Tuesday April 24

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Tuesday April 24 Nicotine and smoking
continued Then Alzheimers Disease and Its
Treatment
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• 8. Distribution of nicotine in body tissues
• Rapid uptake into brain, 8-10 sec after
  inhalation
• Smokers have 10-50 ng/ml of nicotine in blood
• Little binding to plasma proteins
• Low affinity for fat
• Deposits in lungs, brain, spleen, liver
• Freely crosses the placenta found in amniotic
  fluid and umbilical cord blood

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• 9. Metabolism
• Metabolized mostly in liver (90) some in lungs
  (10)
• One metabolite, cotinine, is an important marker
• Metabolism is faster in smokers
• Less likely to get addicted to nicotine if person
  has a genetic variant that decreases the function
  of enzyme, CYP2A6, and slows the breakdown of
  nicotine (drug dev to produce an inhibitor of
  enzyme)

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• 9. Metabolism
• About 70 of nicotine is extracted from blood
  each time it passes through liver
• 10 of elimination is in urine
• Half-life about 2 hours
• During day, repeated smoking causes accumulation
  which plateaus around 400 PM
• Due to accumulation, can maintain levels for 6-8
  hours after cessation (through the night)
• In heavy smokers, levels are persistent for 24
  hrs/day

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• 10. Pharmacodynamics acute actions of nicotine
• Nicotine is an agonist at Ach nicotinic receptors
  of brain and body
• Stimulates the adrenal glands to release
  epinephrine
• Epinephrine causes a sudden increase in glucose,
  blood pressure, respiration and heart rate
• Suppresses insulin release (smokers always have a
  little too much glucose in blood not enough
  insulin to absorb fully)
• Increased blood flow to muscles decreased to
  hands and feet (cold)
• Increases norepinephrine and dopamine release
  (presynaptic nicotinic receptors on NE and DA
  neurons)
• Increases release of serotonin
• --------------------------------------------------
  -----------------------Another alkaloid causes
  reduction in MAO activity (dopamine and
  norepinephrine not broken down as much)

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• 11. Acute effects on novice
• Alerting pattern in EEG (very high dose will
  cause convulsions)
• Facilitates memory and attention
• Reduces aggression
• Hand tremor
• Decreased tone in some skeletal muscles (feedback
  inhibition)
• Nausea/vomiting diarrhea may occur dizziness
• Appetite suppression
• Increased energy expenditure increased fatty
  acids in blood (high cholesterol and
  triglycerides)
• Increased heart rate blood flow to muscles
  (cardiac risks)
• Increased clotting tendency (clogged arteries)
• Stimulates then inhibits lung and salivary
  secretions (the morning cough)

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• 12. Chronic Effects and Tolerance
• Cardiovascular effects
• very rapid tolerance to effects on blood
  pressure and heart rate (even after 1 cigarette,
  second of day does not change HR in smokers)
  exceed normal intakes though and HR effects occur
• after 24 hrs abstinence, some HR tolerance lost
• after 7 days, effects even stronger
• pretreat animals with nicotine 1 hr before a
  lethal dose, changes LD50. Max effect is 5 min
  after pretreatment

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• 12. Chronic Effects and Tolerance
• Nausea and vomiting
• develops over about an 8 hour period
• not complete- nausea occurs if smoking is
  increased by 50
• GI tract stimulation
• modest tolerance still get GI tract stimulation
  in range of normal use (higher level required for
  diarrhea)
• Other physical effects
• no tolerance for blood flow effects
• no tolerance for skin temperature effects

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• 12. Chronic Effects and Tolerance
• CNS Effects
• established after 4 days of regular use - hooked
• in regular smokers, further tolerance develops
  during daily course of smoking
• some tolerance is lost overnight smokers report
  that the first cigarette of the day is the best
• CNS effects show tolerance via down regulation
  of nicotinic receptor numbers or thresholds
  higher dose needed

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• 12. Chronic Effects and Tolerance
• CNS Effects
• CNS effects show tolerance via down regulation
  of nicotinic receptor numbers or thresholds
  higher dose needed
• also increased nicotine metabolism
• higher dose needed to stimulate dopamine release
• of greatest importance appears to be a
  particular type of nicotinic receptor that
  contains the B(beta)2 subunit
• additives that influence smell and flavor get
  conditioned to nicotine effects important cues
  and important reason for brand loyalty

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• 13. Withdrawal
• within 4 hours of deprivation, symptoms begin
• feelings of stress, anger, irritability
• impaired attention and cognitive performance
• smoking alleviates symptoms
• --------------------------------------------------
  ---------------
• less than 7 of those who try to quit are
  successful for more than 1 year
• harder for women to quit than men
• harder for African-Americans than whites
• may be due to a metabolic difference and/or to
  differential effects of other alkaloids in
  tobacco
• Adolescent smokers experience more severe
  withdrawal symptoms upon smoking cessation than
  do adults - despite daily smoking for only a
  short period or with low levels of consumption

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13. Withdrawal Time course 1st 2 weeks (symptoms
peak at 1-4 days) Increased stress and
anxiety Increased negative mood irritability
hostility Mild, but reliable impairment in
attention and cognitive performance Increase in
eating (upon quitting, average person gains 6-9
lb, but timeframe not stated) Restlessness Decreas
ed heart rate
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13. Withdrawal Time course 1st 2 weeks (symptoms
peak at 1-4 days) Weeks 3-4 Anxiety and
irritability lessens Craving continues, but
lessens Increased appetite continues (may last
for 6 months) 6 months 50 report having had a
desire for a cigarette within the last 24 hours
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• 14. General health risks among smokers
• smoking increases cardiovascular and
  cerebrovascular risks in women taking oral
  contraceptives (esp. if over 30 yrs of age)
• women have earlier menopause
• from tars, lung cancer, emphysema, bronchial
  disorders
• carbon monoxide contributes to cardiovascular
  disease
• second hand smoke, increased respiratory illness
  and lung cancer
• smoking during pregnancy increased rates of
  miscarriage, stillbirth, prematurity, low birth
  rate possibly learning disabilities inc
  childhood adiposity (programmed to hold onto fat
  due to early underweight)

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• 15. Treatments for smoking and nicotine addiction
• Nicotine Replacement gum transdermal patch
  nasal spray and inhalers
• Zyban bupropion hydrochloride antidepressant
  and anticraving agent (as antidepressant,
  marketed as Wellbutrin)
• - inhibits dopamine reuptake
• C. Vaccine under development interferes with
  nicotine reaching the brain
• 16. Active research on use of nicotine and other
  nicotinic receptor agonists for treatment of
  multiple diseases

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From Gotti, Zoli, and Clementi, 2006. Trends in
Pharmacological Sciences, 27(9), 482-491.
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• Back to drugs that act via Acetylcholine system
• A. Relevant Drugs - muscarinic
• 1. Muscarinic Cholinergic Receptor Agonists
• 2. Anticholinergic drugs that block muscarinic
  receptors
• B. Relevant Drugs Selective at Nicotinic
  Receptor
• C. Non-selective agents
• Anticholinesterase agents prevent breakdown of
  acetylcholine by acetylcholinesterase. ACh
  accumulates and causes excess action.
• a. Drugs used to treat Myasthenia Gravis
  (Neostigmine, Pyridostigmine, Ambenonium)
• b. Alzheimers Disease (Tacrine)

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Relevant Drugs - NonSelective

• Anticholinesterase agents.
• c. Organophosphate Insecticides parathion,
  carbaryl, malathion, Baygon
• d. Chemical warfare agents nerve gases
  Tabun, Sarin(GB), DFP
• For insecticides and warfare agents, too much
• acetylcholine
• choking sensation blurred vision
• tearing and sweating slow HR
• pupil constriction low blood pressure
• muscle contractions convulsions death

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• Relevant Drugs - NonSelective
• 2. Inhibitors of Acetylcholine Release
• a. Botulinum Toxin
• High amounts cause Botulism (food poisoning)
  bacteria release a toxin that inhibits release of
  Ach at neuromuscular junction in skeletal muscle
  and lungs
• Paralysis of muscles
• Death by respiratory failure

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• From CDC webpage
• Foodborne botulism - symptoms begin within 6
  hours to 2 weeks (most commonly between 12 and 36
  hours) after eating food that contains the toxin.
  
• Symptoms double vision, blurred vision, drooping
  eyelids, slurred speech, difficulty swallowing,
  dry mouth, and muscle weakness that moves down
  the body, always affecting the shoulders first,
  then the upper arms, lower arms, thighs, calves,
  etc. Paralysis of breathing muscles can cause a
  person to stop breathing and die, unless
  assistance with breathing (mechanical
  ventilation) is provided.
• Botulism is not spread from one person to
  another. Foodborne botulism can occur in all age
  groups.
• A supply of antitoxin against botulism is
  maintained by CDC. The antitoxin is effective in
  reducing the severity of symptoms if administered
  early in the course of the disease. Most patients
  eventually recover after weeks to months of
  supportive care.

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• Relevant Drugs - NonSelective
• 2. Inhibitors of Acetylcholine Release
• a. Botulinum Toxin
• In controlled use as a medical agent, Botox
• Botox used to treat involuntary muscle spasms by
  local injection of very small amount
• Used for facial spasms jaw closing mandibular
  dystonia
• Also for strabismus deviation of eye position
  (different for each eye)
• Also forehead grimacing
• Last but not least cosmetic use for anti-aging
  effects

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• From BOTOX webpage
• Almost 3.3 million BOTOX Cosmetic procedures
  were performed in 2005 alone. Not just models and
  movie stars, but people from all types of
  professions.
• BOTOX Cosmetic can temporarily smooth moderate
  to severe frown lines between your brows for up
  to 4 months. Of course, we know that seeing is
  believing. So, take a look at men and women who
  have had BOTOX Cosmetic treatments, and see for
  yourself!

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• From Botox webpage
• How Long Does Botox Last?
• Botox results may last about six months,
  although the range varies from 3 to 12 months.
• Cost of Botox
• Your surgeon will pay 450 for each tiny vial of
  Botox. Your surgeon will charge you about 200 -
  300 for each area injected. Expect to pay this
  amount every six months to maintain your result.
• Risks of Botox
• No negative long-term effects have been observed.
  Very few short-term problems have arisen. If
  Botox is injected too close to your upper
  eyelids, temporary upper eyelid droop may result.
  This can take months to improve. Injection of
  your forehead will diminish your ability to raise
  your eyebrows. This is not a problem for most,
  but those with marked eyebrow droop may find that
  their droop worsens following injection. Risk of
  allergic reaction is extremely small. Women who
  are pregnant or who have nervous system diseases
  such as ALS should not receive injections of
  Botox.

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• 3. Mixed actions Black Widow
  Spider Toxin
• Only female venom is dangerous to humans
• First causes excessive release of Acetylcholine,
  then causes vesicles to clump together, clog up
  presynaptic membrane, and prevent further release
• Paralysis and death

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• Diseases Relevant to Cholinergic System
• Myasthenia Gravis
• Neuromuscular disease characterized by severe
  weakness and fatigability of muscles
• Loss of nicotinic cholinergic receptors on
  surface of muscle produces inability to maintain
  muscle activity for more than a brief period
• Enough Ach, not enough receptors (receptor
  content reduced by 60 in most common form of MG)
• autoimmune reaction where antibodies are built
  against bodys own nicotinic receptors
• May be caused by a virus (possibly transmitted by
  birds), genetic vulnerability
• Treated by anticholinesterase drugs (neostigmine
  pyridostigmine) that help provide more Ach to
  stimulate the limited receptors
• Immunosuppressive drugs (prednisone,
  cyclosporine, and azathioprine) may also be used.
  
• May remove thymus gland

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• Relevant Diseases
• 2. Alzheimers Disease
• Neurocognitive disorder marked by significant
  memory loss
• More common in elderly
• Deficiency of function of cholinergic neurons
  originating in the basal forebrain and sending
  their axons to cortex, hippocampus, and olfactory
  areas
• Buildup of beta amyloid protein causes tangles in
  axons (neurofibrillary tangles) that lead to
  dysfunction then degeneration of axon terminals
• Excess dietary choline does not appear to help
• Long acting anticholinesterase drugs (Tacrine)
  used to take advantage of what little Ach can be
  released - efficacy questionable over years