History Native South America tribes smeared a paste made from
Chondrodendron tomentosum on blow darts and arrowheads to improve chances of obtaining wild game.
1595 was the first published account by Sir Walter Raleigh’s expedition up the Amazon.
1804 Alexander von Humboldt published the first recipe of Native South American’s poison, termed curare, woorari, or wourali.
Charles Waterton 1812Explored Guiana and Brazil Description of a donkey being revived by artificial respiration
after it had been poisoned with wourali, curare. 1935 Harold King isolated compound D-tubocurarine—residue
from ceramic pottery in British Museum
Richard Gill
Gill suffered from painful muscle spasms and he didn’t respond to treatment
1938 led a four month expedition to Ecuador He studied customs and traditions of indigenous
South American people He was appointed as a shaman within the tribe,
where he learned the technique and preparation of the toxin
He returned back to the United States with the recipe for curare and marketed it, but without success
1932 suffered neurological syndrome and muscle damage due to a horse accident which worsened over time
Normal Physiological Action Potential at Neuromuscular Junction
Pre-synaptic neurons contain voltage gated calcium channels
An action potential reaches the pre-synaptic bud causing the channels to open
Calcium ions to flow into the pre-synaptic bud Calcium ions cause vesicles to fuse with pre-
synaptic membrane releasing acetylcholine Acetylcholine diffuses across the synaptic cleft Acetylcholine binds to acetylcholine receptors in
the post-synaptic membrane causing sodium channels to open, sodium flows in
Depolarization of the post-synaptic membrane occurs
Threshold is reached action potential is initiated Acetylcholinesterase breaks down Acetylcholine
Competitive Antagonist of Acetylcholine
Curare binds to the acetylcholine receptor
Sodium channel does not open
No action potential propagated
Resulting in paralysis
Reversal Agents
Acetylcholinesterase inhibitors (Neostigmine, Pyridostigmine, edrophonium)
Hydrolyze acetylcholinesterase Acetylcholine concentration increases in
the synaptic cleft Acetylcholine displaces Curare on the
acetylcholine receptor
Curare Non-depolarizing Neuromuscular Blocking Agent (NMB) Curare prevents signal transduction Curare is the prototypical non-
depolarizing NMB Several more effective synthetic analogs
have since been produced (rocuronium, pancuronium, vecuronium)
Curare is rarely utilized in anesthesia today
Succinylcholine
Depolarizing neuromuscular blocking agent
Synthesized by attaching two molecules of acetylcholine together
Propagates signal transduction by activating acetylcholine receptor
Produces a prolonged depolarization Degraded by plasma
pseudocholinesterase
Ryanodine Receptor Propagated action potential
travels from the motor endplate through T-tubules
In T-tubules dihydropyridine receptors (DHPR) are activated and induce calcium influx
Calcium release leads to activation of Ryanodine receptor 1 (RyR1) in the sacroplasmic reticular (SR) membrane
Calcium release from SR yields excitation contraction coupling
Malignant Hyperthermia Autosomal dominant disease Mutation in DHPRs and RyR1 Causes leak in calcium when exposed to
succinylcholine and inhalation anesthetics Muscle rigidness, hyperkalemia,
arrhythmias, respiratory and metabolic acidosis, greatly increased body temperature
Treatment is with Dantrolene antagonist of RyR1
Conclusion Curare is derived from Chondrodendron
tomentosum Historically used by indigenous tribes for
hunting Active compound D-tubocurarine isolated Used as a non-depolarizing neuromuscular
blocking agent in anesthesia Prototype from which more effective non-
depolarizing NMBs have been synthesized
Bibliography Anderson, Rebecca. “A Tortured Path: Curare’s journey from poison darts to
paralysis by design.” Pubmed. 2010. 5. 252-258. http://www.ncbi.nlm.nih.gov/pubmed/21045238.
Miller, R.D., Skeletal Muscle Relaxants, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 434-449, 1998.
Stoelting, R.K., "Neuromuscular-Blocking Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 182-219, 1999.
White, P. F. "Anesthesia Drug Manual", W.B. Saunders Company, 1996. Sterling, E., Winstead, P. S., Fhay, B. G. Guide to Neuromuscular Blocking
Agents. Anethesiology News. McHammon Publishing, 25-30, 2007. Capes, E. M., Loazia, R., Valdivia, H. H. Ryanodine receptors. Skeletal Muscle,
1:18, 2011. Lanner, J. T., et al. Ryanodine Receptors: Structure, expression, molecular
details, and function in calcium release. Cold Spring Harb Perspect Biol, 2:a003996, 2010.
Bowman, W. C. Neuromuscular Block. British Journal of Pharmacology, 147(S1): S277–S286, 2006.
Gao, Fan. Et al. Curariform Antagonists Bind in Different Orientations to Acetylcholine-binding protein. J Biol Chem. 2003. 278.
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