Neuromuscular junction & autonomic ganglia

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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.

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  • There are 12 alpha and beta subunits found in the brain. These form a channel that regulates the influx of Na.
  • Shipped in tubes (not pots). Physostigmine or neostigmine are therapies.
  • Diplopia = double vision
  • Electric chair is backup form of death penalty in Alabama, Florida, South Carolina and Virginia and only form in Vermont.
  • [mec ah mil a meen]
  • MAO-B preferentially breaks down dopamine & serotonin.
  • Relative Risk: likelihood of event in group A/B: http://en.wikipedia.org/wiki/Relative_risk
  • Neuromuscular junction & autonomic ganglia

    1. 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. 2. Objectives• Neuromuscular Junction Antagonists – Non-depolarizing (tubocurare) – Depolarizing (succinylcholine)• Ganglionic Antagonists (mecamylamine)• Nicotine
    3. 3. 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
    4. 4. 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 contracts0 to 1:20: http://www.youtube.com/watch?v=9FF6UKvDgeE Katzung (2012). p. 470.
    5. 5. 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 - 2001Katzung et al. (2012). Basic & Clinical Pharmacology. p. 470.
    6. 6. No Central or Anesthetic Effects Louis S. Goodman, MD • Healthy volunteer received i.v. tubocurarine and artificial respirationSmith, Brown, Toman & Goodwin (1947). Anesthesiology, 8, 1-14.
    7. 7. 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.
    8. 8. 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
    9. 9. Utility of Neuromuscular Blockers• Adjuvant to surgery• Scopy (x3): laryngoscropy, bronchoscopy, esophagoscopy• Electroconvulsive Therapy: major depression• Electrocution
    10. 10. Succinylcholine• Phase I (depolarization): channel open• Phase II (desensitization): channel acts like closed• Degraded by butyrlcholinesterase• endotracheal intubation• contraindictation: consciousnesshttp://howjsay.com/index.php?word=succinylcholine&submit=Submit
    11. 11. Ganglionic Blocking Drugs • Hexamethonium, mecamylamine • block nACh at both sympathetic & parasympathetic ganglia • popular in 1950s to control blood pressure but now research tool onlyhttp://howjsay.com/index.php?word=hexamethonium&submit=Submithttp://howjsay.com/index.php?word=mecamylamine+&submit=Submit
    12. 12. 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/yearhttp://www.cdc.gov/mmwr/preview/mmwrhtml/mm5745a3.htm
    13. 13. Nicotine by College Plans
    14. 14. Epidemiology: NSDUHMtF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
    15. 15. 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 1912-2005Doll et al. (2004). British Medical Journal, 328, 1519.
    16. 16. But there’s good news!Doll, R. et al. (2004) BMJ, 328:1519
    17. 17. Nicotine over 24 hours • Cotinine > Nicotine • Steady state during dayBenowitz et al. (1983). Circadian blood concentrations of nicotine and cotinineduring unrestricted smoking. Clin Pharmacol Ther, 34, 604-611.
    18. 18. 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 30minutes.Hukkanen et al. (2005) Pharmacology Reviews, 57, 79-115.
    19. 19. 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
    20. 20. Neurotransmitter Cross-Talk
    21. 21. Nicotine & CognitionNicotine was administered either 20 minutes before sample (A), just after sample (B), or20 minutes before choice (C).Picture from Ennaceur, Figure adapted from Puma et al. (1999) Eur J Neuropsychopharm, 9, 323-327.
    22. 22. Whole Body PET of MAO-B
    23. 23. Smoking & Pregnancy• Risks of smoking: – Spontaneous abortion: 26 weeks NHSDUH, 2011 – Small size: SGA – SIDS: 1 month to 1 year – Behavioral issues: ADHD
    24. 24. Benefits of Quitting Smoking• Hypothesis: Smoking during pregnancy, but not quitting, has negative outcomes• Online study of non- smokers, smokers, quittersPiper et al. (2012). Drug & Alcohol Dependence, 121, 62-67.
    25. 25. The nicotinic cholinergic receptorVarenicline: partial α4β2 agonistBupropion: nACh antagonistNicotinic Replacement Therapy (NRT): nACh agonist
    26. 26. Acetylcholine-Dopamine Interaction Smoking Not SmokingStahl (2001) p. 525
    27. 27. 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 = 2.27Calhill et al. (2012) Cochrane Review, 2012(4), 1-114.
    28. 28. Nicotine Vaccine • Rationale: nicotine conjugate produces antibodies which prevent distribution to brainMaurer et al. (2005). European Journal of Immunology, 35, 2031-2040.
    29. 29. 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 afterCornuz (2008). PLOS ONE, 3(6), e2547.
    30. 30. Terminology Refreshermyoid (p. 255): composed of, or resembling, muscleHoffman elimination (p. 259): a process where an amine is reacted to create atertiary amine and an alkene by treatment with excess methyl iodide followed bytreatment with silver oxide, water, and heatfasciculation: a small, local, involuntary muscle contraction and relaxation whichmay be visible under the skin or detected in deeper areas by EMG testing

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