A brief overview of the therapeutic properties of bupropion

[visionarybear]

heres a brief report i had to write (partially) for pharmacology, i didnt write all of it, i didnt write mechanism or summary 3 but can stil answer any questions on it or clarify them, its only brief so can field any other questions nd il see what ive got..

A brief overview of the therapeutic properties of bupropion HCL including three reviewed articles of interest.

Scott Smart and Sam Costelloe


Introduction
Bupropion HCL (BUP) is a novel monocyclic aminoketone (amfebutamone) that is effective in treating major depressive disorder and also as a smoking cessation aid (Daviss et al 2005, Fava et al 2005, Turpeinen et al 2005). BUP has also been proposed as a treatment for attention deficit and hyperactivity disorder (ADHD) and weight loss but only off-label (Daviss et al 2005, Fava et al 2005).
   BUP is sold under the names of Wellbutrinâ,,¢ (depression) and Zybanâ,,¢ (smoking cessation) by GlaxoSmithKline (GSK). Three preparations are available in the US: immediate release (IR), sustained release (SR) and extended release (XR)
BUP has 3 primary metabolites with varying bioactivities: hydroxybupropion (HB), threohydrobupropion (TB) and erythrohydrobupropion (EB) (Daviss et all 2005, Fava et al 2005, Turpeinen et al 2005).   CYP2B6 is responsible for metabolism of BUP into HB (Daviss et al 2005, Turpeinen et al 2005) and CYP3A4 is responsible for metabolism of BUP into TB and EB (Daviss et al 2005).
   Common side effect can include dry mouth, headaches, nausea, insomnia at a prevalence of 5% and severe side effects such as seizures and migraines have been noticed with a dose dependent nature (Fava et al 2005). Withdrawal effects noted include irritable mood, sleeplessness, headache and generalised aches and pains after abrupt discontinuation of treatment (Berigan and Harazin 1999).



Mechanism of action
BUP is a central nervous system (CNS) drug whose site of action is it’s binding to the dopamine (DA) and noradreinaline (NA) reuptake pumps (Fava et al 2005). The efficacy of BUP as both an antidepressant and as a smoking cessation aid seems to be due to this antagonistic action.
BUP by itself appears to have a low affinity for it’s targeted binding sites (Preskorn 2000), so the pharmacokinetics of BUP come into play.
BUP is metabolised into three metabolites HB, EB and TB by CYP enzymes. All of these metabolites are pharmacologically active and due to their slower clearance rate (-ie- longer t1/2) compared to BUP, accumulated in the body to a much greater extent than BUP( Fava et al 2005).
This could indicate (although not pharmacologically proven) that BUP metabolites contribute to the antidepressant effects of BUP (Fava et al 2005). Furthermore, the combined concentration of BUP and it’s metabolites, could show how BUP’s relatively low affinity is negated/increased by it’s metabolites as the total concentration of BUP plus it’s metabolites far exceeds the concentration of most other antidepressant drugs, possibly increasing it’s effectiveness (Fava et al 2005).

Summary 1 â€" Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation
The study aimed to demonstrate the CYP2B6 inhibiting properties of antiplatelet aggregation thienopyridine derivatives clopidogrel (CLOP) and ticlopidine (TICL) as measured by hydroxylation of bupropion (BUP).
   The study consisted of 3 phases; the 1st phase was a control period where all subjects (12 adult males) were given single dose BUP. In phase 2 and 3, subjects were pre-treated for 4 days with either CLOP 75mg once daily or TICL 250mg twice daily. In between phases there was a 1 week and 2 week washout periods respectively. On day 4 of Phase 2 and 3 subjects were dosed with 150mg BUP. Pharmacokinetics for BUP and hydroxybupropion (HB) were measured for 72 hours after BUP administration.
   After analysis it was shown that for bupropion, AUC increased by 60% with CLOP and 85% with TICL. Cmax  increased 40% with CLOP and 38% with TICL. There were no significant changes to T1/2 or tmax. Analysis of  HB showed: AUC decreased by 52% with CLOP and 84% with TICL. Cmax decreased 50% with CLOP and 84% with TICL. There were no significant changes to T1/2 or tmax. The ratio of HB/BUP decreased by 68% with CLOP and 90% with TICL.
   These results show that both CLOP and TICL are effective CYP2B6 inhibitor, with TICL almost completely inhibiting hydroxylation. As the t1/2 and tmax were not significly differentand Cmax BUP increased as Cmax HB decreased, the CYP2B6 hydroxylation represents the distribution phase rather than the elimination phase. This implies that the CYP2B6 metabolism of BUP is primary 1st pass metabolism. When this pathway is blocked, BUP will me metabolised via a ketone reduction pathway into its other metabolites, Erythrohydrobupropion and threohydrobupropion.
   In clinical use, dose adjustment would be required when using CYP2B6 inhibiting drugs. For BUP, the risk of dose dependent effects such as seizures would be increase if this adjustment is not carried out.

Review 2 â€" Steady state pharmacokinetics of Bupropion SR in juvenile patients
This study compared the pharmacokinetics (PK) in juvenile patients aged 7 â€" 17.9 years old (mean age=15.2±1.2) to that of adults in previous studies. 19 patients completed the trial; 11 male and 8 female. Ethnicities were white (n=15), African American (n=3) and Hispanic (n=1).Patients were all previously prescribed bupropion (BUP) or were about to start taking BUP for either ADHD or depressive disorders (or both). Patients were either trialled on 100mg/day or 200mg/day for 14days or less. Blood was drawn from an intravenous port every 1-3 hours after taking the usual morning dose of BUP. The level of sexual development was also measured in all patients for comparison.
   After analysis, it was found that the PK were different in the juvenile test subjects. Mean half life (t1/2) for BUP was 12.1hrs vs. 26.3hrs in adult studies. T1/2 hydroxybupropion (HB) was 21.8 vs. 20.5, t1/2 threohydrobupropion (HB) was 26.3 vs.37 and t1/2 erythrohydrobupropion (EB) was 32.7 vs. 33. The metabolite ratios of HB:TB:EB:BUP were 7.5:6.3:1.2:1 vs. 17:7:1.5:1. All Results were compared to results of adult trials indicated by GSK product info (2002).
These results show that in juvenile patients, the half life of bupropion is decreased which would lead to a faster accumulation of metabolites than in adults which is an increased risk factor towards serious metabolite concentration related effects such as seizure. The differing ratio of metabolites in the metabolite profile also brings into question the importance of each active metabolite to the therapeutic effects of BUP as a medication. Further study into the activity of each individual metabolite is required before the true implications of the differing metabolism in juveniles vs. adults can be fully understood. In clinical use, BUP should also be dose adjusted with these considerations in mind when prescribing to juveniles.   
This study also identified possible racial differences in the African-American patients which would require a larger group study of African-American patients to confirm.

Review 3 -A Comparison of Sustained-release (SR) Bupropion and Placebo For Smoking Cessation.
 This study of Bupropion aimed to assess the efficacy of Bupropion in a SR formulation as aid in smoking cessation due to suspions that nicotine may act as an antidepressant.
Subjects were recruited through the medium of advertising and were eligible if they were over the age of 18, had smoked 15 plus cigarettes a day for at least a period of one year. Subjects were excluded if they had the predisposition to seizures, psychiatric conditions, current depression and/or dependence on other drugs, such as alcohol and so forth.
Subjects were placed into one of four groups receiving either a 100mg/day, 150mg/day, 300mg/day or placebo dosages of SR Bupropion. The treatment with the drug was for seven weeks, all subjects were to stop smoking after the first week of treatment. Of the 612 subjects enrolled in the drug trial, 219 subjects (33%) failed to complete all 12 months of the study, mainly from perceived lack of belief. There were also 15 subjects who withdrew because of adverse reactions and one death.
Of the 393 subjects who completed the 12 month trial, 12.4% of subjects in the placebo group were abstinent from smoking, 19.6% on the 100mg/day, 22.9% on the 150mg/day and 23.1% on the 300mg/day.
It was found that Bupropion was effective in increasing the rate of abstinence from smoking and was well tolerated by the subjects. There was also a recommendation that the dosage be increased as higher doses seem to be more effective.


References
DAVISS W.B., PEREL J.M.,RUDOLF G.R., ALEXSON D.A.,GILCHRIST R.,NUSS S., BIRMAHER B. AND BRENT D. (2005).A. Steady-state Pharmacokinetics of bupropion SR in juvenile patients. Journal of the American Academy of Child and Adolescent Psychiatry. 44(4),349-357

FAVA M., RUSH A.J., THASE M.E., CLAYTON A., STAHL S.M., PRADKO J.F. AND JOHNSTON J.A.(2005) 15 Years of Clinical Experience With Bupropion HCl: From Bupropion to Bupropion SR to Bupropion XL. Primary care companion to the Journal of clinical psychiatry.7(3),106-113

PRESKORN S.H. (2000). Bupropion: What Mechanism of Action?. Journal of Practical Psychiatry and Behavioral Health. Jan. 272-276

TURPEINEN M., TOLONEN A., UUSITALO J., JALONEN J., PELKONEN O. AND LAINE K.(2005) Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. Clinical Pharmacology and Therapeutics. 77(6). 553-559

BERGAIN T.R AND HARAZIN J.S. (1999). Bupropion-associated withdrawal symptoms: a case report. Primary care companion to the Journal of clinical psychiatry. 1. 2

Summaries

1. TURPEINEN M., TOLONEN A., UUSITALO J., JALONEN J., PELKONEN O. AND LAINE K.(2005) Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. Clinical Pharmacology and Therapeutics. 77(6). 553-559

2. DAVISS W.B., PEREL J.M.,RUDOLF G.R., ALEXSON D.A.,GILCHRIST R.,NUSS S., BIRMAHER B. AND BRENT D. (2005).A. Steady-state Pharmacokinetics of bupropion SR in juvenile patients. Journal of the American Academy of Child and Adolescent Psychiatry. 44(4),349-357
3. HURT R., SACHS D., GLOVER E., OFFORD K., JOHNSTON J., DALE L. AND SULLIVAN P. (1997). A comparison of sustained-release bupropion and placebo for smoking cessation. New England Journal of Medicine. 337. 1195-1202

[bYronitos]

good post... saw an article in the paper a few months back that said some women experience spontaneous orgasm with buproprion

[visionarybear]

hehe, and only the best kind of relief from depression...too bad its not more common!women everywhere would flock to buy it!

[Avery L. Breath]

Have been trying this for a month now to try to quite smoking and for relief from seasonal depression.  Over the last week though I've had ringing in my ears that at times in very annoying and trouble sleeping at night w/obsessive like stimulation if I take it too late in the day.  Though I think I'm going to stay on the regiment, just gonna try to half the dosage and see if the ringing goes away.

Am just about ready to quit smoking cigarettes too and don't think I'll have too much of a problem.  Quit smoking other stuff a week ago with absolutely no problem (not that that is hard to quit anyways...... cept hanging around with friends that do.)

[JRL]

I certainly findng out that I am not alone with ths depression thing. Funny too, that when i started taking St John's Wort my lifelong obbsession with cannibal saliva has faded away. I go 2-3 days with nary a puff, as opposed to lighting up every 2-3 hours.

[bYronitos]

...new g/f takes wellbutrin SR (sustained release) once a day... can't take XR (extended release)she says because it makes her too agressive...lol

[senorsalvia]

A few months ago I started taking Buptroprion, and while I did notice a clarity of mind as well as a calming of incessant 'internal dialogue', I abruptly stopped taking it...Had a somewhat bizzare side effect for me, in that a couple hours after dosing I would get flashing lights effects as well as 'trails'...  I was walking around a corner after sundown and the light thing had me assume thee was a cop pulling someone over and that he had his cherries lit up..   Imagine my surprise when I glanced around and nothing was there :roll: ---  'Twas then I noticed the trails and discovered that I was, in fact, getting some fairly haevy side effects.....    (((  Once again, might I suggest Sally 'fer all that ails 'ys :wink: )))--------  sal