Smoking cessation agents

Definition and Overview
Smoking cessation agents are a pharmacologic class of drugs designed to aid individuals in quitting the use of nicotine-containing products, primarily cigarettes. These agents work by reducing nicotine cravings, managing withdrawal symptoms, or antagonizing the reward pathways associated with tobacco use. Smoking is a leading cause of preventable death globally, and the development of pharmacologic interventions is critical for reducing its public health burden.

Smoking cessation agents are usually used in combination with behavioral therapy and are most effective when part of a structured cessation program. The U.S. FDA has approved three main types of pharmacologic therapies: nicotine replacement therapy (NRT), bupropion SR, and varenicline. Other agents, including cytisine and nortriptyline, are used off-label or are approved in other regions.

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Classification of Smoking Cessation Agents

Class	Examples	Route
Nicotine Replacement Therapy (NRT)	Patches, gum, lozenges, sprays, inhalers	Transdermal, oral, nasal
Nicotinic Partial Agonists	Varenicline (Chantix), Cytisine	Oral
Atypical Antidepressants	Bupropion SR (Zyban)	Oral
Tricyclic Antidepressants (Off-label)	Nortriptyline	Oral
Clonidine (Off-label)	Clonidine	Oral, transdermal

Mechanisms of Action

1. Nicotine Replacement Therapy (NRT):

   • Provides a controlled amount of nicotine without harmful combustion products.

   • Reduces withdrawal symptoms (irritability, anxiety, cravings).

   • Binds to nicotinic acetylcholine receptors (nAChRs) in the brain to mimic the effects of nicotine.

2. Varenicline (Chantix):

   • Partial agonist at α4β2 nAChRs.

   • Stimulates dopamine release to reduce cravings.

   • Blocks nicotine binding → diminishes reward if patient relapses.

3. Bupropion SR (Zyban):

   • Norepinephrine and dopamine reuptake inhibitor (NDRI).

   • Reduces nicotine withdrawal symptoms and cravings.

   • Weak antagonist at nicotinic receptors.

4. Cytisine (Europe, Canada):

   • Plant-derived nicotinic partial agonist.

   • Mechanistically similar to varenicline but with shorter half-life.

5. Nortriptyline and Clonidine:

   • Off-label agents used for patients who cannot tolerate first-line options.

   • Affect adrenergic and noradrenergic pathways to reduce withdrawal and anxiety.

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Generic and Brand Names

Generic Name	Brand Name(s)	Class
Nicotine	Nicorette, NicoDerm CQ	NRT
Varenicline	Chantix (USA), Champix (EU)	Nicotinic partial agonist
Bupropion SR	Zyban, Wellbutrin SR	Atypical antidepressant
Cytisine	Tabex, Desmoxan	Nicotinic partial agonist
Nortriptyline	Pamelor (off-label)	Tricyclic antidepressant
Clonidine	Catapres (off-label)	Alpha-2 adrenergic agonist

Dosing and Administration

1. NRT Products:

   • Patch: 21 mg, 14 mg, 7 mg per 24 hours (step-down)

   • Gum/Lozenge: 2 mg or 4 mg per dose every 1–2 hours (max 24 pieces/day)

   • Nasal Spray: 1 spray/nostril = 1 mg/dose (limit: 80 sprays/day)

   • Inhaler: 10 mg cartridge; frequent puffs as needed

2. Varenicline:

   • Day 1–3: 0.5 mg once daily

   • Day 4–7: 0.5 mg twice daily

   • Then: 1 mg twice daily for 12 weeks (extendable)

3. Bupropion SR:

   • Day 1–3: 150 mg once daily

   • Then: 150 mg twice daily for 7–12 weeks

4. Cytisine (Tabex):

   • Loading dose with step-down over 25 days

   • Common: 1 tablet every 2 hours initially → taper

5. Nortriptyline:

   • Start 25 mg/day, titrate to 75–100 mg/day

   • Begin 10–28 days before quit date

6. Clonidine:

   • 0.1 mg orally twice daily or patch once weekly

   • Titrate based on response and side effects

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Efficacy and Comparative Effectiveness

Agent/Class	Quit Rates at 6 Months (Approximate)	Notes
NRT Monotherapy	14–20%	Best when matched to nicotine dependence
NRT Combo Therapy	25–30%	E.g., patch + gum
Bupropion SR	20–25%	Useful in depression
Varenicline	30–35%	Most effective monotherapy
Cytisine	20–25%	Effective, lower cost
Nortriptyline	20%	Off-label; cardiac monitoring advised
Clonidine	15–20%	Off-label; sedation, hypotension common

Combination therapy (e.g., NRT + bupropion or NRT + varenicline) has additive effects in selected populations.

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Side Effects

Agent	Common Side Effects	Serious Reactions
NRT	Mouth/throat irritation, hiccups (gum), skin rash (patch)	Nicotine toxicity if overdosed
Varenicline	Nausea, vivid dreams, insomnia	Suicidal ideation, cardiovascular risk (rare)
Bupropion	Dry mouth, insomnia, tremor	Seizures (dose-dependent), suicidality risk
Cytisine	Nausea, sleep disturbances	Rare hepatotoxicity (rarely reported)
Nortriptyline	Dry mouth, sedation, constipation	Arrhythmias, overdose toxicity
Clonidine	Drowsiness, dry mouth, hypotension	Rebound hypertension if stopped abruptly

Neuropsychiatric symptoms are a shared concern, especially in varenicline and bupropion, although newer studies show safety in patients with stable psychiatric conditions.

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Contraindications and Cautions

Agent	Contraindications	Precautions
NRT	Immediate post-MI, arrhythmias, severe angina	Caution in pregnancy; patch may be safer
Varenicline	Hypersensitivity	Adjust in renal impairment
Bupropion	Seizure disorder, eating disorders, MAOIs	Monitor for neuropsychiatric symptoms
Cytisine	Not FDA-approved in US	Use with care in hypertension
Nortriptyline	Recent MI, arrhythmias	ECG monitoring in elderly
Clonidine	Bradycardia, severe hypotension	Monitor BP closely; taper gradually

Use in Special Populations

Population	Recommendation
Pregnancy	Prefer NRT with physician oversight; bupropion off-label
Adolescents	Limited evidence; behavioral interventions preferred
Psychiatric illness	Bupropion and varenicline safe if well-monitored
Cardiac disease	Caution with bupropion, varenicline; NRT under supervision

Drug Interactions

Agent	Interacts With	Mechanism/Concern
Bupropion	MAOIs, antipsychotics, alcohol	Seizure risk, serotonin syndrome
Varenicline	Alcohol	Enhanced effects, aggression reports
Nortriptyline	SSRIs, MAOIs, anticholinergics	Serotonin syndrome, anticholinergic overload
Clonidine	CNS depressants, beta-blockers	Sedation, bradycardia, rebound hypertension
NRT	Few systemic interactions	Mostly local side effects

Behavioral and Psychosocial Support

Pharmacotherapy should be combined with:

• Counseling sessions (in-person or remote)

• Quit lines and digital tools

• Motivational interviewing

• Cognitive-behavioral therapy (CBT)

This dual approach increases success rates significantly compared to drug therapy alone.

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Regulatory and Access Notes

Region	Available Products	Reimbursement
United States (FDA)	All major agents including varenicline, NRT, bupropion	Some covered by insurance/Medicare
European Union (EMA)	All except bupropion in some countries	National systems may reimburse
Canada	NRT, bupropion, cytisine (Tabex/Cravv)	Available OTC or by Rx
WHO Essential Medicines	Nicotine (patch, gum), bupropion, varenicline	Yes

Future Developments and Research

• E-cigarettes: Not approved but under investigation as harm reduction tools.

• Nicotine vaccines: Aim to block nicotine from entering the brain (still experimental).

• Extended-duration varenicline: Ongoing studies on long-term relapse prevention.

• Digital therapeutics: FDA-cleared mobile applications for behavioral support.