This lecture was delivered to 2nd year pharmacy students enrolled in a pharmacology & toxicology course. This presentation was designed to accompany Goodman & Gilman's (12e) chapter 12.

1. Neuromuscular Junction &
Autonomic Ganglia Agents
Brian J. Piper, Ph.D., M.S.
2 min (skip ad): http://www.youtube.com/watch?v=x4c_wI6kQyE

2. Objectives
• Neuromuscular Junction Antagonists
– Non-depolarizing (tubocurare)
– Depolarizing (succinylcholine)
• Ganglionic Antagonists (mecamylamine)
• Nicotine

4. Nicotinic Acetylcholine
Receptor
• composed of 5 subunits
Type Muscle (2) Ganglion (1) Neuronal (?)*
localization muscle autonomic brain
ganglion, adrenal
medulla, immune
subunit embryonic α3, α3, β4, β4, β4 α3, α3, β4, β4, β4
α1,α1,β1,δ, γ
adult α4, α4, β2, β2, β2
α1,α1,β1,δ, ε
α4, α4, α4, β2, β2,
α7, α7, α7, α7, α7
* α2, α3, α4, α5, α6, α7, α8, α9, α10, β2, β3, β4

5. Neurotransmission at Neuromuscular Junction
• 1) presynaptic depolarization
• 2) Ca2+ influx
• 3) release of acetylcholine into the cleft
• 4) binding to nicotine receptor on muscle
• 5) influx of Na+ through ion channel
• 6) muscle contracts
0 to 1:20: http://www.youtube.com/watch?v=9FF6UKvDgeE
Katzung (2012). p. 470.

6. Curare
• ethnobotanist Richard Evans Schultes identifies 70
plants that contain d-tubocurare
• competitive nACh antagonist of voluntary muscles
• inactive orally
• treatment: respiration & acetylcholinesterase
inhibitors
1915 - 2001
Katzung et al. (2012). Basic & Clinical Pharmacology. p. 470.

7. No Central or
Anesthetic Effects
Louis S. Goodman, MD
• Healthy volunteer received i.v. tubocurarine and
artificial respiration
Smith, Brown, Toman & Goodwin (1947). Anesthesiology, 8, 1-14.

8. No Central or Anesthetic Effects of
Tubocurarine
• Motor function lost in sequence of speech,
forehead, gaze direction (focus retained), 1906-2000
swallowing (histamine mediated salivation)!
Smith, Brown, Toman & Goodwin (1947). Anesthesiology, 8, 1-14.

9. No Central or Anesthetic Effects of
Tubocurarine
• Hearing & smell unimpaired but sensation of shortness
of breath & choking on fluid (histamine) build-up!
• Reversal with acetycholinesterase inhibitor

10. Utility of Neuromuscular Blockers
• Adjuvant to surgery
• Scopy (x3): laryngoscropy, bronchoscopy, esophagoscopy
• Electroconvulsive Therapy: major depression
• Electrocution

11. Succinylcholine
• Phase I (depolarization): channel open
• Phase II (desensitization): channel acts like closed
• Degraded by butyrlcholinesterase
• endotracheal intubation
• contraindictation: consciousness
http://howjsay.com/index.php?word=succinylcholine&submit=Submit

12. Ganglionic Blocking Drugs
• Hexamethonium, mecamylamine
• block nACh at both sympathetic &
parasympathetic ganglia
• popular in 1950s to control blood pressure but
now research tool only
http://howjsay.com/index.php?word=hexamethonium&submit=Submit
http://howjsay.com/index.php?word=mecamylamine+&submit=Submit

13. Public Health Consequences of
Smoking
• Cigarette smoking results in
443,000 premature
deaths/year
• Smoking is the primary
causal factor for at least
30% of all cancer deaths
• 8.6 million people suffer
from a serious illness
caused by smoking/year
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5745a3.htm

14. Nicotine by College Plans

15. Epidemiology: NSDUH
MtF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf

16. Fig 1 Survival from age 60 for continuing cigarette smokers and lifelong non-smokers among UK
male doctors born 1900-1930 (median 1915), with percentages alive at each decade of age.
Sir Richard Doll
Silly ad 1:30-2:20: http://www.youtube.com/watch?v=7k5oJgtCdX8
1912-2005
Doll et al. (2004). British Medical Journal, 328, 1519.

17. But there’s good news!
Doll, R. et al. (2004) BMJ, 328:1519

18. Nicotine over 24 hours
• Cotinine > Nicotine
• Steady state during day
Benowitz et al. (1983). Circadian blood concentrations of nicotine and cotinine
during unrestricted smoking. Clin Pharmacol Ther, 34, 604-611.

19. Nicotine by Route of Administration
Blood nicotine after smoking 1.33 cigarettes for 9 minutes (upper left) or 2.5 g oral snuff
(upper right), 7.9 g chewing tobacco (lower left), two-2 mg pieces of nicotine gum for 30
minutes.
Hukkanen et al. (2005) Pharmacology Reviews, 57, 79-115.

20. Smoking increases nACh
• Smoking increases receptor
levels in human post-mortem
tissue in hippocampus (top) and
thalamus (bottom).
Breese et al. (1997). JPET, 282, 7-13. Non-Sm Smoker Ex-smoker

21. Neurotransmitter Cross-Talk

22. Nicotine & Cognition
Nicotine was administered either 20 minutes before sample (A), just after sample (B), or
20 minutes before choice (C).
Picture from Ennaceur, Figure adapted from Puma et al. (1999) Eur J Neuropsychopharm, 9, 323-327.

23. Whole Body PET of MAO-B

24. Smoking & Pregnancy
• Risks of smoking:
– Spontaneous abortion: 26 weeks NHSDUH, 2011
– Small size: SGA
– SIDS: 1 month to 1 year
– Behavioral issues: ADHD

25. Benefits of Quitting Smoking
• Hypothesis:
Smoking during
pregnancy, but not
quitting, has
negative outcomes
• Online study of non-
smokers, smokers,
quitters
Piper et al. (2012). Drug & Alcohol Dependence, 121, 62-67.

26. The nicotinic cholinergic receptor
Varenicline: partial α4β2 agonist
Bupropion: nACh antagonist
Nicotinic Replacement Therapy (NRT): nACh agonist

27. Acetylcholine-Dopamine Interaction
Smoking
Not Smoking
Stahl (2001) p. 525

28. Modest Benefits of Varenicline
6 month abstinence with
• Partial agonist for α4β2, full agonist 1 mg x 2/day
α7
• Approved in 2004; suicidal ideation
• Meta-analysis (20 trials, 17 by Pfizer,
N=12,000)
• Relative Risk = 2.27
Calhill et al. (2012) Cochrane Review, 2012(4), 1-114.

29. Nicotine Vaccine
• Rationale: nicotine conjugate produces
antibodies which prevent distribution to brain
Maurer et al. (2005). European Journal of Immunology, 35, 2031-2040.

30. Limited Efficacy
• No compensatory increase in smoking
• Mild (flu like) Adverse Events: V-96.5%, P-84.8%
• % Abstainers (2-6): H-56.6%, P-31.3% but no
difference after
Cornuz (2008). PLOS ONE, 3(6), e2547.

31. Terminology Refresher
myoid (p. 255): composed of, or resembling, muscle
Hoffman elimination (p. 259): a process where an amine is reacted to create a
tertiary amine and an alkene by treatment with excess methyl iodide followed by
treatment with silver oxide, water, and heat
fasciculation: a small, local, involuntary muscle contraction and relaxation which
may be visible under the skin or detected in deeper areas by EMG testing