Tobacco and Nicotine Flashcards
What are the forms of tobacco products?
Cigarettes
E-cigarettes
Cigars, cigarillos
Shisha
Smokeless
Patches
Gum
How do vapes work?
Vaporize e-juice containing nicotine; usually glycerin or PG-based
No burning of plant material, no tar
What is the marketing angle of vapes?
Cleaner smoke = healthier
What do flavors and additives in vapes cause?
Severe adverse effects
What is diacetyl?
Butter flavor, obliterates lung tissue and causes popcorn lung in factory workers
What does vitamin E acetate cause?
Allergic reactions
How do vapes damage immune system?
Vapour damages immune system via ROS same as cigarettes, macrophages infiltrate lung tissue over time
How much higher is the nicotine dose in vapes as compared to cigarettes?
5-8x more than a cigarette
How do hookahs work?
Water cools smoke, less irritating, fewer particulates, but much longer sessions
Hot air vaporizes chemicals which produces 11x the CO by weight as compared to cigarettes
What is the most processed flavored tobacco form?
Shisha
How do hookahs increase heart rate?
Due to elevated CO in blood
Increased lung disease, oral/lung cancer risk
What is smoke?
Particulates = nicotine, water, tar , PAHs, benzo[a]pyrene, metals
Gases = nicotine, CO, CO2, NO, nitrosamines, ammonia, nitrites, sulfur, alcohols, ketones, aldehydes, hydrocarbons
What is an aerosol?
Particulates + gases
What is first-hand smoke?
Inhalation of smoke directly from burning tobacco
What is second-hand smoke?
Smoke that has already been inhaled by others
What is third-hand smoke?
1st and 2nd-hand fumes from fingers, clothes, fabric
What is nicotine?
An alkaloid that causes addiction
Competitive acetylcholine receptor agonist
both Ns pick up a H at low pH
-uncharged = free base
Protects the plant from pests
What is governed by pH in nicotine?
Mono and di-protonated forms
What does controlling pH in cigarettes do?
Optimizes lung absorption
What does burning cigarettes generate?
Up to 4000 new chemicals
How much nicotine is in one cigarette?
0.5-2 mg
How much nicotine is a lethal dose?
60 mg
What types of smoke have a lower bioavailability?
Pyrolysis, filter, and sidestream smoke
How many cigarettes are optimal for brain stimulation?
A pack a day
What is the absorption in oral (smokeless) forms of nicotine like?
3-4x greater nicotine absorption, area under the plasma vs time curve
Much slower rate of absorption
What is the distribution of nicotine forms in the blood?
Blood pH = 7.4 so 70% is monoprotonated and 30% are unprotonated
Less than 5% is bound to plasma protein
What organs get the largest amount of nicotine?
Liver, kidney, spleen, lungs
What tissue gets the least amount of nicotine?
Adipose tissue
What percent of binding sites in the brain are occupied after 1 cigarette?
80%
What is most nicotine converted to in the liver?
Cotinine
What is the half life of nicotine?
2 hours
What enzymes metabolize nicotine?
Aldehyde oxidases CYP2A6 and CYP2B6
Monooxygenases process a small amount
What does a CYP2A6 mutation that slows metabolism cause?
Lower tobacco use
What can nicotine cross?
The placenta
How is nicotine excreted?
Kidneys
Breast milk
When does plasma [nicotine] peak?
In the evening
When do nicotine receptors re-sensitize?
Overnight
Which cigarette is the most pleasant?
The first one of the day
How does nicotine affect the brain?
Increased alertness, arousal, memory, vigilance, concentration
Headache, dizziness, sleep disturbances, irritability
Suppressed appetite
Heightened tension in non-smokers, while smokers are calmed
Stimulated brain areas related to pleasure and reinforcement
How does nicotine affect the mouth?
Dry mouth
Possible changed shape and reduced function of taste buds
How does nicotine affect endocrine function?
Increased release of epinephrine, NE, vasopressin (ADH), cortisol, prolactin, growth hormone, insulin
How does nicotine affect respiratory function?
Constricted bronchi so decreased amount of air entering the lungs
Decreased lung capacity
How does nicotine affect cardiovascular function?
Increased HR, BP
Decreased ability to carry oxygen to tissues
Increased blood clotting
Constricted blood vessels of hands, feet, and skin
Increased risk of heart attack and stroke
How does nicotine affect GI function?
Increase nausea and vomiting
Increased gastric HCl secretion
Decreased GI tone and muscle contraction, which can lead to diarrhea
What are the general effects of nicotine?
Sympathomimetic
What NTs do tobacco and nicotine affect?
Ach, DA, GABA, Glu
What is the mechanism of tobacco and nicotine?
Binds and depolarizes cells via nAChR
High affinity leads to inactivation of receptor = biphasic mechanism at high doses
Acetaldehyde from burning may inhibit MAO and boost NT levels
Where are CNS receptors located?
Cortex, hippocampus, midbrain
What do pre-synaptic receptors cause (nicotine)?
Increased glutamate release
Increased GABA release = quickly desensitize
Increased DA release
What is the reinforcing mechanism of nicotine?
DA, Glu, GABA modulation in the VTA + NAc
What are the acute adverse effects of nicotine?
Safe additives turn bad after burning
Stimulation of vomiting center
Headaches, nausea, disrupted autonomic nervous system functioning
Alternating tachycardia and bradycardia
Severe intoxication = seizures, hypotension, respiratory depression
What is the cellular mechanism of reinforcement of nicotine?
Glutamate receptors and nicotinic receptors are activated
GABA is activated briefly but will then not release later to maximize dopamine release
What are the characteristics of nAChRs in the brain?
Heteropentamic receptors with alpha and beta subunits
Conduct cation influx to depolarize neurons
Pre and post synaptic
Trigger neuromuscular activity
How do nAChRs work?
Pre-synaptic will increase NT release
Post-synaptic will depolarize the cell
Receptors inactivate if continuously exposed to an agonist like nicotine
What receptor subunit composition of nAChRs affect?
Reinforcement and reward
What do alpha6 subunits in nAChRs modulate?
Locomotor responses
What do alpha7 subunits in nAChRs facilitate?
Glutamate release
What does beta2 knockout in nAChRs in mice prevent?
DA release, self-administration stops
What do alpha4 beta2 receptor antagonists block?
Reward
What is the most important nAChR for DA reinforcement?
alpha4 beta2
Where are alpha6 beta2 nAChRs found?
on DA-ergic terminals in the NAc
When do alpha6 beta2 nAChRs not release DA?
After systemic nicotine administration
What are the main functional nAChRs on VTA Da-ergic soma?
alpha6 beta2
Activating these on soma drive DA release and reinforcement
What do inactivation rates of nicotine depend on?
Subunit composition
How long does a single dose of nicotine injected into the NAc elevate DA levels for?
80 minutes
alpha4 beta2 governs the release of what NT?
GABA release and will inactivate quickly (30-60 seconds) and for a long time (like an hour)
alpha7 sub-types govern the release of which NT?
Glu release and are not activated
What are the first uses for nicotine like?
Unpleasant
Brain regions/circuits for dizziness, nausea, sweat
What happens during metabolic tolerance to nicotine?
Increased enzyme activity
First cig is the best
What happens during cellular tolerance to nicotine?
Receptor inactivation, affects reward
What happens during behavioral tolerance to nicotine?
Mindset stages experience, a ritual of smoking
What happens to nAChR expression in regard to tolerance to nicotine?
nAChR expression increases, mostly alpha4 beta2 subtype
Enhances sensitivity to nicotine effects
What are the physiological symptoms of nicotine withdrawal?
Headache
Drowsiness
Insomnia
Increase appetite
Weight gain
GI upset
What are the psychological symptoms of nicotine withdrawal?
Cravings
Mood changes
Irritability
Anxiety
Restlessness
Depression
Difficulty concentrating
Poor judgement and psychomotor performance
What are some of the features of nicotine dependence?
Starts to happen within days of habit
Physical and psychological dependence
Quick metabolism leads to withdrawal and needing to seek another dose to avoid symptoms
Cue-driven habit
What types of cancer does long-term use of tobacco cause?
Lung, liver, colarectal
What initiates cancer?
Benzo[a]pyrene which is an intercalating agent
What does nicotine enhance?
Growth/metastasis, not initiation
What does nicotine inhibit in regard to cancer?
Apoptotic signaling by binding alpha7 nAChRs on the mitochondria which allows cells with damaged DNA to replicate
How does nicotine accelerate skin aging?
Due to peripheral vasoconstriction
How does nicotine cause sexual dysfunction?
Impaired NO signaling prevents erections
How does nicotine cause type 2 diabetes?
Stressed vasculature is insensitive to insulin
What are some other long-term adverse effects of tobacco?
Cataracts, macular degeneration
Tooth decay, periodontitis, IBS, Crohn’s
Infection
Rheumatoid arthritis, osteoporosis
Cardiovascular disease
COPD = includes chronic bronchitis and emphysema
What is COPD caused by?
Inflammation of airways covered in tar and ash deposits
Cilia function is impaired by PAH and ketones in smoke
What does a smoker’s cough indicate?
Recovery of cilial function from someone who is quitting smoking
What are people exposed to second-hand smoke more susceptible to?
They have higher rates of lung cancer and heart disease
How does smoking affect pregnancy?
Constriction of umbilical arteries caused reduced oxygen to baby
May affect reward system, leading to increased addiction risk
Higher risk of stillbirth, premature or miscarriage, low birth weight
Cleft palate and lip risk goes up
What is the success rate of quitting smoking?
6% - VERY difficult
What does a 3 day hump correlate with?
Nicotine clearance
What happens within 8 hours of smoking cessation?
Blood [CO] normalizes
What happens within a week of smoking cessation?
Heart, BP, circulation, breathing improve
What happens within 9 months of smoking cessation?
Respiratory cilia recover
What happens within 1 year of smoking cessation?
CHD risk drops 50%
What happens within 5-10 years of smoking cessation?
Risk of stroke matches non-smokers
What happens within 15 years of smoking cessation?
CHD risk matches non-smokers while lung cancer risk is 50% lower than smokers
What are forms of nicotine that aid in smoking cessation? (helps with overcoming withdrawal)
Patches
Gum
Nasal spray
Inhalers
Lozenges
E-cigarettes
What are cons of nicotine gum?
Bad taste, irritate throat, induce nausea
What are the cons of nicotine patches/spray?
Can cause irritation
How does Bupropion help with smoking cessation?
Antidepressant
nAChR antagonist, blocks the channel even when nicotine is present
DAT and NET inhibition
Helps reduce cravings
How does Varenicline help with smoking cessation?
Partial nAChR agonist, reduces reward and cravings
What other smoking cessation drugs are in development?
Methoxsalen
NicVAX
What are some behavioral and psychosocial smoking cessation aids?
Counseling, stress management
Behaviour modification to identify and avoid risky situations
Combine with pharmacological treatments
Large-scale awareness campaigns have led to increased attempts to quit
