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Prof. Dr. I. CHANDRASEKARAN, MD.,DA.,DIRECTOR i/c
INSTITUTE OF ANAESTHESIOLOGY
MADURAI MEDICAL COLLEGE
&
GOVT. RAJAJI HOSPITAL, MADURAI
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INTRODUCTION
WHY?
IS IT POSSIBLE?
HOW?
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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
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• 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
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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
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DISADVANTAGES OF SUXAMETHONIUM
• Depolarising agent
• Fasiculations
• Myalgia in postoperative period
• Rise in intracranial, intra gastric & intraocular pressures
• Hyperkalemia
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• Prolonged block for atypical cholinesterase patients
• Phase 2 block
• Bradycardia on repeat doses
• Malignant hyperthermia
• Anaphylactic reaction
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HYPERKALEMIA
MUSCLE PAIN
MALIGNANT HYPERTHERMIA
PHASE 2 BLOCK
EARLY ONSET FAST RECOVERY
FASCICULATIONS
RAISE IN ICT , IOT
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RELEGATED AGENTS• ETHER • CHLOROFORM• TRILENE• TUBOCURARINE• GALLAMINE• PANCURONIUM• HALOTHANE
THESE DRUGS WERE THOUGHT TO BE INDISPENSIBLE
IN ANAESTHESIA PRACTICE…
SO COULD BE SUXAMETHONIUM !
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ALTRNATIVES TO SUXAMETHONIUM
• ATRACURIUM
• RAPACURIUM
• ROCURONIUM
• MIVACURIUM
• FAZADINIUM
ALL THESE AGENTS WERE TRIED BUT NONE COULD
REPLACE SUXAMETHONIUM
SUXAMETHONIUM
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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
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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
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• 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
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• 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
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Recovery from Neuromuscular Blockade
• Decrease in NMBA concentration
– Metabolism
– Excretion
• Increase in acetylcholine
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NEOSTIGMINE
• ANTICHOLINESTERASE
• INCREASES ACETYLCHOLINE LEVELS IN NMJ
• DISPLACES THE NMBA FROM NMJ
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PROBLEMS WITH NEOSTIGMINE
• RESIDUAL PARALYSIS
• RECURARISATION
• CHOLINERGIC SIDE EFFECTS
• NEED FOR AN ANTICHOLINERGIC
ALONG WITH IT (PROBLEMS OF ANTICHOLINERGIC DRUGS)
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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
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NEW CONCEPT IN REVERSAL
ENCAPSULATION
• INACTIVATION
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CYCLODEXTRINS
• Cyclodextrins are poly saccharide compounds that were analysed as scavenging molecules for toxins and additives for food materials
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•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
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Gamma cyclodextrins proved to be potential agents to facilitate reversal of neuromuscular block of
AMINOSTEROID COMPOUNDS
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• 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
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• UNMODIFIED GAMMA CYCLODEXTRIN HAS A LARGE LIPOPHILIC CAVITY
• BUT IT IS STILL NOT ROOMY TO ACCOMMODATE ROCURONIUM
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• 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
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STUCTURE OF ROCURONIUM
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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.
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• Rocuronium molecule is docked inside the lipophilic core of SUGAMMADEX
• The negatively charged carboxy-ethyl groups hold rocuronium tightly
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• 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
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SUGAMMADEX BINDING REACTION
DRUG SPEED OF REACTION
ROCURONIUM 25
VECURONIUM 10.0
PANCURONIUM 2.6
ATRACURIUM 0.005
SUCCINYL CHOLINE 0
ROCURONIUM > VECURONIUM > PANCURONIUM
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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)
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DRUG INTERACTIONS
TWO TYPES OF BINDING INTERACTIONS
1. DISPLACEMENT
Another drug binding to sugammadex,
displacing NMBA,
causing rise in free NMBA concentration
Potential risk of RE-OCCURRENCE OF NMB
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2. CAPTURING
Sugammadex binding another drug, decreasing its free concentrations
Potential risk of reduction in efficacy
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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
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• 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)
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But no clinical evidence of interactions was found during clinical trials in approximately 2000 patients
ANTON BOM.,MD., PhD, SENIOR RESEARCH FELLOW, PHARMACOLOGY
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SIDE EFFECTS OF SUGAMMADEX• 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)
NONE WERE SERIOUS
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.
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• In one study, PROLONGATION OF THE CORRECTED QT interval was noted in five subjects who received placebo and in three subjects who received sugammadex
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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
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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
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• 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
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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
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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
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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
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WHY IS THIS COMBINATION BETTER THAN
SUXAMETHONIUM?
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• Reversal of profound rocuronium-induced (1.2mg/kg) neuromuscular block with sugammadex was significantly
FASTER THAN SPONTANEOUS RECOVERY FROM SUCCINYLCHOLINE
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• Sugammadex offers the possibility of IMMEDIATE REVERSAL of rocuronium-induced block in a possible scenario of
FAILED VENTILATION / FAILED INTUBATION
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IS ROCURONIUM – SUGAMMADEX SEQUENCE BETTER THAN SUXAMETHONIUM?
Studies using succinylcholine have indicated that the risk of desaturation in the immediate postinduction period is much greater than initially recognized in “cannot intubate, cannot ventilate” situations.
• Hayes ah, breslin ds, mirakhur rk, et al. Frequency of haemoglobin desaturation with the use of succinylcholine during rapid sequence induction of anaesthesia. Acta anaesthesiol scand 2001;45:746–9.
• Naguib m, samarkandi ah, abdullah k, et al. Succinylcholine dosage and apnea-induced hemoglobin desaturation in patients. Anesthesiology 2005;102:35–40.
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NEWER DRUGS
• GANTACURIUM CHLORIDE
It has the desired quality of a rapid onset and an ultrashort duration of action even when administered at 3-4 times the ED95 doses.
Undergoes rapid "chemo-inactivation" via cysteine adduct formation
Followed by slow biodegradation via ester hydrolysis
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The use of extrinsically administered cysteine to deliberately accelerate reversal of gantacurium is being investigated currently.
Inactivation of gantacurium via cysteine adduct formation is independent of body ph and temperature
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SUMMARRY
• SUGAMMADEX is one of the most innovative drugs discovered in anesthesia
• It is the first drug that encapsulates the NMBD, taking it away from the NMJ and terminating its action
• Allows increased flexibility with NMBD intraoperatively
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• Provides complete and rapid reversal of profound neuromuscular blockade
• Minimizes risk of residual postoperative paralysis
• Elimination of managing side effects associated with AChEIs (neostigmine) and muscarinic antagonists (atropine/ glycopyrrolate) and the mechanical mixing of two drugs
• In combination with rocuronium, may provide a safe alternative to suxamethonium
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CONCLUSION
• “Necessity is the mother of inventions”. • Suxamethonium is a drug that had many ideal
charecteristics , it is not without side effects
• Though Rocuronium was introduced in 1994, and had a very fast onset of action, it could not be used in patients with difficult airway since it has a intermediate duration of action.
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• With Sugammadex it is now possible to achieve rapid onset and fast recovery from neuromuscular block
ROCURONIUM SUGAMMADEX COMBINATION IS PROMISING US A SAFER FUTURE IN ANAESTHESIA
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THE DAYS TO SAY
GOOD BYE TO
SUXAMETHONIUM
ARE NOT FAR OFF