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

HYPERKALEMIA

MUSCLE PAIN

MALIGNANT HYPERTHERMIA

PHASE 2 BLOCK

EARLY ONSET FAST RECOVERY

FASCICULATIONS

RAISE IN ICT , IOT

RELEGATED AGENTS• 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

• ROCURONIUM

• MIVACURIUM

• FAZADINIUM

ALL THESE AGENTS WERE TRIED BUT NONE COULD

REPLACE SUXAMETHONIUM

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• WITHDRAWN FROM MARKET WITHIN A YEAR DUE TO FATAL BRONCHOSPASM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

• 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

• 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 0.005

SUCCINYL CHOLINE 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. • 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.

• 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 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

• 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.

• 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