NICOTINE
This record contains general information for nicotine, including statements in the
literature referenced to nicotine without identification of the individual salts under
study. For compound-specific information, refer to the appropriate individual records as
listed in the field for Related HSDB Records (RELT).Human Health Effects:
Human Toxicity Excerpts:
SYMPTOMATOLOGY: 1. BURNING SENSATION IN MOUTH & THROAT, SALIVATION, NAUSEA,
ABDOMINAL PAIN, VOMITING, DIARRHEA. GI REACTIONS ARE LESS SEVERE BUT DO OCCUR AFTER
CUTANEOUS & RESPIRATORY EXPOSURES. 2. SYSTEMIC EFFECT INCL AGITATION, HEADACHE,
SWEATING, DIZZINESS, AUDITORY & VISUAL DISTURBANCES, CONFUSION, WEAKNESS, &
INCOORDINATION. 3. AT FIRST RESPIRATIONS ARE DEEP & RAPID, BLOOD PRESSURE IS HIGH
& PULSE IS SLOW. INTENSE VAGAL STIMULATION MAY CAUSE TRANSIENT CARDIAC STANDSTILL OR
PAROXYSMAL ATRIAL FIBRILLATION. PUPILS ARE GENERALLY CONSTRICTED. 4. CENTRAL NERVOUS
EXCITATION IS ALSO EVIDENCED BY TREMORS AND SOMETIMES BY CLONIC-TONIC CONVULSIONS. 5. AS
DEPRESSION DEVELOPS, THE PUPILS DILATE, THE BLOOD PRESSURE FALLS, & THE PULSE BECOMES
RAPID & OFTEN IRREGULAR. FAINTNESS, PROSTRATION, CYANOSIS & DYSPNEA PROGRESS TO
COLLAPSE. 6. DEATH FROM PARALYSIS OF RESPIRATORY MUSCLES, USUALLY ONLY A FEW MINUTES AFTER
COLLAPSE.
Nicotine is one of the most lethal poisons
known. ... More than 90 percent of toxic exposures from cigarettes in the United States
are reported in children /SRP: from eating cigarettes or cigarette butts/ less than 5
years of age. ... Most of the recently reported serious toxic states from nicotine have been from exposure to nicotine-containing
products.
... SPLASH OF PURE NICOTINE BASE IN PT EYE
CAUSED SEVERE PAIN, MUCH CONJUNCTIVAL REACTION & CORNEAL INFILTRATION. EVENTUALLY, EYE
HEALED WITH PARTIAL OPACIFICATION OF CORNEA.
CLINICAL FINDINGS: PRINCIPAL MANIFESTATIONS OF NICOTINE
POISONING ARE RESPIRATORY STIMULATION & GI HYPERACTIVITY.
NICOTINE CAUSES INITIAL STIMULATION OF
SALIVARY & BRONCHIAL SECRETIONS THAT IS FOLLOWED BY INHIBITION.
... EFFECTS ... ON GI TRACT ARE DUE LARGELY TO PARASYMPATHETIC STIMULATION. COMBINED
ACTIVATION OF PARASYMPATHETIC GANGLIA & CHOLINERGIC NERVE ENDING RESULTS IN INCR TONE
& MOTOR ACTIVITY OF BOWEL. NAUSEA & VOMITING, & OCCASIONALLY DIARRHEA ARE
OBSERVED FOLLOWING SYSTEMIC ABSORPTION OF NICOTINE.
NICOTINE MARKEDLY STIMULATES CNS. ...
PRODUCES TREMORS ... FOLLOWED BY CONVULSIONS. ... STIMULATION OF CNS IS FOLLOWED BY
DEPRESSION, & DEATH RESULTS FROM FAILURE OF RESPIRATION DUE TO BOTH CENTRAL PARALYSIS
& PERIPHERAL BLOCKADE OF MUSCLES OF RESPIRATION.
CARDIOVASCULAR RESPONSES ... ARE DUE TO STIMULATION OF SYMPATHETIC GANGLIA &
ADRENAL MEDULLA ... WHICH ... RESULTS IN VASOCONSTRICTION, TACHYCARDIA, & ELEVATED
BLOOD PRESSURE.
ONSET OF SYMPTOMS OF ACUTE, SEVERE NICOTINE
POISONING IS RAPID; THEY INCL NAUSEA, SALIVATION, ABDOMINAL PAIN, VOMITING, DIARRHEA, COLD
SWEAT, HEADACHE, DIZZINESS, DISTURBED HEARING & VISION, MENTAL CONFUSION, & MARKED
WEAKNESS. FAINTNESS & PROSTRATION ... BLOOD PRESSURE FALLS; BREATHING IS DIFFICULT;
PULSE IS WEAK, RAPID, & IRREGULAR; & COLLAPSE ... FOLLOWED BY TERMINAL
CONVULSIONS. DEATH ... FROM RESP FAILURE.
The intake of tar (estimated as mutagenic activity of the urine), nicotine,
and carbon monoxide during short term cigarette restriction was studied in 13 smokers,
aged 22-61 yr, who initially smoked an average of 37 cigarettes/day. Exposure to nicotine and carbon monoxide was expressed as the area
under the blood concentration time curve for nicotine
or carboxyhemoglobin over 24 hr. When smoking was restricted to 5 cigarettes/ day, there
were 3.4, 2.70, 3.2 fold increases in urine mutagenic activity and intake of nicotine and carbon monoxide per cigarette,
respectively, as compared with values during unrestricted smoking.
With tobacco abstinence, it was expected that nicotine
metabolism would be slower than when smoking. To test this hypothesis, the disposition
kinetics of intravenous nicotine were studied in
20 healthy smokers while smoking, after abstaining from smoking for 1 week, and (in six
subjects) when smoking again. Cardiovascular responses to nicotine
were also measured. Unexpectedly, total and nonrenal clearance of nicotine
increased by 36% and 39%, respectively, during abstinence. The increase in clearance after
brief abstinence suggests that nicotine or its
metabolites or another component of cigarette smoke inhibits nicotine
metabolism in smokers. Cardiovascular responses to nicotine
were greater after 1 week compared with overnight abstinence, consistent with loss of
tolerance.
To test the nicotine effects on the human
fetus, maternal and fetal cardiovascular dynamics were studied in 20 pregnant women when
chewing a chewing gum containing 4 mg of nicotine
and a chewing gum without nicotine given in a
randomized double blind order. The fetal blood flow was measured with a method combining
realtime ultrasonagraphy and pulsed Doppler technique. Registrations were made in ten
fetuses from the thoracic part of the descending aorta and in ten fetuses from the
intra-abdominal part of the umbilical vein. In 15 of the fetuses /measurements/ were also
made from the umbilical artery. Concentrations of nicotine
in plasma were analyzed in six women. Thus maternal plasma nicotine
concentrations increased after the nicotine gum.
Also, 4 mg nicotine gum increased significantly
maternal heart rate, systolic and diastolic blood pressure. There was no influence on
fetal heart rate or fetal blood flow. The maternal nicotine
plasma concentrations after smoking a high dose cigarette are doubled compared with the
levels after a low dose cigarette (0.8-1.1 mg nicotine)
or a 4 mg nicotine gum.
NICOTINE IS OF CONSIDERABLE MEDICAL
IMPORTANCE BECAUSE OF ITS TOXICITY, PRESENCE IN TOBACCO, AND PROPENSITY FOR CONFERRING A
DEPENDENCE ON ITS USERS.
ACUTELY FATAL DOSE OF NICOTINE FOR AN ADULT
IS PROBABLY ABOUT 60 MG OF BASE.
... Toxic by inhalation and by skin absorption.
NICOTINE MAY BE RESPONSIBLE FOR THE HIGHER
INCIDENCE OF PEPTIC ULCER AMONG SMOKERS.
Applications of nicotine were made locally on
the nasal mucosa in human controls and patients suffering from hyperreactive nasal
disorders. Ten normal subjects (controls) (mean age-32 yr, male/female = 50/50%) having no
history of nasal disease or nasal allergy, smoking or ongoing drug treatment, and patients
with vasomotor rhinitis (VMR), having sneezing and rhinorrhea and/or nasal congestion
(mean age = 39 yr, male/female = 37/63%) were tested. Patients were divided into two
groups: patients with the diagnosis of vasomotor rhinitis (n= 10); and patients with
increased nasal secretion as the dominating symptom of the hyperreactive disorder (n= 4).
Nasal application of nicotine (6.5x10-5 M,
6.5x10-4 M and 6.5x10-3 M nicotine bitartrate in
saline) induced only a mild itching sensation in the three groups. However, nicotine challenge caused a significantly larger
secretory response in the vasomotor rhinitis disorder group. Nicotine
(6.5x10-3 M) caused a secretory response on the contralateral side that was similar to
that on the stimulated side. Unilateral pretreatment with ipratropium caused a significant
reduction of the secretion on the nicotine
stimulated side, but not on the contralateral side. After pretreatment with a combination
of lignocaine and naphazoline the secretory effect of nicotine
was abolished.
Two groups of smokers (n = 10 per group) were given nicotine
(15 ug/kg body weight) or placebo, and 1 group of nonsmokers (n = 10 control) were given
placebo. Nicotine was admin with a measured-dose
nasal-spray pump. The energy expenditure of subjects was examined on two occasions, each
including a period of rest and a period of exercise on a modified bicycle ergometer at
workloads designed to simulate and standardize light daily activity. All had abstained
from cigarette smoking the night before the study. The excess energy expenditure
attributable to nicotine was more than twice as
great during exercise between groups (difference between groups, 0.51 kJ/kg/hr, or 12.1%
of the metabolic rate at rest); than during rest (0.23 kJ/kg/hr, or 5.3% of the metabolic
rate at res)t. In contrast, the expenditure was not affected by placebo during exercise or
rest in the smokers or in the control group of nonsmokers. Incr in the heart rate and
systolic blood pressure attributable to nicotine
were equal during activity and rest, but the diastolic blood pressure was unaffected by nicotine during both sessions.
Human semen from 4 nonsmokers was tested within 1 hr after collection. Nicotine was diluted with BWW medium and then added to
ovulatory bovine cervical mucus to achieve concn of 0 (control), 100, 1000, and 5000
ng/ml. 45 min after contact with semen, quantitative assessment of in vitro sperm
penetrability through the mucus samples was made. Greater numbers of motile sperm were
present at each distance (5, 10, and 15 mm) when nicotine
was added as compared with the control. A 0.2 ml aliquot of each of the 8 semen specimens
was added to 5 ml of nicotine (0, 100, 1000, and
5000 ng/ml) in BWW medium and incubated for 2, 3, and 4 hr. The expected decr in motility
over time following incubation was not significantly affected by the concn of nicotine present. Nor did the nicotine
concn affect either mean progressive velocity or mean linearity of sperm in the incubated
samples.
Eight light smokers (<20 cigarettes/day) and ten heavy smokers (> or = 20
cigarettes/day) participated in two sessions on separate days in which they received 4
administrations (1 every 20 min) of a high nicotine
dose (15 ug/kg body wt, equiv to a typical cigarette) or a low nicotine
dose (7.5 ug/kg) while heart rate was monitored during the 5 min following each
administration. Compared with light smokers, heavy smokers had significantly smaller heart
rate responses to the high dose, indicating greater chronic tolerance, but there was no
difference between groups in response to the low dose. Acute tolerance to heart rate
response across the four 5-min periods was not observed with either dose. Subsequent
examination of heart rate response in the first 2 min following each dose administration
did suggest acute tolerance, particularly for the low dose, as this more acute heart rate
response declined from the first to the last administration.
The effects of nicotine administration (2 mg
eight-times daily as nicotine chewing gum for 2
wk) on plasma lipid and lipoprotein concn were studied in young healthy male volunteers.
Plasma levels of the nicotine metabolite,
cotinine, reached levels comparable to those seen in smokers. Plasma concn of
triglyceride, cholesterol, high density lipoprotein cholesterol, low density lipoprotein
cholesterol, and apolipoproteins AI and B, were determined repeatedly before, during and
after cessation of nicotine intake. All these
variables, as well as the activities of lipoprotein lipase and hepatic lipase in post
heparin plasma, remained unchanged throughout the study.
Prior to each exptl session, three male smokers were admin varying amounts of nicotine via either chewing nicotine
gum or smoking low or high nicotine yield
cigarettes. During the 60 min prior to some of the sessions, subjects were given 4 pieces
of nicotine gum to chew. Each piece was either
placebo or contained 2 mg of nicotine (doses
were 0, 2, 4 or 8 mg nicotine total). They were
then exposed to a free operant avoidance schedule in which a lever press postponed a point
subtraction on a counter for 20 sec (points exchangeable for money). Subtractions were
scheduled to occur every 5 sec in the absence of lever presses. Subjects participated
daily in 30 min exptl sessions, Mon through Fri (from 106 to 151 total sessions). Blood
samples were obtained just prior to nicotine
treatment, immediately following the treatment, and 30 min later on particular days.
Smoking cigarettes resulted in increased avoidance responding relative to baseline
nonsmoking rates. Smoking the low nicotine
delivery cigarettes produced increased avoidance responding in 2 of the 3 subjects; high nicotine delivery cigarettes increased avoidance in
all subjects (p < 0.05). The low nicotine
delivery cigarette condition resulted in a 11.8 ng/ml incr in one subject, but only
minimal incr in the other 2. Smoking the high nicotine
delivery cigarettes produced much larger incr in nicotine
blood levels (25.5, 19.5, 23.2 ng/ml). Chewing nicotine
gum did not produce changes in avoidance responding, however, nicotine
blood levels produced by chewing nicotine gum
were similar to levels produced by smoking cigarettes.
40 smokers and 40 nonsmokers were matched for age and gender. Smokers either smoked a
high nicotine (0.77 mg nicotine)
or low nicotine (0.13 mg) cigarette, while
nonsmokers sham smoked. Twelve min after smoking, participants viewed a stress inducing
movie. Smoking higher nicotine delivery
cigarettes during the movie, as compared to smoking for low nicotine
control cigarettes, was associated with reductions in anxiety (p < 0.05) and right
hemisphere activation, increased heart rate (p < 0.05), and enhancement of the ratio of
left hemisphere parietal EEG activation to right hemisphere activation.
Systemic effects of nicotine exposure were
studied in eight healthy male cigarette smokers (ages 27 to 61 yr; mean, 49 yr) during
free use of oral snuff, chewing tobacco, and cigarettes. Participants used either one of
the above 3 substances or abstained from all tobacco during four 3 or 4 day blocks.
Concentrations of nicotine and cotinine,
cardiovascular effects, and urine sodium, catecholamines and mutagenicity were measured
over 24 hr at the end of each treatment block. Mutagenic activity of the urine was
measured by the Salmonella-histidine auxotrophic-reversion assay. Circadian exposure to nicotine and cardiovascular effects, including urinary
catecholamine excretion, were similar for all forms of tobacco use. Urine sodium excretion
was greater while using smokeless tobacco than while smoking. Urine mutagenicity was
markedly increased while smoking cigarettes and tended to be increased while chewing
tobacco but not while using oral snuff.
Autopsy of those who died from acute nicotine
poisoning showed marked dilatation of the right side of the heart, mild pulmonary edema,
hemorrhagic gastritis, acute passive congestion of most internal organs, brain edema, and
marked renal hyperemia.
The common symptoms of moderate intoxication include nausea, vomiting, abdominal pain,
diarrhea, headache, sweating, fatigue, and palpitations. More severe symptoms include
faintness, dizziness, weakness, and confusion progressing to prostration with increasing
muscular weakness, collapse, and respiratory arrest. Most deaths occur within a few
minutes of ingestion and recovery usually occurs if the patient survives 1 to 4 hr. It has
been estimated that approximately 60 mg of nicotine
orally would be a fatal human dose.
Farm workers who hand-harvest tobacco are at risk of developing "green tobacco
sickness" /SRP: from nicotine exposure/.
Drug Warnings:
Drugs of Abuse: Contraindicated during Breast-Feeding: Nicotine
(smoking): Shock, vomiting, diarrhea, rapid heart rate, restlessness; decreased milk
production. (The Committee on Drugs strongly believes that nursing mothers should not
ingest any compounds listed /drugs of abuse/ ... Not only are they hazardous to the
nursing infant, but they are also detrimental to the physical and mental health of the
mother ... No drug of abuse should be ingested by nursing mothers even though adverse
reports are not in the literature.) /from Table 2/ [Report of the American Academy of
Pediatrics Committee on Drugs in Pediatrics 93 (1): 138 (1994)]
Allergic contact sensitization to nicotine,
confirmed by rechallenge in some patients, has been reported in 2-3% of patients receiving
the drug via a transdermal system...
Intranasal administration of nicotine
solution commonly produces local nasopharyngeal and ocular irritation. During the initial
2 days of intranasal nicotine therapy, nearly
all patients experience nasal irritation, which usually is moderate to severe. Both the
incidence and severity of nasal irritation decrease with continued intranasal therapy, but
it still is experienced by about 80% of patients after 3 weeks of therapy...
Patients with cardiac disease, recent myocardial infarction, or irregular heart rate
should consult their clinician before initiating self-medication with nicotine
preparations. A clinician also should be consulted prior to self-medication if the patient
has peptic ulcer disease, is receiving insulin for the management of diabetes mellitus, or
has uncontrolled hypertension or if they are receiving drug therapy for depression or
asthma...and, for the transdermal systems, if they are allergic to adhesive tape or have a
dermatologic condition.
Adverse GI effects occur frequently during the first week of therapy with nicotine polacrilex. The most frequent adverse
systemic effects...are indigestion and nausea, which reportedly occur in about 20-40% of
patients receiving the drug.
Adverse nervous system effect of nicotine
polacrilex include dizziness and lightheadedness, headache, insomnia, and irritability,
which reportedly occur in 1-25% of patients. Euphoria reportedly occurs in less than 1% of
patients.
Patients receiving nicotine polacrilex should
be warned that chewing the gum too rapidly may result in effects similar to those
associated with smoking a cigarette too rapidly or those experienced by nonsmokers when
they inhale a cigarette for the first time.
Medical Surveillance:
Recommended medical surveillance: The following medical procedures should be made
available to each employee who is exposed to nicotine
at potentially hazardous levels: Initial Medical Examination: A complete history and
physical examination: The purpose is to detect existing conditions that might place the
exposed employee at an increased risk, and to establish a baseline for future health
monitoring. Examination of the nervous system and cardiovascular system should be
stressed. Periodic Medical Examination: The aforementioned medical examination should be
repeated on an annual basis.
Populations at Special Risk:
Farm workers who hand-harvest tobacco are at risk of developing "green tobacco
sickness" /SRP: from nicotine exposure/.
Probable Routes of Human Exposure:
NIOSH (NOES Survey 1981-1983) has statistically estimated that 4737 workers (861 of
these are female) are potentially exposed to nicotine
in the US(1). The most probable route of human exposure to nicotine
is by inhalation of tobacco smoke and in indoor air where smoking is allowed(2). Some
segments of the general population may also be exposed to nicotine
in drinking water. Infants breast fed by woman who smoke will tend to be exposed to nicotine in the mother's milk. Worker exposure to nicotine may occur during processing and extraction of
tobacco(SRC).
Exposure of individuals to ambient nicotine
in households, offices, pubs, restaurants, coffee shops, cars, trains, and airplanes was
estimated. An estimate of the amount of nicotine
inhaled was calculated by multiplying nicotine
concentration from the personal monitor by respiratory volume (0.48 cu m/hr). Nicotine exposure was converted to an equivalent of
cigarettes smoked (representing passive smoking) by dividing the inhaled nicotine
values by the known nicotine exposure (1 mg)
from active smoking of one cigarette. Three individual offices yielded nicotine
exposure values ranging from 5.9 to 19.8 ug/cu m. The nicotine
inhaled was estimated to be 2.8 to 9.5 ug/hr, which is equivalent to active smoking of
0.003 to 0.010 cigarettes/hr. In one office where 28 to 48 cigarettes were smoked per day,
an estimated weekly nicotine exposure of 3.0 to
10.2 ug/cu m was calculated. Average nicotine
exposure levels in several public places ranged from 31.5 to 43.2 ug/cu m, with a passive
smoking exposure equivalent to no more than 50 ug nicotine/hr
(0.05 cigarettes/hr). Nicotine exposure levels
in smoking seats of trains and airplanes was 48.6 and 28.8 ug/cu m, respectively. These
values were equivalent to smoking 0.023 and 0.014 cigarettes/hr. Nicotine
intake was particularly high for individuals exposed at the workplace and at home. Daily nicotine inhaled by non-smokers (passive smoking) is
significantly less than that inhaled by active smokers.
Body Burden:
Breast milk from heavy smokers may contain 0.5 mg/l(1). Nicotine
was detected in breast milk from smokers and nonsmokers at a mean concentration of 91 and
0 ppb, respectively(2). Detected (0.2-1.6 ng/ml) in serum of newborn infants nursed by
smoking mothers(3).
Nicotine concns in hair samples taken from a
non-smoker ranged from 1.3 to 2.8 ug/g and in hair samples from a smoker ranged from 36 to
60 ug/g(1).
Urine samples of 2 groups of children (Group A: 10 mo old, 55 children; Group B: 4 yr
old, 54 children) were analyzed for nicotine and
cotinine to study the effects of exposure to environmental tobacco smoke. Twenty of Group
A and 19 of Group B children had not been exposed to environmental tobacco smoke while the
remaining children had been exposed during the last three days. The differences in urinary
nicotine and cotinine levels between the
"exposed" and "unexposed" children were statistically significant in
both age groups. Median urinary nicotine levels
in "exposed" and "unexposed" children were 2.7 ug/l and 1.3 ug/l
respectively in Group A and 2.2 ug/l and 1.1 ug/l respectively in Group B.
Average Daily Intake:
Using sidestream/mainstream ratios of nicotine
and assuming a 10 L/min respiratory rate, the recent Surgeon General's Report estimates
that from 0.6 to 30 ug of nicotine is inhaled in
one hour by passive smoking(1). As a result of all-day monitoring, it was found that the
highest amount of nicotine inhaled in a day was
estimated to be up to 310 ug, equivalent to actively smoking 0.31 ordinary cigarettes(2).
Minimum Fatal Dose Level:
The fatal adult dose is 60 mg.
Emergency Medical Treatment:
Emergency Medical Treatment:
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replication or redistribution of all or part of the POISINDEX(R) database is a violation
of Micromedex' copyrights and is strictly prohibited. The following Overview, *** NICOTINE ***, is relevant for this HSDB record chemical. |
| Life Support: |
o This overview assumes that basic life support measures
have been instituted.
|
| Clinical Effects: |
SUMMARY OF EXPOSURE
0.2.1.1 ACUTE EXPOSURE
o ABSORPTION - Nicotine is well absorbed via ingestion,
inhalation, dermal and rectal exposure. Oral
absorption from ingested cigarettes or cigars is
incomplete.
o Symptoms generally include nausea, vomiting, abdominal
pain and increased salivation. Confusion, agitation,
restlessness followed by lethargy, convulsions and coma
may be noted following severe exposure. Hypertension,
tachycardia and tachypnea may occur, followed by
hypotension, bradycardia and bradypnea. The duration
of symptoms is about 1 to 2 hours following mild
exposure, up to 18 to 24 hours following severe
intoxication. Co-intoxicants may complicate the
clinical course.
o Nicotine causes the blockade of nicotinic cholinergic
receptors in the brain, autonomic ganglia, and
neuromuscular junction. Thus, central nervous system,
sympathetic or parasympathetic autonomic, and
neuromuscular effects may be seen in varying
combinations.
o ONSET and duration of symptoms occur as follows:
1. TOBACCO - symptoms begin 30 to 90 minutes post
ingestion.
2. GUM OR LIQUID - symptoms onset is more rapid, 15 to 30
minutes post ingestion. Onset may be particularly
rapid in children.
3. DURATION - mild exposure: 1 to 2 hours; severe
intoxication: 18 to 24 hours.
o INFANTS may be particularly susceptible to nicotine
toxicity.
o DEATH is usually due to respiratory failure and may
occur as early as 1 hour post ingestion.
VITAL SIGNS
0.2.3.1 ACUTE EXPOSURE
o Hypertension, tachycardia and tachypnea may occur,
followed by hypotension, bradycardia and bradypnea.
Respiratory stimulation is one of the principal signs
of nicotine poisoning. High doses can produce fatal
respiratory depression of both central and peripheral
origin.
HEENT
0.2.4.1 ACUTE EXPOSURE
o Increased salivation and lacrimation may occur.
o Initial miosis followed by mydriasis may occur.
o Burning sensation in mouth and throat may occur.
o Gingival recession has been observed after long-term
oral use of "smokeless" snuff.
CARDIOVASCULAR
0.2.5.1 ACUTE EXPOSURE
o Hypertension (low dose) or hypotension (high dose),
tachycardia or bradycardia, various atrial and
ventricular arrhythmias, and vasoconstriction have all
been reported. Cardiac arrest is a rare complication.
RESPIRATORY
0.2.6.1 ACUTE EXPOSURE
o Initial tachypnea, followed by dyspnea is common. Late
bradypnea may occur. Increased bronchial secretions, a
cholinergic effect, are common. Respiratory tract
irritation may occur. Respiratory failure with apnea
may occur following large ingestions and may occur
quickly (5 minutes postingestion).
NEUROLOGIC
0.2.7.1 ACUTE EXPOSURE
o Headache, dizziness, restlessness followed by lethargy,
coma and seizures may occur. Initial excitation and
agitation may be followed by lethargy progressing to
coma. Headache, agitation, tremor and at higher doses,
CNS and neuromuscular depression and seizures have all
been reported.
GASTROINTESTINAL
0.2.8.1 ACUTE EXPOSURE
o Nicotine initially causes a burning sensation in mouth,
throat, esophagus and stomach. Increased salivation
follows. Nausea, vomiting, abdominal pain, and
diarrhea are common. Vomiting may occur very early
after tobacco ingestion, minimizing absorption and
other toxic manifestations.
GENITOURINARY
0.2.10.1 ACUTE EXPOSURE
o Signs of acute renal failure have been reported.
FLUID-ELECTROLYTE
0.2.12.1 ACUTE EXPOSURE
o Hypokalemia has been reported following elevated serum
nicotine levels.
DERMATOLOGIC
0.2.14.1 ACUTE EXPOSURE
o Intense sweating may be noted. Dermatosis may develop
with chronic exposure.
0.2.14.2 CHRONIC EXPOSURE
o Nicotine sulfate is a sensitizer.
MUSCULOSKELETAL
0.2.15.1 ACUTE EXPOSURE
o Rhabdomyolysis may result from severe overdoses.
IMMUNOLOGIC
0.2.19.2 CHRONIC EXPOSURE
o Nicotine sulfate is a dermal sensitizer.
REPRODUCTIVE HAZARDS
o Nicotine is a possible human teratogen.
o Nicotine is teratogenic in mice but not in several other
species. It crosses the placenta and is excreted in
breast milk. It has reduced fertility in male and
female rats.
CARCINOGENICITY
0.2.21.2 HUMAN OVERVIEW
o Use of smokeless tobacco has been shown to cause
oral-pharyngeal cancer. A correlation between the use
of nicotine-containing sheep dip and esophageal tumors
has been noted in sheep.
GENOTOXICITY
o DNA inhibition, mutagenicity and chromosome aberrations
have been demonstrated experimentally.
|
| Laboratory: |
o Plasma nicotine levels are not usually clinically useful.
o Monitor vital signs and ECG in all symptomatic patients.
o Monitor serum electrolytes and kidney function tests in
symptomatic patients with severe exposures.
|
| Treatment Overview: |
ORAL EXPOSURE
o EMESIS is usually spontaneous. Since rapid onset of
seizures may occur, ipecac-induced emesis is NOT
ADVISED.
o GASTRIC LAVAGE: Consider after ingestion of a
potentially life-threatening amount of poison if it can
be performed soon after ingestion (generally within 1
hour). Protect airway by placement in Trendelenburg and
left lateral decubitus position or by endotracheal
intubation. Control any seizures first.
1. CONTRAINDICATIONS: Loss of airway protective reflexes
or decreased level of consciousness in unintubated
patients; following ingestion of corrosives;
hydrocarbons (high aspiration potential); patients at
risk of hemorrhage or gastrointestinal perforation; and
trivial or non-toxic ingestion.
o ACTIVATED CHARCOAL: Administer charcoal as slurry (240
mL water/30 g charcoal). Usual dose: 25 to 100 g in
adults/adolescents, 25 to 50 g in children (1 to 12
years), and 1 g/kg in infants less than 1 year old.
o SEIZURES: Administer a benzodiazepine IV; DIAZEPAM
(ADULT: 5 to 10 mg, repeat every 10 to 15 min as
needed. CHILD: 0.2 to 0.5 mg/kg, repeat every 5 min
as needed) or LORAZEPAM (ADULT: 4 to 8 mg; CHILD: 0.05
to 0.1 mg/kg).
1. Consider phenobarbital if seizures recur after diazepam
30 mg (adults) or 10 mg (children > 5 years).
2. Monitor for hypotension, dysrhythmias, respiratory
depression, and need for endotracheal intubation.
Evaluate for hypoglycemia, electrolyte disturbances,
hypoxia.
o HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid,
place in Trendelenburg position. If hypotension
persists, administer dopamine (5 to 20 mcg/kg/min) or
norepinephrine (0.1 to 0.2 mcg/kg/min), titrate to
desired response.
o DO NOT ADMINISTER ANTACIDS since nicotine is better
absorbed in a alkaline media.
o ATROPINE: ADULT DOSE: BRADYCARDIA: 0.5 to 1 mg IV
every 5 min. BRADYASYSTOLIC ARREST: 1 mg IV every 5
min. Maximum total dose 0.04 mg/kg. Minimum single
dose 0.5 mg. PEDIATRIC DOSE: 0.02 mg/kg IV repeat
every 5 min, minimum single dose 0.1 mg; maximum single
dose 0.5 mg child, 1 mg adolescent; maximum total dose 1
mg child, 2 mg adolescent.
o MONITOR EKG and vital signs carefully
o Maintain adequate hydration and urine output.
INHALATION EXPOSURE
o INHALATION: Move patient to fresh air. Monitor for
respiratory distress. If cough or difficulty breathing
develops, evaluate for respiratory tract irritation,
bronchitis, or pneumonitis. Administer oxygen and
assist ventilation as required. Treat bronchospasm with
beta2 agonist and corticosteroid aerosols.
o Treatment should include recommendations listed in the
ORAL EXPOSURE section when appropriate.
EYE EXPOSURE
o DECONTAMINATION: Irrigate exposed eyes with copious
amounts of tepid water for at least 15 minutes. If
irritation, pain, swelling, lacrimation, or photophobia
persist, the patient should be seen in a health care
facility.
DERMAL EXPOSURE
o DECONTAMINATION: Remove contaminated clothing and wash
exposed area thoroughly with soap and water. A
physician may need to examine the area if irritation or
pain persists.
|
| Range of Toxicity: |
o Nicotine is highly toxic; about 2 to 5 mg can cause
nausea. The estimated lethal oral dose in adults is
approximately 40 to 60 mg.
o Ingestion of as little as 1 cigarette (or more than 3
butts), one cigar butt, or any amount of nicotine chewing
gum should be considered potentially toxic.
o As little as 1 milligram of nicotine can produce symptoms
in a small child.
o Severe toxicity (eg, hypertension, tachycardia,
vasoconstriction) has occurred via buccal absorption of
the transdermal nicotine patch, Prostep(R), after biting
it (Harchelroad et al, 1992).
|
Antidote and Emergency Treatment:
For immediate first aid: Ensure that adequate decontamination has been carried out. If
victim is not breathing, start artificial respiration, preferably with a demand-valve
resuscitator, bag-valve-mask device, or pocket mask as trained. Perform CPR if necessary.
Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If
vomiting occurs, lean patient forward or place on left side (head-down position, if
possible) to maintain an open airway and prevent aspiration. Keep victim quiet and
maintain normal body temperature. Obtain medical attention. /Nicotine
and related compounds/
For basic treatment: Establish a patent airway. Suction if necessary. Aggressive airway
management may be needed. Watch for signs of respiratory insufficiency and assist
ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min.
Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes
immediately with water. Irrigate each eye continuously with normal saline during transport
... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL
of water for dilution if the patient can swallow, has a strong gag reflex, and does not
drool. Administer activated charcoal ... . /Nicotine
and related compounds/
Animal Toxicity Studies:
Non-Human Toxicity Excerpts:
ALKALOIDAL NICOTINE IS EXTREMELY TOXIC
SUBSTANCE THAT TRANSIENTLY STIMULATES & THEN SEVERELY DEPRESSES CNS. DEATH ... DUE TO
RESPIRATORY PARALYSIS ... & DEPOLARIZING BLOCK OF NERVE MUSCLE JUNCTION OF SKELETAL
MUSCLE. ... NICOTINE ACTIVATES SMOOTH MUSCLES
& SECRETORY GLANDS OF DIGESTIVE TRACT /PRODUCING/ ... EXCESSIVE SALIVATION, INCR
GASTRIC SECRETION, VOMITING, INCR PERISTALSIS, & DEFECATION.
NICOTINE WAS TERATOGENIC IN MICE WHEN
INJECTED @ 25 MG/KG ON DAYS 9-11 OF GESTATION. SKELETAL DEFECTS & OCCASIONAL CLEFT
PALATES WERE PRODUCED.
... Reported an epidemic of limb deformities in the offspring of swine which fed on
tobacco stalks containing 1058 ppm of nicotine
and 115 ppm of maleic hydrazide.
In the rat ... used 0.05 mg per ml of drinking water and found a reduced size in the
newborn.
IN STUDIES WITH SACCHAROMYCES CEREVISIAE, NICOTINE
WAS ... MUTAGENIC AT 100 PPM. IN ... SALMONELLA TYPHIMURIUM, TA-98 WITH METAB ACTIVATION, NICOTINE WAS NOT IMPORTANT IN CONTRIBUTING TO
MUTAGENIC POTENCY OF SMOKE CONDENSATE. USING MAMMALIAN CELL CULTURE SYSTEM (HAMSTER LUNG),
CONCN OF NICOTINE IN CIGARETTE SMOKE HAD NO
INFLUENCE ON OCCURRENCE OF ATYPICAL GROWTH OR MALIGNANT TRANSFORMATION.
EXPTL NICOTINE INJECTED INTO ANTERIOR CHAMBER
/OF THE EYE/ OF RABBITS HAS CAUSED INFLAMMATION OF ANTERIOR SEGMENT OF EYE & MIOSIS.
... WHEN NEAR-LETHAL DOSES WERE ADMIN TO RABBITS DAILY FOR 80 DAYS, NICOTINE
PRODUCED MYDRIASIS & POOR RESPONSE OF PUPILS TO LIGHT, ATTRIBUTABLE TO DEGENERATION
INDUCED IN RETINAL GANGLION CELLS. ... IN DOGS, DAILY SC INJECTIONS ... FOR 18 MO CAUSED
ATROPHY OF RETINA, DISORGANIZATION OF LAYERS, & REDN OF NUMBER OF CELLS. CHANGES IN
BLOOD VESSELS WERE THOUGHT TO BE PRIMARILY RESPONSIBLE.
IN 3-DAY-OLD MICE NICOTINE DID NOT INDUCE
CONVULSIVE PATTERN SEEN IN ADULTS. RATE OF METAB IN VITRO CORRELATED WITH LETHAL TOXICITY
IN YOUNG MICE.
DEFORMITIES WERE FOUND IN SOME RABBIT FETUSES WHOSE DAMS WERE ADMIN 20 MG/KG, 5 TIMES
DURING PREGNANCY.
INJECTION OF 0.07-0.09 MG NICOTINE INTO MICE
RESULTED IN GROSS CHROMOSOMAL ABERRATIONS IN BONE MARROW CELLS.
PREGNANT SWINE FED AQUEOUS LEAF EXTRACTS OF TOBACCO AT RATE OF 16 & 32 MG/KG NICOTINE PRODUCED ARTHROGRYPOTIC NEWBORN PIGS.
NICOTINE WAS AMONG COMPOUNDS FOUND
TERATOGENIC WHEN INJECTED INTO YOLK SACK OF CHICKEN EGGS @ RATE OF 1 OR 2.5 MG/EGG ON DAY
4 OF INCUBATION AS MEASURED ON CHICK SPINALIS MUSCLE. BETWEEN SPINE LENGTH & NICOTINIC
POTENCY OF CMPD A NEG CORRELATION WAS SEEN.
GESTATION WAS PROLONGED BUT BIRTH WT WAS NOT ALTERED IN SPONTANEOUSLY DELIVERED
OFFSPRING OF PREGNANT RATS ADMIN SC 2-10 MG/KG/DAY NICOTINE.
NICOTINE DECR BIRTH WT OF OFFSPRING DELIVERED BY
CESAREAN SECTION ON 21ST DAY OF GESTATION. ADMIN OF 3 MG/KG DURING FIRST 8 DAYS OF
GESTATION OR DURING THE ENTIRE GESTATION PERIOD INDUCED THE SAME EFFECTS. IT APPEARS THAT NICOTINE AFFECTS PROCESSES ALREADY OPERATIVE DURING
THE 1ST WK OF GESTATION & THAT THESE EFFECTS MAY BE MANIFESTED IN DEVELOPMENTAL
DISTURBANCES AT LATER GROWTH STAGES.
NICOTINE CONTINUOUSLY INFUSED INTO ISOLATED
RAT HEART DEPRESSES HEART RATE & CORONARY FLOW IN A DOSE-RELATED MANNER. THESE CHANGES
ARE REVERSIBLE OVER RANGE OF CONCENTRATIONS USED.
Toxic to bees but has a repellent effect.
Numerous cases of livestock poisonings from consumption of cultivated tobacco (Nicotina tabacum) are known. Horses have died from
consumption of tobacco leaves, while pigs have been fatally poisoned when they broke into
a tobacco field. ... An unusual case is the death of a dog which consumed a package of
cigarettes.
Nicotine, at 10 mg/kg/day in rats, promptly
and drastically curtailed water consumption during the first 24 hr. Thereafter, water
intake alternately rose and fell during the rest of the 6 day infusion period, suggesting
that overriding mechanism(s) were activated. When nicotine
was abruptly withdrawn, water intake rose dramatically and remained elevated throughout
the withdrawal period. Mecamylamine at a dose of 5 mg/kg/day did not block nicotine's hypodipsic effect during the first three
days.
The deleterious effects of nicotine treatment
on skin hemodynamics and survival of acute random pattern skin flaps constructed on the
dorsum of the rat were studied. Rats were injected subcutaneously with 0.2 ml of saline
containing varying doses (0, 1, 2, 4, or 8 mg/kg; bid) of nicotine
for 5 weeks, starting 4 weeks before flap surgery. It was observed that nicotine
treatment at the dose of 2 mg/kg (bid), or higher, significantly (p < 0.05) decreased
the length and area of skin flap survival compared with the control. This dose of nicotine treatment also significantly (p < 0.05)
decreased the capillary blood flow and distal perfusion in the skin flaps compared with
the control. However, detrimental effect of nicotine
treatment on the survival of acute random pattern skin flaps was not seen if the treatment
was started 2 instead of 5 weeks postoperatively.
To detect the time after administration of nicotine
and dosage for neurochemical studies, locomotor activity of CD-1 mice was determined at 5
minute intervals between 0-60 minutes. A low nicotine
dosage (0.05 mg/kg) did not alter activity 5-15 minutes after drug injection, but
increased activity 28% at 15-25 minute post-injection. A high dosage (0.8 mg/kg) reduced
total distance 62% and rearing 87% at 5-15 minutes; at 15-25 minutes total distance
declined 56% and rearing 69%; all measures returned to control values after 30 minutes;
rearing then increased at 40 minutes after nicotine.
Pretreatment (15 minutes before nicotine) with
mecamylamine (1.0 mg/kg), but not hexamethonium (1.0 mg/kg), prevented the depressant
effect of nicotine. Dopamine and its metabolites
as well as acetylcholine synthesis were measured at the point of nicotine's
maximal depressant action. Striatal levels of dihydroxyphenylacetic acid were increased
and acetylcholine utilization was reduced in striatum (-25%) and cortex (-24%) 10 minutes
after nicotine (0.8 mg/kg).
Environmental substances were examined for their effect on interferon induction and
delayed type hypersensitivity (DTH) responses in mice. Amaranth, safrole, phenacetin, and nicotine suppressed the delayed type hypersensitivity
response, and suppressed the serum interferon titers induced by virus infection. However,
they did not affect the interferon titers which were induced by tilorone, a chemical
inducer. The peak of interferon titer was 12 hr after infection with Herpes simplex virus
type 2 (HSV-2). Therefore, amaranth, safrole, phenacetin, and nicotine
were given to mice ip 24 hours before, and 2 and 18 hours after infection with Herpes
simplex virus type 2. Safrole and nicotine
shortened the mean survival time of Herpes simplex virus type 2 infected mice when they
were given to mice 2 hour after virus inoculation.
The metabolic response of fetal and neonatal lung tissue to maternal nicotine
exposure (0.25 and 1.0 mg/kg/day) was investigated. White virgin female rats (Wistar) of
200-250 g were mated overnight and randomly assigned to control and exptl groups. One
group received nicotine during pregnancy and
lactation. The second group received nicotine
only during lactation. The suckling rats were killed 24 hr after the last dose of nicotine was administered to the mother. Maternal nicotine administration during pregnancy and lactation
stimulated total glucose turnover by 21.6 and 86.4% respectively but suppressed
glycogenolysis (32.7%), glycolysis by 24.6%. Nicotine
administration during lactation only enhanced total glucose turnover by 19.1% and
glycogenolysis by 30% but inhibited glycolysis by 25.8%. After 4 wk of nicotine
withdrawal when the rats were 7 wk old, glycogenolysis and glycolysis of those animals
exposed to nicotine via the placenta and
mother's milk were still inhibited to the same extent as during exposure. Glycogenolysis
and the glycolytic flux of lung tissue of rats exposed to nicotine
via mother's milk only returned to normal.
... Previously /it has been noted/ that a single dose of nicotine
elevates plasma adrenocorticotropin levels in rats and has a biphasic effect on plasma
prolactin. The stimulatory effect of nicotine on
these stress-responsive hormones desensitizes after a single injection of nicotine. Continuous exposure to nicotine
also induces tolerance to its locomotor depressive and hypothermic effects, which have
been associated with an increase of central (3)H-nicotine
binding. Thus, the acute and chronic administration of nicotine
might induce changes in central nicotinic cholinergic circuits that affect the
adrenocorticotropin and prolactin responses to stress. In the present study, a single dose
of nicotine (0.75-3.0 mg/kg body weight)
significantly inhibited the elevation of plasma prolactin due to restraint stress
initiated 60 min afterward. Five injections of nicotine
during 1 day produced a similar attenuation of the prolactin response to restraint stress
but neither of these paradigms affected adrenocorticotropin. In contrast, intermittent
delivery of nicotine for 7 days failed to affect
the prolactin response to restraint stress; however, after withholding nicotine
for 14 hr, high dose nicotine attenuated the
prolactin response to stress, whereas low dose nicotine
remained ineffective. On the other hand, administration of the same schedule of low dose nicotine did significantly diminish the expected
release of prolactin in response to a final injection of nicotine
(0.5-2.0 mg/kg body weight) in unstressed animals.
Inbred Fischer and Buffalo rats were exposed to nicotine
and ethanol. Fertility was greatly reduced in both strains with nicotine
treatments being much more deleterious than alcohol use. Fischer rats tolerated both
toxins better than Buffalo rats. Both strains became extinct after 1 generation of fetal
and postnatal exposure to nicotine, but alcohol
ingesting Fischer rats had > or = 3 generations of offspring. The total reproductive
period was significantly shortened in both strains under the effect of both toxins, as was
the total life span. The causes of the teratologic effects of both toxins are inflammatory
processes as evidenced by the presence of numerous lymphocytes and/or polymorphonuclear
leukocytes. Their presence occurs earlier in nicotine
than in alcohol use and earlier in Buffalo than in Fischer rats, but the damage done
during nicotine treatment is reversible when the
procedure is terminated. Inflammation is not transmitted to the newborn offspring of nicotine- or alcohol-treated mothers, but occurs in
neonates during the nursing period or later.
Adult female rats were chronically treated with nicotine
administered via the drinking water during pregnancy and/or lactation. The approximate
doses of nicotine consumed per day were 2.4
mg/kg of body weight. The pups were weaned at 20 days of age. The pups were killed by
decapitation on postnatal days 20, 30, 40, and plasma heparinized trunk blood was assayed
for luteinizing hormone. At 30 days of age untreated male and female offspring had the
highest levels of plasma luteinizing hormone compared to 20 and 40 days of age. The level
was not affected by any subsequent dose or treatment. Prepubertal females exposed to nicotine during pregnancy failed to exhibit the
pattern of luteinizing hormone levels seen in control animals, whereas those exposed
during lactation or throughout the perinatal period showed a distinctive pattern of plasma
luteinizing hormone. Chronic exposure of female offspring to the low dose of nicotine during lactation tended to increase plasma
luteinizing hormone levels at 20 and 40 days. Female offspring exposed to nicotine during pregnancy or to the low dose during
lactation showed significant deficits in body weight at 40 days of age which appeared to
correlate with a delay in vaginal opening.
Nicotine was administered iv to DBA mice
through cannulae implanted in the jugular veins. Five groups of animals were treated: a
control group which received saline and four nicotine
treatment groups. All of the nicotine treatment
groups received a dose of 4.0 mg/kg/hr. The first group received continuous infusion, the
second group received 1 mg/kg pulses four times an hour, the third group received 2 mg/kg
pulses twice an hour, the fourth group received 4 mg/kg pulses once an hour. After a 10
day treatment period, the animals were tested for tolerance to an acute ip administration
of nicotine. Mice from each of the four nicotine treatment groups were tolerant to the acute
effect of nicotine, but the extent of tolerance
varied among the groups as follows: continuous infusion < 1 mg/kg pulses four times/hr
< 2 mg/kg pulses twice/hr < 4 mg/kg pules once/hr. Chronic nicotine
infusion resulted in significant increases in the binding of L-(3)H-nicotine
in all six brain regions assayed and in significant increases in the binding of
alpha-(125)I-bungaratoxin binding in cerebral cortex and hippocampus. All increases in
binding resulted from increases in Bmax for these ligands. In contrast to the effects
observed for tolerance development, the increases in (3)H-nicotine
binding were not significantly affected by the kinetics of nicotine
infusion. However, the binding of alpha-(125)I-bungaratoxin tended to increase along with
the peak plasma concern of nicotine and
paralleled the differences in tolerance. While the average blood level of nicotine did not differ significantly among the 4
groups, peak levels were higher after infusion of both the 2 mg/kg and 4 mg/kg pulses.
Female rats were used to examine the effects of chronic nicotine
administration and withdrawal on food and water consumption and body weight. Rats with
chronic nicotine pellet implants consumed
significantly less food and water than controls for the first 5 days and then gradually
returned to control levels of consumption. The lowest level of body weight was reached on
day 9 after which there was a slow return to control weights by day 21. When the nicotine pellets were removed from the short-term
exposure group on day 14, they were removed from the short-term exposure group on day 14,
they showed significantly hyperphagia and hyperdispsia and a very rapid weight gain for
the next several days, which clearly outpaced the recovery of weight in the long-term nicotine exposure group.
The behavioral response to nicotine was
examined in photocell activity cages. Groups of rats were tested using doses from 0.1 to
1.6 mg/kg both before and after all rats were exposed for 5 days to a common dose of 0.2
mg/kg/day. Prior to the 5 day exposure, there was a dose-related stimulant response to nicotine, with a max response seen at 0.4 mg/kg. After
the 5 day exposure, the dose-effective curve was shifted upward, so that greater
stimulation was produced at each dose of nicotine.
Other groups of rats were exposed for 5 days to doses of nicotine
ranging from 0.01 to 0.30 mg/kg/day. On the 6th day all rats received a common test dose
of 0.2 mg/kg and their response was measured in the activity cages. In animals exposed to
0.1 mg/kg/day, the test day response was not different from saline controls, but the
groups exposed to higher doses showed increased stimulation in response to the common test
dose. Measurements of nicotinic receptor binding using (3)H-acetylcholine found increased
binding in groups receiving 0.03 mg/kg/day or more, but not in the group that received
0.01 mg/kg/day. Rats given high doses (1.6 mg/kg, twice/day) did not show increased
behavioral stimulation to a test dose of 0.2 mg/kg.
Behavioral effects of d-nicotine (0.1-10.0
mg/kg), l-nicotine (0.01-1.0), d-nornicotine
(0.1-10.0), l-nornicotine (0.1-10.0) and l-cotinine (1.0-100.0) were studied in two
paradigms. In expt 1, 6 male rats responded under a multiple fixed-interval (FI) 5 min,
fixed-ratio (FR) 20 schedule of food presentation. Aside from differences in potency and
time course, l-nicotine and the stereoisomers of
nornicotine produced qualitatively similar effects on rates of responding. Rate-increasing
effects of cotinine were not blocked by mecamylamine. In expt 2, 2 groups of 8 male rats
were trained to discriminate between l-nicotine
(0.1 mg/kg sc) and saline (0.1 ml/kg sc) in a two-bar, operant conditioning procedure
under a tandem variable-interval 9 min, fixed-ratio 10 schedule of food presentation. Full
generalization was obtained to d-nicotine and to
l- and d-nornicotine. Generalization to cotinine occurred only with large doses that
contained significant amounts of nicotine
present as an impurity. The rank order of potency for nicotine
and its analogs was similar in experiments 1 and 2: l-nicotine
was 10-20 times more potent than d-nicotine and
the stereoisomers of nornicotine (which did not show stereoselectivity in the rat).
Cotinine was at least several hundred times less potent than nicotine.
The response of male Sprague-Dawley rats to nicotine
soln was examined with the brief-exposure, taste reactivity test and a two-bottle, 24 hr
preference test. Groups of 8 naive nondeprived rats were admin intraoral infusions (0.8 mL
infused during 1 min) of distilled water and 1 ug/ml, 5, 10, 25, 50, and 100 ug/ml nicotine. The oral motor, taste reactivity responses
of the rats were recorded during the infusion. Nicotine
soln up to a concn of 50 ug/ml elicited a number of ingestive taste reactivity responses
similar to that by water. Ingestive responses significantly decreased, and aversive taste
reactivity responses significantly increased in response to 100 ug/ml nicotine.
On the basis of these results, two-bottle preferences for water versus 1 ug/ml, 5 ug/ml,
and 0 ug/ml (water control group) nicotine were
measured in three groups of naive rats (n=7-9). Rats initially showed an equal preference
for 0 and 1 ug/ml nicotine. After 16 days of
exposure, however, rats developed a significant preference for 1 ug/ml nicotine.
The preference ratio for 5 ug/ml nicotine
significantly increased during the expt, but the preference ratio remained significantly
less than that for 1 ug/ml and control solutions. TR responses elicited by 0.8 ml
intraoral infusions of 1 ug/ml and 5 ug/ml nicotine
were then measured in 17 rats having had the two-bottle experience. Rats showing a
two-bottle preference for the 1 ug/ml nicotine
solution displayed significantly more ingestive taste reactivity response to 1 ug/ml and 5
ug/ml nicotine than did the control rats.
Groups of 50 male Sprague-Dawley rats (200-250 g) were either given water (controls),
or water containing 1.0 mg% nicotine ad lib.
Mean daily nicotine intake during the 6 wk
treatment period was 0.7 +/- 0.01 mg/kg body wt. At the end of wk 6, both groups were
given daily sc injections of 1 mg/kg haloperidol for 0-12 days. Two days after the last
injection, the rats were killed by decapitation. Rat striata were dissected from the
brain, reacted with (3)H-domperidone (benzene ring (3)H), and assayed for D2-dopamine
receptor. Daily admin of haloperidol to controls led to a progressive incr in maximal
binding capacity or receptor density (Bmax) of striatal D2-dopamine receptor. The maximal
incr in Bmax was observed on the 7th day of haloperiodol treatment (Bmax, day 0 = 848.5
and day 7 = 2161.0; , an incr of more than 150%, and it remained unchanged on further
treatment for at least 12 days. In contrast, haloperidol-mediated incr in Bmax were
completely blocked in rats receiving nicotine in
their drinking water. . The affinity constant of the receptor also seemed to incr with
haloperidol treatment in control but not nicotine-treated
rats.
After a 48 hr prewarming period at 20 to 22 C or 32 to 34 deg C, male NMRI mice were
given nicotine (0, 0.3, 1, or 3 mg/kg sc) 4
times at 30 min intervals. Haloperidol (65 or 160 ug/kg), (+/-)-sulpiride (50 or 100
mg/kg), apomorphine (2 mg/kg), gamma-hydroxybutyric acid (750 mg/kg), or saline (control)
were admin ip after the second nicotine dose. 10
mg/kg hexamethonium was given ip 30 min before the first nicotine
(or saline dose) to prevent the effects of nicotine
on autonomic ganglia. When the effect of body temp on the apomorphine-,
gamma-hydroxybutyric acid-, or nicotine-induced
decr of 3-methoxytyramine was studied, apomorphine (5 mg/kg) and gamma-hydroxybutyric acid
(750 mg/kg) were admin ip after the 4th and 3rd nicotine
doses, respectively. Striatal contents of dopamine and its metabolites homovanillic acid,
3,4-dihydroxyphenylacetic acid and 3-methoxytyramine were measured. Hexamethonium did not
change the striatal dopamine metabolism. At 32 to 34 deg C, nicotine
and haloperidol incr the striatal 3,4-dihydroxyphenylacetic acid and homovanillic acid
contents additively, whereas apomorphine counteracted the effect of nicotine.
Nicotine (3 mg/kg x 4) decr 3-methoxytyramine
content by 42 to 49% in hexamethonium pretreated mice at 20 to 22 deg C. In hypothermic
mice nicotine was better at inhibiting
haloperidol- and (+/-)-sulpiride induced incr of homovanillic acid content than those of
3,4-dihydroxyphenylacetic acid content. In apomorphine-treated mice both the
gamma-hydroxybutyric acid- and nicotine-induced
decr of 3-methoxytyramine fell further. gamma-Hydroxybutyric acid did not alter the nicotine-induced incr of 3-methoxytyramine content.
Unlike gamma-hydroxybutyric acid and apomorphine, nicotine
decr 3-methoxytyramine content only in hypothermic mice.
During a conditioning period, Male albino Wistar rats were given 6 injections of nicotine (0.6 mg/kg sc). In some cases, mecamylamine
was admin ip 30 min before nicotine. After each
injection, rats were transferred to a wire test cage. During test sessions, rats were also
exposed to white noise and smell of acetic acid. Exposure to conditioned stimuli lasted 90
min. On the same day, about 6 hr later, rats were injected with saline and put into their
home cages. Pseudo-conditioned rats were injected with saline before being placed into the
test cage and with nicotine before being
transferred in to the home cage. A third group (naive rats) was exposed to test and home
cages with the same frequency, but injected with solvent only. On the test day (24 hr
after the last nicotine admin), all groups of
rats were injected with nicotine (0.6 mg/kg sc)
and placed into the test cage. Behavior was observed for 10 sec in 5 min intervals.
Subsequently, rats were conditioned (or pseudo-conditioned, respectively) for 4 additional
times and tested with saline injection in the test cage. Nicotine
(0.15, 0.3, and 0.6 mg/kg) produced dose-dependent incr in locomotor activity,
hyperkinesia, and stereotyped sniffing. The effects produced by 0.6 mg/kg nicotine were significantly inhibited by mecamylamine
(1 mg/kg ip), but only in part by haloperidol (0.2 mg/kg ip). When rats were given saline
in presence of the conditioned stimuli 24 hr after the last conditioning session,
locomotor activity, hyperkinesia, and stereotyped sniffing were significantly higher in
conditioned than in pseudo-conditioned drug-naive rats. Similarly, when the rats were
injected with nicotine (0.6 mg/kg sc) in
presence of the conditioned stimuli 2 hr after the last conditioning session, locomotor
activity and stereotyped sniffing were most pronounced in the conditioned animals.
Atrial tissue from denervated dog hearts was incubated with H(3) choline. When compared
with controls, nicotine at concn of 10-5 and
2x10-5 M released more acetylcholine (ACh) from denervated atria, but not at nicotine concn of 5x10-5 M. In parallel contractility
studies using tissue from these same atria, the neg inotropic response to nicotine was enhanced at 5x10-6 and 10-5 M, but not at
2x10-5 or 5x10-5 M nicotine.
The effect of nicotine on growth and
fecundity of Daphnia pulex was tested in 16-day static renewal, full-life-cycle bioassays.
For each concn, 15 Daphnia neonates were placed in individual test tubes in a chamber.
Recovery rates for nicotine at 1 hr after
preparation in water only was 57% and 89% in test media. At 48 and 72 hr after
preparation, nicotine concn in water had dropped
to 24 and 9%, and in test media to 3 and 0%, respectively. Estimated LOEC's (lowest
observable effect concn, were based on nominal concn which were much higher than the
actual concn. Mortality of the original daphnids was 10%, 6%, 4%, 10%, 20% and 66% at 0,
0.02, 0.07, 0.12, 0.18, and 0.24 mg/l, respectively. Nicotine
significantly reduced growth and fecundity of daphnids at nominal concn from 0.02 to 0.24
mg/l. The lowest observable effect concn for length was 0.07 mg/l and the lowest
observable effect concn for fecundity was 0.18 mg/l. Fecundity approached 0 at 0.24 mg/l.
The influence of nicotine on the outflow of
calcitonin gene-related peptide, which is present in sensory nerves, and neuropeptide Y,
which is co-stored with noradrenaline from the isolated guinea-pig heart, was studied in
vitro. 5-min perfusion with 1 x 10-5 M nicotine
was not associated with significant effects on the outflow of calcitonin gene-related
peptide-like activity, while 10-4 M nicotine
induced release of calcitonin gene-related peptide- as well as neuropeptide Y-like
activity in a concn- and Ca +2-dependent manner. After capsaici pretreatment, the nicotine-induced (10-4 M) outflow of calcitonin
gene-related peptide-like activity was abolished, but the change in frequency and the
contractile force inducted by nicotine were not
significantly influenced.
Level of urinary nicotine were measured in 21
non-smokers, 26 smokers of blond tobacco, 9 smokers of black tobacco and 5 smokers of both
types, all eating a similar diet. Two 24 hr samples from the subjects were collected over
a 3 day period. Statistically significant positive dose-effect relationships were obtained
between the urinary nicotine + cotinine levels
and the number of revertants (Salmonella typhimurium TA 98, with a metabolic activation
system. A linear dose-effect relationship between urinary mutagenicity (ie log revertants
of S typhimurium TA98) and nicotine + cotinine
levels or number of cigarettes per day, was established for smokers of blond tobacco.
Smoke condensates prepared from blond and black Italian cigarettes were tested in S
typhimurium TA98 and in E coli PQ37 using liquid incubation procedures. Plate
incorporation assays with Salmonella were also performed. Cigarette smoke condensate from
blond tobacco contained 37 ug nicotine/mg
cigarette smoke condensate, while that of black tobacco contained 67 ug. Smoke condensate
of black tobacco was 1.2 to 1.4 times more mutagenic than that of blond tobacco when
activity is expressed per mg cigarette smoke condensate. The order was reversed when
mutagenicity was expressed per ug nicotine, as
black tobacco cigarette smoke condensate contained 1.8 times more nicotine
than blond cigarette smoke condensate. Liquid incubation assays revealed a 12- to 14-fold
higher mutagenicity than plate incorporation. Both cigarette smoke condensates were found
to be directly active in inducing DNA repair functions.
The comparative acute toxicity of a branded American cigarette and kreteks (Indonesian
cigarettes containing approx 60% tobacco and 40% ground clove buds) was assessed by
exposure of groups of 10 male and 10 female rats to 3 different but equivalent (in terms
of total particulate matter) concn of smoke (1.15 to 6.00% v/v) from each type of
cigarette. The smoke was delivered "nose only" using a rodent smoking machine
within a single 1-hr period, with a total delivery of 30 min smoke and a 15 min
air-breathing period between the 2 smoke exposures. By gross observations of rats and
their respiration during exposure, the only differences observed were more severe signs of
smoke intoxication in the America smoke exposed rats which, at least in part, was
attributed to the higher concn of carbon monoxide. Plasma nicotine
concn wer determined after smoke exposure. Both absolute and relative plasma nicotine values shows plasma nicotine
concn are higher, and are approx linearly related to the incr in total particulate matter
in the American smoke-exposed groups. In the kretek groups, the plasma nicotine
values are also increased at the higher concn of smoke but the relationship between the
two is unclear and appear to be limited at the highest concn of smoke exposure. No
differences were seen upon observation and measurement of body wt, food and water
consumption of a sub-population for 14 days following exposures. No histopathological
differences or differences in lung wt were seen. However, a slight incr in the incidence
and severity of focal alveolar hemorrhage was present in the high dose American group at
24 hr compared with the high dose kretek group.
The influence of nicotine on zymosan
stimulated guinea pig pulmonary alveolar macrophage oxidative metabolism was examined. At
5X10-10 and 5X10-8 M nicotine, the
chemiluminescence response was augmented to 132% and 113%, respectively. At concentrations
of 5X10-7 M and 5X10-4 M, chemiluminescence responses were inhibited to 83% and 51% of the
control, respectively. Superoxide anion release was enhanced to 226% at a nicotine concentration of 5X10-10 M and 209% at 5X10-9
M; and was inhibited to 53% and 58% of the control at concentrations of 5X10-5 M and
5X10-4 M, respectively. The cholinergic antagonists atropine or hexamethonium did not
affect the action of nicotine, a cholinergic
agent.
Groups (n= 5) of adult male Sprague Dawley rats were given 0, 0.5, 1.0, 2.0, 3.0, and
4.0 mg% nicotine water for 60 days. Continuous
oral admin of 2 mg% or less nicotine,
corresponding to a daily oral nicotine intake of
2.35 + or - 0.25 mg/kg or less, did not alter body weight gain or feed intake. Nicotine consumption resulted in a significant incr in
the number of D1 dopamine receptors (p < 0.025 at 0.5, 1.0, and 2.0 mg%), the ratio of
D1 to D2 receptors (p < 0.05 at 1.0, 2.0, 3.0, and 4.0 mg%) and dopamine uptake sites,
but not the number of D2 dopamine receptors. The number of binding sites increased
significantly (p < 0.025) with incr concn of nicotine,
reaching a maximum at 1.0 mg% nicotine, which
then declined steadily at higher nicotine concn.
The effects of 10 nicotine injections (0.8
mg/kg, sc) in 14 days to male Sprague Dawley rats on the levels of brain amines following
challenge with either saline or nicotine (0.8
mg/kg sc) on the 15th day were examined. Dopamine, DOPAC, HVA, 3-methoxytyramine,
norepinephrine, 5-hydroxytyramine, and 5-HIAA were measured in the frontal cortex,
olfactory tubercle, nucleus accumbens, caudate-putamen, substantia nigra and ventral
tegmental area. Ten min after nicotine was given
to rats that had previously received only saline the levels of dopamine and its metabolite
DOPAC indicated an incr in dopamine turnover in the nucleus accumbens. Of the areas
examined the accumbens was the most sensitive to nicotine,
with few significant amine changes in other regions. Twenty-four hours after the last nicotine injection the levels of dopamine and its
metabolites indicated a sustained decr in dopamine turnover in the accumbens induced by
repeated administration. Following repeated nicotine
a nicotine challenge still induced an acute incr
in dopamine turnover in the accumbens, but the response was less than in rats not
previously given nicotine.
The effects of arterial chemoreceptor activation by nicotine
on coronary artery diameter was studied in anesthetized, artificially ventilated greyhound
and mongrel dogs. Left circumflex coronary artery diameter, coronary blood flow,
calculated mean coronary resistance, systemic arterial blood pressure and heart rate were
measured. In control dogs (n = 10) the injection of nicotine
(100 ug) into the carotid artery evoked an incr of arterial pressure (+ 22 + or - 9 mm Hg)
and a decr in heart rate (- 36 + or - 13 beats/min), and tended to incr coronary blood
flow (+ 7 + or - 4 ml/min). Intracarotid nicotine
had no effect on large coronary artery diameter (+ 0.02 + or - 0.03 mm) or total coronary
resistance (+ 0.04 + or - 0.09 mm Hg min/ml) under these conditions. When heart rate was
controlled by beta-adrenoceptor blockade (propranolol, 1 mg/kg iv) plus pacing of the
right ventricle (n = 4) or beta adrenoceptor blockade plus bilateral vagotomy (n = 7), the
chemoreflex-induced constriction of the large coronary artery (- 0.07 + or - 0.02 mm and -
0.12 + or - 0.03 mm, respectively. In contrast, there was no chemoreflex-induced change in
total coronary resistance after beta-adrenoceptor blockade plus pacing (+ 0.01 + or - 0.09
mm Hg min/ml, but after beta-adrenoceptor blockade plus vagotomy coronary resistance was
increased (+ 0.75 + or - 0.31 mm Hg min/ml. The constriction of both large and small
coronary arteries was abolished by phentolamine (0.5 mg/kg iv).
Chronic nicotine treated adult rats were
shown to develop locomotor hyperactivity which was mediated by changes in nicotinic and
dopaminergic receptors in the striatum. The possibility of such changes occurring in pups
that were prenatally exposed to nicotine was
examined in 14-day-old offspring from dams which were implanted with osmotic minipumps
containing nicotine (1.5 mg/kg/day) throughout
the entire gestational period. Prenatal nicotine
treatment lowered the number of male pups born and reduced the postnatal gain in body wt
and length of both male and female offspring. Prenatal exposure to nicotine
did not alter the motor coordination of the pups. A decr in the number of striatal
dopaminergic receptor binding sites (Bmax) was detected in the male pups, however an incr
in the ligand affinity to the receptors (1/KD) had been simultaneously detected. No change
in the characteristics of nicotinic receptor binding sites and the levels of dopamine and
its metabolite, 3,4-dihydroxyphenylacetic acid was found in the striatal region.
The acute administration of nicotine
(0.01-1.0 mg/kg ip) to male albino BKW mice incr the time spent and rearings and line
crossings in the aversive brightly illuminated white area of a two compartment white/black
test box, with a corresponding decr in the black. This profile of change was maintained
during twice daily administration (0.1 mg/kg ip) for 14 days. Eight to 96 hr following
withdrawal of nicotine (14-day treatment), the
behavioral profile was reversed to a preference for the black area. By 240 hr, values had
returned to control levels.
Six naive male Wistar rats were admin 96 daily iv infusions of nicotine
(0.125 mg/kg/infusion, 12 mg/kg/day) for at least 10 days. They were trained to respond on
a tongue operated solenoid driven drinking device that delivered 0.005 ml of a glucose and
saccharin soln per lick. When nicotine access
was terminated for 6 days, there was a marked suppression in behavior (67% of baseline)
reinforced by the sweetened soln, and this disruption was immediately reversed when nicotine was reinstated. In contrast, nicotine removal also resulted in a decr in food
intake on the first day, but on subsequent days food intake was significantly higher than
when nicotine was admin. When cotinine (0.25
mg/kg/infusion) was substituted for nicotine for
6 days, similar disruptions resulted in responding maintained by glucose+saccharin (55 to
70% of baseline on the first day), but food intake was not significantly decr on the first
day of nicotine abstinence.
The most sensitive indicator of nicotine
action is an increase in motor activity, which is seen at dosages as low as 0.05 mg/kg
(subcutaneous) in the rat and is followed by tremor at intravenous doses ranging from 0.35
to 0.6 mg/kg.
...toxicity depends very much on the species; sheep and goats appear to tolerate high
amounts in comparison to other mammals.
IV INJECTIONS OF NICOTINE IN RATS INDUCE VERY
RAPID & DISCRETE REDN OF HYPOTHALAMIC CATECHOLAMINE LEVELS ASSOC WITH INCR OF ACTH,
VASOPRESSIN & PROLACTIN SECRETION GIVING FURTHER EVIDENCE FOR THE EXISTENCE OF NICOTINE-LIKE CHOLINERGIC RECEPTORS INVOLVED IN
REGULATION OF THESE HORMONES.
Cigarette smoking can alter the pharmacokinetics and activity of many drugs. The
mechanism of such interactions usually is induction of liver microsomal enzyme activity by
the polycyclic hydrocarbons in cigarette smoke. This enzyme induction differs
qualitatively and quantitatively from that produced by phenobarbital. Enzyme activity
remains elevated up to six months after cessation of smoking. /Cigarette smoking/
The effect of acute infusion of nicotine on
local cerebral glucose utilization was studied in discreet regions of the central nervous
system of the rat. Nicotine was administered in
3 dosages: 0.5, 1.58, and 5 ug/kg/min. The resulting plasma concentrations of nicotine were 10, 39, 114/ng/ml plasma. During the
experiment, blood pressure, heart rate, body temperature, hematocrit, acid-base status,
and plasma glucose concentrations showed no negative or minor negative changes. Nicotine significantly increased local cerebral
glucose utilization in a dose dependent manner in the following 9 of 45 examined
structures: substantia nigra (compact part), superior colliculus (superficial gray layer),
interpeduncular nucleus, and cingulate cortex; lateral geniculate body, optic chiasm,
anteromedial nucleus of thalamus and mamillary body.
The effects on rat brain tissue monoamine and monoamine metabolite concentrations of
chronic nicotine administration at 3 or 12
mg/kg/day using constant infusion were studied. After 21 days of treatment, tissue
concentrations of dopamine, norepinephrine, 5-hydroxytryptamine, and several metabolites
in striatum, hypothalamus, and frontal cortex were determined by high performance liquid
chromatography with electrochemical detection. Compared with a control group, nicotine treatment decreased norepinephrine in frontal
cortex but not in other regions. The concentration of 5-hydroxytryptamine also was
decreased in frontal cortex but increased in the hypothalamus at the higher dose of nicotine. The 5-hydroxytryptamine metabolite
5-hydroxyindolacetic acid was not altered in any region. The 5-hydroxytryptamine index was
decreased in the hypothalamus and increased in frontal cortex at the higher dose.
Concentrations of dopamine and the metabolite homovanillic acid were not altered by nicotine. Nevertheless, decreases in the dopamine
metabolite dihydroxyphenylacetic acid were observed in both striatum and hypothalamus.
Moreover, the dopamine index was decreased in all 3 brain regions.
Alpha-2 and beta-adrenoceptors, and muscarinic cholinoceptors in cerebral cortex and
hippocampus were measured in rats which received either tap water or nicotine
added to the drinking water (5-8 mg/kg/day) for 4 wk and immobilization stress (daily 2
hr) for the last 5 days. The repeated stress induced a redn in the max number of binding
sites (Bmax) for (3)H-dihydroalprenolol in the cerebral cortex of rats with tap water,
without affecting (3)H-clonidine binding. Nicotine-treatment
also caused a decrease in the Bmax of cortical (3)H-dihydroalprenolol binding comparable
to the case of stress, and increased the (3)H-clonidine binding. However, the combination
of nicotine and stress treatments failed to
induce any further changes in the two radioligands binding.
The fetal and postnatal development of binding sites for (3)H-nicotine
was examined in brain regions of normal rats and rats whose mothers received nicotine injections or infusions, starting before
fetal implantation (gestational day 4) and continuing to gestational day 20. The normal
ontogenic pattern of binding indicated a small but detectable concn of sites during late
gestation, and a substantial increase after birth, primarily during the period in which
the majority of cholinergic synapses is forming. The adult pattern of regional selectivity
of binding capabilities, namely, midbrain plus brainstem > cerebral cortex much greater
than cerebellum, was not present at birth, but rather developed over the ensuing 3 wk
postpartum. Fetal exposure to nicotine produced
an elevation in binding detectable during the course of drug exposure (gestational day
18), a finding similar to that of nicotine's
effects in mature brain. However, examn of the subsequent development pattern of (3)H-nicotine binding indicated a generalized disruption of
receptor acquisition, in that alterations persisted far beyond the period in which drug
exposure was terminated. The greatest effect was seen in a region relatively poor in
receptor sites (cerebellum), and a larger stimulation was obtained with injected than with
infused nicotine.
The properties of the binding sites for radiolabeled acetylcholine (measured in the
presence of atropine), nicotine, and
beta-bungarotoxin were compared in brain tissue prepared from both rat and mouse. These
three binding sites were tested for the following properties: affinity and density of
ligand binding, effects of competitive inhibitors, regional distribution, effects of
treatment with dithiothreitol, and the reversal of these effects by treatment with
5,5-dithiobis(2-nitrobenzoic acid), thermal lability, effects of protease treatment, and
response to chronic administration of nicotine
in vivo. The binding sites for acetylcholine and nicotine
were affected identically for all measurements, whereas the binding site for
alpha-bungarotoxin was affected in a manner different from that for the other two ligands.
Although the regional distribution of nicotine
and acetylcholine binding differed between rat and mouse brain, other properties of this
binding site were very similar between the two species.
Nicotine administration, using mini-osmotic
pumps, to male guinea pigs (31 ug/hr for 10 days) resulted in a significant elevation of
plasma epinephrine and enkephalin-like peptides but not norepinephrine. The increase in
plasma epinephrine-like peptides was not accompanied by corresponding alterations in
either adrenal medullary synthesis or blood pressure and heart rate.
The acute effects of nicotine and ethanol
were studied in low and high rates of intracranial self-stimulation of the medial
prefrontal cortex in the rat. Nicotine tended to
increase low intracranial self-stimulation rates but did not change or even reduce high
intracranial self-stimulation rates.
Non-Human Toxicity Values:
LD50 Rat oral 188 mg/kg
LD50 Rat ip 30 mg/kg
LD50 Mouse oral 24 mg/kg
LD50 Rat oral 50-60 mg/kg
LD50 Rat skin 140 mg/kg
LD50 Rat iv 1 mg/kg
LD50 Rat scu 25 mg/kg
Metabolism/Pharmacokinetics:
Metabolism/Metabolites:
IN VITRO STUDIES WITH RABBIT LIVER MICROSOMES, /NADPH/, & O2, INDICATED THAT
METABOLISM OF NICOTINE PROCEEDED THROUGH
HYDROXYLATION TO 5-(3'-PYRIDYL)-N-METHYLPYRROLIDINE-2-OL; OXIDATION TO COTININE; &
DEAMIDATION OF COTININE TO 4-(3'-PYRIDYL)-4-METHYLAMINO-BUTYRIC ACID. NO CARBON DIOXIDE
WAS OBSERVED.
/AFTER ADMIN OF NICOTINE TO DOGS, ORAL &
IV, CMPD ISOLATED & IDENTIFIED FROM URINE WERE/ (-)COTININE, (-)DESMETHYLCOTININE,
HYDROXYCOTININE, GAMMA-METHYLAMINO-GAMMA-(2-PYRIDYL) BUTYRIC ACID,
BETA-OXO-GAMMA-(3-PYRIDYL)-N-METHYLBUTYRAMIDE, /&/ 3-PYRIDYLACETIC ACID ... NICOTINE ISOMETHONIUM ION WAS ALSO FOUND ...
SPECIES DIFFERENCES WERE FOUND IN IN VITRO METAB OF (R)(+)- & (S)(-)-NICOTINE, USING LIVER SUPERNATANT PREPN FROM RATS,
RABBITS, MICE, GUINEA PIGS, & HAMSTERS. (S)(-)-ENANTIOMER FORMED PREDOMINANTLY
(R,S)-CIS-NICOTINE-1'-N-OXIDE, WHEREAS (R)(+)-NICOTINE GAVE PREDOMINANTLY (S,R)-TRANS-NICOTINE-1'-N-OXIDE.
FORMATION OF NICOTINE-1'-N-OXIDE FROM NICOTINE IS CATALYZED BY GUINEA PIG LIVER 10000XG
SUPERNATANT; REACTION REQUIRES NADPH BUT IS NOT INHIBITED BY SKF-525A /ENZYME INHIBITOR/.
... BASIC AMINES, EG NICOTINE ... ARE
N-OXIDIZED BY NON-CYTOCHROME P-450-DEPENDENT SYSTEM ...
... Cotinine has been shown to be the major metabolic product. ... The route of
cotinine formation is apparently through the immediate hydroxylation product,
2-hydroxynicotine. /2-hydroxynicotine/
... Following the administration of 0.1 mg nicotine/kg
(labeled in 2-(14)C-pyrrolidone) to rats, the assay was used in a pharmacokinetic
investigation. Radioactivity due to nicotine and
cotinine was detected in substantial amounts in plasma samples. Nicotine
disappearance was biexponential, with an elimination half life of 1.0 hour. Cotinine
appeared as the major metabolite in plasma and had elimination half life of 5.2 hours. In
urine, nicotine-1'-N-oxide was the major
metabolite of nicotine.
Mammals metabolize the tobacco alkaloid (S)-nicotine
primarily to the lactam (S)-cotinine by a pathway involving an initial cytochrome p450
catalyzed two-electron oxidation at the prochiral 5'-carbon atom. The stereochemical
course of this oxidation was examined with human microsomal preparations and the E and Z
diastereomers of (S)-nicotine-5'-d1. The
metabolically generated d1'(5')-iminium ion intermediate was trapped and analyzed as the
corresponding diastereomeric 5'-cyano derivatives by a capillary column gas
chromatography-electron ion mass spectrometry selected ion monitoring assay. The results
of these studies established that this biotransformation proceeds with stereoselective
abstraction of the 5'-pro-E proton, that is, the C-5' proton transfers to the bulky
pyridyl group. The observed stereoselectivity was independent of proton vs deuteron
abstraction. Additionally, the extent of (S)-cotinine formation was minor and did not
influence the stereochemical composition of the metabolically derived alpha-cyano amines.
Studies with male Dutch rabbit liver microsomal preparations gave similar results.
Toxicologically, it is of interest that /the microsomal flavin-containing
monooxygenase/ is responsible for the oxidation of nicotine
to nicotine-1'-N-oxide, whereas the oxidation of
nicotine to cotinine is catalyzed by two enzymes
acting in sequence: p450 and a soluble aldehyde dehydrogenase. Thus, nicotine
is metabolized by two different routes, the relative contributions of which may vary with
both the extrinsic and intrinsic factors.
The cytochromes p450 oxidize (S)-nicotine to
a mixture of cis- and trans-N-'-oxides. In contrast, (S)-nicotine
is oxidized by human flavin-containing monooxygenases exclusively to the trans-N-1'-oxide.
Absorption, Distribution & Excretion:
NICOTINE IS READILY ABSORBED FROM RESP TRACT,
BUCCAL MUCOUS MEMBRANES, & SKIN. ... BOTH NICOTINE
& ITS METB ARE RAPIDLY ELIM BY KIDNEY. THE RATE OF URINARY EXCRETION OF NICOTINE IS DEPENDENT UPON PH OF URINE; EXCRETION
DIMINISHES WHEN URINE IS ALKALINE. NICOTINE IS
ALSO EXCRETED IN MILK OF LACTATING WOMEN WHO SMOKE. MILK OF HEAVY SMOKERS MAY CONTAIN 0.5
MG/L. ... APPARENTLY THE GASTRIC ABSORPTION OF NICOTINE
FROM TOBACCO TAKEN BY MOUTH IS DELAYED BECAUSE OF SLOWED GASTRIC EMPTYING, SO THAT
VOMITING MAY REMOVE MUCH OF THE TOBACCO REMAINING IN GI TRACT.
IN MICE, DOGS, & GUINEA PIGS, EXPOSURE TO NICOTINE
SMOKE PERMITS ... DETECTION IN VISCERAL STORAGE COMPARTMENTS, INCL LIVER, KIDNEYS, LUNG,
& BRAIN. ...
... 7.5% OF ALKALOID APPLIED TO INTACT SKIN OF DOG WAS ABSORBED IN 1 HR; 16% OF APPLIED
DOSE WAS ABSORBED IN SAME TIME THROUGH WOUNDS.
ELIMINATION OF NICOTINE FROM PLASMA IS
BIPHASIC IN MAN WITH TERMINAL PHASE T1/2 OF ABOUT 30 MIN. ... EXCRETION OF NICOTINE IN SALIVA IS SPECIES-SPECIFIC IN DOG &
MONKEY & DISTRIBUTION WITHIN BRAIN HAS BEEN SHOWN TO BE AGE DEPENDENT IN MOUSE ...
ALTHOUGH NICOTINE IS ABSORBED RAPIDLY OVER
LARGE SECTION OF GI TRACT, ABSORPTION OF N-OXIDE IS LIMITED TO AREA RELATIVELY HIGH IN
INTESTINE. N-OXIDE IS REDUCED TO NICOTINE IN GUT
& NICOTINE PRODUCED IS ABSORBED LOW ENOUGH
IN GI TRACT TO AVOID FIRST PASS PHENOMENON.
IN CIGARETTE SMOKERS, EXCRETION OF UNCHANGED NICOTINE,
BUT NOT OF COTININE, INCR WITH INCR URINARY VOLUME & DECR URINARY PH ... TUBULAR
RE-ABSORPTION OF THE TWO ALKALOIDS IS INVERSELY PROPORTIONAL TO THEIR METABOLIC TURN-OVER
...
NICOTINE & ITS METABOLITES APPEARED IN
FETUS WITHIN 5 MIN OF IV INJECTION OF TRITIATED (-)-NICOTINE
IN RATS ON DAY 19 OF GESTATION. FROM 30 MIN THROUGH 20 HR, CONCN OF RADIOACTIVITY IN
PLASMA OF FETUS WAS GREATER THAN IN MOTHER. BY 60 MIN, EQUILIBRIUM WAS ESTABLISHED BETWEEN
MATERNAL PLASMA & AMNIOTIC FLUID WITH RESPECT TO CONCN OF RADIOACTIVITY. FETAL PLASMA
AS WELL AS MOST OF THE FETAL TISSUES HAD A GREATER PROP OF TRITIATED NICOTINE
TO METABOLITES THAN DID MATERNAL PLASMA.
FREE ALKALOID IS ABSORBED RAPIDLY THROUGH SKIN AND GASTROINTESTINAL AND RESPIRATORY
TRACTS, BUT ABSORPTION OF ITS ACID SALTS IS LESS COMPLETE.
Male ICR mice, received 4 uCi (0.22 to 0.26 ug/kg) (3)H-nicotine
in 0.9% over 5 sec via the tail vein. Total and nonspecific binding were estimated in mice
pretreated sc with either 0.9% NaCl (2 ml/kg) or unlabeled l-nicotine
(5 mg/kg base), respectively, 2 min before (3)H-nicotine
injection. 5% of mice given 5 mg/kg nicotine
convulsed and died. 10 mg/kg killed most of the mice tested. Radioactivity entered the
brain rapidly, was heterogeneously distributed, and declined after 5 min. Estimated
specific binding was highest in the medial and posterior cortex, midbrain
thalamus/hypothalamus and medulla/pons; intermediate in the cerebellum, caudate/putamen,
frontal and frontoparietal cortex; and lowest in the hippocampus and olfactory bulb.
Autoradiography showed similar patterns. Mice received 0.8 uCi (3)H-nicotine
with incr doses of unlabeled l-nicotine iv.
Either NaCl or 5 mg/kg l-nicotine was injected
sc (2 ml/kg body wt) 5 min before (3)H-nicotine.
The level of specifically bound (3)H- with incr concn of unlabeled l-nicotine,
approaching nonspecific binding. IV doses of l-nicotine
above 0.5 mg/kg were not tolerated by mice. Nicotinic agonists reduced radioactivity in
the thalamus/hypothalamus. Percentage reductions in tissue radioactivity were : l-nicotine (2 mg/kg), 37 + or - 4.4; l-nicotine
(5 mg/kg), 45 + or - 2.6; d-nicotine (2 mg/kg),
24 + or - 3.9; d-nicotine (5 mg/kg), 38 + or -
2.0. Nicotinic antagonists were less active.
Level of urinary nicotine were measured in 21
non-smokers, 26 smokers of blond tobacco, 9 smokers of black tobacco, and 5 smokers of
both types, all eating a similar diet. Two 24-hr samples from the subjects were collected
over a 3-day period. The sum of urinary nicotine
and cotinine levels was used as a measure of exposure to the number of cigarettes smoked.
The nicotine + cotinine content in 24 hr urine
was 0, 0 to 0.5, 0.5 to 1.5, 1.5 to 2.5, and > 2.5 umol/mmol creatinine for subjects
who smoked a average of 0.47, 3.56, 14.3, 18.9, and 19.8 cigarettes in 24 hr,
respectively.
...more slowly absorbed from acidic than alkaline smoke.
Following small doses, about 4-12% is excreted unchanged in the urine. Following larger
doses, a higher proportion is excreted, and the rate of increase is linear; 30% of the
dose was recovered unmetabolized from the urine of a dog dosed intravenously at the rate
of 48 mg/kg. Urinary excretion of nicotine is
virtually complete in the rat in 16 hr and in the dog in 16-36 hr.
Nicotine crosses the placenta and is freely
distributed into milk, reportedly producing concentrations in breast milk averaging 2.9
times those in plasma. Nicotine concentrations
in amniotic fluid, placental tissue, and fetal serum exceed corresponding maternal serum
concentrations in women who smoke cigarettes... Small amounts of nicotine
appear in serum and urine of infants of nursing women who smoke cigarettes.
...nonhuman primate studies show that after absorption, nicotine
is concentrated in the brain (where up to 8% of the dose is localized at 5 minutes after
injection), the kidney (where more than 14% of the dose is localized), the stomach mucosa,
the adrenal medulla, the nasal mucosa, and in the salivary glands.
The kinetics of nicotine elimination are
dose-dependent: 4% to 12% is excreted unchanged in human and dog urine after small doses;
however, after exposure to a large (48 mg/kg) quantity, 30% of the dose appeared in dog
urine as unchanged nicotine. In rats and dogs,
urinary elimination is complete within 16 to 36 hr, respectively.