Varenicline: A Helping Hand for Smokers to Quit SmokingCorrespondence Address :
Jimmy Jose. Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576 104, Karnataka, India. Tel.: 91-820-2922403; fax no: 91-820-2571998. e-mail: firstname.lastname@example.org
Tobacco smoking is one of the leading causes of preventable diseases and deaths worldwide and accounts for 8.8% of global deaths every year (1). Various disease conditions have also been linked with cigarette smoking, including cardiovascular disease, chronic obstructive pulmonary disease, many cancers (lung, mouth, oesophageal, bladder, pancreatic, gastric, cervical, and others) and pregnancy-related complications (2). Smoking cessation confers major health benefits for men and women of all ages.
The basis of effective pharmacotherapy for nicotine addiction is to mimic or replace the effects of nicotine. Different classes of drugs for tobacco dependence include nicotinic receptor agonists and dopaminergic-noradrenergic reuptake inhibitors such as bupropion (3).
Compounds that act as nicotinic alpha-4-beta-2 acetylcholine receptors (4β2 nAChR) partial agonists and simultaneously block the action of nicotine (4),(5) offer a particularly promising new approach to helping smokers quit. Varenicline is a new oral smoking-cessation medication, which has this property and was approved for use on 10 May 2006. Varenicline (6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h](3)benazaprine) is a partial agonist of the nicotinic alpha-4-beta-2 acetylcholine receptors (nAChRs).
Mechanism of Action
Varenicline is a partial agonist that binds to 4β2 nAChR with a greater affinity than nicotine. These specific nAChRs are postulated to be responsible for increased dopamine release when activated by nicotine, leading to dependence on the nucleus accumbens and prefrontal cortex of brain. During smoking cessation, due to nicotine abstinence, dopamine levels become low, which is associated with the cravings that often lead patients to relapse. Varenicline blocks nicotine from binding and stimulates receptor-mediated activity and thus release of dopamine, but to a lesser degree than nicotine.
These nicotinic receptor partial agonists’ action provides a low-to-moderate level of dopamine stimulation to reduce craving and withdrawal symptoms, and the lower level of dopamine release may be less dependence forming than the intermittent spikes in dopamine release by inhaled nicotine (4).
Varenicline is rapidly absorbed across the gastric mucosa, reaching a peak plasma concentration in about 4 hours. With daily dosing, plasma concentrations reach a steady state after 4 days. Varenicline has a half-life of 17–24 hours; it is minimally metabolised and is excreted virtually unchanged by the kidneys (92%). The two minor metabolites are varenicline N-cabamoyl glucuronide and 2-hydroxyvarenicline, which account for 3% and 4%, respectively. Pharmacokinetic profiles in both smokers and non-smokers do not differ (6).
The effect of varenicline was demonstrated in various studies. A phase 2 multi-centred, randomised, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of three varenicline doses compared with sustained-release (SR) buproprion for a period of 7 weeks. Subjects were randomised to receive 0.3 mg of varenicline daily (n = 127) and 1.0 mg of varenicline daily (n = 128), 1.0 mg of varenicline twice daily (n = 127) for 6 weeks plus placebo for 1 week, 150 mg of SR bupropion twice daily for 6 weeks plus placebo for 1 week, or placebo. The continuous quit rates (CQR) were significantly higher for the 1.0 mg of varenicline-daily group (37.3%) and 1.0 mg of varenicline-twice-daily group (48.0%), compared with both placebo (17.1%) and bupropion (33.3%). Varenicline 1.0 mg was also reported to significantly reduce both craving and smoking satisfaction versus placebo. During this tr
Varenicline is a novel smoking-cessation aid approved by the US FDA in 2006, which has a unique mechanism of action compared with the available first-line agents. Studies have demonstrated that varenicline is more effective than bupropion and placebo in CQR and continued abstinence rates up to 1 year. Varenicline has the potential advantage of having fewer nicotine-related side effects. But there are no sufficient data to compare its effects with nicotine replacement therapy.
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