Bupropion

Bupropion is a smoking cessation agent belonging to a cholinergic-receptor agonist.

Bupropion is used in the treatment of Major depressive disorder, Seasonal affective disorder, and Smoking cessation. It is also used to treat Attention-deficit/hyperactivity disorder; Bipolar depression; Selective serotonin reuptake inhibitor-induced sexual dysfunction, and augmentation.

Bupropion is Well absorbed from the GI tract and gets widely distributed. The Volume of distribution was approx 2,000 L with plasma protein binding: ≥80%. It Crosses the placenta and is distributed into breast milk, and gets metabolized hepatically by CYP2B6 isoenzyme to hydroxybupropion as a major metabolite; may undergo extensive first-pass metabolism.

It gets excreted Via urine (mainly as metabolites, <1% as unchanged drug). Terminal plasma half-life: Approx 14 hr (immediate-release); approx 20 hr (modified-release).

The onset of Action of Bupropion was within 1-2 wk.

The Duration of Action of Bupropion was within 1-2 days.

The Tmax of varenicline was achieved within 2 hours. Cmax was about 91 and 143 ng/mL.

Bupropion shows common side effects like Headache, dizziness, Diarrhea, sore throat, runny nose, sneezing, joint pain, etc.

Bupropion is available in Gum, Inhalers, Transdermal kits, Lozenges, and Transdermal Patch, Nasal Solutions.

Bupropion is available in India, Germany, Canada, France, USA

Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine, w/ minimal effect on serotonin reuptake. The mechanism by which it aids in smoking cessation is presumed to be mediated by its noradrenergic and/or dopaminergic actions.

Bupropion is available in the form of tablets.

● Immediate release: Administer 3 to 4 times daily with at least 6 hours between successive doses; do not exceed 150 mg in a single dose.

● 12-hour extended-release (sustained release): Administer two times daily with at least 8 hours between successive doses; do not exceed 200 mg in a single dose.

● 24-hour extended release: Administer once daily with at least 24 hours between successive doses.

Bupropion is used in the treatment of Major depressive disorder , Seasonal affective disorder and smoking cessation. It is also used to treat Attention-deficit/hyperactivity disorder; Bipolar depression; Selective serotonin reuptake inhibitor-induced sexual dysfunction, augmentation.

Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine, and does not inhibit monoamine oxidase or the reuptake of serotonin. Metabolite inhibits the reuptake of norepinephrine. The primary mechanism of action is thought to be dopaminergic and/or noradrenergic.

Bupropion is approved for use in the following clinical indications

● Major depressive disorder (unipolar): Treatment of major depressive disorder (MDD)

● Seasonal affective disorder (24-hour extended release): Prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder (SAD)

● Smoking cessation (12-hour extended-release [sustained release; ]): As an aid to smoking cessation treatment

Although not approved there have been certain off label use documented for Bupropion which includes:

Attention-deficit/hyperactivity disorder; Bipolar depression; Selective serotonin reuptake inhibitor-induced sexual dysfunction, augmentation

Bupropion is available in various strengths as 75 mg, 100 mg,150 mg, 200 mg, 300 mg, 450 mg

Bupropion is available in the form of Tablets and Nasal solution.

• Dosage Adjustment in Kidney Patient

CrCl >60 mL/minute: No dosage adjustment necessary.

CrCl 15 to 60 mL/minute: Use with caution; consider a maximum daily dose of 150 mg/day.

CrCl <15 mL/minute: Use of alternative agent may be preferred. Use with caution; to limit accumulation of active metabolites, initiate therapy at 100 mg every 48 hours or 150 mg every 72 hours. Titrate gradually based on tolerability and response to a maximum daily dose of 150 mg/day.

Hemodialysis, intermittent (thrice weekly): Minimally dialyzable (13%); major active metabolite (hydroxybupropion) is not dialyzable :

Use of alternative agent may be preferred. Use with caution; to limit accumulation of active metabolites, initiate therapy at 100 mg every 48 hours or 150 mg every 72 hours. Titrate gradually based on tolerability and response to a maximum daily dose of 150 mg/day.

Peritoneal dialysis: Not likely to be dialyzable:

Use of alternative agent may be preferred. Use with caution; to limit accumulation of active metabolites, initiate therapy at 100 mg every 48 hours or 150 mg every 72 hours . Titrate gradually based on tolerability and response to a maximum daily dose of 150 mg/day

• Dosage Adjustment in Hepatic impairment Patient

Mild impairment (Child-Pugh score 5 to 6): Use with caution; manufacturer’s labeling suggests a reduction in dose and/or frequency be considered but does not provide specific dosing recommendations. Some experts recommend decreasing the initial dose to 50% of usual dose and reducing dosing frequency. Use of the 450 mg ER tablet is not recommended.

Moderate to severe impairment, including severe hepatic cirrhosis (Child-Pugh score 7 to 15): Use with extreme caution. Some experts recommend decreasing the initial dose to 50% of usual dose and reducing dosing frequency

• Dosage Adjustment for Pediatric Patients:

Attention-deficit/hyperactivity disorder (ADHD):

Note: Bupropion is not recommended as first-line therapy in the management of ADHD in pediatric patients . In comparative trials with methylphenidate, a small volume of evidence suggests Bupropion may have similar efficacy ; however, the role of Bupropion has not been defined.

Children ≥6 years and Adolescents: Oral:

Immediate release, hydrochloride salts: Initial: 1.5 to 3 mg/kg/day in 2 to 3 divided doses; maximum initial dose: 150 mg/day; titrate dose as needed to a maximum daily dose of 6 mg/kg/day or 300 mg/day with no single dose >150 mg .

Note: When determining the initial dose, assess available dosage forms (eg, ¹/₂ of 75 mg tablet may be the lowest achievable dose).

12-hour sustained release and 24-hour extended release, hydrochloride salts: In patients able to swallow tablets whole: May be used in place of regular tablets, once the daily dose is titrated using the immediate-release product and the titrated 12-hour dosage corresponds to a sustained-release tablet or the 24-hour dosage range corresponds to an extended-release tablet size . In pediatric efficacy trials, mean final effective dose ranges for sustained-release formulations were similar to immediate release.

Depression, refractory:

Note: In the management of depression in children and adolescents, if pharmacotherapy deemed necessary with/without psychotherapeutic interventions, Bupropion is not recommended as first-line therapy. Some suggest it may be beneficial in patients with comorbid ADHD . Treatment should be periodically evaluated at appropriate intervals to ensure the lowest effective dose is used.

Immediate release, hydrochloride salt: Children ≥8 years and Adolescents: Oral: Initial: 37.5 mg twice daily; titrate to response; titration intervals of every 1 to 2 weeks have been suggested ; usual reported dosage range: 100 to 300 mg/day in divided doses; maximum reported daily dose: 400 mg/day.

12-hour sustained release, hydrochloride salt: Children ≥11 years and Adolescents: Oral: Initial: 2 mg/kg once daily up to 100 mg administered as a morning dose; may titrate as needed every 2 to 3 weeks using the following titration schedule: Step 2: Increase up to 3 mg/kg every morning; Step 3: Increase up to 3 mg/kg every morning and 2 mg/kg at 5 pm (17:00); Step 4: Increase up to 3 mg/kg/dose twice daily; maximum dose: 150 mg; reported mean effective dose: Morning: 2.2 mg/kg and afternoon: 1.7 mg/kg 24-hour extended release, hydrochloride salt: Children ≥12 years and Adolescents: Oral: Initial: 150 mg once daily; may titrate after 2 weeks to 300 mg once daily if adequate response not achieved; dosing based on a pharmacokinetic study in 8 patients with depression weighing ≥30 kg ; doses as high as 400 mg/day have been reported ; may also be used once the daily dose is titrated using the immediate-release product and the 24-hour dosage range corresponds to an extended-release tablet size

• Take after eating and with a full glass of water to decrease gastric upset.

• Bupropion is contraindicated in patients with Recent cerebrovascular accident. Self-medication in patients who will continue to smoke, chew tobacco, or use snuff or other Bupropion -containing preparations. Non-smokers and occasional smokers.

Concerns related to adverse effects:

● Cognitive impairment: May cause motor or cognitive impairment in some patients, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

● Hypertension: May elevate BP and cause hypertension. Events have been observed in patients with or without evidence of preexisting hypertension.

● Weight loss: May cause weight loss; use caution in patients where weight loss is not desirable.

Disease-related concerns:

● Attention-deficit/hyperactivity disorder (off-label use): All children diagnosed with attention-deficit/hyperactivity disorder who may be candidates for medication therapy, including Bupropion, should have a thorough cardiovascular assessment to identify risk factors for sudden cardiac death prior to initiation of drug therapy.

● Cardiovascular disease: Use with caution in patients with cardiovascular disease, history of hypertension, or coronary artery disease; treatment-emergent hypertension (including some severe cases) has been reported, both with Bupropion alone and in combination with nicotine transdermal systems.

● Hepatic impairment: Use caution in patients with hepatic impairment and use extreme caution in patients with severe hepatic cirrhosis; plasma concentrations are increased. Use caution in patients with hepatic encephalopathy due to the risk of neurocognitive effects (Mauri 2014; Mullish 2014). Consider a reduction in dose and/or frequency.

● Renal impairment: Use with caution in patients with renal impairment; consider a reduction in dose and/or frequency.

Bupropion may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

Bupropion is present in breast milk. Concentrations of Bupropion in breast milk increase with supplementation. When used as a dietary supplement, the recommended dietary allowance of Bupropion is increased in breastfeeding patients compared to non-breastfeeding patients. Doses of Bupropion for the treatment of dyslipidemias are greater than those used as a dietary supplement. Due to the potential for serious adverse reactions in the breastfed infant (including hepatoxicity), the manufacturer recommends that breastfeeding be discontinued when Bupropion is used for treatment of dyslipidemias

• Common Adverse effects

Abnormal dreams, Headache, Insomnia, Nausea

• Less Common Adverse effects:

Appetite changes, chest pain, constipation, dry mouth, dysgeusia, flatulence, GERD, fatigue/lethargy, pruritus, rash, somnolence, upper resp tract d/o, vomiting

• Rare Adverse effects

abnormal LFTs, accidental injury, anemia, angina, angioedema, anxiety, arrhythmia, arthralgia, depression, Diarrhea, dizziness, epistaxis, erythema multiforme, HTN, MI, neuropsychiatric symptoms, polyuria, respiratory d/o, Stevens-Johnson Syndrome

• Observe extreme caution w/ concurrent admin of drugs that lower seizure threshold (e.g., other antidepressants, antipsychotics, theophylline, systemic corticosteroids). Increased risk of side effects w/ levodopa or amantadine. Decreased exposure w/ CYP2B6 inducers (e.g. ritonavir, lopinavir, efavirenz). May increase exposure of CYP2D6 substrates (e.g. venlafaxine, fluoxetine, antipsychotics, β-blockers, type 1C antiarrhythmics.
• Potentially Fatal: Concurrent use w/ MAOIs may cause acute toxicity symptoms and increased risk of fatality

The common side effects of Bupropion include the following

Constipation, Diarrhea, Heartburn, pain in the back, arm, or legs, Headache, joint pain.

Symptoms: Hallucinations, nausea and vomiting, loss of consciousness, tachycardia, seizures.

Management: Supportive treatment. Ensure adequate airway, ventilation and oxygenation. Administer activated charcoal for a dose >450 mg w/in 1 hr of ingestion. Perform gastric lavage to decrease absorption. May give benzodiazepine for seizures.

Pharmacodynamic

Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin reuptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both Bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs).

Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour

Pharmacokinetics

• Absorption

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
• https://reference.medscape.com/drug/colestid-Bupropion -342452
• https://go.drugbank.com/drugs/DB00375
• https://www.sciencedirect.com/topics/medicine-and-dentistry/Bupropion
• https://europepmc.org/article/med/6988203