Transcript GOOD BYE SUXAMETHONIUM - ISAKanyakumari

Prof. Dr. I. CHANDRASEKARAN, MD.,DA.,
DIRECTOR i/c
INSTITUTE OF ANAESTHESIOLOGY
MADURAI MEDICAL COLLEGE
&
GOVT. RAJAJI HOSPITAL, MADURAI
INTRODUCTION
WHY?
IS IT POSSIBLE?
HOW?
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
• 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
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
DISADVANTAGES OF
SUXAMETHONIUM
• Depolarising agent
• Fasiculations
• Myalgia in postoperative period
• Rise in intracranial, intra gastric & intraocular
pressures
• Hyperkalemia
• Prolonged block for atypical
cholinesterase patients
• Phase 2 block
• Bradycardia on repeat doses
• Malignant hyperthermia
• Anaphylactic reaction
EARLY ONSET
HYPERKALEMIA
MUSCLE PAIN
RAISE IN ICT , IOT
FAST RECOVERY
PHASE 2 BLOCK
FASCICULATIONS
MALIGNANT HYPERTHERMIA
RELEGATED AGENTS
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ETHER
CHLOROFORM
TRILENE
TUBOCURARINE
GALLAMINE
PANCURONIUM
HALOTHANE
THESE DRUGS WERE THOUGHT TO BE INDISPENSIBLE
IN ANAESTHESIA PRACTICE…
SO COULD BE SUXAMETHONIUM !
ALTRNATIVES TO
SUXAMETHONIUM
• ATRACURIUM
• RAPACURIUM
SUXAMETHONIUM
• ROCURONIUM
• MIVACURIUM
• FAZADINIUM
ALL THESE AGENTS WERE TRIED BUT NONE COULD
REPLACE SUXAMETHONIUM
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• WITHDRAWN FROM MARKET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
ROCURONIUM - FAST ONSET
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Introduced in 1991
Aminosteroid nondepolarising agent
Dose dependant rapid onset of action
Intermediate duration of action
Excellent haemodynamic stability
No histamine release
• 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
• 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
Recovery from Neuromuscular
Blockade
• Decrease in NMBA concentration
– Metabolism
– Excretion
• Increase in acetylcholine
NEOSTIGMINE
• ANTICHOLINESTERASE
• INCREASES ACETYLCHOLINE
LEVELS IN NMJ
• DISPLACES THE NMBA FROM NMJ
PROBLEMS WITH NEOSTIGMINE
• RESIDUAL PARALYSIS
• RECURARISATION
• CHOLINERGIC SIDE EFFECTS
• NEED FOR AN ANTICHOLINERGIC
ALONG WITH IT (PROBLEMS OF
ANTICHOLINERGIC DRUGS)
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
NEW CONCEPT IN REVERSAL
 ENCAPSULATION
• INACTIVATION
CYCLODEXTRINS
• Cyclodextrins are poly
saccharide compounds that
were analysed as scavenging
molecules for toxins and
additives for food materials
•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
Gamma cyclodextrins
proved to be potential
agents to facilitate
reversal of
neuromuscular block of
AMINOSTEROID
COMPOUNDS
• 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
• UNMODIFIED GAMMA CYCLODEXTRIN HAS A
LARGE LIPOPHILIC CAVITY
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BUT IT IS STILL NOT ROOMY TO ACCOMMODATE
ROCURONIUM
• 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
STUCTURE OF ROCURONIUM
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.
• Rocuronium molecule is docked inside the
lipophilic core of SUGAMMADEX
• The negatively charged carboxy-ethyl
groups hold rocuronium tightly
• 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
SUGAMMADEX BINDING
REACTION
DRUG
SPEED OF REACTION
ROCURONIUM
25
VECURONIUM
10.0
PANCURONIUM
2.6
ATRACURIUM
SUCCINYL CHOLINE
0.005
0
ROCURONIUM > VECURONIUM > PANCURONIUM
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)
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
2. CAPTURING
Sugammadex binding another drug,
decreasing its free concentrations
Potential risk of reduction in efficacy
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
• 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)
But no clinical evidence of
interactions was found during clinical
trials in approximately 2000 patients
ANTON BOM.,MD., PhD, SENIOR RESEARCH FELLOW, PHARMACOLOGY
SIDE EFFECTS OF SUGAMMADEX
• A multicentric trial conducted on 86 subjects the following side
effects were noted.
NONE WERE SERIOUS
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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 dosefinding and safety study. Anesthesiology 2006;104:667–74.
• In one study, PROLONGATION OF
THE CORRECTED QT interval was
noted in five subjects who received
placebo and in three subjects who
received sugammadex
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
DOSAGE
• SHALLOW BLOCK
2.0 – 4.0 mg/kg -Reverses rocuroniuminduced 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
• 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
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
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
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
WHY IS THIS COMBINATION
BETTER THAN
SUXAMETHONIUM?
• Reversal of profound rocuronium-induced
(1.2mg/kg) neuromuscular block with
sugammadex was significantly
FASTER THAN SPONTANEOUS RECOVERY
FROM SUCCINYLCHOLINE
• Sugammadex offers the possibility of
IMMEDIATE REVERSAL of
rocuronium-induced block in a possible
scenario of
FAILED VENTILATION / FAILED
INTUBATION
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.
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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.
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
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
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
• 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
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.
• 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
THE DAYS TO SAY
GOOD BYE TO
SUXAMETHONIUM
ARE NOT FAR OFF