The amount of nicotine contained in a single cigarette is highly variable, ranging from less than 10 mg in a “low nicotine” cigarette to 30 mg in some European cigarettes (Table 85–2). Since most nicotine is either lost in the sidestream (secondhand) smoke, or left in the filter, the absorbed nicotine yield from a smoked cigarette is much less than this, on the order of 0.05 to 3 mg/cigarette.30 The amount of nicotine absorbed by a particular individual from a single smoked cigarette is highly variable among smokers and depends on the puff rate, volume, the depth and duration of inhalation, and the size of the residual.55 Cigars have higher nicotine content than cigarettes (Table 85–2) and potentially greater absorption since cigar and pipe tobacco is typically air cured to achieve a high pH.
TABLE 85–2.Sources of Nicotine ||Download (.pdf) TABLE 85–2. Sources of Nicotine
|Source ||Content (mg) ||Delivered (mg) |
|1 cigarette ||10–30 ||0.05–3 |
|1 cigarette butt ||5–7 ||— |
|1 cigar ||15–40 ||0.2–1 |
|1g snuff (wet) ||12–16 ||2–3.5 |
|1g chewing tobacco ||6–8 ||2–4 |
|1 piece nicotine gum ||2 or 4 ||1–2 |
|1 nicotine patch ||8.3–114 ||5–22 over 16–24 hours |
|1 nicotine lozenge ||2 or 4 ||2–4 |
|1 nicotine nasal spray ||0.5 ||0.2–0.4 |
|30-mL bottle of nicotine liquid refill for e-cigarette cartridges (30, 50, 100 mL bottles also sold) ||0–<36 mg/mL ||<43.2 µg/100mL “puff” of nicotine mist |
The potential for nicotine toxicity from smoking is limited since peak effects by this route will occur within seconds and tend to limit further intake of drug. Most reports of acute nicotine toxicity referable to cigarette exposure are associated with cigarette and cigarette butt ingestion, usually by young children.61,70,79 Although uncommon, severe toxicity from cigarette14,80 ingestion is well reported. Ingesting cigarette soakage water has been recommended on the Internet as a “safe and effective” means of suicide, and several cases are reported.23,76 Intravenous injection of cigarette soakage is also reported.38
Snuff and chewing tobacco are still widely employed by users of smokeless tobacco products,21 despite clear associations with periodontal disease, dental cavities, and up to a 48 times greater risk of oropharyngeal cancers compared with people who do not use tobacco products.22 Snuff, or dip, is a finely ground and sometimes flavored tobacco preparation often sold in small teabaglike pouches that users insert between their lower lips and gums. Chewing tobacco consists of shredded, twisted, or “bricked” dried tobacco leaves. Because nicotine is a weak base, smokeless tobacco is buffered to facilitate buccal absorption. In one survey of major US brands, the pH of marketed oral tobacco products ranged from 5.24 to 8.35, and the nicotine content ranged from 3.37 to 11.04 mg/g.60 Acute nicotine toxicity from smokeless tobacco is rarely reported in adults. A 14 month-old boy had muscle fasciculations and lethargy after ingesting material out of his father’s spittoon, but recovered within 24 hours with supportive care.35 Rectal administration of moist snuff as a treatment for migraine headache resulted in significant toxicity in one patient.44 Presumably the relatively alkaline environment of the rectum facilitated absorption of a high dose.
Nicotine gum has been available without a prescription as an aid to smoking cessation in the United States since 1996. It is sold in 2 mg and 4 mg strengths per piece. Approximately 53% to 72% of the nicotine in the gum is absorbed. It is buffered to an alkaline pH to facilitate buccal absorption. The gum is supposed to be chewed until mouth and throat tingling and a peppery taste develops, signaling nicotine release. The gum is then “parked” in the cheek until the sensation subsides, at which time it may be chewed again to release more drug.65 If used correctly, serum nicotine concentrations rise gradually to a level slightly lower than normally achieved by cigarette smoking.65 If the gum is swallowed whole, then serum concentrations rise even more slowly because the acidic environment of the stomach delays absorption.12 Conversely, if the gum is chewed vigorously and saliva is swallowed, then nicotine concentrations may rise rapidly and adverse reactions may occur.80
Nicotine lozenges containing 2 and 4 mg of nicotine are available for purchase without a prescription in the Unites States. The potential for rapid absorption of nicotine as a bolus dose from chewing the lozenge is a concern.
Nicotine patches have been FDA approved for purchase without prescription in the United States since 1996. Most nicotine transdermal delivery systems are designed to deliver 7, 14, or 21 mg of nicotine over 24 hours.37 Because many patch users have difficulty sleeping, experience vivid dreams, or have nightmares if they wear the patch overnight, systems designed to be applied for only 16 hours are now made. Several reports document consequential nicotine toxicity related to nicotine patch misuse. Toxicity may occur in people who continue to smoke cigarettes after beginning therapy with the nicotine patch. Children have developed symptoms after exploratory self-application of one or more patches to the skin,85,88 and concurrent use of multiple patches has been used as a means of suicide.47,81,87 Severe toxicity may also occur if patches are punctured—for example, by biting or tearing—thus allowing delivery of excess content.88 The patch reservoirs contain an estimated 36 to 114 mg per patch.64 This amount exceeds the estimated LD50 for nicotine in humans of 1 mg/kg for most children and many adults.
A nicotine spray has been available since 1996 to aid efforts at smoking cessation. The most commonly reported adverse effects during initiation of therapy are due to local irritation and include rhinorrhea, lacrimation, sneezing, and nasal and throat irritation.41 One spray delivers 0.5 mg of nicotine and the recommended dose is two sprays every 30 to 60 minutes as needed. The absorption is about 50% of the delivered dose and may be diminished or delayed by rhinitis or by α-adrenergic agonist decongestants.50 No report of acute nicotine toxicity from nicotine inhalers has been published to date.
Electronic cigarettes, or e-cigarettes, are a relatively new nicotine delivery product now widely available in various strengths and flavors.91 The devices resemble cigarettes and contain a rechargeable battery pack along with a small heating element attached to a reservoir of liquid nicotine. An electronic airflow censor activates the heating element when the user inhales, allowing release of a “puff” of nicotine-containing vapor. An FDA analysis of cartridges found that identically labeled products contained variable amounts of nicotine and a number of potentially harmful contaminants.82 The potential for harm is evident, particularly since e-cigarette sales are still unrestricted in many states and large-volume liquid nicotine replacement fluid bottles (used to refill e-cigarette cartridges) are increasingly available. The nicotine content of these bottles is substantial. Formulations of different strengths are sold; the highest strength preparations may contain over a gram of nicotine per 30mL bottle, raising serious concerns about the risk of both unintentional and intentional toxic exposures. Analysis of calls to US poison centers about e-cigarette exposures has shown substantial increase between the years 2010 and 2014, with significantly greater adverse effects reported compared to calls about cigarette exposures.16a
Nicotine Receptor Partial Agonists (Varenicline, Cytisine)
Nicotine receptor partial agonists are used to aid smoking cessation. Theoretically, they work by reducing smoking satisfaction (agonist antagonism effect) while helping to maintain moderate levels of central dopamine release (partial agonist effect). Cytisine is a plant-derived xenobiotic with a chemical structure similar to nicotine that has been used in East and Central Europe as a smoking cessation drug since the 1960s under the trade name Tabex (Sopharma Pharmaceuticals). Despite its widespread use, it has not been well studied for its safety, efficacy, pharmacokinetics, and pharmacodynamics in humans.29 Varenicline (marketed as Chantix in the United States and Champix in Europe) was approved as a prescription-only aid to smoking cessation in 2006. Several randomized controlled trials demonstrated efficacy in controlling nicotine cravings and evidence suggests that varenicline increases the probability of successful abstinence from smoking.16 In 2009, the FDA mandated a black box warning due to an association with increased risk of depression or suicidal behavior. There is still limited experience with effects or outcomes after acute overdose.
Residual moisture or dew drops on tobacco leaves may contain as much as 9 mg of nicotine per 100 mL.34 Sweat wrung out of the shirts worn by workers during tobacco harvest in one study contained up to 98 mg/mL of nicotine.34 Risk factors for GTS include younger age, working in wet tobacco, and a relative lack of work experience.3,5,58,62 These factors may all be related to a lack of nicotine tolerance. The use of impermeable garments or other barrier protection is the only protective factor consistently noted to be useful across multiple studies.4,58,62
Nicotine in the form of tobacco extracts was first reported as effective for pest control in 1690. In 1886 a mixture of tobacco and soapsuds was advocated for aphid control, but it was not until 1912 that the first commercial nicotine insecticides were developed. Crop dusting with nicotine sulfate began in 1917, although at the time this was mostly accomplished by horse-drawn carriage.69 The most widely known application of 40% nicotine sulfate, BlackLeaf 40, was discontinued in 1992. Nicotine is still available as a restricted use pesticide, and a 14% preparation of nicotine is still marketed as a greenhouse smoke fumigator.66 Because nicotine pesticides are highly concentrated, the ingestion of even small amounts may produce serious toxicity, including catastrophic brain injury75 and death.48
The neonicotinoids are a relatively new class of insecticides with theoretical safety by markedly reducing the affinity for vertebrate nicotinic receptors as compared with those in insects.84 Neonicotinoid compounds include the heterocyclics nithiazine, imidacloprid, thiacloprid, and thiamethoxam; and the acyclics nitenpyram, acetamiprid, clothianidin, and dinotefuran. Experience with human poisoning is still limited.
Tobacco has been used for medicinal and therapeutic purposes in many societies for some time. Tobacco extract and tobacco smoke enemas were used in the pre-Columbian Americas by many tribes for both medicinal and spiritual purposes. They are still recommended by some naturopaths and folk healers as a remedy for constipation, urinary retention, pin worm and “hysterical convulsions.” Nicotine has also been recommended as a treatment for migraine, on the basis of its vasoconstrictive properties.36 Nicotine poisoning has resulted from “therapeutic misadventure” in several documented cases.33,44,45 For example, acute nicotine toxicity occurred in an 8 year-old boy after application of a homemade remedy for eczema made from a mixture of tobacco leaves, lime juice, and freeze dried coffee.26