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Pharmacology: Pharmacodynamics: Abrupt cessation of the established, regular use of tobacco-containing products results in the characteristic syndrome, with withdrawal symptoms including cravings (urges to smoke) as described as follows.
Regardless of the means used, a variety of symptoms are known to be associated with quitting habitual tobacco use. These include emotional or cognitive effects such as dysphoria or depressed mood; insomnia; irritability, frustration or anger; anxiety; difficulty concentrating, and restlessness or impatience. There may also be physical effects such as decreased heart rate; increased appetite or weight gain, dizziness or presyncopal symptoms, cough, constipation, gingival bleeding or apthous ulceration, or nasopharyngitis. In addition, and of clinical significance, nicotine cravings may result in profound urges to smoke.
Clinical studies have shown that nicotine replacement products can help smokers abstain from or reduce their smoking by relieving these withdrawal symptoms.
Patch treatment mimics the fluctuations of nicotine over the day in smokers, with no nicotine administration during sleep. Daytime nicotine patch treatment does not give the nicotine induced sleep disturbances seen with nicotine administration during sleep.
Pharmacokinetics: All patches are labelled by the average amount of nicotine absorbed by the average patient over 16 hours.
Representative mean values of Cmax for the patches are presented in the table as follows: (See Table 1.)
Click on icon to see table/diagram/imageThe calculated peak plasma levels are in the same range as true measured peak plasma concentrations: 11 ng/ml for the 10mg patch and 24.2ng/ml for the25mg patch. Interpolation yields a peak plasma concentration of 15.4ng/ml for the 1 5mg 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 is approximately 3 hours. The major eliminating organ is the liver, although the lungs and brain also metabolise nicotine to a small extent. The enzyme primarily involved in biotransformation of nicotine is CYP2 A6. Seventeen 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 considered to be low, about 5%. Therefore, changes in nicotine binding from the 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 terminal half-life of 14 to 20 hours; the plasma concentrations of cotinine exceed those of nicotine by 10-fold.
The primary urinary metabolites are cotinine (10-12% of the dose) and trans-3-hydroxy-cotinine (28-37% of the dose). About 10-15% 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 haemodialysis.
The pharmacokinetics of nicotine is unaffected in cirrhotic patients with mild liver impairment (Child-Pugh score 5) and nicotine clearance is decreased by about40-500/o in cirrhotic patients with moderate liver impairment (Child-Pugh 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.
