Prof. Dr. I. CHANDRASEKARAN, MD.,DA., DIRECTOR i/c INSTITUTE OF ANAESTHESIOLOGY

1. GOOD BYE SUXAMETHONIUM Prof. Dr. I. CHANDRASEKARAN, MD.,DA., DIRECTOR i/c INSTITUTE OF ANAESTHESIOLOGY MADURAI MEDICAL COLLEGE & GOVT. RAJAJI HOSPITAL, MADURAI

2. INTRODUCTION WHY? IS IT POSSIBLE? HOW?

3. HISTORY • In 1906, HUNT and DE TAVEAU first described the cardio vascular effects of succinylcholine in cats. However, they did not identify it’s neuro -muscular blocking properties • DANIEL BOVET studied the chemical and physiological properties of succinylcholine • Received Nobel price for physiology and medicine in 1957

4. It was introduced in clinical practice around 1951 by various people in different parts of the world • Since its introduction, reigned the anesthesia armamentarium of intubation

5. ADVANTAGES OF SUXAMETHONIUM • Suxamethonium is the only relaxant with a fast predictable onset of action and short duration of action • Rapid sequence induction – intubation sequence requires fast onset of action • Awakening a patient when a can’t intubate can’t ventilate situation arises requires fast recovery from paralysis

6. DISADVANTAGES OF SUXAMETHONIUM • Depolarising agent • Fasiculations • Myalgia in postoperative period • Rise in intracranial, intra gastric & intraocular pressures • Hyperkalemia

7. Prolonged block for atypical cholinesterase patients • Phase 2 block • Bradycardia on repeat doses • Malignant hyperthermia • Anaphylactic reaction

8. EARLY ONSET FAST RECOVERY HYPERKALEMIA PHASE 2 BLOCK FASCICULATIONS MUSCLE PAIN RAISE IN ICT , IOT MALIGNANT HYPERTHERMIA

9. RELEGATED AGENTS • ETHER • CHLOROFORM • TRILENE • TUBOCURARINE • GALLAMINE • PANCURONIUM • HALOTHANE THESE DRUGS WERE THOUGHT TO BE INDISPENSIBLE IN ANAESTHESIA PRACTICE… SO COULD BE SUXAMETHONIUM !

10. ALTRNATIVES TO SUXAMETHONIUM SUXAMETHONIUM • ATRACURIUM • RAPACURIUM • ROCURONIUM • MIVACURIUM • FAZADINIUM ALL THESE AGENTS WERE TRIED BUT NONE COULD REPLACE SUXAMETHONIUM

11. RAPACURONIUM • INTRODUCED IN 1999 • FASTEST ACTING NONDEPOLARISER (45 seconds) • FAST RECOVERY WHEN NEOSTIGMINE IS ADMINISTERED (8 minutes) • WITHDRAWN FROM MARKET WITHIN A YEAR DUE TO FATAL BRONCHOSPASM Intubation Conditions Provided by Rapacuronium (ORG 9487) or Succinylcholine in Humans during Anesthesia with Fentanyl and Propofol   Fleming, Neal W. M.D., Ph.D.; Chung, Frances M.D.; Glass, Peter S

12. ROCURONIUM - FAST ONSET • Introduced in 1991 • Aminosteroid nondepolarising agent • Dose dependant rapid onset of action • Intermediate duration of action • Excellent haemodynamic stability • No histamine release

13. Rocuronium is a low potency neuromuscular blocker • Large number of molecules are required to produce neuromuscular block • This large number of administered molecules facilitate fast onset • This property is called MOLAR POTENCY

14. 0.6mg/kg enabled intubation in 90 seconds • 0.9mg/kg enabled intubation in 60 seconds THIS IS COMPARABLE TO SUXAMETHONIUM • The fast onset of action was offset by its intermediate duration of action and need for NEOSTIGMINE to reverse it’s block

15. Recovery from Neuromuscular Blockade • Decrease in NMBA concentration – Metabolism – Excretion • Increase in acetylcholine

16. NEOSTIGMINE • ANTICHOLINESTERASE • INCREASES ACETYLCHOLINE LEVELS IN NMJ • DISPLACES THE NMBA FROM NMJ

17. PROBLEMS WITH NEOSTIGMINE • RESIDUAL PARALYSIS • RECURARISATION • CHOLINERGIC SIDE EFFECTS • NEED FOR AN ANTICHOLINERGIC ALONG WITH IT (PROBLEMS OF ANTICHOLINERGIC DRUGS)

18. THE MEDICAL NEED FOR AN IMPROVED REVERSAL DRUG • An improved reversal drug should quickly and completely reverse NMB, irrespective of the depth of blockade and without the need to manage the side effects of currently available reversal drugs • The properties of an improved reversal drug will offer real and important patient benefits

19. NEW CONCEPT IN REVERSAL • ENCAPSULATION • INACTIVATION

20. CYCLODEXTRINS • Cyclodextrins are poly saccharide compounds that were analysed as scavenging molecules for toxins and additives for food materials

21. Beta cyclodextrins were developed as vehicles for long acting drugs They have been tried as solubilising agents for various drugs like Propofol, bupivacaine, sufentanil Szejtli J. (1988). "Cyclodextrin Technology"vol 1. Springer, New York

22. Gamma cyclodextrins proved to be potential agents to facilitate reversal of neuromuscular block of AMINOSTEROID COMPOUNDS

23. The structure of gamma cyclodextrin is called a TORROID • It contains a hydrophilic exterior and a lipophilic interior • The hydrophilic exterior makes it water soluble , while the interior acts as a host for guest molecules to get encapsulate

24. UNMODIFIED GAMMA CYCLODEXTRIN HAS A LARGE LIPOPHILIC CAVITY • BUT IT IS STILL NOT ROOMY TO ACCOMMODATE ROCURONIUM

25. Eight sugar side chains are added to make the gamma cyclodextrin bigger to accommodate the rocuronium molecule • Ethyl carboxyl groups are added to these side chains to provide negative charges to hold the rocuronium electrostatically • SU = sugar GAMMADEX = gammacyclodextrin

26. STUCTURE OF ROCURONIUM

27. MECHANISM OF ACTION Bom  A, Bradley M, Cameron K, et al. A novel concept of reversing neuromuscular block: chemical encapsulation of rocuronium  bromide by a cyclodextrin-based synthetic host. Angew Chem IntEd Engl 2002;41:266 –70.

28. Rocuronium molecule is docked inside the lipophilic core of SUGAMMADEX • The negatively charged carboxy-ethyl groups hold rocuronium tightly

29. The resulting 1:1 guest host complex does not dissociate • Hence rocuronium is rendered unavailable to the Ach receptor • Sugammadex is, therefore, the first SELECTIVE RELAXANT BINDING AGENT (SRBA) Sugammadex: Another Milestone in Clinical Neuromuscular Pharmacology , Mohamed Naquib, MB, BCh, MSc, FFARCSI, MD

35. SUGAMMADEX BINDING REACTION ROCURONIUM > VECURONIUM > PANCURONIUM

37. PHARMACOKINETICS • Volume of distribution ≈ 12-15 L • Plasma half-life ≈ 2.2 h • Clearance ≈91 mL/min (≈ GFR) • No metabolism • Low plasma protein binding • Blood-brain barrier penetration (< 3% in rat) • Placental transfer (< 2-6%) in rat and rabbit)

38. DRUG INTERACTIONS TWO TYPES OF BINDING INTERACTIONS • DISPLACEMENT Another drug binding to sugammadex, displacing NMBA, causing rise in free NMBA concentration • Potential risk of RE-OCCURRENCE OF NMB

39. 2. CAPTURING Sugammadex binding another drug, decreasing its free concentrations • Potential risk of reduction in efficacy

40. DRUGS SELECTED FOR DETERMINATION OF BINDING AFFINITY FOR SUGAMMADEX • Drugs used in anesthesia • Drugs / hormones with steroidal nucleus • Drugs acting on steroidal receptors • Drugs most commonly prescribed • > 300 compounds tested

41. The highest affinity constant - for REMIFENTANIL ( 0.2% of the affinity constant of sugammadex with rocuronium) • PROGESTOGENS and ESTROGENS show some affinity for sugammadex (affinity 2-22% of that of rocuronium)

42. But no clinical evidence of interactions was found during clinical trials in approximately 2000 patients ANTON BOM.,MD., PhD, SENIOR RESEARCH FELLOW, PHARMACOLOGY

43. SIDE EFFECTS OF SUGAMMADEX NONE WERE SERIOUS • A multicentric trial conducted on 86 subjects the following side effects were noted. • Hypotension (3) • Coughing (3) • Movement (3) • Nausea (3) • Vomiting (3) • Dry mouth (4) • Parosmia (an abnormal smell) (2) • Sensation of a changed temperature (3) • Abnormal levels of n-acetyl-glucosaminidase in the urine (5) Sorgenfrei IF, Norrild K, Larsen PB, et al. Reversal of rocuronium-induced neuromuscular block by the selective relaxant binding agent sugammadex: a dose-finding and safety study. Anesthesiology 2006;104:667–74.

44. In one study, PROLONGATION OF THE CORRECTED QT interval was noted in five subjects who received placebo and in three subjects who received sugammadex

45. SAFETY STUDIES • At clinical exposure there are no data to suggest risk for adverse effects on any target organ for all life stages • Non-clinical Safety Overview -- Diels van den Dobbelsteen, Ph.D. Principal Toxicologist

46. DOSAGE • SHALLOW BLOCK 2.0 – 4.0 mg/kg -Reverses rocuronium-induced neuromuscular blockade within 3 min • INTERMEDIATE BLOCK 8.0 mg/kg - 3 min after the administration of 0.6 mg/kg rocuronium results in the recovery of the TOF ratio to 0.9 within 2 min

47. DEEP (RESCUE)BLOCK 16 mg/kg -Reverses 1.2mg/kg of rocuronium within 3 mins • THE DOSE OF SUGAMMADEX REQUIRED – DEPENDS ON • DOSE OF ROCURONIUM • DEPTH OF THE NEURO MUSCULAR BLOCK

48. SPECIAL POPULATION TRIALS • Rapid and complete recovery from rocuronium-induced NMB in normal and RENALLY Impaired patients • Both doses (2 AND 4 MG/KG ) were efficacious in pulmonary and cardiac patients • No clinical evidence of residual NMB • No dose adjustments necessary in special patient populations

49. ADVANTAGES OF SUGAMMADEX • Non toxic polysaccharide • Easy iv administration • Tight complexes with rocuronium • Fast reaction – occurs within 2 minutes • Does not interfere with other drugs in the body

50. ADVANTAGES OF SUGAMMADEX • Effect is not altered by acid base status of plasma • Does not interfere with anticholinestrase • No autonomic side effects • The complexes are not metabolised and are excreted unchanged in urine