Presented April, 2015 - OOA Convention by Ronald S. Stevens DO Board Certified Anesthesiologist Member Board of Trustees, OOA President/CEO Green Country Anesthesiology Associates PC. Conflict of Interest Statement I have received no fiscal rewards/gifts or contributions Or other enticements for performing this lecture. Ronald S. Stevens DO Goals: By the End of this Lecture, the Participant should be able to: -Recall the Biophysiology of Muscle Contraction -Recall the Classifications of NMJB -Understand the Process of Development of -Be aware of the Suggested Doseages for -Have a BASIC Understanding of the Risk/Benefits re -Have Reference Sources for further Study/Decision Making Ronald S. Stevens DO 1
Muscle Contraction Events at Neruomuscular Junction Excitation-Contraction Coupling Cross-Bridge Cycle Action Potential, Nocotinic Receptor, Synapse, 7 Steps, Sarcoplasm, Ca, Exocytosis, Acetylcholine, Ligand Gated Cation Channels, Na/K, Action Potential along Sarcolemma, T-Tubules, Sarcoplasmic Reticulum, Terminal Cisternae (Triad), Ca, Myofibrils, Sarcommere, Thick and Thin, M-Line, Z-Line, Myosin, Actin, Troponin, Tropomyosin, ATP hydrolyzed to ADP + P, Binding Site, Power Stroke. Reset. Classification of NMJB -Nomenclature -Chemical Structure -Duration of Action Classification of NMJB -Nomenclature Leptocurares - Thin and flexible molecules that tend to have depolarizing properties Pachycurares- Bulky molecules with nondepolarizing activity 2
Classification of NMJB -Chemical Structure -Polymethylene chains of the appropriate length with 2 methonium heads (Acetylcholine, Succinylcholine, Decamethonium) -Amino Steroids (Pancuronium, Rocuronium, Vecuronium) -Tetrahydroisoquinoline Derivatives (Atracurium, Mivacurium, Doxacurium, d-tubocurare, -Gallamine -Asymetric Diester Isoquinolinium and Bis-Benzyltropium Compounds (Faster acting, Shorter duration) Classification of NMJB -Duration of Action -Ultra Short -Short -Intermediate -Long 3
Organon a part of Shering-Polugh Corporation First in Class A selective relaxant binding agent that encapsulates Rocuronium or Vecuronium preventing its action. is an innovative drug that will enable anesthesiologist to rapidly reverse shallow and profound neuromuscular block (NMB) induced by Rocuronium or Vecuronium. What is and How Does It Work? CYCLODEXTRINE -Solubilizing agent since 1953-8 sugar molecules forming a rigid ring with a lipophilic central cavity -Water soluable -Not metabolized -Renally excreted 4
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Safety/Adverse Events 6
At Clinincal Exposure there is no data to suggest risks for adverse effects on any target organ for all life stages. http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4346s1-01-schering-plough-corebackup.pdf Safety Conclusions ' Non-Clinical Safety Profile shows wide safety margins relative to Human exposure. Extensive set of 15 Non-Clinical Safety and Drug Disposition Studies characterized the risk for mineral tissues. The Non-Clinical Models used are relevant and very sensitive Conservative estimates of Safety Margins for effects on bone and teeth are very wide (>48-1000) Presence of NMBA further increases the Safety Margins This addresses the use in sensitive patients, e.g. healing fractures, unborn child, pediatric, and potential repeated use. 1) Potential to address an unmet medical need NDA class Priority 2) Avoids the need to use Acetylcholinesterase Inhibitors (AchEIs) and muscarinic antagonists. (Cost, Side effects Profile, Twin Drugs) 3) Current indication is for use in Adults 4) Rapid reversal of NMB at 3 minutes after administration of Rocuronium 5) Doseage depends on level of NMB to be reversed (2mg/kg for TOF 2 clicks) (4mg/kg for Post-Tetanic 2 clicks) (16mg/kg for 3minute reversal of Rocuronium*) (* There is NO DATA to support the use of for immediate reversal following Vecuronium induced blockade) http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4346s1-01-schering-ploughcorebackup.pdf 7
Options and Risk of a First in Class Reversal Agent https://www.youtube.com/watch?v=1fu733z7dtu NDA 22-225, Anesthetic and Life Support Drugs Advosory Committee http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4346s1-01-schering-ploughcorebackup.pdf Briefing Document http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4346b1-02-organon.pdf NEW WORD TO LEARN Calabadions - Cyclic Glycouril tetramer 7 Things That Will Destroy US Wealth without Work Pleasure without Conscience Knowledge without Character Business without Morality Science without Humanity Religion without Sacrifice Politics without Principle 7 Things That Will Destroy US Wealth without Work Pleasure without Conscience Knowledge without Character Business without Morality Science without Humanity Religion without Sacrifice Politics without Principle M Gandhi 8
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