reversal of muscle relaxant. rocuroniumSugammadex.ppt

anaesthesia

1. Despite its undesirable adverse effects, neostigmine has remained
the most common anticholinesterase agent used by anesthesiologists
worldwide.
Only a few studies have explored the potential of nonclassic reversal
drugs that act independently of acetylcholinesterase inhibition.
One such agent, purified human plasma cholinesterase, has been
shown to be effective and safe in antagonizing mivacurium-induced
neuromuscular blockade.
Similarly, cysteine has been shown to reverse the neuromuscular
blocking effects of gantacurium.
In addition, sugammadex, a novel selective relaxant binding agent, is
able to reverse both shallow and profound aminosteroid-induced
neuromuscular blockade, and has a unique mechanism of action,which
distinguish it from other agents.

2. Sugammadex[6
A
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H
-octakis-S-
(2-carboxyethyl)-6
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H
-octathio-γ-
cyclodextrin octasodium salt] is a modified γ-
cyclodextrin .
Properties of Cyclodextrins:
1.Very water-soluble
2. Not metabolized
3. Renally excreted

3. Cyclodextrins are cyclic dextrose units joined through
1-4 glycosyl bonds that are produced from starch or
starch derivates using cyclodextrin
glycosyltransferase. The three natural unmodified
cyclodextrins consist of 6, 7 or 8 cyclic
oligosaccharides and are called α-, ß-or γ-
cyclodextrin, respectively. α-cyclodextrin, ß-
cyclodextrin and γ-cyclodextrin are naturally
occurring compounds derived from the degradation of
starch by the glucosyl transferase enzyme. They can
be formed naturally from bacteria or manufactured
synthetically.

4. CONTINUED…..
Compared with α-and ß-cyclodextrins, γ-
cyclodextrin exhibits more favorable properties in
terms of the size of its internal cavity, water
solubility and bioavailability. This is because the α-
and ß-cyclodextrins have smaller lipophilic cavities
(<6.5 Å diameters) and form less stable complexes
with the bulky aminosteroid neuromuscular blocker
molecule (e.g., rocuronium or vecuronium;
molecule width ~7.5 Å) compared with the γ-
cyclodextrin molecule, which has a larger lipophilic
cavity (7.5-8.3 Å diameter).

5. CONTINUED…..
Tohave a better fit of the larger rigid structure of the aminosteroid
neuromuscular blocker molecule (e.g., rocuronium or vecuronium)
within the cavity of γ-cyclodextrin, the latter was modified by adding
eight side chains to extend the cavity.This modification allowed the
four hydrophobic steroidal rings of rocuronium to be better
accommodated within the hydrophobic cavity. In addition, adding
negatively charged carboxyl groups at the end of the eight side chains
served two purposes. First, the repellent forces of the negative charges
keep propionic acid side chains from being disordered, thereby
allowing the cavity to remain open and maintain structural integrity.
Second, adding these negatively charged carboxyl groups enhanced
electrostatic binding to the positively charged quaternary nitrogen of
rocuronium

6. CONTINUED…..
These modifications resulted in a sugammadex compound
(with a molecular weight of 2178) that is highly water
soluble, with a hydrophobic cavity large enough to
encapsulate steroidal neuromuscular blocking drugs,
especially rocuronium.
Sugammadex exerts its effect by forming very tight
complexes at a 1:1 ratio with steroidal neuromuscular
blocking agents (rocuronium > vecuronium >>
pancuronium).The intermolecular (van der Waals') forces,
thermodynamic (hydrogen) bonds and hydrophobic
interactions of the sugammadex-rocuronium complex
make it very tight.

7. SUGAMMADEX

8. Sugammadex does not bind to plasma proteins
.
When
administered by itself in volunteers who had not
received a neuromuscular blocking agent, doses of
sugammadex 0.1-8.0 mg/kg had a clearance rate of 88
ml/min, an elimination half-life of 1.8 hand a volume
of distribution of 11-14 l.
[22,60]
Approximately 75%
of the dose was eliminated through the urine. The
mean percentage of the dose excreted in urine up to 24
h after administration varied between 59 and 80%.
[22]
The kinetics of sugammadex appeared to be linear
when the sugammadex dose was increased from 0.1
to 8.0 mg/kg.
[22]

9. CONTINUED…..
In the absence of sugammadex, rocuronium is
eliminated mainly by biliary excretion (>75%)
and to a lesser degree by renal excretion (26%).
As noted earlier, after administration of
sugammadex, the plasma concentration of free
rocuronium decreases rapidly, but the total
plasma concentration of rocuronium (both free
and that bound to sugammadex) temporarily
increases.

10. CONTINUED…..
Owing to the soluble nature of the sugammadex-
rocuronium complex, urinary excretion of the
complex is the major route for the elimination of
rocuronium (65-97% of the administered dose is
recovered in urine). Excretion is rapid:
approximately 70% of the administered dose is
excreted within 6 h, and more than 90% within
24 h. The renal excretion of rocuronium over 24
h is increased by more than 100% after the
administration of sugammadex 4-8 mg/kg.

11. CONTINUED…..
Metabolism of sugammadex is at most very
limited, and is predominantly eliminated
unchanged by the kidneys. In patients with
substantial renal impairment, compared with
healthy subjects, the clearance of sugammadex
and rocuronium was decreased by a factor of
17 and 4, respectively, and the elimination half-
life was increased by a factor of 15 and 2.5,
respectively. Therefore, sugammadex should be
avoided in patients with a creatinine clearance
of less than 30 ml/min.

12. Since sugammadex was first described in the literature in
2002,
[15]
it has undergone Phase I-III clinical trials that
have enrolled 2054 subjects. In spring 2008, a US FDA
Anesthetic and Life Support Advisory Committee
reviewed the available data and unanimously
recommended that an application to the US FDA be
submitted seeking approval for "routine reversal of
shallow and profound rocuronium-or vecuronium-
induced neuromuscular blockade and for immediate
reversal of rocuronium-induced blockade at 3 min
after administration of rocuronium"

13. CONTINUED…..
The specific dosing recommendations for which
approval was sought included:
1. A dose of 2 mg/kg for routine reversal of shallow
blockade (at the reappearance of the T2 of the US TOF);
2.A dose of 4 mg/kg for reversal of profound
blockade (at the appearance of one to two post-tetanic
counts);
3.A dosage of 16 mg/kg for immediate reversal 3
min after administration of rocuronium, such as in a
'cannot ventilate, cannot intubate' (rescue) scenario.

14. The sugammadex clinical development program
included data from 30 worldwide clinical trials in
2054subjects who received sugammadex. In all of
the reported trials made available by the
developer, sugammadex was compared with
neostigmine (and placebo)with regard to the
incidence of adverse effects.
The highest sugammadex dose studied in the
clinical development program was 96 mg/kg (n
= 12 in trial 19.4.106).

15. CONTINUED…..
Sugammadex is rapidly cleared from most organs; however, it
may be retained in the matrices of bone and teeth, possibly due to
reversible binding to the hydroxyapatite (the inorganic matrix)
present in rat bone and teeth.
Owing to its molecular size and charge, sugammadex exhibits
very low transfer across the placenta and the blood-brain
barrier.
Other adverse drug reactions associated with the administration
of sugammadex included a change in taste (dysgeusia), which
occurred with an eight-times greater frequency than in the
placebo group.
CONTRACEPTIVE FAILURE?

16. CONTINUED…..
The safety of sugammadex in patients with end-stage renal
failure was reported recently.In this study, patients with
creatinine clearance less than 30 ml/min had rapid reversal of
rocuronium block that was similar to the reversal in normal
patients. There were no serious adverse events possibly
related to administration of sugammadex.
Sugammadex-related serious adverse events were
reported in seven (0.4%) patients during the clinical
development of sugammadex: these were QTc
prolongation, bronchospasm, respiratory failure,
hypotension and atrial fibrillation.

17. CONTINUED…..
Other adverse events and serious adverse events
reported in the literature included: diarrhea, light
anesthesia and QTc prolongation;headache, slightly
increased liver enzymes, irritation at injection site, dry
mouth and oral discomfort;atrial fibrillation, pyrexia,
rigors, agitation, polyuria, urinary retention and
dyspnea; hypotension beginning 10 min after
sugammadex administration and lasting for 5 min
(although this was temporally related to administration
of propofol and fentanyl) and coughing; and abdominal
discomfort, tachycardia and erythema.

18. Methods: Thirty adult patients were studied:
15 renally impaired [creatinineclearance
(CL
CR) <30 ml min
–1
] and 15 controls
(CL
CR>80ml min
–1
). Anaesthesia was
induced and maintained usingi.v. opiates
and propofol.

19. CONTINUED…..
Neuromuscular monitoring was performedby
acceleromyography and train-of-four (TOF) nerve
stimulation.Rocuronium (0.6 mg kg
–1
) was given, followed
by a singlei.v. dose of sugammadex (2.0 mg kg
–1
) at
reappearanceof the second twitch of the TOF. The primary
efficacy variablewas time from administration of
sugammadex to recovery of theTOF ratio to 0.9.
Results: After sugammadex administration, the mean (SD)
time to recoveryof the TOF ratio to 0.9 was 2.0 (0.72) min in
renal patientsand 1.65 (0.63) min in controls (NS).
Recurrence of NMB wasnot observed in any patient. No
sugammadex-related serious adverseevents were reported.

20. Conclusions: Sugammadex administered at reappearance
of T
2rapidly and effectivelyreverses NMB induced by
rocuronium in renal failure and healthypatients.
Sugammadex was well tolerated by all patients.
Furthersafety studies on sugammadex in patients with
severe renal impairmentare warranted.
L. M. Staals, M. M. J. Snoeck, J. J. Driessen, H. W. van
Hamersvelt, E. A. Flockton, M. W. van den Heuvel, and J.
M. Hunter
Reduced clearance of rocuronium and sugammadex in
patients with severe to end-stage renal failure: a
pharmacokinetic study
Br. J. Anaesth., January1,2010; 104(1): 31 -39.
[

21. Whatcanwelookforwardto?
Doestheintroductionofsugammadexheraldthe
eliminationofmanyoftheshortcomingsinour
clinicalpracticewithregardtoantagonismof
neuromuscularblockers?

22. The deep levels of neuromuscular blockade induced
by rocuronium(and possibly by vecuronium, )can be
promptly antagonized with appropriatedoses of
sugammadex. This should make surgical care much
easierand safer.
Surgeons should no longer encounter inadequate
musclerelaxation, and anesthesiologists should no more
encounter patientswhose neuromuscular blockade is hard
to reverse at the end ofsurgery.
The introduction of sugammadex into clinical
practicewould thus contribute to both increased
patient safety and improvedsurgical conditions.

23. Additionally, no anticholinesterase or anticholinergic
drugswould be needed for the antagonism of residual
neuromuscularblockade, which would mean the end
of the cardiovascular andother side effects of these
compounds .
The postoperativenausea and vomiting associated
with the use of these compoundsshould also be
eliminated .
Will sugammadex replace neostigmineas an
antagonist for rocuronium-induced neuromuscular
blockade?Kopman rightly believes that this will "...
depend at leastin part on economic considerations."

24. Dowestillneedtouseneuromuscular
functionmonitoringwithsugammadex?
Without knowing the depth of the rocuronium-
inducedneuromuscular blockade, it would be difficult
to know the doseof sugammadex needed. Perhaps
conventional nerve stimulatorswould be sufficient to
determine the presence or absence ofthe twitch
response, and the appropriate dose of
sugammadexcould be administered accordingly.
Further, the use of rapid-sequence induction with
rocuroniumcan be facilitated by the presence of
sugammadex.

25. The introduction of propofol almost two decades ago
changedanesthetic practice. Nothing since then, however,
has hadthe same effect.
Unquestionably, the introduction of sugammadexis an
important breakthrough, and one that is likely to changethe
face of clinical neuromuscular pharmacology.
Fornow, however, we still need benzylisoquinolinium
neuromuscularblockers in our practice, so the residual
postoperative muscleweakness caused by this class of drugs
is likely to continueunless objective neuromuscular function
monitors are routinelyused, or until a molecule capable of
binding to benzylisoquinoliniumneuromuscular
blockers is discovered.

26. Kopman AF. Sugammadex: a revolutionary approach
to neuromuscular antagonism. Anesthesiology
2006;104:631–3.
Shields M, Giovannelli M, Mirakhur RK, et al. Org
25969 (sugammadex), a selective relaxant binding
agent for antagonism of prolonged rocuronium-
induced neuromuscular block. Br J Anaesth
2006;96:36–43
Bom A, van Egmond J, Hope F, van de Pol F. Rapid
reversal of rocuronium-induced neuromuscular block
by Org 25969 is independent of renal perfusion.
Anesthesiology 2003;99:A1158.