Mechanism of Action of Wellbutrin (Bupropion)

Introduction

Wellbutrin (bupropion) is an atypical antidepressant and smoking cessation aid. It primarily works by inhibiting reuptake of norepinephrine and dopamine, without affecting serotonin. Additionally, it acts as a nicotinic receptor antagonist, reducing nicotine cravings.

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Step-by-Step Mechanism of Action

1. Inhibits norepinephrine reuptake
   Bupropion blocks the norepinephrine transporter (NET), increasing norepinephrine in synaptic clefts.
2. Inhibits dopamine reuptake
   It also inhibits the dopamine transporter (DAT), previously known to enhance mood and motivation.
3. No significant effect on serotonin
   Lack of SERT inhibition results in lower risk of sexual side effects and weight gain.
4. Antagonizes nicotinic acetylcholine receptors
   This action helps reduce cravings and withdrawal symptoms in smoking cessation.
5. Promotes neurotrophic effects
   Increased dopamine and norepinephrine may elevate BDNF levels, supporting neuronal resilience.

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Pharmacokinetic Parameters

Parameter	Value
Route	Oral (IR, SR, XL formulations)
Bioavailability	~5–20%
Time to Peak (Tmax)	~2 hours (IR); 5 hours (SR/XL)
Protein Binding	~84%
Metabolism	Hepatic via CYP2B6 to active metabolites
Half-life	~21 hours (parent); ~20–37 hours (metabolites)
Excretion	Renal (~87%), fecal (~10%)

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Clinical Uses

• Major depressive disorder
• Seasonal affective disorder
• Smoking cessation aid (as Zyban)
• Off-label: ADHD, neuropathic pain adjunct, weight management

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Adverse Effects

• Stimulating effects: insomnia, dry mouth, headache
• Increased blood pressure and heart rate
• Dose-dependent seizure risk (>450 mg/day or in seizure-prone individuals)
• Rare GI symptoms, diaphoresis, tremors
• Low risk of sexual dysfunction or sedation

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Comparative Analysis

Drug Type	NE & DA Reuptake	Serotonin Effect	Seizure Risk	Common Uses
Bupropion	Moderate	None	Moderate–High	Depression, smoking cessation
SSRIs	None	High	Low	Depression, anxiety
Venlafaxine	High (NE), moderate (5‑HT)	Moderate	Moderate	Depression, neuropathic pain

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MCQs

1. Which transporters does bupropion inhibit?
a) SERT & NET b) DAT & NET c) DAT & SERT d) VMAT
Answer: b) DAT & NET

2. A key advantage over SSRIs is:
a) Weight gain b) Sexual dysfunction c) Sedation d) Lower sexual side effects
Answer: d) Lower sexual side effects

3. What is the main seizure-related risk factor?
a) High dose b) Hypoglycemia c) Hepatic impairment d) Hypertension
Answer: a) High dose

4. Which enzyme metabolizes bupropion?
a) CYP2B6 b) CYP3A4 c) CYP2D6 d) CYP1A2
Answer: a) CYP2B6

5. Bupropion aids smoking cessation by:
a) Increasing nicotine effect b) Blocking nicotine receptors c) Mimicking nicotine d) Enhancing dopamine only
Answer: b) Blocking nicotine receptors

6. Protein binding is approximately:
a) 84% b) 50% c) 10% d) 99%
Answer: a) 84%

7. Tmax for SR/XL formulations is about:
a) 2 hrs b) 5 hrs c) 10 hrs d) 24 hrs
Answer: b) 5 hrs

8. Off‑label use includes:
a) ADHD b) Asthma c) Rheumatoid arthritis d) Migraine
Answer: a) ADHD

9. Bupropion does NOT affect:
a) Dopamine b) Serotonin c) Norepinephrine d) Nicotinic receptors
Answer: b) Serotonin

10. Half-life of the parent drug is:
a) 6 hours b) 21 hours c) 48 hours d) 72 hours
Answer: b) 21 hours

11. Common side effect is:
a) Sedation b) Weight gain c) Dry mouth d) Bradycardia
Answer: c) Dry mouth

12. Metabolites have half-lives of:
a) 5–10 hrs b) 10–20 hrs c) 20–37 hrs d) >48 hrs
Answer: c) 20–37 hrs

13. Bupropion may increase levels of:
a) BDNF b) Morphine c) Cortisol d) Insulin
Answer: a) BDNF

14. Maximum recommended daily dose to minimize seizure risk is:
a) 300 mg b) 450 mg c) 600 mg d) 150 mg
Answer: b) 450 mg

15. Drug class of bupropion is:
a) SSRI b) NDRI c) MAOI d) SNRI
Answer: b) NDRI

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FAQs

1. Does Wellbutrin cause sexual dysfunction?
No—sexual side effects are rare compared to SSRIs.

2. When should dosing exceed 450 mg/day?
It generally shouldn’t, due to increased seizure risk.

3. How quickly does it improve mood?
May take 4–6 weeks to see full antidepressant effect.

4. Can it be combined with nicotine patches?
Yes—but monitor for combined side effects.

5. Is it suitable for adolescents?
Only approved for adults; caution is advised for younger patients.

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References

• Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition
• KD Tripathi. Essentials of Medical Pharmacology, 8th Edition
• DrugBank: Bupropion pharmacology summary
• StatPearls: Bupropion pharmacology
• PubMed review: Dopamine–norepinephrine role in depression