Referring to the chemical structure it can be seen that bupropion has a fairly hydrophilic core benzene ring and polar groups such as the chloro-group, amine and ketone. The amine group does increase water solubility because it is polar but more importantly it is ionisable which significantly increases the water solubility (Jamie, 2011):
Bupropion has a pKa of 7.9 (O'Byrne et al., 2010). The amine on the carbon chain can act as a weak base:
The partition coefficient (logP) equalled 3.21: drugs that are used to target the central nervous system would have a logP value of approximately 2, therefore bupropion was designed to act elsewhere in order to avoid possible central nervous system side effects such as drowsiness (Jamie, 2011).
Depression: bupropion is an effective antidepressant; there have been positive responses from both bipolar and atypical depression. However its clinical efficiency is dependent on the individual (Demyttenaere and Jaspers, 2008)
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Anxiety: it has had an overall positive result in helping patients' social anxiety and other anxiety brought on by depression, though in some cases it has led to increased anxiety
Smoking: recognised as an effective aid to smoking cessation, bupropion does this through the modulation of dopaminergic (dopamine) and noradrenergic (norepinephrine) systems. Although bupropion is known as a relatively weak dopamine reuptake inhibitor and inhibits norepinephrine at high concentrations, its inhibition of transporter function is associated with the increase in extracellular dopamine and norepinephrine concentration which is believed to substitute for nicotine-evoked neurotransmitter releases during smoking. This inhibition mimics nicotine reinforcement and relieving withdrawal symptoms (Imad Damaj et al., 2004).
Weight loss (obesity): long term use of bupropion can lead result in weight loss (Demyttenaere and Jaspers, 2008)
ADHD: there is evidence that it improves attention and impulse control in certain patients (Demyttenaere and Jaspers, 2008)
Bupropion was first synthesised in 1966; the main reason for its synthesis was to design an antidepressant that would be chemically and pharmacologically different to tricyclic antidepressant (figure 1), did not mimic the effects of the sympathetic nervous system (such as dopamine) and prevent the action of acetylcholine, and not be an inhibitor of monoamine oxidase (Carroll et al., 2009).
Figure 1: tricyclic antidepressant
Tricyclics were an antidepressant used in the 1950's to early 1960's. These tricyclic antidepressants had many side effects ranging from blurry vision to hallucinations. The side effects experienced by people taking tricyclic antidepressants kept growing which led to the need for a new drug. The discovery of bupropion was believed to be derived from the psychostimulant drug amphetamine (figure 2) (Carroll et al., 2009).
Figure 2: Amphetamine
Amphetamine is a drug that is used to produce increases in wakefulness and focus of a patient, and in the 1930's was used as an antidepressant with limited success. Other drugs which are believed to have aided the development of bupropion include cathinone (figure 3), which is a monoamine alkaloid that structurally is very similar to that of bupropion (Carroll et al., 2009).
Figure 3: Cathinone
Bupropion was first approved by the US Food and Drug Administration in 1985. Shortly after in 1986 however, bupropion was taken off the market to due patients taking the drug found to have an increased chance of suffering seizures. It was soon discovered after the drug was removed that the recommended dosage of 400-600 mg was too great and was the reason behind the increase in seizures. Therefore the dosage was halved to about 450 mg max per day which results in a dramatic reduction in seizures experienced by patients and was re-released in 1989 (Demyttenaere and Jaspers, 2008).
Soon after bupropion hydrochloride, known as Wellbutrin, a white crystalline powder which is highly soluble was developed which was a sustain release formulation of bupropion, this allowed the drug to release at a slower rate and was approved by the FDA in 1996 (Carroll et al., 2009).
Soon after the release of bupropion hydrochloride, patients using the drug stated that they believed it to easier to quit smoking while taking bupropion hydrochloride. In 1997 the FDA recognised bupropion, also known as Zyban, as an effective aid to smoking cessation.
Bupropion was believed to help with the treatment of nicotine dependence is the modulation of dopaminergic and noradrenergic systems (Carroll et al., 2009).
Structure Activity Relationship (SAR)
Always on Time
Marked to Standard
It is most commonly synthesis using the reaction below;
Chemical, physiological Stability and mode of delivery
While there has been little published on the stability of bupropion it is widely acknowledged that bupropion presents serious stability problems in manufacturing formulation and use (Imad Damaj et al., 2004). This problem with bupropion stability has led to numerous methods to improve the stability of bupropion formulations. One common method to improve the chemical and physiological stability of bupropion in the oral formulation (which is the most common method of delivery) involves the addition of a stabiliser, in many cases cysteine or glycine hydrochloride which acts as a buffer at a pH 0f 0.9-4 (O'Byrne et al., 2010).
Other physical methods have been developed and implemented to allow bupropion to stay within the moisture barrier, such as using polymer coatings around the tablet or polymer microspheres within the tablet. These methods above produce a dry "microenvironment" limiting the effect of bupropion once it is inside the body (O'Byrne et al., 2010).
Studies have shown that the half-life of bupropion dramatically reduces with the increase of temperature, with experimental results showing half-life in plasma at 22 and 37Â°C was 54.2 and 11.4 hours, respectively. The stability of bupropion was shown to improve at lower pH levels, being most stable at a pH of 2.5. At higher pH levels bupropion was readily converted to N-methyl bupropion (O'Byrne et al., 2010)
Mechanism of Action
Bupropion is an antidepressant that is believed to have the pharmacological action of a norepinephrine - dopamine reuptake adapter. Dopamine and norepinephrine are neuron transmitters that bind to specific receptors. The binding of the neurotransmitter opens an ion channel causing a biological response. As long as the neurotransmitter is bound to the receptor a biological response will continue; the way the human body gets rid of the dopamine is by using reuptake transport proteins. Therefore bupropion is believed to work by binding to the transport protein thus blocking the reuptake of neurotransmitter (Hesse et al., 2000).
Assumed interactions of bupropion with transporter proteins;
Bupropion is readily metabolized within the liver creating several active metabolites; below are the major in vivo metabolites (Hesse et al., 2000):
Cytochrome P450 2B6 (CYP2B6) is the major enzyme responsible for the metabolism of bupropion to its active metabolite hydroxybupropion. Other metabolic pathways include the formation of threohydrobupropion and erythrohydrobupropion by carbonyl reductase, which is a nonmicrosomal enzyme in the liver and gut. The mechanism of action on a molecular level within the body is not very well known. The pharmacologically active metabolite hydroxybupropion appears to the major metabolite, since plasma levels of the metabolite greatly exceed that of bupropion (Hesse et al., 2000).
Side effects and Controversial issues
Bupropion is a drug with many side effects, some of the more common side effects include:
The most controversial issue with bupropion was the increased likelihood of seizures when taking the drug, which as discussed above was the why bupropion was taken off the market; however, this was easily fixed by lowering the average dosage. The average dosage is now no more than 1 pill (150 mg) twice a day. Like all antidepressants, suicide is a risk when taking the drugs, and studies have shown that there may be an increase in the risk of suicide particularly in persons younger than 25 (Demyttenaere and Jaspers, 2008).