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PHAR 300 > Nicotine > Flashcards

Nicotine Flashcards

1
Q

how consume nicotine

A

2 major ways of consuming nicotine - both through lungs

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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

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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

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4
Q

what ways can nicotine be consumed

A

Drug people take in cigarettes and vapes

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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

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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

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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

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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

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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

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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

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11
Q

how long after inhaling nicotine does it hit the brain

A

7 seconds of inhaling it
Faster than injections

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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

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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

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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

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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

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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

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17
Q

describe smoking + asbestos

A

50-90x
Exposure to asbestos and cigarette smoke at same time has multiplication effect

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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

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19
Q

what cardiovascular diseases can smoking cause

A

coronary heart disease
strokes
peripheral vascular disease

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20
Q

describe coronary heart disease

A

one third of deaths are due to smoking
Hypertension
CO
Endothelial injury
Atherosclerosis
platelet aggregation

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21
Q

describe strokes

A

50% <age 65
Can kill you or impaired mental function for life
Strokes in younger people much more common

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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

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23
Q

describe effects of nicotine on blood vessels

A

Vasoconstriction
To all these areas =
Skin
Hair
Eyes
Gums - gum disease

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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

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25
Q

describe effects of nicotine on blood vessels - blood flow

A

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

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26
Q

how many smokers do cigarettes kill

A

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

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27
Q

is vaping the same as smoking

A

yuh
Vaping = smoking
Nicotine has the effect

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28
Q

describe secondhand smoke

A

Living with smoker
Very dangerous
Breathe in all this stuff

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29
Q

how many people die from secondhand smoke

A

secondhand smoke kills 900,000 people every year

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30
Q

describe second hand smoke - how

A

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

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31
Q

what is thirdhand smoke

A

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

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32
Q

why is thirdhand smoke bad - for kids

A

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

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33
Q

describe effects of thirdhand smoke in children

A

Increases risk of issues in children
Brain tumours
Other cancers
Asthma
Infections
Sids = sudden infant death syndrome - Risk increased if around smoke

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34
Q

pharmacokinetics of nicotine - describe absorption

A

Absorb nicotine extremely well from lungs
Can absorb it just about anywhere though

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35
Q

pharmacokinetics of nicotine - describe absorption from mouth

A

Well from mouth
Some absorbed during smoking
Also people chew tobacco
People Use nicotine gum
Tobacco stuck under gum - absorbed there

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36
Q

pharmacokinetics of nicotine - describe absorption from skin

A

Absorb from skin = nicotine patches

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37
Q

pharmacokinetics of nicotine - describe absorption from gi tract

A

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

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38
Q

how do they design cigarettes smoke

A

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

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39
Q

faster nicotine absorbed and hits brain =

A

stronger link for addictive potential

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40
Q

describe inhaling smoke

A

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

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41
Q

describe giving cigarette with less nicotine in it

A

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

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42
Q

describe giving cigarette with less nicotine in it- experiment

A

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

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43
Q

describe Blood nicotine concentration - regular smoking

A

Vapes and cigarettes = goes up rapidly then comes down with time if just one cigarettes

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44
Q

describe Blood nicotine concentration - other ways - mouth

A

Oral snuff
Chewing tobacco
Nicotine gum = more slow absorption compared to above 2
Connotation not as high
Nicotine absorbed from mouth

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45
Q

describe Blood nicotine concentration - gi poisoning

A

Excellent GI absorption (poisoning)
Children can swallow cigarettes
Can easily swallow lethal dose of nicotine

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46
Q

describe distribution of nicotine

A

Because highly lipid soluble
Transported everywhere
Gets through blood brain barrier
Affects brain and cns
Pns also

47
Q

describe distribution of nicotine - pregnancy

A

fetus and breast milk
Gets through placenta

48
Q

describe distribution of nicotine - brain

A

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
Q

describe metabolism of nicotine - enzymes

A

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
Q

describe half life of nicotine

A

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
Q

describe CYP2A6 metabolism of nicotine

A

major enzyme that metabolises nicotine
Metabolizes almost all of nicotine to cotinine then CYP2A6 gets rid of cotinine
Metabolites conjugates and excreted

52
Q

describe CYP2A6 metabolism of nicotine- variations

A

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
Q

describe CYP2A6 metabolism of nicotine- variations genetic

A

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
Q

what does CYP2A6 also do

A

also activates procarcinogens
Forms cytotoxic and genotoxic metabolites
Defective CYP2A6 decreases carcinogenicity
Not taking in as many carcinogens
Slightly less risk of cancer

55
Q

describe excretion of nicotine

A

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
Q

where are nicotine receptors

A

Nicotinic receptors all over the place
Autonomic nervous system
Parasympathetic and sympathetic
Ganglion - synapses in the ganglia

57
Q

describe nicotine effects in periphery

A

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
Q

describe nicotine effects on ans

A

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
Q

describe nicotinic receptor

A

Nicotine acts
Ligand gated ion channels
Still lots to learn
Wide distribution in brain and periphery- in ganglia and out in periphery

60
Q

describe ribbon model of nicotinic receptor

A

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
Q

what type of nicotinic receptor are we looking at

A

Not looking at muscle type nicotinic receptor
Can act on muscle type if smoke a lot
Looking at neuronal type nicotinic receptors

62
Q

describe neuronal nicotinic receptors

A

2 common types of neuronal receptors
Heteromeric = alpha and beta
Homomeric = all of units the same

63
Q

where are nicotinic receptors in brain

A

All over the place in the brain
Very common on presynaptic nerve endings for all different major transmitters

64
Q

describe action of nicotinic receptors in brain

A

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
Q

describe effect of nicotine on receptor

A

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
Q

describe effect of nicotine on receptor - consequences on demeanour

A

Initial stimulation followed by sedation, subtle and temporary improvement in performance

67
Q

describe effect of nicotine on receptor - consequences on skin

A

Decreased skin temperature
Vasoconstriction

68
Q

describe effect of nicotine on receptor - consequences on muscles

A

Skeletal muscles relaxation may contribute to tranquillizing effects as well as habituation to unimportant stimuli

69
Q

describe effect of nicotine on receptor - consequences on gi tract

A

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
Q

describe effect of nicotine on receptor - consequences on metabolism

A

Catecholamine release may increase thermogenesis and basal metabolic rate

71
Q

describe nicotine poisoning

A

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
Q

name the receptors nicotine works on

A

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
Q

describe normal nicotinic receptor

A

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
Q

describe nicotinic receptor with nicotine

A

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
Q

describe Studying alpha4beta2 and other receptors

A

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
Q

describe neurotransmitter’s and what they d0

A

Noradrenaline = stimulation, arousal
Acetylcholine = memory, cognition
Glutamate = memory, cognition
GABA = relaxation, anxiolytic (Anti anxiety)
Dopamine = pleasure, arousal

77
Q

describe widespread effects of nicotine - receptors

A

presynaptic nicotinic receptors
Variations in nicotinic receptors = related to different things that we do not understand

78
Q

describe epidemiology of nicotine

A

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
Q

Compare addictive potential of nicotine

A

Around same as crack and other drugs
Longer they smoke = harder for them to give it up

80
Q

which pathway affected when smoke - addiction

A

Dopaminergic reward pathway activated when you smoke
When stop smoking = rebound in other direction
Many physiological changes when stop smoking

81
Q

describe reward pathway - receptor

A

Alpha4beta2 main receptors related to smoking

82
Q

describe reward pathway - dopaminergic neuron

A

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
Q

describe reward pathway - dopaminergic neuron when chronic smoke

A

When chronically smoke = desensitize the GABA
Have less GABA inhibition
So dopamine neuron will release more dopamine

84
Q

describe receptor subtypes of neurons

A

Receptor subtypes very in desensitization by nicotine (I>E)
Alpha 7 does not desensitize
So decreasing inhibition and increasing excitation to dopaminergic neuron

85
Q

describe presynaptic alpha7 nAchRs

A

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
Q

what is gaba transmission modified by

A

alpha4beta2 nAChRs
Decrease in inhibition
Different variation of reception that decreases inhibition

87
Q

describe overall effect of nicotine on reward pathway

A

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
Q

describe menthol

A

Menthol = entices smoking, increases nicotine addiction
Menthol = drug

89
Q

describe menthol - receptors

A

Increases number, alters function of nicotinic receptors, brain

90
Q

describe menthol - bioavailability

A

FURTHER Increases bioavailability of nicotine - lowers CYP2A6
Not metabolising as rapidly
So more present in circulation

91
Q

describe menthol - canada vs usa

A

Canada banned menthol cigarettes in 2017
USA: FDA proposed ban in 2022, delayed again in 2024

92
Q

describe menthol - nicotinic receptors specifics

A

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
Q

describe withdrawal symptoms - gen

A

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
Q

describe withdrawal symptoms - outcome

A

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
Q

is nicotine withdrawal life threatening

A

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
Q

what are craves

A

craves (cravings)
Many times throughout day
Gets better with time
Can be triggered by being near another smoker

97
Q

describe initial distress of withdrawing from nicotine

A

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
Q

what happens in brain when withdraw from nicotine

A

What happens in brain
6-12 weeks later = back to normal
Reversal of the upregulation of nicotinic receptors
Excess nicotinic receptors slowly decline

99
Q

describe relapsing

A

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
Q

what can help addiction - treatment for withdrawal

A

nicotine replacement
or other drugs

101
Q

describe nicotine replacement - things

A

Over the counter patch
Gum
Lozenge
Prescription nasal spray or inhaler
Many different ways to administer nicotine

102
Q

what is the goal of nicotine replacements

A

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
Q

describe drugs to help addiction - Bupropion

A

blocks nAChRs on VTA DA neurons
Blocks nicotinic receptors in reward pathway

104
Q

describe drugs to help addiction - Varenicline

A

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
Q

describe study - nicotine replacement

A

Its a bit better if use nicotine gum or patches
23-27% with nicotine substitute
10-15% without anything

106
Q

describe study - nicotine - drugs to help

A

Placebo = 10% success rate after one year
Bupropion = 15%, blocking agent
Varenicline = 23%, partial agonist = Best one , Better than nothing , Still not great

107
Q

describe another strategy of helping people with addiction - METHOXSALEN

A

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
Q

describe another strategy of helping people with addiction - TOPAMAC, TOPIRAMATE TABLETS

A

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
Q

describe vaping - demographic

A

Middle and high school students in canada who tried an e cigarettes are twice as likely to be susceptible to smoking cigarettes

110
Q

what do people tend to do after they vape

A

move to cigarettes

111
Q

describe major issue with vapes

A

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
Q

describe second hand vape

A

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
Q

describe toxicity of vaping - on all systems

A

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
Q

what is the best strategy to deal with nicotine addiction

A

PREVENTION
Best way to not end up like this

PHAR 300 (15 decks)

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