Pharmacology Page 1
Action And Clinical Pharmacology: Bupropion (generic Wellbutrin) is an antidepressant of the aminoketone class. It is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors or other known
antidepressant agents. Its structure closely resembles that of diethylpropion. It is related to the phenylethylamines.
The mechanism of bupropion's antidepressant activity is unknown but appears to be mediated by noradrenergic (and possibly dopaminergic), rather than serotonergic mechanisms. Preclinical studies have shown that bupropion blocks noradrenalin (NA)
reuptake and dopamine (DA) reuptake. Its major metabolite (hydroxybupropion), which in man is present at blood levels 10 to 20-fold higher than buproprion, blocks only NA reuptake.
In vitro, bupropion and its major metabolites had essentially no affinity for b-adrenergic, dopaminergic, GABA, benzodiazepine, 5HT1A, glycine and adenosine receptors, and only weakly inhibited a-adrenergic receptors in rat brain, a2-adrenergic,
5HT2, and muscarinic cholinergic receptors. High concentrations of bupropion and its major metabolites did not inhibit MAO-A or MAO-B activity. Bupropion and its major metabolites had no significant affinity for the 5HT transport system.
Events Observed During Development and Postmarketing Experience with the Immediate-Release Formulation of Bupropion: The following adverse events have been reported in clinical trials and postmarketing clinical experience with the immediate-release
formulation of bupropion. The extent to which these events may be associated with the sustained-release tablet, is unknown.
Body (General): altered hormone level, body odor, flu syndrome.
Cardiovascular: complete AV block, abnormal ECG, pulmonary embolism, extrasystoles, myocardial infarction, pallor, phlebitis.
Digestive: colitis, esophagitis, gingivitis, gastrointestinal hemorrhage, hepatitis, intestinal perforation, liver damage, rectal disorder, increased salivation, stomach ulcer, toothache.
Endocrine: syndrome of inappropriate antidiuretic hormone.
Hemic and Lymphatic: anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia.
Metabolic and Nutritional: glycosuria.
Musculoskeletal: arthritis, muscle rigidity/fever/rhabdomyolysis.
Nervous System: akinesia, aphasia, coma, delirium, delusions, dysarthria, dyskinesia, tardive dyskinesia, dystonia, abnormal EEG, labile emotions, euphoria, extrapyramidal syndrome, hypokinesia, decreased libido, increased libido, manic reaction,
neuralgia, neuropathy, paranoid reaction, suicidal ideation.
Respiratory: bronchitis, dyspnea, epistaxis, pneumonia, respiratory disorder.
Skin: acne, angioedema, exfoliative dermatitis, hair discoloration, hirsutism, Stevens-Johnson syndrome.
Special Senses: deafness, diplopia, mydriasis.
Urogenital: cystitis, dyspareunia, dysuria, abnormal ejaculation, gynecomastia, urinary incontinence, menopause, ovarian disorder, penis disorder, salpingitis, testis disorder, urinary retention, vaginitis.
Pharmacokinetics: Absorption: Bupropion has not been administered i.v. to humans; therefore, the absolute bioavailability of Wellbutrin SR tablets in humans has not been determined. In rat and dog studies, the bioavailability
of bupropion ranged from 5 to 20%. Following oral administration of Wellbutrin SR to healthy volunteers, peak plasma concentrations of bupropion are achieved within 3 hours. In 2 single-dose (150 mg) studies the mean peak concentration (Cmax)
values were 91 and 143 ng/mL. At steady state, the mean Cmax following a 150 mg dose every 12 hours was 136 ng/mL.
In a single-dose study, food increased the Cmax of bupropion by 11% and the extent of absorption as defined by area under the plasma concentration-time curve (AUC) by 17%. The mean time to peak concentration (tmax) was prolonged by 1 hour. This
effect was of no clinical significance.
Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 µg/mL. The extent of protein binding of hydroxybupropion is similar to that of bupropion, whereas the extent
of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. The volume of distribution (Vss/F) estimated from a single 150 mg dose given to 17 subjects is 1 950 L (20% CV). |
