About the newer drugs in anaesthesia. What are the problems with the existing drugs? Which all drugs failed commercially? And why? Which are the newer drugs in anaesthesia?

1. Recent Advances in
Anaesthetic Drugs
Dr Unnikrishnan P
Additional Professor,
Division of Neuroanaesthesia & Neurocritical Care
SCTIMST,
Trivandrum

2. Disclaimer
▪ The content is only intended as teaching material for students
▪ Please refer other sources for clinical practice
▪ I don’t have any affiliations with any of drug manufacturers mentioned in
this powerpoint
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3. 3
Newer drugs
for
anaesthesia &
sedation
Why we
need..

4. Are the existing agents perfect ?
 Etomidate and ketamine have a remarkable capacity for supporting
BP in compromised patients; however, other shortcomings make them
inferior to propofol
 Respiration is less affected by etomidate, ketamine, and
dexmedetomidine than by propofol.
 Benzodiazepines as anaesthetics: A high variability in drug response, a
relatively slow onset of action and long lasting residual effect-
Flumazenil needed to prevent re-sedation. Dependency. Tolerance.
Tachyphylaxis.
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5. What’s our expectation in this new era?
▪ MAP <80 mm Hg >10 minutes is a cause for organ injury
▪ Postoperative delirium (a perioperative neurocognitive disorder) is
distressing for patients and staff, associated with impaired outcomes and
adds to costs.
▪ Acceleration of drug effect onset and offset
▪ PONV: Propofol, Midazolam are antiemetic
▪ The ability to support swift and atraumatic placement of a supraglottic
airway
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6. PROBLEMS WERE THERE; BUT DIDN’T FAIL
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DRUG Idiosyncratic reaction example
Etomidate PONV, Inconvenient muscle movements
Adrenocortical suppression
Thiopental Anaphylaxis
Propofol Pain on injection, hypotension
Ketamine Hallucination
Dexmedetomidine Bradycardia, Hypotension
Thiopental has been removed from the WHO Model List of Essential Medicines and is no
longer available in the USA after physician and pharmaceutical industry rejection of its
use in judicial killing. In Europe and elsewhere, thiopental remains available and locally
popular, but repeated accidental syringe swaps for antibiotic or local anaesthetic and
clinician unfamiliarity have driven obstetric anaesthesiologists towards propofol.

7. FAILURES
7
DRUG Failed due to Idiosyncratic reactions/ other issues
Pregnanolone Urticaria
Fospropofol Significant perineal pain
ABP 700 (Etomidate
derivative)*
Anaphylaxis
Volatile agents for
sedation
Need for scavenging, equipment issues, sedation with
sevoflurane Diabetes insipidus
Semi-autonomous
SEDASYS®
Lost out to in-person care

8. 8
Ciprofol
Remimazolam
Alfaxalone
Esketamine
Etifoxine
ABP 700

9. Place your screenshot here
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Follow the order

10. 1. CIPROFOL
Structural analogue of propofol

11. CIPROFOL
▪ Intravenous anaesthetic agent
▪ Uses: FDA/EMA (--); sedation & induction of anaesthesia (NMPA-China)
▪ Chemical characteristics/Presentation: Continued use of lipid formulation-
but lesser lipid exposure with 1% emulsion; under the same conditions and
at the same concentrations, ciprofol has a lower free drug concentration in
the aqueous phase less pain on injection. Also less solvent required
▪ MOA: Stronger affinity to GABA receptor
▪ Routes of administration and dosing: IV; 0.15–0.90 mg/kg (Teng Y et al)
0.4–0.9 mg/kg (Qin L et al)
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12. CIPROFOL
▪ Pharmacokinetics: ADME; 4-5 more potent dose requirement↓ less
RS,CVS side effects
▪ Pharmacodynamics: longer duration of action; less rapid recovery.
▪ Side effects: ~; Similar adverse haemodynamic impact to that of propofol;
less respiratory depression. Significantly less pain on injection.
▪ Special Points:
▪ Ciprofol is currently undergoing late-stage clinical trials for procedural
sedation, and trial registries indicate studies in general anaesthesia;
however, none are yet reported. Given that pain on injection of propofol may
be attenuated by co-administration of lidocaine, the case for ciprofol
remains unproved 12

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Champion or Champions?
Only time will tell!

14. 2.REMIMAZOLAM
Short acting benzodiazepine

15. REMIMAZOLAM
▪ Intravenous anaesthetic and sedative agent
▪ Uses: Procedural sedation (US,China), Anaesthesia (Japan, S Korea)
▪ Chemical characteristics/Presentation: 👉
▪ MOA: Similar to midazolam
▪ Routes of administration and dosing: IV- 5 mg over 1 min followed if
necessary by top-up doses of 2.5 mg.
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16. Chemical characteristics/Presentation-
REMIMAZOLAM
An ester linkage Is the
difference
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17. REMIMAZOLAM
▪ Pharmacokinetics: esterase hydrolysis. Marginally greater potency and
maximum effect compared to midazolam. The principal metabolite of
remimazolam CNS-7054 binds with 410 times lower affinity than its
parent and is considered inactive. High first-pass metabolism with
consequentially near-zero oral bioavailability
▪ Pharmacodynamics: Swifter onset and offset; else, broadly similar to
midazolam.. Onset slower than propofol. Offset similar to propofol. Stable
BP & HR..
▪ Side effects: Lesser incidence of hypotension. Respiratory depression or
hypoxaemia incidence is similar to or less than with midazolam
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18. 18

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Remi @6 vs @12 vs
Propofol
▪ Slow onset 120 vs 88 vs
78
▪ Less hypotension
▪ Less vasopressors
▪ Equally less PONV and
awareness
▪ Slower extubation: 15 vs
18 vs 12
▪ Slower RR discharge: 25
vs 25 vs 16
▪ Subsequently in ASA III:

20. REMIMAZOLAM
▪ Special Points:
 Yet to see: Proceduralist and patient satisfaction with
nonanaesthesiologist remimazolam sedation vs that achieved by
anaesthesiologist-provided propofol sedation?
 The possibility of ↓ed perioperative hypotension may be the most rational
reason for considering remimazolam (with opioid) for induction and
maintenance of anaesthesia
 Has not been evaluated for induction of anaesthesia before inhalational
maintenance
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21. REMIMAZOLAM
▪ Special Points:
 In comparison with propofol, the relative haemodynamic stability of
Remimazolam comes at a cost of (minimally) delayed loss of consciousness,
but materially slower recovery
 ICU sedation- delirium?
 Not reserved for use by anaesthesiologist
 But it better needs training- eg use with fentanyl respiratory depression
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22. 3. ALFAXALONE
Neuroactive steroid

23. NEUROACTIVE STEROIDS-Where were you?
▪ Steroids with anaesthetic effects !
▪ Is a steroid, which has direct effects on receptor targets in the CNS and
modulates neuronal excitability- Alfaxalone was used from 1972-84!!
▪ Pain, thrombophlebitis at injection site
▪ Deadly anaphylaxis due to the castor oil vehicle Cremaphor EL
▪ Beta Cyclodextrin is a cyclic oligosaccharide approved by the US FDA for use
in enhancing solubility of nonwater-soluble compounds
▪ The Cremofor EL vehicle was replaced by beta cyclodextrin
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24. ALFAXALONE
▪ Group: It is a progesterone analogue, devoid of progestational, estrogenic,
glucocorticoid, mineralocorticoid, and thymolytic activity and is an
anaesthetic sedative with anticonvulsant and neuroprotective actions
▪ Uses: FDA/EMA (--); iv hypnotic
▪ Chemical characteristics/Presentation: is a 5α-and 3α-reduced neuroactive
steroid, reformulated in beta-cyclodextrin as Phaxan CD. Comes as an
aqueous solution 10 mg/mL in 13% 7-sulfobutyl ether β cyclodextrin
▪ MOA: GABA-A receptor modulation and action at voltage gated Ca
channels
▪ Group: Intravenous anaesthetic and sedative.
▪ Routes of administration and dosing: 0.55 mg/kg (Goodchild et al) 24

25. ALFAXALONE
▪ Pharmacokinetics: Faster onset and recovery
▪ Pharmacodynamics: Hypnotic effect ~ propofol with less hemodynamic
impact. Significant burst suppression in EEG; produces a substantial
decrease in cerebral blood flow
▪ Side effects: Transient tachycardia and hypotension. Lack of neurotoxicity
in the young brain
▪ Special Points: In nonhuman primates, alfaxalone is preferred to ketamine
due to its ease of emergence as well as the quality of anaesthesia on muscle
reflexes and vital signs
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26. 26
Alfaxalone
A phase-3 pilot
study in A&A 2020
suggest that the
favourable
characteristics
described in
volunteers are
repeated in patient
care

27. 4. ESKETAMINE
S-enantiomer of ketamine

28. ESKETAMINE
▪ Intro/Group: Intravenous anaesthetic and sedative
▪ Uses: Depression (FDA), anaesthesia (EMA), perioperative sedation &
analgesia (NMPA-China)
▪ Chemical characteristics/Presentation: S enantiomer;phencyclidine
derivative
▪ MOA: antagonist of NMDA receptors, has a 4 times more affinity to NMDA
receptors and μ opioid receptors.
▪ Routes of administration and dosing: IV; 0.15–0.5 mg/kg-between 12 and 24
mg/h; it may reverse opioid induced respiratory depression (OIRD)
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29. ESKETAMINE
▪ Pharmacokinetics: Rapid onset of action, rapid awakening. It can be used to
reduce the dose of propofol during sedation reducing the latter’s side effects
▪ Pharmacodynamics: There is significant reduction in opioid dosage and pain
scores after S-ketamine supplementation, but effects did not persist after
the first 24 h, mild respiratory depression, and dilated bronchi, is a more
potent analgesic.
▪ Side effects: With intraoperative administration No obvious airway
secretions, less psycotropic side effects compared to racemic ketamine. No
increase in PONV. With postoperative administration more psychotropic
side effects
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30. 5.ABP-700
Etomidate analogue

31. ABP-700
▪ Group/Intro: 2nd generation analogue of etomidate developed to retain etomidate’s
beneficial haemodynamic and respiratory profile but diminishing its suppression of
the adrenocortical axis
▪ Uses: Developed for induction and maintenance of general anaesthesia
▪ Chemical characteristics/Presentation: Cyclopropyl-methoxycarbonyl metomidate
(CPMM or ABP-700 or MDCO-700) 10 mg/ml and 10% sulfobutylether-b-
cyclodextrin with meglumine, an amino sugar derived from glucose, in a 20 ml
USP Type I clear glass vial
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32. ABP-700
▪ MOA: GABA-A receptor agonist
▪ Routes of administration and dosing: IV; 30-60 microgram/ kg/min. Bolus doses of
0.25 mg/kg and 0.35 mg/kg are found to be the most optimal doses for the
induction of anesthesia
▪ Pharmacokinetics: ADME; rapid onset, rapid metabolism (rapid hydrolysis of an
ester bond) and recovery from the hypnotic effect
▪ Pharmacodynamics: longer duration of action; less rapid recovery. MOAA/S
patterns did not always follow BIS profiles closely
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33. ABP-700
▪ Side effects: adrenocortical responsiveness was not significantly different from
that after a propofol infusion- Stimulation with ACTH caused a physiological
cortisol response.
▪ Dose-related involuntary muscle movement (IMM- Rx Midazolam) with
tachycardia and tachypnoea are other S/Es. IMM can also cause airway
obstruction.
▪ Severe hypotension or severe respiratory depression not seen
▪ Special Points: Etomidate is a potent adrenocortical suppressant and a mild
hypnotic!!
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34. 34
ABP-700

35. 35
Proper assignment of roles

36. OTHERS

37. SABER Bupivacaine and HTX 011
▪ Sucrose acetate isobutyrate extended-release bupivacaine
▪ biodegradable depot drug
▪ Has the capacity to hold high concentrations of bupivacaine up to 660 mg.
▪ contains benzyl alcohol and cannot be used for perineural use
▪ HTX-011, is a biodegradable polymer mixture of bupivacaine and meloxicam
▪ has been investigated as a means of delivering long lasting infiltrative pain
relief after hernia and bunion surgery.
▪ Phase 3 infiltration studies show better pain relief compared to bupivacaine
and extended time to first analgesic rescue.
▪ Trials of HTX-011 for nerve block are awaited. 37

38. Quarternary Lidocaine (QLD) + Vanilloids
▪ is a charged molecule that cannot pass through lipid barriers.
▪ Primary afferent nociceptive neurones have transient receptor potential
(TRP) ion channels
▪ TRP is activated by the vanilloid capsaicin, thus providing an aqueous
route for the entry and binding of QLD to the voltage-gated Na channel.
▪ Animal studies  prolonged analgesia with less motor block than
equivalent doses of lidocaine.
▪ However, the use of capsaicin is limited by painful irritation.
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39. Local anaesthetic reversal
▪ Persistent numbness, drooling and inability to eat after LA for dental
surgery are unpleasant.
▪ Phentolamine mesylate is a non-selective alpha-adrenergic antagonist
that causes vasodilation.
▪ This increases the blood flow and is reported to halve the reversal time of
local anaesthesia.
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40. “
Just look at life with
more playful eyes. Don't be
serious. Seriousness becomes like
a blindness. Don't pretend to be a
thinker, or a philosopher…then
you may become a real
thinker…and find something
precious…maybe a new drug!!
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41. Whoa! That’s a big number, aren’t you proud?
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Thanks!
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