Plasma Nicotine Concentrations Research Articles

A clinical pharmacological study of subcutaneous nicotine.

The stable isotope-labeled compound 3',-3'-dideuteronicotine (nicotine-d2) was used to investigate the disposition kinetics and effects of nicotine administered subcutaneously to 6 smokers. Plasma nicotine-d2 concentrations were measured for 8 h after subcutaneous injection of 4 doses (0.4, 0.8, 1.2, and 2.4 mg). Peak plasma nicotine concentration correlated well with the dose, averaging 2.8 to 14.8 ng/ml, 19 to 25 min after injection of the 0.4 mg and 2.4 mg doses, respectively. The plasma clearance over bioavailability ratio (CL/f) averaged 12 to 13 ml.min-1.kg-1, similar to the clearance reported previously for intravenously administered nicotine. Thus, bioavailability appears to be approximately 100%. The heart rate response was more sensitive to the nicotine dose than the blood pressure response. Subjective effects showed large interindividual variability. The results reported herein may be useful in planning future studies. Administration of nicotine by the subcutaneous route appears to be a practical and safe method for studying the human pharmacology of nicotine.

Single‐ and Multiple‐Dose Pharmacokinetics of Nicoderm® (Nicotine Transdermal System)

The pharmacokinetics and tolerability of single and multiple applications of Nicotine Transdermal Systems (NTS), designed to deliver 14 mg of nicotine per 24 hours, were investigated in 20 healthy adult male smokers. After a single application, mean Cmax and tmax for plasma nicotine were 12.2 ng/mL and 4.4 hours, respectively. Plasma nicotine concentrations rose rapidly and then remained steady between 12 and 24 hours after application. The apparent nicotine half-life (t1/2) after system removal was 3.2 hours. Steady state was attained by the second day of multiple application, and mean steady-state nicotine Cavg was 25% higher on day 5 compared with the first NTS application. Steady-state plasma cotinine was reached by the fourth day of multiple application and, as with nicotine, Cavg and Cmax increased, tmax decreased, and t1/2 did not change compared with single application. The mean ratios of cotinine-to-nicotine area under the curve (AUC) values for single and multiple NTS applications were 14.0 and 15.8, respectively. The pharmacokinetics of nicotine and cotinine were linear between single and multiple NTS applications. The nicotine transdermal systems were generally well tolerated.

Pharmacokinetics of a Transdermal Nicotine Patch Compared to Nicotine Gum

AbstractA new transdermal nicotine delivery system (TBS-NCT)was investigated in laboratory and clinical studies with healthy cigarette smokers. Plasma nicotine concentration time profiles were characterized during and after 24-hr application of three doses of TBS-NCT and during and after a 6-hr regimen of nicotine polacrilex gum. Pharmacokinetic analysis revealed dose-related plasma concentrations for transdermal treatments, bracketing the concentrations obtained from nicotine gum. The TBS-NCT system was also well tolerated during a subsequent 4-week open trial and demonstrated a 40% success rate for smoking cessation during the course of the trial. Overall, the TBS-NCT system appears suitable for once-daily application as an aid in smoking cessation treatments.

Effect of nicotine on the enterochromaffin like cells of the oxyntic mucosa of the rat

Smoking has an unfavourable effect on peptic ulcer disease. The pathophysiological mechanisms underlying this effect are not known. The enterochromaffin like (ECL) cell is the cellular source of histamine participating in the regulation of acid secretion. The ECL cell is under functional and trophic control of gastrin and the vagus nerves. Nicotine may affect acid secretion through vagal pathways. Furthermore, nicotine may also stimulate neuroendocrine cells. The present study examined if chronic nicotine administration could stimulate the function and growth of the ECL cell. Rats inhaled nicotine vapour at a concentration of approximately 6.2 μmol/m 3, 20 hours/day, 5 days/week for 11 weeks. Steady state plasma nicotine concentration was 461.8 (137.5 (SD)) nmol/l. The ECL cell density, histamine content and histidine decarboxylase activity of the oxyntic mucosa were similar to the controls. We also examined the effect of acute nicotine stimulation on the acid output and histamine release from the totally isolated vascularly perfused rat stomach. Nicotine did not stimulate acid secretion or histamine release. Thus no evidence could be provided to support the hypothesis that nicotine exerts its negative effects on peptic ulcer disease by stimulating the ECL cell.

Cigarette-Smoking Affects Platelets and Endothelium in Chronic Hemodialyis Patients

Previous work has shown that cigarette-smoking affects platelets and endothelium in men and women without renal failure. The present study compared 10 male habitual smokers receiving maintenance hemodialysis for chronic renal failure with 11 healthy male habitual smokers before and after controlled cigarette-smoking after a 12-hour period of abstinence. Collagen-induced platelet aggregation was not significantly different in the two groups of men before smoking. The platelet aggregate ratio was lower and the plasma concentration of platelet factor 4 was higher in the dialysis patients than in the healthy men (p < 0.05). Mean or median values before and after cigarette smoking by the dialysis patients were 42 and 62 chart units for collagen-induced platelet aggregation, 0.88 and 0.77 for the platelet aggregate ratio, 6.2 and 8.5 ng/ml for the plasma concentration of platelet factor 4, 0.8 and 1.7 per counting chamber for the endothelial cell count and 4 and 37 ng/ml for the plasma nicotine concentration (each p < 0.01). None of the changes which occurred in the dialysis patients was statistically significantly different from those in the healthy men. We conclude that cigarette-smoking has similar effects on platelets and endothelium in patients receiving maintenance hemodialysis and in healthy controls.

Nicotine Absorption after Pulmonary Instillation

Levels of nicotine in plasma were determined by gas chromatography in eight mongrel dogs after instillation of 0.5mg of nicotine in 100 μL of normal saline at three levels of the tracheobronchial tree: the trachea, a subsegmental bronchus of the right middle lobe, and a subpleural location of the right middle lobe (“distal”). An equivalent dose was given intravenously (iv). Peak of nicotine concentrations in plasma were significantly lower after instillation at the trachea (11.5 ± 4.4 ng/mL) and the subsegmental bronchus (18.2 ± 5.0 ng/mL) than after an iv dose (30.3 ± 10.7 ng/mL); p < 0.05 for each comparison. In addition, the peak concentration after instillation at the trachea was significantly lower than that after instillation at the distal site (22.1 ± 6.2 ng/mL, p < 0.05). Time to peak concentration was significantly longer after tracheal instillation (5.3 ± 3.0 min) than after subsegmental instillation (2.0 ± 0.0 min) or iv infusion (2.0 ± 0.0 min); p < 0.05 for each comparison. Total drug absorbed, half-life, and clearance were equivalent from all four sites. This study demonstrated that quantitative absorption of nicotine from the described lung sites is equivalent to that after an iv dose, with slower absorption and lower peak concentrations from the tracheal site.

Hemodynamic effects of the use of oral snuff.

The hemodynamic effects during rest and exercise of oral snuff were investigated in an open, placebo-controlled study of nine habitual users of oral snuff. Blood pressure, heart rate, and central hemodynamics were measured noninvasively. Plasma concentrations of nicotine, cotinine, norepinephrine, and epinephrine, as well as neuropeptide Y-like immunoreactivity were measured before and after snuff intake during rest and exercise. Snuff intake induced a significant increase in heart rate and blood pressure and a decrease in stroke volume during rest. Hemodynamic changes were unrelated to nicotine or cotinine concentrations. Resting levels of norepinephrine and neuropeptide Y-like immunoreactivity were similar with or without snuff, whereas epinephrine was slightly increased 30 minutes after snuff intake. The exercise-induced increase in norepinephrine and neuropeptide Y-like immunoreactivity did not differ between the days subjects received snuff and the days they received placebo. In contrast, maximum work load was associated with a slight increase in circulating epinephrine after snuff intake. The findings suggest that snuff intake is associated with significant hemodynamic effects during rest but not during exercise. These effects could not be readily explained by activation of the sympathetic nervous system.

Psychopharmacological effects of smoking a cigarette with typical "tar" and carbon monoxide yields but minimal nicotine.

Five male smokers were tested, after 48-h abstention from tobacco-product use, smoking a leading "lights" category cigarette (Control-FTC nicotine yield 0.6 mg) and another cigarette yielding similar amounts of "tar" and carbon monoxide (CO), but only 0.06 mg nicotine (Test). Heart rate (HR) and the electroencephalogram (EEG) were monitored before, during and after the smoking of each cigarette. Other measures obtained included the subjects' puffing and breathing behaviors during smoking, plasma nicotine concentrations, blood carboxyhemoglobin concentrations and expired-air CO. The results indicated no significant differences in the way the subjects puffed and inhaled the two cigarettes and they were therefore assumed to have inhaled similar amounts of particulate matter and gas-phase components. Plasma nicotine concentrations were significantly higher following smoking of the Control cigarette. HR (percent relative change) increased following smoking of either cigarette; however, HR increase was significantly greater following smoking of the Control cigarette. Smoking the Test cigarette had no effect on the EEG. Smoking the Control cigarette produced a significant increase in beta 2 magnitude and a significant decrease in delta magnitude. This indicates that the effects of smoking on the EEG are a function of nicotine absorbed from cigarette smoke upon inhalation and not a function of inhaled particulate matter, CO, or other gas-phase components.

Intravenous nicotine retards transdermal absorption of nicotine: evidence of blood flow--limited percutaneous absorption.

For most drugs delivered by the transdermal route, percutaneous absorption is limited by the rate of release of the drug from the device or by diffusion across the stratum corneum. However, systemic absorption also requires that the drug be taken up by dermal blood vessels. As part of a bioavailability study of a transdermal delivery system, we observed that a concomitant intravenous infusion of nicotine had a marked effect on the absorption kinetics of transdermal nicotine. Plasma concentrations of nicotine rose less rapidly, reached a lower peak, and peaked at a later time, indicating delayed absorption of transdermal nicotine after intravenous nicotine versus after transdermal nicotine administered alone. Nicotine is known to produce cutaneous vasoconstriction. The likely explanation for our observation is that intravenous nicotine constricts dermal blood vessels, thereby limiting percutaneous absorption. Other vasoconstrictor drugs would be expected to retard the absorption of transdermal nicotine and perhaps other transdermal drugs as well.

Nicotine intake and dependence in Swedish snuff takers.

Two studies examining nicotine intake in users of Swedish moist oral snuff are reported. Absorption form a single pinch (2 g) in ten users after overnight abstinence was fairly rapid. The increment in plasma nicotine concentrations averaged 9.9 ng/ml (SD 6.5) after 10 min and peaked at 14.5 ng/ml (SD 4.6) shortly after discarding at 30 min. Among groups of habitual snuff takers (n = 27) and cigarette smokers (n = 35) studied on a day of normal snuffing/smoking, peak blood nicotine levels after use were similar [averaging 36.6 ng/ml (SD 14.4) and 36.7 ng/ml (SD 16.1), respectively], but there was a tendency to higher cotinine levels in the snuffers (399.2 ng/ml versus 306.3 ng/ml). The snuff takers and cigarette smokers reported similar levels of subjective dependence on tobacco. Epidemiological study of Swedish snuff users could clarify whether the cardiovascular risks of tobacco are attributable to nicotine or to other smoke components, as in their case nicotine intake is not accompanied by combustion products.

Randomised controlled trial of nasal nicotine spray in smoking cessation

Studies with nicotine chewing gum and nicotine skin patches indicate that nicotine replacement can help people to give up smoking. The rapidity with which nicotine is absorbed when given as a nasal spray suggests that it might be effective for those for whom the other means of replacement are too slow. The efficacy and safety of a nasal nicotine spray as an adjunct to group treatment for stopping smoking were assessed in a randomised, double-blind, placebo-controlled trial in which 227 cigarette smokers attending the Maudsley Hospital Smokers Clinic received 4 weeks of supportive group treatment plus active nicotine (0·5 mg per shot) or placebo nasal spray. The main end-point was biochemically validated complete abstinence from smoking from the third week of group treatment until the 12-month follow-up. Side-effects were assessed by self-reports and, where necessary, by physical examination. Of subjects assigned to active treatment 26% (n=30) were validated abstinent throughout the year, compared with 10% (n = 11) of those assigned to placebo (relative abstinence rate 2·6, 95% Cl 1·5-4·5, p<0·001). The advantage of the active spray was greatest in the heaviest smokers. Plasma nicotine concentrations from the spray were typically between one-half and three-quarters of baseline smoking levels. Tobacco-withdrawal symptoms, craving for cigarettes, and weight gain in abstinent subjects were reduced by the active spray. Minor irritant side-effects were frequent in both active and placebo sprays, but only 2 subjects had the spray discontinued as a result. No serious adverse effects were encountered. Nasal nicotine spray combined with supportive group treatment is an effective aid to smoking cessation.

The effects of oral smokeless tobacco on the cardiorespiratory response to exercise

The purpose of this investigation was to determine the effects of oral smokeless tobacco (OST) usage on oxygen uptake (VO2), cardiac output (Qc), stroke volume (SV), heart rate (HR), and plasma lactate concentration (Lc) during rest and exercise. Fifteen asymptomatic subjects were recruited from 18 to 33-yr-old male users of OST. Comparisons of the responses of VO2, Qc, SV, HR, and Lc were made between 2.5-g OST and placebo experimental conditions during rest and at 60% and 85% maximal VO2 treadmill exercise. Plasma nicotine concentrations (Nc) were determined by radioimmunoassay. There were significant increases in HR and Lc and a decrease in SV during rest and at 60% and 85% maximal exercise (P less than 0.05). Furthermore, there were no significant differences in maximal HR, Lc, and VO2 (P greater than 0.05). In conclusion, these data indicate that the increased Nc incurred by OST usage increases anaerobic energy production and produces an increased tachycardiac response to a given relative submaximal workload.

Absolute bioavailability of nicotine applied to different nasal regions

The absolute bioavailability of nicotine administered nasally, as drops to the nasal conchae and nasal septum, and as a nasal spray, has been studied in eight healthy volunteers. Single nasal doses of 1 mg nicotine were given and plasma concentrations of nicotine were followed for 6 h. Compared to an intravenous infusion of nicotine, the bioavailability of the nasal administrations was 60 to 75%. The rate of absorption was fast, the maximum concentration being reached after about 10 min. In the present study, there was no significant difference in the rate or extent of absorption between the different nasal treatments.

Acute tolerance to the cardiovascular effects of nicotine

Acute tolerance to cardiovascular effects of nicotine was examined by presenting to male smokers a single administration of each of three different doses of nicotine (0.5, 1.0, 2.0 mg) or a placebo (0 mg) in a brief series of nasal spray boluses to mimic nicotine intake via smoking. Each dose was presented on a separate occasion. Changes in heart rate, systolic and diastolic blood pressure, finger pulse amplitude (peripheral vasoconstriction) and, in a subsample, plasma nicotine concentration were assessed during and after dose administration. Acute tolerance to nicotine was determined by comparing responses at ascending plasma nicotine concentrations during dose administration with the responses at comparable descending plasma concentrations following administration. For each nicotine dose, there was substantial acute tolerance to blood pressure, but less tolerance to heart rate (except for 0.5 mg), and little tolerance to pulse amplitude responses. These findings indicate that cardiovascular adaptation to nicotine during cigarette smoking may be rapid but variable in magnitude depending on the response being measured.

Rapid and sensitive determination of low concentrations of nicotine in plasma by gas chromatography with nitrogen-specific detection

Rapid and sensitive determination of low concentrations of nicotine in plasma by gas chromatography with nitrogen-specific detection

Pharmacokinetics of multiple daily transdermal doses of nicotine in healthy smokers.

The plasma concentration-time profiles and pharmacokinetics were characterized for nicotine and its major metabolite, cotinine, after multiple daily application of a nicotine user-activated transdermal therapeutic system (UATTS) to nine healthy smokers. The volunteers abstained from smoking 24 hr prior to and during the course of the study. A 10-cm2 system (designed to deliver 75 micrograms/cm2/hr) was applied every 24 hr for 5 days, with serial blood samples taken on Days 1 and 5 and after system removal on Day 5. Generally, the nicotine UATTS was well tolerated. Predose nicotine concentrations on Days 3 to 5 indicated that steady state was reached by Day 3. The nicotine pharmacokinetic parameters for Day 1 and Day 5 were similar: the mean (SD) AUC(0-24) values for Days 1 and 5 were 271.7 (50.7) and 311.7 (55.0) ng.hr/ml, the mean (SD) Cmax values were 16.3 (2.6) and 16.8 (2.9) ng/ml, and the median (range) Tmax values on Days 1 and 5 were 12 (9-24) hr and 12 (0-24) hr, respectively. There was only slight or no accumulation of nicotine after multiple dosing as indicated by the Day 5 to Day 1 AUC and Cmax ratios of 1.15 (0.09) and 0.98 (0.06), respectively. Overall, the UATTS system maintained relatively constant plasma nicotine concentrations and is suitable for once-daily application.

Effect of ulcerative colitis and smoking on rectal blood flow.

Rectal blood flow was measured by laser doppler flowmetry over 60 minutes in eight patients with colitis in remission and eight healthy male non-smokers. Ten smokers were also examined on two occasions, one of which included smoking a cigarette. Plasma nicotine concentrations were measured in smokers. All subjects showed a pronounced fall in rectal blood flow in the first 30 minutes and patients with colitis had significantly higher values compared with smokers (p less than 0.002; p less than 0.04) and non-smokers (p less than 0.007; p less than 0.002) during the first and second 30 minutes respectively. Values in smokers and non-smokers were similar, but smoking a cigarette was associated with a significant fall in blood flow (p less than 0.04) and this change was inversely related to the rise in plasma nicotine concentration (r = -0.63; p less than 0.05). The findings may be relevant to the association between colitis and the smoking history.

Non-smokers show acute tolerance to subcutaneous nicotine

Plasma nicotine concentrations following subcutaneous (SC) injection were measured in six subjects who included three life-long nonsmokers. On average, a peak plasma level of 8.5 ng/ml (SD = 3.1) was reached 15 min after the mean dose of 13.25 micrograms/kg nicotine base. Subjective effects were reported by five subjects. The peak heart rate response (mean boost 11 beats per min at 10 min) preceded and was already declining by the time plasma nicotine concentrations peaked. Hysteresis plots showed clear evidence of acute nicotine tolerance in subjects who had never smoked, indicating that acute tolerance is not an acquired phenomenon. The acquisition by smokers of chronic tolerance to nicotine has not yet been systematically demonstrated. Reliable dose-response studies in smokers and nonsmokers are needed, and use of the SC route for this purpose is discussed.

Increased hepatic nicotine elimination after phenobarbital induction in the conscious rat

Elimination parameters of [ 14C]nicotine in conscious rats receiving nicotine (0.3 mg/kg) either intravenously or orally were studied. The oral availability of unchanged nicotine, derived by comparison of the respective areas under the concentration vs time curves (AUC), was 89%, indicating low hepatic extraction ratios of about 10%. Pretreatment of rats with phenobarbital (PB) markedly increased hepatic first-pass extraction of nicotine. The oral availability of unchanged nicotine in plasma dropped to 1.4% of the corresponding values obtained from PB-treated rats receiving nicotine iv. After PB pretreatment, the clearance of iv nicotine was increased approximately twofold over controls, much less than the observed more than ninefold increase of hepatic first-pass extraction. It is assumed that extrahepatic metabolism contributed significantly to the rapid removal of nicotine from the plasma. The elimination of cotinine, originating from nicotine administered either po or iv, was significantly increased by PB pretreatment, as determined by the ratio of corresponding AUCs. The pattern of nicotine metabolites in urine also indicated an increase in the rate of cotinine metabolic turnover. The amount of norcotinine in the organic extract of urine paralleled PB microsomal enzyme induction. The ratio between urinary concentrations of the normetabolite and cotinine correlated strongly with the PB-induced state of rat liver. This may be a suitable indicator of PB-inducible hepatic cytochrome P450 isoenzyme(s). Since smoking habits in man are feedback-regulated by nicotine plasma concentrations, a similar increase of nicotine elimination by microsomal enzyme induction in man may be of relevance for tobacco consumption.

Population characteristics and cigarette yield as determinants of smoke exposure

Relationships of population characteristics, smoking history, and cigarette yield with smoke exposure as measured by peripheral blood concentrations of thiocyanate, carboxyhemoglobin, nicotine and cotinine were sought in 170 male smokers. This population of smokers had significant elevations of serum thiocyanate, blood carboxyhemoglobin and plasma nicotine and cotinine concentrations as compared with an equal number of age- and sex-matched nonsmokers and these concentrations correlated significantly with past 24-hour cigarette consumption. Although the nicotine yield of the cigarette correlated significantly with plasma cotinine and marginally with plasma nicotine, the reduction in plasma nicotine and cotinine was not proportionate to the reduced yield of the cigarettes, suggesting that smokers partially compensate for the lower yields of their cigarettes. Blood levels of carboxyhemoglobin, nicotine and cotinine were also significantly associated with the weight of the subjects, presumably due to the relationship between weight and the volume of distribution. Univariate and multiple regression analyses provided evidence that coffee and alcohol consumption and years smoked also may be important determinants of smoke exposure.