Bupropion

2022-08-10: Drugs reference:

Bupropion (Wellbutrin/Zyban) #

• Atypical antidepressant. NET/DAT (in high doses) inhibitor and non-competitive antagonist of α4β2, α3β4 nAChR, and α1β1γδ.
  • Ki-63μΜ Bupropion-induced inhibition of α7 nicotinic acetylcholine receptors expressed in heterologous cells and neurons from dorsal raphe nucleus and hippocampus
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  • Compare to dl-Methylphenidate’s DAT/NET IC50 of 20 and 51 respectively (.35 vs .39 ratio). The difference is in the metabolites as you can see.
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• Associated with a high risk of release of mediators from mast cells. I don’t think it activates H1 though.
• Psychopharmacology of bupropion in normal volunteers.
  • α3β4 nAChR antagonism isn’t cognitively impairing.
• [Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects]
  • Dwoskin (2006) can exacerbate depression and increase suicidal thoughts.
  • Should be administered early in the morning as it exacerbates insomnia.
  • Vivid dreams, hallucinations, unusual thoughts/behavior, confusion, tremors, agitation, anxiety, swollen glands, joint pain, increased blood pressure
  • Non-competitive antagonist of nAChR. Never thought about this before; is that implied???
• Inhibits CYP2D6 (58 mM IC50?)
• [Seizures after overdoses of bupropion intake]
  • Pronounced increase in catecholamines is the main factor, I believe. QT prolongation can be seen.
• [Alcohol significantly lowers the seizure threshold in mice when co-administered with bupropion hydrochloride]
  • In mice, 116mg/kg (660 HED) without, or 89.4 for ethanol/bupropion.
• Bupropion increases striatal vesicular monoamine transport
  • Rapidly, reversibly, and dose-dependently increased vesicular DA uptake; an effect also associated with VMAT2 protein redistribution.

Antidepressive Mechanism #

• Molecular interaction of bupropion with nicotinic acetylcholine receptors
  • Where in the brain it binds is important: *binds to presynaptic α4β2 nAChR on GABAergic neurons in the Ventral Tegmental Area and α3β4 nAChR in the habenulo-intrerpeduncular pathway.
  • Bnding affinity for α4 is rougly equal to α1.
• Recent Developments in Novel Antidepressants Targeting α4β2-Nicotinic Acetylcholine Receptors
• Acute effect of the anti-addiction drug bupropion on extracellular dopamine concentrations in the human striatum: An 11C raclopride PET study
  • Bupropion , 100 mg, had no effect alone but abolished the sedation and auditory vigilance impairment produced by alcohol when co-administered.

Dose #

• 150mg twice daily = ~26% DAT occupance.
• ~5% oral bioavailability; extensive first-pass metabolism (does that mean hella CYP2B6 metabolites?)