Nicotine 2 Flashcards
Explain some of the physiological effects of nicotine on GI
suppresses GI ac&vity and hunger -
weight increase in 70 - 80% of people who quit
effects on hypothalamus and gut tissue
Effects seen on hypothalamus
Explain some of the physiological effects of nicotine on skin
vasoconstric&on in skin (wrinkles) - Botox is an Ach antagonist - but most of its effects are at the muscle
Explain some of the physiological effects of nicotine on respiration
respiration rate increase - nicotine simulates receptors
in carotid artery that indicate need for more oxygen
Some of the substances in nicotine also decrease hemoglobins binding to oxygen
Describe some of the associated behaviours with smoking
Smokers are also more likely to:
use other drugs like alcohol and caffeine
frequently change their jobs
get married and divorced more than average
have more traffic accidents
be more sexually active
perform poorly in academic environments
experience mental illness
people with the gene that makes them take more risks also implicated in smoking
Explain the mechanism of nicotine
the central effects of nicotine are mediated mostly through neuronal nicotinic acetylcholine receptors
ligand-gated pentameric ion channels
nicotine is an agonist at these receptors
neuronal nicotinic acetylcholine receptors when activated:
if postsynap&c, will quickly depolarize the cell and cause cellular excitation (neuromuscular)
if presynaptic,will induce release of neurotransmiWers - dopamine, glutamate, GABA, , noradrenaline, serotonin and others (neuronal)
Describe the structure of the nicotine receptor
5 subunits
there are at least 9 alpha subunits, 3 beta
subunits
when triggered by nicotine, integral ion channel that allows sodium and calcium to flow into the cell (depolariza&on)
different receptor subtypes have different subunit complements
there are two nicotine binding sites per receptor – same site as where Ach usually binds
mostly presynaptic in CNS
postsynaptic at neuromuscular junctions
How do we know which nicotine receptor subtype is important for addiction?
mutations in alpha 4 subunit make animals hyper-sensitive to effects of nicotine
remove (knock out) the beta 2 subunit in mice:
- nicotine no longer causes release of dopamine
- self-administra&on of nico&ne stops
Therefore, good evidence this subtype is probably most important in dopamine release
Others have been implicated as well – α6 and α7
antagonists specific for alpha4 beta 2 receptors block rewarding effects of nicotine
What are the effects of dopamine at the VTA and NA
a single dose of nicotine applied directly to dopamine-releasing nerve terminals from VTA at the nucleus accumbens
note levels remain above baseline for at least 80 minutes (long lasting dopamine release in the brain)
nicotine generally increases firing of neurons in the mesolimbic pathway and enhances dopamine release at the nucleus accumbens
Facilitated by presynap&c receptors on dopaminergic neurons from the VTA
Why does desensitization occur?
continued exposure to nicotine causes receptor desensitization- the receptor enters a state in which it cannot be activated by agonist
initial stimulatory effect no longer present and chronically may selectively decrease neurotransmitter release (mechanism of many antidepressants is to inhibit MAO)
- increasingly reinforcing effect seen in animals and nicotine not involved
Explain the desensitization of GABA vs glutamate release
not all nicotinic receptors desensitize the same way
those that control release of GABA are very sensi&ve to nicotine-induced desensitization and desensitize very quickly (decreased GABA release) -α4β2 type
those that release glutamate are not (still get release) – contain α7 subunit
this indirectly simulates release of dopamine from dopaminergic neurones that are under control of both GABA and glutamate (loss of inhibition and increased stimulation form glutamate)
What are the peripheral effects of nicotine
in periphery, nicotinic receptors are located postsynap&cally at neuromuscular junctions
at low doses, nicotine simulates them and can give rise to tremours
at high doses - paralysis, suffocation (decrease contraction f intercostal muscles) via desensitization
also present in adrenal glands - nicotine can cause release of adrenaline - increases heart rate and blood pressure
Peripheral receptors are structurally similar to central receptors but have unique subunits
What are the effects of smoking on MAO
cigarette smoke inhibits monoamine oxidase (likely via acetaldehyde)
enzyme that degrades neurotransmitters
The increase in dopamine is said to be what leads to elevated mood
What is the role of beta carbolines?
Acetaldehyde may be forming beta- carbolines (eg harman) which is known to inhibit monoamine oxidases (MAOs)
results in increased levels of dopamine, adrenaline, noradrenaline
Explain tolerance with nicotine
with chronic exposure, nicotinic receptor numbers increase
alpha 4 beta 2 containing receptors are major type that is
upregulated
may cause increased sensitization to effects of nicotine especially when receptors are resensitized
Why is there an unregulation of nicotine receptors if it is an agonist?
Because nicotine is so good at desensitizing the receptors that it begins to act as an antagonist so the body upregulate to get more Ach
Remover that smoking is especially reinforcing in the morning due to down regulation then upregulation
What are the harms of smoking in Canada and in relation to lung cancer (percentage globally)
in Canada, 45,000 deaths annually
more than AIDS, car accidents, suicide, murder, fire and poison combined
linked to 85% of new cases of lung cancer
It has been shown that burning organic compounds produce carbon monoxide. Describe the effects of cabin monoxide
extremely toxic gas
200 X greater affinity for hemoglobin than oxygen -oxygen not able to bind
causes subtle asphyxia&on of body
primary culprit in producing cardiovascular disease
What is tar and why is it so bad?
tar is sticky - adheres to cells in airways
full of carcinogens such as polycyclic aromatic hydrocarbons
inhibits function of cilia that line the airways
carcinogenic compounds that normally would be swept away sit on lung tissue
phagocyte (immune cell) function also inhibited
Why does smoking cause cancer?
- nicotine probably not involved
- smoke shown to induce DNA strand breakage, DNA and protein modification
- result in faulty DNA replication
- aromatic and heterocyclic amines produced when proteins burn may be culprits - a lot ends up in the tar
What is benzo-a-pyrene and how does it cause cancer?
benzo[a]pyrene is a product of incomplete combustion
benzo[a]pyrene gets metabolized into an ac&ve form and inserts into DNA
This causes a “bulge” in the double helix and faulty replica&on
How does smoking lead to heart disease
in addition to effects of carbon monoxide (CO), smoke components:
inhibit tissue oxygen absorption
induce hypercoagulation thus promoting blood clots
increase platelet adhesiveness - increased blood clot risk - stroke, heart attack etc
increase serum cholesterol and fatty deposits leading to atherosclerosis
Explains nicotine replacement therapy and the results
Idea is to give a pure, safe version of the addic&ve ingredient of tobacco
Huge industry in NRT – $800 million per year in US
But efficacy is questionable
Many studies have shown no improvement in relapse rate compared to quitting with no NRT
Latest study – 787 subjects – no difference between smokers using NRT and those who didn’t amer six months (Harvard University School of Public Health)
Why does NRT act to poorly?
No rapid increase in the concentration of nicotine in the Brain (no spike seen)
Drug Bupropion can be used to help curb smoking addiction, explains
originally used as an an&depressant
produces moderate increase in dopamine and noradrenaline levels by inhibiting their removal from the synapse
thought to lead to increased levels of dopamine in the nucleus accumbens
also blocks some nico&nic receptors
seems to address some craving issues
up to 30% success rate amer 1 yr
Drug Vareincline (Champix) can be used to help curb smoking addiction, explain:
A PARTIAL (not as string activation as nicotine) agonist at alpha4/beta2 nicotinic receptors (results in 30 – 60% of maximum possible activation of receptors)
blocks the effects of any nicotine added to the system
Seems to reduce craving and reinforcing effects of smoking by
partially substituting for nicotine
Long-term abstinence better than buproprion in phase III trials
But now has warning because of increased suicide risk
Also warning that aggression and hostility may occur and that drinking may may neuropsychiatric events worse
some reports suggest 6 mo success as low as 14%
What are electronic cigarettes?
They do not contain tobacco or require combustion but do provide a dose of nicotine via inhalation
They contain a battery-powered atomizer that heats up and vaporizes a nicotine-containing liquid
Idea is that they are a safe alternative to real cigarettes and provide behavioural cues that salsify some cravings
What are some concerns with using electronic cigarettes and how have they been addressed?
Concerns?
The FDA has published concerns about the inhalation of some of the liquid, propylene glycol, in which nicotine is dissolved in some E-cigs
They also report finding some nitrosamines
Also worry that children will break them and swallow the
nicotine
But..
newer models use distilled water and glycol as a nico&ne carrier
The levels of nitrosamines were lower than can be found in some tradi&onal cessation therapies
CigareWes are legal and contain just as much nicotine as E-cigs
What are the results with using E-cigs
Several surveys and studies indicate they can be a successful component of cessation and may be as good or better than current therapies
Although they do not provide the same plasma levels of nicotine, combined with the behavioural aspects of their use, including producing “throat catch” they appear to be a valid alternative
Most users say they help to control cravings more than some other therapies
However, many in the medical field and in medical agencies feel they should be tightly regulated and not available OTC until more evidence on their safety is collected
