NICOTINE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for NICOTINE (NICOTINE).
Nicotine is a nicotinic acetylcholine receptor (nAChR) agonist; binds to α4β2 and α7 subtypes in the central nervous system, causing release of dopamine and other neurotransmitters, leading to stimulation and reward effects. Also acts on peripheral nicotinic receptors affecting autonomic ganglia, neuromuscular junction, and adrenal medulla.
| Metabolism | Primarily hepatic via CYP2A6 and CYP2B6 to cotinine, then further metabolized to trans-3'-hydroxycotinine. Also metabolized via glucuronidation (UGT1A4, UGT1A9). Renal excretion of metabolites. |
| Excretion | Primarily hepatic metabolism (80-90%) to cotinine and nicotine-N-oxide; renal excretion of unchanged nicotine accounts for 5-10% in non-smokers and up to 30% in smokers with acidic urine; less than 2% excreted in feces via biliary elimination. |
| Half-life | Terminal elimination half-life is approximately 2 hours (range 1-4 hours); short half-life leads to frequent dosing to maintain therapeutic effects. |
| Protein binding | Less than 5% bound to plasma proteins (mainly albumin). |
| Volume of Distribution | Approximately 2-3 L/kg (range 1-4 L/kg), indicating extensive tissue distribution including brain, lungs, and skeletal muscle. |
| Bioavailability | Inhalation (smoking): 80-90% (rapid absorption); intranasal: 50-80%; transdermal: 100% (systemic absorption rate varies by patch); oral (gum/lozenge): 50-80% (buccal absorption avoids first-pass metabolism); oral (swallowed): <50% due to first-pass hepatic metabolism. |
| Onset of Action | Inhalation (smoking): 7-10 seconds; intranasal: 5-10 minutes; transdermal: 2-4 hours; oral (gum/lozenge): 15-30 minutes. |
| Duration of Action | Inhalation: 1-2 hours; intranasal: 1-2 hours; transdermal: 24 hours with steady release; oral: 1-2 hours; duration is limited by rapid clearance and distribution. |
Transdermal patch: 21 mg/24 hours applied to dry, non-hairy skin once daily; gum: 2-4 mg chewed as needed (max 24 pieces/day); lozenge: 2-4 mg dissolved as needed (max 20 lozenges/day); inhaler: 6-16 cartridges/day (each 4 mg delivered); nasal spray: 1-2 doses/hour (1 dose = 0.5 mg, 32 mg/day max).
| Dosage form | FILM, EXTENDED RELEASE |
| Renal impairment | No specific dose adjustment recommended; use with caution in severe renal impairment due to increased risk of accumulation. |
| Liver impairment | For Child-Pugh class A or B: no adjustment; Child-Pugh class C: use with caution due to reduced clearance. |
| Pediatric use | Not recommended in patients <18 years except under specific clinical guidance; weight-based dosing not established. |
| Geriatric use | Start at lower end of dosing range (e.g., 7 mg/24 h transdermal); monitor for adverse effects due to reduced clearance. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for NICOTINE (NICOTINE).
| Breastfeeding | Nicotine is excreted into breast milk with M/P ratio approximately 2.9. Infant exposure correlates with maternal smoking. Adverse effects include colic, vomiting, diarrhea, and reduced milk production. Breastfeeding is discouraged in women using nicotine replacement therapy. |
| Teratogenic Risk | Nicotine is teratogenic. First trimester: Increased risk of spontaneous abortion, preterm birth, and low birth weight. Second/third trimester: Impaired fetal lung development, placental insufficiency, and neurobehavioral deficits. No trimester is safe. |
■ FDA Black Box Warning
WARNING: ADDICTION AND TOXICITY. Nicotine is a highly addictive substance. Keep out of reach of children and pets. Accidental ingestion or exposure can cause severe toxicity, including seizures, respiratory arrest, and death. Do not use in non-smokers or individuals with cardiovascular disease without medical supervision.
| Serious Effects |
["Non-smokers (never smokers or occasional smokers) - risk of addiction","Children under 18 years (unless prescribed)","Patients with severe renal impairment (e.g., end-stage renal disease) - risk of accumulation","Pregnancy (unless smoking cessation benefits outweigh risks; alternative therapies preferred)","Breastfeeding (avoid use or discontinue nursing due to potential for infant exposure)","History of severe cardiovascular disease (e.g., recent MI, life-threatening arrhythmias, unstable angina)","Hypersensitivity to nicotine or any component of the product"]
| Precautions | ["Risk of nicotine toxicity in children and pets; keep products safely stored","Caution in patients with cardiovascular disease (e.g., recent myocardial infarction, serious arrhythmias, unstable angina) - consider risk vs benefit","May cause hypertension, tachycardia, and vasospasm","Avoid in patients with uncontrolled hyperthyroidism or pheochromocytoma","May exacerbate peptic ulcer disease","Use during pregnancy only if benefit outweighs risk; nicotine can cause fetal harm","Do not use in patients with known hypersensitivity to nicotine or components of the formulation"] |
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| Fetal Monitoring |
| Monitor fetal growth via ultrasound every 4-6 weeks after 20 weeks gestation. Non-stress testing and biophysical profile weekly after 32 weeks. Assess maternal blood pressure, heart rate, and nicotine withdrawal symptoms. Urine cotinine levels if adherence concern. |
| Fertility Effects | Nicotine reduces female fertility by impairing oviductal transport, altering endometrial receptivity, and causing ovarian toxicity. Male fertility: decreases sperm count, motility, and increases DNA fragmentation. Reversible upon cessation. |