1. THE Anesthetic Pipeline:
How It Will Change Your Practice
Steven L. Shafer, MD
Professor of Anesthesia, Stanford University
Adjunct Professor of Biopharmaceutical Sciences, UCSF
Incoming Editor in Chief, Anesthesia & Analgesia

2. Disclosure
 This is a talk about the future.
 Most of the drugs discussed are not approved.
 I’ve consulted with AstraZeneca (Propofol),
Theravance (THRX 918661), Cognetix
(Contulakin-G)

3. Outline
 Hypnotics
 Novel Propofol Formulations
 A New Rapidly Metabolized hypnotic
 Muscle Relaxants
 A new relaxant
 A new mechanism of relaxant reversal
 Analgesics
 Novel opioids
 Other centrally acting analgesics
 Peripherally acting analgesics

4. Hypnotics

5. What’s New With Propofol?
 How to improve on propofol:
 Less pain on injection
 Less toxic lipid formulation
 “Propofol ICU syndrome” may be partly caused by the
long chain triglycerides
 Faster offset
 Less contamination risk

6. Propofol Formulations
 Lipuro Propofol
 Propofol in medium chain triglycerides
 Identical PK/PD profile
 Less pain on injection
 Unavailable in the US, perhaps because of the lack
of EDTA

7. Propofol Formulations
 IDD-D Propofol
 Propofol in medium chain triglycerides
 2% formulation
 Slower onset than Diprivan
 Increased pain on injection
 Increased pain on injection makes this a nonstarter in my
view

8. Propofol Formulations
 Cyclodextrin
Propofol
 water-soluble cyclic
carbohydrates
 Egan et al: Equivalent
PK/PD to Diprivan
 Anesthesiology 2001;
95:A490
Baker MT, Naguib M. . Anesthesiology. 2005;103:860-76.

9. Propofol Formulations
 Propofol micelles
 Formulations are clear
 Associated with substantial
increase in pain on injection
 “Cleofol” recently been
introduced in India.
 89% incidence of severe pain
on injection
 Venous phlebitis
 Damages infusion sets,
 “should only be used for
patients who demand a pure
vegetarian induction agent”
Baker MT, Naguib M. . Anesthesiology. 2005;103:860-76.

10. Propofol Prodrug
 “Aquavan”
 Water soluble
 VERY slow onset – 10
minutes or so
 Difficult to titrate
 Being developed for
procedural sedation
 Causes “a transient
unpleasant sensation of
burning or tingling of
moderate severity in the
anal and genital
region.”
Baker MT, Naguib M. . Anesthesiology. 2005;103:860-76.

11. Novel GABAergic Hypnotic:
THRX-918661
Pig EEG study:
• 20 minute infusion (n=4)
100
80
BIS value
60 THRX-918661 (1.5mg/kg/min)
Diprivan (0.5mg/kg/min)
40
20
Infusion
0
0 5 10 15 20 25 30 35 40 45 50 55 60
Time (mins)
Beattie et al, SIVA UK, May 2003

12. THRX-918661 vs propofol in Rats
70
60
Duration (mins) of loss
of the righting reflex
50
Diprivan (20mins)
40 Diprivan (3hrs)
30 Diprivan (5hrs)
20
THRX-918661 (20mins)
10
THRX-918661 (3hrs)
THRX-918661 (5hrs)
0
120
Duration (mins) for
90
total recovery
60
30
0
Beattie et al, SIVA UK, May 2003

13. THRX-918661 vs. propofol in Rats
THRX- 918661 Propofol
3mg/kg i.v.
10mg/kg i.v.
30mg/kg i.v. 10mg/kg i.v.
Beattie et al, SIVA UK, May 2003

14. Xenon
 Anesthetic properties known for years
 Found to be neuroprotective (NMDA antagonist)
 e.g., oxygen/glucose deprivation model below
 Being developed by Protexeon
Sanders et al, British Med Bull 2005 71:115

15. Melatonin hypnosis
 Large doses (312 mg/kg) of IV melatonin in
antifreeze produce hypnosis similar to thiopental
and propofol in a rat.
Naguib et al, Anesth Analg 2003 97:238

16. Melatonin analogs
Shavali et al, Brain Res Bull 2005 64:471

17. Muscle Relaxants

18. Muscle Relaxant: GW280430A
 Similar to mivacurium
 Onset similar to
succinylcholine
 Lasts for about 15
minutes
 Metabolized by
spontaneous
formulation of cysteine
adducts
 Spontaneous in blood
 Closest true replacement J Med Chem. 2003 Jun 5;46(12):2502-15.
for succinylcholine

19. Sugammadex
Anesthesiology. 2006 Apr;104(4):667-74.

20. Sugammadex
 modified γ-cyclodextrin
 Binds 1:1 with rocuronium
 Also binds vecuronium
Epemolu et al, Anesthesiology 2003 99:632

21. Sugammadex
 Very rapid reversal of neuromuscular blockade
Sorgenfrei et al, Anesthesiology 2006;104:667 -674

22. Analgesics

23. Fentanyl morph 3:
E-trans fentanyl
Viscusi et al, JAMA 2004 291:1333

24. Fentanyl morph 5:
Inhaled fentanyl aerosol
Mather et al, Br J Clin Pharmacol 1998 46:37

25. Fentanyl morph 4:
Inhaled liposomal fentanyl
Hung et al, Anesthesiology 1995 83:277-84

26. Fentanyl morph 6:
Effervescent Fentanyl (OraVescent)
Pather et al, http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=5

27. Sufentanil morph 1:
Implantable sufentanil delivery
http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=115

28. Evidence of µ opioid subtypes
 Only about 50% cross tolerance between
morphine, methadone, fentanyl
 Explains why rotating opioids in chronic pain is probably
a good idea
 CXBK mouse is insensitive to morphine, but
has normal response to M6G and fentanyl
 Selective response to opioid antagonists
 Morphine-6-glucuronide, the outlier
Gavril Pasternak, Life Sciences 2001:68, 2213

29. Naloxonazine
 Selectively antagonizes morphine analgesia in
animals
 µ1 is considered naloxonazine sensitive
 Does not antagonize morphine-induced
ventilatory depression or GI effects
 µ2 is considered naloxonazine insensitive
Gavril Pasternak, Life Sciences 2001:68, 2213

30. Morphine-6-glucuronide
 Active metabolite of morphine, about 100 fold more
potent intrathecally, but enters the CNS VERY slowly
 Has analgesic activity in the CXBK mouse that is
insensitive to morphine
 Actions blocked by naloxonazine (hence, µ1)
 Has a unique antagonist, 3-O-methylnaxtrexone
 Also antagonizes heroin self administration, little affect on morphine
 Subtype of µ1
 MOR-1 knockout (exon 1) has normal sensitivity to
morphine-6-glucuronide
Gavril Pasternak, Life Sciences 2001:68, 2213

31. MOR-1 gene splice variants
(gene=OPRM)
Gavril Pasternak, http://www.mskcc.org/mskcc/html/11384.cfm

32. Differential
Expression of
MOR-1 variants
 Each cell expresses
just a single spice
variant
Gavril Pasternak, http://www.mskcc.org/mskcc/html/11384.cfm

33. Antisense lowers morphine analgesia
(no effect on m6g)
Gavril Pasternak, Life Sciences 2001:68, 2213

34. Antisense lowers m6g analgesia
(no effect on morphine)
Gavril Pasternak, Life Sciences 2001:68, 2213

35. M6G in exon 2 knockout mice
M6G response in exon 2
Wildtype M6G response
knockouts
Romberg et al, BJA 2003 91:862

36. Morphine-6-glucuronide
 Very slow transit across blood brain barrier.
 Not a substrate for p-glycoprotein, but appears to be a
substrate for probenecid inhibited transporters
(Anesthesiology 2004:101 1394)
 Recently a peptide based carrier demonstrated 4 fold
increase in uptake and potency (JPET 2005:12 epub).
 Some data show higher affinity for µ1, and lower
affinity for µ2, compared to morphine.
 Some suggestion that M6G is associated with less
ventilatory depression for the amount of analgesia
 (e.g., Romberg et al, Anesthesiology 2004 100:120)

37. µ 1 selective agonists?
 Despite evidence now 25 years old of
differential response to angatonists, nobody has
found a µ1 selective agonist
 Biggest argument against it: Paul Janssen spent
years looking for one, screening over 70,000
possible ligands
 Reason for hope: perhaps our improved
knowledge of MOR-1 splice variants will help
identify the required pharmacofore
 Don’t hold your breath…

38. Next best thing:
give opioids, manage side effects
 Treat constipation, ileus with peripheral
antagonists
 Treat ventilatory depression with 5HT4 agonists

39. Peripheral µ antagonist:
ADL 8-2698, alvimopan
 Restricted to the gut
 very little systemic absorption
 unable to cross blood-brain barrier

40. Peripheral µ antagonist:
ADL 8-2698, alvimopan
Liu et al, CPT 2001, 69:66

41. Peripheral µ antagonist:
ADL 8-2698, alvimopan
Liu et al, CPT 2001, 69:66

42. Methylnaltrexone
 Invented by Leon Goldberg, University
of Chicago
 Effective for a variety of opioid side
effects including
 Opioid induced constipation
 Pruritis
 Post-operative ileus
 Being developed for IV/SQ/Oral
 Progenics
 Phase III trials

43. 5HT4 agonists
 Cisapride, prucalopride, renzapride, tegaserod,
SB207710, TC-2749
 Primary development target is as a prokinetic
agent
 Interesting that 5HT4 agonists reverse two
opioid side effects: ileus and hypoventilation…
 TD-2759 (Theravance) is a once daily drug in
development
 Theravance 2005 investor presentation

44. 5HT4(a)
 Abundantly expressed in Pre-Boetzinger Complex
 Controls ventilation
 Stimulate adenylyl cyclase
 BIMU8 is a specific agonist of 5HT4(a)
 Novartis: endo-N-(8-methyl-8-azabicyclo [3.2.1]oct-3-yl)-2,3-dihydro-(1-methyl) ethyl-2-oxo-1H-
benzimidazole-1-carboxamide
 Co-locate in PBC with opioid receptors
Manze et al, Science 2003 301:226

45. 5HT4(a)
Manze et al, Science 2003 301:226

46. BIMU8 reverse fentanyl ventilatory depression
Manzke et al, Science 2003 301:226

47. Unfortunately
 Based on the Manzke work, the 5HT4
nonspecific agonists have been tried for efficacy
in reversing opioid induced ventilatory
depression.
 They don’t work.
 Need to await development of 5HT4(a) specific
agonists.

48. Peripheral κ agonists
 High affinity for
peripheral κ receptors
 Poor lipophilicity to
reduce transfer to CNS
 Potent antinociceptive
effects in rat formalin
injection and acetic
writhing test
 In development at Kumar et al, Bioorganic and Medicinal
Chemistry Letters 2005:15:1279
Adolor
Kumar et al, Bioorganic and Medicinal
Chemistry Letters 2005:15:1091
Adolor Corporation

49. Other centrally acting
analgesic drugs

50. Cannabinoids
 Dronabinol has modest efficacy as an analgesic in
multiple sclerosis (Svendsen et al, BMJ 2004:31:329)
 THC has minimal analgesic activity
 Ajulemic acid, novel
cannabinoid with no
psychotropic effects
 Shown effective in
human trial of chronic neuropathic pain
 Karst et al, JAMA 2003 290:1757
 Mechanism of action appears to be anti-inflammation

51. Viral cDNA delivery
 Recombinant herpes simplex I
vector applied to skin
 Permits delivery to dorsal root
ganglion via application to skin
 Add cDNA for human
preproenkephalin
 Get profound antihyperalgesic
response
 Can be reversed by i.t. naloxone
Wilson et al, PNAS 1999 96:3211

52. Peripheral targets of analgesic action
Julius, Basbaum, Nature 2001, 13:413

53. TRPV1
 Transient Receptor Potential V1 (aka VR1)
 Mostly located on C fibers in the periphery
 Sensitive to capsaicin, acid, heat, some lipids
 Opening channel causes influx of calcium
http://www.neurogesx.com/NcPnTRPV1.html

54. TRPV1 agonists (capsaicin)
 How capsaicin works:
 TRPV1 kept open ⇒
 Ca++ entry ⇒
 Prolonged cell dysfunction ⇒
 Prolonged analgesia
Malmberg et al, Pain 2004 111:360

55. Resiniferatoxin
 Resiniferatoxin is a potent TRPV1 agonist
 Diterpene ester from Euphorbia resinifera, a cactus
 Causes desensitization without excitation
 Administration induces cytotoxicity by opening up
calcium channel.
 In high doses selectively ablates TRPV1 nerves
 Currently in clinical trials for overactive bladder

56. Resiniferatoxin
 Injected perineurally,
adjacent to the sciatic
and saphenous nerves
 Followed by a plantar
incision.
 Completely abolished
incisional hyperalgesia
with a concentration
dependent duration
Kissin et al, Anesth Analg 2005; 100:774

57. TRPV1 neuroablation
 Resiniferatoxin is a potent TRPV1 agonist
 Administration induces cytotoxicity by opening
up calcium channel.
 Selectively ablates TRPV1 nerves
 In rats and dogs, inflammatory hyperalgesia is
blocked
 Touch, proprioception, mechanosensitive, and
locomotor function remain intact
 Probably requires general anesthesia!
Karai et al, J Clin Invest 2004 113:1344

58. TRPV1 neuroablation
 Resiniferatoxin trigeminal
injection
 Skin burned with ascorbic
acid, Evans blue injected
intravenously
 Eye-wipe in response to
capsaicin tested over 1 year
Karai et al, J Clin Invest 2004 113:1344

59. TRPV1 neuroablation
 Dogs brought in by
owners with poorly
controlled cancer or
arthritis pain.
 Resiniferatoxin
injected intrathecally
under general
anesthesia
 Owners graded pet
response.
Karai et al, J Clin Invest 2004 113:1344

60. TRPV1 agonist/antagonist pipeline
 Olvanil is an agonist, developed as an oral
analgesic
 Phenylacetylrinvanil is an agonist with picomolar
potency
 Addition of iodine to the phenyl ring creates
TRPV1 antagonists
Appendino et al, J PET 2005 312:561

61. Aminoglycoside analgesia?
 Neomycin is a potent
antagonist of TRPV1
 Neomycin blocks NMDA
receptors
 Neomycin blocks
phospholipase C
Raisinghani et al, Pain 2005, 113:123

62. Conotoxins
 Derived from Conus, a predatory snail
 Highly potent peptides, about 2000 known so far
 α-conotoxin – nicotinic antagonists
 Some are neuromuscular blockers
 Some are central nicotinic antigonists with activity in
neuropathic pain in animal models
 ω-conotoxin – calcium channel antagonists
 Ziconitide (Prialt) approved for IT use in chronic or
neuropathic pain
 Several others in development
 Contulakin-G – Neurotensin agonist
 Phase II trials, IT delivery for acute pain

63. Conclusion
 Very promising future for new hypnotics,
muscle relaxants, and analgesics.
 ALL OF THESE WILL CHANGE YOUR
PRACTICE
 Sugammadex will revolutionize the use of muscle
relaxants
 The new hypnotics will be an important incremental
change
 Advances in analgesics will contribute to significant
reductions in patient morbidity and mortality after
surgery