Bupropion
Buproban™, Budeprion™ SR, Wellbutrin®, Wellbutrin® SR, Wellbutrin® XL, Zyban ®
Classification:
Toxicology Agents
 Description: Bupropion is an oral antidepressant drug of the aminoketone class. It is not a tricyclic antidepressant and is unrelated to other known antidepressants. Bupropion has been well tolerated in patients experiencing orthostatic hypotension with tricyclic antidepressant drugs, however, it shows a greater potential for causing seizures than other antidepressants. Bupropion is also indicated for use as an aide to smoking cessation, and is used off-label for addiction to smokeless tobacco. The drug has been shown to help people with COPD quit smoking when combined with behavior modification. Bupropion is also used off-label for multiple neurological/psychological uses, including ADHD and neuropathic pain. Bupropion was originally approved by the FDA in December 1985 but was removed from marketing for several years due to concern over drug-induced seizures. It was reintroduced in July 1989 as an antidepressant (i.e., Wellbutrin®), and later in a sustained-release formulation (i.e., Wellbutrin® SR). Another sustained-release oral dosage form, Zyban ®, was approved for the management of smoking cessation on May 14, 1997. Zyban ® received an additional indication for use in combination with nicotine transdermal systems (NTS) for treating the symptoms of smoking cessation in 1999. A controlled-release formulation (Wellbutrin® XL) was FDA-approved on August 29, 2003 as a once-daily formulation for major depression in adults. On October 15, 2004 the FDA directed manufacturers of all antidepressants to include a Black Box warning, expanded warning statements, and clinical trial results detailing the increased risk of suicidality in children and adolescents. A Patient Medication Guide (MedGuide) will also accompany all prescriptions for antidepressants. The FDA is currently assessing the risk of suicidality in adults taking antidepressants and a final report is expected by mid- to late 2006.
Mechanism of Action: The action of bupropion is not fully understood. Bupropion selectively inhibits the neuronal reuptake of dopamine and is significantly more potent than either imipramine or amitriptyline in this regard. Actions on dopaminergic systems, however, require doses higher than those needed for a clinical antidepressant effect. The blockade of norepinephrine and serotonin reuptake at the neuronal membrane is weaker for bupropion than for tricyclic antidepressants. CNS-stimulant effects are dose-related. Bupropion does not inhibit monoamine oxidase. Bupropion does exhibit moderate anticholinergic effects, and produces a sensation of mild local anesthesia on the oral mucosa. Antidepressant activity is usually noted within 1-3 weeks of intitiation of bupropion treatment; full effects may not be seen until 4 weeks of therapy.
The mechanism by which bupropion enhances the ability to abstain from tobacco smoking is unknown, but is probably related to inhibition of noradrenergic or dopaminergic neuronal uptake. The resultant increase in norepinephrine may attenuate nicotine withdrawal symptoms. Increased dopamine at neuronal sites may reduce nicotine cravings and the urge to smoke. Because the onset of activity is usually after 1 week of treatment, patients should start bupropion 1-2 weeks prior to their chosen smoking ‘quit-day’. In smoking cessation, the ability to abstain from smoking continuously through the seventh week of bupropion therapy is associated with maintenance of long-term abstinence. Patients who have not stopped smoking by the seventh week of treatment are generally considered non-responsive to bupropion treatment.
Pharmacokinetics: Bupropion is administered orally. Based on animal data, the oral bioavailability of bupropion is roughly 5-20%; the oral bioavailability in humans has not been determined. Bupropion XL has been found to be bioequivalent to both the regular-release and sustained-release tablet formulations of bupropion. Peak plasma concentrations are achieved within 1.5 hours after administration of regular-release bupropion and within 3 hours after administration of sustained-release formulations. Food increases the rate and extent of bupropion absorption slightly, but these changes are not clinically significant. Plasma bupropion concentrations are dose-proportional following single doses of 100 to 250 mg; however, it is not known if the proportionality between dose and plasma levels are maintained in chronic use. The drug readily crosses the blood-brain barrier. Plasma protein binding is about 84%. Steady-state concentrations of bupropion and its metabolites are achieved in 5-8 days; antidepressant effects have an onset of roughly 1-3 weeks.
Metabolism takes place in the liver, producing several metabolites; the 3 major active metabolites are hydroxybupropion, threohydrobupropion, and erythrohydrobupropion. Cytochrome P450 isoenzyme CYP2B6 is involved in forming hydroxybupropion, the major metabolite, previously known as morpholinol. All active metabolites are present in higher concentrations in the plasma than the parent compound. In mice, hydroxybupropion appears to have potency similar to bupropion; the other metabolites are one-tenth to one-half as potent. Bupropion appears to induce its own metabolism, but this does not appear to be clinically significant. The terminal elimination half-life of regular-release bupropion is approximately 14 hours with a range of 8-24 hours. The terminal elimination half-life of the sustained-release product is roughly 21 hours. Half-lives for hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion are 20 hours, 33 hours, and 37 hours, respectively.
Less than 1% of bupropion is excreted unchanged in the urine. Over 60% of the drug is excreted as metabolites in the urine within 24 hours; over 80% is eliminated in 96 hours. Less than 10% of metabolites are excreted in the feces.
Special populations: The effect of renal dysfunction has not been determined, but it is likely that renal impairment reduces the elimination of active metabolites and may result in accumulation. Half-lives of bupropion and/or its major metabolites are prolonged in patients with alcoholic liver disease, cirrhosis, or left-ventricular dysfunction. In patients with hepatic disease, the mean AUC increased by roughly 1 1/2-fold for hydroxybupropion and roughly 2 1/2-fold for threo/erythrohydrobupropion. The median Tmax was observed 19 hours later for hydroxybupropion and 31 hours later for threo/erythrohydrobupropion. The mean half-lives for hydroxybupropion and threo/erythrohydrobupropion were increased 5- and 2-fold, respectively, in patients with severe hepatic cirrhosis compared to healthy volunteers. Dosage adjustment is required in patients with hepatic dysfunction.
References
505. Skowron DM, Stimmel GL. Antidepressants and the risk of seizures. Pharmacotherapy 1992;12:18-22.
1420. Bryant SG, Guernsey BG, Ingrim NB. Review of bupropion. Clin Pharm 1983;2:525-37.
[ Revised 8/30/2005 3:06:00 PM ]
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