Varenicline [Chantix, Champix ], a partial agonist at nicotinic receptors, is our most effective aid to smoking cessation. In clinical trials, more patients achieved abstinence with varenicline than with bupropion SR or the nicotine patch. Estimated abstinence rates after 6 months were 33.2% with varenicline, CQ patches are left in place for 24 hours and then immediately
replaced with a fresh one. In contrast, Nicorette patches are applied in the morning and removed 16 hours later at bedtime.
This pattern is intended to simulate nicotine dosing produced by smoking.
Most patients begin with a large patch and then use progres- sively smaller patches over several weeks. Certain patients (those with cardiovascular disease, those who weigh less than 100 pounds, or those who smoke less than one-half pack of cigarettes a day) should begin with a smaller patch.
Adverse effects are generally mild. Short-lived erythema, itching, and burning occur under the patch in 35% to 50% of users. In 14% to 17% of users, persistent erythema occurs, lasting up to 24 hours after patch removal. Patients who experience severe, persistent local reactions (e.g., severe erythema, itching, edema) should discontinue the patch and contact a physician or nurse practitioner.
Nicotine Inhaler
The nicotine inhaler [Nicotrol Inhaler] differs from other NRT products in that it looks much like a cigarette. Puffing on it delivers the nicotine. Because of this delivery method, using the inhaler can substitute for the hand-to-mouth behavior of smoking. In addition to nicotine, the inhaler contains menthol, which is intended to create a sensation in the back of the throat reminiscent of that caused by smoke. Like other forms of NRT, the inhaler doubles cessation success rates.
The nicotine inhaler consists of a mouthpiece and a sealed tubular cartridge. Inside the cartridge is a porous plug containing 10 mg of nicotine. Inserting the cartridge into the mouthpiece breaks the seal. Puffing on the mouthpiece draws air over the plug and thereby draws nicotine vapor into the mouth. Most of the nicotine is absorbed through the oral mucosa—not in the lungs. As a result, blood levels rise slowly and peak 10 to 15 minutes after puffing stops. Blood levels are less than half those achieved with cigarettes. Each cartridge can deliver 300 to 400 puffs. Benefits are greatest with frequent puffing over 20 minutes, after which the cartridge is discarded. Patients generally use 6 to 16 cartridges a day for 3 months, and then taper off over 2 to 3 months.
Adverse effects are mild. The most frequent are dyspepsia, coughing, throat irritation, oral burning, and rhinitis. The inhaler should not be used by patients with asthma. Because the cartridges contain dangerous amounts of nicotine, they should be kept away from children and pets.
Nicotine Nasal Spray
Nicotine nasal spray [Nicotrol NS] differs from other NRT formulations in that blood levels of nicotine rise rapidly after each administration, thereby closely simulating smoking.
Because nicotine levels rise rapidly, the spray provides some of the subjective pleasure associated with cigarettes. As with other forms of NRT, the spray doubles smoking cessation rates.
The spray device delivers 0.5 mg of nicotine per activation.
Two sprays (one in each nostril) constitute one dose and are equivalent to the amount of nicotine absorbed from one cigarette.
Treatment should be started with 1 or 2 doses per hour—and never more than 5 doses per hour, or 40 doses a day. After 4 to 6 weeks, dosing should be gradually reduced and then stopped.
Quitting success with the spray has been good news and bad news. The good news, as reported in one study, is that
revealed a similar risk in patients without cardiovascular disease.
Fortunately, cardiovascular risk appears to be small—much smaller than the risk posed by smoking. Nonetheless, patients should be warned about cardiovascular risk and instructed to notify the prescriber if they experience new or worsening cardiovascular symptoms and to seek immediate medical attention if symptoms of myocardial infarction appear.
Owing to concerns about unpredictable physical and psy- chiatric adverse effects, authorities in the United States have banned the use of varenicline by truck drivers, bus drivers, airplane pilots, and air traffic controllers.
Drug Interactions
Varenicline does not affect the major components of the cytochrome P450 system. Studies with bupropion, transdermal nicotine, digoxin, warfarin, cimetidine, and metformin have shown no significant interactions. To date, no clinically sig- nificant interactions with other drugs have been reported.
Preparations, Dosage, and Administration
Varenicline is formulated in 0.5- and 1-mg tablets. To reduce nausea, each dose should be taken after eating and with a full glass of water. Dosing should begin 8 to 35 days before smoking is stopped. Titrate dosage as follows: on days 1 through 3, take 0.5 mg once daily; on days 4 through 7, take 0.5 mg twice daily; then take 1 mg twice daily for 12 weeks. If abstinence has been achieved, an additional 12 weeks of treatment is recommended. Patients who fail to stop smoking after the initial 12 weeks or who relapse after a full course of treatment should be encouraged to try again when conditions are deemed favorable. Patients with severe renal impairment should begin therapy at 0.5 mg once daily and increase to 0.5 mg twice daily if tolerated. Patients with end-stage renal disease undergo- ing dialysis should take a maximum of 0.5 mg once daily.
Dosage adjustment is unnecessary in patients with mild to moderate renal impairment.
Products That Are Not Recommended
According to Treating Tobacco Use and Dependence: 2008 Update, there is insufficient proof to recommend the following drugs as aids to smoking cessation: naltrexone, silver acetate, beta blockers, benzodiazepines, and antidepressants other than bupropion SR, including the selective serotonin reuptake inhibitors.
Although not mentioned in the 2008 Update, electronic cigarettes, or e-cigarettes, should be avoided. E-cigarettes are battery-powered, cigarette- shaped devices that release a puff of vaporized nicotine, sometimes together with flavoring and other chemicals. According to analyses conducted by the FDA, the amount of nicotine per puff can vary widely, and the vapor may contain trace amounts of diethylene glycol and/or other contaminants.
E-cigarettes are promoted on the Internet as aids to quit smoking, but are not FDA-approved for this use (or any other use, for that matter). At this writing, the FDA is attempting to regulate e-cigarettes as drug-delivery devices (which seems reasonable), but is meeting resistance from the courts. The bottom line:
Because the dose of nicotine with e-cigarettes is unpredictable and because data on safety and efficacy are lacking, the use of e-cigarettes should be discouraged—especially since products of known safety and efficacy are available.
24.2% with bupropion SR, and 23.4% with a nicotine patch.
The most common side effect is nausea. The most troubling side effects are psychologic changes. Unlike bupropion SR and NRT, varenicline does not cause weight loss.
Mechanism of Action
Varenicline acts as a partial agonist at a subset of nicotinic receptors—known as alpha4beta2 nicotinic receptors—whose activation promotes release of dopamine, the compound that mediates the pleasurable effects of nicotine. Compared with nicotine, varenicline binds alpha4beta2 receptors with greater affinity. Hence, when varenicline is present, access of nicotine to these receptors is blocked. Because varenicline is a partial agonist, receptor binding results in mild activation, which promotes some dopamine release and thereby helps reduce both nicotine craving and the intensity of withdrawal symptoms.
At the same time, the presence of varenicline prevents intense receptor activation by nicotine itself and thereby blocks the reward that nicotine can provide.
Pharmacokinetics
Varenicline is readily absorbed from the GI tract, both in the presence and absence of food. Plasma levels peak about 4 hours after dosing. Binding to plasma proteins is low (20%).
Metabolism is minimal, and hence most of each dose (92%) is excreted unchanged in the urine. The plasma half-life is 17 to 24 hours. Moderate to severe renal impairment delays excretion and increases varenicline blood levels.
Adverse Effects
In clinical trials, dose-dependent nausea was the most common adverse effect, occurring in 30% to 40% of users. Nausea is mild to moderate initially and becomes less severe over time.
Other common reactions include sleep disturbances, headaches, abnormal dreams, constipation, dry mouth, flatulence, vomiting, and altered sense of taste. Mild physical dependence develops, but there have been no reports of abuse or addictive behavior.
Rarely, varenicline has been associated with seizures, diabetes, dizziness, disturbed vision, and moderate and severe skin reac- tions, although a causal relationship has not been established.
Early postmarketing reports indicated that varenicline can cause serious neuropsychiatric effects, including mood changes, erratic behavior, and suicidality. At that time, the FDA placed a black box warning on varenicline for this reason. In 2016, the FDA removed the warning, as these cases were deemed more rare than initially expected. Nevertheless, all patients should be advised to contact their prescriber if they experience a significant change in behavior or mental status. Varenicline should be used with caution in patients with a history of psychiatric disease.
In 2011, the FDA warned that varenicline can increase the risk of cardiovascular events (e.g., angina pectoris, peripheral edema, hypertension, nonfatal myocardial infarction) in patients with stable cardiovascular disease. After that, a Canadian study
KEY POINTS
■ Cigarette smoking kills about 480,000 American adults each year, making smoking the largest preventable cause of premature death.
■ The principal cause of death among smokers is lung cancer, followed closely by heart disease.
■ Nicotine in cigarette smoke is absorbed from the lungs, whereas nicotine in cigar smoke and smokeless tobacco is absorbed from the mouth.
■ By activating nicotinic receptors in sympathetic ganglia and the adrenal medulla, nicotine causes vasoconstriction, increases heart rate, and increases force of ventricular contraction, thereby elevating blood pressure and increasing cardiac work. These effects underlie cardiovascular deaths.
■ Through actions in the CNS, nicotine increases alertness, facilitates memory, improves cognitive function, reduces aggression, and suppresses appetite. In addition, by promot- ing the release of dopamine, nicotine activates the same pleasure circuit involved in addiction to cocaine, amphet- amines, and opioids.
■ Although tolerance develops to some effects of nicotine, very little tolerance develops to cardiovascular effects:
Veteran smokers continue to experience an increase in blood pressure and cardiac work whenever they smoke.
■ Nicotine causes physical dependence. Withdrawal is characterized by craving, nervousness, restlessness, irritabil- ity, impatience, increased hostility, insomnia, impaired concentration, increased appetite, and weight gain.
■ Nicotine for replacement therapy is available in five FDA- approved delivery systems: chewing gum, lozenges, transdermal patches, nasal spray, and an inhaler.
■ Although nicotine is harmful during pregnancy, NRT is probably safer than smoking, and hence use of NRT during pregnancy is worth consideration.
■ Bupropion SR [Zyban, Buproban], which blocks reuptake of norepinephrine and dopamine, helps smokers quit by reducing nicotine craving and withdrawal symptoms.
■ Varenicline [Chantix, Champix ] acts as a partial agonist at a specific subset of nicotinic receptors and thereby reduces nicotine craving and withdrawal symptoms. In addition, the drug blocks access of nicotine itself to those receptors and thereby prevents nicotine from producing pleasurable effects.
■ The most effective drug/therapies for smoking cessation are varenicline alone and the nicotine patch combined with PRN nicotine nasal spray or nicotine gum.
■ With the aid of counseling and pharmacotherapy, about 30% of smokers who attempt to quit can expect to achieve long-term abstinence.
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