Article: Bupropion

Bupropion
Systematic (IUPAC) name
(±)-1-(3-chlorophenyl)- 2-[(1,1-dimethylethyl)amino]- 1-propanone
Identifiers
CAS number	34841-39-9
ATC code	N07BA02
PubChem	444
DrugBank	APRD00621
Chemical data
Formula	C13H18NClO
Mol. weight	239.74
Pharmacokinetic data
Bioavailability	5-20% in animals; no studies in humans
Metabolism	Hepatic
Half life	20 hours
Excretion	Urine (87%), feces (10%)
Therapeutic considerations
Pregnancy cat.	B (USA)
Legal status	Prescription only (USA)
Routes	Oral

Bupropion (amfebutamone) (brand names Wellbutrin and Zyban) is an antidepressant of the aminoketone 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. It is often used as a smoking cessation aid.

History

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 Food and Drug Administration (FDA) as an antidepressant in 1989 and marketed under the name Wellbutrin, 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 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. With this altered mechanism of delivery and reduced dosing, incidence of seizures is comparable to, and in some cases lower than, that of other antidepressants. Patients using Bupropion should still be checked for pre-disposing factors that might lead to a lower than normal seizure threshold. It is also important to check for other medications the patient might be using which might also work to lower the seizure threshold.

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 nicotine cravings 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 for several other disorders including overweight or obesity, Attention-Deficit Hyperactivity Disorder, anticipatory prevention of Seasonal Affective Disorder, Restless Leg Syndrome and a possible treatment for increasing sexual functioning in some women.

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 antidepressant effect of bupropion is considered to be mediated by its dopaminergic and noradrenergic action. Bupropion has also been shown to act as an competitive α3β4 nicotinic antagonist, the α3β4-antagonism has been shown to interrupt addiction in studies of other drugs such as ibogaine. This α3β4-antagonism correlates quite well with the observed effect of interrupting addiction.

Pharmacokinetics

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.

Contraindications

• Epilepsy and other conditions that lower the seizure-threshold (alcohol withdrawal, active brain tumors etc.)
• Concomitant treatment with MAO-Inhibitors. When switching medications it is important that there be a short period of about two weeks between the medications in order to reduce risk of complications that might lead to things such as a decrease in seizure threshold.
• Caution with the concomitant use of sympathomimetic drugs (e.g. Ephedrine)
• Active liver damage (e.g. cirrhosis)
• Anorexia and Bulimia which might lead the patient to have a decreased seizure threshold
• Severe kidney disease
• Severe hypertension
• Anxiety disorders (caution), agitated patients
• Pediatric patients (see below)
• Use considerable caution in treating patients where suicide may be a risk

Side effects

Common side effects include dry mouth, tremors, anxiety, loss of appetite, agitation, dizziness, headache, excessive sweating, increased risk of seizure, aggressiveness, and both initial and terminal insomnia. Bupropion causes less insomnia if it is taken just before going to bed, or in the morning after rising. Activation of mania and psychosis have both been encountered. Some patients may also require less than the normal dosing which usually starts at around 150 mg for the first few weeks and is then switched to the normal 300 mg dosage, these patients may be kept on the 150 mg regimen.

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.

The development of mild to moderate skin rashes associated with sensitivity to dye components within the pill coating. This can often be alleviated by simply prescribing a different color pill and consequently, changing the dosage.

Few cases of the urological emergency priapism (painful erection) have been seen. Immediate treatment is necessary, because the untreated patient may totally lose his possibility to have erections.

Interactions

Quite a great number of drugs show clinically significant interactions with bupropion. This may be due to interactions with drugs that are metabolized by CYP2D6 as Bupropion inhibits CYP2D6 activity.

Bupropion is known to lower the seizure threshold. Bupropion, in combination with other medications, has been suspected to induce seizures in some patients with no prior record of seizure activity. [1] While this is not a common side-effect, a growing number of cases world wide validate the need for consideration. It is not uncommon for patients to receive treatment with other antidepressant and/or atypical antipsychotic medications in combination with bupropion. For this reason, care should be taken when prescribing bupropion with other medications prone to lower the seizure threshold. Bupropion has also been known to produce seizures in combination with non-prescription (recreational) drugs such as cocaine, and alcohol. Study the packing insert carefully and ask your prescribing physician about possible interactions.

Abuse liability

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 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 practice, 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.

Additional warnings

Use in pediatric patients

Bupropion has been shown to increase the incidence of suicidal thoughts and attempts in children and adolescents with depression. When treating major depressive disorder in this group of patients, clinical benefits should be weighed carefully against therapeutic hazards. Usually, bupropion is not indicated for pediatric patients under age 18.

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.

Dosage

• depression : usual dose is 300mg daily, starting with 200mg in the first few days
• tobacco withdrawal : 150mg initially, may be increased to 300mg if indicated and directed by physician. In patients also receiving Insulin, sympathomimetic anorectical drugs, or antimalaria agents, the daily dose of bupropion should not exceed 150mg.

Remarks

Limitation to tobacco withdrawal

In some countries bupropion is approved only as a smoking cessation aid and not for treatment of depression.

Potential indications of bipolar and schizoaffective disorder

The effects of bupropion HCl in treating eleven patients with bipolar or schizoaffective disorder were examined in an open trial. Most patients had been intolerant of or showed minimal to moderate improvement on lithium, neuroleptics, antidepressants, or a combination of these drugs. All patients were maintained on bupropion alone or bupropion in combination with low-dose neuroleptics or anxiolytics for one year or more, with little or no relapse and few side effects. Although these results are encouraging, additional larger studies need to be conducted to confirm this indication (study conducted by G. Wright et al., 1985, published in : J Clin Psychiatry, 1985 Jan;46(1):22–5).

UK Alleged Severe Adverse Reactions

Wellbutrin is not licensed for use in the UK; Glaxo Smith Kline withdrew the licensing application from the MHRA before completion of the process as licensing looked unlikely following serious concerns about the safety of the drug. At one point Zyban accounted for 25% of all MHRA yellow card adverse drug reactions in the UK. It has also been allegedly connected with suicides and severe and sometimes permanent psychological disorders including depression, personality change, memory and anger control issues, general psychological disturbance and abnormality as well as psychosis and mania. Stroke, sometimes leading to death, and suicide or suicidal thoughts have also been noted. It is also banned or restricted from use in other developed international countries. In the UK 66 people (or their surviving families) alleged Zyban as being responsible for their problems which were cardio vascular, psychiatric or allergic. The mechanism for the exposure to a toxic dose and/or alleged damage is not fully understood (in fact, the drug's mechanism itself is not fully understood). The latest hypothesis is that a toxic build up of the drug and/or its metabolites can occur in people who may be unable to rid themselves of this drug at the usual speed, thereby allegedly causing a graduated build up which may constitute a toxic dose. This may be characterised by an inherited genetic condition and may be possibly identified by two tests which may identify the condition, a P450 and or 2CYP Cytochrome test to identify genetically inherited poor metabolism and susceptibility to a possible toxic dose exposure. Only a few people in a thousand are in this group, but alleged side effects can be debilitating.

Availability in the United Kingdom

If it is to be used as an aid in quitting smoking, it can be obtained one time only, and cannot be legally prescribed afterwards.

Dose forms

Brand and generic pills are available in three forms: immediate release, sustained release (SR), and extended release (XL, ER).