PharmacologyTier 1Medical Sciences concept

Smoking cessation pharmacotherapy (varenicline, bupropion, NRT) - mechanisms and contraindications

Core concept

Nicotine dependence is alpha4beta2 nicotinic receptor upregulation on VTA dopamine neurons; every pharmacotherapy addresses that receptor or its consequences

Agent	Mechanism
NRT	Full nicotinic agonist - replaces nicotine without the combustion products
Varenicline	alpha4beta2 PARTIAL agonist - dual action: relieves craving/withdrawal (agonist) and blocks the reward of a cigarette (antagonist)
Bupropion	Noradrenaline-dopamine reuptake inhibitor + nicotinic antagonist
Nortriptyline	Second-line, NA reuptake

Efficacy: varenicline > combination NRT ~ bupropion > single NRT > placebo
- Combination NRT (a patch for background + a rapid form for cravings) approaches varenicline

Varenicline
- Start 1 week before the quit date, titrate 0.5 mg daily -> 0.5 mg bd -> 1 mg bd; continue 12 weeks
- Nausea is the commonest effect (~30%), plus vivid/abnormal dreams and insomnia
- Renally cleared - halve the dose if eGFR <30
- EAGLES trial found no excess of serious neuropsychiatric events vs placebo - the old boxed warning was removed
- Caution: history of seizures, and monitor mood in significant psychiatric illness
Bupropion
- Contraindicated: seizure disorder, eating disorder (bulimia/anorexia), abrupt alcohol or benzodiazepine withdrawal, MAOI within 14 days
- Lowers seizure threshold, potent CYP2D6 inhibitor, insomnia, dry mouth
NRT - patch (16 or 24 h), gum, lozenge, inhalator, mouth spray
- Safe in stable cardiovascular disease and after ACS; nicotine itself is not the carcinogen
- Under-dosing is the usual failure - match patch strength to cigarettes/day and add a rapid form
Pregnancy: NRT is preferred (intermittent forms); varenicline and bupropion are not recommended
Smoking induces CYP1A2 - quitting raises clozapine, olanzapine, theophylline and caffeine levels and can precipitate toxicity within days

Brief advice works and is the minimum standard - the 5 As
- Ask about smoking status at every visit
- Advise all smokers to quit, with personalised advice linked to their presenting condition
- Assess readiness to quit
- Assist with a quit plan, pharmacotherapy and referral
- Arrange follow-up
- An abbreviated form is Ask-Advise-Help (AAH) or Ask-Advise-Refer
Combine pharmacotherapy with behavioural support (Quitline 13 7848) - the combination roughly doubles success over either alone
Smoking cessation is the single highest-yield intervention in COPD, ischaemic heart disease, PAD, Crohn disease, and before any surgery
Relapse is the norm - most quitters need multiple attempts; treat it as a chronic relapsing condition, not a failure
Review clozapine and theophylline doses when a patient stops smoking, including on hospital admission to a smoke-free ward

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