Anticholinesterases And

Sugammadex
Dr. Sachana KC
1st year Resident
Department Of Anesthesiology
Overview

 Anticholinesterses
 Neostigmine
 Physostigmine
 Sugammadex
 MOA
 Uses
 Introduction of Anticholinesterases
 Blocking or inhibiting the breakdown of ACh at the NMJ results in an
increase in the available pool of ACh at the synaptic cleft and better
chances of competing with the nondepolarizing NMBA for binding to the
receptor’s α- subunit; this binding of ACh to nAChR results in normal
transmission.
 Clinically available acetylcholinesterase inhibitors (anticholinesterase
agents) in clinical use today: neostigmine, edrophonium, and
pyridostigmine.
 Physostigmine, another cholinesterase inhibitor, is a tertiary amine, but
because it crosses the blood–brain barrier (and has central effects), it is not
used for pharmacologic reversal of neuromuscular block.
Contd…

 They are indirectly acting cholinomimetics.

 They block the enzymatic hydrolysis of acetylcholine, by inhibition
of acetylcholinesterase and plasma pseudocholinesterase.
 They increase the local acetylcholine concentrations and
accumulation of the endogenous ACh. inducing both the Muscarinic
and Nicotinic actions.
Classification
Reversal of Neuromuscular blockade

Theoretically possible by three

principal mechanisms:
 a decrease in enzymatic metabolism
of acetylcholine by cholinesterase,
thereby increasing receptor binding
competition
 an increase in presynaptic release of
acetylcholine
 a decrease in the concentration of
the NMBD, hence, freeing the
postsynaptic receptors
Mechanism of Action

Enzyme inhibition
 Inhibit the enzyme acetylcholinesterase reversibly-results in greater
availability of ACh at its sites of action,
Presynaptic effects
 In the absence of nondepolarizing neuromuscular-blocking drugs,
administration of an anticholinesterase drug may produce spontaneous
contractions (fasciculations) of skeletal muscles
 These presynaptic effects are abolished by a small dose of a
nondepolarizing neuromuscular-blocking drug, suggesting that
acetylcholine receptors are involved
Direct effects on the neuromuscular junction
Contd…

 Neostigmine and to some extent pyridostigmine display some

limited pseudocholinesterase inhibiting activity, but their effect on
acetylcholinesterase is much greater.
 Edrophonium has little or no effect on pseudocholinesterase.
Metabolism and Clearance

 Hepatic metabolism accounts for

 50% elimination of Neostigmine
 30% of Edrophonium
 25% of Pyridostigmine
 Metabolites of anticholinesterases do not contribute significantly to
the effects of parent drug
 Physostigmine is almost completely metabolized by plasma
esterases.
Contd…

 Renal clearance : 50% elimination of Neostigmine

75% elimination of Edrophonium
Pyridostigmine
 Actively secreted into the lumens of renal tubules
 Elimination half times greatly prolonged in Renal dysfunction
Depending Factors

Antagonism of Nondepolarizing neuromuscular blockade by

acetylcholinesterase inhibitors depends primarily on following factors:
 The depth of the blockade when reversal is attempted
 The anticholinesterase chosen
 The dose administered
 The rate of spontaneous clearance of the neuromuscular blocker
from plasma
 The choice and depth of anesthetic agents administered
Contd…

 Reversal of ND-NMB requires only the nicotinic cholinergic effects

of the anticholinesterase drugs
 Muscarinic cholinergic effects of Anticholinesterase drugs are
attenuated or prevented by concurrent administration of
anticholinergic drugs
 When reversing neuromuscular blockade, the primary goal is to
maximize nicotinic transmission with a minimum of muscarinic side
effects
Depth of the blockade when the
antagonist is administered.
 Generally, more time is required to antagonize profound levels than
lesser levels of blockade.
 Neostigmine shortened the recovery time by approximately 40%.
 Maximum antagonistic effect of neostigmine occurs in 10 minutes or
less.
 Adequate recovery does not occur within this time, subsequent recovery
is slow and requires ongoing elimination of the neuromuscular blocker
from plasma.
 Administration of a second dose of neostigmine has no further effect on
recovery because acetylcholinesterase is already maximally inhibited
Concentration of inhaled anesthetic
agent present during reversal

 Antagonism of residual blockade is actually retarded by

anesthetizing concentrations of anesthetic vapors.
 Reversal of rocuronium by neostigmine under sevoflurane
anesthesia occurred more slowly than under Propofol anesthesia.
 Sevoflurane may impede neostigmine-induced antagonism more
than isoflurane does.
Contd…

 When compared with recovery from isoflurane anesthesia, recovery

from that produced by desflurane or sevoflurane is prolonged.
 Withdrawal of the anesthetic vapor at the end of surgery, with
subsequent reduction of its enhancement of neuromuscular
blockade, will speed pharmacologic reversal.
Rate of Spontaneous Recovery from
Neuromuscular Blocker
 Two processes contribute to recovery
 effect of the anticholinesterase at the neuromuscular junction
 natural process of decrease in plasma concentration of NMB.
 Therefore, the more rapid the elimination of the neuromuscular
blocker, the faster the recovery of adequate neuromuscular function
after the administration of an antagonist.
Muscarinic Side Effects
 NEOSTIGMINE

 Carbamate with Quaternary Ammonium Group

 Lipid Insoluble : doesn’t cross BBB
 Onset : 5 to 10 minutes ( peak at 10 min)
 Duration : lasts for more than 1 hour ( upto 4 hrs)
 Bioavailability : Unclear, probably less than 5%
 Biological half-life : 50–90 minutes
 Excretion : Unchanged drug (up to 70%) and alcoholic
metabolite (30%) are excreted in the urine
Contd…

Quaternary
Ammonium group
Carbamate moiety renders lipid
covalent bonding with AChE insoluble
so cannot cross BBB
Contd…

 Glycopyrrolate is the preferred anticholinergic to be

used along with Neostigmine
 0.2 mg Glycopyrrolate per mg of Neostigmine
 If Atropine is used, 0.4 mg per mg of Neostigmine
 Neostigmine crosses placenta and can result in Fetal
Bradycardia
 Atropine preferred in Pregnant patients receiving
Neostigmine
Usual Adult Dose for Reversal of
Neuromuscular Blockade
 Initial dose: 0.03 mg/kg to 0.07 mg/kg injected intravenously over a
period of at least 1 minute
Maximum dose: 0.07 mg/kg or up to a total of 5 mg, whichever is
less

Usual Pediatric Dose for Reversal of Neuromuscular Blockade

 Initial dose: 0.03 mg/kg to 0.07 mg/kg injected intravenously over a
period of at least 1 minute
Maximum dose: 0.07 mg/kg or up to a total of 5 mg, whichever is
less
Contd…

Usual Adult Dose for Myasthenia Gravis

 Oral:
15 to 375 mg orally daily
Average dose: 150 mg (10 tablets) orally over a 24 hour period
 Parenteral:
1 mL of 1:2000 solution (0.5 mg) subcutaneously or intramuscularly
Side effects

General
 The most common side effects included salivation, fasciculation, bowel cramps and
diarrhea.
Cardiovascular
 Common (1% to 10%): Bradycardia, hypotension, tachycardia
 Frequency not reported: Nonspecific EKG changes, cardiac arrest, syncope
 Postmarketing reports: Cardiac arrhythmias (A-V block, nodal rhythm)
Gastrointestinal
 Common (1% to 10%): Dry mouth, nausea (including post-procedural), vomiting
 Frequency not reported: Flatulence, increased peristalsis
 Postmarketing reports: Bowel cramps, diarrhea
Contd…

Dermatologic
 Common (1% to 10%): Pruritus
 Frequency not reported: Rash, urticarial
Genitourinary
 Frequency not reported: Urinary frequency
Hypersensitivity
 Frequency not reported: Allergic reactions and anaphylaxis
Contd…

Musculoskeletal
 Frequency not reported: Muscle cramps and spasms, arthralgia
 Postmarketing reports: Muscle weakness
Nervous system
 Common (1% to 10%): Dizziness, headache, postoperative
shivering, prolonged neuromuscular blockade, insomnia
 Postmarketing reports: Convulsions, drowsiness, dysarthria,
fasciculation, loss of consciousness
Contd…

Respiratory
 Common (1% to 10%): Pharyngolaryngeal pain, dyspnea, oxygen
desaturation (less than 90%)
 Frequency not reported: Increased oral, pharyngeal and bronchial
secretions, dyspnea, respiratory depression, respiratory arrest,
bronchospasm
Ocular
 Frequency not reported: Miosis, visual changes
Contd…

Neostigmine Pregnancy Warnings

 FDA pregnancy category C: Animal reproduction studies have
shown an adverse effect on the fetus and there are no adequate and
well-controlled studies in humans, but potential benefits may
warrant use of the drug in pregnant women despite potential risks.
PHYSOSTIGMINE

 Natural alkaloid derived from Calabar bean (Physostigma

venenosum)
 Tertiary amine
 Lacks quaternary ammonium : lipid soluble
 Penetrates CNS: limits use as reversal agent
 Effective in reversing:
 Central anticholinergic actions due to Atropine or Scopolamine
overdosages
 Benzodiazepine and volatile anaesthetic induced CNS depression
and delirium
Contd…

Has Carbamate group but no quaternary

Ammonium; thus lipid soluble : Crosses BBB
Contd…

 Effective in preventing post-operative shivering (0.04 mg/kg)

 May partially antagonize the respiratory depression caused by
Morphine.
 Glycopyrrolate will not reverse the CNS effects of Physostigmine.
 Almost completely metabolized by plasma esterases-- renal
excretion not important.
Doses

Usual Adult Dose for Anticholinergic Syndrome:

 Post anesthesia care:
Initial dose: 0.5 to 1 mg, IM or slow IV, at no more than 1
mg/minute
May repeat dose at 10 to 30 minute intervals if desired response is
not obtained.
 Overdose of drugs that cause anticholinergic syndrome:

2 mg, IM or slow IV, at no more than 1 mg/minute

May repeat dose if life threatening signs (e.g. arrhythmia,
convulsions, coma) occur.
Contd…

Usual Pediatric Dose for Anticholinergic Syndrome:

 0.02 mg/kg, IM or slow IV, at no more than 0.5 mg/minute
May repeat dose at 5 to 10 minute intervals if toxic effects persist
(and no cholinergic effects) until a therapeutic effect is obtained.
Maximum dose: 2 mg
Side effects

Cardiovascular
 Frequency not reported: Bradycardia
 Bradycardia may occur if intravenous administration is too rapid.
Nervous system
 Convulsions may occur if intravenous administration is too rapid.
Gastrointestinal
 Frequency not reported: Nausea, vomiting, hypersalivation.
 Nausea, vomiting, and salivation can be offset by a reduction in
dosage
Physostigmine Pregnancy Warnings

 US FDA pregnancy category C: Animal reproduction studies have

shown an adverse effect on the fetus and there are no adequate and
well-controlled studies in humans, but potential benefits may
warrant use of the drug in pregnant women despite potential risks.
Uses of Anticholinersterases

 Primary use : to reverse the Nondepolarizing neuro-muscular blockade

 Reversal agents are routinely given to patients who have received non-
depolarizing muscle relaxants.
OTHER USES
 Edrophonium- Tensilon test - diagnosis of Myasthenia gravis
 Neostigmine, Pyridostigmine and Ambenonium – Standard Anticholinesterases used
in Myasthenia gravis.
 Oral dose is much higher as- Neostigmine and Pyridostigmine are lipid insoluble.
 Muscarinic side effects need to be controlled with anticholinergic agents
 Bromide toxicity – with Pyridostigmine Bromide
Contd…

GLAUCOMA
 Decrease intraocular pressure in Narrow angle and wide angle
Glaucoma
 Physostigmine eye drops
 Ecothiophate (Organophosphate with quaternary structure)
 Demecarium
Contd…

ALZHEIMER’S DISEASE
 Neurodegenerative : Cholinergic neurons also affected
 Mild to moderate Alzheimer disease.
 Cerebroselective AChEi :
 donepezil
 rivastigmine
 tacrine (significant liver toxicity)
 galantamine
Contd…

Central Anticholinergic Syndrome

 Overdosage of Atropine or
Scopolamine
 Restlessness and Confusion
 Physostigmine used – Lipid soluble
Contd…

 Physostigmine abolishes the somnolent effects of Opioids and

Volatile anaesthetics
 Physostigmine may also be used to reverse the ventilatory
depression caused by Morphine without decreasing its analgesic
effects
 Physostigmine (40ugm/kg IV) following anaesthesia decreases the
incidence of postoperative shivering
Contd…

 Diagnosis and management of Cardiac Dysrhythmias

 Edrophonium – Paroxysmal SVTs
 5-10mg slows heart rate with no effect on ventricular contractility, conduction or
peripheral vascular tone
 Post-operative Ileus / Urinary Retention
 Neostigmine 0.5 to 1 mg SC
 Organic Obstruction has to be ruled out first

 Belladonna Poisoning
 Anticholinergic excess
 Physostigmine preferred
Contd…

 Neostigmine as neuraxial anaesthesia adjunct

 Intrathecal (50 – 100 mcg)
 Epidural (1 – 4 mcg/kg)
 Analgesia produced is probably by inhibiting the breakdown of
spinal released Ach which is increased in presence of pain
 Disadvantages – High incidence of nausea and vomiting, pruritis,
prolongation of sensory and motor block
Usual doses
Sugammadex (ORG 25969)

 Sugammadex is in the family of cyclic dextrose units used as

solubilizing agents since 1953.
 Modfied gamma-cyclodextrine-comprised of 8 sugar molecules that
form a rigid ring with a central lipophilic cavity.
 Initially discovered when a compound was needed to increase the
solubility of rocuronium in a specific media.
 Observed permanent binding of the rocuronium molecule to the
center of the sugammadex molecule in a 1:1 ratio.
Contd…

 It is the the most exciting drug in clinical neuromuscular

pharmacology.
 The combination of rocuronium and sugammadex could replace
succinylcholine for rapid-sequence induction of anesthesia and
completely eliminate residual paralysis in the post anesthetic
recovery room.
Contd…

 Is the first selective relaxant binding agent.

Su -- sugar, and gammadex --γ-cyclodextrin.
 Three-dimensional structure- doughnut.
 Hydrophobic cavity and a hydrophilic exterior -- presence of polar
hydroxyl groups.
 Hydrophobic interactions trap the drug -- water-soluble guest-host
complex.
Figure : Chemical Sturcture of Sugammadex (Bridion)
Mechanism of action

 Hydrophobic interactions trap the drug in the cyclodextrine cavity

forming a tight water-soluble complex in a 1:1 ratio (encapsulation)
 A concentration gradient is created with no free unbound NDMR in
the plasma as compared to the extravascular compartment
 Favors movement of NDMR (rocuronium or veuronium) into the
plasma where they are rapidly encapsulated
 Terminates the NDMR’s action and restrains the drug in
extracellular fluid where it cannot interact with nicotinic
acetylcholine receptors
Pharmacodyamics

 Sugammadex is biologically inactive and does not bind to plasma

proteins.
 Metabolism of sugammadex very limited, and the drug is
predominantly eliminated unchanged by the kidneys- approximately
75%
 Sugammadex should be avoided in patients with a creatinine
clearance of <30 mL per minute.
Pharmacokinetics

 Sugammadex, used in appropriate doses, is capable of reversing any

depth of neuromuscular blockade (profound or shallow) induced by
rocuronium or vecuronium
 During rocuronium or vecuronium-induced neuromuscular
blockade, intravenous administration of sugammadex results in
rapid removal of free rocuronium or vecuronium molecules from
the plasma.
 Sugammadex is ineffective against succinylcholine and
benzylisoquinolinium neuromuscular blockers such as mivacurium,
atracurium, and cisatracurium because it cannot form inclusion
complexes with these drugs.
Suggamadex Effect on Rocuronium

 Rocuronium volume of distribution ~50 L reduced to 15L with

sugammadex
 14% rocuronium excreted in urine within 24 h increased to 39-68%
with sugammadex
 Renal excretion of rocuronium is increased by more than 100% after
the administration of 4 to 8 mg/kg of sugammadex.
Contd…

 Administration of 8 mg/kg of sugammadex 3 minutes after the

administration of 0.6 mg/kg of rocuronium resulted in recovery of
the TOF ratio to 0.9 within 2 minutes.
 Dose of sugammadex to 4 mg/kg resulted in recovery of the TOF
ratio to 0.9 in less than 4 minutes.
 Sugammadex decreased the median recovery time to 1.1 minutes in
pt given 4.0 mg/kg of sugammadex.
Contd…

 Administration of sugammadex when the TOF count had returned to

two detectable responses resulted in a dose-dependent recovery
from the neuromuscular blockade induced by either rocuronium
(0.60 mg/kg) or vecuronium (0.10 mg/kg).
 After a dose of 4.0 mg/kg of sugammadex, the mean time to
recovery of the TOF ratio to 0.9 was 1.1 and 1.5 minutes after
rocuronium and vecuronium, respectively.
Contd…

 Takes effect more quickly and reliably than either neostigmine or

edrophonium.
 The average time to achieve a TOF ratio of 0.9 with
neostigmine(70ug/kg):edrophonium(1mg/kg):sugammadex(4mg/kg)
was 10:3:1 comparitively
 More complete recovery of neuromuscular function .
 The choice of anesthetic agent (e.g., Propofol versus sevoflurane)
does not appear to influence the ability of sugammadex to
antagonize rocuronium-induced neuromuscular blockade.
Contd…

 Rapid and effective reversal of even more profound rocuronium-

induced neuromuscular blockade.
 Pt receiving an intubating dose of 1.2 mg/kg of rocuronium followed 3
minutes later by 16 mg/kg of sugammadex or an intubating dose of 1.0
mg/kg of succinylcholine.[The mean time to 90% recovery of first
twitch was significantly faster in the rocuroniumsugammadex group
than it was in the succinylcholine group.
 Therefore, the use of rapid-sequence induction with rocuronium can be
facilitated by the presence of sugammadex.
Doses

 Available: 2mL or 5mL vials (100mg/mL)

Contd…

 Delivered as a bolus within 10 seconds.

 Onset: Less than 3 minutes

Compared to Neostigmine
 Mechanism of action, as you can see, is completely different from
neostigmine
 No parasympathetic effects. No anticholinergic drugs required.
 Speed of reversal has been found to be 3-8 times faster than
neostigmine
Side effects

 The ability of sugammadex to form complexes with steroidal and

nonsteroidal compounds such as cortisone, atropine, and verapamil is
probably clinically insignificant and is 120 to 700 times less than that
of rocuronium.
 Most frequently reported side effects have been hypotension, coughing,
nausea, vomiting, dry mouth, parosmia (an abnormal sense of smell), a
sensation of a changed temperature, and abnormal levels of N-
acetylglucosaminidase in urine.
 In one study, prolongation of the corrected QT interval was noted in
five subjects who received placebo and in three who received
sugammadex.
Safety

 The U.S. Food and Drug Administration has expressed

concerns about the safety of sugammadex, citing its possible
association with
 Allergic reactions, and
 Bleeding
 Received U.S. Food and Drug (FDA) approval on December
15th, 2015.
 More than 5 million doses of sugammadex have been
administered worldwide.
Sugammadex Pregnancy Warnings

US FDA pregnancy category: Not Assigned

 US FDA pregnancy category Not Assigned: The US FDA has
amended the pregnancy labeling rule for prescription drug products
to require labeling that includes a summary of risk, a discussion of
the data supporting that summary, and relevant information to help
health care providers make prescribing decisions and counsel
women about the use of drugs during pregnancy. Pregnancy
categories A, B, C, D and X are being phased out.
Contd…

AU TGA pregnancy category: B2

 AU TGA pregnancy category B2: Drugs which have been taken by
only a limited number of pregnant women and women of
childbearing age, without an increase in the frequency of
malformation or other direct or indirect harmful effects on the
human fetus having been observed. Studies in animals are
inadequate or may be lacking, but available data show no evidence
of an increased occurrence of fetal damage.
References

 Stoelting’s Pharmacology and Physiology in Anesthetic Practice 5th

Edition (2015).
 Clinical Anesthesia P. G Barash 8th Edition
 Images : Google images
 Sugammadex: An Update ;The Journal of Critical Care Medicine
2016;2(1):16-21
Thank you
General Findings

 Extensive research and numerous clinical trials have evaluated the

safety, efficacy, and usefulness of sugammadex
 A metaanalysis including 18 randomized controlled trials
demonstrated that sugammadex can reverse rocuronium induced
blockade faster than neostigmine at all levels of blockade in a dose
dependent manner
 In trials of immediate reversal sugammadex (16mg/kg) was
administered 3 minutes after profound blockade by rocuronium and
showed faster recovery than patients who underwent spontaneous
recovery from succinylcholine.