9 Pharmacology 1: Nicotine Flashcards
1
Q
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:
A
- 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
2
Q
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
A
- 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
3
Q
Scope of tobacco and nicotine exposure
- Health effects are brought about by…
- The carcinogen NNK
- The metabolite of NNK, NNAL
- Nicotine
A
- 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
4
Q
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
A
-
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
5
Q
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
A
- 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
6
Q
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
A
- 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
- Serum levels of nicotine
7
Q
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
A
- 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
8
Q
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…
A
- 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
9
Q
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…
A
- 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
- At the neuromuscular junction
- This allows…
- Depolarization of neurons
- Propagation of ion currents
- The alpha subunits contain…
- The acetylcholine (and nicotine) binding sites
10
Q
Mechanisms of nicotine action
- Nicotine stimulates…
- These are found in…
- These receptors have been shown in these cell types to…
A
- 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
11
Q
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…
A
- 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
12
Q
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…
A
-
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
13
Q
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
A
-
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)
14
Q
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
A
- 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
15
Q
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…
A
- 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