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Nicotine

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First-aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
   3.4 Other characteristics
4. USES/CIRCUMSTANCES OF POISONING
   4.1 Uses
   4.2 High risk circumstance of poisoning
   4.3 Occupationally exposed populations
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. TOXICOLOGY
   7.1 Mode of Action
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
      7.2.4 Workplace standards
      7.2.5 Acceptable daily intake (ADI) and other guideline levels
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Others
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ears, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Others
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses and other investigations
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. ADDITIONAL INFORMATION
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESSES
    CHEMICAL SUBSTANCES
    1. NAME
         1.1 Substance
           Nicotine
         1.2 Group
           Alkaloid of Nicotiana Tabacum
         1.3 Synonyms
           (S)-3-(1-Methylpyrrolidin-2-yl)pyridine
         1.4 Identification numbers
           1.4.1 CAS number
                 54-11-5
           1.4.2 Other numbers
         1.5 Brand names, Trade names
           Nicabate
           Nicobrevin
           Nicotinell TTS
           Nicorette
           Nicoret
           Cigarette tobacco
           Black leaf
           Nicocide
           Nico-fume
           
           
           Transdermal patches deliver 5 to 30 mg nicotine over 24 hours;
           used patch has significant nicotine content
                    
           Cigarette tobacco varies in its nicotine content but common
           blends contain 15 to 25 mg per cigarette with a current trend
           towards lower levels.
           
           Nicotine insecticides: 40% solution of the sulfate.
           
           Chewing gum - nicotine polacrilex: 2 and 4 mg nicotine bound 
           to an ion exchange resin in a sugar-free flavoured chewing gum
           base.
         1.6 Manufacturers, Importers
           Ciba Geigy
           Glaxo-Lake Pharmaceuticals
           Lundbeck Ltd
           Merrell
    2. SUMMARY
         2.1 Main risks and target organs
           Nicotine is one of the most toxic of all poisons and has a 
           rapid onset of action. Apart from local caustic actions, the 
           target organs are the peripheral and central nervous systems. 
           Nicotine is also a powerfully addictive drug.
         2.2 Summary of clinical effects
           Burning sensation in the mouth and throat, salivation, 
           nausea, abdominal pain, vomiting and diarrhoea.  
           Gastrointestinal reactions are less severe but can occur even 
           after cutaneous and respiratory exposure.
 
           Systemic 
           effects include:  agitation, headache, sweating, dizziness, 
           auditory and visual disturbances, confusion, weakness and lack 

           of coordination.
           
           A transient increase in blood 
           pressure, followed by hypertension, bradycardia, paroxysmal 
           atrial fibrillation, or cardiac standstill may be observed. 

            
           In severe poisoning, tremor, convulsions and coma occur.  
           Faintness, prostration, cyanosis and dyspnoea progress to 
           collapse.  Death may occur from paralysis of respiratory muscles 
           and/or central respiratory failure. 
         2.3 Diagnosis
           Burning sensation in the mouth and throat, salivation, 
           nausea, abdominal pain, vomiting and diarrhoea  
           Agitation, headache, sweating, dizziness, auditory and visual 
           disturbances, confusion, weakness and lack of coordination.
           
           In severe poisoning, tremor, convulsions and coma occur.  
           Faintness, prostration, cyanosis and dyspnoea progress to 
           collapse.
           
           Plasma nicotine level: nicotine concentrations in the urine 
           are not useful in the management of overdose since these vary
           according to changes in pH and urine flow.
           
           White cell count: polymorphonuclear leucocytosis
           
           Urinalysis: glycosuria.
         2.4 First-aid measures and management principles
           There are no known antidotes.
           
           Immediate establishment of an airway, monitoring of breathing
           patterns, and maintenance of circulation are essential in 
           cases of serious overdose. Preparations for possible seizures 
           or rapid progression to coma and artificial ventilation 
           procedures should be kept ready, oxygen may be required.
           
           If vomiting has not occurred following nicotine ingestion,
           remove stomach contents by gastric lavage.  Induction of 
           emesis is less preferable to lavage since convulsions or coma 
           may intervene.
           
           Single or multiple doses of activated charcoal may be used. 
           Children who ingest more than one cigarette should receive
           activated charcoal and medical observation for at least 
           several hours.
           
           If nicotine is spilled on the skin, immediately wash 
           thoroughly with running water (avoid warm water).
           
           Seizure activity and agitation can be controlled with diazepam
           or barbiturates.
           
           Cholinergic symptoms may be ameliorated with atropine.
    3. PHYSICO-CHEMICAL PROPERTIES
         3.1 Origin of the substance

           Nicotine is a natural alkaloid obtained from the dried 
           leaves and stems of the Nicotiana tabacum and Nicotiana rustica, 
           where it occurs in concentrations of 0.5-8%.  Cigarette tobacco 
           varies in its nicotine content, but common blends contain 15-25 
           mg per cigarette, with a current trend towards lower 
           levels. 
         3.2 Chemical structure
         3.3 Physical properties
           Molecular weight: 162.26
           
           Nicotine is a liquid alkaloid.  It is water soluble and 
           has a pKa of 8.5.  It is a bitter-tasting liquid which is 
           strongly alkaline in reaction and forms salts with acids.
         3.4 Other characteristics
           Store at room temperature, below 86 F (30C).  Protect from 
           light and air.
    4. USES/CIRCUMSTANCES OF POISONING
         4.1 Uses
           Nicotine is most frequently encountered in tobacco 
           products for smoking, chewing, sniffing and tobacco 
           "without smoking".
           
           As an insecticide (now rare), and as an adjunct to 
           smoking cessation programmes (gums, patches).  It is a substance 
           of abuse.
         4.2 High risk circumstance of poisoning
           Nicotine is most frequently encountered in tobacco products 
           for smoking, chewing, sniffing and tobacco "without smoking".
           
           As an insecticide (now rare), and as an adjunct to smoking
           cessation programmes (gums, patches).  It is a substance of
           abuse.
         4.3 Occupationally exposed populations
           People who are involved in the processing and extracting 
           tobacco (green tobacco sickness), as well as mixing, storing 
           and applying certain insecticides.
    5. ROUTES OF ENTRY
         5.1 Oral
           Poisoning occurs in children who ingest cigarettes or 
           cigars or 2nicotine gum.  In adults chewing tobacco or nicotine 
           gum, and people who ingest liquid nicotine in the form of 
           insecticide preparations. 
         5.2 Inhalation
           Inhalation is the most frequent route of entry because of
           worldwide tobacco smoking.
         5.3 Dermal
           Dermal exposure to nicotine can lead to intoxication.  Such
           exposure has been reported after spilling or applying nicotine-
           containing insecticides on the skin or clothes (Loockhart, 
           1933; Benowitz, 1987), and as a consequence of occupational 
           contact with tobacco leaves (green tobacco sickness) 
           (Weizenecker, 1970; Gehlbach, 1974).
         5.4 Eye
           No data available.
         5.5 Parenteral
           No data available.

         5.6 Others
           Tobacco has been used in enemas and poultices (Gosselin, 
           1988).
    6. KINETICS
         6.1 Absorption by route of exposure
           Nicotine is a water and lipid soluble drug which, in the 
           free base form, is readily absorbed via respiratory tissues, 
           skin, and the gastrointestinal tract.  Nicotine may pass 
           through skin or mucous membranes when in alkaline solution (in 
           which nicotine is largely unionized). 
           
           When tobacco smoke reaches the small airways and alveoli of 
           the lung, the nicotine is rapidly absorbed.  The rapid 
           absorption of nicotine from cigarette smoke through the lungs 
           occurs because of the huge surface area of the alveoli and 
           small airways, and because of dissolution of nicotine at 
           physiological pH (approximately 7.4) which facilitates 
           transfer across cell membranes.
           
           Chewing tobacco, snuff, and nicotine polacrilex gum are of
           alkaline pH as a result of the selection of appropriate 
           tobacco and/or buffering with additives by the manufacturers. 
           The alkaline pH facilitates absorption of nicotine through 
           mucous membranes.
         6.2 Distribution by route of exposure
           After absorption, nicotine enters the blood where, at pH 
           7.4, it is about 70% ionized. Binding to plasma proteins is less 
           than 5%.  Studies showed that, after intravenous administration, 
           the distribution of C14-labeled nicotine is immediate, reaching 
           the brain of mice within 1 min. after injection.  Similar 
           findings based on positron emission tomography of the brain, 
           were seen after injection of 11C-nicotine in monkeys. (US 
           Department of Health Report of Surgeon General 1988). 
           
           Nicotine inhaled in tobacco smoke enters the blood almost as
           rapidly as after rapid I.V. injections. Because of delivery 
           into the lung, peak nicotine levels may be higher and lag time
           between smoking and entry into the brain shorter than after IV
           injection.
           
           After smoking, the action of nicotine on the brain is expected
           to occur quickly. Rapid onset of effects after a puff is
           believed to provide optimal reinforcement for the development 
           of drug dependence. The effect of nicotine declines as it is
           distributed to other tissues. The distribution half-life, 
           which describes the movement of nicotine from the blood and 
           other rapidly perfused tissues, such as the brain, to other 
           body tissues, is about 9 min. (Feyerabend, 1985). Distribution
           kinetics, rather than elimination kinetics (half-life about 2
           hr) determine the time course of the CNS actions of nicotine
           after smoking a single cigarette.
           
           The apparent volume of distribution in animals is 
           approximately 1.0 L/kg whereas in one clinical study it was 
           2.0 L/kg in smokers and 3.0 L/kg in nonsmokers (Ellenhorn, 
           1988).

         6.3 Biological half-life by route of exposure
           The elimination half-life of nicotine averages 2 hours
           (Benowitz, 1982;) Feyerabend, 1985). The half-life of a drug 
           is useful in predicting the rate of accumulation of that drug 
           in the body with repetitive dosing and the time course of 
           decline after cessation of dosing. Consistent with a half-life 
           of 2 hours, accumulation of nicotine over 6 to 8 hours during 
           regular smoking and persistence of significant levels of 
           nicotine in the blood for 6 to 8 hours after cessation of 
           smoking, i.e. overnight, has been observed (Benowitz, 1982b). 
           Thus, cigarette smoking represents a situation where the 
           smoker is exposed to significant concentrations and possibly 
           pharmacological effects of nicotine for 24 hours a day.
           
           Apparent acute tolerance to nicotine, determined on the basis 
           of observations of the relationship between venous blood 
           levels and effects, may be due to distribution disequilibrium 
           between venous and arterial blood; venous blood levels 
           substantially underestimate concentrations of nicotine in 
           arterial blood and at potential sites of action. True 
           tolerance does, however, develop rapidly, with a half-life of 
           development and regression of about 35 minutes. The kinetics 
           of tolerance may be another determinant of cigarette smoking 
           particularly when the smoker smokes his next cigarette.
         6.4 Metabolism
           Nicotine is a tertiary amine which is composed of a 
           pyridine and a pyrrolidine ring. Nicotine undergoes a large 
           first pass effect during which the liver metabolizes 80% to 90%; 
           to a smaller extent, the lung also is able to metabolize 
           nicotine. 
           
           The major metabolite of nicotine is cotinine;  nicotine-1'-N-
           oxide is a minor metabolite. Cotinine is also extensively
           metabolized and trans-3'-hydroxycotinine is its a major
           metabolite. The most abundant metabolite in the mice is trans-
           3'-hydroxy-cotinine, accounting for almost 40%, whereas 
           cotinine itself accounts for only about 15% of the dose of 
           nicotine.
           
           Cotinine levels in various biological fluids are widely used 
           to estimate intake of nicotine in tobacco users. The 
           usefulness of cotinine as a quantitative marker of nicotine 
           intake, is limited by individual variability in percentage 
           conversion of nicotine to cotinine and in rate of elimination 
           of cotinine itself. Since it accounts for a much greater 
           percentage of nicotine, trans-3'-hydroxycotinine measurement, 
           either alone or in combination with measurement of other 
           metabolites, may be a superior quantitative marker of nicotine 
           intake.
         6.5 Elimination by route of exposure
           Nicotine and its metabolites (cotinine and nicotine 1-N-oxide)
           are excreted in the urine. At a pH of 5.5 or less, 23% is
           excreted unchanged. At a pH of 8, only 2% is excreted in the
           urine. The effect of urinary pH on total clearance is due
           entirely to changes in renal clearance. (Ellenhorn, 1988).
           

           Nicotine is secreted into saliva. Passage of saliva containing
           nicotine into the stomach, combined with the trapping of
           nicotine in the acidic gastric fluid and reabsorption from the
           small bowel, provides a potential route for enteric nicotine
           recirculation. This recirculation may account for some of the
           oscillations in the terminal decline phase of nicotine blood
           levels after I.V. nicotine infusion or cessation of smoking.
           
           Nicotine freely crosses the placenta and has been found in
           amniotic fluid and the umbilical cord blood of neonates.
           Nicotine is found in breast milk and the breast fluid of non-
           lactating women and in cervical mucous secretions (US 
           Department of Health and Human Services, a report of the 
           Surgeon General 1988).
    7. TOXICOLOGY
         7.1 Mode of Action
           Nicotine is an agonist at nicotinic receptors in the 
           peripheral and central nervous system. In man, as in animals, 
           nicotine has been shown to produce both behavioral stimulation 
           and depression. Pharmacodynamic studies indicate a complex 
           dose response  relationship, due both to complexity of 
           intrinsic pharmacological actions and to rapid development of 
           tolerance.
         7.2 Toxicity
           7.2.1 Human data
                 7.2.1.1 Adults
                         The mean lethal dose has been estimated to be 30 
                         to 60 mg (0.5-1.0 mg/kg) (Gosselin, 1988).
                 7.2.1.2 Children
                         The lethal dose is considered to be about 10 mg 
                         of nicotine (Arena, 1974).
           7.2.2 Relevant animal data
                 Dog:     oral LD50:   9.2 mg/kg 
                 mouse:   oral LD50:   3.3 mg/kg  (RTECS, 1985-86)
                 rat:     oral LD50:   50 mg/kg
           7.2.3 Relevant in vitro data
                 No data available.
           7.2.4 Workplace standards
                 MSHA standard air : TWA = 0.5 mg/m3 (skin)
                 OSHA standard air : TWA = 0.5 mg/m3 (skin)
                 (RTECS, 1985-86)
           7.2.5 Acceptable daily intake (ADI) and other guideline levels
                 Not relevant.
         7.3 Carcinogenicity
           Literature reports indicate that nicotine is neither an
           initiator nor a promoter of tumours in mice. There is
           inconclusive evidence to suggest that cotinine, an oxidized
           metabolite of nicotine, may be carcinogenic in the rat. (PDR,
           1987).
         7.4 Teratogenicity
           Nicotine rapidly crosses the placenta and enters the fetus. 
           Some investigations have reported teratogenic effects of high 
           doses of nicotine, which interfered with osteogenesis in mice 
           and chick embryos. Chronic nicotine treatments of pregnant 
           rats throughout gestation produced subtle neurological changes 
           which manifested themselves as behavioral or 

           electrophysiological alterations in the offspring. Thus, 
           several studies suggest that nicotine, at least in high doses, 
           may have toxic effects on the fetus. Smoking is associated 
           with impaired growth and development of the fetus. Whether 
           cigarette smoking is associated with increased rates of 
           congenital; malformations in humans is controversial. Several 
           studies show no association or a lower incidence of 
           malformations in offspring of smoking mothers, but other 
           reports positive associations. One study has reported an 
           association between paternal smoking and the incidence of 
           congenital malformations (US Department of Health and Human 
           Services (1988)).
         7.5 Mutagenicity
           In the Ames Salmonella typhimurium mutagenesis and mammalian
           cell cytogenic assays, nicotine did not posses any genotoxic
           activity, although it induced separable DNA damage in the
           Escherichia coli pol A+/A-system (US Department of Health and
           Human Services, 1988)
         7.6 Interactions
           Smoking increases the metabolism of certain compounds and 
           lowers blood levels of drug such as phenacetin, caffeine, 
           theophylline, imipramine and pentazocine through enzyme 
           induction. Other reported effects of smoking, which do not 
           involve enzyme induction, include reduced diuretic effects of 
           furosemide and decreased cardiac output, and antagonism of the 
           hypotensive effects of propranolol, which may also relate to 
           the normal effects of nicotine. Both smoking and nicotine can 
           increase the level of circulating cortisol and catecholamines. 
           Therapy with adrenergic agonists or with adrenergic blockers 
           may need to be adjusted according to changes in smoking 
           status.
    8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
         8.1 Material sampling plan
           8.1.1 Sampling and specimen collection
                 8.1.1.1 Toxicological analyses
                 8.1.1.2 Biomedical analyses
                 8.1.1.3 Arterial blood gas analysis
                 8.1.1.4 Haematological analyses
                 8.1.1.5 Other (unspecified) analyses
           8.1.2 Storage of laboratory samples and specimens
                 8.1.2.1 Toxicological analyses
                 8.1.2.2 Biomedical analyses
                 8.1.2.3 Arterial blood gas analysis
                 8.1.2.4 Haematological analyses
                 8.1.2.5 Other (unspecified) analyses
           8.1.3 Transport of laboratory samples and specimens
                 8.1.3.1 Toxicological analyses
                 8.1.3.2 Biomedical analyses
                 8.1.3.3 Arterial blood gas analysis
                 8.1.3.4 Haematological analyses
                 8.1.3.5 Other (unspecified) analyses
         8.2 Toxicological Analyses and Their Interpretation
           8.2.1 Tests on toxic ingredient(s) of material
                 8.2.1.1 Simple Qualitative Test(s)
                 8.2.1.2 Advanced Qualitative Confirmation Test(s)
                 8.2.1.3 Simple Quantitative Method(s)

                 8.2.1.4 Advanced Quantitative Method(s)
           8.2.2 Tests for biological specimens
                 8.2.2.1 Simple Qualitative Test(s)
                 8.2.2.2 Advanced Qualitative Confirmation Test(s)
                 8.2.2.3 Simple Quantitative Method(s)
                 8.2.2.4 Advanced Quantitative Method(s)
                 8.2.2.5 Other Dedicated Method(s)
           8.2.3 Interpretation of toxicological analyses
         8.3 Biomedical investigations and their interpretation
           8.3.1 Biochemical analysis
                 8.3.1.1 Blood, plasma or serum
                         Not relevant
                 8.3.1.2 Urine
                         To detect glycosuria
                 8.3.1.3 Other fluids
           8.3.2 Arterial blood gas analyses
                 Not relevant.
           8.3.3 Haematological analyses
                 White cell count or full blood count.
           8.3.4 Interpretation of biomedical investigations
         8.4 Other biomedical (diagnostic) investigations and their 
           interpretation
         8.5 Overall Interpretation of all toxicological analyses and 
           toxicological investigations
         8.6 References
    9. CLINICAL EFFECTS
         9.1 Acute poisoning
           9.1.1 Ingestion
                 Symptoms of nicotine poisoning may develop within 15
                 minutes. The onset of symptoms is much more rapid after 
                 the ingestion of liquid nicotine (e.g. insecticide 
                 preparations) Death may occur within 5 minutes of 
                 ingestion of concentrated nicotine insecticides. Four to 
                 eight milligrams orally may produce serious symptoms in 
                 individuals not habituated to nicotine. Gastrointestinal 
                 signs and symptoms occur first and include mouth and 
                 throat burning  followed by profuse salivation, nausea, 
                 vomiting, abdominal pain and occasionally diarrhoea.
                 
                 More severe intoxication results in dizziness, weakness 
                 and confusion, progressing to convulsions, hypertension 
                 and coma. Intense vagal stimulation may cause transient 
                 cardiac standstill or paroxysmal atrial fibrillation.  
                 Death is usually due to paralysis of respiratory muscles 
                 and/or central respiratory failure.
           9.1.2 Inhalation
                 In humans, acute exposure to nicotine even in low doses 
                 (similar to the amounts consumed by tobacco users) 
                 elicits autonomic and somatic reflex effects. Dizziness, 
                 nausea and/or vomiting are commonly experienced by 
                 nonsmokers after low doses of nicotine, such as when 
                 people try their first cigarette. However cigarette 
                 smokers rapidly become tolerant to these effects.
           9.1.3 Skin exposure
                 Dermal exposure to nicotine can also lead to 
                 intoxication.  Such exposures have been reported after 

                 spilling or applying nicotine containing insecticides on 
                 the skin or clothes and as consequence of occupational 
                 contact with tobacco leaves.
                 
                 A self-limiting illness known as "green-tobacco 
                 sickness" has been described in young man handling 
                 uncured tobacco leaves in the field; it consists of 
                 pallor, vomiting and prostration and is probably due to 
                 the percutaneous absorption of nicotine from wet leaves.
           9.1.4 Eye contact
                 No data available.
           9.1.5 Parenteral exposure
                 No data available.
           9.1.6 Other
                 Serious poisoning has occurred from the use of aqueous
                 infusions of tobacco as enemas (Gosselin, 1988). 
                 Nicotine 2 mg administered intranasally as a 2% aqueous 
                 thickened solution was better absorbed than the same 
                 dose given as a chewing gum (Russell, 1983)
         9.2 Chronic poisoning
           9.2.1 Ingestion
                 Chronic poisoning by nicotine is possible by chewing
                 tobacco or nicotine gums.
           9.2.2 Inhalation
                 Smoking causes coronary and peripheral vascular disease, 
                 cancer, chronic obstructive lung disease, peptic ulcer 
                 and reproductive disturbances, including prematurity. 
                 Nicotine may contribute to tobacco related disease, but 
                 direct causation has not been determined because 
                 nicotine is taken up simultaneously with a multitude of 
                 other potentially harmful substances that occur in 
                 tobacco smoke and smokeless tobacco. 
           9.2.3 Skin exposure
                 Through transdermal nicotine
           9.2.4 Eye contact
                 No data available.
           9.2.5 Parenteral exposure
                 No data available.
           9.2.6 Other
                 Not relevant
         9.3 Course, prognosis, cause of death
           In fatal cases of nicotine poisoning, death is usually rapid; 
           it occurs nearly always within 1 hour and occasionally within 
           5 minutes. According to the traditional view, death is due to
           paralysis of the respiratory muscles; paralysis of medullary
           centres controlling respiration requires a larger dose.
           Circulatory failure is not necessarily permanent; if heart
           action can be initiated by external cardiac massage or
           intracardiac epinephrine while respiration is maintained, 
           death may be prevented (Franke, 1936). If the patient survives 
           the initial period, the prognosis is good (Gosselin 1988)
         9.4 Systematic description of clinical effects
           9.4.1 Cardiovascular
                 The overall effect on the cardiovascular system leads to 
                 tachycardia, peripheral vasoconstriction and elevations 
                 of blood pressure with an attendant increase in the work 

                 of the heart. Nicotine may induce vasospasm and cardiac 
                 arrythmias. Tolerance does not develop to the 
                 catecholamine-releasing effects of nicotine. 
                 
                 Acute effects 
                 
                 A transient increase in blood pressure followed by
                 bradycardia, paroxysmal atrial fibrillation, or cardiac 
                 standstill is observed.
                 
                 Chronic effects
                 
                 Nicotine could contribute both to the atherosclerotic
                 process and to acute coronary events by several
                 mechanisms. Nicotine could promote atherosclerotic 
                 disease by its actions on lipid metabolism and 
                 coagulation by hemodynamic effects and/or by causing 
                 endothelial injury.
                 
                 Nicotine may act by releasing free fatty acids, 
                 enhancing the conversion of VLDL (very low density 
                 lipoproteins) to LDL (low density lipoproteins), 
                 impairing the clearance of LDL and/or by accelerating 
                 the metabolism of HDL (Brischetto, 1983; Gluette Brown, 
                 1986; Grasso, 1986; Hojnacki, 1986.) 
                 
                 Nicotine could affect platelets by increasing the 
                 release of epinephrine, which is known to enhance 
                 platelet reactivity by inhibiting prostacyclin, an 
                 antiaggregatory hormone secreted by endothelial cells, 
                 or perhaps directly (Sonnenfeld, 1980). Alternatively, 
                 by increasing heart rate and cardiac output and thereby 
                 increasing blood turbulence or by a direct action, 
                 nicotine may promote endothelial injury. Cigarette 
                 smoking, most likely mediated by nicotine, facilitates 
                 AV nodal conduction which could result in an increased 
                 ventricular response during atrial fibrillation (Peters, 
                 1987). Nicotine could aggravate peripheral vascular 
                 disease by constricting small collateral arteries and/or 
                 by inducing local thrombosis. Patients with coronary or 
                 peripheral vascular disease are likely to suffer some 
                 increase in risk when taken nicotine. Nicotine could 
                 contribute to the progression of chronic hypertension by 
                 aggravating vasoconstriction either in sympathetic activation
                 or inhibition of prostaglandin synthesis.
                 
                 Based on its pharmacological actions, it is likely that 
                 nicotine plays a role in causing or aggravating acute 
                 coronary events. Myocardial infarction can be due to one 
                 or more of these precipitating factors: excessive demand 
                 for oxygen and substrates; thrombosis; and coronary 
                 spasm.  Nicotine increases heart rate and blood pressure and,
                 therefore, myocardial oxygen consumption.
                 
                 Nicotine consumed in the form of nicotine gum has been
                 studied in patients with coronary artery disease. 

                 Nicotine gum (4mg) increased myocardial contractility in 
                 healthy people, but in patients with coronary artery 
                 disease, nicotine gum decreased contractility in the 
                 ischaemic regions of the myocardium, consistent with 
                 aggravation of ischaemia (Bayer, 1985). In the most 
                 severe cases of coronary artery disease, overall 
                 contractility decreased after nicotine gum. This study 
                 supports the idea that nicotine contributes to the 
                 induction of myocardial ischaema in susceptible smokers. 
                 
                           
                 In addition to creating an imbalance between myocardial 
                 oxygen supply and demand, nicotine may promote 
                 thrombosis.  Nicotine may also induce coronary spasm by 
                 sympathetic activation or inhibition of prostacyclin. 
                 Coronary spasm has been observed during cigarette 
                 smoking (Maouad, 1984).
                 
                 Sudden cardiac death in smokers might result from
                 ischaemia, combined with the arrhythmogenic effects of
                 increased amounts of circulating catecholamines released 
                 by nicotine.
           9.4.2 Respiratory
                 Acute effects
                 
                 Initial tachypnoea, but later dyspnoea, decreased 
                 respiratory rate, and cyanosis may be seen. Respiratory 
                 arrest may occur within minutes, and resultant death 
                 within 1 hour.
                 
                 Chronic effects
                 
                 Nicotine may directly or indirectly influence the
                 development of emphysema in smokers, but further 
                 research is needed to define the magnitude of the 
                 contribution of nicotine to the pathogenesis of smoking 
                 including chronic lung disease. Nicotine can also worsen 
                 pulmonary function in smokers who already have lung 
                 disease. Acute exposure to nicotine induces constriction 
                 of both central and peripheral airways (Yamatake, 1978). 
                 The increase in airways resistance by nicotine involves 
                 vagal reflexes and stimulation or parasympathetic 
                 ganglia in the bronchial wall (Nakamme, 1986). The 
                 magnitude of bronchoconstriction
                 observed in experimental animals and humans following
                 acute inhalation of cigarette smoke is correlated with 
                 the level of nicotine in the smoke (Beck, 1986) 
                 suggesting that nicotine may be an important factor in 
                 the increased airways resistance of smokers.
           9.4.3 Neurological
                 9.4.3.1 CNS
                         The effects of nicotine are generally dose-
                         dependent and extremely high doses can produce 
                         toxic symptoms such as delirium. These effects 
                         also occur in nicotine tolerant individuals. 
                         Nicotine first stimulates and later depresses 

                         the CNS. Headache, confusion, dizziness, 
                         agitation, restlessness and incoordination develop 
                         initially after serious nicotine overdose; 30 minutes 
                         later, convulsions and coma occur.
                 9.4.3.2 Peripheral nervous system
                         Neuromuscular symptoms include hypotonia, 
                         decreased deep tendon reflexes, weakness, 
                         fasciculations and paralysis of muscles 
                         (including respiratory muscles).
                 9.4.3.3 Autonomic nervous system
                         Cholinergic symptoms often observed initially
                         include diaphoresis, salivation, lacrimation,
                         increased bronchial secretions, miosis and later 
                         mydriasis.
                         
                         Nicotine has actions at the sympathetic ganglia 
                         and on the chemoreceptors of the aorta and 
                         carotid bodies. Nicotine also affects the 
                         adrenal medulla, releasing catecholamines.
                 9.4.3.4 Skeletal and smooth muscle
                         Weakness, fasciculations and paralysis of 
                         muscles (including respiratory muscles)
           9.4.4 Gastrointestinal
                 Acute effects
                 
                 Gastrointestinal symptoms occur first and include 
                 burning of the mouth and throat followed by profuse 
                 salivation, nausea, vomiting, abdominal pain and 
                 occasionally diarrhoea.
                 
                 Chronic effects
                 
                 Cigarette smoking is a risk factor for peptic ulcer
                 disease and an even stronger risk factor for delayed
                 healing, failure to respond to therapy and relapse
                 (Kikendall, 1984). In animals, nicotine potentiates 
                 peptic ulcer formation induced by histamine or 
                 pentagastrin (Konturek, 1971).
           9.4.5 Hepatic
                 No data available.
           9.4.6 Urinary
                 9.4.6.1 Renal
                 9.4.6.2 Others
           9.4.7 Endocrine and reproductive systems
                 The action of nicotine on the adrenal medulla (release 
                 of catecholamines) does not appear to be affected by
                 tolerance, and may aggravate patients with
                 hyperthyroidism, phaeochromocytoma or insulin-dependent 
                 diabetes.
           9.4.8 Dermatological
                 No data available.
           9.4.9 Eye, ears, nose, throat: local effects
                 No data available.
           9.4.10 Haematological
                  No data available.
           9.4.11 Immunological

                  No data available.
           9.4.12 Metabolic
                  9.4.12.1 Acid-base disturbances
                           Not relevant.
                  9.4.12.2 Fluid and electrolyte disturbances
                           Not relevant.
                  9.4.12.3 Others
                           Action on lipids. 
                           
                           Nicotine may act by releasing free fatty acids,
                           enhancing the conversion of VLDL (very low 
                           density lipoproteins) to LDL (low density 
                           lipoproteins), impairing the clearance of LDL 
                           and/or by accelerating the metabolism of HDL. 
                           (Brischetto, 1983; Gluette Brown, 1986; Grasso,
                           1986; Hojnacki, 1986). 
           9.4.13 Allergic reactions
                  No data available.
           9.4.14 Other clinical effects
                  No data available.
           9.4.15 Special risks
                  Pregnancy 
                  
                  Nicotine in any form may be harmful to the fetus. 
                  Exposure to nicotine during the last trimester has been 
                  associated with a decrease in breathing movements. 
                  These effects may be the result of decreased placental 
                  perfusion caused by nicotine. One miscarriage during 
                  nicotine therapy has been reported. Studies of pregnant 
                  rhesus monkeys have shown that maternal nicotine 
                  administration produced acidosis, hypoxia and hypercarbia 
                  in the fetus. Nicotine has been shown to be teratogenic in 
                  mice treated cutaneously with 25 mg/kg, which is 
                  approximately 300 times the human oral dose. Studies in 
                  rats and monkeys have not demonstrated a teratogenic effect 
                  of nicotine in newborn which occur during cigarette smoking. 
                  Cigarette smoking is associated with impaired fetal growth 
                  and development.
                  
                  Breast feeding
                  
                  Nicotine passes freely into the breast milk in small
                  quantities, which are not clinically significant,
                  averaging 91ppb in one study. Heavy smoking (20-30
                  cigarettes per day) may alter the supply of milk and 
                  cause nausea and vomiting in the infant.
         9.5 Others
           Withdrawal Syndrome.  Need for oral gratification and other
           psychological problems may result in the production of 
           symptoms of withdrawal including anxiety, impaired 
           concentration and memory, depression, hostility, sleep 
           disturbances, and increased appetite (Ellenhorn 1988).
         9.6 Summary
    10. MANAGEMENT
          10.1 General principles
             There is no known antidote. Immediate establishment of an

             airway, monitoring of breathing patterns, and maintenance of
             circulation are essential in serious overdose cases.
             Preparations for possible seizures of rapid progressing to 
             coma must be initiated in serious overdose cases by 
             establishment of an intravenous line, supplemental oxygen, 
             cardiac monitoring, and direct observation.
             
             Artificial ventilation procedures should be kept ready; 
             oxygen
             may be required.
          10.2 Relevant laboratory analyses and other investigations
             10.2.1 Sample collection
                    Plasma
             10.2.2 Biomedical analysis
                    Full blood count
                    Urinalysis (glycosuria)
             10.2.3 Toxicological analysis
                    Plasma nicotine levels and metabolites in urine.
             10.2.4 Other investigations
                    No data available.
          10.3 Life supportive procedures and symptomatic treatment
             Artificial ventilation and oxygen therapy until spontaneous
             breathing is adequate.  Keeps the airways clear.       
             
             Profuse salivation may require continuous oral suction. 
             Bronchial secretions, excess salivation, and diarrhoea may 
             be
             ameliorated by atropine. If severe or persistent convulsions
             occur, they may be controlled with small intravenous doses 
             of
             barbiturates or diazepam.
          10.4 Decontamination
             If contact was with the skin, remove contaminated clothing 
             and wash the skin thoroughly with water without rubbing (avoid 
             warm water). If the patient has swallowed nicotine, induce 
             emesis if there are no convulsions and respiration is 
             normal. Wash out the stomach. Activated charcoal may be left 
             in the stomach. 
             
             Children who ingest more than one cigarette should receive
             activated charcoal and medical observation for at least 
             several hours.
          10.5 Elimination
             Haemodialysis and haemoperfusion have not been evaluated in
             acute nicotine poisoning. Acidification of urine may 
             increase excretion of nicotine but although pharmacologically 
             sound, its clinical value remains to be established and could be 
             harmful.
          10.6 Antidote treatment
             10.6.1 Adults
             10.6.2 Children
          10.7 Management discussion
    11. ILLUSTRATIVE CASES
          11.1 Case reports from literature
             Malizia (1983) described four children who ingested two
             cigarettes each and developed salivation, vomiting, 

             diarrhoea, tachypnoea, tachycardia, and hypotension within 30 
             minutes and depressed respiration and cardiac arrhythmias within 
             40 minutes.  Convulsions occurred within 60 minutes of 
             ingestion. All recovered after gastric lavage, activated 
             charcoal, intermittent positive pressure ventilation, and 5 
             mg diazepam intravenously for convulsions.
             
             A 23 year old woman who had smoked two packs per day for 
             several years chewed a single piece of nicotine gum (2 mg 
             nicotine) after which she developed nausea, tremor, flushing,
             
             palpitations, paresthesias, pruritus, vomiting, diarrhoea,
             confusion and abdominal pain. She recovered after treatment 
             and with prochlorperazine, morphine and atropine (Mensch, 
             1984).
          11.2 Internally extracted data on cases
          11.3 Internal cases
    12. ADDITIONAL INFORMATION
          12.1 Availability of antidotes
             No data available.
          12.2 Specific preventive measures
             Preventative measures for occupational exposure to nicotine
             include adequate ventilation, chemical goggles, mechanical
             filter respirator, rubber gloves, aprons and boots.
          12.3 Other
             No data available.
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    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
        ADDRESSES
        Author:        Julia Higa de Landoni
                       Section of Toxicology
                       Hospital de Clinicas San Martin
                       Cordoba 2351
                       Capital Federal
                       Buenos Aires
                       Argentina
        
        Date:          March 1991
        
        Peer Review:   Adelaide, April 1991
    



















    See Also:
       Toxicological Abbreviations
       Nicotine (ICSC)