neuromuscular junction & autonomic ganglia

Neuromuscular Junction & Autonomic Ganglia Agents

Brian J. Piper, Ph.D., M.S.

2 min (skip ad): http://www.youtube.com/watch?v=x4c_wI6kQyE

Objectives• Neuromuscular Junction Antagonists

– Non-depolarizing (tubocurare)– Depolarizing (succinylcholine)

• Ganglionic Antagonists (mecamylamine)• Nicotine

Nicotinic Acetylcholine Receptor • composed of 5 subunits

Type Muscle (2) Ganglion (1) Neuronal (?)*

localization muscle autonomic ganglion, adrenal medulla, immune

brain

subunit embryonicα1,α1,β1,δ, γ

α3, α3, β4, β4, β4 α3, α3, β4, β4, β4

adultα1,α1,β1,δ, ε

α4, α4, β2, β2, β2

α4, α4, α4, β2, β2,

α7, α7, α7, α7, α7

* α2, α3, α4, α5, α6, α7, α8, α9, α10, β2, β3, β4

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.

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.

No Central or Anesthetic Effects

• Healthy volunteer received i.v. tubocurarine and artificial respiration

Smith, Brown, Toman & Goodwin (1947). Anesthesiology, 8, 1-14.

Louis S. Goodman, MD

No Central or Anesthetic Effects of Tubocurarine

• Motor function lost in sequence of speech, forehead, gaze direction (focus retained), swallowing (histamine mediated salivation)!

Smith, Brown, Toman & Goodwin (1947). Anesthesiology, 8, 1-14.

1906-2000

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

Utility of Neuromuscular Blockers

• Adjuvant to surgery • Scopy (x3): laryngoscropy, bronchoscopy, esophagoscopy

• Electroconvulsive Therapy: major depression

• Electrocution

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

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=Submithttp://howjsay.com/index.php?word=mecamylamine+&submit=Submit

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

Nicotine by College Plans

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

Epidemiology: NSDUH

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.

1912-2005

Sir Richard Doll

Silly ad 1:30-2:20: http://www.youtube.com/watch?v=7k5oJgtCdX8

Doll et al. (2004). British Medical Journal, 328, 1519.

But there’s good news!

Doll, R. et al. (2004) BMJ, 328:1519

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.

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.

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

Neurotransmitter Cross-Talk

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.

Whole Body PET of MAO-B

Smoking & Pregnancy

• Risks of smoking:– Spontaneous abortion: 26 weeks– Small size: SGA– SIDS: 1 month to 1 year– Behavioral issues: ADHD

NHSDUH, 2011

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.

The nicotinic cholinergic receptor

Varenicline: partial α4β2 agonistBupropion: nACh antagonistNicotinic Replacement Therapy (NRT): nACh agonist

Acetylcholine-Dopamine InteractionSmoking

Not Smoking

Stahl (2001) p. 525

Modest Benefits of Varenicline

• Partial agonist for α4β2, full agonist 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.

6 month abstinence with 1 mg x 2/day

Nicotine Vaccine

• Rationale: nicotine conjugate produces antibodies which prevent distribution to brain

Maurer et al. (2005). European Journal of Immunology, 35, 2031-2040.

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.

Terminology Refreshermyoid (p. 255): composed of, or resembling, muscleHoffman 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 heatfasciculation: a small, local, involuntary muscle contraction and relaxation which may be visible under the skin or detected in deeper areas by EMG testing