Chemical formula: C₁₀H₁₄N₂ Molecular mass: 162.232 g/mol PubChem compound: 89594
Nicotine, the primary alkaloid in tobacco products and a naturally occurring autonomous substance, is a nicotine receptor agonist in the peripheral and central nervous systems and has pronounced CNS and cardiovascular effects.
Nicotine, the primary alkaloid in tobacco products and a naturally occurring autonomic substance, is a nicotine receptor agonist in the peripheral and central nervous system.
Nicotine has no therapeutic uses except as replacement therapy for the relief of abstinence symptoms in nicotine-dependent smokers.
On consumption of tobacco products, nicotine has proven to be addictive, resulting in craving and other withdrawal symptoms when administration is stopped. This craving and these withdrawal symptoms include a strong urge to smoke, dysphoria, insomnia, irritability, frustration or anger, anxiety, concentration difficulties, agitation and increased appetite or weight gain.
The absorbed amount of nicotine depends on the amount released into the mouth and absorbed through the buccal mucosa.
The main part of nicotine is absorbed through the buccal mucosa. A proportion, by the swallowing of nicotine-containing saliva, reaches the stomach and intestine where it is inactivated. Due to the first-pass effect in the liver, the systemic bioavailability of nicotine is low. Consequently, in the treatment with nicotine the high and quick systemic nicotine concentration, as seen when smoking, is rarely obtained.
Distribution volume after intravenous administration of nicotine is approximately 2-3 1/kg and the half-life is 2 hours. Nicotine is metabolised principally in the liver and the plasma clearance is approximately 1.2 l/min; nicotine also metabolises in the kidney and lungs. Nicotine crosses the blood-brain barrier.
More than 20 metabolites have been identified, all believed to be less active than nicotine. The main metabolite is cotinine which has a half-life of 15-20 hours and with approximately 10 times higher plasma concentration than nicotine. Nicotine’s plasma-protein binding is less than 5%. Changes in nicotine binding from the use of concomitant medicinal products or due to altered disease state are not expected to have significant effect on nicotine kinetics. The main metabolite in urine is cotinine (15% of the dose) and trans-3-hydroxy cotinine (45% of the dose).
About 10% of the nicotine is excreted unchanged. Up to 30% may be excreted with urine in increased diuresis and the acidity under pH 5.
The peak value for the plasma concentration of nicotine after a single dose is approximately 4 ng per ml and the maximal concentration at steady state is approximately 10.6 ng per ml (average plasma concentration of nicotine after smoking one cigarette is 15-30 ng per ml). Peak plasma concentration is reached after about 45 minutes following sucking of a single lozenge and after about 30 minutes at steady state.
The patches are labelled by the average amount of nicotine released over 16 hours.
A linear relationship exists between released amount of nicotine (dose) and plasma levels of nicotine over the therapeutic dose range, 10-25 mg/16 hours The mean peak plasma levels of nicotine (Cmax) achieved are calculated to:
| Dose nicotine (mg/16 hours) | Cmax (ng/ml) |
|---|---|
| 10 | 15.5 |
| 10 | 25 |
| 15 | 26.5 |
The calculated peak plasma levels are in the same range as true measured peak plasma concentrations: 11 ng/mL for the 10 mg patch and 25 ng/mL for the 25 mg patch. Interpolation yelds a peak plasma concentration of 16 ng/mL for the 15 mg patch.
The maximum level of plasma concentration after administration is reached after approximately 9 hours (tmax). The plasma peak is in the afternoon/evening when the risk of relapse is highest.
The volume of distribution of nicotine is about 2 to 3 L/kg and the half-life approximately 3 hours. The major eliminating organ is the liver, and average plasma clearance is about 70 L/hour. The kidney and lung also metabolise nicotine. More than 20 metabolites of nicotine have been identified, all of which are believed to be less active than the parent compound.
Plasma protein binding of nicotine is less than 5%. Therefore, changes in nicotine binding from use of concomitant drugs or alterations of plasma proteins by disease states would not be expected to have significant effects on nicotine kinetics.
The primary metabolite of nicotine in plasma, cotinine, has a half-life of 15 to 20 hours and concentrations that exceed nicotine by 10-fold.
The primary urinary metabolites are cotinine (12% of the dose) and trans-3-hydroxy-cotinine (37% of the dose). About 10% of nicotine is excreted unchanged in the urine.
Progressive severity of renal impairment is associated with decreased total clearance of nicotine. Raised nicotine levels have been seen in smoking patients undergoing hemodialysis.
The pharmacokinetics of nicotine is unaffected in cirrhotic patients with mild liver impairment (Child score 5) and nicotine clearance is decreased in cirrhotic patients with moderate liver impairment (Child score 7).
A minor reduction in total clearance of nicotine has been demonstrated in healthy elderly patients, however, not justifying adjustment of dosage.
Plasma nicotine concentrations show dose proportionality for the three patch doses.
The following information is based on data derived from nicotine 10mg inhalator:
Nicotine given i.v. has a volume of the distribution of 2 or 3 l/kg with a half life of 1-2 hours. Average plasma clearance is about 1-2 l/min mainly in the liver. More than 20 metabolites are known, all less active than nicotine: cotinine, with a half life of 15-20 hours and concentrations ten times that of nicotine is the main one.
Plasma binding of nicotine below 5% means significant displacement of drugs or nicotine is unlikely. Nicotine is excreted in the urine principally as cotinine (15%), 3-hydroxycotinine (45%), nicotine (10%).
Most inhaled nicotine is absorbed via the buccal mucosa. Forced rapid inhalation over 20 minutes, results in a wide range of nicotine doses (1.3-6.2 mg). On average 2 mg of nicotine is released during 20 minutes of intensive use. Uptake is slow and free of the peaks resultant from cigarette smoking. In normal use, plasma levels of 6-8ng/ml nicotine are obtained – about one third that from smoking, which is equivalent to an hourly 2mg nicotine chewing gum.
When used like a cigarette the inhalator on average delivers 1mg in 80 puffs (e.g. 8 puffs per minute for 10 minutes). When used in this way this results in, a degree of nicotine substitution of about 50% compared to hourly smoking. Peak plasma levels occur within 15 minutes after the end of inhalation. Forced rapid inhalation for 20 minutes per hour for 12 hours achieved steady state plasma levels of 20-25ng/ml.
Ambient temperature affects volatilisation of nicotine, the biologically available dose rising by 35% for each 10°C above 20°C. Use below 15°C is not recommended.
Because the pattern of use if decided by the patient up to a limit of 6 cartridges per day to relieve craving, therapeutic levels of nicotine are individual, dictated by the level of dependence.
Nicotine was positive in some in vitro genotoxicity tests but there are also negative results with the same test systems. Nicotine was negative in standard in-vivo tests.
Animal experiments have shown that nicotine induces post-implantation loss and reduces the growth of foetuses.
The results of carcinogenicity assays did not provide any clear evidence of a tumorigenic effect of nicotine.
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