Nicotine Flashcards
1
Q
how consume nicotine
A
2 major ways of consuming nicotine - both through lungs
2
Q
which pathways does nicotine activate
A
Nicotine activates many different pathways in brain - one that’s relevant for addiction is the dopaminergic pathway
3
Q
describe research about nicotine
A
Many people who study nicotine and try to understand it
Know more about action of nicotine than most drugs
One of first models of drug receptors that was studied in detail
Been around for long time
Still a lot we don’t know
4
Q
what ways can nicotine be consumed
A
Drug people take in cigarettes and vapes
5
Q
describe nicotine - plant
A
botanical insecticide - natural
Highly concentrated in Tobacco
Big plant and can be easily grown to extract nicotine from it or just burn leaves to get nicotine out of smoke
6
Q
compare smoking and vaping - actual thing
A
Smoking
= Comes out of head as you are burning it
Vaping
Nicotine extracted first then put into little cartridge
7
Q
describe nicotine addiction
A
Globally = highest number of addicts
More than all other addictive drugs put together
Not necessarily in every country
Kills over 7 million people per year
8
Q
describe control of smoking across the globe
A
ublic becoming aware of all the issues
More attempts to help people stop smoking
Number of smokers dropped remarkably in some developed countries
- Declines in US, UK and Canada
Canada has been one of best countries in terms of educating people and trying to get them to stop
On cigarette packages - pictures, warnings on individual cigarettes
Canada = leader in informing public - Consequence = death rate really dropping
BUT STILL MAJOR KILLER GLOBALLY
Thought we were getting it under control but then different way to get people addicted = vaping
9
Q
compare vaping vs cigarettes - ads and demographic
A
Vaping consumption has gone way up in young people and kids, Start in elementary school, E cigarette sales continually increase
Used to be surrounded by cigarette ads
Now have vape ads - cigarette ads banned
10
Q
describe drug delivery system of vapes or cigs - strategy
A
rapid absorption increases probability of addiction
Deliver drug through lungs
absorption very rapid and effective
Faster the hit - the stronger the link and addictive potential
11
Q
how long after inhaling nicotine does it hit the brain
A
7 seconds of inhaling it
Faster than injections
12
Q
what else do you get when smoke - not just nicotine
A
delivery system for more than 7000 chemicals
Also taking in 4000-7000 chemicals in the smoke
Not just getting nicotine
Many other things that affect body
13
Q
describe toxicity of cigarettes - deaths
A
Death from cigarettes very common in older people
Greater amounts of deaths than from alcohol, car crashes, aids and so on
Cigarettes alone will kill 600 million people currently alive on planet earth
In many countries there are many people who smoke
14
Q
why does smoking kill you
A
15 different cancers caused by smoking - inhaling carcinogens
chronic diseases =
Heart attaches
Strokes
Diabetes
Also affects reproductive system
15
Q
describe mucociliary clearance in smokers
A
Goes down in straight line the more cigarettes you smoke
Correlation between tidal mucociliary clearance rates in the first hour and cigarette consumption
16
Q
what is Mucociliary clearance rate
A
= as we breathing
We breathe in little particles and get trapped on mucous lining cilia
Cilia beat and propel mucous back out
smoke = take in much more particles and also paralyzing mucociliary clearance rate
So do not get rid of it
The longer you smoke = worse you are able to clear stuff out of your lungs
17
Q
describe smoking + asbestos
A
50-90x
Exposure to asbestos and cigarette smoke at same time has multiplication effect
18
Q
describe smoking + asbestos - ex of quebec
A
relevant to quebec since back in town called asbestos = had big asbestos mines
If people smoked = exposed to 2 dangerous things
Lung cancer if smoked and exposed to asbestos = close to 100 times the rate
19
Q
what cardiovascular diseases can smoking cause
A
coronary heart disease
strokes
peripheral vascular disease
20
Q
describe coronary heart disease
A
one third of deaths are due to smoking
Hypertension
CO
Endothelial injury
Atherosclerosis
platelet aggregation
21
Q
describe strokes
A
50% <age 65
Can kill you or impaired mental function for life
Strokes in younger people much more common
22
Q
describe peripheral vascular disease
A
Vessels damaged
So ones to brain can affected brain function
Can impair ability to walk and enjoy life
23
Q
describe effects of nicotine on blood vessels
A
Vasoconstriction
To all these areas =
Skin
Hair
Eyes
Gums - gum disease
24
Q
describe effects of nicotine on blood vessels - study
A
Person - smoker but has not had cigarette for a bit
She puts hand on sensor and it detects blood flow in hand
Starts to smoke
Part way through cigarette = see vasoconstriction in hand
Detects less and less blood flow to periphery
By end of one cigarettes = effect of vasoconstriction
25
describe effects of nicotine on blood vessels - blood flow
Affects continual blood flow - to brain and gums and can get skin damage
Nicotine - skin damage
Wrinkles
Older people = If you didn't smoke and wore sunscreen had less wrinkles
People who smoked = wrinkles
26
how many smokers do cigarettes kill
50% of smokers
es kill 50% of smokers
Kill them in prime of their life
Terrible ways = cancers, cardiovascular diseases
Creates strain on healthcare system as well - Years of impairment before they die, Serious issue
27
is vaping the same as smoking
yuh
Vaping = smoking
Nicotine has the effect
28
describe secondhand smoke
Living with smoker
Very dangerous
Breathe in all this stuff
29
how many people die from secondhand smoke
secondhand smoke kills 900,000 people every year
30
describe second hand smoke - how
Smoker gets what they inhale from end and some of what they exhale back out
Everyone else gets what comes off of burning end of cigarette = Many carcinogens and damaging products
Risks health of people around you =Which is why it was banned in public places
31
what is thirdhand smoke
risk for children
What goes up must come down
So the thousands of chemicals coming off cigarettes go into air and they settle
Then everything in that room has all these chemicals on it
Can get on skin when rub face
32
why is thirdhand smoke bad - for kids
Particularly bad for children
Not many clothes on
Crawling around
Carpet and other things
Toys
Put hands in mouth
Significant hazard for young kids
Pets
People sitting on carpets
33
describe effects of thirdhand smoke in children
Increases risk of issues in children
Brain tumours
Other cancers
Asthma
Infections
Sids = sudden infant death syndrome - Risk increased if around smoke
34
pharmacokinetics of nicotine - describe absorption
Absorb nicotine extremely well from lungs
Can absorb it just about anywhere though
35
pharmacokinetics of nicotine - describe absorption from mouth
Well from mouth
Some absorbed during smoking
Also people chew tobacco
People Use nicotine gum
Tobacco stuck under gum - absorbed there
36
pharmacokinetics of nicotine - describe absorption from skin
Absorb from skin = nicotine patches
37
pharmacokinetics of nicotine - describe absorption from gi tract
Nicotine is a weak base = rate absorption depends on ph
Unionized from of weak acid or base = lipid soluble and can readily transfer itself across membranes
38
how do they design cigarettes smoke
add things to make ph more alkaline
Then nicotine will be in unionized form and will be absorbed fast through lungs and lungs into vasculature
Clever design
Also no first pass metabolism because absorb form lung
39
faster nicotine absorbed and hits brain =
stronger link for addictive potential
40
describe inhaling smoke
hen goes into trachea and trachea subdivides into 2 main bronchi
Inhale straight into lungs
Alveolus = lungs designed for very rapid gas exchange by structure of alveolus - capillaries around = Taking in oxygen and get rid of carbon dioxide
Very rapid intake of nicotine
41
describe giving cigarette with less nicotine in it
Still rapidly absorbed but less rise of nicotine in blood
Look at absorption of nicotine from lungs
Smoker controls bioavailability
Because smoker decided the puffs per minute and how deeply they inhale
Like people in the morning when they wake up = take deep puffs = getting first fix of morning
42
describe giving cigarette with less nicotine in it- experiment
Gave smokers cigarette with more nicotine
Did not smoke as rapidly or inhale as deeply
Decreased level of blood nicotine to around same as regular cigarettes
Gave smokers cigarettes with less nicotine
Smoked rapidly and inhaled deeply and go to almost same level of normal
Smokers control
bioavailability of the nicotine by controlling way they inhale and rate of inhalation
43
describe Blood nicotine concentration - regular smoking
Vapes and cigarettes = goes up rapidly then comes down with time if just one cigarettes
44
describe Blood nicotine concentration - other ways - mouth
Oral snuff
Chewing tobacco
Nicotine gum = more slow absorption compared to above 2
Connotation not as high
Nicotine absorbed from mouth
45
describe Blood nicotine concentration - gi poisoning
Excellent GI absorption (poisoning)
Children can swallow cigarettes
Can easily swallow lethal dose of nicotine
46
describe distribution of nicotine
Because highly lipid soluble
Transported everywhere
Gets through blood brain barrier
Affects brain and cns
Pns also
47
describe distribution of nicotine - pregnancy
fetus and breast milk
Gets through placenta
48
describe distribution of nicotine - brain
Chemoreceptor trigger zone (CTZ) = NO blood brain barrier
Defense mechanism
Detects foreign compounds absorbed into blood and triggers vomiting
Absorb from intestines and vomit out before absorb lethal dose
Saved many children who swallowed cigarettes
Also when kids try cigarettes for first time = can make you sick if you do too much
49
describe metabolism of nicotine - enzymes
Well worked out
Cytochrome P450s
Families - 18 in humans = CYP2
Subfamilies - 43 in humans = CYP2A
Genes - over 60 human = CYP2A6
CYP2A6 is major nicotine metabolizing enzyme
50
describe half life of nicotine
2 hours
Level of plasma concentration of nicotine goes up and then it cycles around steady state
Works for any level of nicotine in cigarettes
Gets to steady state then when sleep it drops and starts whole cycle again
51
describe CYP2A6 metabolism of nicotine
major enzyme that metabolises nicotine
Metabolizes almost all of nicotine to cotinine then CYP2A6 gets rid of cotinine
Metabolites conjugates and excreted
52
describe CYP2A6 metabolism of nicotine- variations
Some people have less effective CYP2A6 enzymes than most and have much slower removal of nicotine
Smoke fewer cigarettes throughout day even though highly addicted because their blood level doesn't come down as fast
Defective CYP2A6 alleles
Individuals with slower removal of nicotine will need to smoke fewer cigarettes to maintain blood nicotine levels
53
describe CYP2A6 metabolism of nicotine- variations genetic
alters nicotine and cotinine plasma levels
Normal
Nicotine = concentration in blood goes up then down as metabolize and distributing
Cotinine = goes up then down with time
Limited CYP2A6 = inactive
Nicotine goes up and stays up for long time
Cotinine metabolite barely visible at all
Do not have to smoke much
CYP2A6 reduced =
Nicotine = will stay high for fair amount of time
Cotinine metabolism will take a while to show up
In the middle of the 2 situations
Most smokers are regular metabolizers but people have some variations
54
what does CYP2A6 also do
also activates procarcinogens
Forms cytotoxic and genotoxic metabolites
Defective CYP2A6 decreases carcinogenicity
Not taking in as many carcinogens
Slightly less risk of cancer
55
describe excretion of nicotine
Urine is carcinogenic
Nicotine excreted in urine and the metabolites
Alkaline urine decreases excretion nicotine
Nicotine in lipid soluble form and some will be resorbed = will not get rid of as much of it
56
where are nicotine receptors
Nicotinic receptors all over the place
Autonomic nervous system
Parasympathetic and sympathetic
Ganglion - synapses in the ganglia
57
describe nicotine effects in periphery
Powerful effects of nicotine in the periphery
Nicotinic receptors in ganglia of sympathetic and parasympathetic
Also have nicotinic receptors of a different type on muscles and cells
58
describe nicotine effects on ans
many nicotinic receptors in autonomic nervous system =
Why you have cardiovascular effects that are prominent
Heart rate increase
Blood pressure increase
Many different cholinergic pathways in brain that have nicotinic receptors
Cholinergic synapses all over the brain
59
describe nicotinic receptor
Nicotine acts
Ligand gated ion channels
Still lots to learn
Wide distribution in brain and periphery- in ganglia and out in periphery
60
describe ribbon model of nicotinic receptor
Ion channel with 5 units
Many different subunits that make up the receptor
So can have many subtypes of nicotinic receptors
Alpha beta subtypes
9 alpha
3 beta
Many variations though
Some more common than others
61
what type of nicotinic receptor are we looking at
Not looking at muscle type nicotinic receptor
Can act on muscle type if smoke a lot
Looking at neuronal type nicotinic receptors
62
describe neuronal nicotinic receptors
2 common types of neuronal receptors
Heteromeric = alpha and beta
Homomeric = all of units the same
63
where are nicotinic receptors in brain
All over the place in the brain
Very common on presynaptic nerve endings for all different major transmitters
64
describe action of nicotinic receptors in brain
Dopamine, norepinephrine, acetylcholine, glutamate, serotonin, beta endorphin, GABA
Modulate these nicotinic receptors
One important for addiction= dopamine
Nicotinic receptors modulate release of excitatory and inhibitory transmitters all over the place - Complex action of nicotine
65
describe effect of nicotine on receptor
Stimulates nicotine receptors for acetylcholine then blocks them due to high affinity = block temporarily
Releases epinephrine from adrenal medulla and norepinephrine from sympathetic nerve endings = Releases adrenaline from periphery
66
describe effect of nicotine on receptor - consequences on demeanour
Initial stimulation followed by sedation, subtle and temporary improvement in performance
67
describe effect of nicotine on receptor - consequences on skin
Decreased skin temperature
Vasoconstriction
68
describe effect of nicotine on receptor - consequences on muscles
Skeletal muscles relaxation may contribute to tranquillizing effects as well as habituation to unimportant stimuli
69
describe effect of nicotine on receptor - consequences on gi tract
Salivation increased, hunger contractions of stomach decreased, activity of colon increased
Less hungry because of effect on mouth and GI tract and also because not eating and smoking
70
describe effect of nicotine on receptor - consequences on metabolism
Catecholamine release may increase thermogenesis and basal metabolic rate
71
describe nicotine poisoning
CNS: excitation followed by inhibition = Tremor, convulsions paralysis then Death from respiratory failure
Nicotine is an insecticide = at high doses can kill you, Used a lot in poor countries = NOW Has been banned here
72
name the receptors nicotine works on
Heteromeric receptor alpha4beta2 =
2 A4 and 3 B2 units
Ion channel in middle
Homomeric receptor alpha 7
7 alpha subunits
many other subtypes tho
73
describe normal nicotinic receptor
Normal nicotinic receptor - acetylcholine released from nerve ending
Then activated and channel opens and ions flow through
Channel closes and is temporarily desensitised
Then goes back to standby
74
describe nicotinic receptor with nicotine
Upregulation of alpha4beta2 by the nicotine
Binds receptor but binds for longer than acetylcholine
Receptor desensitised longer
End up with long term inactivation of the receptor
Body Tries to combat so upregulates nicotinic receptors (Chronic use = will see increased nicotinic receptors in various parts of brain - In prefrontal cortex)
75
describe Studying alpha4beta2 and other receptors
In mice = if knock out either alpha4 or beta2
No dopamine increase
No addiction
Need both of the units in confirmation to be active in reward pathway
76
describe neurotransmitter’s and what they d0
Noradrenaline = stimulation, arousal
Acetylcholine = memory, cognition
Glutamate = memory, cognition
GABA = relaxation, anxiolytic (Anti anxiety)
Dopamine = pleasure, arousal
77
describe widespread effects of nicotine - receptors
presynaptic nicotinic receptors
Variations in nicotinic receptors = related to different things that we do not understand
78
describe epidemiology of nicotine
Increase in smokers who have some sort of psychological distress
Highest prevalence rates are in psychiatric illness and addiction
88% in schizophrenia
75% in depression
80% in alcoholism
20% in general population
Research to figure this out could be useful
79
Compare addictive potential of nicotine
Around same as crack and other drugs
Longer they smoke = harder for them to give it up
80
which pathway affected when smoke - addiction
Dopaminergic reward pathway activated when you smoke
When stop smoking = rebound in other direction
Many physiological changes when stop smoking
81
describe reward pathway - receptor
Alpha4beta2 main receptors related to smoking
82
describe reward pathway - dopaminergic neuron
Can be stimulated by glutamate
More stimulation
Cholinergic input to glutamate so can release more glutamate
Also have alpha4beta2 receptors on dopaminergic neuron
Inhibited by GABA
On GABAminergic neuron you have cholinergic control
Have alpha4beta2 nicotinic receptors on GABAminergic neuron
83
describe reward pathway - dopaminergic neuron when chronic smoke
When chronically smoke = desensitize the GABA
Have less GABA inhibition
So dopamine neuron will release more dopamine
84
describe receptor subtypes of neurons
Receptor subtypes very in desensitization by nicotine (I>E)
Alpha 7 does not desensitize
So decreasing inhibition and increasing excitation to dopaminergic neuron
85
describe presynaptic alpha7 nAchRs
enhance glutamate release
Dopaminergic neuron and have increased release of glutamate because of presynaptic cholinergic receptors = facilitate release of glutamate
More excitation of dopaminergic cell in rewards pathway of brain
Firing rate increases when administer nicotine
86
what is gaba transmission modified by
alpha4beta2 nAChRs
Decrease in inhibition
Different variation of reception that decreases inhibition
87
describe overall effect of nicotine on reward pathway
So inhibition goes up then down and the glutamate goes up then down
Combination of inhibition and excitation
End up with more excitation and less inhibition
Effect of nicotine on rewards pathway
88
describe menthol
Menthol = entices smoking, increases nicotine addiction
Menthol = drug
89
describe menthol - receptors
Increases number, alters function of nicotinic receptors, brain
90
describe menthol - bioavailability
FURTHER Increases bioavailability of nicotine - lowers CYP2A6
Not metabolising as rapidly
So more present in circulation
91
describe menthol - canada vs usa
Canada banned menthol cigarettes in 2017
USA: FDA proposed ban in 2022, delayed again in 2024
92
describe menthol - nicotinic receptors specifics
Menthol alters number of nicotinic receptors on both gabaminergic and dopaminergic cell
Lower inhibition to dopaminergic neuron plus more firing of the dopaminergic neuron
Menthol increases addictive potential of nicotine
Harder for people to give it up
Alters receptors + lower GABA inhibition = more dopamine
93
describe withdrawal symptoms - gen
Acute ones last for several weeks then long standing ones can last for number of months
Sleep disturbance <2 weeks
Tense, irritable, hard time paying attention and doing job, restless and jumping all over the place
Tend to eat more and GI tract takes while to recover
Constipated because nicotine tended to stimulate things
94
describe withdrawal symptoms - outcome
not just on reward pathway
Other pathways in drugs
Receptors in a specific area = were continually stimulated
Withdrawal seems to be more due to absence of nicotine in other pathway
Complicated process
95
is nicotine withdrawal life threatening
Not life threatening
Irritating and distressing
Worst of it is over in a couple of weeks
Some effects can last for long time = Weight gain, increased appetite And cravings
Smoker smokes hundred times a day
psychological input
People do not know how to act without smoking
96
what are craves
craves (cravings)
Many times throughout day
Gets better with time
Can be triggered by being near another smoker
97
describe initial distress of withdrawing from nicotine
4-6 weeks
Then they start to feel better
Not coughing as much
Feel better when wake up in morning
Still very vulnerable to relapsing
98
what happens in brain when withdraw from nicotine
What happens in brain
6-12 weeks later = back to normal
Reversal of the upregulation of nicotinic receptors
Excess nicotinic receptors slowly decline
99
describe relapsing
people relapse
Same relapse rate as people addicted to heroin or alcohol
People in a program
- By 3 months only 30% of people who still are not smoking
- By a year = only 15% still not smoking
100
what can help addiction - treatment for withdrawal
nicotine replacement
or other drugs
101
describe nicotine replacement - things
Over the counter patch
Gum
Lozenge
Prescription nasal spray or inhaler
Many different ways to administer nicotine
102
what is the goal of nicotine replacements
Idea = get person to quit in 2 stages
Get person off habit of puffing and lighting up
Break psychological link
Still give them nicotine so no physiological withdrawal
Then break physiological addiction
These alternatives = are only temporary
But some people cannot and become dependent on alternatives
103
describe drugs to help addiction - Bupropion
blocks nAChRs on VTA DA neurons
Blocks nicotinic receptors in reward pathway
104
describe drugs to help addiction - Varenicline
partial agonist alpha4beta2 receptor
Partial agonist = advantage because provides some stimulation of the pathway
So sometimes its easier to use
Gets some release of dopamine but not same effect as smoking
Eases you off
Take this drug for a while then slowly decrease and stop everything
105
describe study - nicotine replacement
Its a bit better if use nicotine gum or patches
23-27% with nicotine substitute
10-15% without anything
106
describe study - nicotine - drugs to help
Placebo = 10% success rate after one year
Bupropion = 15%, blocking agent
Varenicline = 23%, partial agonist = Best one , Better than nothing , Still not great
107
describe another strategy of helping people with addiction - METHOXSALEN
decrease nicotine metabolism by CYP2A6
If block metabolism= have higher level of nicotine in blood and need to smoke less in order to get same psychological hit
Also take in less of the toxins
Drug = METHOXSALEN
108
describe another strategy of helping people with addiction - TOPAMAC, TOPIRAMATE TABLETS
Decrease dopamine release in reward pathway in brain
If use drug before nicotine = much less dopamine release
Works a bit
14-15%
Not dramatically
109
describe vaping - demographic
Middle and high school students in canada who tried an e cigarettes are twice as likely to be susceptible to smoking cigarettes
110
what do people tend to do after they vape
move to cigarettes
111
describe major issue with vapes
Nicotine flavoured with hundreds of potential flavourings
Hundred of solvents = 7000 different flavours
When heat mixture
Causes chemical changes = chemical reaction from flavours
Thousands more derivatives from high heat
Not designed to have flavours in your lungs
Do not know effect of these chemicals
112
describe second hand vape
Almost as bad as cigarettes
Thousands of unknown compounds present when people vape
Including carcinogens
Millions of teenagers vaping who would never smoke
Quickly become addicted to nicotine and keep vaping
Risks are real but range and magnitude unknown
Long term effects unavoidable
113
describe toxicity of vaping - on all systems
Lungs, cardiovascular system, kidney, brain, periphery
Respiratory = damage includes lung injury, asthma and pneumonia
Cardiovascular = endothelial and myocardial dysfunction, vascular injury, oxidative stress
CNS = blood brain barrier disruption, neuroinflammation and neurotoxicity
Immunological= increased inflammatory and oxidative stress responses and reduced immune efficiency
Do not know all the consequences
114
what is the best strategy to deal with nicotine addiction
PREVENTION
Best way to not end up like this
