Bupropion (amfebutamone) (brand name Wellbutrin)is an antidepressant of the amino ketone class, chemically unrelated to tricyclics or selective serotonin reuptake inhibitors (SSRIs). It is similar in structure to the stimulant cathinone, and to phenethylamines in general. It is a chemical derivative of diethylpropion, an amphetamine-like substance used as an anorectic. Bupropion is both a dopamine reuptake inhibitor and a norepinephrine reuptake inhibitor.
Bupropion was first synthesized by Burroughs Research in 1966, and patented by Burroughs-Wellcome (later Glaxo-Wellcome, and, as of 2000, GlaxoSmithKline) in 1974. It was approved by the FDA in 1985 and marketed under the name Wellbutrin as an antidepressant, but clinical trials indicated that incidence of seizure was two to four times greater than other antidepressants and the drug was quickly pulled from the market. It was subsequently discovered that reducing the dose by about half greatly reduced the risk of seizures. Glaxo then developed a sustained-release (SR) version of Wellbutrin which releases bupropion hydrochloride at a slower rate. The SR formulation is taken twice a day, in order to further decrease the possibility of adverse side effects and seizures. It is also available in generic form (Bupropion SR). Extended Release bupropion, Wellbutrin XL, is the most recent formulation of bupropion and is taken orally once a day. Because of this altered mechanism of delivery and reduced dosing, incidence of seizures with bupropion is comparable to, and in some cases, lower than that of other antidepressants.
In 1997, bupropion HCl was approved by the FDA for use as a smoking cessation aid. Glaxo subsequently marketed the drug under the name Zyban to help people stop smoking tobacco by reducing the severity of craving and addiction/withdrawal symptoms. It can be used in combination with nicotine replacement therapies. Bupropion treatment course lasts for seven to twelve weeks, with the patient halting the use of tobacco around ten days into the course.
Bupropion is also being investigated as a weight loss drug.
Mode of action
Bupropion is a selective catecholamine (norepinephrine and dopamine) reuptake inhibitor. It has only a small effect on serotonin reuptake. It does not inhibit MAO. The actual mechanism behind bupropion's action is not known, but it is thought to be due to the effects on dopaminergic and noradrenergic mechanisms.
Bupropion is metabolised in the liver. It has at least three active metabolites: hydroxybupropion, threohydrobupropion and erythrohydrobupropion. These active metabolites are further metabolised to inactive metabolites and eliminated through excretion into the urine. The half-life of bupropion is 20 hours as is hydroxybupropion's. Threohydrobupropion's half-life is 37 hours and erythrohydrobupropion's 33 hours.
Chronic hepatotoxicity in animals
In rats receiving large doses of bupropion chronically, there was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In dogs receiving large doses of bupropion chronically, various histologic changes were seen in the liver, and laboratory tests suggesting mild hepatocellular injury were noted.
management of depression
adjunctive in tobacco withdrawal
attention deficit disorder
epilepsy and other conditions that lower the seizure-threshold (alcohol withdrawal, active brain tumors etc.)
concomitant treatment with MAO-Inhibitors
caution with the concomitant use of sympathomimetic drugs (e.g. Ephedrine)
active liver damage (e.g. cirrhosis)
severe kidney disease
anxiety disorders (caution), agitated patients
pediatric patients (see below)
use considerable caution in treating patients where suicide may be a risk
Common side effects include dry mouth, tremors, anxiety, loss of appetite, agitation, dizziness, headache, excessive sweating, increased risk of seizure, and insomnia. Bupropion causes less insomnia if it is taken just before going to bed, or in the morning after arising. Activation of mania and psychosis have both been encountered.
Scattered abnormalities of liver function studies are noted, without evidence of hepatotoxicity. Cases of significant liver damage with or without jaundice (icterus) have been seen rarely. In a German database covering side effects, five cases of pancreatitis with elevations of serum-amylase and lipase as well as clinical symptoms (e.g. abdominal pain, anorexia), reversible after termination of bupropion, have been reported. Currently, it is unclear, whether preexisting alcohol abuse or dependence might predispose patients to develop pancreatitis.
Infrequently, dose dependent hypertension is noted. Single cases of myocardial infarction (heart attack) have been noted, but the causal association to the use of bupropion is currently unknown.
Few cases of the urological emergency priapism (painful erection) have been seen. Immediate treatment is necessary, because the untreated patient may lose his possibility to have erections totally.
Quite a great number of drugs show clinically significant interactions with bupropion. Study the packing insert carefully and ask your prescribing physician in any case of doubt.
In animal studies and small studies with persons having experience with the use of amphetamines or cocaine, bupropion caused drug-seeking behaviour (animal experiments) and was recognized as an amphetamine-like drug by the humans. In a scale ranging from placebo on the lower side to benzedrine, it was given an intermediate score indicating moderate likelihood of abuse. In clinical practise, bupropion has been shown that the dose required for significant abuse would cause seizures in most patients. Abuse has not become a significant problem in clinical usage, but the drug should be given with caution to patients with a history of drug or alcohol abuse or dependence. Bupropion is not a controlled substance.
Risks in the treatment of tobacco withdrawal
In the UK, more than 5,000 reports of potentially hazardous side effects have been collected, among them more than 40 cases of death attributable to bupropion treatment. This study is questioning the benefit-risk-ratio in assisted tobacco withdrawal with bupropion. Also, 107 cases of serious side effects have been reported in Germany.
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