Scope of tobacco and nicotine exposure Tobacco use in the U.S. “Low Tar, Low Nicotine” cigarette Increased smoking because thought to be “safe”... Chronic use of tobacco products has been associated with the following health risks:

Tobacco use in the U.S. 17.3% of females age 16 and over smoke 21.5% of males age 16 and over smoke 44 million active smokers in the US today, and 52 million ex-smokers “Low Tar, Low Nicotine” cigarette Backfired—induced stronger inhalation and retention of tobacco smoke, to achieve the same nicotine levels Greater inhalation and retention of tobacco also resulted in the same tar exposures as older cigarette Increased smoking because thought to be “safe”... Has shifted lung cancer from primarily a disease of the central airways (squamous cell carcinoma) to that of the peripheral airways (adenocarcinoma) because of trapping of tar in smaller airways Did not decreased risk of lung cancer or risk of heart disease Chronic use of tobacco products has been associated with the following health risks: Cardiovascular disease (stroke, coronary artery disease, myocardial infarction) Chronic obstructive pulmonary disease, emphysema, asthma Cancer of lung, head and neck, oral cavity, pancreas, bladder, stomach, and cervix Delay healing and recovery after surgery Cataracts Sexual dysfunction, early menopause Osteoporosis Lipid abnormalities Peridontal disease

Scope of tobacco and nicotine exposure Tobacco smoke contains Cigarette smoke contains... Harmful compounds are either... Examples of detrimental compounds (some of which are carcinogens) in tobacco smoke

Tobacco smoke contains An estimated 4,800 compounds _Carcinogens_: Mutations in DNA of bronchial epithelium, eventual cancer. Stimulation of P450 enzymes to cause enhanced metabolism of estrogen, can lead to infertility and early menopause _Carbon Monoxide_: Need for increased cardiac output to sustain oxygen levels, chronic effects on blood vessels, leads to heart disease _Tar and particulates_: chronic inflammation in lungs, leads to COPD, bronchitis, and asthma _Beta-carbolines (harmane, acetaldehyde)_ inhibit monoamine oxidase, decrease degradation of dopamine, norepinephrine and epinephrine _Nicotine_: Chronic stimulation of cardio-vascular system leads to coronary heart disease and myocardial infarction, blood clots, and stroke Cigarette smoke contains... 11 known human carcinogens 7 probable carcinogens 49 animal carcinogens that possibly also are carcinogens in humans Harmful compounds are either... Produced during the combustion of tobacco Released as free agents because of the heat of combustion Examples of detrimental compounds (some of which are carcinogens) in tobacco smoke Carbon monoxide Hydrogen cyanide Ammonia Nicotine Benzene Nitrosamines Benzo(a)pyrene Lead Cadmium Hexavalent chromium Arsenic Polonium-210 Formaldehyde

Scope of tobacco and nicotine exposure Health effects are brought about by... The carcinogen NNK The metabolite of NNK, NNAL Nicotine

Health effects are brought about by... The genetic damage to the bronchial epithelium caused by the carcinogens The long-term effects of stimulation of the cardio-vascular system caused by nicotine The long-term effects of carbon monoxide causing reduced oxygen exchange The chronic inflammatory responses that are caused by the inhaled smoke and tar that is deposited in the lungs The carcinogen NNK Forms from nicotine (found only in tobacco leaves in nature) Spontaneously rearranges to release nitrosamines which are highly active compounds that form DNA adducts The metabolite of NNK, NNAL Can be used to monitor the relative exposure to NNK Found in the urine of smokers and people who are exposed to second hand smoke Nicotine The most important constituent from a pharmacologic perspective of the numerous constituents found in tobacco and tobacco smoke Composed of a pyridine and pyrrolidine ring A natural alkaloid found only in tobacco plants A weak base (pKa = 7.9) that turns brown and acquires the characteristic odor of tobacco following exposure to air Mimics the effects of acetylcholine at the acetylcholine receptor

Pharmacokinetics of nicotine: Absorption Absorption of nicotine is dependent on... Acidic medium Alkaline medium Physiologic conditions Acidity and nicotine absorption Unaltered cigarette smoke Air-cured tobacco Smokeless tobacco products and nicotine gum Cured cigarette tobacco If the pH of the mouth is lowered by drinking acidic beverages

Absorption of nicotine is dependent on pH Because nicotine is a weak base, in an acidic medium, nicotine is ionized and poorly absorbed across membranes In an alkaline medium, nicotine is non-ionized and well absorbed across membranes Under physiologic conditions (pH 7.4 - 7.5), approximately 30% of nicotine is non-ionized and readily crosses cell membranes Acidity and nicotine absorption Unaltered cigarette smoke is acidic, so limited nicotine is absorbed Air-cured tobacco (found in pipe tobacco and cigars) produces smoke with an alkaline pH, allowing for increased buccal absorption of nicotine Even pipe or cigar smokes who don't inhale experience considerable absorption through the buccal mucosa Smokeless tobacco products (snuff and chew) and nicotine gum are buffered to an alkaline pH to facilitate absorption of nicotine Some tobacco companies have altered the pH of cured cigarette tobacco by spraying it with sodium hydroxide or other bases This was done to enhance nicotine absorption as the nicotine content of cigarettes was lowered in the 1970’s and 1980’s If the pH of the mouth is lowered by drinking acidic beverages (e.g., coffee, juice, or cola), absorption of nicotine from nicotine gum is reduced substantially

Pharmacokinetics of nicotine: Absorption Intact skin GI tract Small intestine Lung (droplets) When tobacco smoke reaches the alveoli, nicotine is rapidly absorbed across respiratory epithelial cells due to the following factors

Intact skin Nicotine is readily absorbed across intact skin, allowing for transdermal administration of nicotine as a therapeutic adjunct to tobacco cessation GI tract Conversely, the bioavailability of nicotine in the GI tract is limited Absorption is poor across gastric mucosa because of a low gastric pH Small intestine The absorption of nicotine in the small intestine is better due to increased pH, but the systemic bioavailability is low (30%) because it undergoes significant first-pass metabolism Lung (droplets) Nicotine is "distilled" from burning tobacco and carried in droplets to the small airways of the lung The droplets are composed of water, tar, and alkaloids, including nicotine When tobacco smoke reaches the alveoli, nicotine is rapidly absorbed across respiratory epithelial cells due to the following factors pH of the lung is 7.4, allowing for a larger fraction of non-ionized nicotine Alveolar surface area of the lung is large Capillary system in the lung is extensive Results in extremely high, transient blood levels of nicotine with each inhalation

Pharmacokinetics of nicotine: Distribution Inhalation of tobacco smoke is an effective means of... After inhalation, non-charged nicotine... Blood nicotine concentrations immediately... Via this route nicotine is rapidly delivered to... This results in... Spiking of nicotine levels during each inhalation contributes to... Inhalation of cigarettes vs. buccal absorption from cigars and pipes Serum levels of nicotine Euphoric effect

Inhalation of tobacco smoke is an effective means of... Delivering nicotine to the central nervous system After inhalation, non-charged nicotine... Is rapidly absorbed across pulmonary epithelium and enters the circulation Blood nicotine concentrations immediately... Rise as high as 1 μM Via this route nicotine is rapidly delivered to... The brain, where as a non-charged small molecule it readily crosses the blood-brain barrier This results in... Transient exposure of the brain to high levels of nicotine Spiking of nicotine levels during each inhalation contributes to... Propensity for addiction, as pleasurable sensations are elicited and then decline repeatedly Inhalation of cigarettes vs. buccal absorption from cigars and pipes Serum levels of nicotine Serum levels of nicotine are higher and less prolonged with inhalation of cigarettes than with buccal absorption from cigars and pipes, which does not result is as great “on and off” switching of mood alteration Euphoric effect There is a lower euphoric effect from buccal absorption, hence a lessened decline in euphoria and lowered potential for craving and addiction

Pharmacokinetics of nicotine: Metabolism and excretion Nicotine metabolism Cotinine Metabolism Effects Biologic activities of cotinine vs. nicotine The half-life of nicotine in the body What underlies tobacco users' need for repeated administration of nicotine to prevent withdrawal symptoms Nicotine levels during the day and night The half-life of cotinine Cotinine can be used as a more reliable marker of... Nicotine excretion

Nicotine metabolism Extensively metabolized in the liver and to a lesser extent in the kidney and lung Cotinine ~70-80% of nicotine is metabolized to cotinine, the major metabolite Effects of cotinine are probably also induced through interaction with neuronal acetylcholine receptors, for which it has a low affinity Biologic activities of cotinine vs. nicotine Although cotinine has largely been believed to be inactive, some studies suggest it may have some biologic activities, such as protecting against Alzheimer’s disease and enhancing memory These are shared with nicotine, but cotinine is not addictive and is not associated with cardiovascular disease The half-life of nicotine in the body ~2 hours What underlies tobacco users' need for repeated administration of nicotine to prevent withdrawal symptoms Metabolism to cotinine and subsequent glucuronidation and excretion in urine Nicotine levels during the day and night With regular tobacco use, significant nicotine levels accumulate during waking hours, then decline during sleep The half-life of cotinine ~18-20 hours Cotinine can be used as a more reliable marker of... Tobacco use and exposure to second hand smoke Nicotine excretion Nicotine and its metabolites are excreted in the urine

Pharmacodynamics of nicotine: interaction with nicotine acetylcholine receptors Nicotine is a potent agonist that affects numerous organ systems, including... Following absorption, nicotine... What causes a variety of stimulant and, to a lesser extent, sedative effects Nicotine does not interact with...

Nicotine is a potent agonist that affects numerous organ systems, including... The cardiovascular, adrenal, neurologic, and musculoskeletal systems Following absorption, nicotine... Binds to nicotinic acetylcholine receptors in the brain, the autonomic ganglia, and in other organs such as the adrenal gland Mimics the effect of acetylcholine What causes a variety of stimulant and, to a lesser extent, sedative effects The combination of effects on the different nicotinic acetylcholine receptors (nAchR) Desensitization of some receptors with chronic exposure Nicotine does not interact with... Muscarinic acetylcholine receptors

Mechanisms of nicotine action Nicotine stimulates... These are found in... These receptors have been shown in these cell types to...

Nicotine stimulates... All nicotinic acetylcholine receptors These are found in... In the central nervous system In the ganglia of the peripheral nervous system At the neuromuscular junction In the adrenal gland In many epithelial tissues such as bladder, cervical, and lung These receptors have been shown in these cell types to... Elicit cell signaling similar to that found for hormones or growth factors

Parasympathetic and sympathetic neuronal pathways stimulated by nicotine through autonomic ganglia Parasympathtic effects Sympathetic effects Effects at the neuromuscular junction The adrenal gland also has nicotinic cholinergic innervation, functioning like...

Parasympathtic effects Heart, bronchial smooth muscle, GI tract Slow heart rate, contract bronchial muscle, stimulate GI tract Sympathetic effects Blood Vessels, Heart, bronchial smooth muscle, GI tract Constrict blood vessels, stimulate heart rate, relax bronchial smooth muscle, inhibit GI tract Effects at the neuromuscular junction Contract muscle The adrenal gland also has nicotinic cholinergic innervation, functioning like... A post-ganglionic sympathetic nerve to release epinephrine and norepinephrine Nicotine thus stimulates release of these sympathetic neurotransmitters

Other effects of nicotine Prolonged exposure to nicotine results depolarizing block The predominant effects of nicotine also depend on... Depending upon dose, duration of exposure and frequency of use, nicotine can... With chronic use, effects are mainly to... Nicotine stimulation at muscles In other organs, the end result of nicotine administration in the periphery is...

Prolonged exposure to nicotine results depolarizing block Initially, stimulation of transmission Followed by a form of depolarization blockade than can result in inhibition of transmission Similar to cholinergic blockers such as succylcholine The receptors are unable to faciliate ion flow and are inactivated The predominant effects of nicotine also depend on... The dominant autonomic tone Reflexes to the CNS to oppose primary stimulation The frequency and time interval of nicotine absorption Depending upon dose, duration of exposure and frequency of use, nicotine can... Produce just about any positive or negative effect on an organ With chronic use, effects are mainly to... Stimulate the heart and to constrict blood vessels Nicotine stimulation at muscles Initial constriction is followed by stimulation of the cholinergic spinal reflex via the Renshaw cells, which in turn inhibits motoneurons, and relaxes muscle In other organs, the end result of nicotine administration in the periphery is... The balance between parasympathetic and sympathetic stimulation of the peripheral nervous system Determined by dose and by dominance of each type of transmission However, even when parasympathetic responses dominate, they are often overridden by epinephrine and norepinephrine release from the adrenal gland

Tone predominance in organs Arterioles Predominant tone Most common effect of nicotine Veins Predominant tone Most common effect of nicotine Heart Predominant tone Most common effect of nicotine GI tract Predominant tone Most common effect of nicotine

_Arterioles_ Predominant tone: _sympathetic_ Most common effect of nicotine: _vasoconstriction (including coronary arteries), hypertension_ _Veins_ Predominant tone: _sympathetic_ Most common effect of nicotine: i_ncreased venous return, increased cardiac output_ _Heart_ Predominant tone: _parasympathetic_ Most common effect of nicotine: t_achycardia (because adrenal gland overrides tone)_ _GI tract_ Predominant tone: _parasympathetic_ Most common effect of nicotine: _increased motility and secretions (can be overridden by receptor de-sensitization)_

9 Pharmacology 1: Nicotine Flashcards by Heather Acuff

Scope of tobacco and nicotine exposure

Tobacco use in the U.S.
“Low Tar, Low Nicotine” cigarette
Increased smoking because thought to be “safe”…
Chronic use of tobacco products has been associated with the following health risks:

Tobacco use in the U.S.
- 17.3% of females age 16 and over smoke
- 21.5% of males age 16 and over smoke
- 44 million active smokers in the US today, and 52 million ex-smokers
“Low Tar, Low Nicotine” cigarette
- Backfired—induced stronger inhalation and retention of tobacco smoke, to achieve the same nicotine levels
- Greater inhalation and retention of tobacco also resulted in the same tar exposures as older cigarette
Increased smoking because thought to be “safe”…
- Has shifted lung cancer from primarily a disease of the central airways (squamous cell carcinoma) to that of the peripheral airways (adenocarcinoma) because of trapping of tar in smaller airways
- Did not decreased risk of lung cancer or risk of heart disease
Chronic use of tobacco products has been associated with the following health risks:
- Cardiovascular disease (stroke, coronary artery disease, myocardial infarction)
- Chronic obstructive pulmonary disease, emphysema, asthma
- Cancer of lung, head and neck, oral cavity, pancreas, bladder, stomach, and cervix
- Delay healing and recovery after surgery
- Cataracts
- Sexual dysfunction, early menopause
- Osteoporosis
- Lipid abnormalities
- Peridontal disease

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Scope of tobacco and nicotine exposure

Tobacco smoke contains
Cigarette smoke contains…
Harmful compounds are either…
Examples of detrimental compounds (some of which are carcinogens) in tobacco smoke

Tobacco smoke contains
- An estimated 4,800 compounds
- Carcinogens: Mutations in DNA of bronchial epithelium, eventual cancer. Stimulation of P450 enzymes to cause enhanced metabolism of estrogen, can lead to infertility and early menopause
- Carbon Monoxide: Need for increased cardiac output to sustain oxygen levels, chronic effects on blood vessels, leads to heart disease
- Tar and particulates: chronic inflammation in lungs, leads to COPD, bronchitis, and asthma
- Beta-carbolines (harmane, acetaldehyde) inhibit monoamine oxidase, decrease degradation of dopamine, norepinephrine and epinephrine
- Nicotine: Chronic stimulation of cardio-vascular system leads to coronary heart disease and myocardial infarction, blood clots, and stroke
Cigarette smoke contains…
- 11 known human carcinogens
- 7 probable carcinogens
- 49 animal carcinogens that possibly also are carcinogens in humans
Harmful compounds are either…
- Produced during the combustion of tobacco
- Released as free agents because of the heat of combustion
Examples of detrimental compounds (some of which are carcinogens) in tobacco smoke
- Carbon monoxide
- Hydrogen cyanide
- Ammonia
- Nicotine
- Benzene
- Nitrosamines
- Benzo(a)pyrene
- Lead
- Cadmium
- Hexavalent chromium
- Arsenic
- Polonium-210
- Formaldehyde

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Scope of tobacco and nicotine exposure

Health effects are brought about by…
The carcinogen NNK
The metabolite of NNK, NNAL
Nicotine

Health effects are brought about by…
- The genetic damage to the bronchial epithelium caused by the carcinogens
- The long-term effects of stimulation of the cardio-vascular system caused by nicotine
- The long-term effects of carbon monoxide causing reduced oxygen exchange
- The chronic inflammatory responses that are caused by the inhaled smoke and tar that is deposited in the lungs
The carcinogen NNK
- Forms from nicotine (found only in tobacco leaves in nature)
- Spontaneously rearranges to release nitrosamines which are highly active compounds that form DNA adducts
The metabolite of NNK, NNAL
- Can be used to monitor the relative exposure to NNK
- Found in the urine of smokers and people who are exposed to second hand smoke
Nicotine
- The most important constituent from a pharmacologic perspective of the numerous constituents found in tobacco and tobacco smoke
- Composed of a pyridine and pyrrolidine ring
- A natural alkaloid found only in tobacco plants
- A weak base (pKa = 7.9) that turns brown and acquires the characteristic odor of tobacco following exposure to air
- Mimics the effects of acetylcholine at the acetylcholine receptor

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Pharmacokinetics of nicotine:
Absorption

Absorption of nicotine is dependent on…
- Acidic medium
- Alkaline medium
- Physiologic conditions
Acidity and nicotine absorption
- Unaltered cigarette smoke
- Air-cured tobacco
- Smokeless tobacco products and nicotine gum
- Cured cigarette tobacco
- If the pH of the mouth is lowered by drinking acidic beverages

Absorption of nicotine is dependent on pH
- Because nicotine is a weak base, in an acidic medium, nicotine is ionized and poorly absorbed across membranes
- In an alkaline medium, nicotine is non-ionized and well absorbed across membranes
- Under physiologic conditions (pH 7.4 - 7.5), approximately 30% of nicotine is non-ionized and readily crosses cell membranes
Acidity and nicotine absorption
- Unaltered cigarette smoke is acidic, so limited nicotine is absorbed
- Air-cured tobacco (found in pipe tobacco and cigars) produces smoke with an alkaline pH, allowing for increased buccal absorption of nicotine
  - Even pipe or cigar smokes who don’t inhale experience considerable absorption through the buccal mucosa
- Smokeless tobacco products (snuff and chew) and nicotine gum are buffered to an alkaline pH to facilitate absorption of nicotine
- Some tobacco companies have altered the pH of cured cigarette tobacco by spraying it with sodium hydroxide or other bases
  - This was done to enhance nicotine absorption as the nicotine content of cigarettes was lowered in the 1970’s and 1980’s
- If the pH of the mouth is lowered by drinking acidic beverages (e.g., coffee, juice, or cola), absorption of nicotine from nicotine gum is reduced substantially

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Pharmacokinetics of nicotine:
Absorption

Intact skin
GI tract
Small intestine
Lung (droplets)
When tobacco smoke reaches the alveoli, nicotine is rapidly absorbed across respiratory epithelial cells due to the following factors

Intact skin
- Nicotine is readily absorbed across intact skin, allowing for transdermal administration of nicotine as a therapeutic adjunct to tobacco cessation
GI tract
- Conversely, the bioavailability of nicotine in the GI tract is limited
- Absorption is poor across gastric mucosa because of a low gastric pH
Small intestine
- The absorption of nicotine in the small intestine is better due to increased pH, but the systemic bioavailability is low (30%) because it undergoes significant first-pass metabolism
Lung (droplets)
- Nicotine is “distilled” from burning tobacco and carried in droplets to the small airways of the lung
- The droplets are composed of water, tar, and alkaloids, including nicotine
When tobacco smoke reaches the alveoli, nicotine is rapidly absorbed across respiratory epithelial cells due to the following factors
- pH of the lung is 7.4, allowing for a larger fraction of non-ionized nicotine
- Alveolar surface area of the lung is large
- Capillary system in the lung is extensive
- Results in extremely high, transient blood levels of nicotine with each inhalation

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Pharmacokinetics of nicotine:
Distribution

Inhalation of tobacco smoke is an effective means of…
After inhalation, non-charged nicotine…
Blood nicotine concentrations immediately…
Via this route nicotine is rapidly delivered to…
This results in…
Spiking of nicotine levels during each inhalation contributes to…
Inhalation of cigarettes vs. buccal absorption from cigars and pipes
- Serum levels of nicotine
- Euphoric effect

Inhalation of tobacco smoke is an effective means of…
- Delivering nicotine to the central nervous system
After inhalation, non-charged nicotine…
- Is rapidly absorbed across pulmonary epithelium and enters the circulation
Blood nicotine concentrations immediately…
- Rise as high as 1 μM
Via this route nicotine is rapidly delivered to…
- The brain, where as a non-charged small molecule it readily crosses the blood-brain barrier
This results in…
- Transient exposure of the brain to high levels of nicotine
Spiking of nicotine levels during each inhalation contributes to…
- Propensity for addiction, as pleasurable sensations are elicited and then decline repeatedly
Inhalation of cigarettes vs. buccal absorption from cigars and pipes
- Serum levels of nicotine
  - Serum levels of nicotine are higher and less prolonged with inhalation of cigarettes than with buccal absorption from cigars and pipes, which does not result is as great “on and off” switching of mood alteration
- Euphoric effect
  - There is a lower euphoric effect from buccal absorption, hence a lessened decline in euphoria and lowered potential for craving and addiction

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Pharmacokinetics of nicotine:
Metabolism and excretion

Nicotine metabolism
Cotinine
- Metabolism
- Effects
Biologic activities of cotinine vs. nicotine
The half-life of nicotine in the body
What underlies tobacco users’ need for repeated administration of nicotine to prevent withdrawal symptoms
Nicotine levels during the day and night
The half-life of cotinine
Cotinine can be used as a more reliable marker of…
Nicotine excretion

Nicotine metabolism
- Extensively metabolized in the liver and to a lesser extent in the kidney and lung
Cotinine
- ~70-80% of nicotine is metabolized to cotinine, the major metabolite
- Effects of cotinine are probably also induced through interaction
  with neuronal acetylcholine receptors, for which it has a low affinity
Biologic activities of cotinine vs. nicotine
- Although cotinine has largely been believed to be inactive, some studies suggest it may have some biologic activities, such as protecting against Alzheimer’s disease and enhancing memory
- These are shared with nicotine, but cotinine is not addictive and is not associated with cardiovascular disease
The half-life of nicotine in the body
- ~2 hours
What underlies tobacco users’ need for repeated administration of nicotine to prevent withdrawal symptoms
- Metabolism to cotinine and subsequent glucuronidation and excretion in urine
Nicotine levels during the day and night
- With regular tobacco use, significant nicotine levels accumulate during waking hours, then decline during sleep
The half-life of cotinine
- ~18-20 hours
Cotinine can be used as a more reliable marker of…
- Tobacco use and exposure to second hand smoke
Nicotine excretion
- Nicotine and its metabolites are excreted in the urine

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Pharmacodynamics of nicotine: interaction with nicotine acetylcholine receptors

Nicotine is a potent agonist that affects numerous organ systems, including…
Following absorption, nicotine…
What causes a variety of stimulant and, to a lesser extent, sedative effects
Nicotine does not interact with…

Nicotine is a potent agonist that affects numerous organ systems, including…
- The cardiovascular, adrenal, neurologic, and musculoskeletal systems
Following absorption, nicotine…
- Binds to nicotinic acetylcholine receptors in the brain, the autonomic ganglia, and in other organs such as the adrenal gland
- Mimics the effect of acetylcholine
What causes a variety of stimulant and, to a lesser extent, sedative effects
- The combination of effects on the different nicotinic acetylcholine receptors (nAchR)
- Desensitization of some receptors with chronic exposure
Nicotine does not interact with…
- Muscarinic acetylcholine receptors

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Nicotine achetylcholine receptors (NAchR)

nAchRs
nAchR permeability
- At the neuromuscular junction
- In the central nervous system and the ganglia
This allows…
The alpha subunits contain…

nAchRs
- Act as ion channels
- Increase permeability to sodium and calcium ions
nAchR permeability
- At the neuromuscular junction
  - Sodium
- In the central nervous system and the ganglia
  - Calcium
This allows…
- Depolarization of neurons
- Propagation of ion currents
The alpha subunits contain…
- The acetylcholine (and nicotine) binding sites

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Mechanisms of nicotine action

Nicotine stimulates…
These are found in…
These receptors have been shown in these cell types to…

Nicotine stimulates…
- All nicotinic acetylcholine receptors
These are found in…
- In the central nervous system
- In the ganglia of the peripheral nervous system
- At the neuromuscular junction
- In the adrenal gland
- In many epithelial tissues such as bladder, cervical, and lung
These receptors have been shown in these cell types to…
- Elicit cell signaling similar to that found for hormones or growth factors

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Parasympathetic and sympathetic neuronal pathways stimulated by nicotine through autonomic ganglia

Parasympathtic effects
Sympathetic effects
Effects at the neuromuscular junction
The adrenal gland also has nicotinic cholinergic innervation, functioning like…

Parasympathtic effects
- Heart, bronchial smooth muscle, GI tract
- Slow heart rate, contract bronchial muscle, stimulate GI tract
Sympathetic effects
- Blood Vessels, Heart, bronchial smooth muscle, GI tract
- Constrict blood vessels, stimulate heart rate, relax bronchial smooth muscle, inhibit GI tract
Effects at the neuromuscular junction
- Contract muscle
The adrenal gland also has nicotinic cholinergic innervation, functioning like…
- A post-ganglionic sympathetic nerve to release epinephrine and norepinephrine
- Nicotine thus stimulates release of these sympathetic neurotransmitters

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Other effects of nicotine

Prolonged exposure to nicotine results depolarizing block
The predominant effects of nicotine also depend on…
Depending upon dose, duration of exposure and frequency of use, nicotine can…
With chronic use, effects are mainly to…
Nicotine stimulation at muscles
In other organs, the end result of nicotine administration in the periphery is…

Prolonged exposure to nicotine results depolarizing block
- Initially, stimulation of transmission
- Followed by a form of depolarization blockade than can result in inhibition of transmission
  - Similar to cholinergic blockers such as succylcholine
- The receptors are unable to faciliate ion flow and are inactivated
The predominant effects of nicotine also depend on…
- The dominant autonomic tone
- Reflexes to the CNS to oppose primary stimulation
- The frequency and time interval of nicotine absorption
Depending upon dose, duration of exposure and frequency of use, nicotine can…
- Produce just about any positive or negative effect on an organ
With chronic use, effects are mainly to…
- Stimulate the heart and to constrict blood vessels
Nicotine stimulation at muscles
- Initial constriction is followed by stimulation of the cholinergic spinal reflex via the Renshaw cells, which in turn inhibits motoneurons, and relaxes muscle
In other organs, the end result of nicotine administration in the periphery is…
- The balance between parasympathetic and sympathetic stimulation of the peripheral nervous system
- Determined by dose and by dominance of each type of transmission
- However, even when parasympathetic responses dominate, they are often overridden by epinephrine and norepinephrine release from the adrenal gland

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Tone predominance in organs

Arterioles
- Predominant tone
- Most common effect of nicotine
Veins
- Predominant tone
- Most common effect of nicotine
Heart
- Predominant tone
- Most common effect of nicotine
GI tract
- Predominant tone
- Most common effect of nicotine

Arterioles
- Predominant tone: sympathetic
- Most common effect of nicotine: vasoconstriction (including coronary arteries), hypertension
Veins
- Predominant tone: sympathetic
- Most common effect of nicotine: i_ncreased venous return, increased cardiac output_
Heart
- Predominant tone: parasympathetic
- Most common effect of nicotine: t_achycardia (because adrenal gland overrides tone)_
GI tract
- Predominant tone: parasympathetic
- Most common effect of nicotine: increased motility and secretions (can be overridden by receptor de-sensitization)

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CNS actions of nicotine

Frequency of pre- vs. post-synaptic nAchR neurons in the CNS
Main CNS effects of nicotine
Effects of calcium influx
Acetylcholine in the CNS

Frequency of pre- vs. post-synaptic nAchR neurons in the CNS
- Pre-synaptic nAchR neurons are common
- Post-synaptic nAchR neurons are rare in CNS
Main CNS effects of nicotine
- Activate pre-synaptic nAchR
- Mimic presynaptic release of acetylcholine
- Cause release of other neurotransmitters which act on their post-synaptic receptors
Effects of calcium influx
- Depolarize cell
- Cause release of glutamate which acts on post-synaptic gluamate receptors
Acetylcholine in the CNS
- Occurs as a neurotransmitter in many parts of the CNS
- Some particularly important cholinergic neurons are found…
  - In the basal forebrain (the ones that degenerate in Alzheimers disease)
  - In the septohippocampal pathway
  - Within the striatum where they control movement
- Many of the effects of cholinergic transmission are mediated by muscarinic receptors

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What nicotine does in the brain

Central vs. peripheral effects
Nicotine can produce…
The hippocampus
The effects of nicotine that enhances self-administration is likely to be mediated by…

Central vs. peripheral effects
- Nicotine produces a number of effects that may be mediated centrally
- These are typically hard to distinguish because of additional effects on the periphery at the level of autonomic ganglia
Nicotine can produce…
- Tremors and convulsions
- Acentrally mediated emetic effect
- A stimulation of respiration
The hippocampus
- Rich in cholinergic innervation and nicotinic receptors
- May be the site at which nicotine improves learning and memory, information processing and attention
The effects of nicotine that enhances self-administration is likely to be mediated by…
- The mesolimbic dopaminergic system

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Where nicotine works in the brain

Central vs. peripheral actions of nicotine
Central nicotinic receptors are permeable to…
Nicotine vs. glutamatergic transmission in the hippocampus
Nicotine vs. dopamine release
Neurotransmitters released by nicotine (most likely via pre-synaptic innervation)
Dopaminergic and cholinergic neurons co-localize in…

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Central vs. peripheral actions of nicotine
- There is rather little evidence for fast excitatory (Na-mediated) neurotransmission in the mammalian brain, so it is likely that the central actions of nicotine are distinct from those found in the periphery
Central nicotinic receptors are permeable to…
- Ca2+
Nicotine vs. glutamatergic transmission in the hippocampus
- Nicotine, at concentrations that are found following cigarette smoking, enhances glutamatergic transmission in the hippocampus
- This is associated with an increase in pre-synaptic Ca2+ concentrations which facilitate neurotransmitter release
Nicotine vs. dopamine release
- Similarly , a nicotine mediated increase in dopamine release is thought to account for some of the rewarding effects of smoking
**Neurotransmitters released by nicotine (most likely via pre-synaptic innervation) **
- Glutamate, GABA, dopamine, acetylcholine, serotonin, and beta-endorphin
Dopaminergic and cholinergic neurons co-localize in…
- Brain tissue

Behavioral effects of nicotine on the central nervous system

Behavioral effects of nicotine on the central nervous system
These effects may be mediated selectively by different nuerotransmitters, which have been associated with the following effects

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Behavioral effects of nicotine on the central nervous system
- Pleasure
- Increased ability to concentrate
- Arousal
- Improved task performance
- Anxiety relief
- Appetite suppression
- Increased metabolic rate
These effects may be mediated selectively by different nuerotransmitters, which have been associated with the following effects
- Dopamine: pleasure, reward
- Norepinephrine: arousal, appetite suppression
- Glutamate: learning, memory enhancement
- Serotonin: mood modulation, appetite suppression
- Beta-Endorphin: reduction of anxiety and tension, pleasure
- GABA: reduction of anxiety and tension

A receptor based mechanism for addiction to nicotine

Addictive behavior is established by…
The desire for pleasurable effects of many addictive substance are enhanced by…
Incentives for drug-taking

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Addictive behavior is established by…
- The repeated need to self-administer pleasurable stimuli
The desire for pleasurable effects of many addictive substance are enhanced by…
- The need to aviod unpleasant effects that occur when drug concentrations cycle between high and low levels, according to the rate of self administration
Incentives for drug-taking
- Aoiding a withdrawal reaction
- Delivering a stimulus

Cholinergic block in the brain with chronic nicotine exposure

What accounts for behavior patterns in smokers in the case of nicotine abuse
During smoking, acute higher doses of nicotine…
Following this period, nicotine concentrations…
These sustained lower levels then shift receptors into…
In the inactivated state,…
Prolonged receptor desensitization then results in…
The receptors that mediate the reward effects in the mesolimbic system…

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What accounts for behavior patterns in smokers in the case of nicotine abuse
- Changes in receptor sensitivity
During smoking, acute higher doses of nicotine…
- Activate the reward pathways that provide pleasure
Following this period, nicotine concentrations…
- Are sustained at lower levels because of a half life for nicotine of about 2hr
These sustained lower levels then shift receptors into…
- A desensitized state
  - Because the desensitized state has a higher agonist affinity, which can maintain drug binding in presence of lower drug concentrations
- Possibly also a long-term inactivated state
In the inactivated state,…
- Receptors can still bind agoinst
- Binding does not result in ion flow
Prolonged receptor desensitization then results in…
- A compensatory up-regulation of receptor number, to restore sensitivity to the endogenous system
- Observed effects of the first cigarette of the day being the most enjoyable
The receptors that mediate the reward effects in the mesolimbic system…
- Are fully sensitive through lack of desensitization
- Produce the greatest reward

Nicotine addiction and treatment

Mechanism of nicotine dependence as a chronic condition
Chronic administration leads to…
After overnight abstinence from smoking, tobacco users…
When tobacco users abruptly discontinue nicotine, they…
Health benefits
- Two weeks to three months after quitting smoking
- One to nine months later
- After five to fifteen years
- Fifteen years after quitting
- Even after 30 years of quitting

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Mechanism of nicotine dependence as a chronic condition
- Nicotine stimulates the release of brain neurotransmitters, including dopamine, which activates the dopamine reward pathway
- This induces pleasurable feelings, which are reinforced upon repeated administration
Chronic administration leads to…
- Tolerance of the effects over the course of the day
After overnight abstinence from smoking, tobacco users…
- Regain sensitivity to the effects of nicotine
When tobacco users abruptly discontinue nicotine, they…
- Experience symptoms of withdrawal
- These withdrawal symptoms serve as a powerful stimulus to repeat nicotine administration
Health benefits
- Two weeks to three months after quitting smoking
  - Improvements in circulation
  - Improved ambulation
  - Increased lung capacity up to 30%
- One to nine months later
  - Lung ciliary function is restored
  - Coughing, sinus congestion, fatigue, and shortness of breath decrease
  - Excess risk of coronary heart disease over the next 10 years is decreased to half that of a smoker after quitting for 1 year
  - Lung cancer risk remains unchanged
- After five to fifteen years
  - Stroke risk is reduced to a rate similar to that of people who have never smoked
- Fifteen years after quitting
  - An individual’s risk of coronary heart disease is reduced to a rate that is similar to that of people who have never smoked
- Even after 30 years of quitting
  - Lung cancer risk remains about 2-3 times that of a never smoker

Nicotine withdrawal

When nicotine is abruptly discontinued, the following symptoms develop
Timing ofithdrawal symptoms
To alleviate the symptoms of withdrawal, smokers…
Most dependent smokers…

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When nicotine is abruptly discontinued, the following symptoms develop
- Anger/irritability, anxiety, cravings, difficulty concentrating, hunger/weight gain, impatience, restlessness, drowsiness, fatigue, impaired task performance, nervousness, sleep disturbances
- Tobacco users usually experience a strong desire or craving for tobacco
Timing ofithdrawal symptoms
- Symptoms peak 24-48 hours after cessation and gradually dissipate over the next 2-4 weeks.
- Strong cravings for tobacco may persist for months to years following cessation
To alleviate the symptoms of withdrawal, smokers…
- Re-dose themselves throughout the day
- After smoking the first cigarette of the day, the smoker experiences marked pharmacologic effects, particularly arousal
- No other cigarette throughout the day produces the same degree of pleasure
- Shortly after this first cigarette, tolerance begins to develop
- Accordingly, the threshold levels for both pleasure/arousal and abstinence rise progressively throughout the day as the smoker becomes tolerant to effects of nicotine
- With continued smoking, nicotine accumulates, leading to an even greater degree of tolerance
- Cessation of smoking overnight allows resensitization of drug responses
Most dependent smokers…
- Will smoke a certain number of cigarettes per day (usually more than 10)
- Tend to consume 10-40mg of nicotine per day to achieve the desired effects of cigarette smoking and minimize the symptoms of nicotine withdrawal

Nicotine addictiveness

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By most measures, nicotine is equally as addictive as cocaine
Nicotine users show a 90% proportion of addicted users compared to casual users, higher than any other recreational drug
Nicotine is also a legal and relatively cheap product that is universally available
This increases the impact of nicotine addiction, so that despite its lower level of intoxication and reinforcement compared to other recreational drugs, it is considered the most addictive substance

Fagerstrom test for nicotine dependence

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How many cigarettes do you smoke daily?
a. 10 or less 0 points
b. 11-20 1 point
c. 21-30 2 points
d. 31 or more 3 points
1. If you had to give up one cigarette, which one would be the most difficult to give up?
  a. The first on in the morning 1 point
  b. Any other 0 points
1. How soon after arising in the morning do you smoke the first cigarette of the day?
  a. Within 5 minutes 3 points
  b. 6-30 minutes 2 points
  c. 31-60 minutes 1 point
  d. After 60 minutes 0 points
1. Do you find it difficult to refrain from smoking in places where it is forbidden?
  a. Yes 1 point
  b. No 0 points
1. Do you smoke even when you are so ill that you are in bed most of the day?
  a. Yes 1 point
  b. No 0 points
1. Do you smoke more frequently during the first few hours of each day than the rest of the day?
  a. Yes 1 point
  b. No 0 points
6-10 points highly addicted
4 or 5 points moderately addicted

Genetic susceptibility to nicotine addiction

Variations in the dopamine pathway that may contribute to susceptibility to addiction
SLC6A3
DRD2-A2 allele
DRD4-S allele
Alleles with higher biological activity of dopamine show…
Alleles with lower dopamine activity…
Co-inheritance

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Variations in the dopamine pathway that may contribute to susceptibility to addiction
- Dopamine transporter gene (SLC6A3)
- Dopamine receptor genes (DRD2 and DRD4) involved.
SLC6A3
- Encodes a dopamine reuptake transporter 9-repeat allele
- Shows diminished dopamine reuptake compared to other alleles due to decreased protein expression (more dopamine remains in synapse)
DRD2-A2 allele
- Shows higher density of dopamine receptors (more dopamine signaling)
- Shows lower level for rewarding value of food, less likely to gain weight after smoking cessation
DRD4-S allele
- Shows increased dopamine affinity (heightened overall response to dopamine)
Alleles with higher biological activity of dopamine show…
- Reduced smoking rates
- Reduced probability of nicotine dependence
Alleles with lower dopamine activity…
- Are more likely to be nicotine dependent
- Have decreased ability to respond to smoking cessation aids
Co-inheritance
- Interaction between the SLC6A3 9 allele and DRD2-A2 allele
- Co-inheritance showed 2.6-fold lower probability of being a smoker

Smoking cessation * Two basic methods for quitting * All patients attempting to quit should be encouraged to use... * Two general classes of FDA-approved drugs for cessation, both considered first-line pharmacotherapies * The rationale for using NRT in tobacco cessation * The success rates of smoking cessation

* **Two basic methods for quitting** * **Non-pharmacologic methods** * **Primarily involve counseling and behavioral therapies** * **Alone are rarely successful and even successful attempts are usually not permanent** * **Pharmacologic methods** * **The use of both methods simultaneously has the best response rate** * All patients attempting to quit should be encouraged to use... * Effective pharmacotherapies for smoking cessation except in the presence of special circumstances * **Two general classes of FDA-approved drugs for cessation, both considered first-line pharmacotherapies** * **1. Nicotine replacement therapy (NRT)** * **2. Psychotropics** * The rationale for using NRT in tobacco cessation * NRT reduces physical withdrawal symptoms associated with nicotine cessation * NRT allows the patient to focus on behavioral and psychological aspects of tobacco cessation * The success rates of smoking cessation * Significantly improve with the use of NRT * **All products (gum, patch, inhaler, and nasal spray) resulted in significantly improved abstinence rates when compared to placebo** * Patients using NRT are 1.5-2 times more likely to successfully quit smoking than are those receiving placebos * Majority of patients need... * \> 1 quit attempt, relapse within the first 6-12 months

Nicotine replacement therapy * Currently available formulations of NRT * Patients should discontinue... * Symptoms of nicotine toxicity * NRT should be used with caution in the following cardiovascular patient groups * Other conditions where NRT should be used with caution

* Currently available formulations of NRT * Over-the-counter products (nicotine gum, lozenges and transdermal patches) * Prescription medications (nicotine nasal spray and inhaler) * **Patients should discontinue...** * **Tobacco when using these products to reduce the likelihood of nicotine-related adverse effects** * Symptoms of nicotine toxicity * Headache, nausea and vomiting, abdominal pain, diarrhea, drooling, dizziness, blurred vision, tremor, cold sweats, hypotension, and, in severe cases, respiratory depression * NRT should be used with caution in the following cardiovascular patient groups * Those immediately following post-myocardial infarction (within 2 weeks) * Those with serious arrhythmias * Those with serious or worsening angina pectoris * In general the risks of NRT in patients with cardiovascular disease are small relative the risks of continued tobacco use * Other conditions where NRT should be used with caution * Active temporomandibular joint (TMJ) disease (gum only) * Pregnancy * Lactation

Nicotine replacement therapy * Nicotine gum * Nicotine patch * Use in heart disease * High dose patches * Nicotine inhaler (prescription) * Nicotine nasal spray (prescription)

* Nicotine gum * 2 and 4 mg strengths, initially 10 to 15 pieces per day, taper to 5-8 pieces * Can be used for up to 5 years * Must be chewed intermittently, parked in the buccal area for primary buccal absorption * Nausea or dyspepsia can result in nicotine is swallowed in saliva * Can delay weight gain associated with smoking cessation * Nicotine patch * 21 mg (Fagerstrőm score of 5 or over) for initial dose * 14 mg (Fagerstrőm score of 3 or 4) for initial dose * 7 mg (Fagerstrőm score of 2 or less) for initial dose * Use in heart disease * Not contraindicated, as long as no concomittent smoking * Any additional smoking can cause nicotine toxicity * Total use of patches, tapered, should be no more than 12 weeks * High dose patches * Safe and probably also more efficacious * Nicotine inhaler (prescription) * Oral cavity and GI absorption, does not usually reach lungs * Four inhalers per day achieves adequate nicotine levels initially, taper gradually, use for no more than 12 weeks * Each inhaler contains 500 puffs * Puffing on inhaler is more frequent than smoking, but can substitute for the physical presence of a cigarette * Nicotine nasal spray (prescription) * 4 sprays per hour, maximum 80 sprays per day, taper, use no more than 12 weeks * Delivery of nicotine better than inhaler but more cumbersome

``` Psychotropic drugs: Bupropion SIR (Zyban) ``` * Bupropion * Continuous abstinence rates at 12 months * Mechanism of action * Smokers with the combined DRD2-A2 allele and the SLC6A3-9 (which also protect against nicotine addiction) showed...

* Bupropion * **An antidepressant medication used as a non-nicotine aid to smoking cessation** * The use of bupropion sustained release tablets doubles the long-term abstinence rate when compared to placebo * Combined use with NRT is the most effective * Six-month abstinence rates of 18- 27% reported for bupropion plus NRT, compared to 7-16% for placebo plus NRT * Bupropion use is also associated with less weight gain during smoking cessation * Continuous abstinence rates at 12 months * Both \> Bupropion alone \> NRT alone \> Placebo * Rates were achieved with counseling and support services * Mechanism of action * **An “atypical” anti-depressant** * **Inhibits re-uptake of norepinephrine, serotonin, and dopamine, but does not appear to directly affect transporters** * **Reduces urge to smoke by making neurotransmitters more available** * **A nicotinic cholinergic antagonist that may reduce the rewarding effects of smoking** * Smokers with the combined DRD2-A2 allele and the SLC6A3-9 (which also protect against nicotine addiction) showed... * A 2.5-fold greater chance for prolonged abstinence after smoking cessation using bupropion than smokers who are not carriers of these alleles

Psychotropic drugs: Treatment with Bupropion * General dosing and administration * Side effects * Bupropion is contraindicated in patients... * Bupropion is classified as pregnancy category B, meaning...

* General dosing and administration * Half-life of over 20 hrs * Takes 5 days to reach steady-state blood levels * Dosing should begin before smoking cessation * Motivational support should be offered * Best is weekly individual follow-up consultations with a behavioral specialist. * Initial dose 150 mg per day for 3 days, followed by 150 mg twice daily * Quit date should be 1-2 weeks after therapy is initiated * Continue 8-12 weeks after smoking is ended * Side effects * Dry mouth and sleep disturbance * Severe depression and suicidal thoughts (black box warning) * Bupropion is contraindicated in patients... * With a seizure disorder * With anorexia or bulimia nervosa * Treated with MAO inhibitors * Undergoing abrupt discontinuation of alcohol or sedatives * Bupropion is classified as pregnancy category B, meaning... * No adverse effect on the fetus * Bupropion may be used during pregnancy only if clearly indicated.

``` Psychotropic drugs: Varenicline tartratre (Chantix) ``` * Mechanism of action * Efficacy * Major side effect * Other side effects

* Mechanism of action * Inhibits effects of nicotine on pre-synaptic neurons that control release of dopamine, endorphins, and other neurotransmitters * A selective α4β2 (neuronal) nicotinic receptor partial agonist * Has affinity for the receptor but reduced efficacy * Cannot elicit the maximum pharmacological effect, even at high concentrations * Blunts receptor function and also acts as an antagonist of other molecules, such as nicotine or acetylcholine,that could elicit a full response * By inhibiting nicotine action it may block the reinforcing effects of smoking and could both aid in reducing smoking prior to starting the quit attempt and blunt rewarding effects of renewed smoking * Efficacy * Sgnificantly reduced urge to smoke and reduced psychological reward of smoking * Increasing quite rates as treatment time increased * Could be used over a longer period, or repeatedly in different quit attempts when there is relapse * It’s efficacy could be due to weak agonist effects that diminish craving and withdrawal combined with it’s ability to reduce reward of smoking, since it is a nicotine antagonist * Major side effect * Nausea (either centrally or locally mediated) * Nausea is lessened by giving varenicline as a divided dose, twice per day * Other side effects * Insomnia * Headache

Psychotropic drugs: NicVAX

* Nicotine conjugated to a carrier protein elicits an immune response in the bloodstream * These antibodies then bind nicotine and keep it from crossing the BBB * Although vaccination may not completely eliminate smoking, vaccination has greatly reduced cigarette use

E-Cigarettes * Mechanism of action * FDA * Use * Cardiovascular risks

* Mechanism of action * **Release nicotine in a warm vapor without burning** * **There is no tar, so no hydrocarbon carcinogens, no carbon monoxide, and no volatile carcinogens** * **Deliver 10% of the nicotine level** * **Reduce the number of cigarettes smoked per day** * Not regulated by the FDA * Currently used by 2.5 million Americans, primarily for nicotine dosing when smoking is not possible * Cardiovascular risks should be lower than smoking because of the reduced nicotine delivery

Nicotine in psychiatric disorders

* Individuals diagnosed with psychiatric illnesses are much more likely to smoke than the general population and have more difficulty quitting * Nicotine may be form of “self-medication” that attenuates symptoms of schizophrenia, bipolar disorder, and depression, due to its ability to... * Release neurotransmitters in the CNS * Overcome deficits in acetylcholine signaling associated with these illnesses * Treatment of psychiatric disorders may be enhanced by combining it with nicotine replacement therapy and psychotropic drugs that attenuate smoking * Nicotine may protect against Parkinson’s disease due to enhanced dopamine release

9 Pharmacology 1: Nicotine Flashcards

(33 cards)