Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

ATC Code: N07B A01
Pharmacotherapeutic group: Drugs used in nicotine dependence.

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. 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 lozenge replaces part of the nicotine that would have been administrated via tobacco and reduces the intensity of the withdrawal symptoms and smoking urge.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
The absorbed amount of nicotine depends on the amount released into the mouth and absorbed through the buccal mucosa.
The main part of nicotine in Nicotinell lozenges 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 firstpass effect in the liver, the systemic bioavailability of nicotine is low.
Consequently, in the treatment with Nicotinell lozenges 1mg the high and quick systemic nicotine concentration, as seen when smoking, is rarely obtained.
The peak value for the plasma concentration of Nicotinell lozenges 1 mg 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 peak value for the plasma concentration of Nicotinell lozenges 2 mg after a single dose is approximately 7.0 ng per ml and the maximal concentration at steady state (one 2 mg lozenge/hour for 12 hours) is approximately 22.5 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 48 minutes following sucking of a single lozenge and after about 30 minutes at steady state.

Distribution
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.

Metabolsim
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).

Elimination
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.


Studies have demonstrated that there is a linear dose-concentration proportionality between the 1 mg and 2 mg Nicotinell lozenges for both Cmax and AUC. The Tmax are similar for both strengths.