Varenicline: The Newest Agent for Smoking Cessation

Lisa A. Potts; Candice L. Garwood


Am J Health Syst Pharm. 2007;64(13):1381-1384. 

In This Article

Pharmacology of Nicotine

To understand the pharmacology of varenicline, it is necessary to understand the pharmacology of nicotine and its addiction. Nicotine is distilled from the cigarette as it is smoked and readily absorbed through the alveolar surface of the lung, rapidly reaching circulation through the extensive capillary network within the lung. It is estimated that nicotine rapidly reaches the brain within 11 seconds after inhalation.[6] Nicotine is the primary chemical in tobacco that contributes to tobacco dependency. Nicotine affects many neurotransmitters, but dopamine seems to be most responsible for the major addictive properties of nicotine. Nicotine from tobacco directly stimulates the acetylcholine receptors on dopamine-containing neurons, which are involved in the reinforcing centers of the brain, as a part of the mesolimbic system. The stimulation of these acetylcholine receptors is responsible for the overflow of dopamine in the reward centers of the brain, resulting in extracellular dopamine within the nucleus accumbens and an increased firing of dopaminergic neurons.[7] Many subtypes of acetylcholine receptors are associated with nicotine addiction. Acetylcholine-receptor subtypes, such as α4ß2, are ligand-gated ion channels found on the dopaminergic neurons and on the γ-aminobutyric acid (GABA)-containing cells. These receptors are thought to play a principal role in the mediation of nicotine addiction.[5,8] Unlike acetylcholine, which is degraded quickly by acetylcholinesterase, nicotine remains active at the α4ß2 receptor sites for a prolonged period of time. While prolonged stimulation by most entities usually causes receptor down-regulation, nicotine stimulation at the acetylcholine receptors causes receptor up-regulation. This up-regulation desensitizes acetylcholine receptors, resulting in physical dependence, tolerance, and withdrawal symptoms, thereby adding to the propensity for nicotine addiction.[8] Smokers who try to quit unaided experience symptoms of withdrawal, such as depression, insomnia, irritability, anxiety, difficulty concentrating, restlessness, weight gain, increased appetite, and decreased heart rate. Uncomfortable withdrawal symptoms reinforce the desire to smoke, perpetuating the dependency cycle.[9]


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