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Phys/Pharm Drugs Of Abuse > Nicotine Addiction > Flashcards

Nicotine Addiction Flashcards

1
Q

Tobacco Overview (4)

A
  • Leaves of Nicotiana tobacum cured and (usually) smoked (potent poison for bugs/keeps them away)
  • Indigenous to North America
  • Given to C Columbus when lander in San Salvador in 1492
  • Smoked by natives for medicinal, ceremonial purposes (~1 B.C.) (enhancing fertility, predicting weather,conducting war councils, enabling vision quests, making peace)
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2
Q

Tobacco history (4)

A
  • Jean Nicot de Villemain introduces tobacco to France, promotes importation and cultivation (1556)
  • Chewed recreationally, used for ailments (e.g. headaches, colds) in Europe (1500s)
  • Tobacco becomes major cash crop of American colonies, spurring demand for slave labor (1600s)
  • No society that has adopted tobacco has ever given it up
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3
Q

Smoking - why is it important? (10)

A
  • Tobacco addiction is the LEADING preventable cause of death in Western societies
  • 1.3 Billion smokers worldwide +contributes to appx 5 million death a year (WHO)
  • Half of all smokers die prematurely as a consequence of their addiction
  • WHO data shows that Europe still has the highest overall smoking rates
  • UK rates have fallen to 14.1% (2020)
  • Service cost over £61 million last year (UK)
  • Smoking prevalence is linked to socio-economic status and vulnerable
    populations
  • Non smokers exposed to environmental tobacco smoke have a sig. higher risk of developing cancers +pulmonary diseases
  • Children exposed to second hand smoke develop a variety of respiratory disorders +morbidity.
  • Only 3-5% of smokers who want to quit succeed without NRT and only 1/3 succeed with them
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4
Q

Hazardous components in cigarette smoke (8)

A

Nicotine

N-nitrosamines - carcin.

Benzene - carcin.

aromatic amines - carcin.

Acetaldehyde - animal carcin + maybe human

1.3-Butadiene - carcin. +tetratogen

Acrolein - carcin. + dna mutagen

Polyaromatics - carcin. + dna mutagen

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5
Q

What is the major component causing addiction? (2)

A

major if not sole compound responsible for driving the addiction to smoking and thus a formidable obstacle to the prevention of tobacco related deaths is
NICOTINE

Nicotine mimics some of the actions of acetylcholine

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6
Q

Nicotine action - pharm targets (3)

A

1) has pyrrolidine + pyridine ring

2) acts on nAChr (ligand gated ion channels = depol.)

3) Ach also binds to nAChr but also muscarinic r (GPCR)

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7
Q

Nicotine absorption (4)

A
  • Nicotine is readily absorbed through intact skin.
  • Nicotine is well absorbed in the small intestine but has low bioavailability (30%) due to first-pass hepatic metabolism.
  • Nicotine is rapidly absorbed across respiratory epithelium.
  • Passes freely through the BBB and reaches brain in 11 secs = highly addictive
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8
Q

Nicotine metab. (4)

A

liver metbolises it using CYP enzymes

= 70-80%: cotinine
approx. 10%: other metabolites

= excreted in urine

=10-20% unchanged in urine (not in liver)

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9
Q

Nicotine excr.

A

Half-life:
 Nicotine t½ = 2 hr
 Cotinine t½ = 19 hr - remains in body for longer

Excretion Occurs through kidneys (pH dependent;
 with acidic pH)
 Through breast milk

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10
Q

Nicotine pharmodynamics - body parts affected (9)

A

Nicotine binds to receptors in the brain and other sites in the body = effects every single organ in the body

-CNS
-PNS
-CVS
-GI system
-Exocrine glands
-Adrenal medulla

Other:
Neuromuscular junction
Sensory receptors
Other organs

Nicotine has predominantly stimulant effects

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11
Q

Clinical effects of smoking: (9)

A

heart attacks

cancers (larynx, oral, esophageal, lung, pancreatic, bladder, kidney, cervical)

stroke

doubles cataracts risk

circ diseases

stomach ulcers

Asthma, COPD

impotence

unborn babies: preemie, lowbirthweight, stunted dev., infant death

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12
Q

CNS effects (4)

A

Central nervous system
– Pleasure

– Arousal, enhanced vigilance (at low doses, at high doses anxiety)

– Improved task performance at low doses

– Anxiety relief (perceived benefit) (does cause muscle relaxant so maybe true)

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13
Q

CVS effects (5)

A

Cardiovascular system
– inc. HR
– inc. CO
– inc. BP
– Coronary vasoconstriction
– Cutaneous vasoconstriction

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14
Q

Other (7)

A

– Appetite suppression (sympathetic) -withdrawal
– Increased metabolic rate(sympathetic)
– Skeletal muscle relaxation

– Vomiting, nausea, headache (tolerance)
– Slow stomach secretions
– Laxative
– Constricts blood vessels, wrinkles

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15
Q

Neurochemical + related effects- r’s (7)

A
  • Dopamine= Pleasure, reward
  • Norepinephrine=Arousal, appetite suppression

-Acetylcholine=Arousal, cognitive enhancement

-Glutamate=Learning, memory enhancement

-Serotonin=Mood modulation, appetite suppression

-beta-Endorphin=Reduction of anxiety and tension

  • GABA= Reduction of anxiety and tension
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16
Q

Nicotinic Acetylcholine
Receptors (nAChRs) (5)

A
  • Ligand-gated ion channels (mostly Na+/K+ )
  • Widespread in the CNS
  • Ach= the endogenous ligand
  • The major role in mammalian CNS is to influence neurotrans release
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17
Q

nAChR structure (4)

A
  • Pentamer
    – 5 polypeptide subunits
    – 9 subtypes (alpha1, 2, 3, 4..7, beta1, 2 etc)
    – Potential for 59 = 2 million diff. assemblies
  • Nicotine is a potent agonist at the nicotinic alpha4beta2r
  • Nicotine dependence is modulated primarily through alpha4beta2 nAChr
18
Q

beta2-subunit k/o mice - self admin (2)

A

– normal mice in chamber w/ lever - injection of nicotine = press level(self-admin) (high DA)

  • beta2-subunit k/o mice =mice do not self-administer nicotine: nicotine doesn’t produce reinforcing effect (less da is released).
19
Q

3 drugs on DA neurotransmission levels (4)

A

Meth: highest
Coke: slightly less
nicotine: much less

20
Q

Cholinergic system (4)

A

1) Cholinergic neurons
2) project on nucleus basalis/ striata/ septum of hippo/ SN-Th
3) = ACh release
4) Ach binds + acts on NAChr’s

21
Q

NAChr’s in the brain (6)

A

alpha-4beta-3 and alpha7 in each

prefrontal cortex - DM +craving

Hippo: reward related learning + context info processing

Striatum: Reward, motivation, Habit

Amygdala: Emotional response stress

VTA + SnC : Reward + emotions

22
Q

Reinforcing effect of nicotine: “reward” pathway (4)

A

Nicotine interacts with the ‘reward’ pathway

Nicotine releases da in the nucleus accumbens + dorsal striatum in vitro and in vivo

nAChRs are found on both cell bodies and axon terminals of da neurones

Can also modulate GABA and glutamate release

image

23
Q

nAChRs: functional states (3)

A

Three states of the nAChR ion channels:
– closed (at rest) - not stim. by anything

– open ( binding = cations flow into the cell - depol.)

– desensitised (closed and not responsive to agonists after contin. stim = x depol (tolerance)) - can be activated just needs a lot more

24
Q

Receptor activation (6)

A

1) Ach (or nicotine) binds to the receptor and stabilises the open state of the ion channel for several ms

2) Cations (Na+ and K+) enter and depolarise the cell= initiating cellular response

3) variety of neurotrans released in the CNS
(as presynaptic), nAChRs are present on various types of neurons.

4) ACh is rapidly broken down by acetylcholine-esterase

5)Nicotine has much longer duration of effect than ACh

6)Receptor becomes de-sensitised and unresponsive for a period of time

25
Q

nAChRs with repeated
smoking (3)

A

B/w cigarettes nAChRs are mainly desensitised (acute tolerance)

Next cigarette activates a small pool of receptors that are still responsive, producing pleasurable effects

In chronic smokers (e.g. with daily smoking for 6 months or
longer):
– Tolerance
– Withdrawal syndrome on cessation of smoking
– Long-term desensitisation of nAChRs
– Increase in receptor density (upreg. of nAChRs) as a compensatory response to desensitisation of the large proportion the total no. of nAChRs receptors

26
Q

Mechanism of dependence (α4β2*) studies (3)

A

rat brain treated w/saline (smokers = darker)

Upreg.of nAChRs as a compensatory response to desensitisation of nAChRs

increase in r’s associated w/craving + dependence

27
Q

How do you upreg. more receptors?

A

either

1) incr. protein synth = transc. +translat = not here X

or

2)interfere w/reg. of r’s: nicotine inc. internalised r’s in vesicles to go to membrane to be used

28
Q

Brain of Nonsmoker Versus Brain of
Smoker (2)

A

Autopsy studies comparing smokers to nonsmokers reveal up to 400% increases in brain nicotine receptors

Reversibility extent, time course, and variability is unclear

29
Q

Cycles of pleasure and
withdrawal (6)

A
  • Initial activation causes pleasure response but…
  • Dopamine falls quickly over next 2hrs
  • As levels fall the smoker feels displeasure/withdrawal
  • The next cigarette reduces cravings and other withdrawal symptoms + produces some +ve effects
  • This reinforces the compulsion to smoke
  • Environmental cues are also important in producing addiction
30
Q

Nicotine plasma concentration (7)

A
  • Each cigarette delivers 1.2-2.9mg of nicotine
  • A typical pack-a-day smoker absorbs 20-40mg of nicotine/day
  • Half-life is ~ 2hours
  • During a typical day, nicotine accumulates over 6-8 hours (3-4
    half-lives)
  • The increment is 5-30ng/ml after each cigarette (depending on
    how the cigarette is smoked)
  • More frequent smoking reduces fluctuations in nicotine plasma
    concentration
  • The plateau (10-50ng/ml) is usually reached in the early
    afternoon
31
Q

Nicotine addiction cycle (5)

A

graph w/ uneven bell shaped curve

  • jagged lines throuugh grey shape = fluctuatiosn of nicotine (DA)
  • bottom solid line - threshold below which = withdrawal
  • top solid line - threshold above which you get pleasurable effects
  • grey shape = feeling neutral - neighter pleasure or withdrawal
32
Q

Nicotine addiction types (2)

A
  • Tobacco users maintain a minimum serum nicotine concentration in order to
    – Prevent withdrawal symptoms
    – Maintain pleasure/arousal
    – Modulate mood
  • Users self-titrate nicotine intake by:
    – Smoking/dipping more frequently
    – Smoking more intensely
    – Obstructing vents on low-nicotine brand cigarettes
33
Q

Nicotine withdrawal pt1 (6)

A
  • Nicotine plasma concentration significantly drops overnight, which leads to withdrawal symptoms in the morning in chronic smokers.
  • Withdrawal onset is usually within a few hours after last cigarette
  • Nicotine withdrawal syndrome includes: Mood changes
  • 1st morning cigarette produces the most pleasurable effect – After an overnight abstinence more receptors become available for activation – It also relieves withdrawal symptoms
  • The earlier the smoker begins to smoke after waking in the morning the more severe the dependence
  • If abstinence continues, withdrawal symptoms peak at 24-48hrs and gradually subside over several weeks.
34
Q

Withdrawal mood changes (6)

A
  • dysphoria, depressive mood

– Irritability, frustration or anger

– Anxiety, restlessness

– Difficulty concentrating, impaired attention

– Hunger, increased appetite or weight gain

– Craving

  • Some symptoms persist for months
    – mild depression, dysphoria and anhedonia
35
Q

Factors contributing to tobacco use: (3)

A

Environment
 Tobacco advertising
 Conditioned stimuli
 Social interactions

Physiology
 Genetic predisposition
 Coexisting medical conditions

Pharmacology
 Alleviation of withdrawal symptoms
 Weight control
 Pleasure

36
Q

Contextual smoking (3)

A

Some places, times and situations are closely associated w/smoking and enhance craving:

– Morning coffee with breakfast
– Coffee shop
– Tea breaks

37
Q

Genetics (3

A
  • Heritability ~50% (range 28-84%)
  • Effect of gene polymorphisms:

– People with defective alleles of CYP2A6 gene= slow metabol. of nicotine and lower rates of smoking + tobacco dependence.

– People with CHRNA4 gene polymorphism (gene coding for α4 subunit of the nicotinic Ach receptor) have higher rates of tobacco dependence

38
Q

Habenular α5 nicotinic receptor subunit signalling controls nicotine intake - studies (6)

A

polymorph of alpha5 - inc. chances of nicotine addiction + lung cancer

ko mice - with self-amin test

 Nicotine intake has bell-shaped conc curve - at a higher conc = aversion

 Up-phase represents rewarding component, unaffected by deletion of alpha5

 Down phase reflects the aversive effects of higher doses of nicotine, significantly greater responses in a5 KO

reintroduced alpha5 construct in diff parts of brain - expected results, until introduced in medial habenula =Identification of novel pathway that transmits inhibitory motivational signal which limits nicotine intake (opposes mesoaccubens reward)

39
Q

Smoking and Mental Health (4)

A

People with psychiatric disorders and substance use disorders have 2-4x higher rates of smoking (range 41% and 67% respectively) than the general population

  • 40-88% of patients with schizophrenia smoke
  • Higher rates of depression in smokers
  • Higher rate of smoking in substance abusers
40
Q

Smoking: any health benefits? (3)

A
  • Possibly reduces symptom severity in schizophrenia (self-medication hypothesis)
    – There is deficient endogenous central nicotinic neurotrans in
    schizophrenia = causes a disruption of sensory gating (a possible mechanism for delusions)
    – Exogenous nicotine partly compensates for this deficiency.
    – Schizophrenic patients smoke larger amounts of cigarettes per day and
    extract more nicotine from them – sig. health risk.
    – Therapeutic use of safe forms of nicotine in schizophrenia has been
    proposed.
  • Reduces risk of Parkinson’s disease
    – Lower incidence of PD in smokers
    – Benefit correlates with the intensity and duration of smoking.
    – Does not appear to be due to publication bias
    – Nicotine neuroprotective for nigrostriatal neurons
  • Does it reduce prevalence of Alzheimer’s disease?
    – After controlling for tobacco industry affiliation, smoking has been found to
    increase the risk of Alzheimer’s disease,
41
Q

Tobacco dependence:
A 2-PART PROBLEM (2)

A

Tobacco Dependence: Treatment should address the physiological
and the behavioural aspects of dependence

Physiological: The addiction to nicotine -Treatment =Medications for cessation

Behavioural: The habit of using tobacco- Treatment
=Behaviour change program

Phys/Pharm Drugs Of Abuse (23 decks)

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