) particle deposition with diffusion. In this article we present a physically motivated fundamental model to address nicotine deposition mechanisms (b) and (c) from the vapor phase. The model incorporates nicotine mass transport through estimates for the diffusion time across the epithelial layer and the time for nicotine vapor diffusion from the gas volume to the tissue surfaces in the tracheobronchial and pulmonary regions of the respiratory tract. The model comprises four mass transfer processes for nicotine at the surface of the respiratory tract epithelium: (1) conversion of free base nicotine from protonated nicotine; (2) free base nicotine transport across the epithelium; (3) free base nicotine evaporation; and (4) diffusion of free base nicotine vapor from the surface gas layer into the airway lumen. Results of the nicotine mass transport model suggest that the principal mechanism of nicotine delivery to the lung is by direct deposition of particles to the alveolar fluid lining, followed rapidly by evaporation into the lumen and then gas diffusion back to the surface as nicotine depletes in the surface layer through its transport across the epithelium.
Asunto(s)
Estimulantes Ganglionares/farmacocinética , Pulmón/metabolismo , Nicotina/farmacocinética , Sistema Respiratorio/metabolismo , Transporte Biológico , Bronquios/metabolismo , Humanos , Exposición por Inhalación , Modelos Biológicos , Alveolos Pulmonares/metabolismo , Tráquea/metabolismoRESUMEN
Nicotine sustains tobacco addiction, a major cause of disability and premature death. Nicotine binds to nicotinic cholinergic receptors, facilitating neurotransmitter release and thereby mediating the complex actions of nicotine in tobacco users. Dopamine, glutamate, and gamma aminobutyric acid release are particularly important in the development of nicotine dependence, and corticotropin-releasing factor appears to contribute to nicotine withdrawal. Nicotine dependence is highly heritable. Genetic studies indicate roles for nicotinic receptor subtypes, as well as genes involved in neuroplasticity and learning, in development of dependence. Nicotine is primarily metabolized by CYP 2A6, and variability in rate of metabolism contributes to vulnerability to tobacco dependence, response to smoking cessation treatment, and lung cancer risk. Tobacco addiction is much more common in persons with mental illness and substance abuse disorders, representing a high proportion of current smokers. Pharmacotherapeutic approaches to tobacco addiction include nicotine replacement, bupropion, and varenicline, the latter a selective nicotine receptor partial agonist.
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Conducta Adictiva/inducido químicamente , Conducta Adictiva/tratamiento farmacológico , Estimulantes Ganglionares/toxicidad , Nicotina/toxicidad , Agonistas Nicotínicos/toxicidad , Fumar/efectos adversos , Tabaquismo/tratamiento farmacológico , Tabaquismo/etiología , Animales , Conducta Adictiva/genética , Benzazepinas/uso terapéutico , Bupropión/uso terapéutico , Estimulantes Ganglionares/química , Estimulantes Ganglionares/metabolismo , Estimulantes Ganglionares/farmacocinética , Humanos , Nicotina/química , Nicotina/metabolismo , Nicotina/farmacocinética , Agonistas Nicotínicos/química , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/farmacocinética , Medicamentos sin Prescripción/uso terapéutico , Quinoxalinas/uso terapéutico , VareniclinaRESUMEN
RATIONALE: This review provides insight for the judicious selection of nicotine dose ranges and routes of administration for in vivo studies. The literature is replete with reports in which a dosaging regimen chosen for a specific nicotine-mediated response was suboptimal for the species used. In many cases, such discrepancies could be attributed to the complex variables comprising species-specific in vivo responses to acute or chronic nicotine exposure. OBJECTIVES: This review capitalizes on the authors' collective decades of in vivo nicotine experimentation to clarify the issues and to identify the variables to be considered in choosing a dosaging regimen. Nicotine dose ranges tolerated by humans and their animal models provide guidelines for experiments intended to extrapolate to human tobacco exposure through cigarette smoking or nicotine replacement therapies. Just as important are the nicotine dosaging regimens used to provide a mechanistic framework for acquisition of drug-taking behavior, dependence, tolerance, or withdrawal in animal models. RESULTS: Seven species are addressed: humans, nonhuman primates, rats, mice, Drosophila, Caenorhabditis elegans, and zebrafish. After an overview on nicotine metabolism, each section focuses on an individual species, addressing issues related to genetic background, age, acute vs chronic exposure, route of administration, and behavioral responses. CONCLUSIONS: The selected examples of successful dosaging ranges are provided, while emphasizing the necessity of empirically determined dose-response relationships based on the precise parameters and conditions inherent to a specific hypothesis. This review provides a new, experimentally based compilation of species-specific dose selection for studies on the in vivo effects of nicotine.
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Investigación Conductal/métodos , Relación Dosis-Respuesta a Droga , Guías como Asunto , Nicotina/administración & dosificación , Animales , Estimulantes Ganglionares/administración & dosificación , Estimulantes Ganglionares/metabolismo , Estimulantes Ganglionares/farmacocinética , Humanos , Modelos Biológicos , Nicotina/metabolismo , Nicotina/farmacocinética , Especificidad de la EspecieRESUMEN
BACKGROUND AND OBJECTIVE: The liver enzyme cytochrome P450 (CYP) 2A6 is primarily responsible for the metabolism of nicotine. Variants in the CYP2A6 gene have been associated with altered nicotine metabolism and with effects on smoking behavior. Our objective was to determine the relationship between variant CYP2A6 genotypes and the disposition and metabolism of nicotine administered intravenously. METHODS: Intravenous infusions of deuterium-labeled nicotine and cotinine were administered to 278 healthy twin volunteers, most of whom were white. They were genotyped for CYP2A6*1, CYP2A6*2, CYP2A6*4, CYP2A6*7, CYP2A6*8, CYP2A6*9, CYP2A6*10, and CYP2A6*12. RESULTS: On the basis of the fractional clearance of nicotine to cotinine and on the plasma ratio of 3'-hydroxycotinine to cotinine, both shown to be indicators of CYP2A6 enzymatic activity, subjects were classified into 3 groups. Group 1 included wild-type variant CYP2A6*1/*1 (n=215) and was assumed to have 100% activity. Group 2 included *1/*9 (n=21) and *1/*12 (n=12), which averaged about 80% of normal activity. Group 3 included *1/*2 (n=10), *1/*4 (n=2), *9/*12 (n=3), *9/*4 (n=2), and *9/*9 (n=3), which averaged about 50% of normal activity. The mean total plasma clearance of nicotine (+/-SD) was 18.8+/-6.0, 15.5+/-4.9, and 11.7+/-5.1 mL.min-1.kg-1 in groups 1, 2, and 3, respectively, and group 1 had significantly faster clearance than group 2 (P<.05) and group 3 (P<.01). Overall, groups 2 and 3 also had lower total clearance of cotinine, had longer half-lives for nicotine and cotinine, and excreted in the urine a greater fraction of the nicotine dose as unchanged nicotine and nicotine glucuronide and excreted less as 3'-hydroxycotinine compared with group 1. CONCLUSIONS: We provide novel pharmacokinetic and metabolic data on nicotine after systemic dosing in relation to common CYP2A6 genotypes. Our data will enhance the interpretation of CYP2A6 genotypic data as used in association studies of smoking behavior and its health consequences.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/genética , Cotinina/farmacocinética , Oxigenasas de Función Mixta/genética , Nicotina/farmacocinética , Adolescente , Adulto , Anciano , Alelos , Área Bajo la Curva , Cotinina/administración & dosificación , Cotinina/análogos & derivados , Cotinina/metabolismo , Citocromo P-450 CYP2A6 , Deuterio , Relación Dosis-Respuesta a Droga , Estimulantes Ganglionares/administración & dosificación , Estimulantes Ganglionares/metabolismo , Estimulantes Ganglionares/farmacocinética , Frecuencia de los Genes , Glucurónidos/sangre , Glucurónidos/orina , Semivida , Humanos , Infusiones Intravenosas , Isoenzimas/genética , Tasa de Depuración Metabólica , Persona de Mediana Edad , Nicotina/administración & dosificación , Nicotina/análogos & derivados , Nicotina/metabolismo , Polimorfismo Genético/genética , Factores de Tiempo , Gemelos/genéticaRESUMEN
BACKGROUND AND OBJECTIVE: Grapefruit juice is an inhibitor of the cytochrome P450 (CYP) 3A4 enzyme and transporters such as P-glycoprotein and organic anion transporting polypeptides, leading to clinically important interactions. Our objective was to study the effect of grapefruit juice on the pharmacokinetics of nicotine, which is primarily metabolized by the CYP2A6 enzyme. METHODS: Ten volunteers were given a 2-mg oral dose of deuterium-labeled nicotine on 3 occasions together with 1 L of water, full-strength grapefruit juice, or half-strength grapefruit juice. Concentrations of nicotine and its metabolites were analyzed in plasma and urine for 8 hours. RESULTS: Grapefruit juice inhibited the formation of cotinine from nicotine (area under the plasma cotinine concentration-time curve from 0 to 8 hours of 6807 min.ng/mL, 7805 min.ng/mL, and 8007 min.ng/mL for full-strength grapefruit juice, half-strength grapefruit juice, and water, respectively; repeated-measures ANOVA, P=.009). The time to peak plasma concentration of cotinine was delayed (216 minutes, 159 minutes, and 147 minutes, respectively; ANOVA, P=.011), and the peak plasma concentration was lower with grapefruit juice compared with water (18 ng/mL, 21 ng/mL, and 22 ng/mL, respectively; ANOVA, P=.010). Oral clearance, peak plasma concentration, and time to peak plasma concentration of nicotine were not affected. Grapefruit juice increased the renal clearance of nicotine (231 mL/min, 219 mL/min, and 123 mL/min, respectively; ANOVA, P=.045) and cotinine (19 mL/min, 14 mL/min, and 16 mL/min, respectively; ANOVA, P=.002). CONCLUSIONS: Grapefruit juice inhibits the metabolism of nicotine to cotinine, a pathway mediated by CYP2A6, and increases the renal clearance of nicotine and cotinine. Nicotine oral clearance is not affected by grapefruit juice because the inhibition of hepatic metabolism is offset by the increase in the renal clearance of nicotine. However, other compounds metabolized by CYP2A6, as well as other drugs excreted via renal clearance mechanisms similar to those of nicotine, may be susceptible to significant pharmacokinetic grapefruit juice interactions.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/metabolismo , Bebidas , Citrus paradisi , Riñón/metabolismo , Oxigenasas de Función Mixta/metabolismo , Nicotina/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Hidrocarburo de Aril Hidroxilasas/antagonistas & inhibidores , Cotinina/análogos & derivados , Cotinina/sangre , Cotinina/metabolismo , Cotinina/orina , Citocromo P-450 CYP2A6 , Deuterio , Femenino , Estimulantes Ganglionares/administración & dosificación , Estimulantes Ganglionares/farmacocinética , Glucurónidos/orina , Semivida , Humanos , Hígado/metabolismo , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Oxigenasas de Función Mixta/antagonistas & inhibidores , Nicotina/sangre , Nicotina/orinaRESUMEN
The relationship between CYP2A6 genotype and smoking status remains unclear although several studies have been reported. In this study, we have investigated the significance of CYP2A6 genotype on smoking habit and treatment of nicotine patch. Sixty-one smokers (1.7%) working in a Japanese company (n = 3585) participated in this smoking cessation program. Forty-four of 61 (72.1%) smokers were treated by nicotine patch. A genotyping analysis was carried out for 41 (40 men and 1 women) of 61 participants (67.2%). The smoking cessation rate at 90 days was 54.1% (33/61). Age and smoking years in re-smoking group are significantly lower than those in smoking cessation group. The smoking cessation rate of participants treated with nicotine patch (63.6%; 28/44) was significantly higher than that of the group non-treated with nicotine patch (29.4%; 5/17) at 90 days (p < 0.05). The incidence of homozygotes of CYP2A6 gene deletion (CYP2A619934/19934) in 41 cases (9.8%; 4/41) could be higher than that in 894 healthy controls (3.7%; 33/894) (p = 0.12), while no other variant alleles (CYP2A619932, CYP2A619933 and CYP2A619936) were found. Age and smoking years of participants with CYP2A619934/19934 are significantly higher than those with CYP2A619931 positive. The scores of Fagerstrom test, an analysis for nicotine-dependence, were slightly different between participants with CYP2A619934/19934 and CYP2A619931 positive. Although treatment of nicotine patch is efficacious to smoking cessation, cases with CYP2A619934/19934 might be more sensitive to nicotine adverse effects and more difficult to quit smoking once they have smoking habit.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/genética , Estimulantes Ganglionares/farmacocinética , Oxigenasas de Función Mixta/genética , Nicotina/farmacocinética , Polimorfismo Genético , Cese del Hábito de Fumar , Tabaquismo/genética , Administración Cutánea , Adulto , Citocromo P-450 CYP2A6 , Femenino , Estimulantes Ganglionares/administración & dosificación , Estimulantes Ganglionares/uso terapéutico , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Nicotina/administración & dosificación , Nicotina/uso terapéutico , Resultado del TratamientoRESUMEN
Public health officials and tobacco researchers have raised concerns about the possible contributions of additives to the toxicity of cigarettes. However, little attention has been given to the process whereby additives promote initiation and addiction. Levulinic acid is a known cigarette additive. Review of internal tobacco industry documents indicates that levulinic acid was used to increase nicotine yields while enhancing perceptions of smoothness and mildness. Levulinic acid reduces the pH of cigarette smoke and desensitizes the upper respiratory tract, increasing the potential for cigarette smoke to be inhaled deeper into the lungs. Levulinic acid also may enhance the binding of nicotine to neurons that ordinarily would be unresponsive to nicotine. These findings held particular interest in the internal development of ultralight and so-called reduced-exposure cigarette prototypes. Industry studies found significantly increased peak plasma nicotine levels in smokers of ultralight cigarettes following addition of levulinic acid. Further, internal studies observed changes in mainstream and sidestream smoke composition that may present increased health risks. The use of levulinic acid illustrates the need for regulatory authority over tobacco products as well as better understanding of the role of additives in cigarettes and other tobacco products.
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Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ácidos Levulínicos/química , Ácidos Levulínicos/farmacología , Industria del Tabaco , Tabaquismo/fisiopatología , Estimulantes Ganglionares/farmacocinética , Historia del Siglo XX , Humanos , Nicotina/farmacocinética , Investigación/historia , Industria del Tabaco/historiaRESUMEN
BACKGROUND: The factors that cause children to become smokers in adolescence remain unclear. Although parental smoking and peer pressure may play a role, physiological factors such as lung volume have also been identified. METHODS: To investigate these and other possible childhood predictors of teenage smoking, we gathered follow-up data on 191 Montréal schoolchildren, aged 5-12 years (average 9.2 yr) when first examined. At an average age of 13.0 years, they answered further questions on their health and smoking behaviour and provided a second set of spirometric measurements. RESULTS: At the second survey, 80% of the children had entered high school and 44% had become smokers. Reaching puberty between the surveys was the most significant determinant of becoming a smoker: 56.4% of the 124 children postpubertal at the second survey had taken up smoking, versus 17.9% of the 67 who were still prepubertal (p = 0.001). We found salivary cotinine level, a measure of uptake of environmental tobacco smoke, to be an independent predictor of becoming a teenage smoker; even after adjustment for sex, socioeconomic status of parents, a crowding index, and the numbers at home of siblings, adult smokers and cigarettes smoked, it remained significant for both groups: postpubertal (odds ratio [OR] 1.2, 95% confidence interval [CI] 1.2-3.0) and prepubertal (OR 2.1, 95% CI 1.0- 4.5). The influence of forced vital capacity was marginally significant only in the postpubertal group (OR 5.0, 95% CI 0.88-28.3). INTERPRETATION: The proportion of nicotine absorbed from that available in environmental tobacco smoke during childhood is associated with subsequent smoking in adolescence. The more efficient absorption of nicotine seen in some children may be related to physiological factors such as lung capacity.
Asunto(s)
Conducta del Adolescente , Estimulantes Ganglionares/farmacocinética , Nicotina/farmacocinética , Fumar , Contaminación por Humo de Tabaco , Absorción , Adolescente , Niño , Preescolar , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Pubertad , Quebec , Factores de Riesgo , Espirometría , Listas de EsperaRESUMEN
Cigarette design has changed markedly over the past 60 years and sales-weighed levels of tar and nicotine have decreased. Currently, cigarettes are classified as regular (>14.5 mg tar), light (>6.5-14.5 mg tar), and ultralight (< or =6.5 mg tar), based on a Federal Trade Commission-specified machine-smoking protocol. Epidemiologic studies suggest that there is no difference in lung cancer risk among people who smoke light or ultralight cigarettes compared with regular cigarettes, but the uptake of lung carcinogens in smokers of these types of cigarettes has never been reported. We recruited 175 smokers, who filled out a tobacco use questionnaire in which their current brand was identified as regular, light, or ultralight. Urine samples were collected and analyzed for 1-hydroxypyrene (1-HOP), total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL plus its glucuronides) and total cotinine (cotinine plus its glucuronides). 1-HOP and total NNAL are biomarkers of uptake of polycyclic aromatic hydrocarbons and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, lung carcinogens in cigarette smoke. Total cotinine is a biomarker of nicotine uptake. There were no statistically significant differences in urinary levels of 1-HOP, total NNAL, and total cotinine in smokers of regular, light, and ultralight cigarettes, whether the results were expressed per mg urinary creatinine, per mL of urine, or per mg creatinine divided by cigarettes per day. Levels of machine measured tar were available for the cigarettes smoked by 149 of the subjects. There was no correlation between levels of tar and any of the biomarkers. These results indicate that lung carcinogen and nicotine uptake, as measured by urinary 1-HOP, total NNAL, and total cotinine is the same in smokers of regular, light, and ultralight cigarettes. The results are consistent with epidemiologic studies that show no difference in lung cancer risk in smokers of these cigarettes.
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Carcinógenos/farmacocinética , Neoplasias Pulmonares/etiología , Pulmón/química , Hidrocarburos Policíclicos Aromáticos/efectos adversos , Humo , Fumar/efectos adversos , Adulto , Anciano , Biomarcadores/análisis , Cotinina/análisis , Femenino , Estimulantes Ganglionares/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Nicotina/farmacocinética , Hidrocarburos Policíclicos Aromáticos/análisis , Breas/análisisAsunto(s)
Estimulantes Ganglionares/uso terapéutico , Nicotina/uso terapéutico , Cese del Hábito de Fumar/métodos , Antidepresivos de Segunda Generación/uso terapéutico , Bupropión/uso terapéutico , Estimulantes Ganglionares/metabolismo , Estimulantes Ganglionares/farmacocinética , Semivida , Humanos , Tasa de Depuración Metabólica , Nicotina/metabolismo , Nicotina/farmacocinéticaRESUMEN
Nicotine is of importance as the addictive chemical in tobacco, pharmacotherapy for smoking cessation, a potential medication for several diseases, and a useful probe drug for phenotyping cytochrome P450 2A6 (CYP2A6). We review current knowledge about the metabolism and disposition kinetics of nicotine, some other naturally occurring tobacco alkaloids, and nicotine analogs that are under development as potential therapeutic agents. The focus is on studies in humans, but animal data are mentioned when relevant to the interpretation of human data. The pathways of nicotine metabolism are described in detail. Absorption, distribution, metabolism, and excretion of nicotine and related compounds are reviewed. Enzymes involved in nicotine metabolism including cytochrome P450 enzymes, aldehyde oxidase, flavin-containing monooxygenase 3, amine N-methyltransferase, and UDP-glucuronosyltransferases are represented, as well as factors affecting metabolism, such as genetic variations in metabolic enzymes, effects of diet, age, gender, pregnancy, liver and kidney diseases, and racial and ethnic differences. Also effects of smoking and various inhibitors and inducers, including oral contraceptives, on nicotine metabolism are discussed. Due to the significance of the CYP2A6 enzyme in nicotine clearance, special emphasis is given to the effects and population distributions of CYP2A6 alleles and the regulation of CYP2A6 enzyme.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/genética , Estimulantes Ganglionares , Oxigenasas de Función Mixta/genética , Nicotina , Fumar/metabolismo , Absorción , Animales , Disponibilidad Biológica , Citocromo P-450 CYP2A6 , Femenino , Estimulantes Ganglionares/metabolismo , Estimulantes Ganglionares/farmacocinética , Estimulantes Ganglionares/farmacología , Humanos , Hígado/enzimología , Masculino , Tasa de Depuración Metabólica , Nicotina/metabolismo , Nicotina/farmacocinética , Nicotina/farmacología , Distribución TisularRESUMEN
The subjective and reinforcing effects of drugs of abuse may depend partly on their rate of onset, with faster acting formulations typically producing stronger effects than slower ones. In this within-subjects study, we examined the acute effects of nicotine replacement therapy via nicotine nasal spray (fast delivery) vs. transdermal nicotine patch (slow delivery) on craving, withdrawal, cardiovascular responses, subjective ratings, and reinforcing effects of smoking. Smokers (N=30) not seeking treatment participated in three sessions, each after overnight smoking abstinence, involving 14-mg nicotine (Nicoderm) or placebo patch, followed 4 hr later by intermittent administration of nicotine (Nicotrol) or placebo nasal spray. Specifically, the three group comparisons were nicotine patch condition (with placebo spray), nicotine spray condition (with placebo patch), and placebo condition (placebo spray and patch). Nicotine patch and nicotine spray were never administered in the same session. Blood nicotine levels were similar between nicotine patch and nicotine spray conditions, by design. Heart rate and systolic blood pressure were higher following nicotine spray vs. the other conditions, as hypothesized. However, other than reductions in craving related to nicotine spray and patch at some points, no differences between conditions were observed in withdrawal, subjective effects of sprays and smoking, or smoking reinforcement assessed by a computer task. Thus, under these acute conditions, the speed of nicotine delivery from nasal spray vs. patch differentially affected cardiovascular responses and perhaps craving but did not influence withdrawal, subjective ratings, and smoking reinforcement.
Asunto(s)
Estimulantes Ganglionares/administración & dosificación , Estimulantes Ganglionares/uso terapéutico , Nicotina/administración & dosificación , Cese del Hábito de Fumar/métodos , Tabaquismo/tratamiento farmacológico , Administración Cutánea , Administración Intranasal , Adulto , Presión Sanguínea , Esquema de Medicación , Femenino , Estimulantes Ganglionares/farmacocinética , Frecuencia Cardíaca , Humanos , Masculino , Nicotina/farmacocinética , Placebos , Esquema de Refuerzo , Resultado del TratamientoRESUMEN
The influence of the tobacco additives diammonium hydrogen phosphate (DAP) and urea on the delivery and respiratory tract retention of nicotine and solanesol and on the uptake of nicotine into venous blood was investigated in 10 smokers under mouth-hold and 75 and 500 mL inhalation conditions. Three cigarettes with identical physical specifications were produced from a common lamina tobacco blend. The control cigarette contained nonammoniated reconstituted tobacco sheet (RTS), whereas DAP and other ammonia compounds were added to the RTS of the second cigarette. Urea was added to the tobacco of the third cigarette. The presence of DAP or urea in the test cigarettes did not significantly influence solanesol retention within the mouth during the mouth-hold condition. Nicotine retention within the mouth during the mouth-hold condition was, however, significantly higher for the DAP cigarette (64.3 +/- 10.5%) than for the urea (53.3 +/- 11.3%) or control cigarette (46.3 +/- 8.6%), but this did not result in an increase in nicotine uptake into venous blood. Solanesol retentions during the 75 and 500 mL inhalation volume conditions and nicotine retentions during the 75 mL inhalation volume condition were not significantly different for the three cigarette types. Although the nicotine retention approached 100% with each cigarette type during the 500 mL inhalation condition, the nicotine retention for the urea-treated cigarette (99.6 +/- 0.2%) was marginally, but statistically, significant, higher than for the control (99.1 +/- 0.5%) and DAP-treated cigarettes (98.8 +/- 0.6%). There were no statistically significant differences between the indices of nicotine uptake into venous blood for the three cigarette types in any of the inhalation conditions.
Asunto(s)
Estimulantes Ganglionares/farmacocinética , Nicotiana/química , Nicotina/farmacocinética , Sistema Respiratorio/química , Fumar , Terpenos/farmacocinética , Administración por Inhalación , Adulto , Estimulantes Ganglionares/sangre , Humanos , Masculino , Boca , Nicotina/sangre , Respiración , Terpenos/sangre , Distribución TisularRESUMEN
Smokeless tobacco is a complex chemical mixture, including not only the components of the tobacco leaf but also chemicals added during the manufacturing process. Smokeless tobacco contains the addictive chemical nicotine and more than 20 cancer-causing chemicals, including the potent tobacco-specific nitrosamines. The National Toxicology Program of the National Institutes of Health has concluded that oral use of smokeless tobacco is a human carcinogen. Therefore, smokeless tobacco is not a safe alternative to cigarettes. In fact, smokeless tobacco use begins primarily during early adolescence and can lead to nicotine dependence and increased risk of becoming a cigarette smoker. Under the Comprehensive Smokeless Tobacco Health Education Act of 1986 (15 U.S.C. 4401 et seq., Pub. L. 99-252), tobacco manufacturers report annually to the Centers for Disease Control and Prevention (CDC) on the total nicotine, unprotonated nicotine, pH, and moisture content of their smokeless tobacco products. This information is considered "trade secret," or confidential, in accordance with 5 U.S.C. 552(b)(4) and 18 U.S.C. 1905 and cannot be released to the public. In an effort to provide consumers and researchers with information on the nicotine content of smokeless tobacco, CDC arranged for the analysis of popular brands of smokeless tobacco. The results of this CDC study show that pH is a primary factor in the amount of nicotine that is in the most readily absorbable, unprotonated form. Furthermore, this study found that the brands of moist snuff smokeless tobacco with the largest amount of unprotonated nicotine also are the most frequently sold brands.
Asunto(s)
Estimulantes Ganglionares/análisis , Nicotina/análisis , Tabaco sin Humo/química , Disponibilidad Biológica , Centers for Disease Control and Prevention, U.S. , Estimulantes Ganglionares/química , Estimulantes Ganglionares/farmacocinética , Humanos , Concentración de Iones de Hidrógeno , Nicotina/química , Nicotina/farmacocinética , Valores de Referencia , Industria del Tabaco , Estados Unidos , Agua/análisisRESUMEN
Nicotine is metabolized to the inactive metabolite cotinine by cytochrome P450 2A6. NNK, or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, is a potent procarcinogen shown to be activated to a reactive mutagenic metabolite by the enzyme CYP2A6. We studied the effect of inhibiting CYP2A6 on smoking behavior and metabolism of the procarcinogen NNK. In study 1, abstinent smokers (n=7) received methoxsalen (a potent CYP2A6 inhibitor), 30-50 mg orally, one-half hour before three subcutaneous nicotine injections (31 microg/kg) were given at hourly intervals. Methoxsalen increased mean plasma nicotine by 47% (p<.01) and mean nicotine area under the curve (AUC) by 63% (p<.0001); and decreased nicotine clearance by 39% (p<.0001), relative to placebo. In study 2, smokers (n=11) were told to maintain their same number of cigarettes smoked while receiving methoxsalen, 10 mg orally three times daily for 3 days. On day 3 of methoxsalen treatment, a 29% increase in plasma nicotine/expired-air CO (an index of smoke exposure) (p=0.03) was observed. Urinary levels of trans 3'-hydroxycotinine (metabolized by CYP2A6 from cotinine) also were decreased (p<.0001), and significantly more NNK was metabolized to the inactive NNAL-glucuronide (1.04+/-0.54 pmol/mg on day 1 to 1.37+/-0.74 pmol/mg on day 4, p<.01) relative to placebo. Thus, treatment with the CYP2A6 inhibitor methoxsalen in vivo increases the routing of NNK to the inactive NNAL-glucuronide and decreases smoking. CYP2A6 inhibition may have potential as an exposure reduction or cessation strategy in tobacco dependence.
Asunto(s)
Carcinógenos/metabolismo , Estimulantes Ganglionares/metabolismo , Metoxaleno/farmacología , Nicotina/metabolismo , Nitrosaminas/metabolismo , Fumar , Administración Oral , Adulto , Área Bajo la Curva , Hidrocarburo de Aril Hidroxilasas/farmacología , Citocromo P-450 CYP2A6 , Femenino , Estimulantes Ganglionares/administración & dosificación , Estimulantes Ganglionares/farmacocinética , Humanos , Inyecciones Subcutáneas , Masculino , Oxigenasas de Función Mixta/farmacología , Nicotina/administración & dosificación , Nicotina/farmacocinética , PlacebosRESUMEN
Smoking is a complex behaviour involving both pharmacological and psychological components. Nicotine is the main alkaloid found in tobacco, and is responsible for its addictive potential. Nicotine-positive effects on mood and cognition are strong reinforcements for smokers that contribute to their addiction, and cigarette smoking is particularly addictive because inhaled nicotine is absorbed through the pulmonary venous rather than the systemic venous system, and thus reaches the brain in 10-20 seconds. As the likelihood that a substance will be abused depends on the time between administration and central reinforcement, tobacco smoking can easily become addictive. Nicotine replacement therapy (NRT) is available in different forms (gum, transdermal patch, nasal spray, inhaler, sublingual tablet and lozenge), and has been shown to relieve withdrawal symptoms and to double abstinence rates compared to placebo. Most NRT forms deliver nicotine more slowly than smoking, and the increase in nicotine blood levels is more gradual. Compared to tobacco smoking or even tobacco chewing, few positive (reinforcing) effects are obtained from NRT use. Nasal spray provides faster withdrawal relief than other NRT, but compared to smoking absorption is slower and nicotine blood levels obtained are lower than with smoking. These differences in pharmacokinetic profiles compared with smoking may explain that some smokers still have difficulties quitting smoking even when using NRT (apart from psychological and/or social factors). Combination therapy (e.g., patch+gum, patch+inhaler), higher dosage, temporary abstinence or smoking reduction (using NRT to reduce smoke intake) may be needed to help more smokers to quit.
Asunto(s)
Estimulantes Ganglionares/farmacología , Estimulantes Ganglionares/farmacocinética , Nicotina/farmacología , Nicotina/farmacocinética , Cese del Hábito de Fumar/métodos , Cese del Hábito de Fumar/psicología , Fumar/psicología , Tabaquismo/tratamiento farmacológico , Tabaquismo/fisiopatología , Afecto , Cognición , Estimulantes Ganglionares/administración & dosificación , Humanos , Nicotina/administración & dosificación , Refuerzo en Psicología , Conducta Social , Resultado del TratamientoRESUMEN
This study aimed to investigate the association between biomarkers of fetal exposure to smoking during the whole pregnancy, nicotine in maternal and newborns hair samples, and quantitative measurement of smoking intake and exposure evaluated by maternal self-reported questionnaire. Study subjects were 150 mothers and their newborns from a hospital in Barcelona. A questionnaire including smoking habits was completed in the third trimester of pregnancy and on the day of delivery. Nicotine content was measured in two subsequent segments of maternal hair accounting for the first and last months of pregnancy, and in fetal hair. The geometric mean of nicotine concentration in maternal hair discriminated between nonexposition (3.84 and 2.80 ng/mg in distal and proximal hair segment, respectively) and exposition to cigarette smoke during pregnancy (6.06 and 4.30 ng/mg in distal and proximal hair segment, respectively) (P<0.05), and between these two classes and active smoking (14.40 and 11.08 ng/mg in distal and proximal hair segment, respectively). Maternal hair nicotine was able to differentiate levels of exposure to tobacco smoke and levels of intake. Nicotine concentration in hair from newborns did not differentiate between exposure and nonexposure to environmental tobacco smoke (ETS) in nonsmoking mothers. Finally, chronic exposure to cigarette smoke during pregnancy, assessed by maternal hair nicotine, correlated negatively with anthropometric parameters of newborns.