Mechanism of Action of Bupropion

Introduction

Bupropion is an atypical antidepressant primarily used to treat major depressive disorder, seasonal affective disorder, and as an aid for smoking cessation. Unlike SSRIs, bupropion exerts its effects via modulation of dopamine and norepinephrine neurotransmission, offering a unique mechanism without significant serotonergic side effects.

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Step-by-Step Mechanism of Action

1. Inhibition of norepinephrine reuptake
   Bupropion inhibits the norepinephrine transporter (NET), increasing extracellular norepinephrine in synapses.
2. Inhibition of dopamine reuptake
   It also inhibits the dopamine transporter (DAT), elevating dopamine levels, especially in brain areas related to mood and motivation.
3. No direct effect on serotonin
   Bupropion has no significant serotonin reuptake inhibition, reducing the risk of sexual dysfunction, weight gain, and emotional blunting.
4. Nicotine receptor antagonism
   Bupropion acts as a non-competitive antagonist of nicotinic acetylcholine receptors, aiding in smoking cessation by reducing cravings and withdrawal.
5. Indirect downstream effects
   Elevated norepinephrine and dopamine increase brain-derived neurotrophic factor (BDNF) and neuronal resilience, supporting antidepressant activity.

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Pharmacokinetic Parameters

Parameter	Value
Route	Oral (tablets, sustained-release)
Bioavailability	~5–20%
Time to peak (Tmax)	~2 hours (immediate release); ~5 hours (SR/XL)
Protein Binding	~84%
Metabolism	Hepatic CYP2B6 → active metabolites (hydroxy-, erythro-, threohydrobupropion)
Half-life	~21 hours (parent); metabolites ~20–37 hours
Excretion	Renal (~87%); fecal (~10%)

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Clinical Uses

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

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Adverse Effects

• Stimulant-like effects: insomnia, dry mouth, headache
• Tachycardia, elevated blood pressure in some patients
• Seizure risk, especially at doses >450 mg/day or in susceptible individuals
• GI upset, diaphoresis, tremor
• Low risk: sexual dysfunction, weight gain, sedation

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Comparative Analysis

Drug	NE & DA Reuptake	Serotonin Effect	Seizure Risk	Uses
Bupropion	Moderate	None	Moderate–High	Depression, cessation
SSRIs (e.g. fluoxetine)	None to low	High	Low	Depression, anxiety
Venlafaxine	High (NE), moderate (5-HT)	Moderate	Moderate	Severe depression, pain

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MCQs (15)

1. Bupropion primarily inhibits reuptake of which neurotransmitters?
   a) Serotonin & GABA b) Dopamine & norepinephrine c) Glutamate & acetylcholine d) Histamine & serotonin
   Answer: b) Dopamine & norepinephrine
2. It lacks significant inhibition of which transporter?
   a) DAT b) NET c) SERT d) VMAT
   Answer: c) SERT
3. Bupropion assists smoking cessation by antagonizing:
   a) Nicotinic receptors b) Muscarinic receptors c) Adrenergic receptors d) Dopaminergic receptors
   Answer: a) Nicotinic receptors
4. A key advantage over SSRIs is:
   a) Higher sexual dysfunction risk b) Weight gain c) Lower risk of sexual side effects d) Strong sedative effect
   Answer: c) Lower risk of sexual side effects
5. Which adverse effect is most concerning at high doses?
   a) Seizure b) Weight gain c) Hypotension d) Sedation
   Answer: a) Seizure
6. Major metabolites are produced via which enzyme?
   a) CYP3A4 b) CYP2B6 c) CYP2D6 d) CYP1A2
   Answer: b) CYP2B6
7. Bupropion has a half-life of approximately:
   a) 5 hours b) 21 hours c) 48 hours d) 72 hours
   Answer: b) 21 hours
8. Which off-label use is common?
   a) Hypertension b) ADHD c) Asthma d) Depression
   Answer: b) ADHD
9. Bupropion is contraindicated in patients with:
   a) Hypothyroidism b) Epilepsy c) Diabetes d) Glaucoma
   Answer: b) Epilepsy
10. Compared to bupropion, SSRIs are more likely to cause:
    a) Appetite increase b) Seizures c) Stimulant effects d) Insomnia
    Answer: a) Appetite increase
11. Protein binding is approximately:
    a) 30% b) 60% c) 84% d) 100%
    Answer: c) 84%
12. Time to peak for SR formulation is about:
    a) 1 hour b) 3 hours c) 5 hours d) 10 hours
    Answer: c) 5 hours
13. One key stimulant-like adverse effect is:
    a) Sedation b) Dry mouth c) Bradycardia d) Diarrhea
    Answer: b) Dry mouth
14. Its use in neuropathic pain is due to:
    a) Histamine blockade b) NE elevation c) Serotonin reuptake d) Opioid agonism
    Answer: b) NE elevation
15. Recommended maximum daily dose to minimize seizure risk:
    a) 150 mg b) 300 mg c) 450 mg d) 600 mg
    Answer: c) 450 mg

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FAQs

1. Does bupropion cause sexual dysfunction?
No—bupropion rarely causes sexual side effects, making it useful when these are a concern.

2. When should doses exceed 450 mg/day?
They generally should not—higher doses significantly increase seizure risk.

3. How quickly does it improve depressive symptoms?
Typically within 4–6 weeks of treatment initiation.

4. Can it be used with nicotine patches?
Yes—can enhance smoking cessation outcomes but monitor for combined side effects.

5. Is it safe in adolescents?
It is approved for adults; use in adolescents requires caution regarding seizure risk.

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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: Pharmacology of bupropion and smoking cessation
• PubMed review: Dopamine–norepinephrine mechanisms in depression and cessation

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