NICOTINE
Clinical safety rating
cautionComprehensive 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. |
| Molecular Weight | 162.23 |
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 | Nicotine is a known teratogen. Use is contraindicated during first trimester due to increased risk of congenital anomalies, including orofacial clefts and neural tube defects. Smoking cessation aids should be used only if benefits outweigh risks. |
| 2nd trimester | Use with caution. Second trimester exposure is associated with reduced fetal growth and altered brain development. Avoid use if possible; consider non-pharmacologic smoking cessation. |
| 3rd trimester | Use with caution. Third trimester exposure increases risk of preterm birth, low birth weight, and placental abruption. Nicotine replacement therapy should be avoided unless necessary. |
Clinical note
Comprehensive clinical and safety monograph for NICOTINE (NICOTINE).
| Placental transfer | Nicotine readily crosses the placenta via passive diffusion and active transport. Fetal concentrations are 15% higher than maternal levels. It accumulates in amniotic fluid and fetal tissues. |
| Breastfeeding | Nicotine is excreted into breast milk in concentrations higher than maternal plasma. Infant exposure can cause tachycardia, hypertension, and potential nicotine dependence. Smoking cessation aids are generally discouraged during breastfeeding; non-pharmacologic methods preferred. |
| Lactation Rating | Avoid |
| 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. |
| 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. |
■ 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 |
History of anaphylaxis to nicotine replacement therapyImmediate post-myocardial infarction period (within 2 weeks)Serious cardiac arrhythmiasSevere angina pectoris
| 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 |
| Food/Dietary | Avoid acidic beverages (e.g., coffee, juice, soda) immediately before or while using nicotine gum or lozenge, as they can reduce buccal absorption. Food does not affect nicotine patch absorption. Alcohol does not interact directly but may impair judgment regarding smoking cessation. |
| Clinical Pearls | Nicotine replacement therapy (NRT) should be used with caution in patients with recent myocardial infarction, serious arrhythmias, or severe angina. Smoking while using NRT can cause nicotine toxicity. The transdermal patch may cause skin irritation; rotate application sites. For rapid symptom relief, gum or lozenge is preferred over patch. Monitor for signs of nicotine overdose: headache, dizziness, nausea, abdominal pain. |
| Patient Advice | Do not smoke or use any other tobacco products while using nicotine replacement therapy. · If using the patch, apply to a clean, dry, hairless area on the upper body or arm; rotate sites daily. · Chew gum slowly and park between cheek and gum when peppery taste appears; discard after 30 minutes. · For lozenges, allow to dissolve slowly; do not bite or swallow whole. · Seek medical help if you experience symptoms of overdose: severe headache, dizziness, blurred vision, confusion, weakness, vomiting, cold sweat, or difficulty breathing. |
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