Laura Lorenz Mark Fischer Larvingo Alston

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 1812 Explored 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

Chemical Structure of D-Tubocurarine

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  Miller, R.D., Skeletal Muscle Relaxants, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, ,  Stoelting, R.K., "Neuromuscular-Blocking Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, ,  White, P. F. "Anesthesia Drug Manual", W.B. Saunders Company,  Sterling, E., Winstead, P. S., Fhay, B. G. Guide to Neuromuscular Blocking Agents. Anethesiology News. McHammon Publishing, 25-30,  Capes, E. M., Loazia, R., Valdivia, H. H. Ryanodine receptors. Skeletal Muscle, 1:18,  Lanner, J. T., et al. Ryanodine Receptors: Structure, expression, molecular details, and function in calcium release. Cold Spring Harb Perspect Biol, 2:a003996,  Bowman, W. C. Neuromuscular Block. British Journal of Pharmacology, 147(S1): S277–S286,  Gao, Fan. Et al. Curariform Antagonists Bind in Different Orientations to Acetylcholine- binding protein. J Biol Chem