85: Nicotine

The tobacco plant is native to the Americas, and its use most likely predates the Mayan empire. In 1492 Christopher Columbus and his crew were given tobacco by the Arawaks, but reportedly threw it away not knowing any use for it. Ramon Pane, a monk who accompanied Columbus on his second voyage to America, is credited with introducing tobacco to Europe.⁸³

The principal alkaloid, nicotine, is still primarily derived from members of the genus Nicotiana, collectively known as the tobacco plant, in the family Solanaceae. The most important species in human use today is Nicotiana tabacum and the primary method of nicotine exposure is cigarette smoking. Because of the highly addictive properties of nicotine, the global disease burden related to cigarette use is staggering. Cigarette smoking increases rates of chronic obstructive pulmonary disease (COPD), cardiovascular disease, pulmonary infections, macular degeneration, and cancers, and causes more than 5 million deaths worldwide per year. Chronic nicotine exposure causes cardiovascular damage related to catecholamine release and vasoconstriction, and directly promotes angiogenesis, neuroteratogenicity, and possibly some cancers.⁵¹ However, there are more than 3000 components to tobacco smoke and nicotine per se may not be the crucial determinant of the total health burden associated with its use.

Although the long-term effects of cigarette smoking and tobacco dependency are significant, this chapter is concerned with the sources, effects, and management of acute toxicity referable to nicotinic receptor stimulation and cholinergic activation. Reviews of case data from the National Poison Data System suggest that cigarettes are by far the most common vehicle implicated in acute nicotine exposures and poisoning in the United States.² Smoking cessation products containing nicotine are increasingly available and some of the more novel smokeless tobacco products have the appearance of candy, raising concern about the potential for unintentional poisoning of young children, in particular.²¹

Compared with other xenobiotics, exposure to nicotine containing products is nonetheless a relatively rare cause of acute poisoning. For example, over a period of 27 years from 1983 to 2009, tobacco products accounted for 217,340 calls, or 0.37%, of all pediatric exposures reported to poison centers in the United States,² and accounted for 0.7% of all unintentional poisoning cases in children treated in US hospital emergency departments in one national estimate.³¹ Although fatalities are reported, most patients with nicotine exposure have a benign course, with only mild to moderate symptoms and an infrequent need for hospitalization.

Nicotine receptor partial agonists/antagonists are a relatively new class of drug mimicking the physiologic effects of nicotine. A 2-year review of poison center data from the California Poison Control System found 36 calls regarding human exposures to varenicline (Chantix), which was approved in 2006 by the US Food and Drug Administration (FDA) as a smoking cessation aid.⁴⁶ Of these, 17 cases had no outcome data or involved coingestions. Nine of the remaining cases involved unintentional exposure in children younger than 6 years of age, one of whom was hospitalized; none experienced major adverse events.

Use of nicotine as an insecticide is no longer in widespread use in the United States, but are still used in other countries and can be purchased from some online retailers. The neonicotinoids are a relatively new class of insecticide developed in the last quarter century, and epidemiologic data about their role in acute pesticide poisoning are still limited. A retrospective review of poison center data from Thailand found no reports of neonicotinoid exposures before 1993.⁷¹ Between 1993 and 2007 there were a total of 70 cases, including two deaths. The number of exposures reported annually increased dramatically after 2002, suggesting that neonicotinoid insecticides may still be an emerging cause of acute pesticide poisoning. However, in the year with the highest case incidence, these insecticides still represented less than 3% of all pesticide exposures reported.

Dermal exposure to tobacco plants during harvest remains an important source of occupational nicotine toxicity known as green tobacco sickness (GTS). GTS was first reported in 1970 among tobacco workers in Florida.⁸⁷ In 1992, the US Centers Disease and Control and Prevention estimated the crude 2-month incidence rate of hospital treated GTS was 10 per 1000 workers in a five-county area in Kentucky.⁶² Overall prevalence estimates among seasonal and migrant farmworkers are as high as 25% to 40% of workers.^3,5,73

The pharmacologic characteristics of nicotine are listed in Table 85–1. Nicotine is well absorbed from the respiratory tract, mucosal surfaces, skin, and the intestines. Nicotine is a weak base (pKa = 8.0) and is more readily absorbed in an alkaline environment. Many tobacco and nicotine replacement products are therefore buffered to alkaline pH to facilitate absorption.

Nicotine from cigarette or cigar smoke is carried on inhaled tar particles into the lungs where a large alveolar surface area allows rapid absorption into the pulmonary circulation. In the bloodstream, nicotine is about 69% ionized at pH 7.4 and less than 5% is bound to plasma proteins. Distribution to body tissues is rapid and extensive, with an average volume of distribution of about 2.6 L/kg.⁶ Nicotine readily crosses the placental barrier and is secreted in breast milk. Metabolism occurs primarily in the liver via P450 cytochrome ­oxidases CYP2A6 and CYP2D6, aldehyde oxidase, flavin monooxygenase, and by glycosylation. About 70% of circulating nicotine is metabolized to cotinine, and much smaller amounts to nornicotine, nicotine-1-N-oxide, nicotine glucuronide, and 2′-hydroxynicotine.

Peak plasma concentrations of nicotine and cotinine are influenced most strongly by individual variations in clearance.^10,11 Hepatic nicotine metabolism is inducible and nicotine-dependent individuals metabolize the drug more rapidly than naïve ones.⁴⁰ Nicotine metabolism may also be linked to race and sex. Asians and African Americans metabolize nicotine more slowly than Caucasians, and they have prolonged cotinine clearance in the urine.^10,52,68 Women metabolize nicotine faster than men, which is further accelerated by oral contraceptive use and pregnancy, and is most likely mediated by an influence of estrogen on CYP2A6 activity.⁴⁰

Renal excretion of unchanged nicotine accounts for 2% to 35% of total nicotine elimination,¹⁵ and this is pH dependent. Nicotine is reabsorbed in the proximal tubule and acidification of the urine enhances elimination. The half-life of nicotine in the body is 1 to 4 hours and it decreases with repeated nicotine exposure such as with habitual cigarette smoking. Cotinine and trans-3′-hydroxycotinine are eliminated in the urine as glucuronide esters independent of urine pH. The elimination half-life of cotinine is approximately 20 hours and therefore urinary cotinine is a more useful marker of nicotine exposure. The apparent elimination half-life of nicotine after transdermal patch removal is longer than that noted with nicotine exposure by other routes,⁴³ but this is most likely because a dermal reservoir of drug is established during patch use, from which absorption continues after removal.

Cigarette smoking modulates the bioavailability and effectiveness of numerous medications through effects on drug absorption, metabolism, or pharmacodynamics. Cigarette smoking induces CYP1A2 and accelerates the metabolism of caffeine, clozapine, olanzapine, tacrine, theophylline, and erlotinib.^39,42 This may not be an effect of nicotine. For example, intravenous nicotine administration does not affect theophylline metabolism.¹² Smokers also have diminished effectiveness of opioids, benzodiazepines, β-adrenergic antagonists, and nifedipine,¹⁹ and are more likely to fail antacid and H₂-blocker therapy for peptic ulcer disease.¹² However, these interactions have also not been clearly linked to an effect of nicotine per se.

The LD₅₀ of nicotine has been estimated at about 0.5 to 1 mg/kg in adults.^33,35,54 Severe toxicity is reported with ingestion of less than 2 mg in a child,^59,80 and this dose is sufficient to produce mild symptoms in an unhabituated adult. Children younger than 6 years of age who ingest one or more cigarettes, or three or more cigarette butts, generally develop symptoms of nicotine toxicity.⁸⁰ A retrospective review of 10 pediatric cigarette ingestions found that all four patients with symptoms requiring medical evaluation and treatment had ingested at least two entire cigarettes.⁵⁴

Acute tolerance to nicotine develops in smokers who take in small doses of nicotine regularly throughout the day. Sensitization to the effects of nicotine is restored with overnight abstinence.^9,40 Tolerance may also develop in tobacco workers with regular exposure to tobacco plant leaves. However, the phenomenon of acute tolerance, along with considerable genetic variability in nicotine metabolism, implies a range of susceptibility to drug effect.

Cigarettes and Cigars

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.

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 cigarette^14,80 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

Oral Tobacco

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.

Gum

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

Lozenges

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.

Transdermal Patches

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.

Spray/Inhaler

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

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.

Plants/Leaves

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

Salts (Pesticides)

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

Neonicotinoids

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.

Miscellaneous

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

Nicotine mimics the effects of acetylcholine release by binding to nicotinic receptors (nAChR) in the brain, spinal cord, autonomic ganglia, adrenal medulla, neuromuscular junctions, and chemoreceptors of the carotid and aortic bodies (Chap. 14). Activation of nAChR in the CNS directly stimulates neurotransmitter release. When nicotine binds to this receptor, an ion channel opens allowing an influx of cations, mostly sodium and calcium. Voltage-gated calcium channels are then activated leading to further influx of calcium, and a variety of downstream effects, including depolarization.

At doses generally produced by cigarette smoking there is stimulation of the reticular activating system and an alerting pattern on electroencephalogram.⁹² Nicotine-stimulated release of dopamine occurs in the mesolimbic area, the corpus striatum, the prefrontal cortex, and in the nucleus accumbens; it is an important mediator of nicotine addiction.⁵⁶ Nicotine also stimulates glutaminergic activation and the GABAergic inhibition of dopaminergic neurons in the hippocampus, basal forebrain, and ventral tegmental area of the midbrain.^8,28 These pathways, along with endogenous cannabinoid and opioid systems, are also thought to be important neuromodulatory pathways for drug-induced reward, dependence, and withdrawal.^53,56,67 Norepinephrine, acetylcholine, GABA, serotonin, glutamate, and endorphins are all released by nicotine and are associated with cognitive and mood enhancement as well as appetite suppression, increased basal energy expenditures and anxiety reduction.⁸

Nicotine’s clinical effects are dose-dependent. Low doses of nicotine and related compounds stimulate nicotinic receptors centrally and in autonomic and somatic motor nerve fibers, resulting in sympathetic agonism. At toxic concentrations, prolonged or excessive nicotinergic stimulation ultimately leads to receptor blockade (Chap. 69), with parasympathetic and neuromuscular-blocking effects.

At very high doses nicotine induces seizures. In a mouse model, nicotine-induced seizures are blocked by the nicotine-receptor antagonists mecamylamine, methyllycaconitine citrate, and hexamethonium.²⁴ However, when given to mice at slightly higher doses, these nicotine receptor antagonists are epileptogenic. The specific mechanisms by which nicotine produces seizures are unknown. A disinhibition model has been proposed in which desensitization or antagonism of central nicotinic cholinergic neurons blocks excitatory input to GABAergic neurons and a reduction of inhibitory GABAergic input to pyramidal cells then results in increased excitability and seizures.^1,17,27,32 An alternative hypothesis is that synchronous depolarization from activation of α7*-subtype nicotinic receptors ­promotes kindling-induced seizures.²⁷

Exposure to nicotine in low doses comparable to cigarette smoking in nicotine naïve patients produces fine tremor, cutaneous vasoconstriction, increased gastrointestinal motility, nausea, and increases in heart rate, respiratory rate, and blood pressure. Low-dose nicotine also increases mental alertness and produces euphoria. Because nicotine is poorly absorbed in the acid environment of the stomach, symptom onset may not occur until 30 to 90 minutes after ingestion of nicotine-containing products.

Early signs and symptoms of consequential nicotine toxicity are referable to nicotinic cholinergic excess: increased salivation, nausea, vomiting, diaphoresis, and diarrhea may all occur within minutes of systemic absorption. Vasoconstriction may manifest with pallor and hypertension. Tachycardia may also occur, and nicotine gum chewing has been implicated in the development of atrial fibrillation in several cases.^18,74 Neurologic signs and symptoms include headache, dizziness, ataxia, confusion, and perceptual distortions. Nicotine is an irritant and ingestion of nicotine, including use of nicotine gum, may cause burning and pain in the mouth, and constriction of the throat muscles. Similarly, application of nicotine patches generally results in dermal irritation.

Data from poison centers in the United States suggests that most patients with nicotine exposure rarely display more than mild symptoms and typically have a benign course. Vomiting is the most common adverse effect reported, although agitation also occurs. The relative rarity of life-threatening symptoms may be due to autodecontamination from vomiting, or may reflect selection bias since most reported cases involve unintentional tobacco ingestion by young children. Although less common, ingestion of novel smokeless tobacco preparations, such as gums and lozenges, may be more likely to produce symptoms compared to cigarette ingestion, possibly because these are buffered to promote more rapid nicotine release.⁸⁰

Because nicotine is rapidly metabolized, patients who develop only mild symptoms are expected to recover quickly. Most patients recover fully within 12 hours. An important exception to this rule is patients with symptoms of nicotine toxicity after transdermal nicotine patch application, because a reservoir of drug may persist in the skin after patch removal and can serve as a source of ongoing absorption.

Clinical manifestations of severe poisoning are classically biphasic, reflecting early central stimulation followed by depression. Initial signs may include cardiac dysrhythmias, seizures, and muscle fasciculations in addition to the cholinergic features described above. Bradycardia, hypotension, coma, and neuromuscular blockade with respiratory failure from muscular paralysis may develop later on (Table 85–3).

Exposure to fresh tobacco leaves may produce GTS, which has been likened to the experience of seasickness. The syndrome is characterized by dizziness, headache, nausea, weakness, vomiting, diarrhea, abdominal cramps, and chills. Signs of autonomic instability may also be present in severe cases. Onset of toxicity is typically within 3 to 17 hours after exposure and the duration of illness may be several days.⁵⁷

A limited number of case reports describe the clinical course of patients poisoned by imidacloprid or other neonicotinoid pesticides. Many of the clinical manifestations may actually be attributable to the solvent N-methyl-2-pyrrolidone, which is used to formulate the pesticide and has irritant effects on skin and mucosae.⁹⁰ Published case reports of intentional imidacloprid ingestions describe an initial period of drowsiness, disorientation, dizziness, and tachycardia, with subsequent development of fever, vomiting, and leukocytosis.^71,90 Oral, esophageal, and gastric erosions are demonstrated by upper endoscopy in several patients.^71,72 Late-presenting bradycardia and electrolyte abnormalities have also been reported.^71,77

Determination of serum or urinary concentrations of nicotine or its metabolites is unlikely to be helpful in the management of the acutely poisoned patient. Measurement can be made for confirmation purposes using various chromatographic techniques. Cigarette smokers typically maintain serum nicotine concentrations around 30 to 50 ng/mL during the day, but may achieve concentrations as high as 100 ng/mL.⁶³ Postmortem analyses of nicotine concentrations in blood after fatal acute intoxication range from 5.5 to 800 mg/L.²³

The presence of measurable concentrations of nicotine or cotinine in biologic samples may reflect coincidental or chronic exposure, and does not necessarily imply acute toxicity. Urinary cotinine has a longer detection window than nicotine, and is often used to document exposure to nicotine containing products, including exposure to second-hand smoke, or to guide dosage adjustments in nicotine replacement therapy.^8,49,63 Conversely, the absence of cotinine in the urine may be used to document abstinence from tobacco products.

Most patients with unintentional or low-dose nicotine exposures will not require medical treatment. Patients should be immediately referred for evaluation if they are symptomatic or have ingested any amount of nicotine- or neonicotinoid-containing insecticide or fluid. Children who ingest one or more cigarettes or three or more cigarette butts should also be referred for evaluation without delay. Patients with mild or no symptoms can be observed for several hours and safely discharged home if there are no complicating circumstances such as significant comorbid cardiovascular illness or intent to self-harm.

Patients with dermal exposure to wet tobacco leaves or pesticides should be undressed completely and the skin washed thoroughly with soap and copious amounts of water. Personal protective gear should be worn by medical staff charged with handling both clothes and patients prior to decontamination. Symptomatic patients should have any nicotine patches removed immediately and the skin washed with soap and water.

Vomiting is the most commonly reported adverse effect in patients with acute nicotine toxicity, and may limit absorption in some cases. Induction of emesis should be avoided since it is unlikely to be of added benefit and has the potential for harm. Orogastric lavage may be considered in patients who present immediately after large intentional ingestions of nicotine-containing products. Activated charcoal adsorbs nicotine and can reduce absorption, but the risks of pulmonary aspiration in case of vomiting, seizure, or depressed level of consciousness tend to outweigh the potential benefit.

There is no specific antidote for nicotine toxicity. Treatment of acute nicotine toxicity is symptomatic and supportive. The first priority is to ensure airway protection and respiratory support. Atropine may be used to treat symptoms associated with parasympathetic stimulation such as excess salivation, wheezing, or bradycardia. Endotracheal intubation may be required for airway protection or to assist ventilation in severely poisoned patients. Seizures may be treated with a benzodiazepine. Hypotension should be treated with fluid boluses and an infusion 0.9% NaCl initially. Patients who fail to respond to volume infusion may require treatment with a vasopressor such as norepinephrine. Dysrhythmias should be treated according to standard protocols. Nicotine elimination is enhanced in acidic urine,¹³ but the potential risks outweigh the benefits of this elimination strategy.

• The primary source of nicotine is tobacco made from the leaves of Nicotiana species, but chemically related tobacco substitutes and pesticides are becoming increasingly available.

• Nicotine is well absorbed after inhalation, mucosal, or dermal exposure. It is rapidly distributed to the brain where it activates nicotinic acetylcholinergic receptors, stimulates the reticular activating system, and facilitates neurotransmitter release.

• Metabolism via the hepatic cytochrome oxidase system produces pharmacologically inactive metabolites slowly excreted in urine. The half-life of nicotine in the body is about 1 to 4 hours, with more rapid clearance in individuals who are chronically exposed.

• Clinical manifestations of nicotine toxicity are those of nicotinic cholinergic excess, most commonly including vomiting and agitation. Severe poisoning may cause seizures, cardiac dysrhythmias, hypotension, and neuromuscular blockade with respiratory failure from muscular paralysis.

• There are no antidotes for nicotine, and acute toxicity should be managed with symptom directed, supportive care.

References