Nicotine Flashcards
forms of tobacco product (8)
cigarettes
e-cigarettes
cigars
cigarillos
shisha
smokeless
patches
gum
electronic cigarettes
vapourize e-juice containing nicotine (glycerin or PG-based)
no tar “cleaner smoke is healthier”
flavours + additive → severe adverse effects
diacetyl + vitamin E acetate
vapour damages immune system (same as cigarettes)
5-8x more nicotine per puff than cigarettes
diacetyl
butter flavour of e-cigarettes
obliterates lung tissue → bronchiolitis obliterans
‘popcorn’ lung in factory workers = holes in lungs
vitamin E acetate
antioxidant
severe allergic reactions by inhalation
hookah
water cools smoke → less irritating, fewer particulates
- but, increase time of exposure to chemicals
uses shisha
hot air vapourizes chemicals - 11x more CO
elevated CO in blood → increased hr
increased risk of lung disease, oral/lung cancer
shisha
most processed, flavoured, tobacco form
smoke
an aerosol = particulates + gases
particulates in smoke
nicotine
water
tar
PAHs
benzo[a]pyrene
metals
gases in smoke
nicotine, CO, CO2, NO, nitrosamines, ammonia, nitrites, sulfur, alcohols, ketones, aldehydes, hydrocarbons
first-hand smoke
inhalation of smoke directly from burning tobacco
second hand smoke
smoke that has already been inhaled by others
third hand smoke
fumes from fingers, clothes, fabric
nicotine
alkaloid
uncharged = free base
causes addiction
competitive acetylcholine receptor agonist
protects plants from pests → pesticide
administration
inhalation (11-20% bioavailability)
oral - smokeless forms (50-80% bioavailability)
inhalation
controlling pH in cigarettes optimizes absorption (free base)
burning generates up to 4000 new chemicals
pyrolysis → lower bioavailability
free base
both nitrogens are neutral (no hydrogens)
weak base
easily reduced by plants
pH > 6
monoprotonated
one nitrogen is protonated = +1 charge
3 < pH < 9
diprotonated
both nitrogens are protonated = +2 charge
pH < 6
1 cigarette
~ 8mg nicotine
delivers 0.5-2 mg
occupies 80% of binding sites (nAChRs)
60 mg is lethal
pharmacokinetics + addiction
1-2 puffs/min - 2 sec long
1-2 ug nicotine/kg body weight is delivered to the brain
= one pack/day is optimal for brain stimulation
oral - smokeless forms
3-4x greater nicotine absorption
slower rate of absorption
distribution
blood pH is 7.4 = 70% monoprotonated, 30% unprotonated
<5% is bound to plasma protein
brain, liver, kidney, spleen, lung
least to adipose (less blood supply)
metabolism
nicotine → cotinine
in liver
aldehyde oxidases: CYP2A6 + CYP2B6
monooxygenases process small amount
half life = 2hr
CYP2A6 mutation
slows metabolism = greater [nicotine] for longer time → off target effects
results in lower tobacco use
aversive
excretion
kidneys
nicotine concentration vs time
plasma [nicotine] peaks in the evening
receptors re-sensitize over night
= first daily cigarette is most pleasant
acute effects
sympathomimetic
affects heart rate, bp, GI movement, motor commands, focus, + mood
mechanism of action
affects ACh, DA, GABA, Glu
binds + depolarizes cells via nAChRs
biphasic mechanism
at high doses
high affinity → inactivation of receptor
acetaldehyde
from burning
may inhibit monoamine oxidases and boost NT levels
nAChRs in CNS
cortex, basal forebrain, hippocampus, basal ganglia, thalamus, cerebellum, brainstem
presynaptic nAChRs depolarize terminals → prolonged DA, glu, GABA release
mechanism of reinforcement
presynaptic receptors on GABA, DA, + glu neurons
= more GABA released → disinhibition of DA neuron
= more DA release
= more glu released → increased firing of DA
more dopamine =
pleasure, reward, addiction
acute adverse effects
stimulation of vomiting centre - common in first time users (area postrema - dorsal brainstem)
headaches, nausea, disrupted ANS functioning
alternating tachy- and brachycardia
severe intoxication → seizures, hypotension, respiratory depression
nAChRs
heteropentameric receptors
9 a + 3 b subunits
conduct cation influx to depolarize neurons - Na+, Ca2+
presynaptic nAChRs
increase NT release
postsynaptic nAChRs
depolarize cell
high affinity
continuous exposure to agonist (nicotine) inactivates receptor
receptor subunit composition
affects reinforcement + reward
determine inactivation rates
a6
modulate locomotor responses
a7
facilitate glutamate release
not inactivated
b2
subunit knockout in mice prevents DA release
self-administration stops
= important in reward
a4b2
antagonists block reward
most important for DA reinforcement
main functional nAChRs on VTA DA-ergic soma
activation drives DA release and reinforcement
govern GABA release - inactivate quickly and for a long time
a6b2
mainly on DA-ergic terminals in NAc
do not release DA after systematic nicotine administration
single dose of nicotine injected into NAc
elevates DA levels for 80 minutes
3x baseline
first use
unpleasant
targets brain regions/circuits for dizziness, nausea, sweat
tolerance
little or no decrease in heart effects, tremor, peripheral vasoconstriction
= no change in physical effects
metabolic tolerance
increased enzyme activity
cellular tolerance
receptor inactivation
affects reward
nAChR expression increases in PFC - a4b2
enhances sensitivity to nicotine effects
behavioural tolerance
mindset stages experience
ritual of smoking
withdrawal
physiological: headache, drowsiness, insomnia, increased appetite + weight gain, GI upset
psychological: craving, mood changes, irritability, anxiety, restlessness, depression, difficulty concentrating, poor judgement + psychomotor performance
dependence
addicted if have to smoke within 30 min of waking
occurs within days of habit
physical + psychological
quick metabolism → withdrawal → seek more
cue-driven habit
long term adverse effects
cancer (lung, liver, colorectal)
accelerate skin aging due to peripheral vasoconstriction
sexual dysfunction - impaired NO signaling
type 2 diabetes → stressed vasculature is insensitive to insulin
cancer
benzo(a)pyrene initiates cancer = intercalating agent
nicotine enhances growth/metastasis (not initiation)
- inhibits apoptotic signaling by binding a7 nAChRs on mitochondria → allows cells with damaged DNA to replicate
nicotine → in vitro
enhances cancer cell growth
experiment - mice given cancer
treated with nicotine/saline for 2 weeks
removed tumours
continued treatment
→ nicotine treated mice regrew tumours
long term adverse effects - tobacco
cataracts, macular degeneration
tooth decay, periodontitis, IBS, Chrohn’s
infection
rheumatoid arthritis, osteoporosis
cardiovascular disease - CHD, MI, ischemic stroke
COPD → emphysema, chronic bronchitis
COPD
inflammation of airways covered in tar + ash deposits
cilia function is impaired by PAH + ketones in smoke
smokers’ cough
when quitting
indication of recovery of cilial function
pregnancy
constriction of umbilical arteries → reduced oxygen
increased addiction risk
higher risk of stillbirth, premature or miscarriage, low birth weight
cleft palate + lip - higher risk
smoking cessation
alternate form of nicotine to ease withdrawal and cravings
reduce use instead of complete elimination
3 day hump (withdrawal) → clearance from bloodstream
harder to quit smokeless forms - higher doses
pharmacological cessation aids
bupropion
varenicline
bupropion
antidepressant
nAChR antagonist - blocks channel even when nicotine is present (competitive)
DAT + NET inhibition → decrease sympathomimetic
helps reduce cravings
varenicline
partial nAChR agonist
reduces reward and cravings
